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INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. U n iversity M icrofilm s International A Bell & H ow ell Inform ation C o m p a n y 3 0 0 North Z e e b R o a d . Ann Arbor. Ml 4 8 1 0 6 -1 3 4 6 USA 3 1 3 /7 6 1 - 4 7 0 0 8 0 0 /5 2 1 - 0 6 0 0 O rd e r N u m b e r 9505170 P art I. R eactions o f alpha,beta-unsaturated thioesters and selenoesters w ith enam ines. P art II. A lpha,beta-unsaturated thioesters and selenoesters as dienophiles: Synthesis o f cyclohexene derivatives Byeon, Chang-Ho, Ph.D. T he Ohio S ta te University, 1994 UMI 300 N. Zeeb Rd. Ann Arbor. MI 48106 PART I: R E A C T IO N S OF A L P H A ,B E T A -U N S A T U R A T E D SELENOESTERS PART II: W IT H A L P H A ,B E T A -U N S A T U R A T E D D IE N O P H IL E S : S Y N T H E S IS AND CYCLOHEXENE SELENOESTERS D E R IV A T IV E S DISSERTATION P rese n te d in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Chang-Ho Byeon, M.S. * * if if * The Ohio State University 1994 Reading Committee: Approved by Dr. David J. Hart Dr. Harold Shecter — AND E N A M IN E S T H IO E S T E R S OF T H IO E S T E R S . / Dr. Virsh H. Rawal Adviser Department of Chemistry AS TO MY PA R E N T S A C K N O W LE D G EM EN TS I wish to ex p ress my sincere appreciation to my adviser, P rofessor David J. Hart, for his g u id e n c e a n d co n c e rn th roug ho ut the re s e a rc h . His e n c o u ra g e m e n t a n d excitem ent for chemistry have been invaluable for me last few years. I express my gratitude to all of the present and past m em bers of the Dr. Hart group for their stimulating discussions of chemistry. I especially thank to Dr. Wu for his friendship and concerns about my whereabout. I would also thank to Drs. Chen and S ealey for their stimulating discussions in research and chemistry in general and also to Dr Lai for his humor and friendship. Next, I would like to acknowledge Mr. Carl Engleman and Dr. Chuck Cottrell for performing 2D NMR experiments and also to Dr David Chang for m ass spectral analysis. Finally, I would like to thank to my wife and son for their love and emotional support and especially to my brand new baby daughter who gives me a new perspective of life. VITA J u n e 18, 19 53 .................................................................................. Born, Jan g s u n g , Korea 1 9 8 0 ...................................................................................................... B.S. Korea University Seoul, Korea 1 9 8 2 ...................................................................................................... M.S. (Chemistry) Korea University 1 9 8 6 ..................................................................................................... M.S. (Chemistry) University of Pittsburgh Pittsburgh, PA. 1 9 8 8 -1 9 9 0 ......................................................................................... Teaching Associate Department of Chemistry The Ohio State University Columbus, Ohio 1 9 9 0 -1 9 9 3 ......................................................................................... R esearch Associate Department of Chemistry The Ohio State University Columbus, Ohio Field of Study Major Field: Chemistry Studies in Organic Chemistry TABLE OF CONTENTS DEDICATION....................................................................................................................................................... ii ACKNOWLEDGEMENT.................................................................................................................................. iii VITA....................................................................................................................................................................... iv LIST OF FIG U R ES......................................................................................................................................... vii LIST OF S C H E M E S ..................................................................................................................................... xv LIST OF xvi TABLES......................................................................................................................................... CHAPTER I. II. PAGE REACTIONS OF oc,p-UNSATURATED THIOESTERS AND SELENOESTERS WITH ENAMINES................................................................................................................ 1 Introduction................................................................................................................. 1 B ackg ro und................................................................................................................. 1 Results and D iscussion......................................................................................... 18 Experim ental............................................................................................................... 41 List of R e fe re n c e s .................................................................................................... 81 oc.p-UNSTURATED THIOESTERS AND SELENOESTERS AS DIENOPHILES: SYNTHESIS OF C Y C L O H E X E N E S ............................................................................. 85 Introduction................................................................................................................ 85 B ackgroun d ................................................................................................................ 85 Results and D iscussion......................................................................................... 101 E xperim ental.............................................................................................................. 117 List of R e fe re n c e s .............................................. APPENDIX 1H and 13C NMR spectra of New C om pounds LIST OF FIG U R ES PAGE F IG U R E S 1. ex,p-Unsaturated T hioesters and S e le n o e s te r s ................................................................. 20 2. NOE Experiments with Dione 1 3 .......................................................................................... 25 3. NOE Experiments with Dione 1 4 .......................................................................................... 25 4. NOE Experiments with Dione 5. NOE Experiments with Dione 9 ............................................................................................ 3 0 . 1H NMR spectrum of 1 (250 MHz, CDCI 3 )...................................................................... 156 7. 1H NMR spectrum of 4 (250 MHz, CDCI 3 )........................................................................ 157 . 1H NMR spectrum of 36 (250 MHz, CDCI 3 )...................................................................... 158 9. 1H NMR spectrum of 129 (250 MHz, CDCI 3 ).................................................................... 159 6 8 8 ............................................................................................ 29 10. 13C NMR spectrum of 129 (62.9 MHz, CDCI 3 )................................................................160 11. 1H NMR spectrum of 133 (250 MHz, CDCI 3 )...................................................................... 161 12. 13C NMR spectrum of 133 (62.9 MHz, CDCI 3 )................................................................ 162 13. 1H NMR spectrum of 134 (250 MHz, CDCI 3 )....................................................................163 14. 13C NMR spectrum of 134 (62.9 MHz, CDCI 3 ).................................................................. 164 15. 1H NMR spectrum of 135 (250 MHz, CDCI 3 )...................................................................... 165 16. 13C NMR spectrum of 135 (62.9 MHz, CDCI 3 ).................................................................. 166 17. 1H NMR spectrum of 136 (250 MHz, CDCI 3 )......................................................................167 18. 13C NMR spectrum of 136 (62.9 MHz, CDCI 3 ).................................................................. 168 vii 19. 1H NMR spectrum of 137 (250 MHz, CDCI 3 )......................................................................169 20. 13C NMR spectrum of 137 (62.9 MHz, CDCI 3 )................................................................170 21. 1H NMR spectrum of 138 (250 MHz, CDCI 3 )................................................................ 171 22. 13C NMR spectrum of 138 (62.9 MHz, CDCI 3 )................................................................172 23. 1H NMR spectrum of 139 (250 MHz, CDCI 3 ).................................................................. 173 24. 13C NMR spectrum of 139 (62.9 MHz, CDCI 3 )............................................................. 174 25. 1H NMR spectrum of 140 (250 MHz, CDCI 3 )................................................................ 175 26. 1H NMR spectrum of 13 (500 MHz, C 6 D6)................................................................... 176 27. 13C NMR spectrum of 13 (62.9 MHz, CDCI 3 )..................................................................... 177 28. 1H NMR spectrum of 144 (250 MHz, CDCI 3 )...................................................................... 178 29. 13C NMR spectrum of 144 (62.9 MHz, CDCI 3 )................................................................... 179 30. NOE spectrum of 13 (300 MHz, CDCI 3 )............................................................................180 31 1H NMR spectrum of 145 (300 MHz, CDCI 3 )...................................................................... 181 32. 13C NMR spectrum of 145 (62.9 MHz, CDCI 3 )...................................................................182 33. 1H NMR spectrum of 146 (300 MHz, CDCI 3 )...................................................................... 183 34. 13C NMR spectrum of 146 (75.5 MHz, CDCI 3 )...................................................................184 35. 1H NMR spectrum of 14 (500 MHz, C 6 D6 ).......................................................................... 185 36. 13C NMR spectrum of 14 (62.9 MHz, CDCI 3 ).....................................................................186 37. 1H NMR spectrum of 150 (250 MHz, CDCI 3 ) ......................................................................187 38. 13C NMR spectrum of 150 (62.9 MHz. CDCI 3 ).................................................................. 188 39. 1H NMR spectrum of 151 (250 MHz, CDCI 3 )................................................................... 189 40. 13C NMR spectrum of 151 (62.9 MHz, CDCI 3 )............................................................... 190 41. 1H NMR spectrum of 152 (300 MHz, CDCI 3 ).................................................................. 191 42. 13C NMR spectrum of 152 (62.9 MHz, CDCI 3 )................................................................192 43. COSY 1H NMR spectrum of 14 (300 MHz, CDCI 3 )......................................................... 193 viii 44. C-H correlation NMR spectrum of 14 (300 MHz, CDCI 3 ).................................................. 194 45. NOE spectrum of 14 (300 MHz, CDCI 3 )........................................................................... 195 46. 1H NMR spectrum of 153 (300 MHz, CDCI 3 )...................................................................... 196 47 13C NMR spectrum of 153 (75.5 MHz, CDCI 3 ).................................................................197 48. 1H NMR spectrum of 154 (250 MHz, CDCI 3 )................................................................... 198 49. 13C NMR spectrum of 154 (62.9 MHz, CDCI 3 )............................................................. 199 50. 1H NMR spectrum of 155 (300 MHz, CDCI 3 )......................................................................2 0 0 51. 13C NMR spectrum of 155 (62.9 MHz, CDCI 3 )............................................................. 201 52. 1H NMR spectrum of 156 (250 MHz, CDCI 3 )................................................................... 2 0 2 53. 13C NMR spectrum of 156 (62.9 MHz, CDCI 3 )............................................................. 2 0 3 54. 1H NMR spectrum of 157 (250 MHz, CDCI 3 )................................................................... 2 0 4 55. 13C NMR spectrum of 157 (62.9 MHz, CDCI 3 )................................................................2 0 5 56. 1H NMR spectrum of 8 (500 MHz, C 6 D6 )........................................................................... 2 0 6 57. 13C NMR spectrum of 58. 1H NMR spectrum of 158 (250 MHz, CDCI 3 )................................................................... 20 8 59. 13C NMR spectrum of 158 (62.9 MHz, CDCI 3 )............................................................... 209 60. COSY spectrum of 61. NOE spectrum of 8 (500 MHz, CeDg).................................................................................. 211 62. NOE spectrum of 8 (500 MHz, CeDg).................................................................................. 2 1 2 63. NOE spectrum of 8 (500 MHz, C 6 D6 ).................................................................................. 2 1 3 64. 1H NMR spectrum of 159 (300 MHz, CDCI 3 )..................................................................... 21 4 65. 13C NMR spectrum of 159 (75.5 MHz, CDCI 3 )................................................................ 21 5 . 1H NMR spectrum of 160 (300 MHz, CDCI 3 ).................................................................. 2 1 6 67. 13C NMR spectrum of 160 (75.5 MHz, CDCI 3 )..................................................................217 . 1H NMR spectrum of 9 (500 MHz, C 6 D6 )............................................................................2 1 8 66 68 8 8 (62.9 MHz, CDCI 3 ).................................................................... 2 0 7 (500 MHz, C 6 D6).............................................................................. 210 ix 69. 13C NMR spectrum of 9 (62.9 MHz, CDCI3 )............................................................................. 2 1 9 70. 1H NMR spectrum of 161 (300 MHz, CDCI 3 ).................................................................. 2 2 0 71. 13C NMR spectrum of 161 (62.9 MHz, CDCI 3 ).................................................................. 221 72. COSY spectrum of 9 (500 MHz, CeDe)................................................................................2 2 2 73. NOE spectrum of 9 (500 MHz, CgDe)............................................................................... 2 2 3 74. NOE spectrum of 9 (500 MHz, C 6 D6 )............................................................................... 2 2 4 75. NOE spectrum of 9 (500 MHz, C 6 D6).................................................................................. 2 2 5 76. 1H NMR spectrum of 162 (300 MHz, CDCI 3 )......................................................................226 77. 13C NMR spectrum of 162 (62.9 MHz, CDCI 3 ) .................................................................. 227 78. 1H NMR spectrum of 163 (300 MHz, CDCI 3 )..................................................................... 2 2 8 79. 13C NMR spectrum of 163 (62.9 MHz, CDCI 3 ).................................................................. 229 80. 1H NMR spectrum of 164 (300 MHz, CDCI 3 )................................................................... 2 3 0 81. 13C NMR spectrum of 164 (62.9 MHz, CDCI 3 )..................................................................231 82. 1H NMR spectrum of 165 (300 MHz, CDCI 3 )......................................................................232 83. 13C NMR spectrum of 165 (62.9 MHz, CDCI 3 )..................................................................2 3 3 84. 1H NMR spectrum of 166 (300 MHz, CDCI 3 )................................................................... 2 3 4 85. 13C NMR spectrum of 166 (62.9 MHz, CDCI 3 )............................................................... 2 3 5 86 . 87. 1H NMR spectrum of 6 13C NMR spectrum of (250 MHz, CDCI 3 )....................................................................... 2 3 6 6 (62.9 MHz, CDCI 3 ).................................................................... 2 3 7 . 1H NMR spectrum of 165 (300 MHz, CDCI 3 ).................................................................. 2 3 8 89. 13C NMR spectrum of 165 (62.9 MHz, CDCI 3 )............................................................... 2 3 9 90. 1H NMR spectrum of 167 (300 MHz, CDCI 3 ).................................................................. 2 4 0 91. 13C NMR spectrum of 167 (62.9 MHz. CDCI 3 )............................................................... 241 92. 1H NMR spectrum of 168 (300 MHz, CDCI 3 ).................................................................. 2 4 2 93. 13C NMR spectrum of 168 (62.9 MHz, CDCI 3 )................................................................. 2 4 3 88 x 94. 1H NMR spectrum of 169 (300 MHz, CDCI3)................................................................... 2 4 4 95 13C NMR spectrum of 169 (62.9 MHz, CDCI 3 )................................................................24 5 96. 1H NMR spectrum of 171 (300 MHz, CDCI 3 )...................................................................246 97. 13C NMR spectrum of 170 (62.9 MHz, CDCI 3 )..............................................................2 4 7 98. 1H NMR spectrum of 171 (300 MHz, CDCI 3 )....................................................................248 99. 13C NMR spectrum of 171 (62.9 MHz, CDCI 3 ).............................................................. 24 9 100. 1H NMR spectrum of 172 (300 MHz, CDCI 3 )............................................................... 2 5 0 101. 13C NMR spectrum of 172 (62.9 MHz, CDCI 3 )............................................................. 251 102. 1H NMR spectrum of 173 (300 MHz, CDCI 3 )................. 103. 13C NMR spectrum of 173 (62.9 MHz, CDCI 3 )............................................................... 253 104. 1H NMR spectrum of 174 (300 MHz, CDCI 3 )...................................................................2 5 4 105. 13C NMR spectrum of 174 (62.9 MHz, CDCI 3 )............................................................... 2 5 5 106. 1H NMR spectrum of 176 (300 MHz, CDCI 3 )................................................................ 2 5 6 107. 13C NMR spectrum of 176 (62.9 MHz, CDCI 3 )............................................................ 2 5 7 108. 1H NMR spectrum of 177 (300 MHz, CDCI 3 )................................................................ 2 5 8 109. 13C NMR spectrum of 177 (75.5 MHz, CDCI 3 )............................................................... 259 110. 1H NMR spectrum of 178 (300 MHz, CDCI 3 )................................................................ 260 111. 13C NMR spectrum of 178 (75.5 MHz, CDCI3 )............................................................... 261 112. 1H NMR spectrum of 179 (300 MHz, CDCI 3 )............................................................... 262 113. 13C NMR spectrum of 179 (62.9 MHz, CDCI 3 )...............................................................263 114. 1H NMR spectrum of 180 (300 MHz, CDCI 3 )................................................................ 264 115. 13C NMR spectrum of 180 (75.5 MHz, CDCI 3 ) ............................................................... 265 116. 1H NMR spectrum of 181 (300 MHz, CDCI 3 )................................................................ 2 6 6 117. 13C NMR spectrum of 181 (75.5 MHz, CDCI 3 )...............................................................267 118. 1H NMR spectrum of 193 (250 MHz, CDCI 3 ).................................................................. 268 xi 252 119. 13C NMR spectrum of 193 (62.9 MHz, CDCI 3 )..................................................................269 120. 1H NMR spectrum of 195 (300 MHz, CDCI 3 )................................................................... 270 121. 13C NMR spectrum of 195 (62.9 MHz, CDCI 3 ).................................................................271 122. 1H NMR spectrum of 298 (300 MHz, CDCI 3 ).....................................................................2 7 2 123. 13C NMR spectrum of 298 (75.5 MHz, CDCI 3 ).................................................................2 7 3 124. 1H NMR spectrum of 299 (300 MHz, CDCI 3 ).................................................................... 2 7 4 125. 13C NMR spectrum of 299 (75.5 MHz, CDCI 3 ).................................................................2 7 5 126. 1H NMR spectrum of 303 (300 MHz, CDCI 3 )................................................................ 2 7 6 127. 13C NMR spectrum of 303 (75.5 MHz, CDCI 3 )............................................................... 2 7 7 128. 1H NMR spectrum of 304 (300 MHz, CDCI 3 )................................................................ 278 129. 13C NMR spectrum of 304 (75.5 MHz, CDCI 3 )............................................................. 279 130. 1H NMR spectrum of 305 (300 MHz, CDCI 3 )................................................................ 2 8 0 131. 13C NMR spectrum of 305 (62.9 MHz, CDCI 3 )............................................................... 281 132. 1H NMR spectrum of 307 (300 MHz, CDCI 3 )................................................................ 282 133. 13C NMR spectrum of 307 (62.9 MHz, CDCI 3 )...............................................................28 3 134. 1H NMR spectrum of 309 (300 MHz, CDCI 3 )................................................................ 2 8 4 135. 13C NMR spectrum of 309 (62.9 MHz, CDCI 3 )...............................................................2 8 5 136. INADEQUATE spectrum of 309 (62.9 MHz, CDCI 3 )..................................................... 2 8 6 137. 1H NMR spectrum of 311 (300 MHz, CDCI 3 )...................................................................2 8 7 138. 13C NMR spectrum of 311 (75.5 MHz, CDCI 3 )...............................................................2 88 139. 1H NMR spectrum of 312 (300 MHz, CDCI 3 ).................................................................. 289 140. 13C NMR spectrum of 312 (75.5 MHz, CDCI 3 )...............................................................290 141. 1H NMR spectrum of 313 (300 MHz, CDCI3 )............................................................... 291 142. 13C NMR spectrum of 313 (75.5 MHz, CDCI 3 )............................................................. 29 2 143. 1H NMR spectrum of 314 (300 MHz, CDCI3 )............................................................... 29 3 xii 144. 13C NMR spectrum of 314 (62.9 MHz, CDCI 3 )............................................................... 29 4 145. 1H NMR spectrum ot 316 (300 MHz, CDCI 3 )................................................................... 295 146. 13C NMR spectrum of 316 (62.9 MHz, CDCI 3 )............................................................... 2 9 6 147. 1H NMR spectrum of 317 (250 MHz, CDCI 3 )................................................................ 2 9 7 148. 13C NMR spectrum of 317 (62.9 MHz, CDCI 3 )............................................................... 2 9 8 149. 1H NMR spectrum of 320 (300 MHz, CDCI 3 )................................................................ 2 9 9 150. 13C NMR spectrum of 320 (62.9 MHz, CDCI 3 )............................................................... 3 0 0 151. 1H NMR spectrum of 323 (300 MHz, CDCI 3 )................................................................ 301 152. 13C NMR spectrum of 323 (62.9 MHz, CDCI 3 )............................................................... 3 0 2 153. 1H NMR spectrum of 326 (300 MHz, CDCI 3 )................................................................ 3 0 3 154. 13C NMR spectrum of 326 (62.9 MHz, CDCI 3 )............................................................... 3 0 4 155. INADEQUATE spectrum of 326 (62.9 MHz, CDCI 3 ).....................................................305 156. 1H NMR spectrum of 329 (300 MHz, CDCI3 )................................................................ 3 0 6 157. 13C NMR spectrum of 329 (62.9 MHz, CDCI 3 )............................................................... 3 0 7 158. 1H NMR spectrum of 330 (300 MHz, CDCI 3 )...................................................................3 0 8 159. 13C NMR spectrum of 330 (62.9 MHz, CDCI 3 )...............................................................3 0 9 160. 1H NMR spectrum of 331 (300 MHz, CDCI 3 )................................................................ 3 1 0 161. 13C NMR spectrum of 331 (75.5 MHz, CDCI 3 )............................................................. 311 162. 1H NMR spectrum of 332 (300 MHz, CDCI 3 ).................................................................. 3 1 2 163. 13C NMR spectrum of 332 (62.9 MHz, CDCI 3 )...............................................................3 1 3 164. 1H NMR spectrum of 333 (300 MHz, CDCI 3 )................................................................ 3 1 4 165. 1H NMR spectrum of 334 (300 MHz, CDCI 3 )................................................................ 3 1 5 166. 13C NMR spectrum of 334 (62.9 MHz, CDCI 3 )...............................................................3 1 6 167. 1H NMR spectrum of 335 (300 MHz, CDCI 3 ).................................................................. 3 1 7 168. 13C NMR spectrum of 335 (62.9 MHz, CDCI 3 )...............................................................3 1 8 xiii 169. 1H NMR spectrum of 337 (300 MHz, CDCI3)...................................................................3 1 9 170. 13C NMR spectrum of 337 (62.9 MHz, CDCI 3 ) 171. 1H NMR spectrum of 338 (300 MHz, CDCI 3 )...................................................................321 172. 13C NMR spectrum of 338 (75.5 MHz, CDCI 3 )................................................................3 2 2 173. 1H NMR spectrum of 340 (300 MHz, CDCI 3 }................................................................ 3 2 3 174. 1H NMR spectrum of 341 (250 MHz, CDCI 3 )...................................................................3 2 4 175. 13C NMR spectrum of 341 (62.9 MHz, CDCI 3 )................................................................3 2 5 176. 1H NMR spectrum of 342 (300 MHz, CDCI 3 )................................................................... 3 2 6 177. 13C NMR spectrum of 342 (75.5 MHz, CDCI 3 )............................................................. 3 2 7 178. 1H NMR spectrum of 343 (300 MHz, C 6 D6)................................................................. 3 2 8 179. 13C NMR spectrum of 343 (675.5 MHz, CDCI 3 )........................................................... 3 2 9 180. 1H NMR spectrum of 346 (300 MHz, C 6 D6).................................................................. 3 3 0 181. 13C NMR spectrum of 346 (62.9 MHz, CDCI 3 )............................................................. 331 182. 1H NMR spectrum of 347 (250 MHz, CDCI 3 )................................................................ 3 3 2 183. 1H NMR spectrum of 350 (250 MHz, CDCI 3 )................................................................ 3 3 3 184. 13C NMR spectrum of 350 (62.9 MHz, CDCI 3 )............................................................... 3 3 4 185. COLOC spectrum of 350 (75.5 MHz, CDCI 3 )............................................................... 3 3 5 186. 1H NMR spectrum of 351 (300 MHz, CDCI 3 )............................................................... 3 3 6 187. 13C NMR spectrum of 351 (75.5 MHz, CDCI 3 )............................................................. 3 3 7 188. 1H NMR spectrum of 354(300 MHz, CDCI 3 )................................................................. 3 3 8 189. 13C NMR spectrum of 354 (75.5 MHz, CDCI 3 )................................................................ 3 3 9 190. 1H NMR spectrum of 355 (250 MHz, CDCI3 ).............................................................. 191. 13C NMR spectrum of 355 (62.9 MHz, CDCI 3 )................................................................ 341 192. 1H NMR spectrum of 35 6 (250 MHz, CDCI 3 ).................................................................. 3 4 2 193. 13C NMR spectrum of 356 (62.9 MHz, CDCI 3 )................................................................ 3 4 3 xiv ..................................................... 3 2 0 340 LIS T OF SC H EM ES SCHEME I. PAGE Proposed M echanism for the Enamine Annulation Reaction with Chloride cx,p-Unsaturated Acid Chlorides.................................................................................. 3 II. P roposed M echanism for a ,a '- Annulation Reaction of the E n am ine................ 5 III. Proposed M echanism for the Formation of Keto Thioenol Ether 2 6 ................. 6 IV. Bicyclo[3.3.1]nonan-3-one Derivatives via Michael R eactions.......................... 8 V. S ynthesis of 5-Methylbicyclo[3.3.1]non-3-en-2-one .......................................... 11 VI. Synthesis of Bicyclo[3.2.2]nonan-3-one Derivative via Oxyallyl cation 13 VII. Bicyclic Ketone Synthesis via 9-BBN Methylation............................................... 15 VIII. Determination of the Stereochemistry of Bicyclic Dione 1 3 .............................. 22 IX. Determination of the Stereochemistry of Bicyclic Dione 1 4 .............................. 24 X. Possible Reaction Mechanism via C-Alkylation.................................................... 36 XI. Possible Reaction Mechanism via Hetero Diels-Alder Reactio.......................... 36 XII. Possible Reaction M echanism via C-Acylation..................................................... 36 XIII. Possible Reaction M echanism via N-Acylation..................................................... 36 XIV. Isomerization of Thioester 1 9 6 .................................................................................. 39 XV. Effect of Lewis acid on the Endo Selectivity of Diels-Alder Reaction 94 XVI. M eta-Substituted C yclohexene S y n th e s is .............................................................. 97 XVII. M eta-Substituted C yclohexenone S y n th e sis ......................................................... 97 XVIII. Exo Cycloadduct Synthesis with Bifunctional Dienophile.................................. 101 XIV. Diels-Alder Reaction of Thioester 290 with C yclopentad ien e......................... 103 xv LIST OF TABLES TABLES PAGE 1. Regioselectivity in Cycloadditions of 1-Substituted D ienes.................................. 91 2. Regioselectivity in Cycloadditions of 2-Substituted D ienes.................................. 91 3. Effect of Lewis acid on the Endo Selectivity of Diels-Alder R eactions................ 9 3 4. Reactions of 2,3-Heteroatom Substituted 1,3-Dienes........................................... 9 6 5. Addition of 1-Substituted Dienes to 2 5 8 ...................................................................... 98 6. Diels-Alder Reaction of Methyl p-Formyl acrylate with Lewis Acid...................... 10 0 7. Competition R eactions of Diene 82 with Various Dienophiles............................. 10 4 . Diels-Alder Reactions of Diene 228 with Various Dienophiles.......................... 105 9. Diels-Alder Reactions of Diene 251 with Various Dienophiles......................... 108 10. Diels-Alder Reactions of Diene 82 with Various Dienophiles............................ 110 8 xvi CHAPTER I Reaction of a ,p -U n s a tu ra te d T h io esters and S elen o esters w ith 1. E nam ines In tro d u c tio n The objective of this r e s e a r c h w a s to explore a ,p -u n sa tu ra te d thioesters and s e le n o e s te rs a s olefinic electrophiles in conjugate addition an d Diels-Alder reactions. This ch ap te r will d esc rib e studies of th e synthesis of bicyclic keto n es and stereoselective Michael reactions via enam ine reactions with a.p-unsaturated thioesters and seleno esters. To provide the re a d e r with s o m e perspective, a brief background of bicyclic ketone synth esis via enam in e reactions, acid a n d b a s e ca talyzed c o n d e n s a tio n s, cycloaddition of oxyallyl cations, and stereoselective Michael reactions will be presented. 2. B a c k g ro u n d A. B icyclic K etone S yn th esis via Enam ine Reactions Since the initial report on acylation and alkylation reactions of carbonyl com pou nds via en a m in e s by Stork and coworkers, a wide variety of such reactions have b e e n repo rted . 1 The co urse of the reaction of the enam ine, for example alkylation, acylation and annulation, is very sensitive to the structure of reactants and to the experimental conditions such a s the solvent, the tem perature, and additives such a s tertiary a m in e s .2 -3 -4 The re aso n for the diversity of the behavior is that e n a m in e s are am bident nucleophiles. B e c a u s e of its binucleophilic nature, en am in es have b e e n u sed to construct C-C bonds consecutively. This type of the reaction h a s bee n u sed to prepare bicyclic k eto n es .5 Since this topic has been reviewed an d num erous 2 exam ples have a p p e are d in the literature, only those studies related to bicyclic ketone synthesis will be described. 2-Aminobicyclononanone 3 w a s prepared conveniently from acrolein and the enam ine of cyclohexanone by Stork and Lan desm an in 1956 (equation 1). o dioxane, hydroquinone ( 1) 3 (6 8 %) 1 About ten y e a rs later, Hickmott and coworkers reported the first gen e ral m ethod to construct bicyclic k eton es using reactions b etw een the morpholine enam ine of cyclohexanone (4) and oc,p-unsaturated acid chlorides .4 3 Thus, the reactions of enam ine 4 with acryloyl chloride (5) and cinnamoyl chloride (7) afforded bicyclic dione 8 a n d 9, respectively (equations 2 6 in 45% yield and 4-phenyl bicyclic diones and 3). Two different 4-phenyl bicyclic diones 8 an d 9 were isolated depending on the reaction conditions. O ne w a s an oil (dCo(CCU)= 1730, 1705 c m '1; bp 162-166 °C at 0.05 mm) isolated in 13% yield, and the other w as a solid (uCo(CCl 4 ) = 1 7 3 5 ,1 7 1 4 c m '1; mp 52 °C) isolated in 48% yield. A reaction mechanism which su gg ested why the reaction O (2) 4 6 (45%) (3) cold addition C6 H6, rt to 80 °C 8 (13%) hot addition C6 H6, 80 °C 4 9 (48%) might be stereoselective w as proposed. It w a s su g gested that the reaction might proceed via intial N-acylation of the ena m ine 4 followed by a [3.3]-sigmatropic re arra n g em en t to give keten e intermediate 11, conversion to another enamine, and finally C-acylation of the enam ine followed by a q u e o u s workup to give the bicyclic ketone 9 (S ch e m e I). Even though Hickmott proposed the reaction m echanism shown in S c h e m e 1, the stereochemistry of the isomers w a s not proven. The assig n m e n ts shown in equation 3 are b a s e d on studies perform ed a s part of this th esis research (vide infra). Schem e I. P roposed M echanism for the Enam ine A nnulation Reaction w ith a , p U n saturated Acid C h lo rid es N-acylation 7 4 1 0 [3.3] rearrangem ent C-acylation I n h 9 1 1 Hickmott also reported that crotonyl chloride reacted with enam in e 4 to give a single d ia s te re o m e r.4c Recently, Harding and coworkers u sed the s a m e annulation m ethod to build bicyclic k etones for u s e in the synthesis of the elemanolide sesq u ite rp e n e s .6 In contrast with the Hickm ott re s u lt, th e y m orpholinocyclohexene reported th a t th e re a c tio n of cro tony l ch lo rid e 12 with 4 afforded a stere o iso m e ric mixture 13 and 14 (eq u atio n 4). Unfortunately, Harding did not indicate the ratio of 13 and 14. COCI u H Me O 12 r CgHg, rt ° 98% 4 13 14 T he first s te p of the syn th esis of 2- and 9-m ono or disubstituted n o ra d a m a n ta n e s described by Gravel and Rahal also u sed this annulation reaction .7 Thus, the morpholine enamine 15 of 4-acetoxycyclohexanone reacted with acryloyl chloride (5) to produce the iminium salt 16. The intermediate iminium salt 16 w a s directly treated with ethanedithiol to yield ketodithiane 17 so that the two carbonyl groups could b e easily differentiated (equation 5). n ethanedithiol, rt OAc ■ S ^ COCI OAc (5) N OAc 15 16 17 (1° %) Gravel an d Labelle have constructed bicyclic ketones by reacting the enam ines of cyclic pketo este rs with electrophilic olefins . 8 For example, y-alkylation-functionalization of enam in e 18 with methacrolein (19) provided bicyclic ketoester 20 in 48% yield (equation 6 ). The reaction w as generally slow and they rationalized this on the basis of allylic strain. dioxane, 70 °C, 9 days M e^Z^2 ^ c o 2Me Me0>c - j A j (6) ch3 19 1 8 2 0 (48%) Lawton and coworkers have studied the annulation reaction of enamine with electrophiles via consecutive alkylations or Michael additions .9 For example, treatm ent of ena m ine 1 with methyl a-(brom om ethyl)acrylate, derived in situ from dibrom oester 21 , provided the bicyclic 5 ketoester 24 (S chem e II). The reaction afforded the 3-endo ester 24 a s a sole product. This w as ac co un ted for by assum ing that the cyclohexene ring of the intermediate enam ine 22 w a s in a boatlike conform ation while the newly formed cyclo hexan one ring in 2 3 w a s in a chairlike c o n fo rm ation . This elim inated th e d e v e lo p e m e n t of th e s e v e r e interactio n b e tw e e n carbom ethoxy group at C(3) and hydrogen atom at C(7). It w as su g g ested that after protonation, both rings undergo the conformational ch a n ge to the more stable boat-chair conformer of the endo configuration. Schem e II. Proposed M echanism for a ,a '-A n n u la tio n R eaction of the Enam ine 1 22 kinetic protonation MeO 24 23 A nzeveno and coworkers extended the rx.a'-annulation reaction by employing sulfoxide 25 and sulfone 30 a s biselectrophiles (S chem e III) . 1 0 Thus, treatm ent of en am in e 1 with «,(3u n saturated sulfoxide afforded keto thioenol ether 26 in 41% yield and noncyclized ketone 27 in 16% yield. Thus, the sulfoxide 25 w a s not an effective annulating reagent. However, the sulfone turned out to be an excellent annulating agent. For example, reaction of enam ine 1 with sulfone 30 provided bicyclic ketosulfone 31 in 84% yield without uncyclized product (equation 7). S chem e III. Proposed Pathw ay to the Form ation of Keto Thioenol E ther 26 Q 6 CH2CI 2 5 V SOPh Et3 N ,C H 3 CN, A ‘Ph SPh OH? 2 6(41% ) 2 7(16% ) \+ ' O Cl 28 O 29 c h 2ci . S 0 2Ph 30 S P 2Ph EfeN, C H 3 CN, A A (7) 3 1 (84%) 1 Lu and Huang w ere able to construct bicyclic ketoacetate 33 in 30% yield by reacting allylic diacetate 32 with enam ine 1 in the p re sence of palladium (II) acetate a s a catalyst (equation 8 ) . 11 They proposed the formation of a.oc'-allylpalladium complex which reacted with enam ine nucleophile. ^ .o a c OAc 3 2 1 Pd (OAc)2, THF,—A r^ rf Me'S vi ~I — OAc H ( 8) 3 3 (30%) Strauss and Torres reported that the reactions of methyl, cyclohexyl, and phenyl picryl eth ers with diethylamine in aceto ne produced two different products depending on the substrate 7 s tr u c tu r e s . 1 2 With unhindered picryl ethers, dealkylation w as observed. However, with more hindered picryl ethers 34, the addition of the nucleophiles took place to afford a bicyclic ketone 35 (equation 9). They postulated the in situ formation of the ena m in e b etw een ac eto n e and diethylamine and were actually able to g enerate the enamine separately which, when treated with picryl ether, afforded an isolable zwitterion 35. no. OR Et 2 NH2 CH 2 CI2, rt, 24 h 34 ) 0 35 Diastereoselective m ethods for the construction of bicyclic k eto n es w ere reported by S e e b a c h an d co w o rk ers . 1 3 They u sed nitroallylic e s te rs a s the biselectrophile. For example, trea tm e n t of en a m in e 3 6 with a ,|J -u n s a tu ra te d n itro acetate 3 7 afforded bicyclic o c ta n o n e derivatives 38 and 39 in a ratio of 4:1, respectively, in 57% overall yield (equation 10). When 37 re a c te d with en a m in e 1, bicyclic n o n a n o n e s 4 0 and 41 w ere obtained in a ratio of 3:1, respectively, in 58% overall yield (equation OCOMe 36 1 1 ). THF, 50 h, rt 3 3 7 8 (45%) 3 9 (12%) o OCOMe THF, 50 h, rt 1 37 o 2r ( 11 ) 40 (42%) 41 (16%) B. B icy clic K e to n e S y n t h e s i s via A cid a n d B a s e C a t a l y z e d C o n d e n s a t i o n s Another popular m eth od for constructing bicyclic k eto n es involves b a s e catalyzed condensation reactions such a s intermolecular and intramolecular aldol condensations, Claisen condensations, and Michael addition reactions. For example, Wenkert and coworkers studied the c h e m ic a l b e h a v io r of c y c lo h e x a d i e n o n e to w ard n u cleop hile (S ch em e IV) . 1 4 W hen c y c lo h e x a d ie n e o n e 42 w a s tre a te d with methyl a c e to a c e ta te in the p r e s e n c e of sodium methoxide in methanol, bicyclic p-ketoester 43 w a s formed in 58% yield via consecutive Michael addition an d intramolecular aldol conden sation. Catalytic hydrogenation of 43 followed by decarboxylation afforded bicyclic ketone 45 in 87% overall yield. Schem e IV. B i c y c l o [ 3 . 3 . l ] n o n a n - 3 - o n e D e r i v a t i v e s via M ich ae l R e a c t i o n s o HO CHCIZ a CHCI2 Me 42 HO CHCI? MGO2C 43 (58%) CHCIo '3 '3 OH HO c b M e02C '3 O OH 44 (97%) 45 (90%) (a) methyl acetoacetate, NaOMe (b) H2 , Pd/C (c) 50% HCI, 1 00 °C Danishetsky and coworkers u sed methyl p-vinylacrylate (47) a s a biselectrophile for the construction of bicyclic k e t o n e s . 1 5 For exam ple, treatm ent of diketone 4 6 with methyl pvinylacrylate (41) an d dimsyl anion in DMSO afforded bicyclic dione 48 in 42% yield (equation (12). Similarly, treatment of p-keto e s ters 49 and 51 with conjugated este r 47 under the sam e reaction conditions afforded bicyclic k eto n es 50 and 52 in 76% and 35% yield, respectively (equations 13 and 14). CH 3 SO CH 2 Na, DMSO CH 3 SOCH 2 Na, DMSO CH2C 0 2Me EtO- CO2 M© 49 5 0 (76%) CH 3 SOCH 2 Na, DMSO Q ~ C 0 2Et (1 3 ) ° \ CH2C 0 2Et OMe 0 (1 4 ) 5 2 (35%) 51 S a n d s h a s obtained bicyclic diones via aldol condensations. For example, treatment of dimethyl 3-oxoglutarate (53) with [3-ketoaldehyde 54 in the p re s e n c e of strong b a s e afforded bicyclic dione 55 in 18% yield (equation 15).16 i) 0 M e02C >>^ J ^ J r ^ Z . i 5 4 C 0 2Me Q ^ (15) KOH, MeOH, rt several days 5 3 ° 55 (18%) Marshall and coworkers reported the construction of bicyclo[4.3.1]decanone derivatives by a n intramolecular aldol conden sation reaction (equation 16).17 For example, treatm ent of ketone 56 with dichlorobutene followed by hydrolysis of vinyl chloride 57 in concentrated sulfuric acid in 0 °C afforded 1,5-diketone 58 which cyclized to bicyclic ketone 59 under the reaction conditions. Me a a; Me 56 57 (a) 1. Me 1 Me a O 11 ^ Me 58 (16) 59 NaNH 2 , C 6 H6 ; 2. 2,4-dichloro-2-butene (b) H2 SO 4 , 0 °C, 90 min R aphael and coworkers h ave applied the Dieckman condensation to the synthesis of bicyclic d io n e s . 1 8 For example, intramolecular Dieckmann condensation of triester 60 using high 10 dilution conditions tollowed by hydrolysis and decarboxylation furnished a mixture of bicyclic ketoacids 61 (29%) and 62 (equation 17). CH2C 0 2Mc Me ^ 5 d Z c H 2C02Me — --------------------- !T ^ 4 ^ 7 r-ry u + M 6To2M o ^ < ^ C H O ^TT 2 2COzH (17) ^ O 6 0 61 (a) KO’Bu, xylene, 150 °C (b) (29%) 6 62 N aq HCI, 100 °C H e s s e a n d cow orkers p re p are d bicyclic k eto n es with excellent yield via a fluoride catalyzed Michael reaction followed by an intramolecular aldol condensation . 1 9 Thus, reaction of a-nitrocyclohexanone 63 with acrolein (2) afforded hydroxyketone 64 in 78% yield, which w as oxidized to bicyclic dione 65 (equation 18). OH o T H F ,2 0 °C — — -------------► N° 2 acetone, CrQj (18) •S ^ C H O 2 6 3 6 4 (78%) 6 5 (82%) The first syn thesis of a bicyclo[3.3.l]nonane skeleton by an intramolecular enolate alkylation w as reported by Marvell and cow orkers .2 0 For example, treatment of tosylate 66 with strong b a s e afforded bicyclic ketone 67 in 74% yield (equation 19). t-BuOK, THF (19) ^ G T s \^ o 6 6 4 5 °C, 22 h 6 7 (42%) Schultz and Dittami exten ded the intramolecular enolate alkylation to cyclohexenones to construct bicyclic k e to n e s .2 1 Thus, consecutive alkylation of enol ether 68 with methyl iodide followed by reduction of the carbonyl group and the usual transposition step s produced the 4,4disu b stitu ted c y c lo h e x e n o n e 69. The lithium en olate of the cyclohexenon e derivative did undergo cyclization to give bicyclic enone 71 in 83% yield (Schem e V). Schem e V. S y n th e sis of 5 -M e th y lb ic y c lo [3 .3 .1 ]n o n -3 -e n -2 -o n e o Me a, b, c OEt 68 69 (93%) d Me Me e OSiMe3 71 (83%) 7 0 (96%) (a) 1. LDA, THF, -78 °C 2. Mel (b) 1. LDA, THF, -78 0 2. I(CH2 )3 CI, HMPA, rt (c) 1. LAH, ether, 0 °C, 2. 10% HCI, EtOH, rt (d) 1. LDA, THF, -78 °C 2. Me 3 SiCI, -78 °C (e) HMPA, rt, 18 h T h e acid-catalyzed cyclization ot cyclohexenyl ketones is anoth er reaction that yields bicyclic ketones. For example, Buchi and Wuest treated the trienone 72 with p-toluenesulfonic acid in a n attempt to isomerize it to d a m a s c e n o n e 74 (equation 2 0 ) . 2 2 Even though isomerization took place, the major product w as an epimeric mixture of bicyclic en o n e s 7 3 resulting from a proton catalyzed cyclization of a -d a m a s c e n o n e (75). 72 7 3 (6 2 % ) 7 4 (30 % ) 7 5(5% ) Trost and S e o a n e reported a [6+3] route to nine-m em bered bicyclic k e to n e s .2 3 For example, allylic silane 76 reacted with tropones (77) in the p re s e n c e of a palladium catalyst to afford the [6+3] cycloadduct 78 in good yield (equation 21). 12 Me3Si\ X ^ N ^ OAc + ( 76 C. ^= ° N ess/ Pd -0AC)2 0-*- Toluene, 3 h, 80 °C ^ 77 V oV = / 7 8 (21) ( 6 8 %) B icyclic K etone S yn th esis via O xyallyl C ation The [3+4]-cycloaddition reaction is also a popular method to construct bicyclic octanones. An oxyallyl cation, which is the three carbon unit, is som etim es g en erated from a dihaloketone by reductive m etho ds. The oxyallyl cation c a n b e g e n e r a t e d in situ a n d re a c te d with cyclic conjugated d ien es to give bicyclic and tricyclic ketones. For example, Shimizu and coworkers have prepared bicyclic k etones 83 and 94 by treating dichloroketone 79 with cyclopentadiene (8 8 ) in the p re s e n c e of AgCIC>4 (S ch e m e VI) . 2 4 Several years later, Narula applied the sam e methodology to get the bicyclic k eto n es from cy c lo h e x a d ie n e .2 5 For exam ple, treatm en t of dibrom oketone 85 and cyclohexa-1,3-diene bicyclo[3.2.2]nonenones 87 and 88 in 86 86 with diiron nonacarbonyl in b e n z e n e afforded % overall yield (equation 22). O Me r ^ | X I 8 5 + k j 8 6 Fe 2 (CO )9 b e n z e n e ,3 0 ° C ,24 |T + 8 7 (52%) (22) 8 8 (34%) Schmid and Schmid u sed chloroenamine 85 a s a precursor for the oxyallyl cation instead of a chloroketone. For exam ple, trea tm e n t of e n a m in e 8 5 with 1 ,3 -b u tad ien e (91) and cyclopentadiene (82) in the p re s e n c e of silver tetrafluoroborate in m ethylene chloride g ave the desired [4+3]-cycloaddition. The resulting iminium salts w ere hydrolyzed to give bicyclic ketone 92 in 27% yield and tricyclic ketones 93 and 94 in 73% and 3%, respectively (equation 23).26 13 S ch em e VI. Synthesis of B icyclo [3.2.2 ]n o n an -3-o n e Oxyallyl cation D erivative via O Me Me II H Me Ae Me MesSiCI / Et3N Cl Cl y H . 80 AgCI04, M eN02, 0 X Me Nte M e-V ^r-^ M e -y i-T / £ r% Cl VCl e th er 79 OSiMe3 | OSiMe3 * < ?*% 8 3 (55%) 8 82 Me 4(25%) H 8 1 9 1 9 f \ 2(27% ) AgBF4, -60 °C Cl (23) o 90 82 89 9 3 (73%) 94 (3%) Cha and coworkers adopted the s a m e methodology to a sse m b le the AB ring system of th e t a x a n e d ite r p e n e s .2 7 Thus, ch lo ro e n a m in e 9 6 u n d erw en t the cycloaddition with sp iro h e p ta d ie n e 9 5 in the p re s e n c e of AgBF 4 to afford cycloadduct 97 in 4 2% overall yield (equation 24). 1. AgBF4 2. NaOH (24) o 95 96 97 (42%) 14 D. Bicyclic Ketone Synthesis via C yclooctane and C yclo n on an e derivatives Bicyclic ketones can also b e obtained via annulation of cyclooctane derivatives. Since the sy nthesis of substituted cyclooctane derivatives is not generally a s e a s y that of cyclohexane derivatives, this m ethod is som ew hat limited. Fell and coworkers reported the synthesis of the bicyclononan-9-one (99) by treating 1,5-cyclooctadiene (98) with nickel(0)carbonyl in 60% yield (equation 25).28 Ni(CO) 4 , Me 2 CO, water (25) 98 99 (60%) Bicyclic n o n a n o n e 99 c a n also be obtained from 9-borabicyclo[3.3.l]nonane (100), which is easily prepared by hydroboration of 1,5-cyclooctadiene (98). Thus, Brown and Carlson c o n s tru c te d the bicyclic k e to n e in excellent overall yield by treating 9-BBN with 2,6dim ethylphenol followed by dichloromethyl methyl eth er and a lithium alkoxide a n d then hydrogen peroxide (S chem e VII) 29 Finally, G agneux and Meier have cleaved ad a m a n ta n e s to get the bicyclic com p o u n d s .3 0 For exam ple, heating 1 ,3 -dibro m o adam en tane (102) u n d er reflux in dioxane g a v e hydroxy brom ide 1 0 3 which then ring cleav ed under the reaction conditions to afford the m ethylene bicyclic ketone 104 in 85% yield (equation 26). 1 N NaOH dioxane, 180°C (26) autoclave, 18 h 1 02 1 03 104 (85%) 15 Schem e VII. Bicyclic Ketone Synthesis via 9-BBN Methylation Me a, b Me 98 1 0 0 c, d Me Cl B Me Me 99 (86%) 10 1 (a) BH3, A (b) 2,5-dimethylphenol, THF, rt (c) CH 3 OCHCI2 (d) Et3 COLi, THF, 0 °C (e) 30% aq H2 0 2, NaOH, THF, EtOH, water E. D ia s te re o s e le c tiv e M ich ael R eaction Even though the Michael reaction is o n e ot the most popular C-C bond forming reactions, it h a s b e e n known for som e time that the reaction betw een ketone enolate equivalents and a,[iunsaturated ester derivatives is not generally steroselective. However, reactive Michael acceptors such a s nitroolefins show high stereoselectivity. Risaliti 31 and Kuehne 32 have published a series of p a p e rs which prove that Michael reactions of en a m in e s derived from cyclic keto n es with nitroolefins are kinetically controlled. For exam ple, reaction of morpholine e n a m in e 4 with nitroolefin 105 afforded a 95:5 ratio of anti and syn d iastereom ers 106 and 107 in 80% overall yield (equation 27). Q 16 y ' N° 2 p. h J 4 (8 0 %) ‘ 9 ^ 1 05 Ph ^ 106 : c h 2n o , (95:5) , 27) 1 07 S e e b a c h and Golinski 3 3 have also reported stereoselective Michael reactions of acyclic en am in es an d several cyclic en a m in e s with nitroolefins. For example, treatment of enam ine 108 with nitroolefin 105 afforded a 99:1 ratio of anti and syn d ia s te re o m e rs 109 and 110 in 80% overall yield, o. o N- 1 i 1 08 NOg / = ♦ O / o Ph e, A Ph <8 0 % > ^ - nO , +E1A A , « 0 , (28) L Me 1 05 Ph (99:1) 1 09 n o To overcom e the reactivity problem of the Michael acceptors, acid-catalyzed Michael reactions h av e b e e n developed. Also, different types of reactive e s te r s w ere exam in ed by Mukaiyama a n d coworkers, who reported the first u se of Lewis acids in Michael reactions of e n o n e s with enol s ila n e s .3 4 In the early reports they focused on the reaction itself, and the stereochem istry w as not investigated. Later, they dem onstrated that a,(i-unsaturated orthoesters and thioesters react with silyl enol ethers in the p re sence of Lewis acid. For example, treatment of thioester 111 with silyl enol ether 112 in the p re se n c e of a Lewis acid afforded a diasteromeric mixture of 113 and 112 in a ratio of 87:13, respectively (equation 29). OSiMe3 P,c;- ^ W r r Me — E,S _______ - O E,s A Me r X O ^ O SE, * EtsA Me SbCfe"Sn(OTf)2, -7 8 °C 111 75% Me rX O ^ SE1(29) Me 113 (87:13) 1 1 4 Heathcock and coworkers investigated the stereoselectivity of the Mukaiyama-Michael reaction of a,(3-unsaturated ketones. They u sed a pair of stereoisomeric silyl ketene acetals and 17 enol silanes in their study. For example, reaction of e n o n e 115 with E-116 o rZ - 1 1 6 afforded a 76:24 mixture of anti a n d syn iso m e rs 1 1 7 and 1 1 8 , re spectiv ely, r e g a r d l e s s of the stereochem istry of th e starting enol ether (equation 30).35 However, reactions of silyl ketene acetal 120 with e n o n e 119 showed high syn selectivity. Thus, treatment of e n o n e 119 with silyl k e te n e a c e ta l 1 2 0 afforded d ia s te re o m e ric mixture of 121 an d 1 2 2 in a ratio of 4:96, respectively (equation 31). OSiMe3 < J':::,„0. r Me O Mg O O Me Et SnCl}, CH 2 CI2 , -78 C (30) Me 52 % 1 1 5 O 117 1q (76:24) OSiMe2(t-Bu) JL O Me t - B u O ''^ 5y 'r O Me O 120 1 I 1 Me TiCI4,C H 2Cl2,-78°C 1 % Me JL O X Ot-Bu (3 1 ) 1 Me 119 88 O X + Me (4:96) 121 1 2 2 Machida an d coworkers reported that Michael reactions betw een en a m in e s and a 1,3dioxalane cation gav e predominantly the syn product. 3 6 Thus, treatment of acetal ester 123 with enam ine 124 in the p re s e n c e of titanium tetrachloride afforded Michael adducts 125 and 126 in a ratio of 93:7, respectively (equation 32). O 0 Ph v ^ OMe OMe 123 N 124 Me Ph OMe — ^ Me }, OMe 1 2 5 (syn) + T 1CI4 , CH 2 CI2 , -45 UC O Me (32) O (82%) ph - - — Me - - OMe OMe 1 2 6 (anti) 18 The aforem entioned discussion will hopefully provide the re ad er with reference points with which the following research ca n be compared. I will now turn to the topic of the first portion of the th esis research, a study of the reaction betw een en am ines with « ,p -u n satu rate d thioesters an d selen o e ste rs. 3. Results and Discussion The re searc h described in this section w a s conducted in re s p o n s e to an observation recorded by Chin-Shan Lai during the course of his work on the ax ane sesquiterpenoids. Lai had determ ined that the pyrrolidine-mediated intramolecular conjugate addition of keto e s te r 127 shown in equation 33 proceeded with almost complete stereocontrol at C (1 and Cp. To determine whether the stereochemistry was a c o n se q u en ce of the intramolecularity of the reaction, or simply a property of enam ine-unsaturated es te r conjugate addition, Lai examined the reaction betw een the pyrrolidine enam ine of cyclohexanone and ethyl crotonate. This en am ine-unsaturated ester pair, however, did not react under mild reaction conditions com parable to those used in equation 33 and thus, it w a s not possible to make the desired stereochemical comparison. It w as decided that a thioester would be a better electrophile than ester, so Lai next exam ined the reaction of en am in e 1 with oc,p-unsaturated thioester 129. A reaction occured u nd er mild conditions and it w a s d eterm ined that the product w a s a mixture of 13 a n d 14 in 24% yield (equation 34). Although the yield w as low and the product stereochem istry w a s not proven, the relationship between this observation and the Hickmott reaction (equation 4) w as obvious. H (33) AcOH, THF Me 127 (65%) Me 128 19 o oN Me Me SPh O Me 129 (34) benzene (95:5) (24%) 13 1 14 The purpose of this research w as explore this initialobservation with the following goals: ( 1 ) to improve yields and probe the generality of the p ro c e s s in term s of ena m in e an d a,(iunsaturated thioester structure (2) to extend the p rocess to a,p-unsaturated sele n o e s te rs and (3) to understand the m echanism of the process. The following discussion will a d d r e s s the first two issu es in som e detail and provide so m e commentary on the third issue. We first p re p a re d several cx,p-unsaturated th io e s te rs a n d s e l e n o e s t e r s from the corresponding a c i d s . 3 7 Namely, trea tm e n t of o c,p-unsaturated acid of type 1 3 0 with dicyclohexylcarbodiimide in the p re s e n c e of thiophenol or selenophenol g ave the corresponding e s te rs 132 (equation 35). They w ere also prepared in good yield by treating acid chlorides 3 8 of type 131 with the thiophenol an d sele n o p h e n o l 3 9 in the p re s e n c e of a mild b a s e such a s pyridine. The details of their preparation are provided in the experimental section. The oc.punsaturated thioesters and selen oesters u sed in this study are shown in Figure 1 with their yields. DCC, PhSH OH SPh cat. DMAP 130 kSOCl 2 PhSH 132 (35) O Cl 131 Keck and coworkers reported another approach to unsaturated thioesters using a Wittig olefination (equation 36).40 For exam ple, treatm en t of aldeh y d e 141 with ylid 1 4 2 g av e u n s a tu ra te d thioester 143 in 80% yield. Although this m ethod w as attractive, the acylation 20 reactions with thiophenol and selenophenol w ere so successful, we did not try to u s e the Keck m ethod. o Me ^ A 1 o SPh Me ^ A 2 9 (78%) 1 ^ A ^ 3 3 (79%) A SPh 1 3 4 (87%) O SePh ph COSPh 1 3 i F ig u r e 1. « , p - U n s a t u r a t e d 0Bn 6 (70%) 3 A SePh 3 7 (61 %) o ^ A SPh 1 4 0 (55%) T h io esters COSEt, ^ 1 g (58%) H CHO Ph COSePh Mg0 2C 1 38(67% ) O SPh 1 3 5 (78%) M e02C \pr SePh O iPr o and S elen o este rs OBn f (36) 142 1 41 1 4 3 ( 8 0 % , E:Z=91:9) This study b e g a n with optimization of yield in the reaction betw een enam ine 1 and «,[)unsaturated thioester 129. It w as eventually found that treatment of thioester 129 with enam ine 1 in b en z en e at room tem perature afforded a mixture of bicyclic diones 13 and 14 in a 95:5 ratio, respectively, in 66% overall yield. Under these conditions Michael adduct 144 w a s also isolated in 19% yield (equation 10). Interestingly, the major product of the reaction had stereochemistry at C4 opposite to that of the major product obtained in the Hickmott reaction (equation 6 ).4a Isomers 13 and 14 could be distinguished by differences in the chemical shift of the methyl group signals in their 1H NMR spectra. T hese signals a p p e are d a s doublets (J = 6 . 8 Hz) at 1.19 ppm in 13 and 1.07 ppm in 14. 21 COSPh SPh b en z e n e , rt 129 13 (61%) (37) 144 (19%) 14 (5%) It w as next decided to determine the stereochemical assignm ent at C-4. The assignm ent w a s b a s e d on the following reaction s e q u e n c e (S ch e m e VIII). Dione 13 w a s brom inated with p h e n y ltrim e th y la m m o n iu m trib ro m id e 6 ' 4 1 in an h ydro us tetrahydrofuran at 0 ° C to give bromodione 145 in 73% yield. It had b ee n shown that bromination of bicyclo[3.3.1]nonan-2-one (147) gives the 3p-brom oketone 148 b e c a u s e of the p re s e n c e of a sev e re Br-H 7 a nonbonding interaction of the chair-chair conformer of bromoketone 149 (equation 38) 42 Thus, the structure of a-b rom oketon e 145 w as tentatively assign ed a s shown in the S c h e m e VIII. In addition, H(3) a p p e a re d a s a doublet at 4.65 ppm with a coupling co nstant of 11.8 Hz, in support of the assignm ent. Treatment of bromodiketone 145 with lithium bromide and lithium carbonate in N,Ndimethylformamide at 100 °C g av e crystalline en ed io n e 146 in quantitative yield. Catalytic hy d ro g e n atio n of en e d io n e 146 over palladium on ch a rco a l returned bicyclic dione 13 in quantitative yield. It w as a ssu m ed that the hydrogenation took place from the less hindered p-face of the double bond in 146. Of course, it w as neccesa ry to show that 14 also gave 13 upon subjection to this reaction seq u e n ce and that w as eventually done (vide infra). PhN*Me3 Br3' (38) THF 147 148 14 9 (incorrect) Though the chemical yield of the reaction was not so bad, it w as realized that so m e of the Michael acceptor w as being lost through formation of 144. Thus, experim ents using e x c e s s 129 were performed. W hen 1.3 equivalent of 129 were u sed , the com bined yield of d io n es did improve to 74%, but this w a s not too significant. Since thiophenoxide g eneratio n is also responsible for lost of 129, the u s e of dichloromethane a s a thiophenoxide trap w a s investigated. 22 Schem e VIII. Determination of the Stereochem istry of Bicyclic Dione 13 1 4 6(100% ) (a) PhN+Me 3 Br3- (b) LiBr, Li2 C 0 3 (c) H2, Pd/C Thus, n ea t thioester 129 w as slowly a d d e d by syringe pum p to a solution of en am ine 1 in b e n z e n e containing 1 equivalent of dichloromethane. Formation of 144 w as still a problem. We next turned our attention to the corresponding a,|3-unsaturated s e le n o e ste r 133 a s we expected it would be more reactive than its sulfur anolog. When the s a m e reaction condition w as u s e d for selen o e ste r 133, the result w as som ewhat disappointing. For example, treatment of s e le n o e s te r 133 with enam ine 1 in b en z e n e afforded a 43% yield of diones 13 and 14 in a ratio of 25:75, respectively. Even though the reaction yield and the diastereoselectivity w ere not satisfactory, a significant difference from the reaction of thioesters could be easily recognized. Specifically, the major product w as 14, and not 13. E ncouraged by this result we investigated different reaction conditions. We hoped that dichloromethane might accelerate the reaction by stabilizing a possible polar transition state. Thus, treatment of s e len o e ste r 133 with enam ine 1 at -15 °C in dichloromethane afforded diastereomerically pure dione 14 in 84% yield and selenides 151 and 152 in 62% and 14% yields, respectively, following an a q u e o u s workup. To search for an intermediate, the reaction mixture w as diluted with hot dry ethyl ac etate before hydrolysis to 23 Me COSePh + P hSeC htC I + (PhSe) 2 CH2 (39) 133 14 150 (84%) 151 (51%) 152 (28%) get a white solid in 84% yield. Spectral analysis confirmed that this material w a s iminum salt 150. A silver nitrate test w as positive indicating that chloride w as a counter ion of the iminum salt. The iminium salt 150 w as easily hydrolyzed with wet silica gel in dichloromethane to give 14 in 85% yield. Having diasteroisom er 14 at hand, it w as subjected to the aforementioned halogenationdehyd ro halog en ation-h ydrogenation sequence. Thus, trea tm e n t of d io n e 1 4 with phenyltrimethylammonium tribromide in anhydrous tetrahydrofuran at 0 °C afforded bromodione 153 in quantitative yield. The structure of 4 p -b ro m o k e to n e 153 w a s assig n ed a s shown in the S c h e m e IX b a s e d on the p re s e n c e of nonbonding interaction betw e en Br and H(7ra) in 4abromoketone. In addition, a coupling constant (J = 4 Hz) betw een H(3) and H(4) supported the structural assignm ent. Treatment of bromoketone 153 with lithium bromide and lithium carbonate in N,N-dimethylformamide at 100 °C g ave crystalline en edione 146 in 85% yield and catalytic hydrogenation of the ened io n e 146 over palladium on charcoal, of c o u se , g ave dione 13 in quantitative yield. Before continuing with a d iscu ssion of the s c o p e and limitation of this reaction, a conformational analysis of diones 13 and 14 will be presented. A spin-off of this analysis is further s u p p o rt for th e s te re o c h e m ic a l a s s i g n m e n t s up to now b a s e d o n th e brom inationdehydrohalogenation-reduction s e q u e n c e . 24 S c h e m e IX. D e te r m i n a t io n of t h e S t e r e o c h e m i s t r y of B icyclic D io n e 14 Me O h a Br 1 5 3 (100%) 14 b o c 1 3 (100%) 14 6 (85%) (a) PhN+Me 3 Br3- (b) LiBr, Li2 C 0 3 (c) H2, Pd/C Although conformational analysis of bicyclo[3.3.1]nonane 4 3 and bicyclo[3.3.1]nonan-9o n e 4 4 derivatives have been investigated by several groups in depth, bicyclo[3.3.1]nonan-2,9diones have not b ee n studied yet. The 1H NMR signals of the diones w ere first established by decoupling experiments and then later COSY experiments. The conformational p referen ces of diones 13 and 14 w ere determined by the aid of 1D and 2D 1H NMR spectroscopy. The COSY spectrum of 4 a-iso m er 13 show ed long range W-couplings betw een H( 1 ) and H(5), H(1) and H(3P). However, 4 [H som er 14 did not show W-coupling betw een H(1) and H(3[i). The lack of Wcoupling can be rationalized if the cyclohexanone ring containing the methyl substituent adopts a boat conformation. Other convincing evidence for a boat-chair conformation for 14 co m e s from NOE experiments. For the 4p-isomer (14), a large NOE was observed at H(3oc) upon irradiation of methyl group at C(4). This indicates the proximity of H(3ra) and methyl group and can be explained only if the cyclohexanone ring containing the methyl group adopts a boat conformation. For the 4a-isom er (13), a large NOE w as also observed at H(3a) upon irradiation of methyl group at C(4). 25 Thus, 4 a-iso m er 13 favors a chair-chair conformer. O ne c a n rationalize th e s e conformational differences b a s e d on the nonbonding interactions betw een H(3ra)-H(7«) and Me-H(7a). Me H Me '3a F ig u r e 2. NOE E x p e r i m e n t s w ith D io n e 13 Irrad iated C h e m i c a l S h ift (CDCI 3 ) NOE Me O bserved C h e m i c a l S h ift H3(i (1%) 2 .6 9 H5 (3%) 2 .4 8 H3(x (8 %) 2 .3 5 H4 (8 %) 2 . 12 1.16 '3a Me Me l7a F ig u r e 3. NOE E x p e r i m e n t s w ith D io n e 14 Irrad iated C h e m i c a l S hift (CDCI 3 ) NOE Me 1.09 O bserved C h e m i c a l S h ift H3|$ (3%) 2 .7 6 H5 (7%) 2 .4 7 H3 a and H4 (11%) 2 .0 9 (40) chair-chair boat-chair 26 chair-chair boat-chair To investigate the sc o p e and the limitations of the reaction betw een oc,p-unsaturated th io esters an d s e le n o e s te r s with pyrrolidine e n a m in e 1 , several (J-substituted u n s a tu ra te d thioesters an d se le n o e ste rs w ere investigated. Thus, treatment of thioester 134 with enam ine 1 g av e a 32% yield of diones 154 and 155 in a 80:20 ratio, respectively, a n d 4 5% of Michael adduct 156 (equation 42). The yield and stereochemistry of the reaction w as not improved by changing the reaction conditions. However, selenoester 135 smoothly reacted with enam ine 1 at -15 °C to yield iminium salt 157 in 55% yield and dione 155 in 15% yield along with selenides 151 (53%) and 152 (8 %) (equation 43). O nce again, thio ester an d s e le n o e s te r g a v e the opposite stereoisom ers a s major product. Iminium salt 157 could be hydrolyzed to dione 155 in 80% yield using wet silica gel in dichloromethane. The stereochem ical assignm ent at C(4) of dione 154 w a s b a s e d on the a p p e a ra n c e ot H(3oc) and H(3[3) a s two doublets ot doublets at 8 2.34 and 8 2.86, respectively. The coupling constant betw een H(3rx) and H(4) w a s 12.2 Hz, indicating a trans diaxial relationship betw een H(3«) and H(4). The coupling constant between H(3fi) and H(4) w as 7.3 Hz, which w as relatively large tor an axial-equatorial coupling. This may be b e c a u s e of the flattened structure of the cyclohexanone ring. The stereochemistry of dione 155 w as also b a s e d on the values of coupling co nstants for H(3(3) and H(3«) which ap pe are d a s two doublets of doublets at 8 2.08 and 2.56, respectively. The coupling constant b etw een H(3(i) and H(4) w a s 12.1 Hz, indicating a trans diaxial relationship betw een th e s e protons. The coupling betw een H(3oc) and H(4) w as 5.6 Hz which is indicating an axial-equatorial coupling. These data could once again be explained by the two different conformations adopted by diones 154 and 155. Thus, 4(i-substituted dione 155 27 actually a d o p ts a boat-chair conform ation, but 4 a -su b s titu te d dione 1 5 5 principally a d o p t s a chairchair conformation at room te m p e ra tu re. COSPh 'Pr SPh e n a m in e 1 'Pr C 6 H6, rt 'Pr 3 2% 134 154 cosePh . COSPh (42) 156 (45%) O !* cr 'Pr 'Pr (70:30) 1 5 5 A enamine 1 CH2CI2,-15U VI ,2'w/lif' 1^ ^C 1 35 / J PhSeCt-feCI + (PhSe) 2 CH 2 / | 1 5 5(1 6 % ) 157 (55%) 151(53% ) (43) 152(8% ) The reaction of 1 with cinnamic acid derivatives w a s next exam ined. Treatm ent of thioester 136 with enamine 1 in b en z e n e at room tem perature afforded a 3 6% yield of separable d io n es 8 and 9 a s a 70:30 ratio, respectively, along with Michael adduct 158 in 32% yield (equation 44). The stereochemistry at C(4) of dione d e h y d r o b r o m in a t io n - h y d r o g e n a ti o n 8 sequence. w as assigned on the basis of a brominationThus, d io n e 8 w a s b ro m in a te d with phenyltrimethylammonium tribromide in anhydrous tetrahydrofuran at 0 °C to give bromoketone 159 in 56% yield. Treatment of bromoketone 159 with lithium bromide and lithium ca rbo nate in DMF gave crystalline enedione 160 in 64% yield. Catalytic hydrogenation of 160 over palladium on charcoal returned dione COSPh 8 in quantitative yield (equation 45). e n a m in e 1 SPh Ph CgHg, rt 144 P h^^^ COSPh 35% 8 (70:30) 158 (32%) 9 Ph Ph (45) 159 (56%) 160 ( 64%) (a) PhN+Me3 Br3- (b) LiBr, Li2 C 0 3 (c) H2, Pd/C 8 (1 0 0 % ) (4 4 ) 28 Treatment ot «,p-unsaturated selen o e ste r 137 with enam ine 1 aftorded iminium salt 161 in 96% yield and dione 9 in 12% yield (equation 46). We could not detect the minor isom er 8 in the reaction mixture. Dione 9 w as the s a m e a s the minor isomer isolated from the unsatu rated thioester reaction (equation 44). Iminium salt 161 w as hydrolyzed to dione 9 in 87% yield using wet silica gel in dichlorom ethane at room tem perature. T he stru ctu res ot the d io n es were rigorously established by 1H NMR experim ents such a s decouplng and COSY along with a C-H correlation experim ent. T he s te re o ch em istry of dione 9 w a s a s s ig n e d on th e basis of a bromination-dehydrobromination-hydrogenation s e q u e n c e . Thus, dione 9 w a s brominated with phenyltrimethylammonium tribromide to give brom odione 162 in 79% yield .51 T reatm ent of brom oketone 162 with lithium bromide and lithium carbon ate in DMF gave crystalline enedione 160 in 79% yield. Catalytic hydrogenation ot 160 gave dione 8 in quantitative yield (equation 47). co seP h enam ine 1 + CH 2 CI2, -15 uC 1 45 9(12% ) Ph n Ph n 161 (8 6 %) PhSeCFfeCI + (PhSe) 2 CH 2 1 5 1(56% ) 1 5 2(11% ) O Ph (46) O (47) 162 (79%) 9 160 (79%) 8 ( 100%) (a) PhN+Me 3 Br3- (b) LiBr, Li2 C 0 3 (c) H2, Pd/C Once again, the conformations of diones 8 and 9 were examined using a series of NMR experim ents (decoupling, COSY, an d difference NOE). Relevent difference NOE experim ents are sum m arized in Figures 4 and 5. For dione 8 , a chair-chair conformation w as assig n ed b a s e d on the proximity ot H(3a) and H(7«), and H(3[i) and H(4). A large NOE w a s o b serv ed at H(7a) upon irradiation of H(3a) and at H(4) upon irradiation of H(3P). Large NO Es w ere o b served b e c a u s e dione 8 adopts a chair-chair conformation. 29 For dione 9, a boat-chair conformation w as assigned on the basis of the proximity of H(7ot) to H(4) and the a b s e n c e of an NOE betw een H(3ra) and H(7cx). In addition, a small NOE w as observed at H( 1 ) and H(5) upon irradiation of H(3(3). The assignment of the stereochemistry at C(4) w a s b a s e d on the proximity of H(3[5) and the phenyl substituent. The observation of a large NOE of appropriate protons in the phenyl substituent upon irradiation of H(3(3) indicated that they were located on the s a m e side of the molecule. Ph H Chair-Chair Boat-Chair Figure 4. NOE Experim ents with Dione 8 Irr a d ia te d Chemical Shift (C 6D6) NOE O b served C hem ical Shift H3o 2 .6 2 Ph (10%) 6 .7 7 H3(j (17%) 2 .4 2 H7a (8 %) 1.35 H4 (4%) 2 .73 H3a ( 1 3 % ) 2 .6 2 H3k (4%) 2 .6 2 H5 (2%) 2 .4 2 H6ot (1%) 1.61 He (1 1 %) 1.50 H7|J (11%) 0 .8 3 H3(j H 7 0 C, H 8 2 .4 2 1.25 30 '3a 7a Chair-Chair Boat-Chair Figure 5. NOE Experim ents with Dione 9 Irra d ia te d Chemical Shift (CeDg) H3 ra 2 .4 9 H3(j 2 .1 0 H7a NOE O b s e rv e d Ch em ical H3p (15.5%) 1.23 Shift 2 .1 0 Ph (5%) 6 .8 9 l-H (2%) 2 .9 8 H5 (1%) 2.71 H3a (18%) 2 .4 9 Hi (0.6%) 2 .9 8 H5 (0.6%) 2.71 H4 (7%) 2 .5 8 H3a (2 %) 2 .4 9 H8 (4%) 2 .2 0 H7fl (18%) 0.91 Studies next turned toward unsymmetrical tumarate derivatives. Treatment of unsaturated thioester 13 8 with enam ine 1 g av e a 64% yield of diones 163 and 164 a s an 85:15 mixture, re s p e c tiv e ly . T he stereochem istry d e h y d ro b ro m in a tio n - h y d ro g e n a tio n was assig n ed sequence. T h u s, on th e d io n e b asis of a b rom ination - 1 6 3 w a s b rom in ated with phenyltrim ethylam m onium tribromide to give b ro m okeo ne 165 in 70% yield. Treatm ent of brom oketone 165 with lithium bromide and lithium carbonate in DMF g ave crystalline enedione 166 in 59% yield. Catalytic hydrogenation of 166 returned dione 163 in 62% yield (equation 49). 31 C 02Me MgOj C 0 MgOoC _ COSPh CH 2 CI2, -40 °C (85:15) O Me02C MeOX MgO'iC MeOX O' > • 165 (70%) " 166 (59%) ° 1 6 3 (5 0 % ) (a) PhN+Me 3 Br3‘ (b) LiBr, Li2 C 0 3 (c) H2, Pd/C Treatment of seleno ester 139 with enamine 1 gave a red oil which failed to crystallize upon dilution with ethyl acetate. Several attempts at crystallization were not successful, so the oil w as purified by column chromatography to give a single isomeric product, 164, in 68% yield along with selenides 151 (41%) and 152 (13%) (equation 50). O uoo20 ^ COSon 7 C 02Me O cHaCb.-40 ®c ” 1 39 T 7 } 0 * (PhSe,CH!0U (PhSe)20H2 1 6 4 (6 8 % ) 1 5 1 (4 2 % ) <50) 152(13% ) Synthetic asp e c ts of reactions with enam ine 1 were concluded a s shown in equation 51. Thus, treatment of thioester 140 with enam ine 1 gave a crystalline bicyclic dione 6 in 20% yield and Michael adduct 172 in 30% yield. ^ cosph 1 4 0 ~ * 6 (20%) ^ ^ « ch* cos™ 165 <5 , » (32%) We next turned our attention to the synthesis of diones with different ring sizes by using e n a m in e s of cyclopentanone (36) and cycloheptanone (166). The reaction b etw een enam ine 36 and thioester 129 in b en z en e gav e a single isomeric product 167 in 30% and Michael adduct 144 in 10% yield (equation 52). To determ ine the su b stra te effect, we ran the reaction of 32 se le n o e s te r 133 with enam ine 36 in dichloromethane at -15 °C and found that the s a m e product (167) w a s formed in 31% yield (equation 53). Attempts to isolate the iminium salt failed. The assignm ent of stereochemistry for dione 167 w as b a s e d on the a p p e a ra n c e of H(3cx) and H(3P) as doublets of doublets at 5 1.57 an d 5 1.87, respectively. The coupling constant of the doublet of doublets at 5 1.57 w as 12.9 Hz, an indication of a trans diaxial relationship with the adjacent methine proton H(4). The coupling constant of the doublet of doublets at 8 1.87 w a s 5.8 Hz, an indication of an axial-equatorial relationship with H(4). Me s. COSPh COSPh 129 M e^ ^ -^ 167 (30%) COScPh (52) 1 4 4 (10%) (PhSe)CH 2 CI+ (PhSe) 2 CH2 (53) CH2 CI2, -46 UC 133 167 (31%) 151 (48%) 152(11% ) R eaction of s e le n o e s te r 1 3 3 and enam ine 166 in dichlorom ethane at -15 ° C gav e iminium salt 168 in 75% yield an d hydrolyzed dione 169 in 15% yield along with selenides 151 (42%) and 152 (13%) (equation 54). Hydrolysis of 168 using wet silica gel in dichloromethane gave bicyclic dione 169 in 52% yield. Me^ COSePh 133 enam ine 166 ► CH2 CI2, -15 °C + PhSeCH>CI + (PhSe) 2 CH2 (54) o 168 (75%) o 169 (15%) 151(42% ) 152(13% ) Treatm ent of s e le n o e s te r 135 with enam ine 166 gave iminium salt 170 in 61% yield, diketone 171 in 13% yield, and selenides 151 (42%) and 152 (13%) (equation 55). Hydrolysis of 170 using wet silica gel in dichloromethane g ave bicyclic dione 171 in 65% yield. iPr enamine 166 + PhSeCH>CI + (PhSe) 2 CH 2 (55) COSePh CH2CI2,- 1 5 ° C 135 q 170(61% ) o 171 (13%) 1 5 1(42% ) 1 52(13% ) Treatment of s e le n o e s te r 137 with enamine 166 g ave iminium salt 172 in 64% yield and dione 1 7 3 in 13% yield along with selen id e s 151 (38%) an d 152 (15%). Hydrolysis of 1 7 2 using wet silica gel in dichloromethane gave bicyclic dione 173 in 73% yield. The stereochemistry of diones 1 6 9 ,1 7 1 , and 173 w ere assign ed on the basis of the a p p e a ra n c e of H(3a) and H(3P) a s doublets of doublets at the region of 5 2.5 in 1H NMR spectra. T h e s e protons show ed similar coupling con stant values to their 4fi-substituted nonan dio ne counterparts. For exam ple, the coupling co n stan ts of two doublets of doublets of H(3a) and H(3P) at 173 were 9.7 Hz and 5.8 Hz, com pared to 11.0 Hz and 6.4 Hz for H(3o.) and H(3P) in nonandione 9. enam in e 166 + PhSeCFfeCI + (P hS e) 2 CH 2 (56) COSePh CH2 CI2, -15 °C 137 o 172(64% ) 173(13% ) 1 5 1(38% ) 1 5 2(15% ) Even though u n s a tu r a te d s e l e n o e s te r s g a v e the excellent results, u n s a tu ra te d thioesters g av e only m oderate yields and stereoselectivities. Hickmott and coworkers reported that changing from pyrrolidine to morpholine enam ines in the acid chloride annulation (equation 6 ) c a u s e d a m arked in c re ase in the yield of bicyclic diones. Thus, the morpholine e n a m in e of cyclohexanone (4) w as examined. Treatment of thioester 129 with enam ine 4 surprisingly gav e Michael a d d u c ts 174 a n d 175 in a 9:1 ratio, respectively, in 55% overall yield, in stead of annulation products. W hen the reaction w a s c o n d u c te d u n d er reflux, 1 7 4 and 1 7 5 w ere obtained a s a 1 :1 mixture in 60% yield. f N 8^ C 0 S P . . N— f CeH&rt Me H Me ^ 55 % 1 2 9 H 174 C (9:1) CHjCOSPh (ST) 175 The stereochem istry of the Michael ad d u c ts 174 and 175 w a s b a s e d on independent synthesis from 13 and 14. That is, treatment of dione 14 with 0.1 N a q u e o u s sodium hydroxide at room tem perature afforded a 10:1 inseparable mixture of ketoacids 176 and 177. T h ese were directly trea ted with dicyclohexylcarbodiimide (DCC) and thiophenol to give an inseparable mixture of ketothioesters 174 and 178 in an 8:1 ratio, respectively. On the other hand, treatment of d ione 1 3 with 0.1 N aqueous sodium hydroxide in te tra h y d ro fu ra n followed by thioesterification gave Michael adducts 178 and 174 in a 9:1 ratio. 0.1 N NaOH /^ 7 3 * THF. it ,51 %> elher, 0 °C ,69%) 1?6 ^ Me PhSH, DCC. ^ ^ H Me 0 .1 N NaOH ^ ch^ osp ,, «») H Me PhSH, DCC CH2C 0 2H ---------------- —► THF' rt (5 6% ) H ° ether, 0 ° C (75%) 177 CH2COSPh 0 178 Although the aforem en tio ned result did not provide the e x p e cted diones, reactions b e tw e en enam ine 4 and unsatura te d thioesters w ere investigated further. Thus, treatment of thioester 136 with enam ine 4 gave Michael adduct 179, but in only 13% yield. Since thioester 136 might not be so reactive a s a Michael acceptor, we thought that a Lewis acid might increase its electrophilicity. This turned out to be the ca se. Treatment of thioester 136 with enam ine 4 in the p re s e n c e of titanium tetrachloride at -78 °C afforded 179 a s a single d iastereom er in 46% yield with recovery of 35% starling material 136. The assignm ent of the stereochemistry at C(3) an d C(1') of 179 w as b a s e d on the s a m e s e q u e n c e of chemical reactions u s e d with 174 and 1 7 8 . Thus, treatm ent of dione 9 with 0.1 N sodium hydroxide in tetrahydrofuran at room 35 tem perature g av e ketoacid 180 in 9 7% yield a s a white solid. This w a s directly treated with DCC an d thiophenol to give k e to e s te r 1 79 in 90% yield. In addition, the 1H NMR s p ec tru m of ketoester 179 show ed two well resolved signals at 8 2.71 and 5 3.59 which were assigned a s H(3) and H(1'), respectively, b a s e d on decoupling experiments and a C-H correlation experiment. A coupling constant of 9.4 Hz at 5 2.71 indicated a trans relationship of H(3)with adjacent protons at H(2) and H(1'). A coupling constant of 9.4 Hz at 5 3.59 indicated a trans relationship of H(1') with H(3) and o n e of the methylene protons of the cyclohexanone ring. o-c° Ph -^ C O S P h ----- Ph „ 3 2 --------- ^ P ^ C H ^ O S P h 0 ' CH2CI2,- 7 8 ° C Hi - 136 1 7 9 (6 0 ) 2 (48%) H H ^ 0.1 N NaOH THF, rt P h S H .D C C ^ ether, 0 ° C ° 9 1 80(97% ) (61) o/ CH2c o s p h 1 7 9(90%) Finally, treatm ent of u nsatu ra te d thioester 138 with titanium tetrachloride followed by enam ine 4 at -65 °C afforded Michael adducts 181 and 182 in a 6:1 ratio, respectively, a s a white solid. We could not determine the stereochemistry of 181 b e c a u s e hydrolysis of diones 163 and 164 only g av e complex mixtures even under mild reaction conditions. We feel reasonably secure with the assignm ents shown in equation 62 b a s e d on analogy with equations 57 and 60. ° Me0 2C ^ ^ S P h / n' O 4 W CH2CI2 TiCI4 -78°C 1 38 62% M o02C H;j C 0 2Me ► ^ X ^ O c O S P h + ^ C Z J-v ^ C O S P h ° h (62) . 181 (6 1 ) 182 A num ber of m echanism s ca n be imagined for the annulation reactions described above. T h ese include (1) C-alkylation of the enam ine followed by intramolecular acylation (S chem e X) (2) a Diels-Alder reaction followed by ring opening, and then intramolecular acylation (S chem e XI) (3) 36 C-acylation of the enam ine followed by intramolecular alkylation (S chem e XII) and (4) N-acylafion followed by an aza-Claisen rearrangem ent to give a ketene intermediate, and then intramolecular C-acylation (Schem e XIII). An evaluation of th ese possiblities will now be presented. S c h e m e X. P o s s i b l e R e a c t io n M e c h a n i s m v ia C -A lk ylation Q i ^ 11 1 O - 1 83 1 84 1 8 5 (anti) S c h e m e XI. P o s s i b l e R e a c t i o n M e c h a n i s m via H e te r o D ie ls -A ld e r R e a c t io n PhSO C PhS N • Mo I Mg ^ N+ a Mo 1 18 3 1 8 5 (anti) S c h e m e XII. P o s s i b l e R e a c t io n M e c h a n i s m via C -A c y la tio n o Me Me Me 1 8 9 (syn) 1 S c h e m e XIII. P o s s i b l e R e a c t io n M e c h a n i s m via N -A cylation O N ® Me N Me Me ___ H 1 191 1 8 5 (anti) 37 The m echanism shown in S c h e m e X s e e m s quite reasonable. Since it requires enamine 18 4 a s an intermediate, it w a s thought that treatm ent of thioester 174 with pyrrolidine might produce iminium salt 185. In the event, treatment of 174 with pyrrolidine and a catalytic amount of p-toluenesulfonic acid failed to give 1 8 5 or the d esire d diketone (equation 63). This observation s u g g e s ts that the annulation d o e s not proceed via the conjugate addition-acylation s e q u e n c e . The Diels-Alder m echa nism (S ch e m e XI) requires 184 and 186 a s interm ediates. Although cycloadditions betw een en am ines and aldehydes and ketones are known, no evidence for the formation of 186 could be g athered and, of course, the experiment described in equation 63 also su ggests that this m ech a n sm is not operating. Me Mo H H- N Me COSPh COSPh CgHg, p-TsOH, A H 1 74 SPh (63) 185 The m echanism shown in S ch em e XII requires initial carbon-acyl carbon bond formation, while the other three mechanistic suggestions require carbon-alkyl carbon bond formation. Thus, it w a s re a s o n e d that enam ine 192 should give 194 if the initial event w a s acylation (S chem e XII), or 193 if the initial carbon carbon bond formation involved alkylation (other S ch em es). In the event, en am in e 192 reacted with thioester 129 to give only dione 193 in 35% yield along with Michael adduct 144 in 42% yield. This result s u g g e s ts that the m echanism depicted in S chem e XII is not opperating. This brings us to the m echnism shown in S c h e m e XIII. If this m echanism o perates, then ketene 191 must be an intermediate. Thus, experiments d esigned to trap 191 Me o Me C-acylation 194 o O + M c ^ W COSPh N-acylation^ 192 129 Me (6 4 ) 193 w ere performed. For example, treatment ot thioester 129 with enam ine 1 in the p re s e n c e of 2 38 equivalents of the absolute ethanol in b en z en e at room tem perature g av e ketoester 195 in 32% yield and th e Michael adduct 1 4 4 in 42% yield, respectively (equation 65). U nder the s a m e reaction conditions, ethyl crotona te and en a m in e 1 g av e no 19 5 b a s e d on the crude NMR spectrum. To m ake sure that k eto este r 195 ca m e from trapping of the k etene intermediate by ethanol, w e performed a series of experim ents to exclude other possible so u rc es of 195. First, treatm ent of thioester 174 with ethanol und er the s a m e reaction conditions did not give any ketoester 195 (equation 66 ). Another possible source of 195 is the ethanolysis of dione 14, but treatm ent of dione 14 with ethanol under the s a m e conditions also did not give any keto ester 195 (equation 67). T hese experiments support the m echanism shown in S c h e m e XIII. 0:0 Me ^ C O S P P - o Mg . C 0 2Et 1 SPh . (6 5 ) 2 eq EtOH, ben zen e, rt 1 29 195 (32%) EtOH, CgHg, rt Me H COSPh 144 (42%) Mo H --------------ft C 0 2E! (6 6 ) 195 EtOH, CgHg, rt -H- (6 7 ) 195 The s a m e reactions were re p eated with s e le n o e s te r 133 and the k etene intermediate w a s again trapped with ethanol u n d er the sa m e reaction conditions (CH 2 CI2 at -15 °C) to give 3 4% of 195 and s elene n ides 151 (36%) and 152 (8 %) (equation COSoPh 0-0 2 eq EtOH, CH 2 CI2 , -15 1 33 °cL J 195 68 ). C 0 ’ E I + (3 4 %) (PhSeJCFkCI + (P hS e) 2 CH2 151 152 (6 8 ) There are som e problems, however, with the proposed ketene m echanism. This pathway (S ch em e XIII) predicts that iminium ion 185 and the desired diketone 14 should be the major stereoisom eric products. This is the c a s e for u nsatu ra te d s e le n o e s te r su b strates, but not for unsaturated thiosters. Why this is so remains an open question. In addition, es te r 195 formed in the p re su m e d ketene trap experim ents (equattion 65 and 68 ) w a s obtained a s a 2:1 mixture of diastereom ers. It is puzzling that clean stereochemistry w as not obtained if S ch em e XIII is the sole mechanistic pathway. The N-acylation-rearrangement-acylation s e q u e n c e also su g g ests that a cisolefin, for example 196,45 should afford a different stereochem ical result, but this w as not the ca se. For example, treatment of 1 with 196 gave only 13 in 35% yield. There are several ways in which this result ca n be explained. For example, a conjugate addition-elimination s e q u e n c e proceeding via 197 or 198 could isomerize 196 to 129 (S ch em e XIV). Mg COSPh (69) b en z en e, rt 196 14 S c h e m e XIV. I s o m e r iz a t i o n of T h i o e s t e r 196 Me Me / = \ 196 O COSPh COSPh + Me SPh 1 29 198 In conclusion, it h a s b e e n shown that a,[i-u n s a tu ra te d th io e s te rs and s e le n o e s te r s undergo annulation reactions with pyrrolidine en am ines and Michael reactions with morpholine enam ines. The stereochem ical course of most of the thioester and sele n o e s te r annulations are 40 complementary. Although m echanistic a sp e cts of th e s e reactions are not fully understood, it is hoped that th ese reactions will find u s e in the broad area of carbocycle synthesis. 41 E x p e rim e n ta l All melting points w ere tak en using a Thom as-H oover capillary melting point app a ratu s an d a re uncorrected a s are all boiling points. 1H NMR spectra are reported a s follows: chemical shifts [multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), coupling con stants in hertz, integration, interpretation], 13C NMR d ata were obtained with Bruker WP-80, Bruker AM-250 or Bruker AM-500 spectrom eters. Infrared spectra were taken with a Perkin-Elmer 457 instrument. M ass spec tra w ere obtained on Kratos MS-30 or Kratos VG70-250S instruments at an ionization energy of 70 ev. C om pounds for which an exact m a ss is reported exhibited no significant peaks at m le g reater than that of the parent. Combustion analysis w ere performed by Micro-Analysis, I n c . , Wilmington, DE. Solvents a n d re ag en ts w ere dried and purified prior to u s e w h en d e e m e d n ec essary : tetrahyd rofu ran , diethyl ether, b e n z e n e , and to lu en e w e re distilled from sod ium metal: dichlorom ethane a n d xylene w ere distilled from calcium hydride. R eactions requiring an inert atm osphere w ere run under argon. Analytical thin-layer chromatography w as conducted using EM L aboratories 0.25 mm thick p re c o a te d silica gel 60F -254 p lates. Medium p re s s u r e liquid ch rom ato grap hy (MPLC) w a s perform ed using EM Laboratories Lobar p re p a c k e d silica gel columns. All Grignard reagents were titrated prior to u s e with s-butanol using 1,10-phenanthroline a s the indicator. 1 42 1 -W -P y rro lid in o c y c lo h e x e n e ( l ) . 2a To a solution of 12.3 g (125 mmol) of cyclohexanone and 13.2 g (185 mmol) of pyrrolidine in 60 mL of b en z e n e w a s added 30 mg of ptoluenesulfonic acid. The mixture w as refluxed for 8 h with water removal using a Dean-Stark trap. The reaction mixture w as concentrated in vacuo and the residue w as distilled to give 17.2 g (91%) of enam ine 1 a s a colorless oil: b.p. 95-98 at 22 mm (lit2a b.p. 88-92 at 15 mm). 4 1 -A /-M o rp h o lin o c y c lo h e x e n e (4).2a A mixture of 4.4 g (45 mmol) of cyclohexanone and 5.7 g (65 mmol) of morpholine in 50 mL of b en z en e w as refluxed in the p re s e n c e of 20 mg of p-toluenesulfonic acid while removing w ater with Dean-Stark trap. The reaction mixture w as c o n c e n trate d in vacuo and the residue w a s distilled to yield 6.0 g (80%) of ena m in e 4 a s a colorless oil: b.p. 93-95 °C at 4.5 mm (lit2a b.p. 117-120 °C at 20 mm). 36 1 -A /-P y rro lid in o c y c lo p e n te n e ( 3 6 ) . 2 a A mixture of 8.41 g (100 mmol) of c y c lo p e n ta n o n e a n d 8.53 g (120 mmol) of pyrrolidine in the p r e s e n c e of 20 mg of ptoluenesulfonic acid in 50 mL of b en z e n e w as refluxed for 8 h while removing w ater with Dean- Stork trap and the mixture w as concentrated in vacuo and the residue w as distilled to yield 11.27 g (82%) of enamine 36 a s a colorless oil: b.p. 60-67 at 3.5 mm (lit2a b.p. 97-98 at 15 mm). 43 6 136 1 -A /-P y rro lid in o c y c lo h e p te n e ( 1 3 6 ) . 2 a A mixture of 1.9 g (17 mmol) of cycloheptanone and 1.6 g (22 mmol) of pyrrolidine with 200 mg of p-toluenesulphonic acid in 40 mL of toluene w a s refluxed for 48 h while removing w ater with Dean-Stark trap. The reaction mixture w as concentrated in vacuo and the residue w a s distilled to yield 2.5 g (89%) of enam ine 136 a s a colorless oil: b.p. 112-116 °C at 4 mm (lit2a 133-135 °C at 7 mm). 192 1 - A /- P y r r o l id i n o - 6 - m e t h y lc y c l o h e x e n e (1 9 2 ).2a A mixture of 4.62 g (41.2 mmol) of 2-methylcyclohexanone, 5.86 g (82.4 mmol) of pyrrolidine and 50 mg of p-toluenesulfonic acid in 25 mL of b e n z e n e w as refluxed with w ater removal using a Dean-Stark trap until no more sep aration of w ater w a s observed. The reaction mixture w a s con cen trate d in vacuo and the residue w as distilled to yield 5.6 g (82%) of enam ine 192 a s a colorless oil: b.p. 78-82 °C at 4.2 mm (lit2a 112-114 °C at 15 mm). COSPh 129 E -P henyl 2 -B u te n e th io a te (1 2 9 ). To a solution of 6 .82 g (61.9 mmol) of thiophenol and 4.89 g (61.9 mmol) of pyridine in 150 mL of diethyl e th er at 0 ° C w a s ad d e d dropwise a solution of 6.54 g (61.9 mmol) of crotonyl chloride in 10 mL of diethyl ether. The 44 mixture w a s stirred at 0 °C for 2 h an d poured into 100 mL of 1 N hydrochloric acid. The organic p h a s e w a s w a sh e d with 50 mL of saturated a q u e o u s sodium bicarbonate. The a q u e o u s layers w ere com bined and extracted with three 80-mL portions of diethyl ether. The com bined organic p h a s e s w ere dried (Na 2 S 0 4 ), concen trate d in vacuo, and distilled to afford 8.62 g (78%) of thioester 129 a s a colorless oil: bp 105-107 °C at 2.0 mm; IR (neat) 1694 c m ' 1; 1H NMR (CDCI 3 , 250 MHz) 5 1.92 (dd, J = 6 .8 , 1.5 Hz, 3H, =CCH 3 ), 6.22 (dq, J = 15.0, 1.5 Hz, 1H, =CHCH 3 ), 7.01 (dq, J = 15.0, 6.9 Hz, 1H, =CH), 7.41-7.48 (m, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 17.91 (q), 127.61 (s), 128.99 (d), 129.16 (d), 129.27 (d), 134.52 (d), 141.85 (d), 187.60 (s); m a s s sp ectru m , m /e (relative intensity) 178 (M+ , 7), 69 (100); exact m a s s calcd. for C 1 0 H 1 0 OS m /e 178.0444, found m /e 178.0450. H3c vs. ^ -COSoPh 133 E -P henyl 2 -B u ten ese len o ate (1 33). To a solution of 4 .4 3 g (28.0 mmol) of selen o p h e n o l 3 8 and 2.24 g (28.0 mmol) of pyridine in 60 mL of diethyl ether at 0 °C w a s ad ded dropwise a solution of 2.9 g (27.8 mmol) of crotonyl chloride in 10 mL of diethyl ether. The mixture w a s stirred at 0 3C for 2 h and poured into 80 mL of 2 N hydrochloric acid. The organic p h a s e w as sep a rated and w ash e d with 50 mL of saturated aq u e o u s sodium bicarbonate. The aq u e o u s layers w e re extracted with th ree 50-mL portions of dichloromethane. The com bined organic p h a s e s w ere dried (Na 2 S 0 4 ), concentrated in vacuo, and distilled to afford 4.94 g (79%) of se le n o e ste r 133 a s a pale yellow oil: bp 99-100 °C at 0.35 mm; IR (neat) 1685 c m ' 1 ; 1H NMR (CDCI 3 , 250 MHz) 5 1.89 (dd, J= 6 .8 , 1.5 Hz, 3H, =CCH 3 ), 6.21 (dq, J = 15.0, 1.5 Hz, 1 H, =CH), 6.96 (dq, J = 15.0, 6.9 Hz, 1H, =CHCH 3 ), 7.38-7.42 (m, 3H, ArH), 7.51-7.56 (m, 2H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 5 18.00 (q), 126.15 (s), 128.77 (d), 129.21 (d), 131.71 (d), 135.86 (d), 142.03 (d), 190.51 (s); m a s s spectrum, m /e (relative intensity) 226 (M+ , 1.5), 157 (9), 69 (100); exact m a s s calcd. for C i o H i o O S e ^ 225.9887, found m /e 225.9893. 45 O iPr , SPh 134 E - P h e n y l 4 - M e th y l - 2 - p e n t e n e t h i o a t e (134). To a solution of 2.1 g (19.5 mmol) of thiophenol in 20 mL of ether at 0 3 C was simultaneously added a solution of 2.6 g (19.8 mmol) of E-4-methyl-2-pentenoyl chloride in 10 mL of ether and a solution of 1.5 g (19.8 mmol) of pyridine in 10 mL of ether. The mixture w a s stirred for 4 h and poured into 20 mL of 2 N hydrochloric acid. The aq u e o u s layer w as extracted with two 50-mL portions of ether. The combined organic p h a s e s w ere dried (Na 2 S 0 4 ), concentrated in vacuo. The residue w as distilled to yield 3.49 g (87%) of thioester 134 a s a colorless oil: bp 118-122 °C at 0.8 mm; IR (film) 1694 c m '1; 1H NMR (CDCI 3 , 300 MHz) 8 1.11 (d, J = 6.7 Hz, 6 H, CH3 ), 2.50 (hd, J = 6.7, 1.5 Hz, 1 H, CHMe 2 ), 6.14 (66,J = 15.0, 1.5 Hz, 1H, =CH), 6.97 (dd, J = 15.0, 7.0 Hz, 1H, =CH), 7.38-7.48 (m, 5H,. ArH); 13C NMR (CDCI 3 , 62.9 MHz) 5 21.07 (q), 31.02 (d), 125.19 (d), 127.72 (s), 129.04 (d), 129.21 (d), 134.57 (d), 152.64 (d), 188.15 (s); m a s s spectrum, m /e (relative intensity) 206 (M+, 4), 165 (9), 97 (100), 77 (3), 69 (18), 41 (50); exact m a s s calcd. forC -| 2 H i 4 0 S m/e 206.0760, found m /e 206.0766. O 135 E -P henyl 4 -M e th y l-2 -p e n te n e se le n o a te (13 5). To a solution of 4.71 g (30 mmol) of selenophenol in 40 mL of ether at 0 °C w a s simultaneously a d d e d a solution of 2.37 g (30 mmol) of pyridine in 10 mL of ether and a solution of 4-methyl-2-pentenoyl chloride in 10 mL of ether. The mixture w as stirred for 6 h an d poured into 50 mL of 2 N hydrochloric acid. The aq u e o u s layer w a s extracted with two 40-mL portions of ether. The com bined ether layers were dried (Na 2 S 0 4 ), concentrated in vacuo, an d distilled to give 5.9 g (78%) of selen o e ste r 135 a s a yellow oil: bp 116-120 °C at 0.6 mm; IR (neat film) 1689 c m '1; 1H NMR (CDCI 3 , 250 MHz) (6,J = 7.0 Hz, 6 H, CH 3 ), 2.47 (sextet,J = 7.0 Hz, 1 H, 8 1.10 CH), 6.14 (dd, J = 15.0, 1.5 Hz, 1H, =CH), 6.91 (dd, J = 15.0, 5.0 Hz, 1H, =CH), 7.34-7.58 (m, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 20.97 (q), 31.06 (d), 126.24 (s), 127.56 (d), 128.74 (d), 129.19 (d), 135.84 (d), 152.68 (d), 190.97 (s); m a s s spectrum, m /e (relative intensity) 254 (M+, 0.5), 97 (100); exact m ass calcd. tor C-| 2 H i 4 0 S e m /e 254.0221, tound m/e 254.0215. o 136 S - P h e n y l (E ) -T h io c in n a m a te (136). To a mixture of 2.93 g (20 mmol) of cinnamic acid and 2.4 g (22 mmol) of thiophenol in 20 mL of ether at 0 °C w as ad ded 4.13 g (20 mmol) of dicyclohexylcarbodiimide three portions over 15 min period and the solution w a s stirred for 4 h. The resulting solution w as filtered and the filtrer cake w a s rinsed with 30 mL of ether. The filtrate w as concentrated in vacuo to give 3.58 g of yellow powder which w as recrystallized from 150 mL of hexane to yield 3.35 g (70%) of thioester 136 a s a white solid: m.p. 90.5-91.0 3 C; IR (CHCI 3 ) 1 6 7 8 ,1616 cm -1; 1H NMR (CDCI3 , 250 MHz) 5 6.82 (d, J = 16.0 Hz, 1H, =CH), 7.40-7.60 (m, 10H, ArH), 7.71 (d, J= 16.0 Hz, 1 H, =CH); m a ss spectrum m /e (relative intensity) 240 (0.3), 131 (100), 109 (8 ); exact m ass calcd. f o r C i 5 H i 2 0 S m /e 240.0596, found m /e 240.0602. O 137 S e - P h e n y l ( E ) - S e l e n o c i n n a m a t e (137). To a solution of 3.14 g of selenop henol (20 mmol) in 40 mL of diethyl ether at 0 °C was simultaneously added dropwise 3.3 g (20 mmol) of cinnamoyl chloride in 5 mL of ether and 1.6 g (20 mmol) of pyridine in 5 mL of ether and the solution w as stirred for 4 h. The reaction mixture was poured into 20 mL of 2 N of hydrochloric acid and the aq u e o u s layer w a s extracted with two 40-mL portions of ether. The com bined organic layers were dried (Na 2 SC>4 ) and concentrated in vacuo to give 6.1 g of yellow powder which w as recrystallized from 150 mL of hexane to yield 3.3 g (61%) of s e len o e ste r 137 a s a yellow solid: 47 m.p. 79.0-80.5 °C ; IR (CHCI 3 ) 1679, 1619 c m '1; 1H NMR (CDCI 3 , 250 MHz) 5 6.80 (d, J = 16.0 Hz, 1H, =CH), 7.26-7.46 (m, 6 H, ArH), 7.54-7.67 (m, 5H, =CH and ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 124.19 (d), 127.70 (S), 128.48 (d), 128.98 (d), 129.18 (d), 129.39 (d), 130.72 (d), 134.04 (s), 134.59 (d), 141.50 (d), 187.78 (s); m a s s spectrum m /e (relative intensity) 288 (0.03), 153 (1.75), 131 (100), 77 (49); exact m a s s calcd. for C i 5 H -| 2 0 S e m /e 288.0019, found m / e 2 8 8 .0 0 2 2 . ^ X O S P h h 3c o 2c 138 E-P henyl 3 -M e th o x y -4 -o x o -b u te n e th io a te (1 3 8 ). To a solution of 6.7 g (60.7 mmol) of thiophenol and 4.8 g (60.7 mmol) of pyridine in 100 mL of diethyl ether at 0 ° C w as ad d e d dropwise a solution of 9.0 g (60.7 mmol) of methyl fumaroyl chloride 2 in 20 mL of diethyl ether. The mixture w as stirred for 4 h and poured into 50 mL of 2 N hydrochloric acid. The organic p h a s e w a s w a sh e d with 50 mL of saturated aq u e o u s sodium bicarbonate. The aq u e o u s layer w as extracted with three 100-mL portions of dichloromethane. The com bined organic p h a s e s were dried (CaCl 2 ) and concentrated in vacuo to afford 12.8 g of red solid which w as recrystallized from 150 mL of pentan e to yield 9.08 g (67%) of thioester 138 a s a pale yellow solid: mp 68-69 °C; IR (CCI4 ) 1735, 1687 c m '1 ; 1H NMR (CDCI 3 , 250 MHz) 8 3.82 (s, 3H, OCH 3 ), 6.81 (d, J = 15.6 Hz, 1H, =CHCOSPh), 7.16 (d, J = 15.6 Hz, 1H, =CHCC>2 Me), 7.44 (m, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 52.48 (q), 126.42 (s), 129.31 (d), 129.41 (d), 129.94 (d), 134.31 (d), 138.32 (d), 165.35 (s), 187.32 (s); m ass spectrum, m/e (relative intensity) 222 (M+, 1), 131 (11), 113 (100), 85 (25); exact m a s s calcd. for C 1 1 H 1 0 O 3 S m /e 222.0363, found m /e 222.0364. Anal. Calcd. for C 1 1 H 1 0 O 3 S : C, 59.44; H, 4.53. Found: C, 59.38; H, 4.54. 48 COSePh h 3c o 2c ^ V /' 139 E - Ph e n y l 3-Methoxy-4-oxo-buteneselenoate ( 1 3 9 ) . To a solution of 3.58 g (22.8 mmol) of s e le n o p h e n o l in 100 mL of diethyl e th er at 0 C w a s a d d e d d ropw ise simultaneously a solution of 3.39 g (22.8 mmol) of methyl fumaroyl chloride 2 in 15 mL of diethyl ether an d a solution of 1.8 g (22.8 mmol) of pyridine in 10 mL of diethyl ether. The mixture w as stirred at 0 3 C for 6 h and poured into 50 mL of 2 N hydrochloric acid. The organic p h a s e w as w a s h e d with 50 mL of sa tu ra te d a q u e o u s sodium bicarbonate. The a q u e o u s layers w ere extracted with three 100-mL portions of diethyl ether. The combined organic p h a s e s w ere dried (Na 2 SC>4 ) and concentrated in vacuo to afford 6.32 g of red solid that w as recrystallized from 200 mL of p e n tan e to yield 3.59 g (58%) of seleno ester 139 a s a pale yellow solid: mp 64.5-65.5 3 C; IR (CCI4 ) 1735, 1703 c m '1; 1H NMR (CDCI3 , 250 MHz) 5 3.83 (s, 3H, OCH 3 ), 6.74 (d, J= 15.6 Hz, 1H, =CHCOSePh), 7.13 (d, J= 15.6 Hz, =CHCC>2 Me)), 7.39-7.42 (m, 3H, ArH), 7.51-7.55 (m, 2H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 5 52.50 (q), 125.38 (s), 128.20 (d) 129.43 (d), 129.58 (d), 135.56 (d), 140.13 (d), 165.35 (s), 190.84 (s); m ass spectrum, m /e (relative intensity) 270 (M+, 1), 157 (11), 113 (100); exact m a ss calcd. for C 1 -|H io 0 3 Se m /e 269.9796, found m /e 269.9796. o 140 S-Phenyl Thioacrylate (140).37 To a solution of 7.93 g (110 mmol) of acrylic acid a n d 11.02 g (100 mmol) of thiophenol at 0 3 C w a s a d d e d 22.7 g (110 mmol) of dicyclohexylcarbodiimide portionwise. The mixture w a s stirred for 4 h at room tem perature. The resulting precipitate was filtered and the filter cake w as rinsed with 50 mL of ether. The filtrate w as concentrated in vacuo and the residue w as distilled to yield 8.95 g (55%) of thioester 140 a s a colorless oil which polymerized in the freezer: b.p. 96-98 3 C at 2.0 mm (lit.3 7 115-116 °C at m m )). 6 49 H O Me SPh O Me SPh 144 13 4a-Methylbicyclo[3.3.1]nonane-2,9-dione ( 13 ) and S-Phenyl (± )-p - (phenylthio)thiobutanoate (144). To a solution of 1.97 g (13.1 mmol) of en a m in e 1 in 10 mL of b e n z e n e w a s add ed 2.33 g (13.1 mmol) of neat unsaturated thioester 129 in o n e portion at room temperature. The mixture w as stirred for 12 h, diluted with 30 mL of ether, and poured into 10 mL of 1 N a q u e o u s hydrochloric acid. The a q u e o u s layer w a s extracted with two 80-mL portions of ether. The combined ethereal layers were w a sh e d with saturated brine solution, dried ( N a 2 SC>4 ), a n d c o n c e n trate d in vacuo to give 4.31 g of.yellow oil. The residual oil w a s chrom atographed over 120 g of silica gel (eluted with ethyl acetate-h exan e, 1:12) to yield 1.34 g (61%) of dione 13 and 0 .11g (5%) of dione 14 a s a colorless oil (95:5 by 1H NMR integration) and 0.35 g (19%) of thioester 144 a s a colorless oil. The mixture w a s s e p a r a t e d by se c o n d chrom atography (silica gel; eluted with ethyl acetate-h ex an e, 1 :6 ). The pure major isom er 13 slowly crystallized in the freezer while the minor isomer 14 remained a s an oil. Dione 13: mp 36.539 °C; IR (CCI 4 ) 1739, 1716 c m ' 1 ; 1H NMR (C 6 D6 , 500 MHz) 5 0.54 (d, J = 0.92-0.91 (m, 1H, CH), 1.06-1.18 (m, 1 H, 1 H, Hz, 3H, CH 3 ), CH), 1.42-1.49 (m, 1H, CH), 1.57-1.69 (m, 2H, CH), 1.70-1.79 (m, 2H, CH2), 1.87 (dd, J = 18.3, 12.4 Hz, = 18.3, 7.3 Hz, 6.8 1 H, CHCO), 2.19 (bs, 1H, COCH), 2.33 (dd, J CHCO), 3.29 (bs, 1H, COCH); 13C NMR (CDCI 3 , 62.9 MHz, major isomer) 8 17.99 (q), 19.99 (t), 28.29 (t), 28.39 (d), 34.30 (t), 47.53 (t), 50.64 (d), 65.35 (d), 208.31 (s), 211.08 (s); m a s s spectrum m /e (relative intensity) 166 (M+, 7), 69 (100); exact m a s s calcd for C 1 0 H 1 4 O 2 m /e 166.0993, found m / e 166.0976. Thioester 144: IR (neat film) 1716 cm "1 ; 1H NMR (CDCI 3 , 250 MHz) 5 1.38 (d, J = 6.9 Hz, 3H, CH 3 ), 2.76 (dd,J = 15.0, 9.0 Hz, 1H, CH 2 ), 3.00 ( d d ,J = 15.0, 5.0 Hz, 1H, CH 2 ), 3.64-3.78 (m, 1H, CHSPh), 7.23-7.48 (m, 10H, ArH); 13C NMR 50 (CDCi 3 , 62.9 MHz) 5 20.53 (q), 39.65 (d), 50.28 (t), 127.49 (d), 129.00 (d), 129.18 (d), 129.47 (d), 130.68 (s), 132.68 (d), 133.66 (s), 134.37 (d), 195.30 (s); m a s s spectrum , m /e (relative intensity) 288 (M+ , 6 ), 137 (100); exact m a s s calcd. for C i 6 h 1 6 0 S m / e 288.0622, found m / e 288.0620. Spectral d a ta for dione 13 w ere in accord with th o se reported elsew here in this experimental section (vide infra). 145 3 p -B ro m o -4 a -m e th y lb ic y c lo [3 .3 .1 ]n o n a n e -2 ,9 -d io n e ( 1 4 5 ) . To a stirred solution of 0.35 g (2.1 mmol) of bicyclic dione 13 in 10 mL of THF under argon at 0 3C was added a solution of 0.5 g (2.1 mmol) of benzyltrimethylammonium tribromide in 10 mL of anhydrous tetrahydrofuran over a period of 15 min .41 A white precipitate started to form a couple of minutes after completion of the addition. The mixture w as stirred for 1 h and the solution w as filtered. The filtrate w a s poured into 50 mL of 1:1 mixture of saturated aq u e o u s bicarbonate and ether. The aq ueou s layer w as extracted with two 50-mL portions of ether. The combined ethereal layers were w a s h e d with s a tu ra te d brine, dried (CaCl 2 ), an d co n c en trate d in vacuo. T he residue w a s chrom atographed over 20 g of silica gel (eluted with ethyl acetate-petroleum ether, 1:4) to yield 375 mg (73%) of bromide 145 a s a white solid: mp (CDCI 3 , 300 MHz) 8 6 °C; IR (CHCI 3 ) 1719 c m '1; 1H NMR 1.40 (d, J = 6.9 Hz, 3H, CH 3 ), 1.55-2.47 (m, 7H, CH 2 ), 2.57-2.65 (m, CHCO), 3.52 (bq, J= 2.3 Hz, MHz) 86-88 1 H, 1 H, CHCO), 4.65 (d ,J = 11.8 Hz, 1 H, CHBr); 13C NMR (CDCI 3 , 62.9 17.26 (q), 20.40 (t), 28.51 (t), 34.01 (t), 39.05 (d), 51.66 (d), 59.97 (d), 65.19 (d), 199.96 (s), 208.64 (s); m a s s spectrum, m/e (relative intensity) 246 ((M+, 8 ), 165 (26), calcd. for C-| 2 H i 3 0 2 81Br m /e 246.0070, found m /e 246.0074. 68 (100); exact m ass 4 -M e th y lb ic y c lo [3 .3 .1 ]n o n -3 -e n e -2 ,9 -d io n e (1 4 6 ) . A mixture of 37 5 mg (1.5 mmol) of bromodione 120, 0.55 g (7.5 mmol) of lithium carbonate and 1.0 g (12.0 mmol) of lithium bromide in 10 mL of anhydrous N,N-dimethylformamide w a s w arm ed to 95 °C u nd er an argon atm o sp h ere . The mixture w as stirred for 2 h, allowed to cool to room tem perature, and then poured into 30 mL of a 1:1 mixture of saturated brine and ether. The a q u e o u s solution w as , extracted with three 20-mL portions of ether and three 20-mL portions of dichloromethane. The com bined organic p h a s e s w ere dried (CaCl 2 ) and concentrated in vacuo. The residual oil w as chrom atographed over 10 g of silica gel (eluted with ethyl acetate-dichloromethane, 1 :2 ) to yield 0.24 g (100%) of enedione 146 a s a white solid: mp 54-55 °C; IR (CCI4 ) 1726, 1674, 1620 c m '1; 1.54-1.58 (m, 2H, CH2), 1.84-1.95 (m, 3H, CH2), 2.03 (d, J = 1.0 Hz, 1H NMR (CDCI3i 300 MHz) 8 3H, =CMe), 2.07-2.11 (m, 1 H, CH), 3.05 (d, J = 1.5 Hz, 1H, CHCO), 3.15 (bd, J = 1.0 Hz, CHCO), 6.27 (s, 1H, =CH); 1 3 c NMR (CDCI3 , 75.5 MHz) 8 1 H, 16.90 (t), 22.49 (q), 29.56 (t), 32.62 (t), 54.38 (d), 61.41 (d), 129.97 (d), 159.81 (s), 197.73 (s), 208.11 (s); m a s s spectrum, m /e (relative intensity) 164 (M+ , 78), 108 (100); exact m a s s calcd. for C 1 0 H 1 2 O 2 m /e 164.0837, found m /e 16 4 .0 8 3 6 . 13 4 a - M e t h y l b i c y c l o [ 3 .3 . 1 ] n o n a n e - 2 , 9 - d i o n e (13). A solution of 0.24 g (1.4 mmol) of en ed ione 121 in 10 mL of absolu te ethanol w as hydrog en ated u n d er on e atm o s p h e re of hydrogen over 50 mg of 10% palladium-on-charcoal. The slurry w a s filtered through Celite while 52 rinsing with ethyl acetate. The filtrate w as w a sh e d with 20 mL of 5% aq u e o u s sodium bicarbonate, dried (Na 2 S 0 4 ), and concentrated in vacuo. The residue w as chrom atographed over 10 g of silica gel (eluted with ethyl acetate-hex ane, 1:6) to yield 0.24 g (100%) of bicyclic dione 13 a s a white oil. Spectral data were identical to those of an authentic sample (vide supra). 14 4 p -M e th y lb ic y c lo [3 .3 .1 ]n o n a n -2 -9 -d io n e (14). To a solution of 0.45 g (2.0 mmol) of unsaturated selen oester 133 in 3 mL of dichloromethane at -15 °C w a s ad d e d dropwise 0.28 g (2.0 mmol) of neat enam ine 1 over a period of 3 min. The solution w a s stirred for 5 h and then poured into 4 mL of 1 N a q u e o u s hydrochloric acid. The aq u e o u s layer w as extracted with two 30-mL portions of ether. The com bined ethereal layers w ere w a sh e d with brine, water, dried (Na 2 S 0 4 ), and concentrated in vacuo. The residue w as chrom atographed over 40 g of silica gel (eluted with ethyl ac etate-h exan e, 1 :36 followed by 1:6) to yield 255 mg (84%) of bicyclic dione 14 a s a colorless oil: IR (neat) 1728, 1703 c m ’1; 1H NMR (C 6 D6 , 300 MHz) 5 0.56 (d, J = 6.9 Hz, 3H, CH 3 ), 0.80-0.91 (m, 1H, CH), 1.01-1.19 (tq, J= 13.4, 4.8 Hz, 1H, CH), 1.26-1.37 (m, 2H, CH), 1.40-1.57 (m, 2 H, CH), 1.62 (dd, J= 16.0, 8.7 Hz, 1H, CHCO), 2.06 (ds, J = 15.2,2.5 Hz, 1H,CH), 2.09 (s, J = 2.3 Hz, 1 H, CH), 2.19 (dd, J = 16.0, 6.5 Hz, 1 H, CHCO), 2.93 (bt, J = 4.5 Hz, 1 H, CHCO); 13C NMR (CDCI3 , 62.9 MHz) 5 18.45 (t), 23.07 (q), 29.80 (d), 34.84 (t), 35.22 (t), 48.21 (t), 53.19 (d), 62.48 (d), 209.40 (s), 211.90 (s); m ass spectrum m /e (relative intensity) 166 (M+, 7), 69 (100); exact m a ss calcd. for C 1 0 H 1 4 O 2 m /e 166.0978, found m /e 166.0976. 53 Me 150 (±)-1-[(1 R \ 2 R * , 5 R * ) - 2 - m e t h y l - 4 - o x o b i c y c l o [ 3 . 3 . l ] n o n - 9 - y l i d e n e ] pyrrolidinium chloride ( 1 50 ) , Phenyl(chloromethyl)selenide ( 151) , and 1,1- D i p h e n y l s e l e n o m e t h a n e (152). To a solution of 1.39 g (6.17 mmol) of u n s a t u r a t e d s e le n o e s te r 133 in 10 mL of dichloromethane at -15 ° C w as ad d e d 1.06 g (6.95 mmol) of neat enam ine 1 dropwise and the solution w as stirred for 6 h. The resulting precipitate w a s collected and rinsed with 40 mL of hot ethyl acetate to give 1.33 g (84%) of iminium salt 150 a s a white solid which w as hydrolyzed on wet silical gel in dichloromethane at room tem perature to dione 14 in 8 0% yield.. The filtrate w as concentrated in vacuo to give 1.08 g of yellow oil. The residue w as chrom atographed over 30 g of silica gel (eluted with ethyl ac etate-hexane, 1 :20 followed by 1:6) to afford 0.66 g (51%) of 151 a s a colorless oil and 0.28 g (28%) of 152 a s a colorless oil: Iminium salt 150: mp 125-132 °C; IR (CHCI3 ) 3378, 1731, 1665 c i r r 1 ; 1H NMR (CDCI3 , 250 MHz) 5 1.201.1.38 (d, J = 7 Hz, 3H, CH 3 ), 1.38-1.72 (m, 2H, CH 2 ), 1.89-2.72 (m, 10H, CH 2 ), 2.98-3.27 (m, 2H, CH 2 CO), 3.69 (bs, 1H, CHCO), 3.94-4.58 (m, 4H, NCH 2 ); 13C NMR (CDCI 3 , 62.9 MHz) 5 17.50 (t), 23.26 (q), 24.25 (t), 24.30 (t), 31.04 (d), 35.82 (t), 36.23 (t), 47.35 (d), 48.25 (t), 54.41 (d), 54.91 (t), 55.12 (t), 188.86 (s), 205.54 (s); m a s s spectrum, m /e (relative intensity) 220 (M+, 15), 41 (100); exact m a s s calcd. for C 1 4 H 2 2 NO m / e 220.1701, found m / e 2 2 0 .1 6 9 9 . Phenyl(chlorom ethyl)selenide 151: 1H NMR (CDCI 3 , 250 MHz) 5 4.94 (s, 2H, CH 2 ), 7.31-7.39 (m, 3H, ArH), 7.61-7.70 (m, 2H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 40.36 (t), 128.21 (d), 128.66 (s), 129.10 (s), 129.25 (d), 131.42 (s), 133.40 (d); m a s s spectrum, m /e (relative intensity) 152 (M+-CH 2 CCI), 16), 51 (100), 77 (78); exact m a s s calcd. for C y H yS e m /e 170.9763, found m /e 170.9768. 1,1 -D iphenylselenom ethane 152: 1H NMR (CDCI 3 , 300 MHz) CH 2 ). 7.29-7.40 (m, 6 8 4.25-4.32 (m, H, ArH), 7.56-7.63 (m, 4H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 2 H, 20.93 (t), 54 127.43 (d), 129.04 (d), 130.76 (s), 132.84 (d); m a s s spectrum, m /e (relative intensity) 170 (M+PhSe, 38), 154 (9), 91 (100); exact m ass calcd. for C g H s S e m /e 152.9549, found m /e 152.9546. Me 153 3 p -B rom o 4 p -m e th y lb ic y c lo [3 .3 .1 ]n o n a n -2 ,9 -d io n e (153). To a solution of 1.3 g (7.8 mmol) of bicyclic dione 14 in 10 mL of dry THF w as added a solution of 3.5 g (14.5 mmol) of phenyltrimethylammonium tribromide in 40 mL of anhydrous tetrahydrofuran over a period of 3 min at 0 °C. A precipitate started to form few minutes later and the mixture w as stirred for 1 h. The solution w as filtered and the filtrate w a s poured into 100 mL of a 1 :1 mixture of saturated aq u eou s sodium bicarbonate and ether. The organic layer was w a shed with 1N aq u e o u s hydrochloric acid, brine, and water. The com bined a q u e o u s layers were extracted with th ree 50-mL portions of ether. The com bined ethereal layers w ere dried (Na 2 S 0 residue w a s chrom atographed over 1 :6 10 4 ) and con cen trate d in vacuo. The g of silica gel (eluted with ethyl acetate-petroleum ether, ) to yield 2.25 g (100%) of bromodione 153 a s a white solid: mp 105-108 c m '1; 1H NMR (CDCI 3 , 250 MHz) 5 1.28 (d, J= 6.8 3 C; IR (CHCI 3 ) 1720 Hz, 3H, CH 3 ), 1.43-1.54 (m, 2H, CH2), 1.99- 2.16 (m, 3H, CH2 ), 2.28-2.41 (m, 2H, CH2 ), 2.50-2.56 (m, 1H, CH), 3.28-3.32 (m, 1 H, CHCO), 4.49 (d, J = 4.0 Hz, 1H, CHBr); 13C NMR (CDCI 3 , 75.5 MHz) 5 17.96 (t), 20.10 (q), 33.42 (d), 36.31 (t), 36.31 (t), 51.85 (d), 57.90 (d), 58.97 (d), 201.53 (s), 211.40 (s); m a s s spectrum (relative intensity) 246 (M+ , 8 ), 165 (26), found m /e 246.0074. 68 (100); exact m a s s calcd. for C i o H i 3 0 2 81Br m /e 246.0070, 4 -M e th y lb ic y c lo [3 .3 .1 ]n o n -3 -e n -2 ,9 -d io n e (1 4 6 ). A mixture of 2.25 g (7.78 mmol) of brom oketone 153, 3.0 g (40.5 mmol) of lithium carbo nate and 5.0 g (57.7 mmol) of lithium bromide in 5 mL of dry DMF w as h eated at 96 °C under argon atm osp here for 2 h. The reaction mixture w as cooled to room temperature and poured into 100 mL of a 1 :1 mixture of brine and ether. The a q u e o u s layer w a s extracted with three 50 mL-portions of ether. The combined e th e re a l layers w e re dried (C aC l 2 ) a n d c o n c e n tra te d in vacuo. T he residual oil chrom atographed over 10 g of silica gel (eluted with ethyl ac etate-h exan e, 1 :2 was ) to yield 1.08 g of enedione 146 a s a pale yellow oil which w as crystallized slowly from pen tane at -4 °C to give 1.07 g (85%) of enedione 146 a s a white solid: mp 54-55 °C; m a s s spectrum (relative intensity) 164 (M+, 78), 108 (100); exact m a s s calcd. for C 1 0 H 1 2 O 2 m /e 164.0837, found m /e 164.0836. This material w a s identical to that obtained by dehydrohalogenation of bromide 145 (vide supra). 154 156 4 p -/-P ro p y lb ic y c lo [3 .3 .1 ]n o n a n -2 .9 -d io n e (P h e n y lth io )-v -m e th y l-th io p e n ta n o a te (156). (1 5 4 ) and S -P henyl (± )-p- To a solution of 470 mg (3 mmol) of thioester 134 in 4 mL of toluene w a s added three 100 mg (0.67 mmol) portions of enam ine 1 at 8 h intervals while the mixture w as heated under reflux and stirred for a total of 24 h. The mixture w as diluted with 20 mL of CH 2 CI 2 and poured into 5 mL of 2 N a q u e o u s hyhrochloric acid. The a q u e o u s layer w a s extracted with two 30-mL portions of dichlorom ethane. T he com bined organics were dried (Na 2 S 0 4 ) and concentrated in vacuo. The residue w a s chrom atographed 56 over g of silica gel (eluted with ethyl ac etate-hex ane, 20 1:20 followed by 1 :6 ) to yield 126 mg (32%) of bicyclic dione 154 an d 156 a s a 80:20 ratio of sep arab le mixture and 445 mg (45%) of thioester 156 a s a colorless oil. Bicyclic dione 154: IR (neat) 1731, 1701 cm "1 ; 1H NMR (CDCI 3 , 300 MHz) 8 0.97 (d, J = 6.5 Hz, 3H, CH 3 ), 0.99 (d, J = 1.68-1.79 (m, 3H, CH 2 ), 1.93-2.04 (m, 1 H, 6.6 Hz, 3H, CH 3 ), 1.53-1.56 (m, 1H, CH), CH), 2.08-2.36 (m, 3H, CH 2 ), 2.34 (dd,J = 16.7, 12.2 Hz, 1H, CHCO), 2.79 (bt, ^ = 2.1 Hz, 1H, CHCO), 2.86 (dd, J = 16.7, 7.3 Hz, 1 H, CHCO), 3.25 (bs, 1H, CHCO); 13C NMR (CDCI 3 , 62.9 MHz) 5 20.32 (t), 20.62 (q), 20.92 (q), 28.53 (t), 30.69 (d), 34.45 (t), 40.38 (d), 45.35 (t), 47.41 (d), 65.47 (d), 208.67 (s), 211.51 (s); m a s s spectrum, m/e (relative intensity) 194 (11), 97 (100), 79 (4); exact m a s s calcd. for C 1 2 H 1 8 O 2 m /e 194.1306, found m /e 194.1303. Thioester 156: IR (neat) 3058, 2961, 2928, 1705 cm "1 ; 1 H NMR (CDCI 3 , 250 MHz) 5 1.07 (d, J = 2.92 (dd, 6.8 15.8, 7.4 Hz, (d, J = 6.8 Hz, 3H, CH 3 ), 2.12 (m, CH), 3.02 (dd, J = 15.8, 6.8 Hz, 1H, CH), 3.69 (ddd, J = 11.3, 6.7, Hz, 3H, CH 3 ), 1 H, 1.11 1 H, CHMe 2 ), 4.0 Hz, 1H, CHSPh), 7.22-7.39 (m, 3H, COPh), 7.42 (bs, 5H, SPh), 7.45-7.50 (m, 2H, COPh); 13C NMR (CDCI 3 , 62.9 MHz) 8 18.75 (q), 19.73 (q), 31.73 (d), 46.49 (t), 52.20 (d), 126.85 (d), 127.47 (s), 128.94 (d), 129.10 (d), 129.37 (d), 131.67 (d), 134.33 (d), 135.27 (s), 195.76 (s); m a s s spectrum, m /e (relative intensity) 316 (M+, 12), 165 (100), 109 (59); exact m a s s calcd. for C 1 8 H 2 0 O S 2 m /e 316.0949, found m/e 316.0958. i-Pr 155 4 p -/-P ro p y lb ic y c lo [3 .3 .l]n o n a n -2 -9 -d io n e 157 (1 55) and 2 -i-P ro p y l> 4 -o x o b ic y c lo [3 .3 .1 ]n o n -9 -y lid e n e ]p y rro lid in iu m (± )-1-[(1R *,2R *,5R *)ch lo rid e (1 5 7 ). To a solution of 0.5 g (2 mmol) of selen o e ste r 135 in 7 mL of dichloromethane at -15 °C w as ad ded 0.3 g (2 mmol) of neat enam ine 1 dropwise followed by stirring tor 10 h. The reaction mixture w as further stirred for 24 h after removing the cold bath. The solution w a s concentrated in vacuo to yield an oily solid. The solid w as collected while rinsing with 50 mL of hot ethyl acetate to give 0.31 g (55%) of iminium salt 157 a s a white solid. The filtrate w as concentrated in vacuo. The residue w a s chrom atographed over 30 g of silica gel (eluted with ethyl ac etate-h exane, 1:20 followed by 1:6) to yield 51 mg (16%) of bicyclic dione 155 a s a pale yellow oil and selenylated com pounds 151 (53%) and 152 (8 %). Bicyclic dione 155: IR (neat) 1731, 1703 cm ’1 ; 1H NMR (CDCI 3 , 300 MHz) 8 0.88 (d, J = 6.5 Hz, 3H, CH3 ), 0.89 (d, J = 6 . 6 Hz, 3H, CH 3 ), 1 .49-1.59 (m, 2H, CH 2 ), 1.61 - 1.85 (m, 2H, CH 2 ), 1.87-2.05 (m, 3H, CH 2 ), 2.08 (dd, J = 15.0, 12.1 Hz, 13.1, 3.0 Hz, 1 H, CH), 2.56 (dd, J= 15.0, 5.6 Hz, 1 H, 1 H, CHCO), 2.44 (dq, J = CHCO), 2.59 (bs, 1H, CHCO), 2.91 (dd, J = 6.1, 3.9 Hz, 1H, CHCO); 13C NMR (CDCI 3 , 62.9 MHz) 5 18.11 (t), 18.87 (q), 18.87 (q), 33.20 (d), 35.12 (t), 36.61 (t), 40.26 (d), 44.28 (t), 49.76 (d), 61.27 (d), 210.30 (s), 213.28 (s); m a s s spectrum, m /e (relative intensity) 248 (M+, 0.1), 151 (3), 70 (59), 43 (100); exact m a s s calcd. for C 16H 2 6C IO N m /e 248.2008, found m /e 248.2003. Iminium salt 157: m .p .125-129 3 C ; IR (CHCI 3 ) 3351, 1731, 1697, 1649 c m ' 1 ; 1H NMR (CDCI 3 , 300 MHz) 8 0.90 (d, J = 6.5 Hz, 3H, CH 3 ), 0.96 (d, J= 6.7 Hz, 3H, CH 3 ), 1.44-1.99 (m, 5H, CH 2 ), 2.26-2.55 (m, 14.0 Hz, 1 H, CHCO), 3.17-3.24 (m, 1H, CHCO), 3.70 (d, J = 3.0 Hz, 1 H, 8 H, CH 2 ), 3.01 (t, J = CHC=N+), 4.08 (m, 1H, CHN), 4.19 (m, 1H, CHN), 4.34 (m, 1H, CHN), 4.59 (m, 1H, CHN); 13C NMR (CDCI 3 , 62.9 MHz) 8 17.40 (t), 19.84 (q), 19.96 (q), 24.37 (t), 24.46 (t), 33.38 (d), 36.05 (t), 37.51 (t), 42.06 (d), 44.12 (d), 45.11 (t), 54.65 (d), 54.86 (t), 55.28 (t), 189.99 (s), 205.77 (s); m a s s spectrum m /e (relative intensity) 248 (M+-CI, 0.1), 205 (M+-C3 H 7 , 0.2), 151 (M+-C 6 H k )0 , 3), 43 (13); exact m a s s calcd. for C-|6H26n O m /e 248.1992, found m /e 248.2003. SPh O Ph SPh 8 158 4a-P henylbicyclo[3.3.1]nonan-2,9-dione (Phenylthio)thiohydrocinnamate u n s a tu ra te d thioester 144 in 6 (8) and S-Phenyl (±)-p- To a solution of 360 mg (1.5 mmol) of ( 15 4) . mL of b e n z e n e at room tem peratu re w a s ad d e d 226 mg (1.5 mmol) of neaf enamine 1 dropwise and the solution w as stirred for 24 h. The reaction mixture w as diluted with 30 mL of dichlorom eth ane and w a s h e d with 20 mL of 5% a q u e o u s sodium bicarbonate. The a q u e o u s solution w as extracted with two 50-mL portions of dichloromethane. The combined organic p h a s e s w ere dried (Na 2 S 0 4 ) and concentrated in vacuo. The residual oil w a s chrom atographed over 30 g of silica gel (eluted with ethyl acetate-h exane, 1:20 followed by 1:6) to yield 125 mg (36%) of bicyclic diones 8 and 9 (70:30 by NMR integration) a s a pale yellow oil and 0.17 g (32%) of thioester 158 a s a colorless oil. The major isomer 8 slowly solidified in the freezer. Bicyclic dione 60.82-0.91 (m, 1 H, 8 : mp 111-112 3 C; IR (CCI4 ) 1738, 1712 c m ' 1; 1H NMR (C 6 D6 , 500 MHz) CH 2 ), 1.21-1.33 (m, 2H, CH 2 ), 1.51-1.53 (m, 1.78-1.83 (m, 1H, CH), 2.52 (dd, J= 17.5, 6.9 Hz, 1 H, 17.5, 12.7 Hz, CHCO), 2.78 (ddd, J = 12.7, 6.9, 4.5, (m, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 6 1 H, CH), 1.54-1.67 (m, 1 H, CH), CHCO), 2.51 (bs, 1H, CHCO), 2.63 (dd, J = 1 H, CHPh), 3.39 (bs, 1H, CHCO), 6.75-7.08 20.25 (t), 29.11 (t). 34.80 (t), 39.51 (d), 44.20 (t), 52.12 (d), 65.64 (d), 127.40 (d), 127.54 (d), 128.91 (d), 138.90 (s), 207.94 (s), 210.92 (s); m a s s spectrum, m /e (relative intensity) 228 (2), 131 (100), 77 (6 ); exact m a s s calcd. for C 1 5 H 1 6 O 2 m /e 228.1155, found m /e 228.1152. Thioester 154: IR (CCI 4 ) 1700 c m ' 1 ; 1H NMR (CDCI 3 , 250 MHz) 6 3.30 (d, J = 7.8 Hz, 2H, CH 2 ), 4.78 (t, J = 7.8 Hz, 13C NMR (CDCI 3 , 62.9 MHz) 6 1 H, CHSPh), 7.25-7.40 (m, 15H, ArH); 49.18 (d), 49.32 (t), 127.24 (s), 127.67 (d), 127.77 (d), 128.50 (d), 128.50 (d), 128.90 (d), 129.15 (d), 129.46 (d), 133.10 (d), 133.56 (s), 134.35 (d), 139.86 (s), 194.62 (s); m ass spectrum, m /e (relative intensity) 350 (M+, 4), 199 (100), 109 (6 6 ), 77 (15); exact 59 m a s s calcd. for C 2 1 H 1 8 O S 2 m /e 350.0809, found m /e 350.0804. Bicyclic dione 9 w a s identical to an authentic sam ple (vide infra). 159 3 p -B ro m o -4 a -p h e n y lb ic y c lo [3 .3 .1 ]n o n a n -2 ,9 -d io n e 0.11 g (0.5 mmol) of bicyclic dione 8 (15 9). To a solution of in 10 mL of anhydrous tetrahydrofuran at 0 3 C w a s added dropwise 0.12 g (0.5 mmol) of phenyltrimethylammonium tribromide in 3 mL of tetrahydrofuran. A precipitate started to form few minutes later and the mixture w a s stirred for 1 h followed by filtration. The filtrate poured into 20 mL of 1 :1 mixture of saturated a q u e o u s sodium bicarbonate and ether. The organic layer w a s dried (Na 2 SC>4 ) and concentrated in vacuo. The residue w as ch rom atog raph ed over 10 g of silica gel (eluted with ethyl a c etate-h ex an e, 1:1) to yield 84 mg (56%) of bromodione 159 a s a white solid: mp 184-186 °C; IR (CHCI 3 ) 1736, 1714 c m '1 ; 1H NMR (C 6 D 6 , 300 MHz) 6 0.70-0.86 (m, 2 H, CH 2 ), 1.04-1.17 (m, 1 H, CH 2 ), 1.36-1.52 (m, 2 H, CH2 ), 1.57-1.61 (m, 1H, CH), 2.39 (bs, 1H, CH), 3.24 (dd, J = 12.0, 5.0 Hz, 1H, CHPh), 3.49 (bs, 1H, CHCO), 4.85 (d, J = 12.0 Hz, 1H, CHBr), 6.66-7.06 (m, 5H, Ar); 13C NMR (CDCI 3 , 300 MHz) 8 20.67 (t), 29.30 (t), 34.55 (t), 50.55 (d), 53.60 (d), 55.22 (d), 65.22 (d), 127.60 (d), 127.89 (d), 128.12 (d), 136.94 (s), 199.81 (s), 209.42 (s); m a s s spectrum, m /e (relative intensity) 308 (M+, 34), 227 (M+-Br, 65), 3 0 8 .0 2 3 8 . 68 (100); exact m a s s calcd. for C-| 5 H i 5 8 1 Br 0 2 m /e 308.0230, found m /e 60 Ph ° 160 4 -P h e n y lb ic y c lo [3 .3 .1 ]n o n -3 -e n -2 ,9 -d io n e (1 6 0 ). A mixture of 8 4 mg (0.27 mmol) of bromodione 1 5 9 ,1 1 9 mg (1.62 mmol) of UCO3 and 210 mg (2.43 mmol) of LiBr in 5 mL of dry DMF was w arm ed to 95 3C an d stirred for 2 h. The mixture w as cooled to room tem perature and poured into 5 mL of brine. The a q u e o u s solution w a s extracted with two 50-mL portions of dichloromethane. The combined organic layers were w a sh e d with brine, water, dried (CaCl 2 ) and concentrated in vacuo. The residual oil w a s chrom atographed over 30 g of silica gel (eluted with ethyl ac etate-h exan e, 1 :2) to yield 0.39 g (64%) of enedione 160 a s a white solid: mp 98-99 °C; IR (CHCI3 ) 3017, 1733, 1661 cm ’1; 1 H NMR (CDCI3 , 300 MHz) 5 1.62-1.84 (m, 2H, CH2), 1.952.30 (m, 4H, CH2), 3.34(t, J = 3.5 Hz, CHCO), 3.84-3.87 (m, 1 H, CHCO), 6.87 (d, J = 1Hz, 1 H, =CH), 7.43-7.61 (m, 5H, Ar); 13C NMR (CDCI3 , 62.9 MHz) 5 16.98 (t), 30.88 (t), 33.10 (t), 51.56 (d), 61.72 (d), 126.67 (d), 127.90 (d), 129.15 (d), 130.92 (d), 135.67 (s), 156.99 (s), 197.93 (s), 2 08.1 7 (s); m a s s spectrum (relative intensity) 226 (70), 170 (100); exact m a s s calcd. for C 1 5 H 1 4 O 2 m /e 226.0993, found m /e 226.0995. Anal. Calcd. for C 1 5 H 1 4 O 2 : C, 79.65; H, 6.19. Found: C, 79.61; H, 6.19. 8 4 a - P h e n y l b i c y c l o [ 3 . 3 . 1 ] n o n a n - 2 , 9 - d i o n e ( 8 ). A solution of 0.56 g (2.5 mmol) of e n e d io n e 160 in 10 mL of absolute ethanol w a s hy d ro g e n ated u n d er o n e a tm o s p h e re of hydrogen over 65 mg of 10% palladium-on-charcoal. The slurry w as filtered through Celite while rinsing with ethyl a c etate. The filtrate w a s w a s h e d with 20 mL of 10% a q u e o u s sodium 61 bicarbonate, dried (Na 2 SC>4 ), concentrated in vacuo. The residual oil w as chrom atographed over 20 g of silica gel (eluted with ethyl acetate-hexane, 1 :6 ) to yield 0.57 g (100%) of bicyclic dione 8 a s a white solid (mp 109-111 °C). Spectral d ata w ere identical to those of an authentic sam ple (vide supra). 9 161 4 p -P h e n y lb ic y c lo [3 .3 .l]n o n a n -2 ,9 -d io n e (9) and p h e n y l-4 -o x o b ic y c lo [3 .3 .l]n o n -9 -y lid e n e ]p y rro lid in iu m solution of 556 mg (2 mmol) of selen o e ste r 137 in 6 (± )-1 -[(lR \2 R \5 R * )-2 c h lo rid e mL of dichloromethane at -15 ( 1 6 1 ) . To a w a s ad ded 302 mg (2 mmol) of neat e n a m in e 1 in o ne portion. The mixture w a s stirred for 4 h and concentrated in vacuo to give red oil. This oil w as diluted with 100 mL of dry ethyl acetate to afford a solid. T he solid w as collected while rinsing with ethyl acetate to yield 602 mg (96%) of iminium salt 161. This salt w as easily hydrolyzed in the p re sen ce of wet silica gel to give bicyclodione 9 in 87% yield. The filtrate w a s concentrated in vacuo. The residual oil w as chrom atographed over 50 g of silica gel (eluted with ethyl ac etate-hex ane, 1:30 followed by 1:15) to give 56% yield of 151 a s a red oil and 11% yield of 152 a s a red oil. Bicyclic dione 9: mp 62 °C (lit.2a 52 °C); IR (CHCI 3 ) 1735, 1714 c m '1; 1H NMR (C 6 D6 , 500 MHz) 5 0.88-0.96 (m, 1H, CH), 1.16-1.29 (m, 1H, CH), 1.46-1.54 (m, 3H, CH 2 ), 2.10 (dd, J = 15.7, 11.0 Hz, (dd, J = 15.7, 6.4 Hz, 1 H, 1 H, CH 2 CO), 2.11-2.22 (m, 1H, CH), 2.48 CH 2 ), 2.57 (ddd, J = 11.0, 6.4, 5.0, 1 H, CHPh), 2.72 (bs, 1H, CHCO), 2.99 (bs, 1H, CHCO), 6.88-7.09 (m, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 18.20 (t), 35.09 (t), 35.91 (t), 40.81 (d), 49.21 (t), 53.81 (d), 61.83 (d), 126.63 (d), 127.04 (d), 129.05 (d), 144.66 (s), 208.63 (s), 212.12 (s); m a s s spectrum (relative intensity) 228 (M+ , 15), 131 (100), 77 (9); exact m a s s calcd. for C 1 5 H 1 6 O 2 rn/e 228.1155, found m /e 228.1152. Iminium salt 161: mp 143-148 62 °C; IR (CDCI3 ) 1732, 1699, 1650 c m '1; 1H NMR (CDCI 3 , 300 MHz) 8 2.41-2.45 (m, 1H, CHC=N+), 2.58-2.87 (m, 3H, CHCO), 3.14-4.50 (m, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 1.62-2.27 (m, 7H, CH 2 ), 8 H, CH 2 ), 7.18-7.32 (m, 17.93 (t), 24.23 (t), 24.32 (t), 35.50 (t), 35.78 (t), 42.47 (d), 46.34 (t), 48.96 (d), 54.99 (t), 55.04 (t), 55.85 (d), 126.76 (d), 127.68 (d), 129.37 (d), 142.95 (s), 187.81 (s), 205.15 (s); m a s s spectrum, m /e (relative intensity) 228 (M+-PhCH, 14), 131 (100), 77 (9), 70 (4), 55 (13). 162 3 a -B ro m o -4 [)-p h e n y lb ic y c lo [3 .3 .1 ]n o n a n -2 ,9 -d io n e (162). To a solution of 1.0 g (4.4 mmol) of bicyclic dione 14 in 10 mL of anhydous tetrahydrofuran at 0 °C w a s added dropwise 1.36 g (5.6 mmol) of phenyltrimethylammonium tribromide in 20 mL of tetrahydrofuran. A precipitate started to form after few m inutes later. The mixture w as stirred for 2 h and the precipitate w a s removed by filtration. The filtrate w as poured into 20 mL of a 1:1 mixture of saturated sodium bicarbonate and ether. The aq u e o u s layer w as w a sh e d with two 50-mLportions of ether. The com bined ethereal layers w ere dried (Na 2 SC>4 ) and concentrated in vacuo. The residue w a s ch ro m ato graphed over 10 g of silica gel (eluted with ethyl ac eta te -h e x a n e , followed by 1:4) to yield 1.06 g (79%) of bromodione 162 a s a white solid: mp 182-185 (CHCI 3 ) 3023, 1745, 1721 c m '1; 1H NMR (CDCI 3 , 300 MHz) (m, 2H, CH 2 ), 2.18-2.26 (m, 1 H, 8 3 1:12 C; IR 1.64-1.75 (m, 2H, CH 2 ), 1.99-2.15 CH), 2.66-2.74 (m, 1H, CH), 3.12-3.15 (m, 1 H, CHCO), 3.18 (dd, J = 12.0, 2.0 Hz, 1H, CHPh), 3.30 (dd, J = 6.2, 3.5 Hz, 1H, CHCO), 4.63 (d, J = 11.9 Hz, 1H, CHBr), 7.14-7.39 (m, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 18.05 (t), 35.87 (t), 36.08 (t), 50.25 (d), 56.29 (d), 60.60 (d), 62.83 (d), 127.29 (d), 127.74 (d), 129.07 (d), 142.62 (s), 199.68 (s), 210.28 (s); m a s s spectrum m /e (relative intensity) 308 (M+, 34), 227 (M+-Br, 65), 182 (27), 68 (100); exact m a s s calcd. for C-| 5 H-| 5 8 1 Br0 2 m/e 308.0230, found m/e 308.0238. Anal. Calcd. for C i 5 H is B r 0 2 : C, 58.63; H, 4.88. Found: C, 58.18; H, 4.53. 160 4 -P h e n y lb ic y c lo [3 .3 .1 ]n o n -3 -e n -2 ,9 -d io n e mmol) of bromodione 162, 1 (1 6 0 ). A mixture of 1.0 g (3.25 .5 g (20.3 mmol) of UCO 3 and 2.5 g (28.8 mmol) of LiBr in 20 mL of dry DMF w as warmed to 95 °C and stirred for 2h. The mixture w as cooled to room temperature and poured into 20 mL of brine. The a q u e o u s solution w as extracted with two 100-mL portions of dichloromethane. The combined organic layers were w a sh e d with brine, water, dried (CaCl 2 ) and concentrated in vacuo. The residual oil w a s chrom atographed over 30 g of silica gel (eluted with ethyl ac etate-hexane, 1:2) to yield 0.57 g (79%) of enedione 160 a s a white solid: mp 98-99 ^C; This material w as identical to that obtained by dehydrohalogenation of bromide 159 (vide supra). 163 164 4 a -C a rb o m e th o x y b ic y c lo [3 .3 .1 ]n o n a n -2 ,9 -d io n e g (1.0 mmol) of thioester 138 in 8 (16 3). To a solution of 0.22 mL of dry dichloromethane w a s ad d e d 0.15 g (1.0 mmol) of neat enam ine 1 dropwise at -40 ^C. The mixture w a s stirred for 3 h and poured into 10 mL of 1 N a q u e o u s hydrochloric acid. The a q u e o u s layer w as extracted with two 30-mL portions of ether. The combined ethereal layers were w a sh e d with brine, water, dried (Na 2 SC>4 ), and concentrated in vacuo. The residue w as chrom atographed over 15 g of silica gel (eluted with ethyl acetate- 64 petroleum ether, 1:3 ) to yield 134 mg (64%) ot diones 163 and 164 a s a colorless oil which slowly crystallized in the freezer to give pure major product 163 a s a white solid. The oil w as a 85:15 mixture of 163 and 164, respectively, by integration of s e le c te d p e a k s in the NMR spectrum of the mixture. Dione 163: mp 300 MHz) 6 1.62 (m, 2 66-68 °C; IR (CHCI3 ) 1733, 1704 cm*1; 1H NMR (CDCI 3 , H, CH 2 ), 1.97-2.28 (m, 4H, CH 2 ). 2.75 (dd, J = 19.6, 7.5 Hz, 1 H, CHCO), 2.97-3.05 (m, 2H, CHCO), 3.19 (dd, J= 19.6, 10.6 Hz, 1H, CHCO), 3.28 (bs, 1H, CHCO), 3.76 (s, 3H, OCH 3 ); 13C NMR (CDCI 3 , 62.9 MHz) 5 19.73 (t), 31.25 (t), 35.00 (t), 39.12 (d), 41.09 (t), 47.22 (d), 52.52 (q), 65.64 (d), 171.84 (s), 206.62 (s), 208.65 (s); m a s s spectrum, m /e (relative intensity) 210 (M+ , 3), 150 (90), 55 (100); exact m ass calcd. for C 1 1 H 1 4 O 4 m /e2 1 0 .0 8 9 2 , found m / e 210.0892. 165 3 p -B ro m o -4 a -c a rb o m e th o x y b ic y c lo [3 .3 .l]n o n a n -2 ,9 -d io n e (165). To a solution of 340 mg (1.6 mmol) of dione 163 in 10 mL of anhydrous tetrahydrofuran at 0 °C was a d d e d a solution of 388 mg (1.6 mmol) of benzyltrimethylammonium tribromide in anhydrous tetrahydrofuran over a period of 20 min. The reaction mixture w as stirred for an additional 2 h and the precipitate w as removed by filtration. The filtrate w as poured into 50 mL of a 1:1 mixture of saturated a q u e o u s sodium bicarbonate and ether. The aq u e o u s layer w as extracted with two 50mL portions of ether. The combined organics were dried (CaCl 2 ) and concentrated in vacuo. The residual oil w as chrom atog rap hed over 20 g of silica gel (eluted with ethyl acetate-petroleum ether, 1:4) to yield 328 mg (70%) of bromodione 165 a s a pale yellow oil: IR (film) 3024, 1739, 1733 cm*1; 1H NMR (CDCI3 , 250 MHz) 8 1.65-2.31 (m, 6 H, CH 2 ), 2.29-3.00 (m, 1H, CHCO), 3.31- 3.45 (m, 1H, CHCO), 3.50-3.3.54 (m, 1H, CHCO), 3.82 (s, 3H, CH 3 ), 5.36 (d, 11 Hz, 1H, CHBr); 13C NMR (CDCI 3 , 75.5 MHz) 5 19.97 (t) 31.19 (t), 34.56 (t), 48.97 (d), 50.67 (d), 51.10 (d), 52.89 (q), 65.28 (d), 170.04 (s), 198.30 (s), 205.86 (s); m a s s spectrum, m / e (relative intensity) 290 (M+ , 13), 209 (M+-Br, 31), 150 (90), 55 (100); exact m a s s calcd. for C-| 1 H 1 3 O 4 8 1 Br m /e 290.2314, found m /e 290.2318. 166 4 -C a rb o m e th o x y b ic y c lo [3 .3 .1 ]n o n -3 -e n -2 ,9 -d io n e (166). A mixture of 0.97 g (3.35 mmol) of bromoketone 165, 1.5 g (20.6 mmol) of lithium carbonate, an d 2.5 g (28.8 mmol) of lithium bromide in 20 mL of dimethylform amide w as w arm ed to 95 8 C and stirred for 2 h under an argon atm osphere. The reaction mixture was poured into 100 mL of brine after cooling down to room tem perature. The a q u e o u s layer w a s extracted with three 80-mL portions of ether. The com b ined e th ereal layers w e re dried (CaCl 2 ) and co n centrated in vacuo. The residue w a s chrom atographed over 60 g of silica gel (eluted with ethyl ac etate-h exan e, 1 :6 ) to yield 418 mg (59%) of enedione 166 a s a pale yellow oil: IR (neat) 1733, 1700, 1664 c m '1; 1H NMR ( C D C ^ 300 MHz) 5 1.56-1.64 (m, 2 H, CH2), 1.87-2.07 (m, 3H, CH2), 2.13-2.19 (m, 1 H, (m, 1H, CHCO), 3.68-3.73 (m, 1H, CHCO), 3.83 (s, 3H, OCH 3 ), 7.1 1 (d, J = 1.0 Hz, NMR (CDCI 3 , 62.9 MHz) 8 CH), 3.25-3.29 1 H, =CH); 13C 16.56 (t), 30.46 (t), 33.71 (t), 48.72 (d), 52.98 (d), 62.55 (d), 135.77 (d), 145.93 (s), 164.86 (s), 198.61 (s), 206.90 (s); m ass spectrum, m /e (relative intensity) 208 (M+, 100), 149 (71); exact m ass calcd. for C 1 1 H 1 2 O 4 m /e 208.0735, found m /e 208.0736. 66 163 4 a -C a rb o m e th o x y b ic y c lo [3 .3 .1 ]n o n a n -2 ,9 -d io n e (1 6 3 ). A solution of 0.25 g (1.2 mmol) of endione 1 6 6 in 10 mL of abso lu te ethanol w a s h y d ro g e n a te d u n d e r o n e a tm o sp h e re of hydrogen over 35 mg of 10% palladium-on-charcoal. The slurry w a s filtered through Celite, which w a s rinsed with ethyl acetate. The filtrate w a s w a sh e d with 20 mL of 10% a q u e o u s sodium bicarbonate, dried (Na 2 SC>4 ), and concentrated in vacuo. The residual oil w as ch rom atographed over 20 g of silica gel (eluted with ethyl acetate-petroleum ether, 1 :1 ) to yield 0.16 g (62%) of bicyclic dione 163 a s a colorless oil. This material w as spectroscopically identical to an authentic sample (vide supra). 164 4 p -C a rb o m e th o x y b ic y c lo [3 .3 .l]n o n a n -2 ,9 -d io n e (1 6 4 ). To a solution of 0.27 g (1.0 mmol) of selen o e ste r 139 in 9 mL of dry dichloromethane w as add ed 0.15 g (1.0 mmol) of neat enam ine 1 dropwise at -40 ^C. The mixture w as stirred for 3 h and poured into 10 mL of 1 N a q u e o u s hydrochloric acid. The aq u e o u s layer w as extracted with three 50-mL portions of ether. The com bined ethereal layers were w a sh e d with brine, water, dried (Na 2 S 0 4 ) an d concentrated in vacuo. The residual oil w a s chrom atographed over 20 g of silica gel (eluted with ethyl acetatepetroleum ether, 1:3) to yield 0.15 g (6 8 %) of carbom ethoxy dione 164 a s a white solid and selenylated com pound 151 and 152 in 42% yield and 13% yield, respectively. Dione 164: mp 71-72 °C ; IR (CHCI3); 1739, 1709 c m ' 1; 1H NMR (CDCI 3 , 250 MHz) 5 1.62-1.70 (m, 1.99-2.12 (m, 1 H, CH), 2.15-2.21 (m, 2H, CH2), 2.33-2.39 (m, 1 H, 2 H, CH 2 ), CH), 2.70 (dd, J = 17.1, 7.8 Hz, 67 1H, CHCO), 2.82 (dd, J = 17.1, 6.9 Hz, 1H, CHCO), 2.94-2.97 (m, 2 H, CHCO, C H C 0 2 Me), 3.12- 3.15 (m, 1H, CHCO), 3.67 (s, 3H, OCH 3 ); 13C NMR (CDCI 3 , 62.9 MHz) 6 18.68 (t), 35.42 (t), 35.63 (t), 40.55 (d), 42.01 (t), 47.98 (d), 52.58 (q), 63.20 (d), 173.27 (s), 207.19 (s), 209.43 (s); m a s s spectrum , m /e (relative intensity) 210 (M+, 2), 151 (21), 55 (100); exact m a s s calcd. for C 1 1 H 1 4 O 4 m /e 210.0892, found m /e 210.0893. H 6 165 B ic y c lo [3 .3 .i ] n o n a n e -2 ,9 -d io n e (6 ) and S -P h en y l (± )-2 -o x o th io c y c l o h e x a n e p r o p i o n a t e (165). To a solution of 1.1 g (7.35 mmol) of enam ine 1 in 10 mL of b e n z e n e at room tem perature w as ad d e d 1.2 g (7.35 mmol) of neat thioester 140 in one portion. The mixture w a s stirred for 12 h and poured into 10 mL of 2 N aq u e o u s hydrochloric acid. The a q u e o u s layer w a s extracted with two 80-mL portions of dichlorom ethane. The com bined organics were w a sh e d with brine, dried (Na 2 SC>4 ), and concentrated in vacuo. The residue was chrom atographed over 70 g of silica gel (eluted with ethyl acetate-hexane, 1 :20 followed by 1:6) to yield 0.2 g (20%) of bicyclic dione colorless oil. Dione 6 6 a s a white solid and 0.58 g (30%) of keto thioester 165 a s a : mp 115-118 °C (lit.4a 117 °C); IR (CCI4 ) 1740, 1712 c m '1; 1H NMR (CDCI 3 , 250 MHz) 5 1.56-2.20 (m. 7H, CH 2 ), 2.34-2.52 (m, 2.82 (m, 1 H, CHCO), 3.13 (bs, 1 H, 2 H, CH 2 ), 2.60-2.78 (m, 1H, CHCO), 2.79- CHCO); 13C NMR (CDCI 3 , 62.9 MHz) 8 18.71 (t), 22.32 (t), 35.12 (t), 35.79 (t), 39.29 (t), 44.44 (d), 64.22 (d), 210.00 (s), 211.71 (s); m a s s spectrum (relative intensity) 152 (M+, 32), 55 (100); exact m a s s calcd. for C 9 H 1 2 O 2 rn/e 152.0821, found m /e 152.0829. Keto thioester 165; IR (CCI 4 ) 1716 c m ’1; 1H NMR (CDCI 3 , 300 MHz) 5 1.33-1.87 (m, 5H, CH 2 ), 1.99-2.16 (m, 3H, CH 2 ), 2.21-2.42 (m, (m, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 3 H, CH 2 ), 2 .6 2 - 2 . 8 1 (m, 2 H, CH 2 ), 7.35-7.40 24.96 (t), 25.21 (t), 27.89 (t), 34.13 (t), 41.08 (t). 42.05 (t), 49.37 (d), 127.73 (s), 129.01 (d), 129.17 (d), 134.32 (d), 197.26 (s), 212.17 (s); m ass 68 spectrum, m /e (relative intensity) 153 (M+-SPh, 100), 109 (19); exact m a s s calcd. for C 9 H 1 3 O 2 (M+-SPh) m /e 153.0903, found m /e 153.0909. 167 4 a -M e th y lb ic y c lo [3 .2 .1 ]o c ta n -2 ,8 -d io n e (1 6 7 ). To a solution of 0.46 g (3.3 mmol) of thioester 129 in 7 mL of b e n z e n e at room tem perature w a s added 587 mg (3.3 mmol) of neat enam ine 3 in one portion. The solution w as stirred for 10 h and poured into 15 mL of 1 N a q u e o u s hydrochloric acid. The a q u e o u s layer w a s ex tracted with two 30-mL portions of dichlorom ethane. The organic layers w ere com bined, dried (Na 2 SC>4 ), a n d co ncen trate d in vacuo. The residual oil w a s c h ro m a to g ra p h e d ov er 40 g of silica gel (eluted with ethyl ac etete:h ex a n e, 1:17 followed by 1:6) to yield 137 mg (30%) of bicyclic dione 167 a s a pale yellow oil and 87 mg (10%) of Michael adduct 144 a s a colorless oil. Dione 167: IR (CDCI 3 ) 1750, 1712 c m '1: 1H NMR (CDCI 3 , 300 MHz) 8 1.97 (d, J = 6.5 Hz, 3H, CH 3 ), 1.88-2.08 (m, 3H, CH2), 1.97 (dd, J = 15.5, 5.8 Hz, 1H, CHCO), 2.08-2.20 (m, 1H, CH), 2.38 (dd, J = 15.5, 12.9 Hz, 1H, CHCO), 2.38-2.41 (m, 2H, CH), 3.06 (d, J= 6.9 Hz, 1H, CHCO); 13C NMR (CDCI 3 , 62.9 MHz) 8 16.79 (t), 17.82 (q), 23.32 (t), 30.06 (d), 42.00 (t), 50.14 (d), 62.93 (d), 205.02 (s), 208.38 (s); m ass spectrum, m /e (relative intensity) 152 (M+, 19), 137 (2), 111 (6 ), 100 (14), 69 (100); exact m ass calcd. for C 9 H 1 2 O 2 m /e 152.0600, found m /e 152.0604. o 167 4 a -M e th y lb ic y c lo [3 .2 .1 ]o c ta n e -2 ,8 -d io n e (167). To a solution of 0.45 g (2.0 mmol) of selen o e ste r 133 in 7 mL of dichloromethane at -15 °C w as added 270 mg (2.0 mmol) of 69 neat en am ine 36 dropwise. The solution w a s stirred for 10 h and concen trated in vacuo. The residual oil w as chrom atographed over 40 g of silica gel (eluted with ethyl acetete:h ex a n e, 1 :17 followed by 1 :6 ) to yield 95 mg (31%) of bicyclic dione 167 a s a pale yellow oil and 195 mg (48%) of 151 a s a red oil and 70 mg (11%) of 152 a s a red oil. This material w a s spectroscopically identical to an authentic sample (vide supra) o o 168 169 (± )-1-[(l R * ,2 R * ,5 R * )- 2 -M e th y l-4 -o x o b ic y c lo [4 .3 .l]d e c a n -1 0 -y lid e n e ] p y rro lid in iu m c h lo rid e (168 ) and 4 [i-M e th y lb ic y c lo [4 .3 .1 ] d e c a n e - 2 ,l 0 - d i o n e (169). To a solution of 0.45 g (2 mmol) of s e len o e ste r 8 in 7 mL of dichlorom ethane at -15 3 C w as add ed 0.33 g (2.0 mmol) of neat enamine 166 dropwise. The mixture w a s stirred for 12 h and co ncentrated in vacuo to give red solid. The solid w as collected while rinsing with 80 mL of hot ethyl acetate to yield 0.41 g (75%) of iminium salt 168 a s a white solid which w a s hydrolyzed to dione 169 in 52% yield by wet silica gel in dichloromethane at room temperature. The filtrate w as w a sh e d with 20 mL of 1 N a q u e o u s hydrochloric acid and saturated brine. The aq u e o u s layers w ere com bined and extracted with three 30-mL portions of dichlorom ethane. The com bined organics w ere dried (Na 2 SC>4 ) and concentrated in vacuo. The residue w a s chrom atographed over 10 g of silica gel (eluted with ethyl ac etate-h exan e, 1:4) to yield 42% of 151, 13% of 152 a nd 70 mg (15%) of bicyclic dione 169. Iminium salt 168: mp 164 °C (decom posed); IR (CHCI 3 ) 3359, 2938, 1731, 1697, 1649 c m '1 ; 1H NMR (CDCI 3 , 300 MHz) 8 1.20 (d, J = 7.0 Hz, 3H, CH 3 ), 1.28-1.68 (m, 5H, CH 2 ), 1.91-2.47 (m, 9H, CH 2 ), 3.26-3.35 (m, 2 H, CHCO), 3.86-3.92 (m, CHCO), 3.92-4.03 (m, 2 1 H, H, CH 2 N), 4.52-4.69 (m, 2H, CH 2 N); 13C NMR (CDCI 3 , 62.9 MHz) 8 70 20.85 (q), 24.32 (t), 24.32 (t), 24.37 (t), 24.91 (t), 25.72 (t), 27.38 (t), 31.04 (d), 45.75 (t), 48.73 (d), 54.64 (d), 54.92 (t), 55.20 (t), 188.38 (s), 203.95 (s); m a s s spectrum, m /e (relative intensity) 269 (M+, 0.1), 234 (M+-CI, 5), 164 (2 1 ), 70 (46), 69 (100); exact m a s s calcd. for C 1 5 H2 4 CINO m/e 269.1544, found m /e 269.1545. Bicyclic dione 169: IR (film) 1732, 1700 c m '1; 1H NMR (CDCI 3 , 300 MHz) 5 1.02 (d, J= 6.7 Hz, 3H, CH 3 ), 1.40-2.08 (m, 2.66 (m, 1 H, 8 H, CH 2 ), 2.14-2.28 (m, 2H, CH 2 ), 2.61- CHCO), 2.76 (dd, J = 15.6, 5.7 Hz, 1H, CHCO), 3.17-3.21 (m, 1H, CHCO); 13C NMR (CDCI 3 , 62.9 MHz) 6 20.88 (q), 25.79 (t), 26.18 (t), 27.87 (t), 28.71 (t), 29.52 (d), 44.81 (t), 54.45 (d), 63.32 (d), 209.09 (s), 210.66 (s); m a s s spectrum, m /e (relative intensity) 180 (M+ , 22), 110 (14), 69 (100); exact m a s s calcd. f o r C - |i H - | 6 0 2 m /e 180.1145, found m /e 180.1149. O O 170 171 (± )-1 -[(1 R \2 R \5 R * )-2 -/-P ro p y l-4 -o x o b ic y c lo [4 .3 .1 ]d e c a n -l0 -y lid e n e ] p y rro lid in iu m ch lo rid e (1 7 0 ) a n d 4 [3 -/-P ro p y lb ic y c lo [4 .3 .1 ] d e c a n - 2 ,1 0 - d i o n e (171). To a solution of 0.35 g (2 mmol) of selen oester 135 in w as ad d e d 0.3 g (2 6 mL of dichloromethane at -15 °C mmol) of neat enam ine 166 dropwise. The reaction mixture w a s stirred for 8 h and concentrated in vacuo to give a red solid. The solid w as collected while rinsing with 80 mL of hot ethyl ac etate to yield 0.36 g (61%) of iminium salt 170 a s a white solid which w as hydrolyzed to dione 171 in 65% yield by wet silica gel in dichloromethane at room tem perature. The filtrate w as concentrated in vacuo. The residue w a s chrom atographed over 20 g of silica gel (eluted with ethyl ac eta te -h e x a n e , 1:35 followed by 1:4) to yield 70 mg (13%) of bicyclic dione 171 a s a colorless oil. Iminium salt 170: m.p.146-153 °C ; IR (CHCI 3 ) 3351, 2939, 1731, 1697, 1649 c m '1 ; 1H NMR (CDCI3 , 300 MHz) 5 0.95 (d, J = 6.7 Hz, 3H, CH 3 ), 0.99 (d, J = 6.6 Hz, 3H, CH 3 ), 1.25- 71 2.53 (m, 15H, CH 2 ), 3.36-3.50 (m, CH 2 N), 4.46 (q, 8 2 H, CHCO), 3.80 (q, J = 6.2 Hz, 1 H, CHCO), 4.02-4.09 (m, 2H, 6.0 Hz, 1H, CHN), 4.91 (q, J = 6.0 Hz, 1H, CHN); 13C NMR (CDCI3 , 62.9 MHz) 19.05 (q), 20.68 (q), 23.26 (t), 23.51 (t), 24.47 (t), 24.53 (1), 25.17 (1), 30.60 (t), 32.20 (d), 42.10 (t), 43.63 (d), 45.42 (d), 54.57 (d), 54.70 (t), 55.45 (t), 189.08 (s), 204.81 (s); m a s s spectrum, m/e (relative intensity) 262 (M+-CI, 13), 219 (M+-C3 H 7 CI, 15), 70 (96), 41 (100); exact m ass calcd. for C 1 7 H 2 8 NO m /e 262.2121, found m /e 262.2146. Dione 171; 1H NMR (CDCI 3 , 250 MHz) 5 0.87 (d, J = 6.7 Hz, 3H, CH 3 ), 0.93 (d, J= 6.9 Hz, 3H, CH 3 ), 1.32-1.83 (m, CH 2 ), 2.30 (dd, J = 15.2, 9.0 Hz, (m, 1H, CHCO), 3.09-3.12 (m, 1 H, 1 H, 8 H, CH 2 ). 1.89-2.09 (m, CHCO), 2.63 (dd, J = 15.2, 5.8 Hz, CHCO); 13C NMR (CDCI 3 , 62.9 MHz) 1 H, 8 2 H, CHCO), 2.78-2.85 18.92 (q), 20.23 (q), 25.02 (t), 26.21 (t), 27.09 (t), 30.08 (t), 31.87 (d), 41.16 (t), 41.96 (d), 51.04 (d), 62.57 (d), 209.11 (s), 211.33 (s); m a ss spectrum, m /e (relative intensity) 208 (M+, 13), 165 (13), 97 (100), 43 (10); exact m a s s calcd. for C 1 3 H2 0 O 2 m /e 208.1469, found m/e 208.1466. o 172 173 (± )-1 -[(1 R * , 2 R * , 5 R * ) - 2 - p h e n y l - 4 - o x o b i c y c l o [ 4 . 3 . 1 ] d e c a n - 1 0 - y l l d e n e ] p y rro lid in iu m ch lo rid e (1 72 ) and 4 [3 -P h e n y lb ic y c lo [4 .3 .1 ] d e c a n - 2 ,1 0 - d i o n e (173). To a solution of 0.83 g (3 mmol) of selen o e ste r 137 in 15 mL of dichlorom ethane at -15 3C w as ad d e d 0.5 g (3 mmol) of neat enam ine 166 dropwise. The mixture w as stirred for 9 h and concentrated in vacuo to give 1.34 g of a red oil. This oil w a s crystallized from 60 mL of ethyl acetate. The solid w as collected while rinsing with hot ethyl a c e ta te to yield 628 mg (64%) of iminium salt 172 a s a white solid which was hydrolyzed to dione 173 in 65% yield by wet silica gel in dichlorom ethane at room tem perature. The filtrate w as w a sh e d with 20 mL of 1 N a q u e o u s 72 hydrochloric acid and saturated brine. The aquous layers were combined and extracted with three 30-mL portions of d ichlo rom eth ane. T he co m b in ed org a n ic s w e re dried (Na 2 S 0 4 ) and concentrated in vacuo. The residual oil w a s chrom atographed over 20 g of silica gel (eluted with ethyl a c e ta te -h e x a n e , 1:20 followed by 1:4) to give 92 mg (13%) of bicyclic dione 173 a s a colorless oil. Iminium salt 172: mp 118-122 °C ; IR (CHCI 3 ) 3326, 1731, 1651 c m ' 1 ; 1H NMR (CDCI 3 , 300 MHz) 5 1.08-2.62 (m, 13H, CH 2 ), 2.89-3.13 (m, 2H, CH 2 CO), 3.51-4.68 (m, C H 2 N), 7.09-7.68 (m, 5H, ArH); 1 3 C NMR (CDCI 3 , 62.9 MHz) 6 6 H, 24.09 (t), 24.09 (t), 24.26 (t), 25.00 (t), 25.83 (t), 26.77 (t), 41.13 (d), 44.98 (t), 50.20 (d), 54.57 (d), 54.73 (t), 55.37 (t), 127.63 (d), 127.63 (d), 129.05 (d), 141.08 (s), 187.47 (s), 203.70 (s); m a s s spectrum, m / e (relative intensity) 331 (M+, 0.1), 295 (M+-CI, 4), 57 (100), 70 (30); exact m ass calcd. for C 2 0 H 2 6 CINO m/e 331.1704, found m/e 331.1703. Bicyclic dione 173: IR (neat film) 2931, 1731, 1700 c m ' 1; 1 H NMR (CDCI 3 , 300 MHz) 6 1.52-2.11 (m, 8 H, CH 2 ), 2.71 (dd, J = 16.0, 9.7 Hz, 1 H, CHCO), 2.88 (dd, J = 16.0, 5.8 Hz, 1H, CHCO), 2.95-3.02 (m, 1H, CHPh), 3.28-3.40 (m, 2H, CHCO), 7.13-7.16 (m, 2H, ArH), 7.21-7.36 (m, 3H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 5 25.57 (t), 26.10 (t), 27.38 (t), 28.74 (t), 39.93 (d), 45.39 (t), 55.65 (d), 62.86 (d), 126.95 (d), 127.26 (d), 129.01 (d), 142.54 (s), 207.72 (s), 210.50 (s); m a s s spectrum, m /e (relative intensity) 242 (M+, 45), 214 (7(, 131 (100), 115 (18), 104 (40), 55 (23); exact m a s s calcd. for C 1 6 H 1 8 O 2 m /e 2 42.1298, found m / e 2 4 2 .1 3 0 6 . 174 S -P henyl and S -P henyl 175 (± )-(R * ,S * )-p -M e th y l-2 -o x o th io c y c lo h e x a n e (± )-(R * ,R * )-p -M eth y l-2 -o x o th io cy c lo h ex an e p ro p io n a te (174) p r o p i o n a t e ( l 7 5 ) . To a solution of 2.44 g (14.6 mmol) of morpholineenamine 4 in 10 mL of b e n z e n e w as ad d e d 2.61 g (14.6 mmol) of neat thioester 129 at once at room tem perature The mixture w a s stirred for 48 h at 73 room tem perature and poured into 10 mL of 0.2 N hydrochloric acid. The a q u e o u s solution w as extracted with three 50 mL-portions of ether. The combined ethereal layers w ere dried (Na 2 S 0 4 ), d e c a n te d , an d co n c e n tra te d in v acu o to give 4.75 g of yellow oil. This residual oil w as chrom atographed over 150 g of silica gel (eluted with ethyl acetate-hexane, 1 :20 followed by 1 :6 ) to yield 2.2 g (55%) of k etoesters 174 and 175 in a ratio of 9:1 in sep arable diastereom eric mixture, respectively, a s a colorless oil: IR (neat) 3059, 2936, 2862, 1705 c m '1; 1H NMR (C 6 D6 , 300 MHz, major isomer) 5 0.86 (d, J = 6.8 Hz, 3H, Me), 0.97-1.28 (m, 3H, CH 2 ), 1.35-1.40 (m, 1 H, CH), 1.47-1.55 (m, 2H, CH2), 1.78 (ddd, J = 13.0, 13.0, 5.6 Hz, 1H, CHCOSPh), 1.92 (dt, J = 11.9, 5.1 Hz, 1H, CHCO), 2.10-2.13 (m, 1H, CHCO), 2.42 (dd, J = 15.0, 8.3 Hz, 1H, CHCOSPh), 2.51 (dd, J = 15.0, 5.6, 1H, CHCOSPh), 2.65 (m, 1H, CHCO), 6.96-7.07 (m, 3H, ArH), 7.33-7.36 (m, 2H, ArH); 13C NMR (C 6 D6, 75.5 MHz) 5 16.53 (q), 24.96 (t), 27.61 (t), 29.10 (t), 29.82 (d), 42.27 (t), 48.52 (t), 54.06 (d), 128.79 (s), 129.22 (d), 134.70 (d), 195.57 (s), 209.74 (s); m ass spectrum, m /e (relative intensity) 276 (M+, 0.1), 69 (100); exact m a s s calcd. for C 1 6 H 2 0 O 2 S m /e 276.1155 found m /e 276.1152 H 176 (± )-{ R * ,S * )-(J-M eth y l-2 -o x o cy clo h ex a n e p r o p i o n i c a c i d (176). To a solution of 0.33 g (2.0 mmol) of bicyclic dione 14 in 5 mL of tetrahydrofuran w as a d d e d 15 mL of 0.1 N aqueoud sodium hydroxide at room temperature and stirred for 1 h. The mixture w as acidified with 0.5 N a q u e o u s hydrochloric acid to pH 2. The reaction mixture w as extracted with four 50-mL portions of ether. The com bined ethereal layers w ere w a s h e d with 5% a q u e o u s sodium bicarbonate, brine, dried (CaCl 2 ), and concentrated in vacuo. The residue w as chromatographed over 20 g of silica gel (eluted with ethyl acetate-hexane, 1:2) to yield 0.19 g (51%) of ketoacids 176 and 177 (8:1 by 1H NMR integration) a s a colorless oil and 102 mg (31%>) ol starling material 74 14: IR (neat film) 1705 c m '1; 1H NMR (CDCI 3 , 300 MHz, major isomer) 5 0.93 (d, J= 7.0 Hz, 3H, C H 3 ), 1.42-1.74 (m, 3H, CH 2 ), 1.82-2.12 9m, 3H, CH 2 ), 2.27-2.58 (m, 6 H, CHCO); 13C NMR (CDCI 3 , 75.5 MHz) 5 16.98 (q), 25.15 (t), 28.06 (t), 28.96 (d), 29.45 (t), 39.52 (t), 42.64 (t), 54.68 (d), 179.32 (s), 212.80 (s); m a s s spectrum, m /e (relative intensity) 184 (M+- 0.1) , 69 (100); exact m a s s calcd. for C 1 0 H 1 6 O 3 m /e 184.1155 found m /e 184.1152 174 S -P henyl ( ± ) - ( R * ,S * ) - [ i - m e t h y l - 2 - o x o t h i o c y c lo h e x a n e p ro p io n ate (174). To a solution of 0.18 g (0.99 mmol) of ketoacid in 20 mL of ether and 0.11 g (1.0 mmol) of thiophenol at 0 0C w as add ed 0.21 g (1.02 mmol) of dicyclohexylcarbodiimide portionwise and stirred for 1 h at room temperature. The solution w a s filtered through Celite while washing with ether. The filtrate w a s concentrated in vacuo. The residue w as chromatogrphed over 10 g of silica gel (eluted with ethyl acetate:hexan e, 1 :6 ) to yield 0.19 g (69%) of ketoester 174 a s a colorless oil. This material w as the sa m e a s that obtained from a Michael reaction (vide supra). H 177 ( ± ) - ( R * ,R * ) - p - m e t h y l - 2 - o x o c y c l o h e x a n e pro p io n ate ac id (177). A mixture of 0.33 g (2.0 mmol) of dione 13 and 25 mL of 0.1 N aqueous sodium hydroxide w as stirred for 3 h at room tem perature and acidified with 0.5 N hydrochloric acid until a pH of 2 w a s reached. The reaction mixture w a s extracted with four 50-mL portions of ether. The com bined organics were w a sh e d with 5% aq u e o u s sodium bicarbonate, brine, dried (CaCl 2 ), and concentrated in vacuo. The residue w a s chrom atographed over 20 g of silica gel (eluted with ethyl acetate-h exane, 1 :2) 75 to yield 0.19 g (51%) of ketoacid 177 a s a colorless oil and 102 mg (31%) of starting material: IR (neat film) 1703 c m '1: 1H NMR (CDCI 3 , 300 MHz, major isomer) 8 0.97 (d, J = 7.0 Hz, 3H, CH 3 ), 1.42-1.71 (m, 3H, CH 2 ), 1.82-2.10 (m, 3H, CH 2 ), 2.18 (dd, J= 14.5, 8.7 Hz, 1 H, CHCO 2 H), 2 .2 2 - 2.45 ((m, 4H, CHCO), 2.52 (dd, J= 14.5, 4.2 Hz, 1H, C H C 0 2 H); 13C NMR (CDCI 3 , 75.5 MHz) 8 17.44 (q), 24.75 (t), 27.63 (t), 28.96 (d), 29.72 (t), 37.98 (t), 42.25 (t), 54.80 (d), 179.36 (s), 212.37 (s); m a s s spectrum, m /e (relative intensity) 184 (M+- 0.1) , 69 (100); exact m a s s calcd. for C 1 0 H 1 6 O 3 m /e 184.1155 found m /e 184.1152. H 178 S -P henyl (± )-(R * ,R * )-p -m eth y l-2 -o x o th io cy c lo h e x an e p ro p io n a te (1 7 8 ) ; To a solution of 0.18 g (0.99 mmol) of ketoacid 17 7 in 20 mL of ether and 0.11 g (1.0 mmol) of thiophenol at 0 °C w a s ad d e d 0.21 g (1.02 mmol) of dicyclohexylcarbodiimide portionwise and stirred for 1 h at room temperature. The precipitate w as filtered off through Celite while washing with ether. The filtrate w as concentrated in vacuo. The residue w as chrom atographed over 10 g of silica gel (eluted with ethyl acetate:hexane, 1:6 ) to yield 0.19 g (69%) of 8:1 inseparable mixture of ketoesters 176 and 178, respectively, a s a colorless oil: 1H NMR (C6 D6 , 300 MHz) 6.8 8 0.93 (d, J = Hz, 3H, Me), 0.97-1.25 (m, 3H, CH2), 1.34-1.50 (m, 3H, CH2), 1.72-1.88 (m, 2H, CHCO), 2.07- 2.14 (m, 1H, CHCO), 2.37 (dd, 1H, J= 14.5, 8.9 Hz, 1H, CHCO), 2.43-2.51 (m, 1H, CHCO), 2.73 (dd, J= 14.5, 4.3 Hz, 1H, CHCO), 6.97-7.07 (m, 3H, Ph), 7.34-7.39 (m, 2H, Ph); 13C NMR (C 6 D6, 75.5 MHz) 8 17.10 (q), 25.00 (t), 27.54 (t), 29.90 (t), 30.48 (d), 42.30 (t), 47.84 (t), 54.52 (d), 128.88 (s), 129.17 (d), 129.21 (d), 134.74 (d), 195.70 (s), 209.69 (s); m a s s spectrum , m /e (relative intensity) 276 (M+' 0.1) , 69 (100); exact m a s s calcd. for C 1 6 H 2 0 O 2 S m /e 2 7 6 .1 1 5 5 found m /e 276.1152. 76 H 179 S -P henyl (± )-(R * ,S * )-p -p h e n y l-2 -o x o th io c y c lo h e x a n e p ro p io n ate (179). To a solution of 0.45 g (2.0 mmol) of thioester 136 in 10 mL of dichloromethane at -20 °C w a s added 0.2 mL of neat titanium tetrachloride dropwise and the tem perature w as lowered to -78 °C. To the mixture w a s add ed dropwise 0.34 g (2.0 mmol) of neat morpholine enam in e 4. The mixture w as stirred for 1 h and poured into 15 mL of 5 % a q u e o u s potassium carbonate. The a q u e o u s layer w a s extracted with two 50-mL portions of dichloromethane The com bined organics w ere dried (CaCl 2 ) and concentrated in vacuo. The residue w a s chrom atographed o v er 30 g of silica gel (eluted with ethyl acetate:hexane, 1 :6 ) to yield 0.33 g (48%) of ketoester 179 a s a white solid and 35% of the starting material 136: mp 118-119 °C; IR (CHCI3) 3018, 2941, 1705 c m ’1; 1H NMR (CDCI 3 , 300 MHz) 8 1.18-1.28 (m, 1H, CH), 1.51-1.60 (m, 1H, CH), 1.64-1.79 (m, 3H, CH2), 1.95- 2.03 (m, 1H, CH), 2.31-2.49 (m, 2H, CH 2 CO), 2.71 (ddd, J = 9.4, 9.4, 4.5 Hz, CHPh), 2.98 (dd, J = 15.2, 9.4 Hz, 1H, CHCOSPh), 3.16 (dd, J = 15.2, 4.5 Hz, 1 H, CHCOSPh), 3.59 (ddd, J= 9.4, 9.4, 4.5 Hz, 1H, CHCO), 7.17-7.35 (m, 10H, Ph); 13C NMR (CDCI3i 75.5 MHz) 8 24.32 (t), 28.46 (t), 32.43 (t), 42.02 (d), 42.34 (t), 48.38 (t), 55.06 (d), 126.64 (d), 127.85 (s), 128.48 (d), 129.01 (d), 129.16 (d), 134.37 (d), 140.97 (s), 195.89 (s), 212.69 (s); m a s s spectrum, m /e (relative intensity) 338 (M+- 0.1) , 69 (100); exact m a s s calcd. for C 2 1 H 2 2 O 2 S m /e 338.1155 found m /e 338.1152. H 180 S -P henyl (± )-(R * ,S * )-p -P h en y l-2 -o x o c y clo h ex a n e p ro p io n ic a c id (180). A mixture of 0.25 g ( 1 . 1 mmol) of dione 9, 20 mL of 0.1 N a q u e o u s NaOH, a n d 5 mL of tetrahydrofuran w a s stirred for 1 h at room te m p eratu re and acidified with 2 N a q u e o u s 77 hydrochloric acid. The product solidified. The reaction mixture w a s extracted with three 100-mL portions of dichloromethane. The com bined organics were w a sh e d with brine, dried (CaCl 2 ), and concentrated in vacuo to yield 260 mg of white solid. The crude product w as recrystallized from 30 mL of ethyl ac etate and hex ane (1:2 ) to yield 238 mg (97%) of ketoacid 180 a s a white solid: mp 129-131 °C; IR (CHCI 3 ) 1708 cm ’1; 1H NMR (CDCI 3 , 300 MHz) 5 1.17-1.25 (m, 1.77 (m, 4H, CH 2 ), 1.95-2.02 (m, 1 H, CHPh), 2.87 (dd, J = 15.8, 4.3 Hz, 1 H, CH), 1.50- CH), 2.30-2.47 (m, 2H, CHCO), 2.54-2.65 (m, 2 CHCO 2 H), 3.44 (ddd, J = 9.7, 9.7, 4.3 Hz, 1 H, 1 H, H, CHCO, CHCO), 7.15-7.33 ((m, 5H, ArH), 11.18 (bs, 1H, C O 2 H); 13C NMR (CDCI3 , 75.5 MHz) 5 24.71 (t), 28.81 (t), 32.79 (t), 39.78 (t), 41.41 (d), 42.66 (t), 55.57 (d), 127.16 (d), 128.64 (d), 128.86 (d), 141.79 (s), 178.25 (s), 213.50 (s); m a s s spectrum, m /e (relative intensity) 246 (M+, 48), 107 (89), 171 (100); exact m a s s calcd. f o r C i 5 H i s 0 3 m /e 246.1249 found m /e 246.1242. H 179 S -P henyl (± )-(R * ,S * )-(i-P h en y l-2 -o x o th io cy c lo h e x an e p ro p io n ate (179). To a solution of 0.24 g (0.97 mmol) of ketoacid 180 in 20 mL of ether and 0.11 g (1.0 mmol) of thiophenol at 0 °C w a s ad d e d 0.21 g (1.02 mmol) of dicyclohexylcarbodiimide portionwise. The resulting mixture w as stirred for 2 h at room temperature. The solution w a s filtered through Celite while w a sh in g with ether. The filtrate w a s c o n c e n tra te d in v ac u o . T he re s id u e w a s ch rom ato grap hed over 10 g of silica gel (eluted with ethyl a c e tate:h ex a n e, 1:6) to yield 0.3 g (90%) of ketoester 179 as a white solid (mp = 116-118.5 °C). This ketoester w a s the s a m e a s that obtained from the Michael reaction (vide supra). 78 H H 181 0-M eth yl and 0 - M e th y l S -P h e n y l S-P h enyl 182 ( ± ) - ( R * ,S * ) - 2 -o x o - y - t h io c y c lo h e x a n e (± )-(R *,R *)-2 -o x o -y -th io c y c lo h e x a n e s u c c in a te s u ccin ate (1 8 1 ) (182). To a solution of 0.44 g (2.0 mmol) of thioester 138 in 15 mL of dichloromethane at -65 °C w as added 0.2 mL (2.0 mmol) of neat titanium tetrachloride dropwise followed by stirring for 5 min. To the ab ove mixture w as ad d e d 0.17 g (1.0 mmol) of morpholine enam ine 4 slowly. The solution w as stirred for an additional 30 min and poured into 10% aq u e o u s potasium carbonate. The aq u e o u s layer w a s extracted with two 50-mL portions of dichloromethane. The com bined organics were dried (CaCl 2 ) and concentrated in vacuo to yield 0.2 g (62%) of a 6:1 mixture of ketoesters 181 a nd 182, respectively, a s a white solid: mp 65-66 °C ; IR (CHCI 3 ) 1735, 1709 cm"1; 1H NMR (CDCI 3 , 300 MHz, major isomer) 5 1.55-1.71 (m, 3H, CH2), 1.91-2.12 (m, 3H, CH2), 2.26-2.37 (m, 1H, CHCO), 2.41-2.46 (m, 1 H, CHCO), 2.78-2.90 (m, 1 H, C H C 0 2 Me), 2.88 (dd, J= 16.4, 4.8 Hz, 1H, CHCOSPh), 3.08 (dd, J = 16.4, 8.4 Hz, 1H, CHCOSPh), 3.36 (ddd, J = 8.4, 4.8, 4.8 Hz, 1H, CHCO), 3.68 (s, 3H, OMe), 7.37-7.43 (m, 5H, ArH); 13C NMR (CDCI3 , 75.5 MHz) 8 24.97 (t), 27.33 (t), 31.29 (t), 41.00 (d), 41 97 (t), 42.43 (t), 51.48 (d), 51.88 (q), 127.34 (s), 129.05 (d), 129.29 (d), 134.38 (d), 173.58 (s), 195.98 (s), 210.04 (s); m a ss spectrum, m /e (relative intensity) 321 (M+ , 0.1) , 211 (94), 183 (70), 151 (100); exact m a s s calcd. f o r C i 7 H 2 oC>4 S m /e 321.1156 found m /e 321.1149. 193 1 ,4 - D im e t h y lb ic y c lo [ 3 .3 .1 ] n o n a n e - 2 ,9 - d io n e (193). To a solution of 1.07 g (6.0 mmol) of unsaturated thioester 129 in 5 mL of b e n z e n e w as ad d e d 0.31 g (1 .9 mmol) of neat 79 en a m in e 1 9 2 2 in three portions at 10 h intervals at room tem perature. The mixture w as diluted with 20 mL ot dichloromethane an d poured into 12 mL of 2 N a q u e o u s hydrochloric acid. The a q u e o u s layer w as extracted with two 50-mL portions of dichloromethane. The combined organic p h a s e s were w a sh e d saturated brine, dried (Na 2 SC>4 ), and concentrated in vacuo. The residual oil w as chrom atographed over 60 g of silica gel (eluted with ethyl acetate-h exane, 1 :20 followed by 1:6) to give 0.35 g (35%) of bicyclic dione 193 a s a colorless oil: IR (film) 1756, 1702 c m '1 ; 1H NMR (CDCI 3 , 250 MHz) 5 1.17 (s, 3H, CH3), 1.18 (d, J = C H 2 ), 2.32-2.39 (m, 1 H, 6.8 Hz, 3H, CH 3 ), 1.60-2.23 (m, 6 H, CH), 2.42 (dd, J = 17.0, 12.0 Hz, 1H, CHCO), 2.59 (bt, J = 2.6 Hz, 1H, CHCO), 2.79 (dd, J = 17.0, 8.0 Hz, 1 H, CHCO); 13C NMR (CDCI 3 , 62.9 MHz) 8 16.19 (q), 18.18 (q), 20.97 (t), 28.37 (t), 28.55 (d), 42.75 (t), 47.57 (t), 50.88 (d), 64.21 (s), 210.12 (s), 212.81 (s); m a s s spectrum, m /e (relative intensity) 180 (M+, 23), 69 (100); exact m a s s calcd. f o r C n H i 6 0 2 m /e 180.1156 , found m /e 180.1153. H 195 O - E th y l (± )-(R * ,S * )-p -M e th y l-2 -o x o c y c lo h e x a n e p ro p io n ate (1 9 5 ) . To a solution of 534 mg (3.0 mmol) of unsaturated thioester 129 and 138 mg (3.0 mmol) of absolute ethanol in 5 mL of b e n z e n e w as a d d e d 453 mg (3.0 mmol) of neat enam ine 1 in o n e portion at room temperature. The solution w as stirred for 10 min and the reaction mixture w a s then w ashed with 1 N aq u e o u s hydrochloric acid and saturated brine. The combined aq u e o u s solutions were extracted with three 20 -mL portions of ether. The combined ethereal layers w ere dried (CaCl 2 ) and concentrated in vacuo. The residue w as chromatographed over 30 g of silica gel (eluted with ethyl acetate-hexane, 1 :12) to yield 360 mg (42%) of thioester 144 a s a colorless oil and 221 mg (35%) of ketoesters 195 a s a 2:1 mixture by integration of the NMR peak s at 0.88 and 0.92 ppm. K etoester 195: IR (neat film) 2937, 2864, 1733, 1708 c m '1; 1H NMR (CDCI3 , 300 MHz, major 80 isomer) 8 0.88 (d, J= 6.8 Hz, 3H, Me), 1.20 (t, J = 7.1 Hz, 3H, CH 2 CH3), 1.38-1.70 (m, 1.83-2.00 (m, 3H, CH2), 2.04-2.52 (m, (CDCI 3 , 75.5 MHz, major isomer) 8 6 6 H, CH2), H, CH2), 4.07 (q, J = 7.1 Hz, 2H, OCH2 ); 13C NMR 14.09 (q), 16.38 (q), 24.61 (1), 27.53 (1), 28.58 (d), 28.76 (t), 39.28 (t), 42.12 (t), 54.24 (d), 59.99 (t), 172.75 (s), 211.88 (s); 1H NMR (CDCI 3 , 300 MHz, minor isomer) 8 0.92 (d, J= 7.4 Hz, 3H, Me), 1.21 (t, J = 7.1 Hz, 3H, CH 2 CH3), 1.38-1.70 (m, 3H, CH2), 1.83-2.00 (m, 3H, CH2), 2.04-2.52 (m, (CDCI 3 , 75.5 MHz, minor isomer) 8 6 H, CH2), 4.08 (q, J = 7.1 Hz, 2H, OCH2 ); 13C NMR 17.42 (q), 29.19 (d), 29.811 (t), 38.23 (t), 54.92 (d), 172.97 (s); m a s s spectrum , m /e (relative intensity) 212 (M+ , 9), 81 (20), 41 (100); exact m a s s calcd. tor C 1 2 H 2 0 O 3 m /e 212.1403 , found m /e 212.1400. List of R e f e r e n c e s 1. (a) Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chm. Soc. 1954, 76, 2029. (b) Stork, G.; L andesm an, H. J. Am. C hem . Soc. 1956, 78, 5128. 2. (a) Stork, G.; Brizzolara, A.; L andesm an, H.; Szmuszkovicz, J.; Terrell, R. J. Am . C hem . Soc. 1963, 85, 207. (b) Whitesell, J. K.; Whitesell, M. A. S y n th e sis, 1983, 517. (c) Hickmott, P. W. T etrahedron 1982, 38, 1975, 3363. 3. Dyke, S. F., "The C hem istry of Enamines", Cambridge University P ress, 1973 and references cited therein. 4. (a) Hickmott, P. W.; H argreaves, J. R. T etra h ed ro n 1967 , 23, 3151. (b) Hickmott, P. W. C hem istry a n d Industry, 1974, 731. (c) Hickmott, P. W.; Miles, G. J.; S heppard, G.; Urbani, R.; Yoxall, C. T. J. Chem . Soc. Perkin 1 197 3,15 14. 5. Peters, J. A. S y n th e s is , 1979, 321. 6 . Harding, K. E.; Clement, B. A.; Moreno, L.; Peter-Katalinic, J. J. Org. Chem . 1981, 46, 940. 7. Gravel, D.; Rahal, S. Can. J. Chem . 1975, 53, 2671. 8 . Gravel, D.; Labelle, M. Can. J. Chem . 1985, 63, 1874. 9. (a) McEuen, J. M.; Nelson, R. P.; Lawton, R. G. J. Org. C hem . 1969, 35, 690. (b) Nelson, R. P.; Lawton, R. G. J. Am . C hem . S o c. 1 9 6 6 , 88, 3884. (c) Nelson, R. P.; McEuen, J. M.; Lawton, R. G. J. Org. C hem . 1969, 34, 1225. 10. Anzeveno, P. B.; Matthews, D. P.; Barney, C. L.; Barbuch, R. J. J. Org. Chem . 1984, 49, 3134. 11. Lu, X.; Huang, Y. Tetrahedron Lett. 1986, 27, 1615. 81 82 12. Strauss, M.; Torres, R. J. Org. Chem . 1989, 54, 756. 13. S eeb a ch , D.; Missbach, M.; Calderari, G.; Eberle, M. J. Am. Chem . Soc. 1990, 112, 7625. 14. Wenkert, E.; Haviv, F.; Zeitlin, A. J. Am. C hem . Soc. 1969, 91, 2299. 15. Danishefsky, S.; Koppel, G.; Levine, R. Tetrahedron Lett. 1968, 2257. 16. S an d s, R. D. J. Org. Chem. 1983, 48, 3362. 17. (a) Marshall, J. A.; Partridge, J. J. Tetrahedron Lett. 1966, 2545. (b) Marshall, J. A.; Schaeffer, D. J. J. Org., Chem . 1965, 30, 3642. 18. Murray, R. D. H.; Parker, W.; Raphael, R. A. Tetrahedron, 1961, 16, 74. 19. Lorenzi-Riatsch, A.; Nakashita, Y; H esse, M. Helv. Chim. Acta 1984, 67, 249. 20. Marvell, E. N.; Sturmer, D.; Rowell, C. Tetrahedron, 1966, 22, 861. 21. (a) Schultz, A. G.; Dittami, J. P. J. Org. Chem. 1983, 48, 2318. (b) Schultz, A. G.; Dittami, J. P. J. Org. C hem . 1984, 49, 2615. 22. Buchi, G.; Wuest, H. Helv. Chim. Acta 1971, 54, 1767. 23. Trost, B. M.; S e o a n e , P. R. J. Am. Chem. Soc. 1987, 109, 615. 24. Shimizu, N; Tanaka, M.; Tsuno, Y. J. Am. Chem . Soc. 1982, 104, 1330. 25. Narula, A. S. Tetrahedron Lett. 1979, 1921. 26. Schmid, R.; Schmid, H. Helv. Chim. Acta 1974, 57, 1883. 27. Oh, J.; Choi, J.; Cha, J. K. J. Org. Chem. 1992, 57, 6664. 28. Fell, B.; Seide, W.; Asinger, A. Tetrahedron Lett. 1968, 1003. 83 29. Brown, H. C.; Carlson, B. A. Org. Synthesis, Coll. Vol. 6 , 137. 30. Gagneux, A. R.; Meier, R. Tetrahedron Lett. 1969, 1365. 31. Risaliti, A.; Forchiassin, M; Valentin, E. Tetrahedron, 1968, 24, 1889. 32. Kuehne, M.; Foley, L. J. Org. C hem . 1965, 30, 4280. 33. S e e b a c h , D.; Golinski, J. Helv. Chim. A cta 1981, 64, 1413. 34. Narasaka, K.; Soai, K.; Aikawa, Y.; Mukaiyama, T. Bull. Soc. Chem. Jpn. 1976, 49, 779. 35. (a) Heathcock, C. H.; Norman, M. H.; Uehling, D. E. J. Am. Chem . Soc. 1985, 107, 2797. (b) Oare, D. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 157. 36. Machida, S.; Hashimoto, Y.; Saigo, K.; Inoue, J.; H asegaw a, M.; Tetrahedron, 1991, 47, 3737. 37. Sumrell, G.; Ham, G. E.; Hornbaker, E. D. J. Am. Chem . Soc. 1958, 80, 2509. 38. Spatz, S. M.; Stone, H. J. Org. C hem . 1958, 23, 1559. 39. Foster, D. G. Org. Syn. Coll. Vol. 3, 771. 40. Keck, G. E.; Boden, E. P.; Mabury, S. A. J. Org. C hem . 1985, 50, 709. 41. Marquet, A.; Jac q u e s , J. Bull. Soc. Chim. Fr. 1962, 90. 42. Appleton, R. A.; Egan, C. J.; Evans, J. M.; Graham, S. H.; Dixon, J. R. J. Chem. Soc. (C) 1 9 6 8 , 1110. 43. (a) Zefirov, N. S. R ussian C hem ical Review, 1975, 4 4 , 196. (b)Raber, D. J.; Janks, C. M.; Johnston, M. D.; Raber, N. K. Tetrahedron Lett. 1980, 21, 677. (c)Mastryukov, V. S.; Popik, M. V.; Dorofeeva, O. V.; Golubinskii, A. V.; Vilkov, L. V.; Belikova, N. A.; Allinger, N. L. J. Am. Chem. S o c . 1 981 , 103, 1333. 44. (a) Peters, J. A.; van derToorn, J. M.; van Bekkum, H. Tetrahedron 1974, 30, 633. (b) Jaime, C.; Osaw a, E.; Takeuchi, Y.; Camps, P. J. Org. Chem. 1983, 48, 4514. (c) C am ps, P.; Iglesias, C. T etrahedron Lett. 1985, 26, 5463. 45. Kobuki, Y.; Fueno, T.; Furukawa, J. J. Am. C hem . Soc. 1970, 92, 6548. CHAPTER II a .p -U N S A T U R A T E D S Y N T H E S IS 1. T H IO E S T E R S OF AND S U B S T IT U T E D SELENOESTERS CYCLOHEXENE AS D IE N O P H IL E S : D E R IV A T IV E S In t r o d u c t io n This chapter will describe studies of Diels-Alder reactions of a ,p -u n satu ra ted thioesters and se le n o e ste rs. The objective of this re searc h w a s to explore and develop methodology to construct m eta disubstituted cyclohexenes and exo cycloadducts which are generally difficult to obtain via normal Diels-Alder reactions. To provide the reader with background for th e s e studies, a s p e c ts of thermal and Lewis acid catalyzed Diels-Alder reactions and related reactions will be reviewed. 2. B ackground A. T h erm al D iels-A ld er R eactions A few ways are known to construct substituted cyclohexene derivatives. O ne of the most popular m ethods is the Diels-Alder cycloaddition reaction.1 The Diels-Alder reaction h a s been o ne of the most fundamental and useful tools in organic synthesis since its discovery. Its wide s p read utility is attributed not only to its ability to construct substituted cyclohexenes in one step, but also to its remarkably high regioselectivity and stereoselectivity. Another re a s o n for the popularity of the Diels-Alder reaction is that a large variety of dien es and dienophiles bearing various functional groups a s substituents are readily available. 85 86 The reaction betw een a conjugated 1,3-diene and an olefinic or acetylenic dienophile, which is known a s Diels-Alder reaction, forms a substituted six-m em bered ring a s a 1:1 adduct (equation 11). In the reaction two new a-b o n d s are formed at the e x p e n se of two 7t-bonds. The reaction generally p ro c eed s easily with gentle warming in a suitable solvent, although in som e c a s e s with unreactive dienes or dienophiles more vigorous conditions may be necessary. Since a few Diels-Alder reactions a re reversible, so m e cycloadducts formed from the cycloaddition reaction dissociate into their com po nents at high tem perature. Use of o ne co m ponent in e x c e s s som etim es overcom es this problem. The reactivity of a diene d e p e n d s on several structural features. First, it is essential that the conjugated diene be able to adopt a cis conformation. That is, its conjugated double bonds must be situated cis coplanar. Acyclic conjugated dien es exist in a conformational equilibrium betw een cisoid and transoid forms. Only the cisoid conformer can participate in the reaction. 1d-1e If the c o n ju g ate d dou ble bond c a n not adopt the cisoid conformation u n d e r the reaction conditions, the cycloaddition reaction will not take place. The conformational equilibrium is very sensitive to the size and the position attached of substituents on the diene. T rans- 1 -substituted dienes are much more reactive than their cis isomers. This is bec au se the distance between the nearest hydrogen atoms at Ci and C 4 is only a little less than the sum of their van d er W aals radii. Trans-1-substituted dienes do not experience steric hindrance in the cisoid conformer. However, in cis-1-substituted dienes, the distance b etw een the substituent and the n ea rest hydrogen atom at C 4 is considerably smaller than the sum of the van der Waals radii and suffers s ev e re steric hindrance in the cis conformation. Therefore, the equilibrium is shifted far to the transoid conformer. For example, the reaction of c/s-piperylene (202) with maleic anhydride (200) gives only a 4 % yield of the cycloadduct 2 0 3 (equation 71). In the contrast, frans-piperylene (199) gives cycloadduct 201 in a quantitative yield (equation 70).2 ’3 As the size of the substituents bec o m e more bulky, the equilibrium is shifted further in the favor of transoid conformer. 87 1 9 9 (transoid) 202 (transoid) 1 9 9 (cisoid) 202 (cisoid) 2 0 3 (4 % ) In contrast to 1-substituted dienes, increase in the size of a substituent at the 2-position disp lace s the conformational equilibrium to the cisoid conform er for the s a m e r e a s o n .4 2,3Disubstituted dienes c a n accom od ate the planar cisoid conformation u nless the substituents are too big. So, 2 ,3 -d im e th y lb u tad ien e re a c ts rapidly with maleic anhydride, but 2,3-di-tbutylbutadiene d o e s not b e c a u s e of the lack of the coplanarity .5 Cyclic dienes are generally more reactive th an their acyclic co u n te rp a rts b e c a u s e they are co n stra in e d in a p lan ar cisoid conformation. However, a s the size of the ring increases the reactivity starts to d e c r e a s e b e c a u s e the double bonds can no longer adopt the n ecessary coplanar configuration .6 A se c o n d factor determining the reactivity of d ien es and dienophiles is the nature of s u b s titu e n ts . Alder stu d ie d the influence of activating s u b s titu e n ts in the d i e n e s a n d d ie n o p h ile s . 7 He o b serv ed that the reaction rate is generally in creased by electron donating g rou ps on the dienes, and d e c r e a s e d by electron withdrawing substituents. In contrast to the diene substituents effects, electron withdrawing groups on the dienophiles increase the reaction rate of Diels-Alder cycloadditions. Stereochemical studies conducted by Alder and Stein lead to two very important empirical rules about the stereochem ical outcome. T h ese are the cis principle and the endo addition rule .8 According to the cis principle, the steric a rran g e m e n t of the su b stituents in the dien e and dienophile is retained in the cycloadducts. That is, the reaction takes place by a cis addition. Thus, 88 the reaction of dimethyl m aleate 2 0 6 with cyclopentadiene (82) yielded the cis adducts 207 and 208, and dimethyl fum arate 204 with 82 gave the trans adduct 205 (equation 72).9 | COjMe COjjM© COzMe 82 205 2 07 (75:25) 2 08 The cis principle applies also to substituents in the diene com ponent. Diels-Alder reaction of maleic anhydride (200) with tra n s,tra n s-1 ,4-diphenyl-butadiene 209 g av e the cycloadducts 210 an d 211 in which two phenyl substituents were cis to each other (equation 73). C is,trans- 1 - methyl-4-phenyl-1,3-butadiene 212 gav e cycloadduct 213 with a trans relationship betw een two substituents (equation 74). This widely applicable principle is explained by the sy nchronous formation of the bonds betw een the two com ponents in a o ne step reaction. o (73) 209 210 (endo) 211 (exo) o (74) Mo 212 21 3 Even though the cis principle defines the position of the substituents in cycloadducts, their relative spatial positions are still not clearly defined b e c a u s e they d e p e n d on the relative orientation of the reactants during the reaction. W hen a symmetrical cyclic diene reacts with a dienophile containing even o n e substituent, two Diels-Alder adducts ca n be formed, that is, endo (216) and exo (217) isomers. The endo product is formed from an orientation in which the diene a n d dienophile approach each other to overlap their pi bonds effectively (s e e equation 75). One h a s to take into account not only th ose rt-bonds which actually participate in the cycloaddition reaction, but also the n-bonds of the activating grou ps in th e dienophile. For exam ple, it is possible to get a mixture of en d o a n d exo isom ers w hen cyclic dien es react with cyclic 1: 1 dienophiles (equations 75 and 76). However, the endo adduct is usually the major product. The thermodynamically more stable exo adduct is obtained in a substantially lower yield . o o (75) 2 1 4 (endo) o (76) o o 2 1 5 (exo) Although the Diels-Alder reaction of the cyclic dienes and dienopiles generally obey the en d o rule, there are a few exceptions . 1 0 For example, the cycloaddition reaction betw een furan (216) and maleic anhydride (200) affords a mixture of exo (217) a n d en d o (218) isom ers at room tem perature, but at higher tem p e ra tu re the exo isom er (217) is o btained exclusively (equation 77). Thus, the Diels-Alder reaction is reversible such that the initially formed endo adduct (218) isomerizes to the thermodynamically m ore stable exo isom er (217). Very recently, Lee and Herndon show ed that the initial endo-addition undergo 500 times faster than the e x o addition . 1 1 The Diels-Alder reaction of cyclic dienophiles with trans,trans- 1,4-disubstituted d ien es usually follows the e nd o rule a s h a s already b e e n shown in equation 2 . The e n do rule is not always followed in reactions of cyclic dienes with acyclic mono- and disubstituted dienophiles, and acyclic dien es with acyclic dienophiles. It is well known that endo/exo ratios are sensitive to the tem perature. In general, the ratio betw een endo and exo isom ers ca n be increased by lowering reaction tem peratures. Another essential characteristic of the Diels-Alder reaction is regioselectivity. A reaction b e tw e e n the unsym m etrical d ie n e 2 1 9 and dienophile 2 2 0 , in principle, could yield equal a m o u n ts of two p o ssible regioisom ers 221 and 2 2 2 . However, in most c a s e s o n e of the regioisom ers is preferentially formed. Thus, the reaction of 1-substituted d ie n e s 2 1 9 with electron-poor dienophiles 2 2 0 afford the "ortho" cycloadducts 221 predominantly (Table 1).1b For example, trans-] -phenyl-1,3-butadiene reacted with acrolein to give a single regioisomer in 73% yield (entry 5 Table 1). 2-S ubstituted 1 ,3 -bu tad ien es 2 2 3 react with unsym m etrical electron-poor dienophiles 2 2 0 to give "para" isom ers 224 a s major products (Table 2).1e Meta isom ers 225 are once again only minor products. It is clear that the orientation of substituents in the cycloadducts d e p e n d s upon the position of the substituents in the diene com ponents. Steric and electronic factors of the substituents do not s e e m to effect orientation in the cycloadducts. Thus, both electron-donating and electron-attracting substituents on the d ien es lead to the s a m e orientation with a given dienophile. Regioselectivity in the cycloaddition reaction of 2 -substituted dienes is som ew hat depe n d en t on the chemical nature of the substituent in the dienophile, but the effect d o es not s e e m to be significant . 113 91 T a b l e 1. R e g i o s e l e c t i v i t y in C y c l o a d d i t i o n s of 1 - S u b s t i t u t e d D i e n e s R R 219 220 221 R (ortho) 222 (meta) E n try R EW Gi C o n d itio n s (° C , h) Yield (%) R a tio (o/m ) 1 Me Me Me Me Ph Ph Ph C 0 2H c o 2h MeO CH 3 C 0 2 NMe 2 Ph CHO CO 2 H CN CHO C 0 2H Ph C 0 2H Ph CHO C 0 2H CHO 200, 2 1 2 0 ,6 1 3 0 ,7 100, 24 80, 6 80, 6 150, 50 150, 6 1 5 0 ,6 1 0 0 ,6 80, 5 0, 5 40 75 70 56 73 5.7:1 2 3 4 5 6 7 8 9 10 11 12 6:1 Only ortho 7:1 Only ortho Only ortho 8 .1:1 8 .8 : 1 5.7:1 Only ortho Only ortho Only ortho 33 86 80 60 80 T a b le 2. R e g i o s e l e c t i v i t y in C y c l o a d d i t i o n s of 2 - S u b s t i t u t e d D i e n e s Rv ^ ew g, + 22 3 E n try E lec tro n ic — ~ 220 T X — + EWG, 224 (para) v ' EWG' u 225 (meta) R EWG-i T e m p e ra tu re (°C ) R atio (p /m ) OEt Me Ph Cl CN C 0 2Me C 0 2Me C 0 2Me C 0 2Me COMe 160 Only para 5.4:1 4.5:1 Only para Only para 86 n-Pr CH(Me ) 2 C(Me ) 3 C 0 2Me C 0 2Me C 0 2Me 2.4:1 3.0:1 3.5:1 81 65 47 Yield e f fe c t 1 2 3 4 5 S te ric if Rv ^ 20 150 160 95 50 54 73 60 effect 6 7 8 200 200 200 92 B. Lewis Acid Catalyzed D iels-A lder Reactions Lewis acids are commonly u s e d a s catalysts in Diels-Alder reactions. They frequently provide milder reaction conditions and improve both regioselectivity and stereoselectivity. The remarkable acceleration of Diels-Alder cycloadditions by Lewis acid catalysis w a s first reported by Y ates an d E ato n . 1 2 From extrapolation of a rate curve, it w a s estim ated that the reaction of a n th ra cen e (226) and maleic anhydride (200) require 4800 h to go to 95% completion at room tem perature in dichloromethane. But, upon the addition of o ne mole of aluminum trichloride, the reaction w a s co m pleted in 1.5 min (equation 78). It w as su b seq u e n tly found by Fray and Robinson that catalysts of the Friedel-Crafts type, for example tin(IV) chloride, boron trifluoride, iron(lll) chloride, and titanium(IV) chloride, w ere effective even with m onoactivated dienophiles such a s acrolein, methyl vinyl ketone, and acrylic acid . 13 o AICI3 (78) CH 2 CI2 , rt 226 200 227 (95%) A few years later, Lutz and Bailey o bserved that Lewis acids not only ac celerated the reaction, but also improved regiochemistry . 1 4 When isoprene (228) reacted with acrolein (2) in refluxing toluene, two cycloadducts, 229 and 230, were obtained in a 59:41 ratio, respectively. The reaction catalyzed by tin tetrachloride in b e n z e n e at room tem perature afforded 22 9 and 230 in a 96:4 ratio, respectively (equation 79). o „ Me u 228 toluene, 100 °C, no catalyst b enzen e, 25 °C, SnCI 4 » 5 Fl2 0 59:41 96:4 (79) 93 Inukai and Kojima reported the effect of Lewis acid catalysis on endo-exo stereoselectivity (Table 3 ) . 1 5 They found that Lewis acids ac celerate the reaction rate a n d also e n h a n c e the proportion of the endo adducts. Thus, treatment of methyl acrylate with cyclopentadiene (82) in b e n z e n e un der reflux afforded cycloadducts 232 and 233 in a 80:20 ratio, respectively (entry 1 in Table 3). The Diels-Alder reaction catalyzed by aluminum chloride in b en z e n e at 30 °C afforded cycloadducts 232 and 2 33 in a ratio of 95:5, respectively (entry 2 in Table 3). S a u e r an d Kredel reported similar results with cy clo pen tad ien e a n d methyl acrylate in d ich lo ro m eth an e . 1 6 In addition, they observ ed that the acceleration is considerable, and the reaction tem perature can be lowered by more than 100 °C with no d e c re a s e in reaction rate. T a b le 3. Effect of L e w is a c id o n t h e E n d o S e le c tiv ity of D ie ls -A ld e r R e a c t io n FL AICI3 .O o CO2 MG OMe 82 E n try CO2 MG 231 D ien o p h ile 232 S o lv e n t C ataly st (endo) 23 3 T im e (h) (exo) R atio endo C. 1 Methyl acetonitrile 2 acrylate benzene 3 Methyl benzene 4 crotonate benzene AICI3 AICI3 exo 7.5 80 20 1.0 94 6 24 54 46 1.0 93 7 R e v e r s a l of R e g i o c h e m i s t r y a n d S t e r e o c h e m i s t r y As ca n be s e e n from Tables 1 and 3, the Diels-Alder reaction is not always highly regioselective and stereoselective. This can som etim es be overcom e by employing Lewis acid cata lysts. However, it is very difficult to obtain m eta-su b stitu ted c y c lo a d d u cts a n d exocycloadducts b e c a u s e of the inherent ortho-para selectivities and endo stereoselectivity of the 94 Diels-Alder reaction. In o rd e r to resolve th e s e problem s, sev e ral a p p r o a c h e s h av e b e e n developed. Fundamentally, to get a meta substituted cyclohexene derivative, the regioselectivity inherent to the Diels-Alder reaction h as to be reversed. O ne way to accomplish this reversal of regiochemistry involves the u s e doubly activated dienes or dienophiles for the cycloadditions. It is well known that electron donating substituents at dienes control the regiochemistry of the cycloadducts. However, if th ere are two electron donating substituents on the diene, the regiochemical control of the reaction might be ex p e cted to d e p e n d on their relative electron donating abilities. Doubly activated dien es in which the relative activating abilities of the substituents are quite different, may produce single cycloadduct in which su bseq u e n t removal of on e activating group gives a m eta substituted cyclohexene. For exam ple, the cycloaddition reaction betw een diene 234 and dienophile 220 always yields 237 a s a minor product (S chem e XV). On the contrary, diene 2 3 5 containing two activating groups, would give cycloadduct 236 a s the major product if EDG 2 is the dominant substituent. If the EDG 2 is later easily removed, the meta-substituted cycloadduct 237 ca n be obtained. Schem e XV. M eta-S ub stituted EWG, C yc lo h e x e n e D erivative E D G 1>v^ ^ E W Synthesis G ) u 234 220 edg2 237 E DGp . r 235 220 236 As an example of this strategy, Trost and Cohen studied the regiochemical effect of two different heteroatom substituents in the diene. C ohen a n d cow orkers c h o s e diene 2 3 8 a s a starting point b e c a u s e Evans and coworkers had reported that 238 w a s a useful d ie n e . 1 7 When they treated 238 with methyl acrylate (239), cycloadducts 240 and 241 w ere obtained in a 1:1 ratio, respectively (equation 80). The regioselectivity w a s a s e x p e c te d . 1 8 Surprisingly, doubly activated 1 ,3-diene 242 reacted with methyl acrylate (239) to aftord the single regioisomeric cycloadduct 243 in 66% yield (equation 81). Thus, the sulfur substituent controlled the regio SPh SPh SPh (80) 238 239 240 SPh 1:1 (90%) 241 SPh ( 81 ) 242 2 4 3(66%) 239 chemistry of the cycloaddition. The desulfurization of the cycloadduct offers an approach to m eta-substituted cyclohexenes. Trosl and coworkers investigated the Diels-Alder reaction of 2,3-disubstituted diene 244 with unsym m etrical dienophiles 2 4 5 . 19 For example, the cycloaddition reaction of 2 4 4 with methacrolein yielded 1 ,2,4-trisubstituted adduct 246 and 1 ,2,5-trisubstituted adduct 2 4 7 in a 13:1 ratio, respectively (see entry 1 in Table 4). Once again, the sulfur substituent controls the regiochemistry of the cycloaddition and one can get the m eta-subsituted cyclohexene derivative by the desulfurization of the cycloadducts. O n e ca n also u s e the doubly activated dienophiles to re v e rs e the regiochemistry of cycloaddition reactions. O nce again, if there are two electron withdrawing substituents on the dienophile, the regiochemical control of the reaction might be e x p e c te d to d e p e n d on their relative electron attracting ability. Doubly activated dienophiles w hose relative activating ability of the substituents is quite different will give ortho-substituted or para-substituted cyclohexenes a s 96 Table 4. R eactio ns of 2,3-H etero ato m R 'O 1,3-D ienes R3 X* r ^ J O 244 E n try Substitu ted R1 245 R2 • ,Xl R3 246 R3 EWG EWG 247 Yield (%) R a tio 247 1 Ac Ar Me CHO 84 13 2 Ar Ar Me C 02M e 93 9 3 Ar Ar H COMe 86 10 4 Me Ar H C 0 2Me 91 10 5 Me Ph H CN 63 4 6 Me Ph H COMe 75 4 7 Me Ph H C 0 2Me 65 4 8 Me Ph Me CHO 72 8 248 major products. If the prevailing activating groups are easily removable or can be transformed to o th e r functional groups, the p ro c e s s ac co m p lishes the construction of a m eta substituted cyclohexene. For example, the cycloaddition reaction betw een 234 and 220 always gives 248 a s a minor product (S ch e m e XVI). On the contrary, dienophile 2 49 containing two activating groups, would give cycloadduct 25 0 a s a major product if EWG 2 is the controlling substituent. Removal of EWG 2 would then give the meta-substituted cycloadduct 248 a s a major product. As a specific example of this strategy, Danishefsky and coworkers described the DielsAlder reaction ot p-nitro-acrylate 252 with several electron-rich dienes.20 For example, treatment of dienophile 252 with diene 251 in b e n z e n e at room tem perature g av e only cycloadduct 254. T h e re w a s no regioisom eric prod uct co rre sp o n d in g to 25 3 ( S c h e m e XVII). T h u s, the regiochemical outcom e w as controlled by the nitro group. Treatment of 254 with a q u e o u s sulfuric acid followed by DBU at room tem perature afforded a 3-carbomethoxy-3-cyclohexenone 256 in 97 99% yield. This p ro c e ss accom plished the equivalent of a cycloaddition betw een a diene 251 and methyl propiolate with m eta regioselectivity. S ch em e XVI. M e ta-S u b stitu ted EDG' ^ ^ .EWG, V X* + S ynth esis EDG1N^ ■ X 220 . L X E D G ,^ ^ E W G 1 + J ew g2 234 EWG1 248 .E W G , ^ S - if- if 234 EDG, C yc lo h e x e n e ------------ X 249 — I ew g2 250 EWG2 = electron withdrawing group which is easily removable and also transformable to other functional group S ch em e XVII. OTMS 0 2N M e ta-S u b stitu ted y s. f \ — C y c lo h e x e n o n e C 0 2Me ™ SOv / n ^ N O . , — — CgHg, rt, 42 h - X^ ^ j" ' C 0 2Me ether, X 6 + T M S O| ^ —J 10% C0 2Me 254 H 2 SO 4 DBU, THF, rt c o *Me 25 . N 02 2 5 3 (not detected) 2 5 1 X Synthesis (99%) " c o 2Me 2 5 5 (72%) Kakushima and Scott applied the s a m e concept to an other bifunctional dienophile .2 1 They show ed that unsymmetrical dienophile 2 i 7 reacted with electron rich 1-substituted dienes 258 to produce regioisomer 259 a s the major product (se e Table 5). Thus, the formyl group of 257 controls regioselectivity better than the carbomethoxy group. The regiochemical relationship 98 betw e en the R group and carbom ethoxy group in cycloadducts 259 and 261 is meta. Since the formyl group is easily converted into a hydrogen, a methyl group, or other substituents, the net result is the reversal ot the regiochemistry, that would be obtained using a simple acrylate. They rationalized the observ ed regioselectivity in term s of FMO theory. T a b le 5. A d d itio n of 1 - S u b s t i t u t e d D i e n e s t o 258 R , C 0 2M g R R r ,vC02Me 6 OHC "CHO 257 258 C o n d itio n 259 (°C , h) 260 261 262 Y ie ld R atio 259 260 261 262 22 Me CH2Cl 2 , 4 0 , 3 5 90 54 15 9 OMe CH 2 CI2 , 2 5 , 4 8 90 80 3 1 7(2 6 1 + 2 6 2 ) OSiMe 3 CH 2 CI2 , 4 0 , 4 8 90 83 17 ( 2 6 0 + 2 6 1 + 2 6 2 ) C ava and coworkers reported the dienophilic behavior of thionomaleiimide in reactions with terminally o x y g e n a te d unsym m etrical d i e n e s .22 Reaction of thionoimide 2 6 4 with 1m ethoxy-1,3-cyclohexadiene 2 6 3 g av e a mixture of e n do adducts 2 6 5 and 2 6 6 in the ratio of 2:1 (equation 82). However, dieneophile 2 6 4 re a c te d with 1-benzoyloxy-5-benzoyloxy-1,3p en tad ien e (267) to give a single product 268 in 58% yield (equation 83). OMe s N-Me + O e th e r (82) MeO Me 2 63 264 265 (42%) 266 (21%) 99 OCOPh OCOPh CH 2 CI2, 60 °C N-Me N -M e O ‘ OCOPh 267 (83) CH2OCOPh 268 (58%) 264 Lewis acid catalysts have also b e e n u s e d to obtain m eta-su bstitu ted cyclo hexenes derivatives from doubly activated dien es and dienophiles. For example, Valenta and coworkers show ed that Lewis acids could reverse the regiochemistry of Diels-Alder cycloadditions of dienes an d doubly activated d ien oph iles . 2 3 Thus, treatment of diene 269 a n d 2,6-xyloquinone 2 7 0 with 1.3 mol of boron trifluoride etherate in ether at room tem perature g av e the cycloadduct 271 a s a major product (equation 84). The minor product 272 w a s identical to the product of the thermal Diels-Alder reaction in boiling benzene. Later, they reported a simple method to reverse the regiochemistry using a formyl group a s a directing Lewis b a se (Table 6).24 The catalyst guided the cycloaddition such that the formyl group dom inated regioselectivity. They prop osed that com plexation of the Lewis acid with the formyl group m ade it the most electron withdrawing substituent. 270 1.3 mol.eq. BF3 »OEt 2 MoO' 2 69 MeO 271 (69%) 272 (14%) Proteau and Hopkins reported that the ZnCl 2 -catalyzed Diels-Alder reaction of methyl vinyl k eton e (275) with doubly activated diene 27 6 gav e a mixture of cycloadducts 277 a n d 278 (equation 85).25 The ratio of 277:278 w as determined, after removing thiophenyl group by oxidation followed by desulfonation, to be 95:5, respectively. Thus, they dem onstrated that the 100 phenylthio group controlled the regiochemistry and m eta substituted cy clohexene derivatives could b e obtained by temporary introduction of a phenylthio group a s an activating group. O ne c a n apply the s a m e concept to cyclic diene and doubly activated dienophiles to get the exo-cycloadducts a s the major products in Diels-Alder reactions (Schem e XVIII). For example, very recently Yamamoto and coworkers reported high regiochemical and stereochemical control in Diels-Alder reactions of unsymmetrical fumarates 283 in the p re sence of Lewis acids .2 6 Thus, T a b le 6 . D iels-A ld e r R e a c t i o n of Methyl p - F o r m y l a c r y l a t e w ith L e w is a c id COoMe Me C 0 2Mg CO., Me OHC 201 253 E n try 274 273 M olar ra tio C ataly st T (°C ) T im e Y ie ld 35 h 3 adducts (5:3:1) 2 5 3:2 0 1 :c a t a ly s t 1 1:2.5:0 - 40 2 1:1.01:1.01 AICI3 0 3 1:1.03:0.85 BF 3 Et2 0 1 40 h 10 min 273 (44%) + 274 (30%) 273 (55% ) + 274 (5%) + 2 epi-273 (5%) 4 1:1.15:1 SnCLj 0 5 min 273 (75% ) 5 1:1.1:0.1 SnCl 4 0 30 min 2 7 3 (75% ) COMe Me Me (85) SPh 275 SPh Me' + 276 SPh 277 Me (95:5) 278 treatment of fert-butyl methyl fum arate 283 with 1.1 equivalent of methyl aluminum bis(2,6-di-tertbutyl-4-methylphenoxide) (MAD) in dichloromethane at -78 followed by the addition of a diene such a s cyclopentadiene (82) afforded cycloadducts 284 and 285 in a 1:99 ratio, respectively 101 (equation 86 ). The thermal reaction in b e n z e n e under retlux yielded 2 8 4 and 2 8 5 in a 48:52 ratio, respectively. The exceptionally bulky Lewis acid, MAD, selectively com plexed with the least hindered of the two carbonyl groups. Selective removal of the e n do carboxylate group would have com pleted a s e q u e n c e of the type outlined in Sch em e XVIII. Sch em e XVIII. Exo Cycloadduct Synthesis with Bifunctional Dienophile ew g, • J K £ _ ew g, ? R 82 279 o* ew g2 s 282 —- jv™' ew g2 82 280 CH2 CI2, -78 UC Lewis acid 283 3. 281 (86) c o 2tQj 28 4 ( 1 :9 9 ) C 0 2Me 285 Results and Discussion The research described in this section, a study of Diels-Alder reactions of a,p-unsaturated thioesters an d selenoesters, b egan in re sp on se to a problem that arose during the initial s ta g e s of a natural product synthesis. A cycloaddition reaction b etw een diene 2 8 6 and a ,p -u n s a tu ra te d e s te r 288 w as to be the initial critical step in a synthesis of the ste m o n a alkaloid stenine. In the event, Cheng-Yi C hen found that the desired reaction failed under thermal conditions and the dienophile 288 w a s incom patable with Lewis acid catalysts. C hen re a s o n e d that a thioester should be a better electron withdrawing group than an ester, and thus studied the reaction of 286 with a.p -u n s a tu ra te d thioester 2 8 7 .27 In fact, this reaction took place in 43% yield without acid catalysis. C hen showed that thioester 129 also gave cycloadducts with 286. T h e s e results were encouraging and it w a s decided to further explore this initial observation with the following goals: (1) to explore the s c o p e a n d the limitation of the p ro c e s s by varying the diene, the dienophile, a n d examining Lewis acid catalysts (2) to extend the p ro c e s s to cx,p-unsaturated selen o e ste rs and (3) to develop synthons for reverse polarity dienophiles. MeO(CH?)p MeO(CH2)2 nr-i— — c0 2 E t ^ 28 8 C O S P I ^ ^ (CH2)2OMe — ii?— ^ « y r ^ 150 C, 24 h (CH2)3CN 286 43% + 11 (CH2)2OMe ^ ^ '''c o s P h ^^"co sP h (CH2)3CN (CH2)3c n 289 (1.1:1) <87> 290 It is well docum ented that thioesters show higher reactivity toward nucleophiles than the corresponding oxygen analogs.28 However, ra,p-unsaturated thioesters and s elen o e ste rs have not b e e n widely u sed as electrophilic olefins. Even though there are m any known dienophiles, we w ere surprised to find only o n e report about Diels-Alder reactions of a , p - u n s a t u r a t e d thioesters. In this example, oxidation of furan 291 with pyridinium chlorochrom ate at room t e m p e ra tu re g av e the intram olecular Diels-Alder add u c t 293 in 4 0 % yield (equation 88), presum ably via thioester interm ediate 2 9 2 .29 The intermolecular Diels-Alder reaction of a,p u n satu ra te d thioester Z-295 with cyclopentadiene (82) w a s also reported. Thus, oxidation of furan 294 with two equivalents of pyridinium chlorochromate at room tem perature for 2 h gave thioester Z-295 which isomerize to E-295 if longer reaction time w as u sed . Treatment of Z-295 with cyclopentadiene (82) afforded cycloadducts 296 and 297 in a ratio of 6:1, respectively, in 85% yield (Scheme XIX). 103 S c h e m e XIX. D ie ls -A ld e r R e a c t io n of T h i o e s t e r 2 9 0 w ith C y c l o p e n t a d i e n e J To k MeS PCC ppp Me Me0C 294 . COSMe M e O C '^ 5 ^ COSMe Z -295 82, E -295 o COSMe A ^ c° s m« + COMe 296 85% (6:1) ^ __COM e 2 97 Given this background, we decided to start by investigating the dienophilicity of oc,p-unsaturated thioesters and selen o e ste rs systematically. In initial studies, w e investigated the relative reactivity of a ,p -u n s a tu ra te d esters, thioesters, and se le n o e s te rs with cyclopentadiene (82) (Table 7). W hen 1 equivalent of cyclopentadiene (82) w a s reacted with 10 equivalents of thioester 129 and 10 equivalents of methyl crotonate (231) at 80 °C in a bom b tube, the reaction gave cycloadducts 300 an d 301 in a ratio of 10:1, respectively, b a se d on 1H NMR integration (entry 1 in Table 7). S elen o este r 133 gave identical results in a competition reaction with ester 231 (entry 2 in Table 7). The reactivity difference of fumaric acid derivatives w as also investigated with diene 82. For exam ple, treatm ent of 1 equivalent of cyclopentadiene (82) with 10 equivalents of dimethyl fum arate (204) and 10 equivalents of thioester 29 8 in dichlorom ethane at room tem perature g av e cycloadducts 303 and 195 in a 30:1 ratio, respectively (entry 3 in Table 7). When the sa m e competition reaction w a s performed for s elen o e ste r 299, only cycloadducts 304 were obtained a n d cycloadduct 195 w as not d etec ted in the 1H NMR spectrum of crude product (entry 4 in Table 7). Although o ,p -u nsatu rated thioesters and sele n o e s te rs were more reactive dienophiles than their oxygen analogs, the poor stereoselectivity and regioselectivity had to b e overcom e if 104 th e s e reactions w ere to be useful in the organic synthesis. In an attempt to improve selectivity, Lewis acid catalysis w as examined alongside thermal reactions without catalysis. Thus, treatment of thioester 129 with isoprene (228) at 150 °C in a sea le d tube g ave a 3:2 ratio of cycloadducts 305 and 306, respectively, in 84% overall yield (entry 1 in Table 8). It w as eventually found that t r e a tm e n t of th io e s te r 1 2 9 with ethylalum inium dichloride at -23 ° C in a n h y d r o u s dichlorom ethane followed by the addition of iso prene (228) at room tem peratu re afforded a single product 3 0 5 in 8 0% yield (entry 2 in Table 8). A proof of regiochem istry w a s not undertaken b e c a u s e of the well known regioselectivity of Lewis acid catalyzed Diels-Alder T a b le 7. C o m p e t it i o n R e a c t i o n s of D ie n e 82 w ith V a r i o u s D i e n o p h i l e s R' R Nn^ ' V' COX + R CO?Me 82 COX COzMe E n try R R1 X P ro d u ct C o n d itio n R atio 1 Me Me SPh 3 0 0 and 301 C6H6, A 10:1 2 Me Me SePh 3 0 2 and 30 1 C6H6, A 10:1 3 C O SPH C 02M e SPh 3 0 3 and 1 9 5 CH2Cl2 , rt 30:1 4 CO SePh C 02M e SePh 304 a n d 195 CH 2 CI2 , rt 100:0 PhSOC COSPh Me 298 PhSeOC COSePh 299 COSPh 300 COzMe 301 COSePh COSePh 302 COSPh COSePh 303 304 reactions. The thermal Diels-Alder reaction of unsaturated s elen o e ste r 133 with isoprene (228) in xylene under reflux gave cycloadducts 307 and 308 in a 60:40 ratio, respectively, in 71% 105 yield (entry 3 in Table 8). The u se of ethylaluminium dichloride a s a Lewis acid catalyst again im proved the regioselectivity of th e Diels-Alder reaction dramatically. Thus, tre a tm e n t of s e le n o e s te r 133 with ethylaluminium dichloride at -23 °C, followed by adding isoprene (228) at room tem p eratu re afforded cycloadduct 307 in 80% yield without detection of cycloadduct 308 in the 1H NMR spectrum of the crude product (entry 4 in Table 8). T a b l e 8. D ie ls -A ld e r R e a c t i o n s of D ie n e 228 w ith V a r i o u s D i e n o p h i l e s x Me Me 228 E n try D ie n o p h ile para X Y meta Y ield P ro d u ct R atio (p /m ) (% ) 1 129 Me COSPh M eth o d 84 3 0 5 and 3 0 6 60 :4 0 B 80 305 100:0 A 71 3 0 7 and 3 0 8 60 :4 0 B 80 307 100:0 A 90 3 0 9 an d 3 1 0 55 :4 5 B 6 84 309 a n d 310 80 :2 0 A 7 72 309 100:0 A 81 3 1 4 and 3 1 5 55 :4 5 B 77 314 100:0 A 2 133 3 Me CO SePh 4 5 1 38 1 39 8 CC>2Me CC>2Me COSPh C O SePh 9 A = Lewis acid catalyzed reactions; B = Thermal reactions (see text for details). .COSPh f i ,c h 3 1 1 H3C/ k ^ C H 3 305 j c~ c H3C ' 309 1 1 H ^ ^ ^ C O S P h H3C/ ^ 1 1 V CH3 307 306 COSPh C 0 2Me COSPh C 0 2Me 31 0 Xy vX •>4CH3 ' J COSePh 308 COSePh C 0 2Me H,C' 314 COSePh C 0 2Me J U u C' 315 COSePh 106 The reaction of d iene 2 2 8 with fum arate derivative 138 w a s ex am ined next. When thioester 138 w a s treated with isoprene (228) at 100 °C in a bom b tube, it afforded a 90% yield of cy clo a d d u cts 3 0 9 and 3 1 0 in a 55:45 ratio, respectively (entry 5 in Table 8). However, treatm ent of thioester 138 with ethylaluminium dichloride at -23 °C followed by the addition of dien e 228 g a v e a 80:20 ratio of cycloaddu cts 3 0 9 and 3 1 0 , respectively, in 68% yield. Lowering th e te m p e ra tu re to -78 ° C before adding th e diene 2 2 8 did not improve the stereoselectivity much. It w as eventually found that titanium tetrachloride w a s the best Lewis acid for this type of dienophile. For example, treatment of thioester 138 with titanium tetrachloride at 23 ° C in dichlorom ethane followed by adding diene 228 at -78 °C g av e a cycloadduct 309 in 72% yield without any cycloadduct 310 detectable in the 1H NMR spectrum of the crude product (entry 6 in Table 8). The regiochem istry of cycloadduct 309 w a s e s ta b lis h e d a s follows. Treatment of cycloadduct 309 with mercury (II) chloride and calcium carbo nate in wet acetonitrile gav e olefinic acid 311 in 53% yield.29’30 When 311 w a s treated with iodine in tetrahydroturan, it gave y-lactone 312 in 42% yield (equation 89). The regiochemistry of cycloadduct 309 w a s also proven by an NMR experiment (INADEQUATE) which established carbon-carbon connectivities (se e Appendix). COSPh ,.C 0 2H T H F i N a H C O g C0 2Me w etC H gC N .A 53% 309 Me 42 % 311 312 To dem onstrate the utility of the reaction shown above, cycloadduct 309 w as treated with sodium borohydride in ethanol at room tem peratu re to afford hydroxyester 3 13 in 74% yield (equation 90).31 This illustrated the u s e of fum arate derivative 1 3 8 a s a re v erse polarity yhydroxycrotonate equivalent. 107 COSPh (90) EtOH Me Me 74% 309 313 The therm al Diels-Alder reaction of u n satu ra te d s e le n o e s te r 139 with diene 2 2 8 in xylene g ave cycloadducts 314 a n d 315 in a 55:45 ratio, respectively, in 81% yield (entry 7 in T able 8). T he u s e of titanium tetrachloride a s a Lewis acid catalyst ag a in improved the regioselectivity of the Diels-Alder reaction dramatically. Thus, treatment of s e le n o e s te r 139 with titanium tetrachloride at -23 °C followed by adding isoprene (228) at -78 °C afforded cycloadduct 3 1 4 in 77% yield without detection of cycloadduct 315 in the 1H NMR spectru m of the crude product (entry 8 in Table 8). As described in the introduction of this chapter, it is difficult to obtain 1,3-disubstituted cyclohexene derivatives via Diels-Alder reactions. Since tin hydride promoted decarboxylation of s e le n o e s te rs 32 is a well known method, it w as hoped that a m eta substituted cyclohexene could b e obtained from adduct 314. Thus, treatment of cycloadduct 31 4 with tri-n-butyltin hydride in the p re s e n c e of catalytic amount of AIBN afforded 315 in 56% yield along with aldehyde 316 in 16% yield (equation 91). This transformation estab lish es that 13 9 ca n serve a s a reverse regiochemistry equivalent of methyl acrylate (see equation 92). j j 'V .C O S eP h e BifrSnH, AIBN r xylene, A C0 2Me r j^ | T , * ^ 228 s s s , ''CH0 I T V M e ^ ^ '^ X O g M e M e^^^^C O aM e 315 (56%) 316 (16%) 31 4 MGs ^ / + (91) Lewis acid [i — C 0 2Me 239 x x M e ^ ^ '^ C O j M e 315 We next exam ined oxygenated b utadien e 2 5 1 .33 The Diels-Alder reaction b etw een diene 251 and dienophile 129 g av e a 65:35 mixture of cycloadducts in a 78% yield (entry 1 in Table 9). Lewis acid catalysis not only improved the regioselectivity but also hydrolyzed the initially 108 formed silyl enol ether cycloadducts u nd er the reaction conditions. For example, treatm ent of un satu ra te d thioester 129 with titanium tetrachloride at -23 °C followed by adding neat diene 251 g av e k etoester 320 a s the only isolable product in 51% yield (entry 2 in Table 9). Thermal reaction of s elen o e ste r 133 with diene 251 g ave a 74% yield of a 65:35 mixture of cycloadducts (entry 3 in Table 9). Titanium tetrachloride catalyzed reaction of sele n o e s te r 133 with diene 251 afforded a single regioisomeric adduct 323 in 47% yield (entry 4 in Table 9). O nce again, the regiochemistry of cycloadducts 3 2 0 and 32 3 were not rigorously proven, but s e e m reason able b a s e d on the behavior of other crotonates. T a b l e 9. D ie ls -A ld e r R e a c t i o n s of D ie n e 251 w ith V a r i o u s D i e n o p h i l e s v OTMS v + TMSO X 251 E n try D ie n o p h ile ™ so para X Y meta Y ield P ro d u cts 1 29 Me COSPh 2 133 3 Me CO SePh 4 5 1 38 C02M e COSPh 6 7 1 39 C 02M e CO SePh 8 R atio M eth (p /m /k ) (% ) 1 k e to n e 78 3 1 8 and 3 1 9 6 5 :3 5 :0 B 51 320 0:0:1 0 0 A 74 321 and 3 2 2 6 5 :3 5 :0 B 47 323 0 :0 :1 0 0 A 66 3 2 4 and 3 2 5 65 :3 5 :0 B 59 326 0:0 :1 0 0 A 72 3 2 7 and 3 2 8 6 5 :3 5 :0 B 45 329 0 :0 :1 0 0 A A = Lewis acid catalyzed reactions; B = Thermal reactions (see text for details). ^ X ,..C O S P h XX T M S O ^ V ' ^ ^ * Me 318 rj^V M ° Me XX T M S O ^ \^ ^ C O S P h 319 r^Y'COSePh ^ \ ^ IX 320 324 XX ^ Me 321 C 0 2Me 323 COSePh T M S C r S''/ ^"\.,'COSPh T M S O ^ S s^ " ^ C O S o P h 322 COSPh ^ ^ 0.C02M e T M S O ^ S' ^ X ^ C O S P h 325 109 r- COoMe TMSO J 6 326 ,2 Me 1 39 C O SePh 87 3 3 7 and 3 3 8 87 8 60 :40 B 9 6:4 A 53 :4 7 B 95:5 A 50 :5 0 B 8 5 :1 5 A 53 :4 7 B 85 :1 5 A A = Lewis acid catalyzed reactions; B = Thermal reactions (see text for details). H1. syn '7anti Me , COSPh COSPh COSePh Me Me COSePh 330 331 332 333 111 vsyn '7anli COSPh COSePh C OSPh COSePh 335 J V 336 Me 337 1 ^ 7 ' HgCI2, C a C 0 3, CH3C N ,H 20 COSePh 338 ^ I I u 332 (93) sn O 334 The thermal reaction of thioester 138 with diene 82 gave a 1 :1 ratio of cycloadducts 335 an d 336, respectively, in 76% overall yield (entry 5 in Table 10). The Lewis acid catalyzed DielsAlder reaction of thioester 138 with diene 82 at -78 °C afforded cycloadducts 33 5 and 336 in a ratio of 85:15, respectively, a s an inseparable mixture in 76% overall yield (entry 6 in Table 10). Thermal reaction of se le n o e s te r 139 with diene 82 gave a 53:47 mixture of cycloadducts 337 and 338, respectively, in 81% overall yield (entry 7 in Table 10). Lewis-acid catalyzed Diels-Alder reaction of se le n o e s te r 139 with diene 82 at -78 °C afforded cycloadducts 3 3 7 and 3 3 8 in a ratio of 85:15, respectively (entry 8 in Table 10). The major isom er 3 3 7 w a s isolated a s a crystalline solid. We failed to improve the stereoselectivity by lowering the reaction tem perature or employing other Lewis acids such a s ethylaluminum dichloride, diethylaluminium chloride, and boro n trifluoride e th e ra te . Even th ou gh the regioselectivity of bifunctional dien oph iles is excellent, it is clear at this moment that stereoselectivity is not so good. The assignm ent of the stereochem istry to 337 w as b a s e d on decoupling experim ents and the a p p e a ra n c e of two doublets of doublets at 5 2.79 and 8 6 3.72. The doublet of doublets at 3.72 w as assigned to H(5) which is adjacent to the selen oester group. This proton is located on the beta face b e c a u s e it w a s not W-coupled with H 7 Syn. Instead, H(4) w as coupled with H 7 Syn. To dem o nstrate the p re s e n c e of W-coupling, a series of decoupling experiments were performed for cyclo add uct 3 3 7 . W hen H(5) w a s d ecoupled, the doublet of d oublets at H(4) collapsed to doublet with coupling constant of 1.7 Hz. 112 Conclusive evidence for en d o stereochem istry of the major isom ers 3 3 5 and 3 3 7 w as o b tain ed by the oxym ercuration reaction. For exam ple, tre a tm e n t of c y c lo a d d u ct 3 3 7 , contam inated by the minor isomer 338, with mercury (II) chloride and calcium carbon ate in wet acetonitrile afforded y-lactone 341 in 51% yield and hydrolyzed exo isom er 340 in 11% yield (eq uation 94). We p r e s u m e d th at th e initial s te p of th e o x ym ercu ration reaction w a s chem oselective hydrolysis of se le n o e s te r group to give half acid half e s te rs 339 an d 340. Only endo olefinic carboxylic acid 335 underwent the cyclization by the mercury (II) chloride. Since hydrolyzed exo olefinic acid 3 4 0 could not u nd ergo cyclization to the lactone, we could determine that the minor isomer 340 w a s the exo-adduct. 3 3 7 COSePh HgCI2, C a C 0 3, CH3CN, h 2o 3 39 + c o 2H O Cs 341 (51%) + '° 04) COSePh 338 C 0 2Me ( 11 %) We next ex am in ed piperylene a s a dien e with th io e ste rs an d s e le n o e s te rs . Thus, treatment of thioester 129 with piperylene 199 in boiling xylene in a bom b tube gave a mixture of cycloadducts in 83% overall yield (equation 95). When the reaction w a s run in the p re s e n c e of ethylaluminium dichloride at -23 °C, only 3 4 2 and 3 4 3 w e re o btained in a ratio of 9:1, respectively, in 71% overall yield (equation 96). The regiochemistry and stereochem istry of the major product 342 w as identified by the a p p e a ra n c e of H(4) a s a doublet of doublets at 5 2.80. This peak w a s assig ned to the alpha proton of thioester group b a s e d on the chemical shift and coupling pattern. The coupling c o n stan ts of doublet of doublets at 5 2.80 are 10.3 and 5.5 Hz, which indicate the endo stereochemistry, that is, the large coupling constant (10.3 Hz) indicates the trans diaxial relationship betw een H(4) and adjacent H(5) and small coupling constant (5.5 Hz) 113 indicates a diequatorial relationship betw een H(4) and adjacent H(3). The coupling co n stan ts betw een H(4) at 5 2.14 of minor isom er 3 4 3 are 10.3 and 10.3 Hz which indicate two diaxial relationships b e tw e e n H(4) a n d vicinal pro ton s H(3) a n d H(5). T h e o th e r two p o ssib le re g ioiso m ers, 3 4 4 and 3 4 5 , would b e e x p e cted to have different coupling p a ttern s for the proton alpha to the thioester group. Me ^^cosp, > u . . 83% . Me X d Me ^ Me ♦ L X.* V X <95) 'CC OOS SP hP >h fV ^ C O SS PPhh^>Yf ^ ^ " Me Me Me 129 342 343 ^ . EtAICfe, -23 °C ---------------------- , IMe COSPh COSPh 344 345 3 , Me COSPh Me ^ (96) Me 199 71% 129 COSPh COSPh 34 2 (9:1) T reatm ent of s e le n o e s te r 133 with diene 199 in xylene u n d er reflux in a s e a le d tube also gav e a mixture of cycloadducts in 72% overall yield (equation 97). O nce again, the Lewis acid catalyzed reaction gav e only two cycloadducts 346 and 347 in a ratio of 93:7 , respectively, in 56% overall yield (equation 98). The assignm ent of regiochemistry an d stereochem istry of the major product 346 w a s b a s e d on the sa m e argument a s before. ^ ^ M e ^ \„ M e M e-~V'COS°Ph 1" • 72% 133 ^v„M o Elfl'C ^ ' 2 3 ° C. M e ^ 5^ 1 33 Me M^COScpJV•'M t Me Me 346 ^C O SePP Mo COSePh 347 L A * COSePh *| g Q Me 5 6 o/o 346 348 349 » » : COSePh Me (93:7) M o (97’ COSePh 347 114 The thermal reaction of thioester 138 with diene 199 g ave four isom ers in a ratio of 30:30:20:20 in 89% yield (equation 99). The Lewis acid catalyzed reaction of thioester 138 with diene 199 in dichlorom ethane at -23 °C g av e an 8:1 mixture of cycloadducts 3 5 0 and 351 in 51% yield (equation 100). The regiochemistry and stereochem istry of th e major product (350) w a s determ ined by a s e q u e n c e of chemical reactions, decoupling experim ents, an d 2D NMR experiments such a s C-H correlation and COLOC experiments a s follows. Me C , A COSPh + C ii a Mc o , c ' ^ COSPh — LJLi? 51% COzMe 138 EtA.Cb,- 2 3 ° C ------------------ J 351 J4 6V 1 9 9 136 51% + C O SPhJ C 0 2Me 350 COSPh Me r ^ V + Me C 0 2M e ^ ^ C 0 2Me COSPh 352 f ^ L A 4 COSPh COzMe 350 Me ^ COSPh 353 “ Me (100) Y ^C O SPh C 0 2Me (8:1) 351 Hydrolysis of thioester 350 with mercury (II) chloride gave olefinic acid 354 in 67% yield (equation 101). Treatm ent of the acid with iodine an d potassium iodide afforded y-iodolactone 355 in 8 3 % yield. The regiochemistry w as also determ ined by the long rang e C-H correlation experiments. For example, a doublet of doublets at 5 3.37, assigned to H(4) in 350, w as coupled with carbonyl carbon of the thioester and a signal at 5 2.95, assigned to H(5), w a s coupled to the carbonyl carbon of carbom ethoxy group. The stereochem istry of the major isom er 3 5 0 w as determ ined by the coupling constants in the 1H NMR spectra. That is, the coupling constants of the doublet of doublets at 3.37 ppm (H4)are large and small (11.4 and 5.7 Hz). The coupling co n stan ts of the doublet of doublets at 5 2.71 (H4)of the minor isom er 351 are large and large (11.1 and 10.1). So, we a s sig n ed the major product a s endo isomer and the minor one a s exo isomer. Other convincing evidence for the endo stereochem istry of the adduct 350 co m es from the coupling pattern of the iodolactone 355. For example, there is no coupling betw een H(1) and 115 H(8) b e c a u s e the dihedral angle betw een them is 90 d egree, an indication ot cis relationship betw een lactone ring and the methyl group. Me HgCI2 CO,Me H - Mo ki , i 2 wet CH3CN ► I (101) Me 'COoH 'C O SPh C 0 2Me COgMe 350 355 (83%) 3 5 4(67%) Finally, the thermal reaction of selen o e ste r 139 with diene 199 again gave four isomeric ad d u c ts in 53% yield (equation 102). However, treatment of s elen o e ste r 139 with ethylaluminium dichloride at -23 °C followed by adding diene 199 g av e cycloadducts 356 and 357 in a ratio of 95:5, respectively, in 53% yield (equation 103). The endo stereochem istry of major product 356 w a s b a s e d on the ap p e a ra n c e of H(4) a s a doublet of doublets at 8 3.44 with coupling constants of 11.3 and 5.6 Hz, an indication of the trans diaxial relationship b etw een H(4) an d H(5) and an axial-equatorial relationship between H(4) and H(3). M eO gC ''^5* ^ ^ Me ls S ^ ,' ' C O S e h P | SSv ^ ^ 1* C O S e P h ^ Y ^ 1'' c O - . M>r e V ' ^ COgMe COSePhY^OgM ‘ 11 9 g 9g 1 39 COgMe 53% CO,Me 356 COSePh 357 358 COSePh 359 3 „ Me ^ MeOgC COSoPh \ EtAICb,-23 C ’5!555/ ^ 5s^ Me 270 118 + 6 lc 'C O S e P h CO2 MG 3 COSePh COgMo 53% In conclusion, it h a s b e e n shown that oc,p-unsaturated th io e s te rs and s e l e n o e s te r s undergo Diels-Alder cycloadditions with a variety of 1,3-dienes. When placed in competition with e s te rs , thioesters and s e le n o e s te rs will dom inate regiochemistry and stereochem istry when cycloadditions are conducted with Lewis acid catalysis. In a few instances, it h a s dem o nstrated that th e chemistry of thioesters a n d s e le n o e s te rs allows o ne to establish s o m e interesting 116 equivalencies. The potential of this asp e ct of thioester an d sele n o e s te r cycloaddition chemistry, however, w a s not fully developed. 117 Experimental Ail melting points w ere taken using a T hom as-H oover capillary melting point app aratus a nd are uncorrected a s are all boiling points. 1H NMR spectra are reported a s follows: chemical shifts [multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), coupling con stan ts in hertz, integration, interpretation], 13C NMR data were obtained with Bruker WP-80, Bruker AM-250 or Bruker AM-500 spectrom eters. Infrared spectra were taken with a Perkin-Elmer 457 instrument. M ass spectra w ere obtained on Kratos MS-30 or Kratos VG70-250S instruments at an ionization energy of 70 ev. Com pounds for which an exact m a s s is reported exhibited no significant peaks at m le g re ater than that of the parent. Combustion analysis were performed by Micro-Analysis, Inc., Wilmington, DE. Solvents and re ag en ts w ere dried and purified prior to u s e w hen d e e m e d n ec essary: tetrah y d ro fu ra n , diethylether, b e n z e n e , a n d to lu en e w e re distilled from so d iu m metal; dichlorom ethane and xylene w ere distilled from calcium hydride. R eactions requiring an inert atm osphere w ere run under argon. Analytical thin-layer chromatography w as conducted using EM L aboratories 0.25 mm thick p r e c o a te d silica gel 60F-254 plates. Medium p re s su r e liquid ch rom ato grap hy (MPLC) w a s perform ed using EM Laboratories Lobar p re p a c k e d silica gel columns. All Grignard reagents were titrated prior to u s e with s-butanol using 1,10-phenanthroline a s the indicator. COSPh PhSOC 298 118 S , S '- D i p h e n y l 1 ,4 -D ith io fu m a ra te ( 2 9 8 ) . To a solution of 4.4 g (40 mmol) of thiophenol in 100 mL of ether at -4 ° C w as a d d e d dropwise a solution of 2.06 g (20 mmol) of fumaroyl chloride in 20 mL of eth er a n d a solution of 3.2 g of pyridine in 10 mL of eth er simultaneously. The mixture w a s stirred for 30 min and poured into cold 50 mL of 1 N aq u e o u s hydrochloric acid. The organic p h a s e w as w a sh e d with 5% a q u e o u s sodium bicarbonate and brine. The com bined a q u e o u s layers were extracted with three 100-mL portions of ether. The co m b in e d o rg a n ic s w e re dried (C aC l 2 ) a n d c o n c e n tra te d in vacuo . The re s id u e w a s chrom atographed over 150 g of silica gel (eluted with ethyl ac etate-hexane, 1:12) to give 1.85 g (31%) of thioester 2 9 8 a s a pale red solid: mp 135-136 ®C; IR (CCI 4 ) 1674 c m ' 1 ; 1H NMR (CDCI 3 , 300 MHz) 6 7.09 (s. 2H, =CH), 7.48 (s, 10H, ArH); 13C NMR (CDCI 3 , 75.5 MHz) 5 126.33 (s), 129.29 (d), 129.82 (d), 133.86 (d), 134.11 (d), 187.00 (s); m a s s spectrum , m/e (relative intensity) 300 (M+ , 1), 137 (23), 163 (100), 109 (53), 77 (7); exact m a s s calcd. for C 1 6 H 1 2 O 2 S 2 m /e 300.0268, found, m /e 300.0269. PhSoOC ^ COSoPh ^J-^ 299 S e . S e '- D i p h e n y l 1 ,4 -D is e le n o fu m a ra te ( 2 9 9 ) . To a solution of 3.14 g (20.0 mmol) of selenophenol in 40 mL of diethyl ether at -4 °C w as added dropwise a solution of 1.03 g (10.0 mmol) of fumaroyl chloride in 10 mL of diethyl ether and a soiution of 1.6 g of pyridine in 10 mL of ether simultaneously. The mixture w as stirred for 30 min and poured into cold 30 mL of 1 N aq u e o u s hydrochloric acid. The organic p h a s e w a s w a shed with 5% aq u e o u s sodium bicarbonate an d brine. The combined aq u e o u s layers w ere extracted with two 100-mL portions of ether. The com bined organic p h a s e s were dried (Na 2 SC>4 ) an d concen trated in vacuo. The residue w as ch rom atographed over 50 g of silica gel (eluted with ethyl acetate-h ex an e, 1:12) to give 0.61 g (15%) of thioester 299 a s a red solid: mp 121-122 °C; IR (CCI4 ) 1689 c m '1 ; 1H NMR (CDCI3.300 MHz) 8 7.09 (s, =CH), 7.42-7.47 (m, 6 H, ArH), 7.53-7.59 (m, 4H, ArH); 13C NMR (CDCI 3 , 75.5 119 MHz) 8 125.40 (s), 129.49 (d) 129.61 (d), 134.29 (d), 135.49 (d), 190.83 (s); m a s s spectrum, m /e (relative intensity) 396 (M+ , 2), 314 (22), 211 (85), 157 (100), 77 (71); exact m a s s calcd. for C l 6 H 12O280S e2 m /e 393.9176, found, m /e 393.9176. COSPh COSPh 303 S -P h en y I (± )-(1 R * ,2 S \3 S \4 S * )-2 ,3 -D ith io -5 -n o rb o rn e n e -2 ,3 - d i c a r b o x y l a t e (303). A mixture of 0.3 g (1.0 mmol) of thioester 298 an d 0.33 g (5.0 mmol) of cyclopentadiene in 10 mL of b e n z e n e w as heated under reflux for 1 h and allowed to cool to room tem perature. The solution w a s concentrated in vacuo to give 379 mg of pale yellow solid which w a s recrystallized from hexane to yield 300 mg (82%) of cycloadduct 303 a s a white solid: mp 86.5-87.5 °C; IR (CHCI 3 ) 1697 cm ’1 ; 1H NMR (CDCI 3 , 250 MHz) 5 1.51-1.56 (m, 1H, CH 2 ), 1.771.83 (m, 1 H, CH 2 ), 3.15 (dd, J = 3.5, 1.5 Hz, 1H, CHCOSPh), 3.26 (bs, 1H, CH), 3.45 (bs, 1H, CH), 3.77 (dd, J = 4.5, 4.5 Hz, 1H, CH), 6.20-6.23 (dd, J = 5.6, 3.1 Hz, 1H, =CH), 6.32-6.35 (dd, J = 5.6, 3.1 Hz, 1H, =CH), 7.34-7.47 (m, 10H, ArH): 13C NMR (CDCI3 , 75.5 MHz) 8 46.93 (t), 47.08 (d ), 49.04 (d), 55.13 (d), 56.81 (d), 127.35 (s), 127.64 (S), 129.09 (d), 129.13 (d), 129.30 (d), 129.37 (d), 134.44 (d), 134.49 (d), 135.14 (d), 137.39 (d), 196.64 (s), 198.34 (s); m a s s spectrum m /e (relative intensity) 366 (M+, 1), 257 (50), 191 (100), 163 (78), 109 (55); exact m a s s calcd. for C 2 1 H 1 8 O 2 S 2 m /e 366.0744, found, m /e 366.0746. COSePh COSoPh 304 12 0 S e-P h en y l (± )-(lR * ,2 S * ,3 S * ,4 S * )-2 ,3 -D is e le n o -5 -n o rb o rn e n e -2 ,3 - d i c a r b o x y l a t e (304). A mixture of 0.4 g (1.0 mmol) of sele n o e ste r 299 and 0.33 g (5.0 mmol) of cyclopentadiene in 10 mL of b e n z e n e w as h eated under reflux for 1 h and allowed to cool to room tem perature. The solution w a s concentrated in vacuo to give 679 mg of red oil. The residual oil w a s chrom atographed over 20 g of silica gel (eluted with ethyl acetate-hexane, 1 :9) to yield 340 mg (75%) of cycloadduct 304 a s a white solid: mp 88-88.5 °C; IR (CHCI 3 ) 1700 c m ' 1 ; 1H NMR (CDCI 3 , 250 MHz) J = 3.5, 1.5 Hz, 8 1 H, 1.53 (dd, J= 9.0, 1.7 Hz, CHC 0 2 1 H, CH 2 ), 1.73 (bd, J = 9.0 Hz, 1 H, CH 2 ), 3.20 (dd, Me), 3.28 (bs, 1H, CH), 3.43 (bs, 1H, CH), 3.79 (d d,J = 4.2, 3.9 Hz, 1 H, CH), 6.24 (dd, J = 5.9, 2.3 Hz, 1H, =CH), 6.28 (dd, J = 5.9, 2.3 Hz, 1H, =CH), 7.43-7.52 (m, 6 H, ArH), 7.53-7.57 (in, 4H, ArH); 13C NMR (CDCI 3 , 75.5 MHz) 8 46.68 (t), 46.91 (d), 48.54 (d), 58.64 (d), 60.22 (d), 126.00 (s), 126.41 (s), 128.96 (d), 129.04 (d), 129.36 (d), 129.40 (d), 135.38 (d), 135.85 (d), 135.87 (d), 137.27 (d), 199.45 (s), 201.35 (s); m a s s sp ectru m m / e (relative intensity) (M+ -C O S eP h , 3), 211 (73), 91 (100), 66 (31); ex act m a s s calcd. for C i 4 H i 3 O 80S e m /e 277.0126, found, m /e 277.0129. .COSPh COSPh 305 S -P henyl a n d S -P henyl 306 (±)-(1 R \ 2 S * ) - 4 , 6 - D i m e t h y l - 3 - c y c l o h e x e n e - l - c a r b o t h i o a t e (± )-(lS * ,6 S * )-3 ,6 -D im e th y l-3 -c y c lo h e x e n e -1 -c a rb o th io a te (3 0 5 ) (306). M eth od A. To a solution of 0.5 g (2.8 mmol) of thioester 129 in 16 mL of dichloromethane at 23 °C w as added dropwise 3 mL (3.0 mmol) of 1 M ethylaluminium dichloride in hexane. The mixture w as stirred for 20 min and the cold bath was removed. To above mixture w a s added 0.57 g (8.4 mmol) of neat isoprene (228) dropwise. The reaction mixture w as stirred for 12 h at room tem perature, diluted with 15 mL of dichlorom ethane, and poured into 10 mL of 1 N aq u e o u s hydrochloric acid. The organic p h a s e w as w ashed with two 10 mL-portions of 5% aq u e o u s sodium 121 bicarbonate. The a q u e o u s layers w ere com bined and extracted with th ree 50-mL portions ot dichlorom ethane. T he com bined organic p h a s e s w ere dried (Mg 2 S 0 4 ) and co n cen trated in vacuo. The residual oil w a s chrom atographed over 30 g of silica gel (eluted with ethyl acetatehexane, 1:17) to yield 0.55 g (80%) of cycloadduct 305 a s a pale yellow oil: IR (neat film) 3059, 2961, 1703 c m -1 ; 1H NMR (CDCI 3 , 300 MHz) 5 1.09 (d, J = 6.2 Hz, 3H, CH 3 ), 1.68 (bs, 3H, =CCH 3 ), 1.66-1.74 (m, 1 H, CH), 2.02-2.10 (m, 2 H, =CCH 2 ), 2.30-2.36 (m, 2 H, =CHCH 2 ), 2.49- 2.55 (m, 1H, CHCOSPh), 5.40 (bs, 1H, =CH), 7.40 (m, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 5 19.58 (q), 23.13 (q), 29.78 (t), 31.57 (d), 38.39 (t), 55.60 (d), 118.68 (d), 128.04 (s), 129.03 (d), 129.13 (d), 133.41 (s), 134.30 (d), 200.89 (s); m ass spectrum, m /e (relative intensity) 246 (M+, 2), 137 (23), 109 (100); exact m a s s calcd. for C 1 5 H 1 8 OS m/e 246.1070, found, m /e 246.1071. Anal, calcd. for C 1 5 H 1 8 OS: C, 73.19; H, 7.32. Found: C, 73.14; H, 7.38 M eth o d B. A mixture of 178 mg (1.0 mmol) of thioester 129 and 1.36 g (20 mmol) of isoprene (228) in 5 mL of xylene in a sealed tube w as heated under reflux for 24 h, allowed to cool to room temperature, and concentrated in vacuo. The residue w as chrom atographed over 10 g of silica gel (eluted with ethyl acetate-hex ane, 1 :12) to yield 206 mg (84%) of cycloadducts 305 and 306 a s a colorless oil. This material w a s a 60:40 mixture of isom ers 3 0 5 and 3 0 6 , respectively, by integration of selected p e a k s in the 1H NMR spectrum of the mixture: 5 1.08 (d, J = 6.2 Hz, 3H, CH 3 for 306), 1.09 (d, J = 6.2 Hz. 3H, CH 3 for 305). COSePh COSePh 307 S e-P henyl (3 0 7 ) a n d 308 (±)-(1 R * , 2 S * ) - 4 , 6 - D i m e t h y l - 3 - c y c l o h e x e n e - 1 - c a r b o s e l e n o a t e S e-P h en y l (± )-(1 S * ,6 S * )-3 ,6 -D im e th y l-3 -c y c lo h e x e n e -l- c a r b o s e l e n o a t e (308). M eth o d A. To a solution of 0.69 g (3.06 mmol) of sele n o e s te r 133 in 25 mL of dichloromethane at -23 °C w as ad d e d dropwise 3.7 mL (3.7 mmoL) of 1 M solution of 122 ethylaluminium dichloride in hexane. The mixture was stirred for 20 min and the cold bath was removed. To above mixture was added dropwise 0.91 g (6 . 2 mmol) of neat isoprene (228). The solution was stirred for 6 h at room temperature, diluted with 15 mL of dichloromethane, and poured into 10 mL of 1 N aqueous hydrochloric acid. The organic phase was washed with two 10 mL of 5% aqueous sodium bicarbonate and brine. The aqueous washes were extracted with three 20-mL portions ot dichloromethane. The combined organic phases were dried (Mg2 SC>4 ) and concentrated in vacuo. The residual oil was chromatographed over 30 g of silica gel (eluted with ethyl acetate-hexane, 1:16) to yield 0.73 g (80%) of cycloadduct 307 as a pale yellow oil: IR (film) 1719 cm-1; 1H NMR (CDCI3 , 250 MHz) 5 1.09 (d, J = 6.5 Hz, 3H, CH3 ), 1.68 (bs, 3H, =CCH3 ), 1.65-1.80 (m, 1 H, CH), 2.01-2.13 (m, 2 H, =CCH2 ), 2.29-2.36 (m, 2 H, =CHCH2 ), 2.59 (dt, J = 9.4, 5.8 Hz, 1H, CHCOSePh), 5.49 (bs, 1H, =CH), 7.37 (m, 3H, ArH), 7.50 (m, 2H, ArH); 13C NMR (CDCI3 , 62.9 MHz) 8 19.64 (q), 23.13 (q), 29.34 (t), 31.45 (d), 38.21 (t), 58.97 (d), 118.35 (d), 126.63 (s), 128.65 (d), 129.20 (d), 133.46 (d), 135.65 (d), 204.14 (s); mass spectrum, m/e (relative intensity) 292 (M+, 2), 109 (100); exact mass calcd for CisHisOSe m/e 292.0564, found m/e 292.0568 Method B. A mixture of 225 mg (1.0 mmol) of selenoester 133 and 1.36 g (20 mmol) ot isoprene (228) in 5 mL of xylene in a sealed tube was heated under reflux for 24 h, allowed to cool to room temperature, and concentrated in vacuo. The residue was chromatographed over 10 g of silica gel (eluted with ethyl acetate-hexane, 1:12 ) to yield 207 mg (71%) of cycloadducts 307 and 308 as a pale yellow oil. This material was a 60:40 mixture of isomers 307 and 308, respectively, by integration of selected peaks in the 1H NMR spectrum of the mixture: = 6.5 Hz, 3H, CH3 for 308), 1.09 (d, J = 6.5 Hz, 3H, CH3 for 307). COSPh COSPh 309 31 0 8 1.08 (d,J 123 0-M ethyl dicarboxylate S-phenyl ( 3 0 9 ) and c y cl o he xe ne -1, 2- di ca r bo xy la t e ( ± ) - t r a n s - 4 - M e t h y M - t h i o - 4 - c y c l o h e x e n e - l , 2O-Methyl S-phenyl (±)-trans-5-Methyl-1-thio-4- (310). Method A. To a solution of 0.44 g (2.0 mmol) of thioester 138 in 20 mL of dichloromethane at -61 °C w as ad d e d dropwise 0.38 g (2.2 mmol) of neat titanium tetrachloride. The mixture w as stirred for 20 min and the temperature w a s lowered to -23 ®C. To above mixture w a s ad d e d 0.68 g (10.0 mmol) of neat isoprene (228) dropwise. The mixture w a s stirred for 12 h, diluted with 30 mL of dichloromethane, and poured into 15 mL of 5% a q u e o u s p o tassium ca rb onate. The organic p h a s e w a s w a s h e d with two 20-mL portions of saturated aq u e o u s sodium bicarbonate and brine. The aq u e o u s layers were combined, extracted with three 30-mL portions of dichloromethane, dried (Na 2 SC>4 ) and concentrated in vacuo. The residual oil w as chrom atographed over 30 g of silica gel (eluted with ethyl acetate-hex ane, 1:20 followed by 1 :6 ) to yield 0.48 g of a pale yellow solid which w a s recrystallized from 30 mL of hex an e to yield 0.42 g (72%) of cycloadduct 309 a s a white solid: mp 52-53 ®C; IR (CCI 4 ) 1741, 1709 c m ' 1 ; 1H NMR (CDCI 3 , 300 MHz) 5 2.54 (m, 1 H, 1.68 (bs, 3H, =CCH 3 ), 2.13-2.35 (m, 3H, CH 2 ), 2.46- CH), 2.99 (ddd, J = 10.7, 10.7, 5.8 Hz, 1 H, CHC 0 2 Me), 3.13 (ddd, J = 10.7, 10.7, 5.5 Hz, 1H, CHCOSePh), 3.70 (s, 3H, OMe), 5.41 (bs, 1H, =CH), 7.40 (m, 5H, ArH); (CDCI 3 , 62.9 MHz) 8 13c NMR 22.86 (q), 29.24 (t), 32.64 (t), 42.12 (d), 42.40 (d), 51.84 (q), 118.71 (d), 127.57 (s), 129.05 (d), 129.20 (d), 132.28 (s), 134.42 (d), 174.58 (s), 199.92 (s); m a s s spectrum, m /e (relative intensity) 290 (M+ , 1), 181 (54), 93 (100); exact m a s s calcd. for C 1 6 H 1 8 O 3 S m /e 290.1002, found m /e 290.1000. Anal, calcd. for C 1 6 H 1 8 O 3 S: C,66.18; H, 6.25. Found: C, 6 6 .1 1 ; H, 6.29. Method B. A mixture of 222 mg (1.0 mmol) of thioester 138 and 1.36 g (20.0 mmol) of diene 228 in 5 mL of xylene in a sea le d tube w as heated under reflux for 24 h, allowed to cool to room temperature, and concentrated in vacuo. The residual oil w as chromatographed over 10 g of silica gel (eluted with ethyl ac etate-h exane, 1:12) to yield 260 mg (90%) of cycloadducts 309 and 310 as a colorless oil. This material w a s a 55:45 mixture of isom ers 309 and 310, respectively, by integration of the selected pea k s in the 1H NMR spectrum of the mixture: 5 1.68 (bs, 3H, =CCH 3 for 309), 1.71 (bs, 3H, =CCH 3 for 310). 31 1 1-M ethyl Hydrogen ( ± ) * ( 1 S * , 2 S * ) - 5 - M e t h y l - 4 - c y c l o h e x e n e - l , 2- dicarboxylate (311). To a s uspension of 260 mg (1.2 mmol) of mercuric oxide in 6 mL of 0.2 N a q u e o u s perchloric acid w a s a d d e d a solution of cycloadduct 30 9 in 3 mL of anhydrous tetrahydrofuran in the p re s e n c e of 500 mg (4.1 mmol) of sodium perchlorate. The solution w as stirred for 3 h in the dark, diluted with 20 mL of dichloromethane, filtered through 20 g of Celite, and the filter cake w as rinsed with 100 mL of dichloromethane. The filtrate w a s w a sh e d with 20 mL of 0.1 N a q u e o u s sodium hydroxide and brine. The combined aq u e o u s layers were extracted with three 100 -mL portions of dichloromethane. The organic p h a s e s w ere combined, dried (CaCl 2 ), an d co n cen trated in vacuo to afford 127 mg (53%) of olefinic acid 311 a s a yellow oil: IR (film) 1704 c m '1 ; 1H NMR (CDCI3 , 300 MHz) 8 1.64 (s, 3H, =CCH3), 2.03-2.31 (m, 3H, CH2), 2.41-2.49 (m, 1H, CH), 2.82-2.89 (m, 2H, CH2 ), 3.69 (s, 3H, OCH 3 ), 5.37-5.39 (m, 1H, =CH), 10.03 (s, 1H, C 0 2 H); 13C NMR (CDCI 3 , 75.5 MHz) 8 22.94 (q), 27.87 (t), 32.31 (t), 40.98 (d), 41.40 (d), 51.91 (q), 118.80 (d), 132.23 (s), 175.21 (s), 181.07 (s); m ass spectrum, m /e (relative intensity) 198 (M+, 1 ), 171 ( 1 2 ), 153 (8 ); exact m a s s calcd. for C 1 0 H 1 4 O 4 m /e 198.0238; found m /e 198.0236. 125 re l-(1 S * ,4 S * ,5 S * ,7 S * )-5 -lo d o -7 -m e th o x y c a rb o n y l-5 -m e th y l-3 -o x a b lc y c lo [ 3 .2 .1 ] h e p t a n - 2 - o n e (312). To a solution of 127 mg (0.6 mmol) of olefinic acid 311 in 2 mL of anhydrous tetrahydrofuran and 4 mL of aq u e o u s sodium bicarbonate w a s a d d e d a solution of 0.33 g (1.4 mmol) of iodine and 0.7 g (2.5 mmol) of potassiu m iodide in 2 mL of water. The resulting mixture w a s stirred for 12 h in the dark. The mixture w as diluted with 100 mL of d ichlorom ethane an d w a sh e d with 10% a q u e o u s sodium thiosulfate. The organic layer w a s sep a rated , dried (CaCl 2 ), and concentrated in vacuo. The residual oil w a s chrom atographed over 10 g of silica gel (eluted with ethyl acetate-h exane, 1:9) to yield 114 mg (42%) of iodolactone 312 a s a pale yellow oil: IR (neat film) 1766, 1737 c m '1; 1H NMR (CDCI3 , 300 MHz) 8 1.53 (s, 3H, Me), 2.07 (ddd, J = 16.5, 11.5, 3.7 Hz, 1H, CH), 2.48 (ddd, J = 14.9, 6.4, 2.3 Hz, 1H, CH), 2.62 (dddd, J = 10.8, 10.8, 4.4, 2.3 Hz, 1H, CHCO), 2.82 (m, CH), 2.99 (m, 1 H, 1 H, CHC 0 2 Me), 2.90 (dd, J = 14.9, 5.1 Hz, 1H, CHCO), 3.74 (s, 3H, OMe), 4.10 (ddd, J = 9.9, 6.4, 2.3 Hz, 1 H, CHOCO); 13C NMR (CDCI3 , 75.5 MHz) 5 23.82 (d), 26.50 (q), 30.01 (t), 33.80 (t), 38.08 (d), 39.07 (t), 52.61 (q), 83.87 (s), 171.46 (s), 173.09 (s); m a s s spectrum, m /e (relative intensity) 324 (M+, 1); exact m ass calcd. for C 1 0 H 1 3 O 4 I m /e 323.9850, found m /e 323.9854. 313 M eth y l (± )-(lS * ,2 S * )-2 -H y d ro x y m e th y l-5 -m e th y l-4 -c y c lo h e x e n e -1 - c a r b o x y l a t e (313). To a solution of 290 mg (1.0 mmol) of cycloadduct 309 in 10 mL of ethanol w as add ed 175 mg (4.5 mmol) of sodium borohydride portionwise at 0 °C followed by stirring for 6 h at room tem perature. The reaction mixture w a s poured into 10 mL of sa tu ra te d a q u e o u s ammonium chloride. The resulting solution w as w a sh e d with cold 1 N aq u e o u s hydrochloric acid. The a q u e o u s layer w as extracted with three 50-mL portions of dichloromethane. The organic layers w e re com bined, dried (C aC l 2 ), and c o n c e n tra te d in vacuo. The residual oil w a s 126 chrom atographed over 10 g of silica gel (eluted with ethyl acetate-petroleum ether, 1 :2 ) to yield 135 mg (74%) of hydroxy e ste r 313 a s a colorless oil: IR (neat film) 3585-3120, 1728 c m ' 1 ; 1H NMR (CDCI 3 , 300 MHz) 8 1.60 (bs. 3H, =CCH 3 ), 1.82-1.89 (m, 1H, CH), 1.93 (ddd, J = 9.5, 9.5, 4.7 Hz, 1H, =CCH), 2.00-2.27 (m, 3H, CH), 2.39 (bs, 1 H, OH), 2.48 (ddd, J = 9.8, 9.8, 5.6 Hz, 1 H, =CCH), 3.49 (dd, J = 9.8, 2.5 Hz, 2H, CH 2 OH), 3.61 (s, 3H, OMe), 5.30-5.32 (m, 1H, =CH); 13C NMR (CDCI 3 , 75.5 MHz) 5 22.96 (q), 27.44 (t), 32.44 (t), 37.89 (d), 42.37 (d), 51.56 (q), 65.19 (t), 119.59 (d), 131.62 (s), 176.52 (s); m a s s spectrum, m/e (relative intensity) 184 (M+, 3), 166 (19), 152 (17), 107 (100), 106 (34), 93 (47), 91 (41); exact m a s s calcd. for C 1 0 H 1 6 O 3 w /e 184.1095; found m /e 184.1098. COSoPh COSePh 314 O -M eth y l d ica rb o x y la te S e-phenyl 315 ( ± ) - t r a n s - 4 - M e t h y l - 1 - s e l e n o - 4 - c y c l o h e x e n e - l ,2- (3 1 4 ) a n d O -M eth y l c y c lo h e x e n e -1 ,2 -d ic a rb o x y la te S e-p h en y l (± )-tran s-5 -M eth y l-l-sele n o -4 - (315). M e th o d A. To a solution of 0.54 g (2.0 mmol) of s e le n o e s te r 139 in 20 mL of dichloromethane at -23 3C w as ad d e d dropwise 0.22 mL (2.2 mmol) of neat titanium tetrachloride. The mixture w as stirred lor 30 min an d 0.68 g (10 mmol) of neat isoprene (228) w as ad d e d dropwise. The solution w a s stirred for 2 h at -61 °C and poured into 20 mL of 5% aq u e o u s potassium carbonate. The organic p h a s e w as w a sh e d with 25 mL of saturated a q u e o u s sodium bicarbonate. The a q u e o u s layers were extracted with three 20-mL portions of dichloromethane. The organic layers were combined, dried (Na 2 S 0 4 ) and concentrated in vacuo. The residue w a s chrom atographed over 10 g of silica gel (eluted with ethyl acetate-hexane, 1 :12) to afford 0.63 g of 314 a s a pale yellow solid which w as recrystallized from 10 mL of p en tan e to yield 0.55 g (77%) of cycloadduct 314 a s a white solid: mp 48-49 °C; IR (CHCI 3 ) 1732 c m ' 1 ; 1H NMR (CDCI 3 , 300 MHz) 6 1.68 (bs, 3H, =CCH 3 ), 2.13-2.35 (m, 3H, CH 2 ), 2.47-2.53 (m, 1 H, 127 =CCH), 2.98 (ddd, J = 10.4, 10.4, 5.6, 1 H, CHCC>2 Me), 3.24 (ddd, 10.4, 10.4, 5.6 Hz, 1 H, C HCOSePh), 3.70 (s, 3H, OCH 3 ), 5.41 (bs, 1H, =CH), 7.37 (m, 3H, ArH), 7.52 (m, 2H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 5 22.88 (q), 28.70 (t), 32.55 (t), 42.12 (d), 51.92 (q), 52.75 (d), 118.44 (d), 126.20 (s), 128.76 (d), 129.24 (d), 132.40 (s), 135.77 (d), 174.49 (s), 202.99 (s); m a s s spectrum , m /e (relative intensity) 307 (M+-OMe, 1), 181 (17), 156 ( 1 ), 93 (100), 77 (23); exact m a s s calcd. for C i 5 H i 5 0 2 S e m /e 307.0238; found m /e 307.0236. Anal, calcd. for C-| 6 H i 8 C>3 S e: C, 56.98; H, 5.38. Found: C, 56.91; H, 5.40. M eth o d B. A mixture of 269 mg (1.0 mmol) of selen o e ste r 139 and 1.36 g (20.0 mmol) of diene 2 2 8 in 5 mL of xylene in a s e a le d tube w as h ea te d u nd er reflux for 24 h, cooled to room tem perature, and concentrated in vacuo. The residue w as chrom atographed over 15 g of silica gel (eluted with ethyl acetate-hex ane, 1 :15) to afford 272 mg (81%) of cycloadducts 314 and 31 5 a s a pale yellow oil. This material w a s a 55:45 mixture of isom ers 314 and 315, respectively, by integration of the selected pea k s in the 1H NMR spectrum of the mixture: 5 1 . 6 8 (bs, 3H, =CCH 3 for 314), 1.71 (bs, 3H, =CCH 3 for 315). .CHO c o 2ch Me 316 M e th y l 317 3 - M e t h y l - 3 - c y c l o h e x e n e - 1 - c a r b o x y l a t e (3 1 6 ) a n d 6 -F o rm y l-3 -m e th y l-3 -c y c lo h e x e n e -1 -c a rb o x y la te M ethyl (± )-tra n s - (3 1 7 ). A mixture of 550 mg (1.6 mmol) of cycloadducts 314 and 315, 332 mg (1.8 mmol) of tri-n-butyltin hydride, and 50 mg of AIBN in 40 mL of xylene w as h ea te d under reflux for 5 h and cooled to room tem p erature .3 The reaction mixture w as p a s s e d through short column packed with 30 g of silica gel while rinsing with hex a n e. The eluent w as co ncen trate d in vacuo and the residue w a s diluted with 10 mL of dichloromethane and w a sh e d with 5 mL of saturated aq u e o u s sodium fluoride. The organic p h a se w as dried (Na 2 SC>4 ), and concentrated in vacuo. The residue w as chrom atographed over 10 g of 128 silica gel (eluted with ethyl acetate-hex ane, 1 :20 followed by 1:3) to afford 148 mg (56%) of ester 316 a s a pale yellow oil and 47 mg (16%) of aldehyde 317 a s a colorless oil. Ester 316: IR (neat) 2951, 2926, 1736 c n r 1: 1H NMR (CDCI 3 , 300 MHz) 5 1.58-1.66 (m, =CCH 3 ), 1.91-2.22 (m, 5H, CH 2 ), 2.56 (tdd, J = 9.2, 3.0, 2.1 Hz, OMe), 5.38 (t, J = 1.5 Hz, 1 H, -CH); 13C NMR (CDCI3 , 62.9 MHz) 1 H, 8 1 H, CH), 1.65 (bs, 3H, CHCC>2 Me), 3.67 (s, 3H, 23.42 (q), 24.47 (t), 24.87 (t), 32.10 (t), 39.71 (d), 51.46 (q), 120.52 (d), 132.21 (s), 172.26 (s); m a s s spectrum, m /e (relative intensity) 154 (M+, 2 ), 105 (100), 95 (24); exact m ass calcd. for C 9 H 1 4 O 2 m /e 154.0976; found m /e 154.0979. Aldehyde 317 : IR (neat) 2952, 2916, 1733 c m ’1; 1H NMR (CDCI 3 , 250 MHz) 1.68 (s, 3H, =CCH3 ), 2.04-2.40 (m, 4H, =CCH2), 2.80-2.97 (m, OMe), 5.40-5.43 (m, 1 H, =CH), 9.70 (d, J = 1.0 Hz, 1 H, 2 8 H, CHCC>2 Me), 3.71 (s, 3H, CHO); 13C NMR (CDCI 3 , 62.9 MHz) 8 23.07 (q), 24.07 (t), 31.34 (t), 39.49 (q), 47.21 (d), 51.92 (d), 118.20 (d), 132.82 (s), 174.84 (s), 202.57 (s); m a s s spectrum, m /e (relative intensity) 182 (M+ , 2), 152 (16), 93 (100); exact m a s s calcd. for C 1 0 H 1 4 O 3 m /e 182.0939; found m /e 182.0943. COSPh Me 320 S -P henyl (± )-tra n s-2 -M e th y l-4 -o x o c y c lo h e x a n e c a rb o th io a te solution of 267 mg (1.5 mmol) of thioester 129 in 8 ( 3 2 0 ) . To a mL of dichloromethane at -23 ° C w a s added titanium tetrachloride. The solution w a s stirred for 30 min a n d 426 mg (3.0 mmol) of 2trimethylsilyloxy-1,3-butadiene 5 (251) w as added. The mixture w as stirred at -23 3 C for 12 h and poured into 5 mL of 1 N aq u e o u s hydrochloric acid. The organic p h a s e w a s w a sh e d with 15 mL of 5% a q u e o u s sodium bicarbonate. The aq u e o u s layers were extracted with two 30-mL portions of dichloromethane. The combined organic p h a s e s were dried (CaCl 2 ) and concentrated in vacuo. The residue w a s chrom atographed over 10 g of silica gel (eluted with ethyl acetate-hexane, 1 :1 2 ) to afford 192 mg (51%) of cycloadduct 320 a s a pale yellow oil: IR (neat) 1713 cm"1 ; 1H NMR 129 (CDCI 3 , 300 MHz) 5 1.11 (d, J = 6.5 Hz, 3H, CH 3 ), 1.91-2.09 (m, 2 H, CH 2 ), 2.10 (dd, J = 13.7, 11.8 Hz, 1H, CHCO), 2.25-2.54 (m, 4H, CH 2 CO), 2.67-2.75 (ddd, J = 9.6, 9.6, 3.5 Hz, CHCOSPh), 7.41 (s, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 1 H, 20.34 (q), 28.99 (t), 35.63 (d), 39.69 (t), 47.99 (t), 57.13 (d), 127.23 (S), 129.23 (d), 129.53 (d), 134.33 (d), 199.27 (s), 208.76 (s); m a s s spectrum, m /e (relative intensity) 248 (M+, 0.3) 139 (M+-SPh, 38), 111 (45), 55 (100); exact m a s s calcd. fo rC -| 4 H i 6 0 2 S m /e 248.0890; found m /e 248.0883. M e th o d B. A mixture of 178 mg (1.0 mmol) of thioester 129 and 0.57 g (4.0 mmol) of diene 251 in 5 mL of toluene in a sealed tube w a s h eated under reflux for 24 h, allowed to cool to room temperature, and concentrated in vacuo. The residue w as chrom atographed over 30 g of silica gel (eluted with ethyl ac etate-hexane, 1 :12) to yield 251 mg (78%) of a 65:35 mixture of cycloadducts 318 an d 319 a s a colorless oil. COSePh 323 S e-P henyl (± )-tran s-2 -M eth y l-4 -o x o c y clo h ex an e carb o selen o ate (3 2 3 ). To a solution of 450 mg (2.0 mmol) of sele n o e s te r 133 in 15 mL of dichlorom ethane at -23 °C w as a d d e d dropwise neat titanium tetrachloride followed by stirring for 5 min. To above mixture w as ad d e d 528 mg (4.0 mmol) of diene 251 dropwise. The solution w as stirred for an additional 6 h and poured into 20 mL of 1 N a q u e o u s hydrochloric acid. The organic p h a s e w a s w ash e d with 20 mL of 5% a q u e o u s sodium bicarbonate. The a q u e o u s layers w ere extracted with two 30-mL portions of dichloromethane and the combined organics were dried (CaCl 2 ) and concentrated in vacuo. The residue w a s chro m a to g rap h ed over 15 g of silica gel (eluted with ethyl ac etatehexane, 1:12) to afford 178 mg (47%) of cycloadduct 323 a s a colorless oil: IR (neat) 3057, 2960, 1715 c m -1 ; 1H NMR (CDCI 3 , 300 MHz) 2.08 (dd, J = 13.9, 11.8 Hz, 1 H, 8 1.10 (d, J = 6.5 Hz, 3H, CH3 ), 1.88-2.02 (m, 1H, CH), CHCO), 2.30-2.36 (m, 3H, CHCO), 2.42-2.51 (m, 2H, CHCO), 130 2.77 (ddd, J = 9.6, 9.6, 3.5 Hz, 1H, C HCOSePh), 7.35-7.40 (m, 3H, ArH), 7.48-7.51 (m, 2H, ArH); 1 3 C NMR (CDCI 3 , 62.9 MHz) 5 20.24 (q), 28.43 (t), 35.33 (d), 39.38 (t), 47.72 (t), 60.26 (d), 125.91 (s), 128.93 (d), 129.28 (d), 135.55 (d), 202.48 (s), 208.48 (s); m a s s spectrum , m / e (relative intensity) 296 (M+, 0.1) 157 (M+-P hS e, 17), 139 (43), 55 (100); exact m a s s calcd. for C-| 4 H-| 6 0 2 S e m /e 296.0311; found m /e 296.0304. M eth o d B. A mixture of 225 mg (1.0 mmol) of se le n o e s te r 133 and 0.57 g (4.0 mmol) of diene 251 in 5 mL of xylene in a se a le d tube w as heated under reflux for 24 h, allowed to cool to room tem perature, and concentrated in vacuo. The residue w as chrom atographed over 20 g of silica gel (eluted with ethyl ac etate-hexane, 1:12 ) to yield 270 mg (74%) of a 65:35 ratio of cycloadducts 321 and 322 a s a pale yellow oil. COSPh 326 O -M e th y l To a solution of 888 S -P henyl (± )-tra n s-4 -O x o c y c lo h e x a n e -1 ,2 -d ic a rb o x y la te (326). mg (4.0 mmol) of thioester 138 in 40 mL of dichloromethane at -23 °C w as ad d e d dropwise 0.45 mL (4.1 mmol) of neat titanium tetrachloride. The solution w a s stirred for 20 min and 1.3 g (9.0 mmol) of diene 251 w as ad ded slowly .5 The mixture w a s stirred for 5 h at -23 3C an d poured into 15 mL of 5% aq u e o u s potassium carbonate. The organic p h a s e w a s w ashed with 15 mL of saturated a q u e o u s sodium bicarbonate an d brine. The a q u e o u s w a s h e s were extracted with three 80-mL portions of dichlorom ethane. The com bined organic p h a s e s were dried (CaCl 2 ) and concentrated in vacuo. The residue w as chromatographed over 45 g of silica gel (eluted with ethyl a c e ta te - h e x a n e 1:3) to afford 738 mg of pale yellow solid which w a s recrystallized from 20 mL of p e n tan e to yield 689 mg (59%) of cycloadduct 326 a s a white solid; m p 81-82 °C; IR (CHCI 3 ) 1725, 1699 cm -1 ; 1H NMR (CDCI3.300 MHz) 8 1.96-2.09 (m, 1H, CH 2 ), 2.36-2.50 (m, 3H, CHCO), 2.51 (dd, J = 15.1, 10.9 Hz, 1H, CHCOSPh), 2.70 (ddd, J = 15.1, 5.1, 131 1.6 Hz, 1 H, CHC 0 2 Me), 3.27 (ddd, J = 9.3, 9.3, 5.0 Hz, 1H, CHCO), 3.37 (ddd, J = 9.3, 9.3, 5.0 Hz, 1H, CHCO), 3.73 (s, 3H, CH 3 ), 7.42 (s, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 27.88 (t), 38.99 (t), 41.40 (t), 44.36 (d), 50.68 (d), 52.32 (q), 126.80 (s), 129.20 (d), 129.55 (d), 134.39 (d), 172.54 (s), 198.27 (s), 206.30 (s); m a s s spectrum, m /e (relative intensity) 292 (M+ , 1), 183 (100), 77 (12); exact m a s s calcd. tor C 1 5 H 1 6 O 4 S m /e 292.0738, found m/e 292.0735. Anal, calcd. for C 1 5 H 1 6 O 4 S: C, 61.62; H, 5.52; Found C, 61.40; H, 5.50. M eth o d B. A mixture of 222 mg (1.0 mmol) of thioester 138 a n d 0.71 g (5.0 mmol) of diene 251 in 5 mL of toluene in a sea le d tube w as heated under reflux for 24 h, allowed to cool to room temperature, and concentrated in vacuo. The residual oil w a s chromatographed over 30 g of silica gel (eluted with ethyl a c e ta te - h e x a n e , 1:12) to yield 240 mg (6 6 %) of 65:35 mixture of cycloadducts 324 and 325 a s a colorless oil. a C OScPh C 0 2CH3 329 O -M e th y l S e-P h en y l (± )-tra n s-4 -O x o c y c lo h e x a n e -1 ,2 -d ic a rb o x y la te (3 2 9 ) . To a solution of 270 mg (1.0 mmol) of s elen o e ste r 139 in 10 mL of dichloromethane w a s add ed dropwise 0.13 mL (1.2 mmol) of neat titanium tetrachloride at -23 °C. The mixture w as stirred for 10 min and 426 mg (3.0 mmol) of diene 251 w as added dropwise. The mixture w a s stirred for 24 h at -23 3 C and poured into 15 mL of 5% a q u e o u s potassium carbonate. The organic p h a s e w as w a s h e d with 15 mL of satu rated a q u e o u s sodium bicarbonate and brine. The a q u e o u s layers w ere extracted with three 60-mL portions of dichlorom ethane. The com bined organic p h a s e s w ere dried (CaCl 2 ), filtered, and concentrated in vacuo. The residue w a s chrom atographed over 15 g of silica gel (eluted with ethyl ac etate-hex ane, 1:2) to attord 170 mg of a pale yellow solid which w as recrystallized trom 20 mL of p e n ta n e to yield 153 mg (45%) of cycloadduct 329 a s a white solid; mp 70-71 °C; IR (CHCI 3 ) 1741, 1728 c m '1 ; 1H NMR (CDCI 3 , 300 MHz) 5 1.95-2.05 132 (m, 1H, CH), 2.34-2.56 (m, 3H, CH 2 C 0 ), 2.52 (dd, J = 15.1, 10.8 Hz, 1H, CHCO), 2.70 (ddd, J = 15.1, 5.3, 1.5 Hz, 10.8, 10.8, 2.2 Hz, CHCO), 3.26 (ddd, J = 8.9, 7.9, 5.3 Hz, 1 H, 1 H, CHC 0 2 1 H, CH C O SePh), 3.44 (ddd, J = Me), 3.72 (s, 3H, OMe), 7.35-7.43 (m, 3H, ArH), 7.47-7.54 (m, 2H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 6 27.37 (t), 38.86 (t), 41.32 (t), 44.21 (d), 52.43 (q), 53.95 (d), 125.60 (s), 129.16 (d), 129.42 (d), 135.78 (d), 172.55 (s), 201.63 (s), 206.24 (s); m a s s spectrum, m /e (relative intensity) 183 (M+-PhSe, 57); exact m a s s calcd. for C 9 H 1 1 O 4 m /e 183.0632, found m /e 183.0629. Anal, calcd. for C-| 5 H i 6 0 4 Se: C, 53.11; H, 4.75; Found C, 52.87; H, 4.71. M etho d B. A mixture of 269 mg (1.0 mmol) of sele n o e s te r 139 and 0.71 g (5.0 mmol) of diene 251 in 5 mL of xylene in a sealed tube w a s heated under reflux for 24 h, allowed to cool to room temperature, and concentrated in vacuo. The residual oil w a s chromatographed over 20 g of silica gel (eluted with ethyl a c etate-h ex an e, 1:12 followed by 1:4) to yield 293 mg (72%) of a 65:35 mixture of cycloadducts 327 and 328 a s a pale yellow oil. Me COSPh COSPh 330 S -P henyl (3 3 0 ) an d Me 331 (± )-(l R * ,2 S * ,3 R \4 S * ) - 3 - M e th y l- 5 - n o r b o r n e n e - 2 - c a r b o th io a te S -P h en y l (± )-(1 R * , 2 R \ 3 S \ 4 S * ) - 3 - M e t h y l - 5 - n o r b o r n e n e - 2 - c a r b o t h i o a t e (331). M ethod A. To a solution of 0.9 g (5.0 mmol) of thioester 129 in 25 mL of dichlorom ethane at -23 ° C w as a d d e d dropwise 5.5 mL (5.5 mmol) of 1 M ethylaluminium dichloride in h e x a n e . T he solution w a s stirred for 30 min and 0.99 g (15.0 mmol) of cyclopentadiene (82) was added dropwise. The mixture w as stirred for an additional 2 h at -23 ®C, diluted with 40 mL of dichloromethane, and poured into 10 mL of 1 N aq u e o u s hydrochloric acid. The organic p h a s e w as w a sh e d with 30 mL of 5% a q u e o u s sodium bicarbonate and brine. The aq u e o u s layers were com bined and extracted with three 30-mL portions of dichloromethane. The com bined organic p h a s e s w ere dried (CaCl 2 ) and concentrated in vacuo. The residual oil w as chrom atographed over 40 g of silica gel (eluted with ethyl acetate-h ex an e, 1:17) to afford 0.9 g (73%) of cycloadducts 33 0 and 331 in a 96:4 ratio, respectively, a s a colorless oil. T he mixture w a s furthur purified by preparative TLC plate (developed three times with ethyl acetate-petroleum ether, 1:35) to obtain s am p les of pure 330 a n d 331. Endo isom er 330: IR (neat) 3060, 2961, 1708 c m '1; 1H NMR (CDCI 3 , 300 MHz) Hz, 1 H, CH 2 ), 1.62 (bd, J = 8 . 6 Hz, 8 1 H, 1.28 (d, J = 6 .6 Hz, 3H, CH 3 ), 1.52 (ddd, J= CH2), 1.97-2.06 (m, 1H, CHMe), 2.54 (bs, 8 .6 1 H, , 3.3, 1.7 CH), 2.79 (dd, J = 4.4, 3.4 Hz, 1H, CHCOSPh), 3.30 (bs, 1H, CH), 6.10 (dd, J = 5-5, 2.9 Hz, 1H, =CH), 6.32 (dd, J = 5.5, 2.9 Hz, 1H, =CH), 7.41 (m, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 20.84 (q), 38.21 (d), 45.8 7 (t), 47.20 (d), 48.94 (d). 61.92 (d), 127.99 (s), 128.89 (d), 128.89 (d), 132.76 (d), 134.38 (d), 138.47 (d), 198.04 (s). Exo isomer 331: 1H NMR (CDCI 3 , 300 MHz) Hz, 3H, CH 3 ), 1.47 (dd, J = 8 .6 , 1.6 Hz, 1H, CH 2 ), 1.76 (bd, J = 8 .6 Hz, 1 H, 8 1.00 (d, J = 6.9 CH2 ), 2.01 (dd, J = 5.0, 1.6 Hz, 1H, CHC OSPh), 2.41-2.47 (m, 1H, CHMe), 2.75 (bs, 1H, =CCH), 3.0 6 (bs, 1H, =CCH), 6.18 (dd, J= 5.6, 2.7 Hz, 1H, =CH), 6.26 (dd, J = 5.6, 3.1 Hz, 1H, =CH), 7.39-7.46 (m, 5H, ArH); 13C NMR (CDCI 3 , 75.5 MHz) 8 19.04 (q), 39.83 (d), 47.38 (d), 47.99 (t), 48.34 (d), 60.52 (d), 128.30 (s), 129.01 (d), 129.09 (d), 134.38 (d), 135.99 (d), 136.39 (d), 199.75 (s); m a s s sp ec tru m , m /e (relative intensity) 244 (M+ , 2), 135 (36), 69 (100); exact m a s s calcd. for C 1 5 H 1 6 OS m /e 244.0931, found m /e 244.0932. M e th o d B. A mixture of 356 mg (2.0 mmol) of thioester 129 and 660 mg (10.0 mmol) of cyclopentadiene (82) in 5 mL of xylene in a sealed tube w as heated under reflux for 24 h, allowed to cool to room temperature, and concentrated in vacuo. The residue w a s chrom atographed over 15 g of silica gel (eluted with ethyl acetate-hexane, 1 :30) to afford 453 mg (93%) of cycloadducts 3 3 0 an d 331 a s a pale yellow oil. This material w a s a 55:45 mixture of 3 3 0 and 3 3 1 , respectively, by integration of selected peaks in the 1H NMR spectrum of the mixture: 8 0.98 (d, J 134 = 6 .6 Hz, 3H, CH 3 for 330), 1.28 (d, J = 6.9 Hz, 3H, CH 3 for 331), 3.03 (bs, 1H, CH for 330), 3.30 (bs, 1H, CH for 331). Me COSePh COSePh 332 S e-p h en y l sele n o a te (3 3 2 ) Me 333 (± )-[l R * ,2 S * ,3 R \4 S * ) - 3 - M e th y l- 5 - n o r b o r r n e n e - 2 - c a r b o x y and S e-phenyl (±)-[1 R * ,2 R * ,3 S * , 4 S * ) - 3 - M e t h y l - 5 - n o r b o r n e n e - 2 - c a r b o x y s e l e n o a t e (333). M e th o d A. To a solution of 0.22 g (1.0 mmol) of s e le n o e s te r 133 in 8 mL of dichlorom ethane at -23 °C w a s a d d e d dropwise 1.1 mL (1.1 mmol) of 1.0 M ethylaluminium dichloride in hexane and the mixture w as stirred for 30 min. To above mixture was ad d e d 0 .6 6 g ( 1 0 . 0 mmol) of cyclopentadiene (82) dropwise followed by stirring for an additional 2 h at -23 °C. The mixture w as diluted with 20 mL of dichloromethane, and poured into 20 mL of 1 N a q u e o u s hydrochloric acid. The organic layer w a s w a sh e d with 25 mL of 5% a q u e o u s sodium bicarbonate and brine. The combined aqu eo us layers were extracted with three 20-mL portions of dichloromethane. The combined organic p h a s e s were dried (CaCl 2 ) and concentrated in vacuo. The residual oil w a s chrom atographed over 15 g of silica gel (eluted with ethyl ac etate-hex ane, 1:20) to afford 0.16 g (53%) of cycloadducts 332 and 333 in a 95:5 ratio, respectively, a s a pale yellow oil. The mixture w as furthur purified by preparative TLC plate (developed three times by ethyl acetate-petroleum ether, 1:35) to afford sa m p le s of pure 332 a n d 333. Adduct 332: IR 6 1.23 (d, J = 7.0 Hz, 3H, CH 3 ), 1.50 1 H, CH), 1.93-1.97 (m, 1H, CHMe), 2.51 (neat film) 2962, 1720 c m ’1 ; 1H NMR (CDCI 3 , 300 MHz) (ddd, 8.7, 3.5. 1.7 Hz, 1 H, CH), 1.60 (bd, J= 8.7 Hz, (bs, 1H, =CCH), 2.80 (dd, J = 4.4, 3.5 Hz, 1H, CHCOSePh), 3.25 (bs, 1H, CH), 6.06 (dd, J= 5.6, 3.5 Hz, 1H, =CH), 6.27 (dd, J = 5.6, 3.5 Hz, 1H, =CH), 7.32-7.37 (m, 3H, ArH), 7.44-7.48 (m, 2H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 8 21.00 (q), 38.27 (d), 45.81 (t), 47.16 (d), 49.02 (d), 65.80 135 (d), 126.62 (s), 128.55 (d), 129.12 (d), 132.83 (d), 135.76 (d), 138.66 (d), 200.89 (s); m a s s s p ec tru m , m /e (relative intensity) 292 (M+, 2), 155 (5), 135 (100); exact m a s s calcd. for C l 5 H-| 6 0 S e m /e 292.0330, found m /e 292.0338. Cycloadduct 333: 1H NMR (CDCI3 , 250 MHz) 5 0.99 (d, J = 6.9 Hz, 3H, CH3 ), 1.49 (ddd, J = 8.7, 3.5, 1.7 Hz, 1H, CH 2 ), 1.70 (bd, J = 8.7 Hz, 1H, CH2), 2.08 (dd, J= 5.0, 1.7 Hz, 1H, CHCOSePh), 2.39-2.49 (m, 1H, CHMe), 2.76 (bs, 3.08 (bs, 1H, =CCH), 6.17 (dd, J = 5.6, 3.0 Hz, 1 H, 1 H, =CCH), =CH), 6.24 (dd, J = 5.6, 3.0 Hz, 1H, =CH), 7.34-7.41 (m, 3H, ArH), 7.46-7.56 (m, 2H, ArH). M eth o d B. A mixture of 225 mg (1.0 mmol) of se le n o e s te r 133 a n d 660 mg (10.0 mmol) of cyclopentadiene (82) in 5 mL of xylene in a sealed tube was h eated under reflux for 18 h, cooled to room tem perature, and concentrated in vacuo. The residue w a s chrom atographed over 10 g of silica gel (eluted with ethyl acetate-h ex an e, 1:12) to afford 180 mg (62%) of cycloadducts 332 and 33 3 a s a pale yellow oil. This material w as a 53:47 mixture of 332 and 333, respectively, by integration of selected p e a k s in the 1H NMR spectrum of the mixture: 8 0.99 (d, J = 6.7 Hz, 3H, CH 3 for 333) 1.23 (d, J= 6.7 Hz, 3H, CH 3 for 332), 3.08 (bs, 1H, CH for 333), 3.25 (bs, 1H, CH for 3 32). 0— °* o 334 r e l - ( 3 R * 13 a R * 15 S * , 6 S * , 6 a S * , 7 S ‘ ) - 6 - ( C h l o r o m e r c u r i c ) - h e x a h y d r o - 2 - o x a 3 ,5 -m e th a n o -7 -m e th y l-2 H -c y c lo p e n ta [b ]fu ra n (334). A mixture of 145 mg (0.5 mmol) of cycloadduct 332, 272 mg (1.0 mmol) of mercury (II) chloride, and 220 mg (2.0 mmol) of calcium carbonate in 3 mL of acetonitrile and 0.2 mL of water was stirred for 5 h at room tem perature .4 The reaction mixture w as filtered through 20 g of Celite while rinsing with 100 mL of dichloromethane. The filtrate w as w a sh e d with 20 mL of saturated aq u e o u s sodium bicarbonate and brine. The 136 a q u e o u s layers were combined and extracted with three 20-mL portions of dichloromethane. The com bined organic p h a s e s w ere dried (CaCl 2 ) and co ncentrated in vacuo to afford a yellow solid which w a s recrystallized from 20 mL of ethyl acetate to yield 135 mg (35%) of mercurial lactone 334 a s a white solid: mp 191-192 °C ; IR (CHCI 3 ) 1771 c m '1 ; 1H NMR (CDCI 3 , 300 MHz) 8 1.09 (d, J = 6.9 Hz, 3H, CH 3 ), 1.77-1.92 (m, 2H, CH), 2.15 (m, 2H, CH), 2.40 (bs, 1H, CH), 2.52 (d, J = 3.5 Hz, 1H, CHHgCI), 3.27 (m, 1 H, CH), 5.14 (d, J = 5.2 Hz, 1H, OCH); 13C NMR (CDCI 3 , 62.9 MHz) 5 21.17 (q), 37.33 (t), 45.28 (d), 47.25 (d), 47.46 (d), 48.71 (d), 60.62 (d), 85.04 (d), 180.12 (s); m a s s spectrum, m /e (relative intensity) 151 (M+-HgCI, 22), 66 (100); exact m a s s calcd. for C 9 H 1 1 O 2 m /e 151.0780, found m /e 151.0778. Anal, calcd. for CqHt 1 0 2 CIHg: C, 28.57; H, 2.91; Found C, 28.97; H, 2.97. COSPh C O SPh 335 O -M eth y l d icarb o x y la te S -p h en y l (3 3 5 ) and no rb o rn en e-2 ,3 -d ica rb o x y late COzMe 336 (± )-(1 R * , 2 S * I3 S * , 4 S * ) - 2 - T h i o - 5 - n o r b o r n e n e - 2 , 3 - O -M eth y l S -p h en y l (±)-(1 R * ,2 R * ,3 R * ,4 S * ) -2 -T h io -5 - (336). M eth od A. To a solution of 444 mg (2.0 mmol) of thioester 138 in 5 mL of dichloromethane at -23 3 C w as added dropwise 0.25 mL (2.2 mmol) of titanium teterachloride. The solution w a s cooled to -78 °C, stirred for 30 min, and 660 mg (5.0 mmol) of cyclopentadiene (82) w a s ad d e d dropwise. The mixture w a s stirred for 24 h at -78 3 C an d poured into 15 mL of 5% a q u e o u s potassium carbonate. The organic layer w a s w a sh e d with 15 mL of saturated aq u e o u s sodium bicarbonate and saturated brine. The a q u e o u s p h a s e s were extracted with th ree 20-mL portions of dichlorom ethane. The com bined organic p h a s e s were dried (CaCl 2 ) and concentrated in vacuo. The residue w as chromatographed over 20 g of silica gel (eluted with ethyl ac etate-hex ane, 1:12) to afford 465 mg (81%) of inseparable mixture 335 and 137 336 a s a colorless oil (85:15 by NMR integration) which w as failed to crystallize: IR (neat) 1731, 1703 c m '1; 1H NMR (CDCI3 , 300 MHz, major isomer) 5 1.50-1.58 (m, 1 H, CH 2 ), 1.67-1.70 (m, 1 H, C H 2 ), 2.79 (dd, J = 4.1, 1.5 Hz, 1H, CHCO 2 CH 3 ), 3.18 (bs, 1H, CH), 3.43 (bs, 1H, CH), 3.76 (s, 3H, OCH 3 ), 3.70-3.73 (m, 1H, CH), 6.12-6.34 (m, 2H, =CH), 7.39 (s, 5H, ArH): 13C NMR (CDCI 3 , 62.9 MHz, major isomer) 8 46.68 (d), 47.04 (d), 47.16 (t), 47.70 (d), 52.06 (q), 56.75 (d), 127.42 (S), 129.00 (d), 129.18 (d), 134.41 (d), 134.45 (d), 137.58 (d), 174.34 (s), 196.87 (s); m a s s s p e c tru m , m /e (relative intensity) (288 M+ , 1), 179 (18), 109 (16); exact m a s s calcd. for C 1 6 H 1 6 O 3 S m /e 288.0820, found m /e 288.0823. M e th o d B. A mixture of 222 mg (1.0 mmol) of thio ester 138 an d 462 mg (7.0 mmol) of cyclopentadiene (82) in 5 mL of xylene in a sea le d tube w as heated under reflux for 24 h, cooled to room tem perature, and concentrated in vacuo. The residue w as chrom atographed over 20 g of silica gel (eluted with ethyl acetate-h ex an e, 1:12) to afford 219 mg (76%) of cycloadducts 33 5 and 336 a s a pale yellow oil: This material w as a 50:50 mixture by integration of selected p ea k s of the 1H NMR spectrum of the mixture: 8 3.66 (s, 3H, CH 3 for 336), 3.76 (s, 3H, CH 3 for 335), 7.39 (s, 5H, ArH for 335), 7.43 (s, 5H, ArH for 336 ). COSePh C 0 2Me 337 O -M eth y l d icarb o x y late S e-p h en y l (3 3 7 ) a n d 338 (±)-(1 R * , 2 S * , 3 S * , 4 S * ) - 2 - S e l e n o - 5 - n o r b o r n e n e - 2 , 3 - O -M e th y l S e-p h eny l ( ± ) - ( l R * ,2 R * ,3 R * ,4 S * ) - 2 - S e l e n o - 5 - n o r b o r n e n e - 2 , 3 - d i c a r b o x y l a t e (338). M e th o d A. To a solution of 538 mg (2.0 mmol) of se le n o e s te r 139 in 5 mL of dichloromethane at -23 3 C w as added dropwise 0.22 mL (2.2 mmol) of neat titanium tetrachloride. The solution w as cooled to -78 °C, stirred for 30 min, and 462 mg (7.0 mmol) of neat cyclopentadiene (82) w as add ed dropwise. The mixture w a s stirred for 30 h at 138 -78 °C, diluted with 20 mL of dichloromethane, and poured into 20 mL of 5% a q u e o u s potassium carbonate. The organic layer w as w a sh e d with 15 mL of saturated aq u e o u s sodium bicarbonate an d brine. T he a q u e o u s p h a s e s w e re com bined and extracted with three 20-mL portions of dichloromethane. The combined organic p h a s e s were dried (CaCl 2 ) and con cen trated in vacuo. The residue w a s chromatographed ov er 20 g of silica gel (eluted with ethyl acetate-hex ane, 1 :17) to afford 585 mg (87%) of cycloadducts 3 3 7 and 3 3 8 in a ratio of 85:15, respectively. The mixture in p e n ta n e slowly crystallized in the treezer to give endo isom er 337 co ntam in ated by exo isom er 338 a s a white solid. The pen tane solution w a s concentrated in vacuo to give isomer 3 3 8 contam inated by endo isom er 3 3 7 a s a white solid. Cycloadduct 337: IR (CHCI3 ) 1727, 1702 c m ' 1; 1H NMR (CDCI3 , 250 MHz) 5 1.50 (ddd, J= 8.9, 3.5, 1.7 Hz, 8.9 Hz, 1H, CH 2 ), 2.79 (dd, J = 4 . 5 , 1.7 Hz, 1H, CHC 0 2 1 H, CH 2 ), 1.68 (bd, J = Me), 3.18 (bs, 1 H ,C H ),3 .4 2 (bs, 1H, CH), 3.73 (s, 3H, OMe), 3.79 (d d ,J = 4.5, 3.7 Hz, 1H, CH), 6.17 (dd, J = 5.9, 2.8 Hz, 1H, =CH), 6.28 (dd, J= 5.9, 3.1 Hz, 1H, =CH), 7.33-7.41 (m, 3H, ArH), 7.44-7.55 (m, 2H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 5 46.58 (d), 46.75 (d), 46.84 (t), 47.57 (d), 51.99 (q), 60.41 (d), 126.08 (s), 128.62 (d), 129.07 (d), 134.37 (d), 135.81 (d), 137.49 (d), 174.04 (s), 199.45 (s); m a s s spectrum , m /e (relative intensity) 336 (M+ , 1), 113 (100), 66 (14); exact m a s s calcd. for C-| 6 H i 6 0 3 S e m /e 336.0281, found m /e 336.0283. Anal, calcd. for C i 6 H i 6 C>3 Se: C, 57.31; H, 4.77; Found C, 57.10; H, 4.85. Cycloadduct 338: 1H NMR (CDCI 3 , 300 MHz) 5 1.47 (ddd, J = 8.9, 3.6, 1.6 Hz, 1 H, C H2), 1.68 (bd, J = 8.9 Hz, 1H, CH 2 ), 3.10 (dd, J= 4.5, 1.6 Hz, 1H, C HCOSePh), 3.22 (bs, 1H, =CCH), 3.29 (bs, 1H, =CCH), 3.38 (dd, J = 4.5, 3.6, 1H, C H C H C 0 2 Me), 3.68 (s, 3H, OMe), 6.02 (dd, J = 5.9, 2.8 Hz, 1H, =CH), 6.29 (dd, J= 5.9, 3.0 Hz, 1H, =CH), 7.36-7.40 (m, 3H, ArH), 7.51-7.55 (m, 2H, ArH); 13C NMR (CDCI 3 , 75.5 MHz) 8 45.68 (d), 47.02 (t), 47.87 (d), 48.36 (d), 51.96 (d), 59.21 (d). 126.53 (s), 128.91 (d), 129.32 (d), 135.82 (d), 136.01 (d), 137.07 (d), 173.16 (s), 201.75 (s). M e th o d B. A mixture of 135 mg (0.5 mmol) of s e le n o e s te r 139 and 330 mg (5.0 mmol) of cyclopentadiene (82) in 5 mL of xylene in a sealed tube w as h eated under reflux for 24 h, cooled 139 to room tem perature, and concentrated in vacuo. The residue w a s chrom atographed over 10 g of silica gel (eluted with ethyl ac etate-hexane, 1:16) to afford 147 mg (87%) of a pale yellow oil. This material w a s a 53:47 ratio of 336 an d 337, respectively, by integration of selected p e a k s in the 1H NMR spectrum of the mixture: 6 3.73 (s, 3H, OMe for 337), 3.68 (s, 3H. OMe for 338). o CO2 MG co 341 O -M eth y l 340 ( ± ) - ( 3 R * , 3 a R * ,5 S * )6 S * , 6 a S * , 7 S * ) - 6 - ( C h l o r o m e r c u r i c ) h e x a h y d r o -2 -o x o -3 ,5 -m e th a n o -2 H -c y c to p e n ta [b ]fu ra n -7 -c a rb o x y la te H y d ro g en (3 4 0 ) (± )-(lR * ,2 S \3 S * ,4 S * )-5 -N o rb o rn e n e -2 ,3 -d ic a rb o x y la te and 2 - M e th y l (341). To a mixture of 0.33 g (1.0 mmol) of cycloadducts 337 a n d 338, 0.54 g (2.0 mmol) of mercuric chloride and 0.44 g (4.0 mmol) of calcium chloride in 6 mL of acetonitrile w a s ad d e d 0.4 mL of w ater at room tem perature an d the mixture w a s stirred for 4h. The solution w a s filtered while rinsing with 100 mL of dichloromethane. The filtrate w a s w a sh e d with brine, dried (CaCl 2 ), and concentrated in vacuo. The residue w as chromatographed over 30 g of silica gel (eluted with ethyl a c e ta te :h e x a n e , 2:1).to yield 0.23 g (51%) of lactone 340 a s a white solid and 45 mg (11%) of hydrolyzed exo isom er 341 contam inated with lactone 340. Lactone 340: mp 146-149 °C ; IR (CHCI3) 1777, 1734 c m '1; 1H NMR (CDCI 3 , 250 MHz) 6 1.93-2.35 (m, 2H, CH 2 ), 2.83 (s, 1 H, CH), 3.02 (s. 1H CH), 3.07-3.22 (m, 2H, CH), 3.73 (s, 3H, OMe), 3.88 (d, J = 2.5 Hz, 1H, CH), 5.12 (d, J= 5.0 Hz, 1 H, CHOCO); 13C NMR (CDCI 3 , 62.9 MHz) 5 27.75 (d), 35.08 (t), 40.98 (d), 46.10 (d), 50.15 (d), 50.41 (d), 52.81 (q), 88.43 (d), 170.57 (s), 177.15 (s); m a ss spectrum, m /e (relative intensity) 401 (M+-OMe, 0.3), 195 (4), 135 (13), 66 (100); exact m a s s calcd. for CgHsOsCIHg (M+- OMe) m /e 400.9906; found m /e 400.9909. Anal, calcd. for C i o H n 0 4 HgCI: C, 27.85; H, 2.57; Found C, 27.67; H, 2.57 140 Acid 341: IR (film) 1735 c m '1 ; 1H NMR (CDCI 3 , 300 MHz) 5 1.46 (bd, J = 8.9 Hz, 1H, CH), 1.62 (bd, J = 8.9 Hz, 1H, CH), 2.71 (bs, 1H, CHCO 2 H), 3.19 (bs, 1H, =CCH), 3.27 (bs, 1H, =CCH), 3.36 (d, J= 3.8 Hz, 1H, CHC 0 = 5.6, 2.8 Hz, 1 H, 2 Me), 3.65 (S, 3H, OMe), 6.08 (dd, J= 5.6, 2.8 Hz, 1H, =CH), 6.28 (dd, J =CH). aia 342 S -P henyl [3 4 2 ] and ca rb o th io ate COSPh 343 (±)-(1 R * , 2 R \ 6 R * ) - 2 , 6 - D i m e t h y l - 3 - c y c l o h e x e n e - l - c a r b o t h i o a t e S -P h en y l (± )-(l S * ,2 R * ,6 S * )- 2 ,6 -D im e th y l-3 - c y c lo h e x e n e -1 - [343]. To a solution of 356 mg (2.0 mmol) of thioester 1 2 9 in 12 mL of dichloromethane at -23 °C w as ad d e d dropwise 2.2 mL of 1.0 M of ethylaluminium dichloride in hexane, and the solution w a s stirred for 30 min. After removing cold bath, 552 mg (8.0 mmol) of neat diene 199 w a s add ed dropwise. The reaction mixture stirred for 36 h at room tem perature, diluted with 10 mL of dichloromethane and poured into 20 mL of 1 N aq u e o u s hydrochloric acid. After p h a s e sep a ratio n , the a q u e o u s layer w a s extra cted with th re e 30-mL portions of dichloromethane. The com bined organics w ere dried (CaCl 2 ) and concentrated in vacuo. The residue w as chromatographed over 50 g of silica gel (eluted with hexane-dichloromethane, 5:1) to give 558 mg of a pale yellow oil. This crude product w as bulb-to-bulb distilled to yield 356 mg (71%) of cycloadducts 3 4 2 and 3 4 3 in a ratio of 90:10, respectively, a s a colorless oil. An analytical sam ple w as prepared by preparative TLC (developed three times with ethyl acetatepetroleum ether, 1:50). Cycloadduct 342: IR (neat film) 3021, 2 9 6 1 ,1 7 0 4 c m '1; 1H NMR (CDCI 3 , 300 MHz) 5 0.98 (d, J = 7.1 Hz, 3H, CCH 3 ), 1.02 (d, J = 6.2 Hz, 3H, =CCCH 3 ), 1.72 (dddd, J = 18.1, 8.2, 4.6, 2.3 Hz, 1 H, J = 10.3, 5.5 Hz, CHCOSPh), 5.61-5.66 (m, 1 H, =CCH). 2.11-2.22 (m, 2H, CHMe), 2.68-2.73 (m, 2 1 H, =CCH), 2.80 (dd, H, =CH), 7.37-7.42 (m, 5H, ArH); 13C NMR 141 (CDCI 3 , 75.5 MHz) 8 17.04 (q), 19.64 (q), 25.55 (d), 32.68 (d), 33.48 (t), 59.31 (d), 125.03 (d), 128.24 (s), 129.05 (d), 129.09 (d), 131.14 (d). 134.33 (d), 198.25 (s). Cycloadduct 343: 1H NMR (C 6 D6, 300 MHz) 5 1.02 (d, J= 6 .6 Hz, 3H, CCH3), 1.08 (d, J= 6 .6 Hz, 3H, =CCCH3), 1.49 (dddd, J = 18.1, 7.9, 4.7, 2.2, 1H, =CCH), 1.78-1.90 (m, 1H, =CCH), 1.93-2.12 (m, 1H, CH), 2.14 (dd, J = 10.3, 10.3 Hz, 1 H, CHCOSPh), 2.65-2.78 (m, 1 H, =CHMe), 5.33-5.53 (m, 2H, =CH), 6.96-7.08 (m, 3H, ArH), 7.38-7.41 (m, 2H, ArH);13C NMR (CDCI 3 , 75.5 MHz) 8 19.62 (q), 20.00 (q), 32.28 (d), 33.95 (t), 34.92 (d), 63.82 (d), 125.20 (d), 128.02 (s), 129.12 (d), 129.28 (d), 131.93 (d). 134.31 (d), 201.40 (s); m ass spectrum, m /e (relative intensity) 246 (M+, 0.5), 137 (19), 109 (100): exact m a s s calcd. for C 1 5 H 1 8 OS m /e 246.1078, found m /e 246.1084. M eth o d B. A mixture of 434 mg (3.0 mmol) of thioester 129 and 660 mg (10 .0 mmol) of diene 199 in 15 mL of anhydrous xylene w a s heated under reflux in a sea le d tube for 30 h and allowed to cool to room tem perature. The reaction mixture w as concentrated in vacuo. The residue w as chrom atographed over 50 g of silica gel (eluted with ethyl ac etate-hex ane, 1 :12) to yield 642 mg (83%) of a complex mixture of cycloadducts. COSoPh 346 S e-P h en y l selen o ate COSePh 347 (± )-(1 R * ,2 S * ,6 S * )-2 ,6 -D im e th y l- 3 - c y c l o h e x e n e - 1 - c a r b o (3 4 6 ) and S e - P h e n y l (± )-(1 S * ,2 S * ,6 R * )-2 ,6 -D im e th y l-3 -c y c lo h e x e n e -l- c a r b o s e l e n o a t e (347). To a solution of 225 mg (1.0 mmol) of s e le n o e s te r 133 in 6 mL of dichlorom ethane at -23 ®C w as a d d e d dropwise 1.1 mL (1.1 mmol) of 1.0 M ethylaluminium dichloride in hexane and the mixture was stirred for 10 min. After the cold bath w as removed, 276 mg (4.0 mmol) of neat diene 199 w a s ad ded dropwise to above mixture. The solution w as stirred for an additional 2 h at room temperature, diluted with 20 mL of dichloromethane, and poured into 15 mL of 1 N a q u e o u s hydrochloric acid. The organic p h a s e w a s w a sh e d with 15 mL of 5% of a q u e o u s sodium bicarbonate and brine. The a q u e o u s layers w ere extracted with three 30-mL portions of dichlorom ethane. T he com bined organics w e re dried (CaCl 2 ) an d co ncentrated in vacuo. The residual oil w as chrom atographed over 20 g of silica gel (eluted with ethyl acetatehexane, 1:35) to afford 156 mg (56%) of cycloadducts 346 and 3 4 7 a s a pale yellow oil. GLC analysis (tr=7.53 for 346, tr=7.77 for 347, 100 °C, 2 min, 25 deg/min, 2 min, 300 °C, HP Ultra II column packed with 5% phenylmethylsilicon gum, 25 m) indicated a 93:7 mixture of 3 4 6 and 347, respectively. Analytical sam ple w as prepared from preparative TLC (developed four times with ethyl acetate-petroleum ether, 1:50). Cycloadduct 346: IR 1719 c m ' 1; 1H NMR (C 6 D6 , 300 MHz) 5 0.99 (d, J = 6.3 Hz, 3H, CH 3 ), 1.03 (d, J = 7.0 Hz, 3H, =CCHMe), 1.70 (dddd, J = 18.0, 8.1, 4.7, 2.3 Hz, 1 H, =CCH), 2.11-2.20 (m, 2H, CH 2 ), 2.68-2.75 (m, 1H, =CCMe), 2.90 (dd, J = 10.3, 5.4 Hz, 1H, CH C O SePh), 5.56-5.69 (m, 2 H, =CH), 7.33-7.55 (m, 5H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 5 17.01 (q), 19.64 (q), 25.72 (d), 32.26 (d), 33.41 (t), 63.12 (d), 125.02 (d), 128.61 (d), 129.12 (s), 129.20 (d), 130.90 (d), 135.58 (d), 201.54 (s). Cycloadduct 347: IR (film) 1716 c m ' 1 ; 1H NMR (CDCI 3 , 300 MHz) 5 0.96 (d, J= 6.4 Hz, 3H, Me), 0.98 (d, J= 7.0 Hz, 3H, Me), 1.34-1.50 (m, 1H, CH), 1.73-1.84 (m, 1H, CH), 1.92-2.07 (m, 1H, CH), 2.12 (dd, J = 10.9, 10.9 Hz, 1H, C H C O SePh), 2.59-2.70 (m, 1H, =CCH3), 5.28-5.48 (m, 2H, =CH), 7.01-7.09 (m, 3H, ArH), 7.497.56 (m, 2H, ArH); 13C NMR (CDCI 3 , 75.5 MHz) 6 19.68 (q), 20.06 (q), 32.28 (d), 33.97 (t), 34.91 (d), 66.99 (d), 125.21 (d), 126.66 (s), 128.77 (d), 129.28 (d), 131.78 (d), 135.72 (d), 204.89 (s); m a s s spectrum, m /e (relative intensity) 294 (M+, 1), 157 (10), 109 (100), 79 (7); exact m a s s calcd. for C i s H - i s O S e m /e 294.0516, found m /e 294.0523. M e th o d B. A mixture of 450 mg (2.0 mmol) of s e le n o e s te r 133 an d 660 mg (10.0 mmol) of diene 199 in 15 mL of anhydrous xylene was heated under reflux in a sea le d tube for 30 h and allowed to cool to room tem perature. The reaction mixture w as concentrated to its half volume in vacuo. The residue w as chrom atographed over 50 g of silica gel (eluted with 100% of hexane 143 followed by ethyl a c e ta te - h e x a n e , 1:15) to yield 442 mg (76%) of a com plex mixture of cycloadducts. g | a COSPh : 330 S -P h en y l d icarb o x y late iC OSPh 351 l-m e th y l-(± )-(lR * ,2 R * ,3 R * )-3 -M e th y l-4 -c y c lo h e x e n -1 ,2 (3 5 0 ) a n d S - P h e n y l c y c lo h e x e n -1 ,2 -d ic a rb o x y la te 1 -m e th y l-(± )-(lS * ,2 S * ,3 R * )-3 -M e th y l-4 - (351). M eth o d A. To a solution of 222 mg (1.0 mmol) of thioester 138 in 10 mL of dichlorom ethane at -23 w as a d d e d dropwise a solution of 1.1 mL (1.1 mmol) of 1.0 A/f ethylaluminium dichloride in hexane, stirred for 20 min. To above mixture was ad d e d dropwise 204 mg (3.0 mmol) of neat diene 199. The mixture w a s stirred for an additional 24 h at -23 °C , diluted with 20 mL of dichloromethane, and poured into 15 mL of 5% a q u e o u s p o ta s s iu m c a rb o n a te . The o rg a n ic p h a s e w a s ex tra c te d with th re e 50-mL portions of dichlorom ethane. The com bined organic layers w ere w a sh e d with satu ra te d aq u e o u s sodium bicarbonate, brine, dried (CaCl 2 ), an d concentrated in vacuo. The residue w a s chromatographed over 20 g of silica gel (eluted with ethyl ac eta te -h e x a n e , 1:20) to atford 152 mg (51%) of cycloadducts 350 and 351 a s a pale yellow oil. This material w as a 88:12 mixture of 350 and 351, respectively, by integration of selected peaks in the 1H NMR spectrum . Cycloadduct 350 slowly crystallized from pen tane in the freezer. Cycloadduct 350: mp 68-69 °C ; IR (neat) 1737, 1713, 1698 c m '1 ; 1H NMR (CDCI 3 , 250 MHz, major isomer) 5 0.98 (d, J = 6.9 Hz, 3H, CH 3 ), 2.062.20 (m, 1 H, CHCH 2 ), 2.38-2.49 (dt, J= 17.7, 4.8 Hz, CHMe), 2.95 (ddd, J = 11.4, 11.4, 5.7 Hz, 1 H, =CHCH), 2.86 (bq, J = 5.9 Hz, 1 H, CHCC>2 Me), 3.37 (dd, J = 11.4, 5.7 Hz, 1 H, 1 H, CHCOSPh), 3.67 (s, 3H, OCH 3 ), 5.59-5.77 (m, 2H, =CH), 7.36-7.43 (m, 5H, ArH); NMR (CDCI 3 , 62.9 MHz) 5 16.79 (q), 29.25 (t), 32.62 (d), 37.23 (d), 52.17 (q), 53.61 (d), 123.81 (d), 144 127.73 (s), 129.37 (d), 129.52 (d), 131.58 (d), 134.80 (d), 175.57 (s), 188.99 (s); m a s s spectrum, m /e (relative intensity) 259 (M+-OMe, 2), 181 (M+-SPh, 50), 93 (100); exact m a s s calcd. for C 1 5 H 1 5 O 2 S m /e 259.0796, found m /e 259.0794. Cycloadduct 351; 1H NMR (CDCI 3 , 300 MHz, exo isomer) 1 H, 8 1.17 (d, J = 6.9 Hz, 3H, CH 3 ), 2.23-2.61 (m, 3H, =CCH), 2.71 (dd, J= 11.1, 10.1 Hz, CHCOSPh), 3.00 (ddd, J = 11.1, 11.1, 5.7 Hz, 1 H, CHC 0 2 Me), 3.72 (s, 3H, OMe), 5.49-5.54 (m, 1H, =CH), 5.63-5.69 (m, 1H, =CH), 7.37-7.43 (m, 5H, ArH); 13C NMR (CDCI 3 , 75.5 MHz) 8 19.92 (q), 28.37 (t), 34.20 (d), 43.49 (d), 51.92 (q), 57.57 (d), 123.52 (d), 127.83 (s), 129.15 (d), 129.34 (d), 131.98 (d), 134.24 (d), 174.19 (s), 199.96 (s). M ethod B. A mixture of 222 mg (1.0 mmol) of thioester 138 and 351 mg (5.1 mmol) of diene 199 in 5 mL of xylene in a sealed tube w a s heated under reflux for 24 h, allowed to cool to room tem perature, an d concentrated to half its volume in vacuo. The residue w a s chrom atographed over 15 g of silica gel (eluted with 100% of hexane followed by ethyl a c etate-h ex an e, 1:20) to afford 259 mg (89%) of cycloadducts a s a colorless oil. This material w a s a 30:30:20:20 mixture by integration of selec ted p e a k s of the 1H NMR spectrum of the mixture: 350), 3.69 (s, 6 8 3.67 (s, 3H, OCH 3 for H, OCH 3 for 352 an d 353), 3.72 (s, 3H, OCH 3 for 351). Me C°2H CO zMq 354 1 -M e th y l H y d ro g en (± )-(1 R * , 2 R * , 3 R * ) - 3 - M e t h y l - - 4 - c y c l o h e x e n - 1 ,2 - d i c a r b o x y l a t e (354). A mixture of 290 mg (1.0 mmol) of cycloadduct 350, 541 mg (2.0 mmol) of mercury(ll) chloride, and 710 mg (4.0 mmol) of cadmium carbonate in 10 mL of wet acetonitrile w as h eated under reflux for 6 h. The mixture was allowed to cool to room tem perature and p a s s e d through Celite while rinsing with 30 mL of acetonitrile. The filtrate w a s w a sh e d with brine, dried (Na 2 S 0 4 ), and concentrated in vacuo to yield 132 mg (67%) of acid 354 a s a white solid: mp 142- 145 145 °C; IR (CHCI 3 ) 3019, 1733, 1709 c m '1; 1H NMR (CDCI 3 , 300 MHz) 5 0.95 (d, J = 7.0 Hz, 3H, CH 3 ), 2.10 (dddd, J= 18.1, 11.4, 4.6, 2.3 Hz, 1H, =CCH), 2.40 (bdt, J= 18.1, 4.6 Hz, 1H, =CCH), 2.70 (bq, J = 5.7 Hz, 11.7, 5.7 Hz, 1 H, 1 H, CHMe), 2.83 (ddd, J = 11.7, 1 1 .7, 5.7 Hz, 1 H, CHC 0 2 Me), 3.05 (dd, J = CHCO 2 H), 3.69 (s, 3H, OMe), 5.59-5.74 (m, 2H, =CH); 13C NMR (CDCI 3 , 75.5 MHz) 5 16.67 (q), 28.73 (t), 30.71 (d), 36.44 (d), 45.19 (d), 51.81 (q), 123.32 (d), 131.27 (d), 175.84 (s), 179.63 (s); m ass spectrum, m /e (relative intensity) 198 (M+, 1), 181 (16), 153 (10), 93 (100); exact m a s s calcd. for C 1 0 H 1 4 O 4 m /e 198.0516, found m /e 198.0523. COjMeH ° d [ o 355 re l-(1 S \4 S * ,5 S \7 S \8 S * )-5 -lo d o -7 -m e th o x y c a rb o n y l-8 -m e th y l-3 o x a b ic y c lo -[3 .2 .l]h e p ta n -2 -o n e (355). To a solution of 122 mg (0.67 mmol) of olefinic acid 194 in 6.0 mL of tetrahydrofuran-diethyl e th e r-satu ra te d a q u e o u s sodium b icarbonate ( 1 :1 :2 ) cooled to 0 °C w as ad ded 0.48 g (2.0 mmol) of iodine in one portion. The reaction mixture w a s stirred for 6 h at room te m p e r a tu re in the dark a n d th e n diluted with 20 mL of dichloromethane. The reaction mixture w as w a sh e d with 10% a q u e o u s sodium thiosulfate and brine. T he co m b in e d aqueous lay ers w e re e x tra c te d with th r e e 10-mL po rtio n s of dichloromethane. The combined organics were dried (Na 2 SC>4 ), and concentrated in vacuo. The residue w as chrom atographed over 30 g of silica gel (eluted with ethyl acetate-petroleum ether, 1:9) to yield 180 mg (83%) of iodolactone 355 a s a pale yellow oil: IR (neat film) 1 7 8 9 ,1 7 3 3 c m '1; 1H NMR (C 6 D6 , 300 MHz) 8 0.67 (d, J= 8 .6 Hz, 3H, CH 3 ), 2.03 (ddd, J = 17.0, 7.5, 5.0 Hz, 1H, CH), 2.24 (dd, J= 17.0, 1.0 Hz, 1H, CH), 2.36 (ddd, J= 7.5, 3.7, 1.6 Hz, 1H, CHC 0 J= 3.7 Hz, 1 H, CHCO), 2.95 (q, J= 7.0 Hz, 1 H, 2 Me), 2.56 (d, CHMe), 3.30 (s, 3H, OMe), 3.80 (dd, J = 5 .0 , 3.5 Hz, 1H, CHI), 3.91 (d, J = 5.0 Hz, 1H, OCH); 13C NMR (CDCI 3 , 75.5 MHz) 8 16.75 (q), 20.66 (d), 146 29.39 (t), 36.62 (d), 38.94 (d), 46.75 (d), 52.47 (q), 85.32 (d), 171.68 (s), 176.49 (s); m a s s s p ec tru m , m/e (relative intensity) 324 (M+ , 1), 197 (25), 93 (100); exact m a s s calcd. for C 1 0 H 1 3 O 4 I m /e 323.9850, tound m /e 323.9854. COSePh C 0 2Mo 356 Se-Phenyl 1-Methyl-(±)-(1R*,2R*,3R*)-3-methyl-4-cyclohexen-1,2- d i c a r b o x y l a t e (356). M eth od A. To a solution of 269 mg (1.0 mmol) of s e le n o e s te r 139 in 10 mL of dichloromethane at -23 ° C w a s added dropwise a solution of 1.1 mL (1 . 1 mmol) of 1.0 M ethylaluminum dichloride in h ex a n e. The mixture w a s stirred for 10 min, the cold bath w a s removed, an d 242 mg (3.5 mmol) of neat diene 199 w as ad ded dropwise. The mixture w as stirred for 30 min, diluted with 20 mL of dichlorom ethane, and poured into 25 mL of 5% a q u e o u s potassium carbonate. The organic p h a s e w a s w a sh e d with 20 mL of saturated a q u e o u s sodium b icarbon ate and brine. T he a q u e o u s layers w ere com bined and extracted with three 30-mL portions of dichloromethane. The combined organic layers were dried (CaCl 2 ) and concentrated in vacuo. The residual oil w as chrom atographed over 30 g of silica gel (eluted with ethyl acetateh exane, 1 :35 followed by 1 :12) to afford 205 mg of cycloadducts 356 an d 357 in a ratio of 95:5, respectively, a s a pale yellow oil which w as crystallized from 20 mL of p e n tan e in the freezer to yield 178 mg (53%) of cycloadduct 356 a s a white solid. Adduct 356: mp 79-80 °C ; IR (CHCI 3 ) 1731 cm*1 ; 1H NMR (CDCI 3 , 250 MHz) 5 0.99 (d, J = 7.1 Hz, 3H, CH 3 ), 2.13 (dddd, J = 18.1, 11.3, 4.5, 2.3 Hz, 1H, =CCH), 2.44 (bdt, J= 18.1, 5.6 Hz, 1H, =CHCH), 2.84 (bq, CHMe), 2.96 (ddd, J = 11.3, 11.3, 5.6 Hz. 1H, CHC 0 2 5.6 Hz, 1H, Me), 3.44 (dd, J = 11.3, 5.6 Hz, 1H, C HCOSePh), 3.68 (s, 3H, OCH 3 ), 5.58-5.77 (m, 2H, =CH), 7.26-7.38 (m, 3H, ArH), 7.48-7.55 (m, 2H, ArH); 13C NMR (CDCI 3 , 62.9 MHz) 5 16.56 (q), 28.98 (t), 32.02 (d), 37.18 (d), 51.97 (q), 147 56.82 (d), 123.56 (d), 126.09 (S ), 128.79 (d), 129.27 (d), 131.16 (d), 135.82 (d), 175 17 (S), 201.93 (s); m a s s spectrum, m /e (relative intensity) 181 (M+-SePh, 78), 157 (8 ), 153 (6 ), 93 (100); exact m a s s calcd. for C 1 0 H 1 3 O 3 m /e 181.0858, found m /e 181.0862. Anal, calcd. for C i 6 H i s 0 3 Se: C, 56.98; H, 5.38. Found: C, 56.87; H, 5.39. M eth o d B. A mixture of 269 mg (1.0 mmol) of selen o e ste r 139 and 117 mg (1.7 mmol) of diene 199 in 5 mL of xylene in a sea le d tube w a s h eated under reflux for 24 h, allowed to cool to room tem perature, an d co ncentrated to half its volume in vacuo. The residue w a s ch rom atographed over 15 g of silica gel (eluted with 100% hexane followed by ethyl acetate-hex ane, 1:20) to afford 202 mg (60%) of cycloadducts a s a pale yellow oil. This material w a s a 30:30:20:20 ratio cycloadducts by integration of selected peaks in the 1H NMR spectrum of the mixture: 5 0.90 (d, J = 7 Hz, 3H, CH 3 ), 0.99 (d, J= 7 Hz, 3H, CH 3 for 356), 1.05 (d ,J = 7 Hz, 3H, CH 3 for 357), 1.18 (d, J= 7 Hz, 3H, CH3) List of R eferences 1. (a) Huisgen, R.; Grashey, R.; Sauer, J. in Patai, S.: The Chemistry of Alkenes. Interscience, London 1964. (b) W asserm an, A. "Diels-Alder Reactions", Elsevier: New York, 1965. (c) Onishchenko, A. S. "Diene Synthesis" Translated from Russian by Israel Program for Scientific Translations, J eru sa lem 1964. (d) Martin, J. G.; Hill, R. K. Chem . R ev iew s 1961, 61, 537. (e) Sau er, J. A ngew . C hem . Int. Ed. Engl. 1966, 5, 211. (f) Sauer, J. A ngew . Chem . Int. Ed. Engl. 1967, 6, 16. (g) Carruthers, W. "Cycloaddition Reactions in Organic Synthesis, P ergam on Press: New York, 1990. (h) Charlton, J. L.; Alauddin, M. M. Tetrahedron 1987, 43, 2873. 2. Craig, D. J. Am . C hem . Soc. 1950, 72, 1678. 3. Frank, R. L.; Emmick, R. D.; Johnson, R. S. J. Am. C hem . Soc. 1947, 69, 2313. 4. Craig, D.; Shipman, J. J.; Fowler, R. B. J. Am. Chem . Soc. 1961, 83, 2885. 5. Wynberg, H.; De Groot, A.; Davies, D. W. Tetrahedron Lett. 1963, 7, 1083. 6 . C ope, A. C.; Bumgardner, C. L. J. Am. Chem . Soc. 1956 , 78, 2812. 7. Alder, K. Experientia S u p p lem e n tu m II, 1955, 8 86 . . Alder, K; Stein, G. Angew . C hem . 1937, 50, 510. 9. Sauer, J.; Wiest, H.; Mielert, A. C hem . 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APPENDIX 1H and 13C NMR Spectra of New Compounds 0 6 1 CHB-l-47 (250 MHz, CDCI3 ) k — i— e.o —,— s.e — i— 5.4 —I— —I— —I— 5.2 5.0 4.0 4.6 4.4 3.0 T ' I 1 I ' 1 ' I 3.4 3.2 3.0 2.0 2.6 2.4 ' I 1---I— 2.2 2.0 J PPH Figure 6 . 1H NMR spectrum of 1 (250 MHz, CDCI3) O*) o 6 CHB-l-54 (250 MHz, CDCI3) J A u 7.0 Figure 7. 6.5 6.0 '~ l • * 5.5 5.0 o 4.5 '—I—' 4. 0 1—I- 3.5 2.5 1H NMR spectrum of 4 (250 MHz, CDCI3 ) Ol "J IMTE6AAL 36 CHB-l-91 (250 MHz, CDCI3 ) 7.3 Figure 8 . 7.0 6.5 6.0 3.5 5.0 <. 5 4.0 PPH 3. 5 2.5 2.0 1 H NMR spectrum of 36 (250 MHz, C D C I3 ) 158 Mo N X 'S P h 129 CHB-ll-31 (250 MHz, CDCI3 ) s.5 Figure 9. 1 1 ' 1 ' 1-- 5. 0 4.5 PPM 1H NMR spectrum of 129 (250 MHz, CDCI3) on CO Me ^ 'S P h 129 CHB-ll-31 (62.9 MHz. CDCI3 ) p u J rtm w e e w F ig u re 'H i * *w 10. m '»«wm h h h 'h »>4«i»»»V m^fk 13 C NMR spectrum of 129 (62.9 MHz, C D C I3 ) 05 O o M« X^ ^ ^ ' S e P h 133 CHB-1I-6 (250 MHz, CDCI3) -1 1 1 7.5 ■ 1 1 1 7.0 1 1 1 ■ 1 6.5 ' 1 1 1 1 6.0 1 1 1 1 1 5.5 1 ■ 1 1 1 5.0 1 1 PPH 1 1 1 4.5 1 1H NMR spectrum of 133 (250 MHz, CDCI3) 1 1— 1 1— 1— 1— 1— 1— 1— ■ — ■— ■— ■— 1— ■— '— '— ■— 1— 1— 1— '— ■— r * 4.0 3.5 3.0 2 5 2 0 161 Figure 11. 1 M o '^ V '^ S e P h 133 CHB-ll-6 (62.9 MHz. CDCI3 ) »**• Figure 12. 13C NMR spectrum of 133 (62.9 MHz, CDCI3) IN*#* ******** iP r SPh 134 CHB-l-223 (250 MHz, CDCI3 ) / / / JL 7. 5 7. 0 6.0 5.5 5. 0 4. 5 ' I~1' 4. 0 ' I ■’ PPM Figure 13. 3. 5 ~t~i n 3.0 2. 5 1.5 1.0 .5 1H NMR spectrum of 134 (250 MHz, CDCI3) 05 CO o iP r" % ^ " s P h 134 CHB-l-223 (62.9 MHz, CDCI3 ) Figure 14. 13C NMR spectrum of 134 (62.9 MHz, CDCI3 ) o> IPr 's « P h INTEGRAL 135 CHB-l-303 (250 MHz, CDCI3 ) •) N B ■ 6. 5 5.0 PPM 1H NMR spectrum of 135 (250 MHz, CDCI3 ) 3.5 Z.5 165 Figure 15. 5.5 i P r * '^ X ^ S8ph 135 CHB-l-303 (62.9 MHz, COCI3 ) . 1..—,... j. Figure 16. ..... . . [L- ... . ... | 1.........r--t - .r 13C NMR spectrum of 135 (62.9 MHz, C D C I3 ) rn.mv+ |I; a 5 fsi ** u r. IT VI n u a M e O jC ' ^ 5 ^ c ° S e P h INTEGRAL 139 CHB-l-280 (250 MHz, CDCI3 ) 7 .5 Figure 23. 7 .0 6 .5 6 .0 5 .5 5 .0 4. 5 •—I—' 4 .0 ' " 'I 3. 5 3. 0 ' ’—I—r P *5 1H NMR spectrum of 139 (250 MHz, CDCI3 ) •vj CO MeOjC COSePh 139 CHB-l-280 (62.9 MHz, CDCI3) Figure 24. 13C NMR spectrum of 139 (62.9 MHz, CDCI3 ) o SPh 140 CHB-l-61 (250 MHz, CDCI3 ) r l —UUA*__*- k 7.5 7. 0 6.5 5.5 5. 0 4. 5 4. 0 PPM Figure 25. 1H NMR spectrum of 140 (250 MHz, CDCI3 ) H c 13 CHB-l-57 (500 MHz, C6 D6) T 1 1 ' ■ i ■ 7. 0 1 1 ' I 6. 5 ' 1 i ............................. — i— ■— ■— i— |— i— i— i— '— |— i— i— i— 1 |— i— i— i— i— | 6.0 5. 5 5.0 4. 5 4 0 3 5 • I 2. 5 I 2.0 I 1. 5 T 1. 0 5 PPM Figure 26. 1H NMR spectrum of 13 (500 MHz, CgDg) a> 13 CHB-l-57 (62.9 MHz, CDCI3 ) ^ ■ i l..iiiMpr m Figure 27. ry-.-.ni^^^y^-r L '-n*i‘V~[-fn‘i’^r,ir|i1j(iTii;;A)/rni.ti,tiirj1(l/trijj/u‘ilrl.'j 13C NMR spectrum of 13 (62.9 MHz, C D C I3 ) SPh M* 0 SPh 144 CHB-l-57 (250 MHz, CDCI3 ) u u PPM Figure 28. 1H NMR spectrum of 144 (250 MHz, CDCI 3 ) ft-■O »ic ff c o * £s r»*rr\ \ \ r\ rv 323:/ ^ SPh W#- k A w 0 SPh 144 CHB-l-57 (62.9 MHz, CDCI3) Figure 29. 13C NMR spectrum of 144 (62.9 MHz, COCI3 ) (/ a iM y 13 CHB-l-57 (300 MHz, CDCI3) k k k A A k k V-Al_JUUu r —r— 3.? Figure 30. i 3.0 —T— 2.6 “ r~ 2 .4 —T“ 2.0 PPM NOE spectrum of 13 (300 MHz, CDCI3 ) • w 145 CHB-IV-32 (300 MHz, CDCy / o n \* / W \SJ 4 1—i""' 7. 0 ’—I—' 6.S 6.0 '—I—T 5. 6 ' — I— ■ 5. 0 4.5 4. 0 PPM Figure 31 1H NMR spectrum of 145 (300 MHz, CDCI3 ) 3. 0 2. 5 0 ' I‘1 2.0 0 -~ r 1. 5 • i < ^S e M ( i 1 3 c : 1 i * i I c c c i i 5 1 w 1 I I ; • 145 CHB-IV-32 (62.9 MHz, CDCIj) Figure 32. 13C NMR spectrum of 145 (62.9 MHz, CDCI3) 00 ro CHB-lll-56 (300 MHz, COCI3) XT Figure 33. r— ' I.S 0.0 '—I—' 3.6 p-, 9.0 O r—'—1—' 4 .0 PPM 1H NMR spectrum of 146 (300 MHz, CDCI3) ► • I • tj ■ ; c < E iE £ g ► m S * 5 5 j 9 p e *" 1 1 t a i 1 * 146 CHB-lll-56 (75.5 MHz, CDCb) HMfuMf IH W M IU Figure 34. 13c NMR spectrum of 146 (75.5 MHz, CDCI3) 00 ■ft. v 14 CHB-ll-16-3 (500 MHz, C6D6) /// / 1AAa a _ 1 lA iU U i 7. 5 1 ’ ’ I 7. 0 ' - ’ ■ I 6. 5 ■ ■ ■ ■ i 6. 0 1 ’ 1 r~ I 5.5 ’ ' ' 1 | 5.0 1 ' ' ' | 4. 5 ' 1 ' '— i— ' 1 *— >— |— 4. 0 3 5 PPM Figure 35. 1H NMR spectrum of 14 (500 MHz, C6D6) ■r ■ 2. 5 2.0 1.0 “V 14 CHB-ll-16-3 (62.9 MHz. CDCI3) Figure 36. 13C NMR spectrum of 14 (62.9 MHz, CDCI3 ) Mo " ty Cf INTEGRAL u • i ■- ’ ■r 7. 5 7. 0 J" • ■' i ■ ■ 1 ■ i * 1 ’ 1—i"1 • 1—•—i 1 1—1 1—r~ 6.5 6. 0 5.5 5.0 4. 5 231 150 CHB-ll-23-2 (250 MHz, COCI3) 4. 0 PPM Figure 37. 1H NMR spectrum of 150 (250 MHz, CDCI3 ) 00 ^4 150 CHB-ll-23-2 (62.9 MHz, CDCI3) Figure 38. 13C NMR spectrum of 150 (62.9 MHz, CDCI3 ) 188 PhSeCH2CI 151 CHB-ll-23-3 (250 MHz, CDCI3 ) JL U e .o 7 .5 7 .0 6 .5 6 .0 5 .5 5 .0 4 .5 PPM Figure 39. ■ i » 4. 0 3. 5 1 r-r 3.0 1 — 1 — 2. 5 r ---(---2.0 1 1. 5 1H NMR spectrum of 151 (250 MHz, CDCI3 ) 00 CO PhSeCHjCI 151 CHB-ll-23-3 (62.9 MHz, CDClj) i^ ~ l Figure 40. 13C NMR spectrum of 151 (62.9 MHz, CDCI3 ) r ^ i ’m n * l^ .ij ij_ i & (PhSe) 2 CH2 152 CHB-ll-23-4 (300 MHz, CDCI3 ) I A U 1 I 1 '■ 1 1 \ ' 7.5 Figure 41. 7. 0 6.5 6.0 1 1 1 1 » ~r~ ' 5.5 ' T 1 ’ « ' 5n \ a ■; 1H NMR spectrum of 152 (300 MHz, CDCI3 ) 4 * PPM (PhSe) 2 CH2 152 CHB-H- 23-4 (62.9 MHz. CDCI3 ) uJvvA. Figure 42. 13C NMR spectrum of 152 (62.9 MHz, CDCI3 ) CO PO "V 14 CHB-ll-16-3 (300 MHz, CDCI3 ) jJAA^Jk. rTJ O 0 03(0 «22? Figure 43. COSY 1H NMR spectrum of 14 (300 MHz, CDCI3 ) V 14 CHB-ll-1 6-3 (300 MHz, CDCI3 ) 2.9 C-H correlation NMR spectrum of 14 (300 MHz, CDCI 3 ) 194 55 Figure 44. “V 14 CHB-ll-1 6-3 (300 MHz, COCI3) A —1------------3.2 Figure 45. il L Am 1--------- ■---1------------- 1---1------------3.0 2.8 2.6 1--------- 1---1-------- 1 2.4 2.2 NOE spectrum of 14 (300 MHz, CDCI3 ) r— 2.0 CHB-lll-51 (300 MHz, CDCI3 ) 1 7.4 1 1 7.? 1 7. 0 Figure 46. 1 1— 1— 1— 1— 1— 1— 1— ■— 1— 1— 1— ■— 1— '— 1— •— 1— ■— 1— • - i — ■— f 6. B 6.6 6.4 6.2 6.0 5.6 5.6 5.4 5.2 5.0 4. 8 4.6 H — ■— 1— ■— 1— 4.4 4.2 PPM 4 0 1H NMR spectrum of 153 (300 MHz, CDCI3 ) 1 H Dr V 153 CHB-lll-51 (75.5 MHz, CDCI3 ) ■■■■■■■■ ) ■ F ig u re 47 13C NMR spectrum of 153 (75.5 M Hz, C D C I 3 ) iP r 154 CHB-l-206-1 (250 MHz, CDCI3 ) 7.0 6.5 6.0 5.5 PPH F ig u re 48. 3.5 2.5 1 H NMR spectrum of 154 (250 MHz, C D C I 3 ) 198 Sip Y H C IPr 154 CHB-l-57 (62.9 MHz. CDCI3) Figure 49. 13C NMR spectrum of 154 (62.9 MHz, CDCI 3 ) CD CD " V r INTCSAM. 155 CHB-ll-301-2 (300 MHz, CDCI3) •i1 7.5 Figure 50. 11 ' 6.5 • 1 fi.O * T~ r - r 4.0 3. 5 1H NMR spectrum of 155 (300 MHz, CDCI3) ‘V 155 CHB-ll-301-2 (62.9 MHz, CDCI3 ) .. 1.. ■>, Figure 51. 13C ( Tf r y - NMR spectrum of 155 (62.9 MHz, C D C I3) (l- T V r ' rift-Arlfir » ' f r r ir r n t t1* ! i » i j |Y |i *tynfV 'i‘A.~i‘ifl,t'i.i " nf-t-.-.TrtiMf'ii SPh O I P r '^ N- ^ S P h 156 CHB-l-206-2 (250 MHz, CDCI3 ) / A s / A u A U ....................................................... * — ■ 1 ■ 1 ■ J i * ■ * * i 1 ■ * 1 i ................. r 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 1 » ' 2.5 * I '■ 2.0 U 1.5 P PM Figure 52. 1H NMR spectrum of 156 (250 MHz, CDCI 3 ) no o no SPh IPr O X A . SPh 156 CHB-l- 206-2 (62.9 MHz, CDCI3 ) ................................................................................................ F ig u re 53. 1 3C f r - . r n i NMR spectrum of 156 (62.9 MHz, C D C I3) ., -U l 1 — i- . - r - - j ro o co r \ IPr 157 CHB-1I-30M (250 MHz, CDCI3 ) 7. 0 6.5 6.0 r, •1 . 0 PP M Figure 54. 1H NMR spectrum of 157 (250 MHz, CDCI3) ro o Y IPr r- £ i 17.<03 oJH r * tv 1 I o 157 CHB-ll-301-1 (62.9 MHz. CDCI3 ) Figure 55. NMR spectrum of 157 (62.9 M Hz, C D C I 3 ) ro 0 01 8 8323 CHB-IV-5-1 (500 MHz. C6 D6) '' 0.5 8.0 7.5 7.0 I' I 6.5 ' ' ' ' 1 I ........................... | 6.0 5.5 . I I . 5.0 | . I ■ | . I . J.5 . | <1. 0 ' p" i 3.5 1 3.0 2.5 1 .5 5 PP M Figure 56. 1H NMR spectrum of 8 (500 MHz, C 6 D 6) ro o 05 8 CHB-IV-5-1 (62.9 MHz. CDCI3) * Figure 57. M r* M bW 13C NMR spectrum of 8 (62.9 MHz, CDCI3) SPh Phx^ O ^S P h 158 CHB-IV-5-2 (250 MHz, CDCI3 ) Figure 58. 1H NMR spectrum of 158 (250 MHz, CDCI3 ) — I— ' — I— ' 4. 0 3.0 —I— 2.0 T— 1.5 ro o 00 SPh 158 CHB-IV-5-2 (62.9 MHz, CDCI3 ) Figure 59. 13C NMR spectrum of 158 (62.9 MHz, CDCI3 ) u .3 1.0 1. 5 S ^ i ItpT fl E? 2. 0 03 trvk 2.3 3.0 , ‘i'tglri ^ r W v <>1y r r t ,•,- V t|W ^ ro ro (O Me°2C' A V 164 CHB-III-43 (300 MHz, CDCI3) J s fb i ilJlllii ,------ 6.5 Figure 80. .5 i't>M 1H NMR spectrum of 164 (300 MHz, CDCI3 ) J / ) / M Aa, J-J . . . . A -I. 0 ro CO o 164 CHB-IM-43 (62.9 MHz. CDCI3) mNh Figure 81 “ r"'" 13C NMR spectrum of 164 (62.9 MHz, CDCI3 ) ro co 165 CHB-lll-52 (300 MHz, CDCI3 ) J1iLA.IL... . a 7.5 7.0 6 .5 6 .0 5 .5 5.0 - . W .A . 3.5 PPM 1H NMR spectrum of 165 (300 M Hz, C D C I 3 ) 232 Figure 82. 165 CHB-lll-52 (75.5 MHz. CDCI3 ) Figure 83. 13C NMR spectrum of 165 (62.9 MHz, CDCI3) ro CO CO MeOjC in t e g r a l 166 CHB-lll-69 (300 MHz. CDCI3) PPM Figure 84. 1H NMR spectrum of 166 (300 MHz, CDCI3 ) 234 MeOjC 166 CHB-lll-69 (62.9 MHz. CDCI3) m m & m Figure 85. 13C NMR spectrum of 166 (62.9 MHz, CDCI3 ) ro co oi CHB-l-66-2 (250 MHz, CDCI3 ) 6.5 PPM Figure 86 . 1H NMR spectrum of 6 (250 MHz, CDCI3 ) n> CO 05 ft rv in in CHB-l-66-2 (62.9 MHz. C D C y - n i^ Figure 87. itf 1 3 c NMR spectrum of 6 (62.9 MHz, CDCI3 ) 237 o SPh H 165 CHB-l-66-1 (300 MHz, CDCI3) L L 1t * 1 1 1 v ' 1 ' 1 i 1 1 ' 1 i 7.5 Figure 88 . 7.0 6.5 6.D 5.D 4 .5 PPH r-T— 4.0 1H NMR spectrum of 165 (300 MHz, CDCI3 ) J H H 9 SPh 165 CHB-l-66-1 (62.9 MHz, CDCI3 ) Figure 89. 13C NMR spectrum of 165 (62.9 MHz, CDCI3 ) 167 CHB-1IM3 (300 MHz, CDC13) t ~i ■ 7. 0 Figure 90. ‘i ■ 6 .5 r—p-1 3.r» tM Ji 1H NMR spectrum of 167 (300 MHz, CDCI3) PO o TTf 80S 167 CHB-lll-13 (62.9 MHz, CDCI3 ) lyyt Figure 91. 13C NMR spectrum of 167 (62.9 MHz, CDCI 3 ) ro CHB-m-2-1 (300 MHz, CDCI3 ) k ’ 1 7.5 1 ■ 1 ' i"1 7.0 1 ■-»' 1 6.5 i »»* 1 6.0 ■ 4 -^ - , . 5.0 , , 4.5 j. 4.0 PPM Figure 92. 3.5 1 3.0 ■’ ■1 I 1 1 1 1 I ' 1 ' 2.5 2.0 1. 5 1.0 1H NMR spectrum of 168 (300 MHz, CDCI3 ) ro ro JyU M i NW CHB-lll-15 (300 MHz. CDCI3) JL bTs ' ' ' 7.0 ' 7.5 4!g <7 PPM Figure 94. 1H NMR spectrum of 169 (300 MHz, CDCI3 ) ro ■t*. ° 169 CHB-lll-15 (62.9 MHz, COCI3) Figure 95 13C NMR spectrum of 169 (62.9 MHz, CDCI3) CHB'M-21 (300 MHz, CDCI3 ) A _A _ j —r-T 1 7.3 7.0 Figure 96. ' I ' 6.3 r— j— r 6.0 3.3 1H NMR spectrum of 170 (300 MHz, CDCI3 ) 246 H.iU oViPr H A1 1 Cf \JTl ° 170 CHB-lll-21 (62.9 MHz, CDCI3 ) Ww M wNrtw iiiiMiVww. Figure 97. 13C NMR spectrum of 170 (62.9 MHz, CDCI3) ro a 171 CHB-M-4 (300 MHz, COCI3 ) r >\k> \) Vis 1 ' ' Figure 98. e!o ' ' r sis1 ' ' s!o ' ' 4I3 ' ' ' | | l«*J.^L.^..f. ^ [. ^ k |,|rf^ t.^ .f.||t1Wfri1r( ^||t1lllf<|)rT1|||^ r^r|>J|)t |f|J 13C NMR spectrum of 174 (62.9 MHz, CDCI3 ) ■m# L ro tn cn ° H 176 CHB-lll-154 (300 MHz, CDCI3) — | 7.5 ' ' ' ' I ' 7.0 I I ■ | 6.5 I • ' ' | 6.0 i i----- '----- ■-----1-----1-----1-------- 5.5 1--1----- 5.0 1----- 1----- 1-----•-----1-------- 4.5 1--1-----.----- - 4 0 PPM Figure 106. ~~T 3.5 l . . . . 3.0 2.5 I --------— r- !" ■ 1 1 1 I 2.0 1.5 1.0 1H NMR spectrum of 176 (300 MHz, CDCI3) ro cn & H Me O OH H 176 CHB-lll-154 (62.9 MHz. CDCI3 ) Figure 107. 257 13C NMR spectrum of 176 (62.9 MHz, CDCI3 ) Mo H 0 OH 177 CHB-IV-35 (300 MHz, CDCI3) JL r ■ • • 7 *0 Figure i ®-5 108. ■ ■ ■ • • #.0 ■— 1— — ■— ■ — 5.3 f^ 1 5.0 * .3 r» » -■ ■ i * .0 PPM 3.5 jm w x 3.0 2.9 2.0 1.5 t.O 1H NMR spectrum of 177 (300 MHz, CDCI 3 ) ro cn 00 Me H O OH H 177 CHB-IV-35 (75.5 MHz, CDCI3) k'iw it** Fig u re 109. 13C NMR spectrum of 177 (75.5 MHz, C D C I 3 ) H O ‘ SPh 178 CHB-IV-36 (300 MHz, COCI3 ) f y s ?.o F ig u re 110. 6.5 6.0 9.9 9.0 4.9 4. 0 1 H NMR spectrum of 178 (300 MHz, C D C I 3 ) H178 CHB-IV-36 (75.5 MHz, CDCy 13C NMR spectrum of 178 (75.5 MHz, C D C I3 ) 261 F ig u re 111. H Ph ° SPh H 179 C H B -lll-1 5 2 (300 MHz, CDCI 3) I------------------- 1--- '------ •’----'—I— 7.5 7.0 6.5 --- 1---------6.0 ■1-1--- 1--- r - , — X— 1 - ' 5.5 5.0 4.5 4.0 | 3. 5 . . I i r - r 3.0 . 2.5 2.0 1.5 PPM Figure 112. 1H NMR spectrum of 179 (300 MHz, CDCI3) t\3 03 ro H Ph O H 179 CHB-lll-152 (75.5 MHz. CDCI3 ) Figure 113. 13C NMR spectrum of 179 (62.9 MHz, CDCI3 ) ro 05 CO H Ph ° ° H 180 CHB-lll-152 (300 MHz, COCI3 ) ~Ts Figure 7.0 114. 6. 5 6.0 I ’ 5. 0 t—J—T 4. 5 4. 0 I ’—'—'—'— 3. 5 3. 0 ’—’ r 1— 2.5 -1 -r . 2. 0 . 1 .5 1H NMR spectrum of 180 (300 MHz, CDCI3 ) ro 03 t:; I : Y( H P h ? OH 180 CHB-lll-152 (75.5 MHz, CDCI3) Figure 115. 13C NMR spectrum of 180 (75.5 MHz, CDCI3 ) 265 / MeOjC H O H ° 181 CHB-lll-156 (300 MHz, CDCb) i J ' 1 1 r ' 1 . T 8.0 Figure I ‘j 7. 5 116. j . . . i 7.0 r i i ■ j 6.5 , j . i 6.0 I 5. 5 I I I I I 5. 0 I I P -V J-'I 4. 5 PPM 1H NMR spectrum of 181 (300 MHz, CDCI3 ) 1. 0 ro o CD b MeOjC H ° SPh 1S1 CHB-lll-156 (75.5 MHz, CDCI3) - a— .J ------ ----------- Figure 117. ----- - ------ .....A ...J U .................................. ................ 13C NMR spectrum of 181 (75.5 MHz, CDCI3 ) ' L.i iii., j_ j I ro cn 193 CHB-l-111 (250 MHz, CDCI3 ) m!J A lL l\ . U U k x * L— —[ «•« Figure 118. 4.6 ^ 4 .1 , .T , ^ 4.2 4 .0 3 . . H :t f : ».j :i. ;? j .o :-.n c.r. , :. -t - 1 . 1 - 1 • j 0 l m -1 1 * ■ i j.4 1.2 1.0 1H NMR spectrum of 193 (250 MHz, CDCI3 ) 268 b M o* €m ¥ 193 CHB-l-111 (62.9 MHz, CDCI3 ) WUmW*iUnhAWwfc - h ^ Figure 119. 13C NMR spectrum of 193 (62.9 MHz, CDCI3 ) ro O) co ° H 195 CHB-IV-36 (300 MHz. CDCI3 ) I ' 6.S '—I—' 6.0 — ,— i — I— ' — (— ' 5.5 5.0 4.5 —1— 1— .— ;— 1 4.0 3.5 PPM Figure 120. 1H NMR spectrum of 195 (300 MHz, CDCI3 ) ro ■vi o Me 9 OEt ° H 195 CHB-IV-36 (62.9 MHz. CDCI3) uiiAl al muU Figure 121. 13C NMR spectrum of 195 (62.9 MHz, CDCI3 ) P h s o c ' ^ COSPh 298 CHB-IV-24 (300 MHz, CDCI3) 7.5 7 .0 6 .5 6 .0 5 .5 5 .0 A. 5 PPM Figure 122. A. 0 3.5 '—I—1 3.0 1 — 1— 2.5 1 2.0 1H NMR spectrum of 298 (300 MHz, CDCI3 ) 27 2 PhSOC''^^'COSPh 29B CHB-IV-24 (75.5 MHz. CDCy M M) 13C NMR spectrum of 298 (75.5 MHz, CDCI3) 273 Figure 123. * COSePh P hS eO C 299 CHB-IV-29 (300 MHz, CDC13) f u_JL ’—1—» 8.5 Figure 8.0 124. T 7.5 •“T 7.0 6 .5 6.0 --1--r 5.5 PPH i 1 1 ' 1 r 1 ■1 1 4.5 4.0 1 3.5 ' '—'—1—1—•—»—•—i— 3.0 2.5 1H NMR spectrum of 299 (300 MHz, CDCI3 ) ro -sj PhS eO C ^ ^ ^ C O S e P h 299 CHB-IV-29 (75.5 MHz, CDCy 13C NMR spectrum of 299 (75.5 MHz, COCI3 ) 275 Figure 125. COSPh COSPh 303 CHB-IV-27 (300 MHz, CDCI3 ) J f I If J ___K 7.5 7.0 F igu re 126. 6.5 6.0 5.5 5.0 4.5 PPM 3.5 2.5 2.0 1H NMR spectrum of 303 (300 MHz, C D C I 3 ) 276 * »l*l Is !35 i i \/ P ' h s ^ Tl .C O S P h COSPh 303 CHB-IV-27 (75.5 MHz, CDCI3 ) 13C NMR spectrum of 303 (75.5 MHz, CDCI3 ) 277 Figure 127. COSePh „ COSePh 304 CHB-IV-27 (300 MHz, CDCI3) PPM 1H NMR spectrum of 304 (300 M Hz, C D C I 3 ) 278 F ig u u re re 128. 128 Fig COSePh C O S eP h 3U4 CHB-IV-27 (75.5 MHz. CDCI3 ) »> Figure 129. m !> 13C NMR spectrum of 304 (75.5 MHz, CDCI 3 ) MM COSPh XX HjC ^ CH3 305 CHB-l-234 (300 MHz, CDCI3) r fi Figure 130. 1H NMR spectrum of 305 (300 MHz, CDCI 3 ) ro CO o COSPh XX HjC CHJ 305 CHB-l-234 (62.9 MHz. CDCI3 ) Figure 131. 13C NMR spectrum of 305 (62.9 MHz, CDCI3 ) COSePh H3C CH, 307 CHB-l-246 (300 MHz. CDCI3) I NTEGRAL \K r/'fi 1H NMR spectrum of 307 (300 M Hz, C D C I 3 ) 282 Fig u re 132. 0 ,,«COSePh ^CHj 307 CHB-l-246 (62.9 MHz. CDCI3 ) Figure 133. 13C NMR spectrum of 307 (62.9 MHz, CDCI3 ) 283 COSPh XX HjC CHB-ll- 8 8 Figure 134, COjMe 309 (300 MHz, CDCI3 ) 1H NMR spectrum of 309 (300 MHz, CDCI3 ) { > \( CO SPh Hj C jCC' COjMe 309 GHB-ll- 8 8 (6 2 . 9 MHz, CDCI3 ) Figure 135. 13C NMR spectrum of 309 (62.9 MHz, CDCI3) 285 - COSPh .XX.. HjC COjM« 309 CHB-l-243 (62.9 MHz, CDCI3 ) ll ll 1 . ' 1 H N 1 II 1 II II II II ' 1 11 '1 11 1 II n , I 1 F ig u re 136. *8® 160 190 HO 130 120 he rt : r lio 100 90 IN A D EQ U A TE spectrum of 309 (62.9 M Hz, C D C I 3 ) 60 70 60 50 4 0 30 j0 286 1 190 X 'S y'K 'iH H,C/ ^^^C O jM e 311 CHB-l-273 (300 MHz. COCI3 ) Jli / ■ 10.0 PPM JL U 7.0 6. 5 6. 0 5. 5 5.0 4.5 4.0 PPM Figure 137. 1H NMR spectrum of 311 (300 MHz, CDCI3 ) 3. 5 2 .5 ro 00 -4 i 1 X r • M i : c * ; 5 a i « e 1 g K a A A a / , . . c o 2h H,C XX C O jMo 311 CHB-l-263 (75.5 MHz, CDCI3 ) L> Figure 138. i ...............^ ^■■|.|,r||.-jin ^ ‘~iriT^'i'|.frrrn^iyiVwwiwrwiwi(iiMl^»iiif|»^y^ 13C NMR spectrum of 311 (75.5 MHz, CDCI3 ) I\5 00 00 CHB-l-264 (300 MHz, CDCI3) / . J iL aJ I j] di } K) ■s 1 > • -» 70 Figure 139. I—'—’---•—>—I— 6.3 6. 0 , - t—r—r— 3 .3 3 .0 <.3 PPM T" 1.0 3.5 ....... I I 1 r~ 1.5 1H NMR spectrum of 312 (300 MHz, CDCI3) ro 00 co I Me 312 0 C H B - l- 2 6 4 ( 7 5 . 5 M H z , C D C I 3 ) 13C NMR spectrum of 312 (75.5 MHz, CDCI 3 ) 290 l*W|W,WwiiV*wW #»«4ll >wW wwW *«r**i« Figure 140. , X \ >>>«CHrOH X —^COjMe X Mo 313 CHB-l-249 (300 MHz, CDCI3 ) / I 1 ’ I" 7 .5 I 7. 0 6.0 5. 5 ~l~ 5. 0 4.5 PPM Figure 141. 1H NMR spectrum of 313 (300 MHz, CDCI3) i £ * 5 a c 1p c \ t 8 i R t * a jC T Mo^'vX,^COsMa 313 C H B -ll-1 0 2 (75.5 MHz, CDCI 3) * -V - Figure 142. 13C NMR spectrum of 313 (75.5 MHz, CDCI3 ) ro co ro COSePh HjO 314 CHB-ll-102 (300 MHz, CDCI3 ) u ; JL ^ » uL _ a A _ J L U U U U s> u PPM F ig u re 143. 1 H NMR spectrum of 314 (300 MHz, C D C I 3 ) 293 28.7(16 V COSePh XX H3C COjMs 314 CHB-IM02 (62.9 MHz. CDCI3 ) ro CO Figure 144. 13C NMR spectrum of 314 (62.9 MHz, CDCI3 ) XX HjC CO,M8 316 CHB-IV-10-1 (300 MHz. CDCfe), J JL /v U '--1--7. 5 1 — 7.0 6.5 6.0 5.5 I— 5.0 4.5 PPM Figure 145. 1H NMR spectrum of 316 (300 MHz, CDCI3 ) y vV XX, HjC COjMo 316 CHB-IV-10-1 (62.9 MHz, CDCI3 ) Figure 146. 13C NMR spectrum of 316 (62.9 MHz, CDCI3 ) ro to 05 ^ »C H 0 XL. HjC CO,Me 317 CHB-IV-10-2 (250 MHz, CDCI3 ) A INTEGRAL I 5.0 Figure 147. . 1H NMR spectrum of 317 (250 MHz, CDCI3) 4. 5 4.0 3.5 Al {) 3.0 Ju 2.5 2.0 ro co ■si CHO XL H jC ' ~ COjMe 317 CHB-IV-10-2 (62.9 MHz. CDCI3) J L * Figure 148. 13C NMR spectrum of 317 (62.9 MHz, CDCI3 ) w t f w bfii JUjLi XX O v COSPh Me 320 CHB-ll-223 (300 MHz, COCI3 ) jo iA J ijU u e - e - j - e - , - - . --- f—■,---' •r*/.0 Figure 149. F.5 fi.O !i.5 1H NMR spectrum of 320 (300 MHz, COCI3 ) r I COSPh XX O ^ Me 320 CHB-ll-223 (62.9 MHz, CDCI3) Figure 150. 13C NMR spectrum of 320 (62.9 MHz, CDCI3 ) 300 1 COSePh XX O Ms CHB-lll- 1 323 (300 MHz, CDCI3 ) JUu. t —r—s /.3 Figure 151. /. 0 P.* * * 1" ’ ft.O I,r> I IN A D E Q U A T E -100 spectrum of 326 (62.9 MHz, CDCI3 ) 1( 305 Figure 1 1 1 I I,1 I 1 1 1 i | 1 1 1 1 1 1 < 1 COSePh XX O ' ^ COjMo 329 CHB-ll-135 (300 MHz, CDCI3) u. uu *f~; ■’ ’ r. 1 7.0 Figure 156. T .............. *I h .C .* 1H NMR spectrum of 329 (300 MHz, CDCI3 ) A ii V COSePh & O ' ^ 'C O jM e 329 CHB-ll-135 (62.9 MHz, COCI3 ) Figure 157. 13C NMR spectrum of 329 (62.9 MHz, CDCI3) CO O •vj J tr ~ COSPh 330 CHB-ll-177-1 (300 MHz, CDCI3) '— I— \ 5 i A Jl VJl 7 .0 Figure 158. r i- *7 —r fi. 5 6.0 3.5 4.5 ^1— 4 .0 Ll r - J ----3 .5 .A . 1 — r ?. 5 ’ 2.0 1H NMR spectrum of 330 (300 MHz, CDCI 3 ) CO o 00 COSPh 330 CHB-ll-177-1 (62.9 MHz, CDCI3 ) | IfL Figure 159. 13C NMR spectrum of 330 (62.9 MHz, CDCI3 ) .Ihil i b . COSPh — 331 CHB-ll-177-2 (300 MHz, CDCy f J_L U 7.0 Figure 160. 6.5 6.0 5.5 1 ~1 ........ ... 4.5 (’PM I ■ 4.0 —j . . »- t 1 3 5 U U — 3.0 2.5 2.0 1 .5 1.0 1H NMR spectrum of 331 (300 MHz, CDCI3 ) CO o .COSPh __ 1 Ms 331 CHB-ll-177-2 (75.5 MHz, CDCI3) m m m i i m n i i^n w m i m «-» — F ig u re 161. . ■■■ .......... m «,■« 13C NMR spectrum of 331 (75.5 MHz, C D C I 3 ) j y COSePh 332 CHB-ll-188-1 (300 MHz, CDCI3 ) vv. F ig u re 162. 1 H NMR spectrum of 332 (300 MHz, C D C I 3 ) CO IV) j y COSoPh 332 CHB-ll-188-1 (62.9 MHz, Figure 163. CDCI3) 13C NMR spectrum of 332 (62.9 MHz, CDCI3) J b .I COSePh Me 333 CHB-II-188-2 (300 MHz, CDCI3) LJ JUiu u ‘I ' 3.5 Figure 164. .1.0 r- —f-1 —r-^—T-f- T" 2.5 2.0 1.5 V 1.0 1H NMR spectrum of 333 (300 MHz, CDCI 3 ) CO CIHfl CH. 334 ° CHB-ll-216 (300 MHz, CDCI3 ) *’• n 3.5 Figure 165. 1H NMR spectrum of 334 (300 MHz, CDCI3 ) 315 cmb^ J ^ ch> °__ C 334 ° CHB-ll-216 (62.9 MHz. CD2 Cl2 ) Figure 166. . . a u i L j i l h a . ^ 1 ^ —Xlitj. - I - . - 13C NMR spectrum of 334 (62.9 MHz, CDCI3 ) . — ,i..- JL .. 316 L L tJ q . c° JMe r COSPh 335 CHB-ll-153 (300 MHz, CDCy ^ -- 1-- ' 5 .0 '—I—1 4 .5 PPM Figure 167. 1H NMR spectrum of 335 (300 MHz, CDCI3 ) ^ _A~jl_A.__ ,A PPM EO%y. a n **■ it cv r \ tv c\ c\ YY a ? COSPh 335 CHB-ll-153 (62.9 MHz. CDCI3) I Figure 168. 13C NMR spectrum of 335 (62.9 MHz, CDCI3) lU L K COjMe d ? C O S eP h 337 CHB-ll-151-1 (300 MHz, CDCI3 ) I PPM Figure 169. 1H NMR spectrum of 337 (300 MHz, CDCI3) 3 .3 1 ^ I . . . i i i—i—.—i—|—.—i—' ‘ ' 1 — 3 .0 2 .5 2 .0 1 .5 CO CO K C02Me COSePh 337 CHB-ll-151-1 (62.9 MHz, CDCI3 ) Figure 170. 13C NMR spectrum of 337 (62.9 MHz, CDCI3) k Y ^ COSePh 338 CO*Me CHB-ll-151-2 (300 MHz, CDCI3 ) ilJUL J _ k i J li i — 1— ■ 7 .0 Figure 171. — I— . 6 .9 T—' 6.0 i— (—. 9 .9 — I— 1— .— 1— .— j— 9 .0 1 4 .9 PPM 1H NMR spectrum of 338 (300 MHz, CDCI3 ) j U _ COSoPh COjMe 338 CHB-ll-151-2 (300 MHz, COCI3 ) Figure 172. 13C NMR spectrum of 338 (75.5 MHz, CDCI3) 322 COjMe 340 CHB-lll-81 -2 (300 MHz, CDCI3 ) /// / ML ju I f JL -J INTEGRAL 1 1 UW r».s 6 .0 u 5.5 1—r~T ’■'T * ' 5.0 •1.5 PPM 1H NMR spectrum of 340 (300 MHz, CDCI3 ) 3.5 3.0 u ; r""*t—• 3.5 "T .’ . 0 ’ t .5 323 Figure 173. . a AK CIH®V COjMo O CO 341 CHB-lll-81-1 (250 MHz, CDCI3 ) 3.0 Figure 174. NMR spectrum of 341 (250 MHz, CDCI3 ) 3.0 CJ ro •e* C IH g O CO 341 CHB-lll-81-1 (62.9 MHz, CDCI3 ) Figure 175. 13C NMR spectrum of 341 (62.9 MHz, CDCI 3 ) 325 Figure 176. 1H NMR spectrum of 342 (300 MHz, CDCI3) '''COSPh Me 342 CHB-ll-211-1 (75.5 MHr, CDCI3 ) < M u J iu m m m «« ■ ii Figure 177. ............... - .......................... i- l M. ... , r . 13C NMR spectrum of 342 (75.5 MHz, CDCI3 ) CO ro -Nl x CO SPh Me 343 CHB-ll-211-2 (300 MHz, CSD$) —i—1—1—1—1—i— 6 .9 Figure 178. 6 .0 1H NMR spectrum of 343 (300 MHz, CeDg) 329 CDCI3 ) Ms ''COSePh Me 346 CHB-ll-190-1 (300 MHz, C6 D6) // t w / A ) 1"I 5.0 Figure 180. 1 1‘I 1 »•' 4.5 PPM I •» 4.0 1H NMR spectrum of 346 (300 MHz, C6D 6) '—i—' 3.0 CO CO o 'COSsPh 13C NMR spectrum of 346 (62.9 MHz, C D C I 3 ) 331 Fig u re 181. or >T^COSePh Ma 347 CHB-ll-190'2 (300 MHz. CDCI3 ) I , i,i-j 7 .*» Figure 182. i f , - 1- . /.o r . 6.5 .-I - . 0.C ■r 5.S ’ I* ■ 3.0 1H NMR spectrum of 347 (250 MHz, CDCI3) .~ r , 3.5 3.0 2.3 ’I • 2.0 CO CO ro C f 'COSPh COjMa 350 CHB-ll-209-1 (250 MHz, CDCI3 ) A Aa M * 1— 7.0 6.5 6.0 5.5 5 *0 5 4.0 PPM Figure 183. 1H NMR spectrum of 350 (250 MHz, CDCI3) 3.0 ?.5 m» 1 I 1’ I * ’ 2.0 \ .5 r~’ t.O CO CO CO {( Me Q r COSPh COjMo 350 CHB-ll-209-1 (62.9 MHz. CDCI3 ) aj w Figure 184. 13C NMR spectrum of 350 (62.9 MHz, CDCI3 ) co co Me r^ V 'C O S P h C O jM e 350 CHB-ll-209-1 (62.9 MHz, CDCy 3.0 3.0 3.3 6.3 - 7.0 - 7.3 PPM 185. COLOC spectrum of 350 (75.5 MHz, CDCI 3 ) 335 Figure Y^^COSPh COjMe 351 CHB-ll-209-2 (300 MHz, CDCI3 ) JUL _a J /.o Figure 186. ill l .- j - r 0 I'•1I'.M 1H NMR spectrum of 351 (300 MHz, CDCI 3 ) , —[ :i. 0 lLrv>AM^ ----2 .5 2 .0 PPM iaa^ si 1 Cc' COSPh COjM» 351 CHB-ll-209-2 (75.5 MHz, CDCI3 ) Figure 187. •+* ***** 13C NMR spectrum Of 351 (75.5 MHz, CDCI 3 ) ***** *1+ co co -Vj 354 CHB-IV-36 (300 MHz. CDCI3) /// / / // I 7 lN _ 111 r * i“ 1 /.o Figure 188. fi.3 IllU I II —I— 1 3.r» •-T --r —r--t •I. T» »VM , 4 .0 1H NMR spectrum of 354(300 MHz, CDCI3 ) “1 3.r> ...0 —r 1.0 CO CO 00 354 CHB-IV-36 (75.5 MHz, CDCI3 ) fJ-,-—• Figure 189. 13C NMR spectrum ot 354 (75.5 MHz, CDCI 3 ) AiA»yt jLj- r M9 355 u CHB-IV-35 (300 MHz. C6 D6) "~1 /.«* ' ■ ' ' I ■ • ■ ■ I 7 .0 6 .5 Figure 190. ' ' l^ 1 6 .0 r I ' 5 .5 1 r_~1 — '— '— 5 .0 — 1— 1— '— 4 .5 , 4 .0 PPM ,— r -M - i— . - ^ r 3 .5 3 .0 -.■■■— M-J— # 1 ■* 11— r1-1!— >— I—I— . 1 2 .5 2 .0 1 .5 t ■ .— j— r l 0 —I— .5 1H NMR spectrum of 355 (250 MHz, CDCI3 ) 340 ICO,Me X ' 355 ° CHB-IV-35 (300 MHz, C6 0 6) WiM **nJrtWln > i« Mr t i« *»iiiiHli.iH i m i t i .1 co C f 'cOSePh COjMe 356 CHB-ll-191 (250 MHz, CDCI3 ) 7/ /// / / SK l it I l l i A aA m 7 0 6 5 h ’.JS 5 .5 5.0 -1.5 4.0 3.0 v Vu . x 2.5 2.0 CO Figure 192. 1H NMR spectrum of 356 (250 MHz, CDCI3) to Figure 193. 13C NMR spectrum of 356 (62.9 MHz, CDCI3 ) GO -fc. CO

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