The synthesis of Taxane precursor and seco-Taxane backbone

• Main Authors: Yang, Chang-an, 楊章安
• Other Authors: Sha, Chin-Kang
• Format: Others
• Language: zh-TW
• Published: 1998
• Online Access: http://ndltd.ncl.edu.tw/handle/39044260381974302665

博士 === 國立清華大學 === 化學系 === 86 === The objective of this thesis is to find a rapid and efficient synthetic methodfor taxane and its biogenetic precursor -- seco- taxane. In the first section, we described the initial approach for the taxane synthesis. The ring expansion of bicyclo[3.3.0]octane to cyclooctane-ring and subsequently to taxane B,C ring and taxane A,B ring. However this approach was unsucessful. Later, we efficiently and successfully synthesized taxane A-ring precursor, compound 219, with 53% yield. Then compound 219 was subjected to Claisen rearrangement, reduction and Swern oxidation to form compound 243, a taxane A-ring analogue, with 42% overall yield. In the second section, we described the utilization of compound 243 as starting material in synthesis of taxane. Compound 243 on further alkylation, phenylselenyl cyclization, deprotection and Swern oxidation (4 steps) to yield a rigid compound 274 -- a taxane precursor. The alkylation of compound 243 resulted in two diastereomers 268 and 269. Compound 269 hence formed can be converted to 268 by Mitsunobu esterification and hydrolysis. Attempted intramolecular McMurry reductive cyclization on compound 274 failed. Although the molecular model suggests that the two carbonyls can be close enough to undergo cyclization, NOE experiments on compound 274 at various temperature revealed that the two carbonyl groups of compound 274 could be in close proximity only at temperature above 60℃ which is much higher than the McMurry coupling temperature. In the third section, we described the use of compound 219 as starting material in the synthesis of taxane and seco-taxane. The compound 219 was converted to 302 and 303 by a series of transformations including three key reactions: (1) macrolactonization (2) Tebbe reaction and (3) Claisen rearrangement. We tried to lactonize 278, 287 and 283 respectively to form 10-, 12-, and 14-member ring compounds, However only 283 underwent lactonization and afforded the 14-member ring compound 282 in 75% yield. Compound 282 was finally converted to compounds 302 and 303 in three steps, both having bicyclo[9.3.0]pentadecane backbone.