Insights into Long-Range Structural Effects on the Stereochemistry of Aldol Condensations: A Practical Total Synthesis of Desoxyepothilone F
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- 作者：Chul Bom Lee ; Zhicai Wu ; Fei Zhang ; Mark D. Chappell ; Shawn J. Stachel ; Ting-Chao Chou ; Yongbiao Guan ; and Samuel J. Danishefsky
- 刊名：Journal of the American Chemical Society
- 出版年：2001
- 出版时间：June 6, 2001
- 年：2001
- 卷：123
- 期：22
- 页码：5249 - 5259
- 全文大小：155K
- 年卷期：v.123,no.22(June 6, 2001)
- ISSN：1520-5126
文摘
A processable total synthesis of a potent antitumor agent, desoxyepothilone F (dEpoF, 21-hydroxy-12,13-desoxyepothilone B, 21-hydroxyepothilone D), has been accomplished. The route is highly convergent.The new technology has also been applied to a total synthesis of 12,13-desoxyepothilone (dEpoB). The crucialpoint of departure from previous syntheses of dEpoB and dEpoF involves presentation of the C1-C11 sectorfor Suzuki coupling with C3 in reduced form. Hitherto, the required S stereochemistry at C3 had beenimplemented via reduction of a keto function after Suzuki coupling. Whereas that chemistry worked quitewell in a synthesis of dEpoB, it was not transferable to a high-yielding synthesis of dEpoF. The reduction ofthe keto group at C3 via a Noyori protocol after Suzuki coupling had proved to be very difficult. In ourcurrent approach, two consecutive aldol reactions are used to fashion the acyl sector. In the first aldolcondensation, C6 becomes attached to C7. Following protection at C7, a two-carbon acetate equivalent is usedto join C2 and C3 with very high asymmetric induction at C3. Only after this center has been implemented isthe Suzuki reaction conducted. This major advance allowed us to synthesize dEpoF in a straightforward fashion.These findings found ready application in the total synthesis of dEpoB. Another part of the study involvedanalysis of the factors associated with aldol condensations joining C6 to C7. In the work described herein, theconsequences of the status of C3 in promoting the C6-C7 aldol coupling are probed in detail. Dramaticstereochemical long-range effects uncovered during the study are described, and a working model to explainthese effects has emerged.