A Novel Application of a Pd(0)-Catalyzed Nucleophilic Substitution Reaction to the Regio- and Stereoselective Synthesis of Lactam Analogues of the Epothilone Natural Products
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- 作者：Robert M. Borzilleri ; Xiaoping Zheng ; Robert J. Schmidt ; James A. Johnson ; Soong-Hoon Kim ; John D. DiMarco ; Craig R. Fairchild ; Jack Z. Gougoutas ; Francis Y. F. Lee ; Byron H. Long ; and Gregory D. Vite
- 刊名：Journal of the American Chemical Society
- 出版年：2000
- 出版时间：September 20, 2000
- 年：2000
- 卷：122
- 期：37
- 页码：8890 - 8897
- 全文大小：108K
- 年卷期：v.122,no.37(September 20, 2000)
- ISSN：1520-5126
文摘
Several lactam analogues of the epothilones were prepared using a concise semisynthetic approachstarting with the unprotected natural products. Highlighted in this strategy is a novel regio- and stereoselectivePd(0)-catalyzed azidation reaction of a macrocyclic lactone. Subsequent reduction and macrolactamization ofthe resulting azide acid intermediates provided the desired macrolactams in satisfactory overall yields. Theentire three-step sequence was streamlined into a "one-pot" process for the epothilone B-lactam, BMS-247550,which is currently undergoing phase I clinical trials. An initial total synthesis route to prepare the lactamanalogue of epothilone C was completed and compared to the more direct semisynthesis approach. All of thelactam analogues were evaluated in vitro and the results are discussed.