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

Several lactam analogues of the epothilones were prepared using a concise semisynthetic approach starting with the unprotected natural products. Highlighted in this strategy is a novel regio- and stereoselective Pd(0)-catalyzed azidation reaction of a macrocyclic lactone. Subsequent reduction and ma...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2000-09, Vol.122 (37), p.8890-8897
Main Authors: Borzilleri, Robert M, Zheng, Xiaoping, Schmidt, Robert J, Johnson, James A, Kim, Soong-Hoon, DiMarco, John D, Fairchild, Craig R, Gougoutas, Jack Z, Lee, Francis Y. F, Long, Byron H, Vite, Gregory D
Format: Article
Language:English
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Summary:Several lactam analogues of the epothilones were prepared using a concise semisynthetic approach starting with the unprotected natural products. Highlighted in this strategy is a novel regio- and stereoselective Pd(0)-catalyzed azidation reaction of a macrocyclic lactone. Subsequent reduction and macrolactamization of the resulting azide acid intermediates provided the desired macrolactams in satisfactory overall yields. The entire 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 lactam analogue of epothilone C was completed and compared to the more direct semisynthesis approach. All of the lactam analogues were evaluated in vitro and the results are discussed.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja001899n