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

• 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
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja001899n

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.