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Pure Appl. Chem. 75(1), 29-38, 2003

Pure and Applied Chemistry

Vol. 75, Issue 1

Stereocontrolled total synthesis of (+)-vinblastine

S. Yokoshima, T. Ueda, S. Kobayashi, A. Sato, T. Kuboyama, H. Tokuyama, and T. Fukuyama+

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Abstract: Stereocontrolled total synthesis of (+)-vinblastine (1) has been achieved using a novel radical-mediated indole synthesis developed in our laboratories. The isothiocyanate 18, prepared readily from quinoline 17, underwent a facile addition of the malonate anion to give 19. The o-alkenylthioanilide 19 was then converted to indole 20 by radical cyclization and protection. (–)-Vindoline (2) was prepared from this key intermediate 20 in a highly efficient manner. The indole core of the 11-membered intermediate 3 was constructed similarly from quinoline. The critical coupling reaction between 2 and the chloroindolenine derived from 3 proceeded with complete control of stereochemistry to give the desired product 66 in 97 % yield, which could be successfully converted to (+)-vinblastine (1).

*Lecture presented at the 14th International Conference on Organic Synthesis (ICOS-14), Christchurch, New Zealand, 14-18 July 2002. Other presentations are published in this issue, pp. 1-70.

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