Approaches to the synthesis of dolastatin 11.

Abstract

A synthetic route to a stereoisomer of dolastatin 11, a potent antineoplastic agent from the sea hare Dolabella auricularia, is explored. Synthons for the three unusual acids were prepared as follows: (1) Hmp was prepared by a reaction used previously, but the yield was doubled and the isolation procedure greatly simplified. (2) An indirect procedure was developed for putting in the Ibu unit, with the gem-dimethyls added later. (3) Asymmetric syntheses of two Map stereoisomers established the two configurations in this unit in dolastatin 11 and in the related substances dolastatin 12, majusculamide C and 57-normajusculamide C. The nine pieces required for the 3R, 4S, 12S-stereoisomer of dolastatin 11 were assembled in a convergent synthesis to give a product which probably contains a stereoisomer of 1. An analogous route starting from the correct Map stereoisomer will very likely yield dolastatin 11 itself.