Convergent Synthesis of Dolastatin 15 by Solid Phase Coupling of anN-Methylamino Acid

Abstract

Convergent synthesis of dolastatin 15 (1), a cytostatic depsipeptide isolated from the Indian Ocean sea hare, has been described. For construction of the backbone, a single-step condensation of peptide fragment 2 and pyrrolidone fragment 3 was successfully performed using 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate (CIP) developed by us as an efficient coupling reagent. Coupling of an N-methylamino acid on solid support was first achieved using CIP for the efficient synthesis of peptide fragment 2. The effectiveness of CIP for the coupling of N-methylamino acids in solution and on solid support were clarified by the syntheses of model di- and tripeptides.