The Dolastatins 20. A Convenient Synthetic Route to Dolastatin 15

Abstract A segment synthetic strategy was utilized for obtaining the Dolabella auricularia (Indian Ocean sea hare) depsipeptide dolastatin 15. Reaction of protected (S)-Hiva-(S)-Phe 2c with isopropenyl chloroformate followed by Meldrum's ester, cyclization (2c → 3a) of the product in toluene and finally methylation afforded the key (S)-dolapyrrolidine (Dpy) derivative 3b. Condensation of tripeptide 8 with the three unit Dpy segment 5b followed by deprotection and coupling (diethyl phosphorocyanidate) led to dolastatin 15 in 11% overall yield. The powerful and selective activity of dolastatin 15 against the U.S. National Cancer Institute's panel of human cell lines has been summarized.