TOTAL SYNTHESIS OF SECO (-OXADUOCARMYCIN AND ENT-(-)-OXADUOCARMYCIN SA - CONSTRUCTION OF THE (CHLOROMETHYL)INDOLINE ALKYLATING SUBUNIT BY ANOVEL INTRAMOLECULAR ARYL RADICAL CYCLIZATION ONTO A VINYL-CHLORIDE())

A practical, total synthesis of seco-(+)-oxaduocarmycin 3a, an analogu e of the highly cytotoxic natural product, duocarmycin SA (1), is desc ribed. The 13-step synthesis features a novel and efficient intramolec ular aryl radical cyclization onto a vinyl chloride as a direct entry to the (chloromethyl)indoline alkylating subunit 14. Subsequent resolu tion, utilizing a preparative Chiralpak AD column, provided enantiomer ically pure alkylating subunits 14a and 14b which were elaborated to s eco-(+) and ent-(-)-oxaduocarmycins, 3a and 3b, respectively. The natu ral enantiomer 3a was active at pM concentrations and exhibited 7-50-f old higher potentcy than its enantiomer 3b in in vitro cytotoxicity as says.