Metathesis at an Implausible Site: A Formal Total Synthesis of Rhizoxin D

Abstract

The new approach to the anticancer agent rhizoxin D described herein does not cohere with the conventional logic of metathesis, according to which macrocycles are best closed at a disubstituted olefinic site; rather, the trisubstituted C11-C12 alkene flanked by an allylic -OH group served as the pivot point for synthesis. This motif was attained in good yield and excellent selectivity by a sequence of alkyne metathesis, trans-hydrostannation and cross coupling. Because the exact same substructure is prominently featured in numerous other natural products, the underpinning strategy, though unusual, might bear more general relevance.