Total synthesis and stereochemical reassignment of (+)-dolastatin 19, a cytotoxic marine macrolide isolated from Dolabella auricularia

Abstract

Using conformational analysis and biogenetic considerations, a revised configurational assignment for the cytotoxic marine macrolide dolastatin 19 is proposed, together with its validation by completion of the first total synthesis. Key features of the highly stereocontrolled route include an asymmetric vinylogous Mukaiyama aldol reaction to simultaneously install both the remote C13 stereocenter and the C10–C11 ( E)-trisubstituted olefin, two sequential 1,4- syn boron-mediated aldol reactions, and a late-stage, α-selective Mukaiyama glycosylation to append the l-rhamnose-derived pyranoside.