Evolution of a Gram-Scale Synthesis of (+)-Discodermolide

Abstract

An efficient, highly convergent, stereocontrolled total synthesis of the potent antimitotic agent (+)-discodermolide ( 1 ) has been achieved on gram scale. Key elements of the successful strategy include (1) elaboration of three advanced fragments from a common precursor ( CP ) which embodies the repeating stereochemical triad of the discodermolide backbone, (2) σ-bond installation of the Z trisubstituted olefin, exploiting a modified Negishi cross-coupling reaction, (3) synthesis of a late-stage phosphonium salt utilizing high pressure, and (4) Wittig installation of the Z disubstituted olefin and the terminal ( Z )-diene.