Total Synthesis of Dolabriferol C by a Highly Stereoselective One-Pot Coupling of a meso-3,7-Diketone with Two Chiral Aldehydes.

Abstract

Total synthesis of the noncontiguous polypropionate dolabriferol C was achieved by retro-Claisen fragmentation of its putative contiguous precursor under mild conditions, thus establishing the former as a plausible isolation artifact. The precursor was prepared by a novel one-pot three-component bisaldol coupling of a meso (Z,Z)-bisenolate (generated in situ from a 3,7-diketone) with two enantioenriched aldehydes to set the absolute configuration of seven stereocenters in one step. The first aldol reaction proceeded with enantioselective desymmetrization of the bisenolate to produce an enantiomerically pure enolate-aldolate. Quenching at this stage enabled a streamlined synthesis of dolabriferol. Addition of a racemic aldehyde to the enolate-aldolate resulted in aldol coupling with kinetic resolution of the "matched" aldehyde; overall, a sequential enantiotopic-group-selective (SEGS) bisaldol reaction. Because the desired adduct results from the "mismatched" aldol reaction, use of enantioenriched aldehyde was required.