Divergent Asymmetric Total Synthesis of All Four Pestalotin Diastereomers from ()-Glycidol.

All four chiral pestalotin diastereomers were synthesized in a straightforward and divergent manner from common ()-glycidol. Catalytic asymmetric Mukaiyama aldol reactions of readily-available bis(TMSO)diene (Chan's diene) with ()-2-benzyloxyhexanal derived from ()-glycidol produced a -aldol adduct with high diastereoselectivity and enantioselectivity using a Ti(OPr)/()-BINOL/LiCl catalyst. Diastereoselective Mukaiyama aldol reactions mediated by catalytic achiral Lewis acids directly produced not only a (1',6)-pyrone precursor via the -aldol adduct using TiCl, but also (1',6)-pyrone precursor via the antialdol adduct using ZrCl, in a stereocomplementary manner. A Hetero-Diels-Alder reaction of similarly available mono(TMSO)diene (Brassard's diene) with ()-2-benzyloxyhexanal produced the (1',6)-pyrone precursor promoted by Eu(fod) and the (1',6)-pyrone precursor EtAlCl. Debenzylation of the (1',6)-precursor and the (1',6)-precursor furnished natural (-)-pestalotin (99% ee, 7 steps) and unnatural (+)-epipestalotin (99% ee, 7 steps), respectively. Mitsunobu inversions of the obtained (-)-pestalotin and (+)-epipestalotin successfully produced the unnatural (+)-pestalotin (99% ee, 9 steps) and (-)-epipestalotin (99% ee, 9 steps), respectively, in a divergent manner. All four of the obtained chiral pestalotin diastereomers possessed high chemical and optical purities (optical rotations, H-NMR, C-NMR, and HPLC measurements).