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

Abstract

All four chiral pestalotin diastereomers were synthesized in a straightforward and divergent manner from common (R)-glycidol. Catalytic asymmetric Mukaiyama aldol reactions of readily-available bis(TMSO)diene (Chan's diene) with (S)-2-benzyloxyhexanal derived from (R)-glycidol produced a syn-aldol adduct with high diastereoselectivity and enantioselectivity using a Ti(iOPr)₄/(S)-BINOL/LiCl catalyst. Diastereoselective Mukaiyama aldol reactions mediated by catalytic achiral Lewis acids directly produced not only a (1'S,6S)-pyrone precursor via the syn-aldol adduct using TiCl₄, but also (1'S,6R)-pyrone precursor via the antialdol adduct using ZrCl₄, in a stereocomplementary manner. A Hetero-Diels-Alder reaction of similarly available mono(TMSO)diene (Brassard's diene) with (S)-2-benzyloxyhexanal produced the (1'S,6S)-pyrone precursor promoted by Eu(fod)₃ and the (1'S,6R)-pyrone precursor Et₂AlCl. Debenzylation of the (1'S,6S)-precursor and the (1'S,6R)-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, ¹H-NMR, ¹³C-NMR, and HPLC measurements).

Keywords: Brassard’s diene; Chan’s diene; Mitsunobu inversion; asymmetric Mukaiyama aldol reaction; asymmetric total synthesis; divergent synthesis; epipestalotin; hetero Diels-Alder reaction; pestalotin; pyran-2-one.