ChemInform Abstract: Enzyme-Assisted Asymmetric Total Synthesis of (-)-Podophyllotoxin and (-)-Picropodophyllin.

Abstract

Described is the first catalytic, asymmetric synthesis of (−)-podophyllotoxin and its C2-epimer, (−)-picropodophyllin. Asymmetry is achieved via the enzymatic desymmetrization of advanced meso diacetate 20, through PPL-mediated ester hydrolysis. A second key feature of the synthesis is the strategically late introduction of the highly oxygenated natural ring E through an arylcopper species. The successful implementation of this approach augers well for the introduction of other functionalized rings E for future SAR work. The synthesis begins from piperonal, which is fashioned into isobenzofuran (IBF) precursor 14 in three steps (bromination, acetalization, and halogen−metal exchange/hydroxymethylation). Interestingly, treatment of 14 with HOAc in commerical dimethyl maleate (contains 5% dimethyl fumarate) leads to a nearly equimolar mixture of fumarate− (15) and maleate−IBF Diels−Alder adducts (16 and 17), indicating that IBF 11 reacts about 15 times faster with dimethyl fumarate than with dimethyl maleat...