Enantioselective Construction of β-Substituted γ-Lactone through Catalytic Asymmetric Oshima–Utimoto Reaction: Divergent Total Syntheses of (−)-Podophyllotoxin and Its Eleven Congeners

Abstract

We report the first highly enantioselective Oshima–Utimoto reaction, which is combined with subsequent one-pot oxidation to construct synthetically important enantioenriched β-substituted γ-lactones with high enantioselectivity (up to 97% ee) from two chemical feedstocks (allylic alcohols and vinyl ethers). Significantly, the absolute configuration of chiral β-substituted γ-lactones can be precisely controlled by strategically selecting Z- or E-allylic alcohol substrates, thereby providing an alternative access to both enantiomers of chiral γ-lactones. Capitalizing on this catalytic asymmetric transformation as a key step, we have achieved a concise and stereodivergent total synthesis of the natural aryltetralin lignan drug (−)-podophyllotoxin and its 11 structural congeners in only 6–8 steps from commercial materials through the combination of chemical and chemoenzymatic strategies. The present protocol, featuring the development of a catalytic asymmetric Oshima–Utimoto reaction, not only offers a concise route to the synthetically valuable β-substituted γ-lactones, but also establishes a potential platform for preparing structurally diverse natural drug (−)-podophyllotoxin derivatives through minor modifications of synthetic precursors.