Asymmetric synthesis of (S)-dihydrokavain from l-malic acid

Abstract

A practical and efficient asymmetric synthesis of (S)-dihydrokavain from known ethyl (S)-2-hydroxy-4-phenylbutanoate which is, in turn, readily available from l-malic acid as a cheap chiral pool material is described using regioselective ring-opening of the 1,2-cyclic sulfate with lithium-3,3,3-triethoxypropiolate and subsequent HgO/H2SO4-mediated lactonization as the key steps. Its opposite enantiomer (R)-dihydrokavain was also synthesized from d-malic acid using the same sequences of reactions for the purpose of optical purity determination.