An Enantioselective Synthesis of (-)-Coniine

Abstract

Enantioselective syntheses have become increasingly important since the FDA declared enantiomers as separate chemical entities in the late nineties. (-)-coniine, a natural product derived from spotted Hemlock is responsible for killing Socrates in 399 B.C. Our synthesis begins by treating trans-2-hexenal with ethereal HCN in the presence of the enzyme oxynitrilase. Oxynitrilase is an enzyme isolated from consumer grade raw almonds. The cyano and hydroxy moieties then undergo an ethyl esterification and ethoxy carbonylation respectively. The resulting product is then reacted with Pd0 and an unsaturated sulfonamide which transposes the stereocenter and shifts the α,β-double bond into conjugation with the ester. Further manipulation of the palladium adduct affords the title compound, (-)-coniine.