Stereocontrolled synthesis of carbocyclic compounds with a quaternary carbon atom based on SN2′ alkylation of γ,δ-epoxy-α,β-unsaturated ketones

Abstract

We developed a new method for stereoselective construction of an all-carbon quaternary stereogenic center on a carbocyclic ring based on regio- and stereoselective S_N2′ alkylation reactions of γ,δ-epoxy-α,β-unsaturated cyclic ketones. Treatment of the ketones, which were readily prepared in enantiomerically pure form by means of aldol condensations between 3-ethoxy-2-cycloalkenones and α,β-epoxy aldehydes, with a R₂Zn–CuCN reagent afforded anti-S_N2′ products stereoselectively. Conversely, the corresponding syn-S_N2′ products were stereoselectively obtained through two-step transformations of the same γ,δ-epoxy-α,β-unsaturated cyclic ketones: (1) conversion of the epoxide moiety to a chlorohydrin by treatment with MgCl₂ and (2) subsequent S_N2′ substitution of the chlorohydrin with a R₂Zn–CuCN reagent. These substitution products with their chiral trans-allylic alcohol moieties are promising precursors for complex molecules. For example, Eschenmoser–Claisen rearrangement of one of the substitution products resulted in stereoselective formation of a keto amide having contiguous quaternary and tertiary stereogenic centers.