A sequential asymmetric ketene heterodimerization-hydrogenation methodology facilitating access to stereodefined deoxypropionate and propionate building blocks has been developed. Quinine and quinidine derivatives were used to catalyze the asymmetric synthesis of a range of ketene heterodimers from two different ketenes (including two monosubstituted ketenes) with excellent enantioselectivity (up to 98% ee) and regioselectivity. Pd/C was found to be the optimal heterogeneous catalyst for promoting the hydrogenation of ketene heterodimers to give stereodefined carboxylic acids bearing two chiral centers or �-lactones bearing three chiral centers. High diastereoselectivity (dr up to >99:1) was obtained in most cases. Pd/C-catalyzed hydrogenation is effective for the reduction of a variety of ketene heterodimers derived from alkylarylketenes, diarylketenes, dialkylketenes, and monosubstituted TMS-ketenes. The reduction reaction was found to be stereodivergent whereby hydrogenation of the Z-isomer of the ketene heterodimer favored formation of a carboxylic acid bearing two chiral centers (deoxypropionate derivative), while the E-isomer of the ketene heterodimer favored formation of a �-lactone bearing three chiral centers (propionate derivative). Details of the catalyst optimization, substrate scope and mechanistic studies will be presented. Application of this catalytic asymmetric methodology to the synthesis of complex molecules will also be discussed.

Asymmetric synthesis of deoxypropionate and propionate derivatives via a catalytic ketene heterodimerization-hydrogenation sequence

247th National Meeting (2014)

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