Promoting Highly Diastereoselective gamma-C-H Chalcogenation of alpha-Amino Acids and Aliphatic Carboxylic Acids

A Pd(II)-catalyzed highly regioselective gamma-chalcogenation, thioarylation, and selenoarylation of aliphatic carboxylic acids has been demonstrated. The present protocol provides a direct access to make structural modifications of a amino acids such as valine, isoleucine, and tert-leucine with high diastereoselectivity (up to 52:1). Sequential hetero-bifunctionalizations have been carried out at gamma-sp(3) C-Hs, resulting in desymmetrization of quaternary centers. The applicative potential of the chalcogenated products was exhibited by using them as precursors for the synthesis of the biologically relevant benzothiepinone moiety. Preliminary studies were carried out to gain insights into the mechanism.