Synergistic organocatalysis in the kinetic resolution of secondary thiols with concomitant desymmetrisation of an anhydride.

Abstract

An organocatalytic process mediated by a single small-molecule catalyst involving the highly enantioselective desymmetrisation of an achiral electrophile while it simultaneously kinetically resolves a racemic nucleophile has been developed which allows the efficient direct acylative kinetic resolution of sec-thiol substrates for the first time. The levels of enantioselectivity associated with both processes (which exhibit verifiable synergy) are excellent using a readily accessible cinchona alkaloid-derived organocatalyst at low loadings. The inexpensive achiral glutaric anhydride electrophiles are desymmetrised as the resolution progresses with excellent levels of stereocontrol and can be later cleaved to afford highly enantioenriched products (up to 97% ee). The potential synthetic utility of the methodology was demonstrated by the synthesis of a drug precursor antipode in excellent yield and enantioselectivity as a by-product of a process which also resolved a sec-thiol substrate with a selectivity of S=226 (i.e. both thiol antipodes produced in >95% ee at 51% conversion).