Enantiospecific cross-coupling of cyclic alkyl sulfones

Abstract

Methods to form carbon–carbon bonds efficiently and with control of stereochemistry are critical for the construction of complex molecules. Cross-coupling reactions are among the most efficient and widely used reactions to construct molecules, with reactions enabling the retention or installation of chirality as recent additions to this powerful toolbox. Sulfones are robust, accessible organic electrophiles that have many attractive features as cross-coupling partners; however, since the first example of their use in 1979, there have been no examples of their use in enantioselective, enantiospecific or entantioconvergent cross-couplings. The high acidity of sulfones makes it unclear whether this transformation is even possible outside tertiary systems. Here we report the enantiospecific cross-coupling of cyclic sulfones and Grignard reagents. Up to 99% chirality transfer is observed despite the strong basicity of the Grignard components. In situ monitoring reveals that the cross-coupling is kinetically competitive with competing deprotonation, resulting in a highly enantioselective transformation. Cross-coupling reactions are among the most important carbon–carbon bond-forming reactions. Now the nickel-catalysed cross-coupling of chiral sulfones with Grignard reagents has been achieved with up to 99% retention of chirality. The speed of the cross-coupling relative to sulfone deprotonation and racemization is critical to enabling this enantiospecific process.