Controlling phosphorus(v)-stereogenicity via organocatalytic acylative desymmetrisation of bisphenols

Abstract

The enantioselective construction of phosphorus(v)-stereogenic centres is of broad importance due to the utility of these compounds both as ligands in catalysis and as scaffolds in medicinal chemistry. This manuscript demonstrates the effective acylative desymmetrisation of ortho-bisphenols to access P(v)-stereogenic products using low 1 mol% loadings of the chiral isothiourea HyperBTM as a Lewis base catalyst and readily available anhydride feedstock starting materials. The scope and limitations of this method have been investigated (24 examples, up to 95% yield, 98 : 2 er). Control experiments reveal the role of bis-acylation in the amplification of stereocontrol through a chiroablative kinetic resolution of the monoester product. A chromatography-free process towards the standard starting material has been developed on decagram scale, facilitating the catalytic application of the process on multigram scale, with 98% catalyst recovery. Synthesis of a polymer-supported isothiourea catalyst facilitated transfer of the catalytic reaction into continuous flow in a packed-bed reactor.