Phosphorus (V) stereocenters are prevalent in bioactive molecules, including pharmaceuticals. Nucleophilic substitution at stereogenic phosphorus centers provides a general strategy for the synthesis of optically active, complex P(V) compounds from simple P(V) building blocks bearing one or more leaving groups. We hypothesized that enantioenriched phosphonamidic chlorides could serve as P(V) building blocks for the synthesis of chiral P(V) targets bearing a broad range of substitution patterns. These compounds possess two orthogonally reactive leaving groups that could each be sequentially and stereospecifically displaced. We report the development of an enantioselective method for the synthesis of phosphonamidic chloride intermediates using a commercially available hydrogen-bond-donor catalyst and the application of these P(V) building blocks to the synthesis of P(V) compounds featuring diverse substitution patterns. The utility of this method is highlighted by the synthesis of advanced bioactive compounds.

Enantioselective synthesis of stereogenic phosphorus building blocks via hydrogen-bond-donor catalysis

ACS Spring 2022

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