LAUSR

The stereoselective synthesis of molecules bearing stereogenic phosphorus(V) centers represents an enduring challenge in organic chemistry. Although stereospecific nucleophilic substitution at P(V) provides a general strategy for elaborating optically active P(V) compounds, existing methods for accessing the requisite chiral building blocks rely almost entirely on diastereocontrol using chiral auxiliaries. Catalytic, enantioselective methods for the synthesis of synthetically versatile stereogenic P(V) building blocks offer an alternative approach to stereogenic-at-P(V) targets without requiring stoichiometric quantities of chiral control elements. Here, we report an enantioselective hydrogen-bond-donor–catalyzed synthesis of aryl chlorophosphonamidates and the development of these products as versatile chiral P(V) building blocks. We demonstrate that the two leaving groups on these chlorophosphonamidates can be displaced sequentially and stereospecifically to access a wide variety of stereogenic-at-P(V) compounds featuring diverse substitution patterns. Description Chiral-at-P products via H-bond catalysis Hydrogen (H)–bonding catalysis has recently proven useful for activating carbon-chlorine bonds to form just one of two possible mirror-image products. Forbes and Jacobsen now extend this approach to desymmetrization of phosphorus(V) [P(V)] dichloride compounds (see the Perspective by Verdaguer). Using chiral urea catalysts, the authors could displace just one of two chlorides with an amine, thereby producing a versatile P(V) intermediate. Subsequent selective displacement of the remaining chloride and/or amine offers access to a wide range of chiral-at-P compounds, a class of increasing pharmaceutical interest. —JSY Desymmetrization of phosphorus(V) dichlorides by chiral H-bonding catalysts accesses many enantio-enriched P(V) compounds.