Isothiourea-catalysed enantioselective synthesis of phosphonate-functionalised β-lactones

Abstract

Despite growing interest in the reactivity and biological activity of phosphonate-containing molecules, the application of α-ketophosphonates in enantioselective formal [2 + 2] cycloadditions to generate β-lactones bearing a pendant phosphonate group remains unreported. In this manuscript, a highly diastereo- and enantioselective isothiourea-catalysed formal [2 + 2] cycloaddition of both alkyl- and aryl substituted C(1)-ammonium enolates and α-ketophosphonates is established. This strategy allows a mild, practical and scalable approach to highly enantioenriched C(3)-unsubstituted and C(3)-alkyl β-lactones bearing a phosphonate motif from their corresponding α-silyl acids, via a desilylative pathway (30 examples, up to 98%, >95 : 5 dr, >99 : 1 er). Alternatively, the use of (hetero)arylacetic acids allows the preparation of C(3)-(hetero)aryl β-lactones to be accessed in high yields and stereocontrol (19 examples, up to 98%, >95 : 5 dr, 99 : 1 er).