Issue 16, 2025

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).

Graphical abstract: Isothiourea-catalysed enantioselective synthesis of phosphonate-functionalised β-lactones

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Article information

Article type
Edge Article
Submitted
14 Jan 2025
Accepted
05 Mar 2025
First published
06 Mar 2025
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2025,16, 6828-6836

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

F. M. Platt, Y. Wang, D. B. Cordes, A. P. McKay, A. M. Z. Slawin, H. Panchal and A. D. Smith, Chem. Sci., 2025, 16, 6828 DOI: 10.1039/D5SC00322A

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