Platt Ffion M, Wang Yihong, Cordes David B, McKay Aidan P, Slawin Alexandra M Z, Panchal Heena, Smith Andrew D
EaStCHEM, School of Chemistry, University of St Andrews St Andrews Fife KY16 9ST UK
Chemical Development, PT&D, AstraZeneca Etherow Building, Silk Road Business Park, Charter Way Macclesfield Cheshire SK10 2NA UK.
Chem Sci. 2025 Mar 6;16(16):6828-6836. doi: 10.1039/d5sc00322a. eCollection 2025 Apr 16.
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, 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).
尽管人们对含膦酸酯分子的反应活性和生物活性越来越感兴趣，但α-酮膦酸酯在对映选择性形式[2 + 2]环加成反应中用于生成带有膦酸酯侧基的β-内酯的应用仍未见报道。在本论文中，建立了一种高度非对映和对映选择性的异硫脲催化的烷基和芳基取代的C(1)-铵烯醇盐与α-酮膦酸酯的形式[2 + 2]环加成反应。该策略提供了一种温和、实用且可扩展的方法，可从相应的α-硅基酸制备具有高对映体富集的带有膦酸酯基序的C(3)-未取代和C(3)-烷基β-内酯，这是一条脱硅途径（30个例子，产率高达98%，非对映选择性>95:5，对映选择性>99:1）。另外，使用（杂）芳基乙酸可以高产率和立体控制地制备C(3)-（杂）芳基β-内酯（19个例子，产率高达98%，非对映选择性>95:5，对映选择性99:1）。
