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).

Fig. 1. (a) Importance of organophosphorus compounds; (b) previous methods of generating C(1)-ammonium enolates using isothiourea catalysts; (c) relevant background formal [4 + 2] cycloaddition with α-ketophosphonates; (d) and this work.

Fig. 2. Scope and limitations of the formal [2 + 2] cycloaddition of α-silyl acids with α-ketophosphonates. All yields are isolated yields, dr determined by ¹H NMR of crude reaction mixture, er determined by HPLC analysis on a chiral stationary phase, reaction scale 0.4 mmol, 25 °C maintained using an oil bath. ^a10 mol% HyperBTM 1 used; ^b1.6 equiv. of acid used, performed at 20 °C; ^cinitial reaction carried out on 0.4 mmol scale, scale up reaction carried out on 4.0 mmol scale, both gave 31 in 76% yield, >95 : 5 dr, >99 : 1 er; ^dmorpholine (5.0 equiv.) added after full conversion to β-lactone 31, 20 °C, 16 h.

Fig. 3. Probing double stereodifferentiation. All yields are isolated yields, dr determined by ¹H NMR of crude reaction mixture, er determined by HPLC analysis on a chiral stationary phase.

Fig. 4. Epimerisation studies.

Fig. 5. Scope and limitations of formal [2 + 2] cycloaddition of (hetero)arylacetic acids with α-ketophosphonates. All yields are isolated yields, dr determined by ¹H NMR of crude reaction mixture, er determined by HPLC analysis on a chiral stationary phase. *α-ketophosphonate starting material showed dimerization over time (see ESI†).

Fig. 6. Proposed mechanism and stereochemical rationale.