Catalytic enantioselective synthesis of perfluoroalkyl-substituted b-lactones via a concerted asynchronous [2+2] cycloaddition: a synthetic and computational study

The enantioselective preparation of a range of perfluoroalkyl-substituted beta-lactones through an isothiourea (HyperBTM) catalysed reaction using symmetric anhydrides as ammonium enolate precursors and perfluoroalkylketones (R-F = CF3, C2F5, C4F9) is reported. Following optimisation, high diastereo- and enantioselectivity was observed for beta-lactone formation using C2F5- and C4F9-substituted ketones at room temperature (26 examples, up to >95 : 5 dr and >99 : 1 er), whilst -78 degrees C was necessary for optimal dr and er with CF3-substituted ketones (11 examples, up to >95 : 5 dr and >99 : 1 er). Derivatisation of the beta-lactones through ring-opening, as well as a two-step conversion to give perfluoroalkyl-substituted oxetanes, is demonstrated without loss of stereochemical integrity. Density functional theory computations, alongside C-13 natural abundance KIE studies, have been used to probe the reaction mechanism with a concerted asynchronous [2 + 2]-cycloaddition pathway favoured over a stepwise aldol-lactonisation process.