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

Abstract

The enantioselective preparation of a range of perfluoroalkyl-substituted β-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 β-lactone formation using C₂F₅- and C₄F₉-substituted ketones at room temperature (26 examples, up to >95 : 5 dr and >99 : 1 er), whilst −78 °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 β-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 ¹³C 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.