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

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 = CF 3 , C 2 F 5 , C 4 F 9 ) is reported. Following optimisation, high diastereo- and enantioselectivity was observed for β-lactone formation using C 2 F 5 - and C 4 F 9 -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 CF 3 -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 13 C 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. A study into the Lewis base-catalysed enantioselective synthesis of polyfluorinated β-lactones.