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

Chemical Science Pub Date: 2019-04-29 DOI: 10.1039/C9SC00390H

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 (RF = 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.

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