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

Diego-Javier Barrios Antunez, Mark D. Greenhalgh, Alexander C. Brueckner, Daniel M. Walden, Pilar Elías-Rodríguez, Patrick Roberts, Benjamin G. Young, Thomas H. West, Alexandra M. Z. Slawin, Paul Ha-Yeon Cheong, Andrew D. Smith

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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 enantioselectivty 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.
Original languageEnglish
Pages (from-to)6162-6173
Number of pages12
JournalChemical Science
Volume10
Issue number24
Early online date29 Apr 2019
DOIs
Publication statusPublished - 28 Jun 2019

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