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

Chemical Science
Diego-Javier Barrios AntúnezAndrew David Smith

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.

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Citations

Oct 28, 2019·Chemistry, an Asian Journal·Si-Cong LiuDonghui Wei
Jul 25, 2020·Beilstein Journal of Organic Chemistry·Alyn T DaviesAndrew D Smith
Jun 20, 2020·Chemistry : a European Journal·Calum McLaughlin, Andrew D Smith
Feb 7, 2020·Organic Letters·Honglei LiuAndrew D Smith
Mar 3, 2021·Organic & Biomolecular Chemistry·Jacqueline BitaiAndrew D Smith
Mar 30, 2021·The Journal of Organic Chemistry·Yamato FujihiraNorio Shibata
Dec 7, 2021·Journal of the American Chemical Society·Harvey J A DaleGuy C Lloyd-Jones

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Methods Mentioned

BETA
column chromatography
X-ray

Software Mentioned

Onyx
Gaussian

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