Catalytic enantioselective synthesis of perfluoroalkyl-substituted β-lactones via a concerted asynchronous [2+2] cycloaddition : a synthetic and computational study
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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.
Barrios Antunez , D-J , Greenhalgh , M D , Brueckner , A C , Walden , D M , Elías-Rodríguez , P , Roberts , P , Young , B G , West , T H , Slawin , A M Z , Cheong , P H-Y & Smith , A D 2019 , ' Catalytic enantioselective synthesis of perfluoroalkyl-substituted β-lactones via a concerted asynchronous [2+2] cycloaddition : a synthetic and computational study ' , Chemical Science , vol. 10 , no. 24 , pp. 6162-6173 . https://doi.org/10.1039/C9SC00390H
Copyright © 2019 The Author(s). Open Access Article. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
DescriptionThe research leading to these results (D.-J.B.A., T.H.W., A.D.S.) has received funding from the ERC under the European Union’s Seventh Framework Programme (FP7/2007-2013)/E.R.C. Grant Agreement No. 279850. A.D.S. thanks the Royal Society for a Wolfson Research Merit Award. We also thank the EPSRC UK National Mass Spectrometry Facility at Swansea University. P.H.Y.C. is the Bert and Emelyn Christensen professor of OSU, and gratefully acknowledges financial support from the Vicki & Patrick F. Stone family. P.H.Y.C., A.C.B., D.M.W. and B.G.Y. gratefully acknowledge support from the National Science Foundation (NSF CHE-1352663) and the computing infrastructure in part provided by the NSF Phase-2 CCI, Center for Sustainable Materials Chemistry (NSF CHE-1102637).
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