Enantioselective isothiourea-catalysed reversible Michael addition of aryl esters to 2-benzylidene malononitriles
Abstract
Catalytic enantioselective transformations usually rely upon optimal enantioselectivity being observed in kinetically controlled reaction processes, with energy differences between diastereoisomeric transition state energies translating to stereoisomeric product ratios. Herein, stereoselectivity resulting from an unusual reversible Michael addition of an aryl ester to 2-benzylidene malononitrile electrophiles using an isothiourea as a Lewis base catalyst is demonstrated. Notably, the basicity of the aryloxide component and reactivity of the isothiourea Lewis base both affect the observed product selectivity, with control studies and crossover experiments indicating the feasibility of a constructive reversible Michael addition from the desired product. When this reversible addition is coupled with a crystallisation-induced diastereomer transformation (CIDT) it allows isolation of products in high yield and stereocontrol (14 examples, up to 95 : 5 dr and 99 : 1 er). Application of this process to gram scale, plus derivatisations to provide further useful products, is demonstrated.
Citation
Nimmo , A , Bitai , J , Young , C M , McLaughlin , C , Slawin , A M Z , Cordes , D B & Smith , A D 2023 , ' Enantioselective isothiourea-catalysed reversible Michael addition of aryl esters to 2-benzylidene malononitriles ' , Chemical Science , vol. 14 , no. 27 , pp. 7537-7544 . https://doi.org/10.1039/D3SC02101G
Publication
Chemical Science
Status
Peer reviewed
ISSN
2041-6520Type
Journal article
Description
Funding: The research leading to these results has received funding from the EaSI-CAT Centre for Doctoral Training (AJN), the University of St Andrews (JB), and the EPSRC (CMY, EP/S019359/1; CM, EP/M508214/1).Collections
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.