Understanding divergent substrate stereoselectivity in the isothiourea-catalysed conjugate addition of cyclic α-substituted β-ketoesters to α,β-unsaturated aryl esters
Abstract
The development of enantioselective synthetic methods capable of generating vicinal stereogenic centres, where one is tetrasubstituted (such as either an all-carbon quaternary centre or where one or more substituents are heteroatoms), is a recognised synthetic challenge. Herein, the enantioselective conjugate addition of a range of carbo- and heterocyclic α-substituted β-keto esters to α,β-unsaturated aryl esters using the isothiourea HyperBTM as a Lewis base catalyst is demonstrated. Notably, divergent diastereoselectivity is observed through the use of either cyclopentanone-derived or indanone-derived substituted β-keto esters with both generating the desired stereodefined products with high selectivity (>95:5 dr, up to 99:1 er). The scope and limitations of these processes are demonstrated, alongside application on gram scale. The origin of the divergent substrate selectivity has been probed through the use of DFT-analysis, with preferential orientation driven by dual stabilising CH···O interactions. The importance of solvation with strongly polar transition-states is highlighted and the SMD (Solvent Model Density) is demonstrated to capture solvation effects reliably.
Citation
Yuan , D , Goodfellow , A S , Duan , Z , Kang , T , Kasten , K , Cordes , D B , McKay , A , Buehl , M , Boyce , G R & Smith , A D 2023 , ' Understanding divergent substrate stereoselectivity in the isothiourea-catalysed conjugate addition of cyclic α-substituted β-ketoesters to α,β-unsaturated aryl esters ' , Chemical Science , vol. 14 , no. 48 , pp. 14146-14156 . https://doi.org/10.1039/D3SC05470E
Publication
Chemical Science
Status
Peer reviewed
ISSN
2041-6520Type
Journal article
Description
The research leading to these results has received funding from the CSC (DY), the EPSRC (TK, KK, EP/T023643/1) and the EaSI-CAT centre for Doctoral Training (ASG). ADS thanks the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517) for support.Collections
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