Issue 48, 2023

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-ketoesters 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-ketoesters 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 solvation model is demonstrated to capture solvation effects reliably.

Graphical abstract: Understanding divergent substrate stereoselectivity in the isothiourea-catalysed conjugate addition of cyclic α-substituted β-ketoesters to α,β-unsaturated aryl esters

Supplementary files

Article information

Article type
Edge Article
Submitted
15 Okt. 2023
Accepted
20 Nov. 2023
First published
21 Nov. 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2023,14, 14146-14156

Understanding divergent substrate stereoselectivity in the isothiourea-catalysed conjugate addition of cyclic α-substituted β-ketoesters to α,β-unsaturated aryl esters

D. Yuan, A. S. Goodfellow, K. Kasten, Z. Duan, T. Kang, D. B. Cordes, A. P. McKay, M. Bühl, G. R. Boyce and A. D. Smith, Chem. Sci., 2023, 14, 14146 DOI: 10.1039/D3SC05470E

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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