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

Ding Yuan, Alister S. Goodfellow, Zhuan Duan, Tengfei Kang, Kevin Kasten, David B. Cordes, Aidan McKay, Michael Buehl, Gregory R. Boyce, Andrew D. Smith

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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.
Original languageEnglish
Pages (from-to)14146-14156
Number of pages11
JournalChemical Science
Volume14
Issue number48
Early online date21 Nov 2023
DOIs
Publication statusPublished - 28 Dec 2023

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