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

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 alpha-substituted beta-ketoesters to alpha,beta-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 beta-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 C...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.

Automated summary

This study demonstrates the enantioselective conjugate addition of carbo- and heterocyclic alpha-substituted beta-ketoesters to alpha,beta-unsaturated aryl esters using HyperBTM as a catalyst. Divergent diastereoselectivity is observed depending on the substituents of the beta-ketoesters, but both cyclopentanone-derived and indanone-derived beta-ketoesters generate desired products with high selectivity.