Copper-catalysed enantioconvergent O-alkylation of alcohols with racemic α-tertiary haloamides to access enantioenriched hindered dialkyl ethers

Abstract

The cross-coupling of bulky electrophiles and nucleophiles to form sterically congested molecules is a challenging issue in modern synthetic chemistry. Among them, chiral hindered dialkyl ethers are one class of valuable motifs, but the catalytic asymmetric synthesis of such motifs from readily available tertiary alcohols and racemic electrophiles remains underexplored. Challenges arise from the steric hindrance of both reactants, the difficulty in enantiodiscriminating the three substituents of tertiary electrophiles and the low nucleophilicity of bulky alcohols. Here we show the copper-catalysed enantioconvergent radical O-alkylation of diverse alcohols with racemic α-tertiary haloamides to access enantioenriched hindered dialkyl ethers. Successful realization of this strategy relies on the development of anionic N,N,N-ligands with a side arm to form coordinatively saturated key Cu(iii) intermediates, therefore exerting remarkable chemo- and enantioselectivity. The synthetic potential is showcased by the late-stage functionalization and stereodivergent synthesis of four stereoisomers of a product with two stereocentres. The O-alkylation of tertiary alcohols with racemic tertiary electrophiles to access chiral hindered dialkyl ethers has remained elusive. Now this synthetic challenge has been accomplished by copper-catalysed C–O cross-coupling between tertiary haloamides and alcohols using designed ligands.