Stereodivergent synthesis of benzylic alcohol derivatives enabled by Pd/Cu co-catalyzed asymmetric benzylic substitution reaction.

Despite their significant synthetic value, transition-metal-catalyzed asymmetric benzylic substitution reactions remain underexplored compared to the Tsuji-Trost reaction, primarily due to the inherent challenge associated with dearomatization. This reaction becomes much more challenging when constructing a stereogenic center at the benzyl position. Herein, we report a Pd/Cu co-catalyzed enantio- and diastereodivergent benzylic substitution reaction with benzyl geminal dicarboxylate, which is successfully applied for concurrent construction of two stereocenters at the benzyl position and nucleophile moiety. Various benzylic alcohol derivatives bearing adjacent stereocenters are easily synthesized in high yields with excellent diastereo- and enantioselectivities (up to 94% yield, generally >20:1 dr and >99% ee). Notably, this protocol allows for stereodivergent synthesis of benzylic alcohol derivatives only by changing the combination of ligand configurations. Furthermore, density functional theory (DFT) calculations reveal that the stereochemical outcome of the reaction is governed by the nucleophilic attack on the key η³-oxybenzyl-Pd intermediate.