A Modular Three-Component Asymmetric Tsuji–Trost Reaction Enabled by Cooperative Palladium/Lewis Acid Catalysis

Abstract

Asymmetric allylic substitution (AAS) reactions, named as the Tsuji–Trost reaction, stand as a landmark in modern organic synthesis. The merge of AAS reactions with the concept of multicomponent modular synthesis could allow flexible customization of molecular architectures from fundamental feedstocks, which remains underdeveloped. Herein, we disclose our recent observations on a novel three-component asymmetric Tsuji–Trost reaction enabled by cooperative palladium/Lewis acid (LA) catalysis. This ‘1C + 2C + NuH’ approach starts from fundamental organic feedstocks, i.e., aldehyde, allylboronate, and a nucleophile with the in situ formation of a C═C double bond. Diverse nucleophiles have been demonstrated to be applicable in this three-component AAS reaction, including malonates, acetylacetone, acetoacetate, phosphine oxides, sulfonyl hydrazides etc. The protocol successfully offers a novel platform to integrate two distinct bioactive molecular scaffolds to access diverse array of hybrids. Mechanistic studies suggest that the three-component AAS approach proceeds via a reaction sequence of LA-catalyzed allylation of aldehyde, olefin shift under palladium catalysis, and Pd/LA-cocatalyzed asymmetric allylic substitution.