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

Area of Science:

• Organic Synthesis
• Catalysis
• Green Chemistry

Background:

• Asymmetric allylic substitution (AAS), or the Tsuji-Trost reaction, is a cornerstone of modern organic synthesis.
• Integrating AAS with multicomponent modular synthesis offers a powerful yet underdeveloped strategy for flexible molecular construction from basic feedstocks.

Purpose of the Study:

• To develop a novel three-component asymmetric Tsuji-Trost reaction.
• To establish a versatile platform for synthesizing hybrid molecules by combining distinct bioactive scaffolds.

Main Methods:

• A cooperative palladium/Lewis acid (LA) catalyzed three-component AAS reaction was developed.
• The reaction utilizes a '1C + 2C + NuH' approach, starting from aldehydes, allylboronates, and various nucleophiles.
• Mechanistic studies were performed to elucidate the reaction pathway.

Main Results:

• The protocol accommodates a wide range of nucleophiles, including malonates, acetylacetone, acetoacetate, phosphine oxides, and sulfonyl hydrazides.
• The reaction proceeds through a sequence involving LA-catalyzed allylation, olefin shift, and Pd/LA-cocatalyzed AAS.
• Diverse hybrid molecules integrating two distinct bioactive scaffolds were successfully synthesized.

Conclusions:

• A novel and efficient three-component asymmetric Tsuji-Trost reaction has been established.
• This method provides a new platform for the modular synthesis of complex organic molecules and hybrid compounds.
• The cooperative catalysis approach offers a powerful strategy for accessing diverse molecular architectures from simple starting materials.