Enzyme-Catalyzed Umpolung Strategy for the Green Synthesis of Schiff bases and their Derivatives

Abstract

In organic chemistry, umpolung reaction is an important concept that significantly expands the chemical space and provides unique structures. Although prior research focused on constructing complex molecular frameworks using phase transfer catalysts, it is well known for its roles in 1,4-conjugate addition and Stetter reactions. Herein, we report a novel enzymatic approach using immobilized transaminase CV2025 as a catalyst for the umpolung conjugate addition reaction. This method enables the nucleophilic addition of 2-(Nitrophenyl)-N-(trifluoromethyl) imine to cyclopentanone, efficiently synthesizing the complex Imine and their derivatives up to 78% yield. Unlike traditional methods, this enzymatic strategy eliminates the need for transitional-metal and chemical (acid, base) catalysis, broadens substrate scope, and operates under milder conditions. Mechanistic studies, supported by molecular dynamics calculations and alanine scanning mutagenesis, identify key residues influencing regioselectivity. Furthermore, it was demonstrated that Imine substrates (1A), not its isomers (1K), produced the target product (3A), confirming that the reactions proceed via polarity reversal rather than isomer addition. This study presents a sustainable, enzyme-catalyzed method for constructing complex frameworks with broad potential in pharmaceutical synthesis and beyond.