An enzyme catalyzed umpolung strategy for the green synthesis of Schiff bases and their derivatives

Abstract

In organic chemistry, the 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, the umpolung reaction is well known for its roles in 1,4-conjugate addition and Stetter reactions. Herein, we reported a novel enzymatic approach using immobilized transaminase CV2025 to catalyze the umpolung conjugate addition reaction. This method facilitates the nucleophilic addition of 2-(nitrophenyl)-N-(trifluoromethyl) imine to cyclopentanone, efficiently synthesized a complex imine and its derivatives up to 78% yield. Unlike traditional methods, this enzymatic strategy eliminates the need of a transition metal or chemical (acid, base) catalyst, broadens the substrate scope, and operates under milder conditions. Mechanistic studies, supported by molecular dynamics calculations and alanine scanning mutagenesis, identified key residues influencing regioselectivity. This study presents a sustainable, enzyme-catalyzed method for constructing complex frameworks with broad potential in pharmaceutical synthesis and beyond.