Development of a photoenzymatic one-pot hybrid system for the direct synthesis of 3,3-disubstituted indole-2-ketones from N-methyl indoles

Abstract

The effective combination of photocatalysis and enzyme catalysis has been widely utilized for the synthesis of high-value-added products. However, the synthesis of valuable substances through the coexistence of photocatalytic and enzymatic reactions in one pot remains challenging, due to the potential deactivation of most hydrolases by the free radicals generated during photocatalysis. Herein, we report an efficient, green, and mild photo-enzyme catalysis integrated system for synthesizing 3,3-disubstituted indole-2-ketone derivatives using simple indoles and acetone. The process involves photocatalytic oxidation of indoles to isatins, followed by aldol reactions with ketones catalyzed by wheat germ lipase (WGL). In this photo-enzymatic system, a series of indole substrates with different substituents can undergo dearomatization and aldol reaction to be successfully converted into 3,3-disubstituted indole-2-ketones with moderate to excellent yields (up to 85%). Mechanistic studies confirmed the crucial role of the structure and catalytic activity of WGL in this system. This hybrid system has good universality and application potential for industrial production, as demonstrated by a gram scale experiment.