The Catalytic Oxidative Cyclization Synthesis of Isochromanoindolenines by Multicopper Oxidase in a Microflow System

Herein, we disclose a microflow system-mediated oxidative cyclization process catalyzed by multicopper oxidase, employing 2,3-dihydroxybenzoic acid and a range of substituted tetrahydrocarbazoles to afford structurally complex isochromanoindolenines. The reaction proceeds under mild conditions without the need for external oxidants or metal catalysts, thereby enhancing its environmental sustainability. Through reaction-process intensification of the microflow system, the reaction time is significantly shortened (16 min vs 72 h), which is more conducive to the occurrence of the enzymatic reaction and the maintenance of enzyme activity in enzyme kinetics. Notably, the use of cell lysates obviates the need for enzyme purification, significantly improving operational efficiency and practicality. This microflow-based strategy exhibits a broad substrate scope. 22 examples are efficiently obtained in moderate to good yields. Furthermore, the integration of microflow technology intensifies the reaction process, leading to a marked improvement in overall efficiency. The successful gram-scale experiment further demonstrates the potential of this process for industrial scale-up.