Exploiting the Reverse Function of Ene‐Reductase Enzymes in the Continuous Flow Synthesis of Naphthols From Tetralones

Ene‐reductases (EREDs) are ubiquitous enzymes frequently employed for the stereoselective reduction of activated prochiral alkenes, yet their reverse, i.e., oxidizing function can also be harnessed when using air as the terminal oxidant. While several batch studies showcase the use of EREDs for either function, procedures that enable their use for the scalable synthesis of valuable building blocks are lacking. Herein, we report on the development of continuous flow approaches using compressed air along with an ERED variant both in solution and as immobilized enzyme preparations. The investigated process development highlights different immobilization strategies, the effect of added cofactor (flavin mononucleotide), catalase as a coenzyme, as well as the impact of substituents on the tetralone substrates rendering functionalized naphthols. Ultimately, a robust process is realized for the expedited synthesis of naphthols in a streamlined and potentially scalable manner.