Ene Reductase Enabled Intramolecular β‐C−H Functionalization of Substituted Cyclohexanones for Efficient Synthesis of Bridged Bicyclic Nitrogen Scaffolds

Abstract Herein we report that ene reductases (EREDs) can facilitate an unprecedented intramolecular β‐C−H functionalization reaction for the synthesis of bridged bicyclic nitrogen heterocycles containing the 6‐azabicyclo[3.2.1]octane scaffold. To streamline the synthesis of these privileged motifs, we developed a gram‐scale one‐pot chemoenzymatic cascade by combining iridium photocatalysis with EREDs, using readily available N ‐phenylglycines and cyclohexenones that can be obtained from biomass. Further derivatization using enzymatic or chemical methods can convert 6‐azabicyclo[3.2.1]octan‐3‐one into 6‐azabicyclo[3.2.1]octan‐3α‐ols, which can be potentially utilized for the synthesis of azaprophen and its analogues for drug discovery. Mechanistic studies revealed the reaction requires oxygen, presumably to produce oxidized flavin, which can selectively dehydrogenate the 3‐substituted cyclohexanone derivatives to form the α,β‐unsaturated ketone, which subsequently undergoes spontaneous intramolecular aza‐Michael addition under basic conditions.