This work applied photoexcitation of enzyme−substrate electron donor−acceptor complexes to expand the scope of abiological photobiocatalysis to intermolecular enantioselective transformations.

No abstract

Herein we report that ene reductases (EREDs) can facilitate an unprecedented intramolecular β-CÀ H functionalization reaction for the synthesis of bridged bicyclic nitrogen heterocycles containing the 6azabicyclo[3.2.1]octane scaffold. To streamline the synthesis of these privileged motifs, we developed a gramscale 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 6azabicyclo[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.

Herein we report that ene reductases (EREDs) can facilitate an unprecedented intramolecular β-CÀ H functionalization reaction for the synthesis of bridged bicyclic nitrogen heterocycles containing the 6azabicyclo[3.2.1]octane scaffold. To streamline the synthesis of these privileged motifs, we developed a gramscale 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 6azabicyclo[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.