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

Jiang, Guangde; Huang, Chunshuai; Harrison, Wesley; Li, Hongxiang; Zhou, Megan; Zhao, Huimin

doi:10.1002/ange.202302125

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

Journal Article · Tue Apr 25 00:00:00 EDT 2023 · Angewandte Chemie

DOI:https://doi.org/10.1002/ange.202302125· OSTI ID:1971392

Jiang, Guangde ^[1]; Huang, Chunshuai ^[2]; Harrison, Wesley ^[1]; Li, Hongxiang ^[2]; Zhou, Megan ^[2];

^[1]

Department of Chemical and Biomolecular Engineering Center for Advanced Bioenergy and Bioproducts Innovation Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign Urbana IL 61801 USA
Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign Urbana IL 61801 USA

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.

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Sponsoring Organization:: USDOE

OSTI ID:: 1971392

Journal Information:: Angewandte Chemie, Journal Name: Angewandte Chemie Vol. 135 Journal Issue: 22; ISSN 0044-8249

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Germany

Language:: English

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