Multifunctional Glucose Dehydrogenase Enabled Synthesis of Chiral-Bridged Bicyclic Nitrogen Heterocycles

Guangde Jiang, Jingxia Lu, Megan Zhou, Wesley Harrison, Huimin Zhao

Research output: Contribution to journalArticlepeer-review

Abstract

Herein, we report that enzymatic cascade reactions using a glucose dehydrogenase (GDH) and an ene-reductase (ERED) can be utilized for the synthesis of chiral 3-substituted cyclic alcohols and chiral-bridged bicyclic nitrogen heterocycles. The crucial step in these cascade reactions is a kinetic resolution reaction by the multifunctional GDH mutant BsGDH_Q252K. This reaction selectively reduces the R-enantiomers of racemic ketone substrates, yielding enantiopure alcohols with high enantiomeric excess (ee) values of the remaining S-enantiomers. When the reaction is coupled with an ERED-promoted dehydrocyclization reaction, chiral-bridged bicyclic nitrogen heterocycles with a configuration of (1S, 5R) can be conveniently synthesized in one pot. Meanwhile, the chiral alcohol products generated from the kinetic resolution reactions can be further converted to the R-enantiomers of the racemic ketone substrates through the cyclohexanol dehydrogenase activity of BsGDH_Q252K when coupled with an NAD(P)H oxidase. When the oxidase is replaced by an ERED, chiral-bridged bicyclic nitrogen heterocycles with a configuration of (1R, 5S) can also be efficiently synthesized in one pot. Mechanistic studies revealed key amino acid residues in BsGDH_Q252K for the kinetic resolution reaction. Subsequent rational design of BmGDH, a homolog of BsGDH, yielded can also enable a quintuple mutant capable of performing this reaction, while the wild type BmGDH cannot.

Original languageEnglish (US)
Pages (from-to)7074-7079
Number of pages6
JournalACS Catalysis
Volume14
Issue number9
DOIs
StatePublished - May 3 2024

Keywords

  • cascade reactions
  • enzyme catalysis
  • heterocycles
  • kinetic resolution
  • multifunctional glucose dehydrogenase

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry

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