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Asymmetric Reductive Carbocyclization Using Engineered Ene Reductases.

ABSTRACT: Ene reductases from the Old Yellow Enzyme (OYE) family reduce the C=C double bond in ?,?-unsaturated compounds bearing an electron-withdrawing group, for example, a carbonyl group. This asymmetric reduction has been exploited for biocatalysis. Going beyond its canonical function, we show that members of this enzyme family can also catalyze the formation of C-C bonds. ?,?-Unsaturated aldehydes and ketones containing an additional electrophilic group undergo reductive cyclization. Mechanistically, the two-electron-reduced enzyme cofactor FMN delivers a hydride to generate an enolate intermediate, which reacts with the internal electrophile. Single-site replacement of a crucial Tyr residue with a non-protic Phe or Trp favored the cyclization over the natural reduction reaction. The new transformation enabled the enantioselective synthesis of chiral cyclopropanes in up to >99?% ee.

SUBMITTER: Heckenbichler K

PROVIDER: S-EPMC6033016 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Asymmetric Reductive Carbocyclization Using Engineered Ene Reductases.

Heckenbichler Kathrin K Schweiger Anna A Brandner Lea Alexandra LA Binter Alexandra A Toplak Marina M Macheroux Peter P Gruber Karl K Breinbauer Rolf R

Angewandte Chemie (International ed. in English) 20180514 24

Ene reductases from the Old Yellow Enzyme (OYE) family reduce the C=C double bond in α,β-unsaturated compounds bearing an electron-withdrawing group, for example, a carbonyl group. This asymmetric reduction has been exploited for biocatalysis. Going beyond its canonical function, we show that members of this enzyme family can also catalyze the formation of C-C bonds. α,β-Unsaturated aldehydes and ketones containing an additional electrophilic group undergo reductive cyclization. Mechanistically, ...[more]

PMID: 29689601

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