Multienzymatic Stereoselective Reduction of Tetrasubstituted Cyclic Enones to Halohydrins with Three Contiguous Stereogenic Centers

Silvia Venturi, Elisabetta Brenna, Danilo Colombo, Marco W. Fraaije, Francesco G. Gatti*, Piero Macchi, Daniela Monti, Milos Trajkovic, Emilio Zamboni

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The asymmetric hydrogenation of conjugated tetrasubstituted alkenes with transition-metal catalysts is a challenging reaction, especially for substrates bearing a halide substituent. We describe a two-step multienzymatic reduction of a series of α-halo β-alkyl tetrasubstituted cyclic enones, affording halohydrins with three contiguous stereogenic centers, in good yield and with a high stereoselectivity. The reduction is catalyzed by a stereospecific ene-reductase (OYE2-3 or NemA) and a highly enantioselective alcohol dehydrogenase (ADH). The use of two enantiodivergent ADHs allows the control of the diastereoselectivity. The absolute stereochemical configurations of the products have been determined from the analysis of single-crystal structures (Flack's parameter). The enantiomeric excess (ee) has been determined by derivatization of the products with (R) Mosher's acid. Lastly, we extended our methodology also to a nonhalogenated substrate: the α-methyl ketoisophorone was reduced by two distinct enantiodivergent ene-reductases (flavin mononucleotide- and F 420-dependent), affording each enantiomer of the saturated ketone with ee > 98%.

Original languageEnglish
Pages (from-to)13050-13057
Number of pages8
JournalACS Catalysis
Volume10
Issue number21
DOIs
Publication statusPublished - 6-Nov-2020

Keywords

  • Alcohol dehydrogenases
  • Biocatalysis
  • Chlorohydrins
  • Ene-reductases
  • Tetrasubstituted enones

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