Chemoenzymatic conversion of amides to enantioenriched alcohols in aqueous medium

• Published in: Communications chemistry Vol. 2; no. 1
• Main Authors: Dander, Jacob E., Giroud, Maude, Racine, Sophie, Darzi, Evan R., Alvizo, Oscar, Entwistle, David, Garg, Neil K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2019; Nature Publishing Group
• Subjects: 639/638/403/933; 639/638/77/603; 639/638/77/888; Alcohol; Alcohols; Amides; Antipodes; Aqueous solutions; Carbon; Chemical reactions; Chemical synthesis; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Chemists; Conversion; Nickel; Reduction; Stereoselectivity; Streamlining
• ISSN: 2399-3669; 2399-3669
• DOI: 10.1038/s42004-019-0182-8

One-pot reactions that combine non-enzymatic and biocatalytic transformations represent an emerging strategy in chemical synthesis. Some of the most powerful chemoenzymatic methodologies, although uncommon, are those that form a carbon–carbon (C–C) bond and a stereocenter at one of the reacting carbons, thereby streamlining traditional retrosynthetic disconnections. Here we report the one-pot, chemoenzymatic conversion of amides to enantioenriched alcohols. This transformation combines a nickel-catalyzed Suzuki–Miyaura coupling of amides in aqueous medium with an asymmetric, biocatalytic reduction to provide diarylmethanol derivatives in high yields and enantiomeric excesses. The synthetic utility of this platform is underscored by the formal syntheses of both antipodes of the pharmaceutical orphenadrine, which rely on ketoreductase enzymes that instill complementary stereoselectivities. We provide an explanation for the origins of stereoselectivity based on an analysis of the enzyme binding pockets.
The merger of chemical and biocatalysis can offer powerful new options to synthetic chemists. Here a combination of a nickel-catalyzed Suzuki-Miyaura reaction and an enzymatic stereoselective reduction provides enantiomerically-enriched alcohols from amides in a single reaction vessel, in water.