Protoglobin‐Catalyzed Formation of cis‐Trifluoromethyl‐Substituted Cyclopropanes by Carbene Transfer. (19th December 2022)

• Record Type: Journal Article
• Authors: Schaus, Lucas; Das, Anuvab; Knight, Anders M.; Jimenez‐Osés, Gonzalo; Houk, K. N.; Garcia‐Borràs, Marc; Arnold, Frances H.; Huang, Xiongyi
• Is Part Of: Angewandte Chemie. Volume 135:Number 4(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-19
• Subjects: Biocatalysis -- Carbenes -- Cyclopropanes -- Organofluorines -- Protoglobins; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202208936
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Trifluoromethyl‐substituted cyclopropanes (CF3 ‐CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of trans ‐CF3 ‐CPAs, stereoselective production of corresponding cis ‐diastereomers remains a formidable challenge. We report a biocatalyst for diastereo‐ and enantio‐selective synthesis of cis ‐CF3 ‐CPAs with activity on a variety of alkenes. We found that an engineered protoglobin from Aeropyrnum pernix ( Ape Pgb) can catalyze this unusual reaction at preparative scale with low‐to‐excellent yield (6–55 %) and enantioselectivity (17–99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron‐carbenoid and substrates to adopt a pro‐ cis near‐attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF3 ‐CPAs for drug discovery. Abstract : Protoglobins were engineered to catalyze stereodivergent cyclopropanation to afford a variety of trifluoromethyl‐substituted cyclopropanes using trifluorodiazoethane as the trifluoromethyl‐carbene precursor.