Dehaloperoxidase Catalyzed Stereoselective Synthesis of Cyclopropanol Esters

• Published in: Journal of organic chemistry Vol. 88; no. 12; pp. 7630 - 7640
• Main Authors: Siriboe, Mary G., Vargas, David A., Fasan, Rudi
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.06.2023; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; HEMOGLOBIN; AMPHITRITE-ORNATA; ASYMMETRIC-SYNTHESIS; OLEFIN CYCLOPROPANATION; PRECURSORS
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.2c02030

Chiral cyclopropanols are highly desirable building blocks for medicinal chemistry, but the stereoselective synthesis of these molecules remains challenging. Here, a novel strategy is reported for the diastereo- and enantioselective synthesis of cyclopropanol derivatives via the biocatalytic asymmetric cyclopropanation of vinyl esters with ethyl diazoacetate (EDA). A dehaloperoxidase enzyme from Amphitrite ornata was repurposed to catalyze this challenging cyclopropanation reaction, and its activity and stereoselectivity were optimized via protein engineering. Using this system, a broad range of electron-deficient vinyl esters were efficiently converted to the desired cyclopropanation products with up to 99.5:0.5 diastereomeric and enantiomeric ratios. In addition, the engineered dehaloperoxidase-based biocatalyst is able to catalyze a variety of other abiological carbene transfer reactions, including N–H/S–H carbene insertion with EDA as well as cyclopropanation with diazoacetonitrile, thus adding to the multifunctionality of this enzyme and defining it as a valuable new scaffold for the development of novel carbene transferases.