An Enzymatic Platform for the Highly Enantioselective and Stereodivergent Construction of Cyclopropyl‐δ‐lactones

• Published in: Angewandte Chemie
• Main Authors: Ren, Xinkun, Liu, Ningyu, Chandgude, Ajay L., Fasan, Rudi
• Other Authors: National Institutes of Health, National Science Foundation
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2020
• Subjects: Sperm whale
• Online Access: http://dx.doi.org/10.1002/ange.202007953; https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fange.202007953; https://onlinelibrary.wiley.com/doi/pdf/10.1002/ange.202007953; https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ange.202007953; https://onlinelibrary.wiley.com/doi/am-pdf/10.1002/ange.202007953

Abstract Abiological enzymes offers new opportunities for sustainable chemistry. Herein, we report the development of biological catalysts derived from sperm whale myoglobin that exploit a carbene transfer mechanism for the asymmetric synthesis of cyclopropane‐fused‐δ‐lactones, which are key structural motifs found in many biologically active natural products. While hemin, wild‐type myoglobin, and other hemoproteins are unable to catalyze this reaction, the myoglobin scaffold could be remodeled by protein engineering to permit the intramolecular cyclopropanation of a broad spectrum of homoallylic diazoacetate substrates in high yields and with up to 99 % enantiomeric excess. Via an alternate evolutionary trajectory, a stereodivergent biocatalyst was also obtained for affording mirror‐image forms of the desired bicyclic products. In combination with whole‐cell transformations, the myoglobin‐based biocatalyst was used for the asymmetric construction of a cyclopropyl‐δ‐lactone scaffold at a gram scale, which could be further elaborated to furnish a variety of enantiopure trisubstituted cyclopropanes.