An enzymatic platform for the highy enantioselective and stereodivergent construction of cyclopropyl-δ-lactones

• Published in: Angewandte Chemie International Edition
• Main Authors: Ren, Xinkun, Liu, Ningyu, Chandgude, Ajay L., Fasan, Rudi
• Format: Text
• Language: English
• Published: 2020
• Subjects: Article; Sperm whale
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346518/; http://www.ncbi.nlm.nih.gov/pubmed/32667122; https://doi.org/10.1002/anie.202007953

Abiological enzymes offers new opportunities for sustainable chemistry. Here 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 readily applied to enable 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.