Abstract
Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Methods for the asymmetric synthesis of these molecules are therefore highly desirable, particularly through the selective functionalization of unreactive aliphatic C–H bonds. Here we show the development of a strategy for the asymmetric synthesis of β-, γ- and δ-lactams via the haemoprotein-catalysed intramolecular C–H amidation of readily accessible dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation, yielding the desired lactam products in high yields with high enantioselectivity and on a preparative scale. Mechanistic and computational studies were conducted to elucidate the nature of the C–H amidation and enantiodetermining steps and provide insights into the protein-mediated control of the regioselectivity and stereoselectivity. Additionally, an alkaloid natural product and a drug molecule were synthesized chemoenzymatically in fewer steps (7–8 versus 11–12) than previously reported, further demonstrating the power of biosynthetic strategies for the preparation of complex bioactive molecules.
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Data availability
The crystallographic data of the small molecules have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers CCDC 1893087 (2a), 2157011 (2m), 2157007 (4j) and 2157010 (6c). The data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.
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Acknowledgements
This work was supported by the US National Institute of Health (grant no. GM098628, to R.F.) and Cancer Prevention and Research Institute of Texas (CPRIT, RR230018 to R.F.). R.F. acknowledges endowed professorship support from the Robert A. Welch Foundation. D.A.V. acknowledges support from the National Science Foundation Graduate Fellowship Program. K.N.H. acknowledges support from the US National Science Foundation (grant no. CHE-1764328), and the Natural Science Foundation of China (grant no. 22103060) provided the computational resources used in the QM analyses. We are grateful to W. Brennessel (University of Rochester) for assistance with the crystallographic analyses. MS and X-ray instrumentation at the University of Rochester are supported by US National Science Foundation (grant nos. CHE-0946653 and CHE-1725028) and the US National Institute of Health (grant no. S10OD030302).
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D.A.V., S.R. and R.F. conceived the project and designed the experiments. S.R. and D.A.V. performed the experiments with guidance from R.F. K.N.H. mentored P.M., A.S. and L.Z. in the molecular dynamics and quantum mechanics calculations and contributed to the writing of the mechanistic parts of the paper. D.A.V., S.R., A.S.and R.F wrote the paper. All authors discussed the results and contributed to the final paper.
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Roy, S., Vargas, D.A., Ma, P. et al. Stereoselective construction of β-, γ- and δ-lactam rings via enzymatic C–H amidation. Nat Catal 7, 65–76 (2024). https://doi.org/10.1038/s41929-023-01068-2
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DOI: https://doi.org/10.1038/s41929-023-01068-2