Regio- and stereodivergent antibiotic oxidative carbocyclizations catalysed by Rieske oxygenase-like enzymes

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Abstract

Oxidative cyclizations, exemplified by the biosynthetic assembly of the penicillin nucleus from a tripeptide precursor, are arguably the most synthetically powerful implementation of C–H activation reactions in nature. Here, we show that Rieske oxygenase-like enzymes mediate regio- and stereodivergent oxidative cyclizations to form 10- and 12-membered carbocyclic rings in the key steps of the biosynthesis of the antibiotics streptorubin B and metacycloprodigiosin, respectively. These reactions represent the first examples of oxidative carbocyclizations catalysed by non-haem iron-dependent oxidases and define a novel type of catalytic activity for Rieske enzymes. A better understanding of how these enzymes achieve such remarkable regio- and stereocontrol in the functionalization of unactivated hydrocarbon chains will greatly facilitate the development of selective man-made C–H activation catalysts.

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Figure 1: Key oxidative cyclization reactions in the biosynthesis of clinically used natural products.
Figure 2: Roles of Rieske non-haem iron-dependent oxygenases and oxidative cyclases, together with associated enzymes, in the biosynthesis of natural products and the degradation of organic compounds.
Figure 3: Data that elucidate the role of RedG and McpG in streptorubin B (9) and metacycloprodigiosin (7) biosynthesis, respectively.

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Acknowledgements

The authors acknowledge financial support from the University of Warwick, the National Institutes of Health (1R01GM77147-01A1), the Engineering and Physical Sciences Research Council and the European Union (contract no. 005224). The authors also thank R. Thomson for kindly providing the synthetic sample of the carbocyclic derivative of 2-undecylpyrrole. The assistance of D. Oves-Costales with the chemical conversion of desmethylundecylprodigiosin to undecylprodigiosin is gratefully acknowledged.

Author information

P.K.S., S.M.B., O.M.O., F.B.G., S.W.H, C.C., L.S. and G.L.C. designed the research. P.K.S., S.M.B., O.M.O., F.B.G., S.W.H, C.C. and L.S. performed the research. P.K.S., S.M.B., O.M.O., F.B.G., S.W.H, C.C., L.S. and G.L.C. interpreted the data. G.L.C., P.K.S. and S.M.B. wrote the paper.

Correspondence to Gregory L. Challis.

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Sydor, P., Barry, S., Odulate, O. et al. Regio- and stereodivergent antibiotic oxidative carbocyclizations catalysed by Rieske oxygenase-like enzymes. Nature Chem 3, 388–392 (2011) doi:10.1038/nchem.1024

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