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Total synthesis and study of 6-deoxyerythronolide B by late-stage C–H oxidation

Nature Chemistry volume 1, pages 547–551 (2009)Cite this article

Abstract

Among the frontier challenges in chemistry in the twenty-first century are the interconnected goals of increasing synthetic efficiency and diversity in the construction of complex molecules. Oxidation reactions of C–H bonds, particularly when applied at late stages of complex molecule syntheses, hold special promise for achieving both these goals. Here we report a late-stage C–H oxidation strategy in the total synthesis of 6-deoxyerythronolide B (6-dEB), the aglycone precursor to the erythromycin antibiotics. An advanced intermediate is cyclized to give the 14-membered macrocyclic core of 6-dEB using a late-stage (step 19 of 22) C–H oxidative macrolactonization reaction that proceeds with high regio-, chemo- and diastereoselectivity (>40:1). A chelate-controlled model for macrolactonization predicted the stereochemical outcome of C–O bond formation and guided the discovery of conditions for synthesizing the first diastereomeric 13-epi-6-dEB precursor. Overall, this C–H oxidation strategy affords a highly efficient and stereochemically versatile synthesis of the erythromycin core.

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Figure 1: Macrocyclization approaches to macrolide antibiotics.
Figure 2: Synthesis of C–H macrolactonization precursor 2.
Figure 3: Synthesis of macrolides 1 and epi-1.
Figure 4: Synthesis of 6-deoxyerythronolide B.

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Acknowledgements

Financial support was provided by the National Institutes of Health/National Institute of General Medicine (grant no. GM076153), Eli Lilly, Bristol-Myers Squibb, Pfizer and Amgen. E.M.S. is the recipient of a R. C. Fuson graduate fellowship, Pfizer graduate fellowship and the Roche Excellence in Chemistry Award. We thank Professor Jerome Baudry for assisting with the molecular modelling studies, D. J. Covell for his insight into π-allyl-Pd fluoride complexes and I. Patterson and P. B. Dervan for discussions.

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  1. Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, 61801, Illinois, USA

    Erik M. Stang & M. Christina White

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  1. Erik M. Stang
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Contributions

E.M.S. and M.C.W. conceived and designed the experiments, E.M.S. performed the experiments and E.M.S. and M.C.W. co-wrote the paper.

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Correspondence to M. Christina White.

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Crystallographic information for compound 13 (CIF 27 kb)

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Stang, E., Christina White, M. Total synthesis and study of 6-deoxyerythronolide B by late-stage C–H oxidation. Nature Chem 1, 547–551 (2009). https://doi.org/10.1038/nchem.351

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