Journal
NATURE CHEMISTRY
Volume 1, Issue 7, Pages 547-551Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEM.351
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Funding
- National Institutes of Health/National Institute of General Medicine [GM076153]
- Eli Lilly
- Bristol-Myers Squibb
- Pfizer
- Amgen
- R. C. Fuson graduate fellowship
- Roche Excellence in Chemistry Award
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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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