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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. A synthesis of 6-deoxyerythronolide B is reported that uses a late-stage C–H oxidative macrocyclization reaction to forge the key macrocyclic core found in the erythromycins. By installing oxygen at a late-stage, this strategy improves synthetic efficiency by minimizing the ‘oxygen load’, and provides stereochemical versatility at the site of oxidation. Cite this article
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 