Among the frontier challenges in chemistry in the 21st century are the interconnected goals of increasing synthetic efficiency and diversity in the construction of complex molecules. C—H Oxidation reactions, 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 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.

Traditionally, C–H oxidation reactions install oxidized functionality onto a preformed molecular skeleton, resulting in a local molecular change. The use of C–H activation chemistry to construct complex molecular scaffolds is a new area with tremendous potential in synthesis. We report a Pd(II)/bis-sulfoxide catalyzed dehydrogenative Diels-Alder reaction that converts simple terminal olefins into complex cycloadducts in a single operation.

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Graphical Abstract

Anders als vermutet ist eine Vororganisation für die effiziente Cyclisierung des Erythromycin‐Kerns keine zwingende Voraussetzung. Deshalb können durch Cyclisierungen unter C‐H‐Oxidation oder durch Yamaguchi‐Makrocyclisierungen stereochemisch modifizierte Erythromycin‐Strukturen aufgebaut werden, die unter Einsatz beeinflussender Elemente zuvor nicht zugänglich waren (siehe Schema; PG=Schutzgruppe).