Macrocyclic pyrrolobenzodiazepine dimers as antibody-drug conjugate payloads.

Macrocyclic pyrrolobenzodiazepine dimers were designed and evaluated for use as antibody-drug conjugate payloads. Initial structure-activity exploration established that macrocyclization could increase the potency of PBD dimers compared with non-macrocyclic analogs. Further optimization overcame activity-limiting solubility issues, leading to compounds with highly potent (picomolar) activity against several cancer cell lines.

Molecular complexity via C-H activation: a dehydrogenative Diels-Alder reaction.

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.

On the macrocyclization of the erythromycin core: preorganization is not required.

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

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.