The stereoselective oxidative coupling of cyclic ketones via silyl bis-enol ethers followed by ring-closing metathesis is shown to be a general and powerful reaction sequence for the preparation of diverse polycyclic scaffolds from simple precursors. The modular strategy successfully constructs substructures prevalent in numerous bioactive natural product families, varying in substitution and carbocyclic composition. Several of the prepared compounds were shown to possess potent cytotoxic activity against a panel of tumor cell lines. The utility of this strategy was further demonstrated by a concise and highly convergent 17-step formal synthesis of the complex antimalarial marine diterpene, (+)-7,20-diisocyanoadociane.

Monoalkyl diazene species are versatile intermediates that have enabled many useful synthetic transformations in complex chemical environments. Herein we report the reductive transposition of 1,2-allenols for the direct synthesis of dienes through an alkene walk process.

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Appropriate control of impurities from all sources is critically important during the development of a pharmaceutical product. One class of impurity that has gained considerable attention over the past few years is extractables and leachables. We report a model for assessment of the risk posed by leachable impurities for a small-molecule drug substance. The first step of this study consists of a high-level assessment of the risk posed by leachable impurities in the drug substance, by taking into account the drug product’s route of administration. In the case of parenteral route of administration, a more comprehensive process-specific second step risk assessment is typically warranted. This second step consists of risk assessment of polymer component(s) for the potential to release leachable impurities, risk scoring, and classification. For high-risk components, risk mitigation studies can be performed in step 3, such as leachable impurity removal via component pre-flush with the process solvent, extractables’ studies under harsher conditions, and toxicity assessments.