The methoxime group has emerged as a versatile directing group for a variety of C-H functionalizations. Despite its importance as a powerful functional handle, conversion of methoximes to the parent ketone, which is often desired, usually requires harsh and functional group intolerant reaction conditions. Therefore, the application of methoximes and their subsequent conversion to the corresponding ketone in a late-stage context can be problematic. Here, we present an alternative set of conditions to achieve mild and functional group tolerant conversion of methoximes to the parent ketones using photoexcited nitroarenes. The utility of this methodology is showcased in its application in the total synthesis of cephanolide D. Furthermore, mechanistic insight into this transformation obtained using isotope labeling studies as well as the analysis of reaction byproducts is provided.

Skeletal modifications enable elegant and rapid access to various derivatives of a compound that would otherwise be difficult to prepare. They are therefore a powerful tool, especially in the synthesis of natural products or drug discovery, to explore different natural products or to improve the properties of a drug candidate starting from a common intermediate. Inspired by the biosynthesis of the cephalotane natural products, we report here a single-atom insertion into the framework of the benzenoid subfamily, providing access to the troponoid congeners - representing the reverse of the proposed biosynthesis (i.e., a contra-biosynthesis approach). Computational evaluation of our designed transformation prompted us to investigate a Büchner-Curtius-Schlotterbeck reaction of a p-quinol methylether, which ultimately results in the synthesis of harringtonolide in two steps from cephanolide A, which we had previously prepared. Additional computational studies reveal that unconventional selectivity outcomes are driven by the choice of a Lewis acid and the nucleophile, which should inform further developments of these types of reactions.