Oxidative cleavage of ketoximes to ketones using photoexcited nitroarenes.

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.

Author Correction: Deconstructive diversification of cyclic amines.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

C─C Cleavage Approach to C─H Functionalization of Saturated Aza-Cycles.

Saturated cyclic amines (aza-cycles) are ubiquitous structural motifs found in pharmaceuticals, agrochemicals, and bioactive natural products. Given their importance, methods that directly functionalize aza-cycles are in high demand. Herein, we disclose a fundamentally different approach to functionalizing cyclic amines which relies on C─C cleavage and attendant cross-coupling. The initial functionalization step is the generation of underexplored N-fused bicyclo α-hydroxy-ß-lactams under mild, visible light conditions using a Norrish-Yang process to affect α-functionalization of saturated cyclic amines. This approach is complementary to previous methods for the C─H functionalization of aza-cycles and provides unique access to various cross-coupling adducts. In the course of these studies, we have also uncovered an orthogonal, base-promoted opening of the N-fused bicyclo α-hydroxy-ß-lactams. Computational studies have provided insight into the origin of the complementary C─C cleavage processes.

Deconstructive diversification of cyclic amines.

Deconstructive functionalization involves carbon-carbon (C-C) bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis1 and olefin metathesis2,3 have allowed each carbon in C=C double bonds to be viewed as a functional group. Despite the substantial advances in deconstructive functionalization involving the scission of C=C double bonds, there are very few methods that achieve C(sp3)-C(sp3) single-bond cleavage and functionalization, especially in relatively unstrained cyclic systems. Here we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, which are important moieties in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C(sp3)-N and C(sp3)-C(sp3) single-bond cleavage followed by C(sp3)-halogen bond formation. The resulting acyclic haloamines are versatile intermediates that can be transformed into various structural motifs through substitution reactions. In this way we achieve the skeletal remodelling of cyclic amines, an example of scaffold hopping. We demonstrate this deconstructive strategy by the late-stage diversification of proline-containing peptides.

Deconstructive fluorination of cyclic amines by carbon-carbon cleavage.

Deconstructive functionalizations involving scission of carbon-carbon double bonds are well established. In contrast, unstrained C(sp3)-C(sp3) bond cleavage and functionalization have less precedent. Here we report the use of deconstructive fluorination to access mono- and difluorinated amine derivatives by C(sp3)-C(sp3) bond cleavage in saturated nitrogen heterocycles such as piperidines and pyrrolidines. Silver-mediated ring-opening fluorination using Selectfluor highlights a strategy for cyclic amine functionalization and late-stage skeletal diversification, establishing cyclic amines as synthons for amino alkyl radicals and providing synthetic routes to valuable building blocks.