Direct functionalization of natural products is important for studying the structure-activity and structure-property relationships of these molecules. Recent advances in the transition-metal-catalyzed functionalization of C(sp )-H bonds, the most abundant yet inert bonds in natural products, have allowed natural product derivatives to be created selectively. Strategies to achieve such transformation are reviewed.

Selective functionalization of complex scaffolds is a promising approach to alter the pharmacological profiles of natural products and their derivatives. We report the site-selective azidation of benzylic and aliphatic C–H bonds in complex molecules catalyzed by the combination of Fe(OAc)2 and a PyBox ligand. The same system also catalyzes the trifluoromethyl azidation of olefins to form derivatives of natural products containing both fluorine atoms and azides. In general, both reactions tolerate a wide range of functional groups and occur with predictable regioselectivity. Azides obtained by functionalization of C–H and C=C bonds were converted to the corresponding amines, amides, and triazoles, thus providing a wide variety of nitrogen-containing complex molecules.

Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer’s disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems.

2-Iodylphenol ethers were prepared by the dimethyldioxirane oxidation of the corresponding 2-iodophenol ethers and isolated as chemically stable, microcrystalline products. Single-crystal X-ray diffraction analysis of 1-iodyl-2-isopropoxybenzene 8c and 1-iodyl-2-butoxybenzene 8d revealed pseudopolymeric arrangements in the solid state formed by intermolecular interactions between IO2 groups of different molecules. 2-Iodylphenol ethers can selectively oxidize sulfides to sulfoxides and alcohols to the respective aldehydes or ketones.

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