Acc Chem Res. 2026 Jul 21. doi: 10.1021/acs.accounts.6c00368. Online ahead of print.

ABSTRACT

ConspectusModern organic synthesis aims to prepare the target molecule in a minimal number of steps. Hence, the efficiency, selectivity, and predictability of each of these steps need to be carefully optimized, even at a late stage of a synthetic route. This is particularly true in the case of aliphatic C-H functionalization, since differentiating one C-H bond among many others with similar properties in organic molecules often stands as an open challenge. Remote, inactivated C-H sites are especially difficult to target. Supramolecular catalysis represents one of the tools to overcome such problems. As occurs in enzymes, substrate binding to a supramolecular catalyst constrains their relative orientation, and the resulting preorganization can increase reactivity and unlock unusual selectivity in a rational and predictable manner, meeting late-stage functionalization requirements. In fact, supramolecular catalysis, which was initially oriented to the comprehension of the mechanisms of the involved reactions, is currently and rapidly evolving into a synthetically useful tool.One decade ago, in 2017, we described Fe- and Mn-based supramolecular catalysts equipped with crown ether recognition sites able to efficiently catalyze the oxidation of inactivated C-H bonds in protonated primary amines. Substrate preorganization induced by recognition enables elusive oxidation at remote C8 and C9 sites in linear alkyl chains. Since then, a number of follow-up investigations allowed us to rationally elicit unnatural reactivity and selectivity in different bioinspired oxidation reactions, including predictable, late-stage C-H oxidation of steroids. In addition, an in-depth analysis of such oxidation processes provides a deep comprehension of the action mechanism of these supramolecular catalysts.In this Account, we discuss the above investigations aiming to show (i) the rational approach to the design of a supramolecular oxidation catalyst, (ii) the experimental and theoretical tools that help understand and assess its mechanism of action, and (iii) its potential to address synthetic challenges. Eventually, a section that compares our approach to the one of other research groups illustrates the state of the art in supramolecular oxidation catalysis.

PMID:42479475 | DOI:10.1021/acs.accounts.6c00368