The ability to differentiate between highly similar C−H bonds in a given molecule remains a fundamental challenge in organic chemistry. In particular, the lack of sufficient steric and electronic differences between C−H bonds located distal to functional groups has prevented the development of site-selective catalysts with broad scope. An emerging approach to circumvent this obstacle is to utilize the distance between a target C−H bond and a coordinating functional group, along with the geometry of the cyclic transition state in directed C−H activation, as core molecular recognition parameters to differentiate between multiple C−H bonds. In this Perspective, we discuss the advent and recent advances of this concept. We cover a wide range of transition-metalcatalyzed, template-directed remote C−H activation reactions of alcohols, carboxylic acids, sulfonates, phosphonates, and amines. Additionally, we review eminent examples which take advantage of non-covalent interactions to achieve regiocontrol. Continued advancement of this distance-and geometry-based differentiation approach for regioselective remote C−H functionalization reactions may lead to the ultimate realization of molecular editing: the freedom to modify organic molecules at any site, in any order.

The design of synthetic routes by retrosynthetic logic is decisively influenced by the transformations available. Transition‐metal‐catalyzed C−H activation has emerged as a powerful strategy for C−C bond formation, with myriad methods developed for diverse substrates and coupling partners. However, its uptake in total synthesis has been tepid, partially due to their apparent synthetic intractability, as well as a lack of comprehensive guidelines for implementation. This Review addresses these issues and offers a guide to identify retrosynthetic opportunities to generate C−C bonds by C−H activation processes. By comparing total syntheses accomplished using traditional approaches and recent C−H activation methods, this Review demonstrates how C−H activation enabled C−C bond construction has led to more efficient retrosynthetic strategies, as well as the execution of previously unattainable tactical maneuvers. Finally, shortcomings of existing processes are highlighted; this Review illustrates how some highlighted total syntheses can be further economized by adopting next‐generation ligand‐enabled approaches.

The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the Ru II (arene) pharmacophore and even less with an Os II (arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M−C NHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal−NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η 6 -p-cymene)ruthenium(II) 1b I was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future.

The first X-ray structures of adducts formed between a RuII(N-heterocyclic carbene)(η6-p-cymene) compound and a protein are reported. Coordination to the protein induced the cleavage of the cymene ligand and EPR spectroscopy demonstrated the oxidation of the Ru centre.

No abstract