Organic molecules are rich in carbon-hydrogen bonds; consequently, the transformation of C-H bonds to new functionalities (such as C-C, C-N, and C-O bonds) has garnered much attention by the synthetic chemistry community. The utility of C-H activation in organic synthesis, however, cannot be fully realized until chemists achieve stereocontrol in the modification of C-H bonds. This Review highlights recent efforts to enantioselectively functionalize C(sp)-H bonds via transition metal catalysis, with an emphasis on key principles for both the development of chiral ligand scaffolds that can accelerate metalation of C(sp)-H bonds and stereomodels for asymmetric metalation of prochiral C-H bonds by these catalysts.
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.
Herein we report acid-directed β-C(sp3)–H arylation of α-amino acids enabled by pyridine-type ligands. This reaction does not require the installation of an exogenous directing group, is scalable, and enables the preparation of Fmoc-protected unnatural amino acids in three steps. The pyridine-type ligands are crucial in the development of this new C(sp3)–H arylation.
A conformationally flexible template for the meta-C-H olefination of benzoic acids was designed through both experimental and computational efforts. The newly designed template favors a silver-palladium heterodimer low barrier transition state, and demonstrates that it is feasible to lengthen templates so as to achieve meta-selectivity when the distance between the functional handle of the native substrate and target C-H bond decreases. Analysis of the ortho-, meta-, and para-C-H cleavage transition states determined that the new template conformation optimizes the interaction between the nitrile and palladium-silver dimer in the meta-transition state, enabling palladium to cleave meta-C-H bonds with moderate-to-good yields and generally high regioselectivity. Regioselectivity is governed exclusively by the template, and kinetic experiments reveal that there is a 4-fold increase in rate in the presence of monoprotected amino acid ligands. Using a Boltzmann distribution of all accessible C-H activation transition states, it is possible to computationally predict meta-selectivity in a number of investigated templates with reasonable accuracy. Structural and distortion energies reported may be used for the further development of templates for meta-C-H activation of hitherto unexplored arene substrates.
One long-standing issue in directed C-H functionalization is that either nitrogen or sulfur atoms present in heterocyclic substrates may bind preferentially to a transition-metal catalyst rather than to the desired directing group. This competitive binding has largely hindered the application of C-H functionalization in late-stage heterocycle drug discovery. Reported here is the use of an oxazoline-based directing group capable of overriding the poisoning effect of a wide range of heterocycle substrates. The potential use of this directing group in pharmaceutical drug discovery is illustrated by diversification of Telmisartan (an antagonist for the angiotensin II receptor) through copper-mediated C-H amination, hydroxylation, thiolation, arylation, and trifluoromethylation.
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