The discovery of the copper-promoted Chan-Lam coupling reaction with boronic acids more than ten years ago has greatly advanced the carbon-heteroatom cross-coupling chemistry. The N-arylation/O-arylation methodology is now a powerful new synthetic tool, made even more attractive by the mild conditions required. Significant progress has been made in expanding the scope and the applications as well as understanding the mechanism of this reaction. This review includes an examination of various C-X cross-couplings using boronic acids and their derivatives, and a survey of the mechanistic studies that have been carried out.
Directed C–H activation has emerged as a major approach for developing synthetically useful reactions, owing to the proximity-induced reactivity and selectivity enabled by coordinating functional groups1–6. In contrast, development of palladium-catalyzed non-directed C–H activation has faced significant challenges associated with the lack of sufficiently active palladium catalysts7–8. Current palladium catalysts are only reactive with electron-rich arenes unless an excess of arene is used9–18, which limits synthetic applications. Herein, we disclose a 2-pyridone ligand that significantly enhances the reactivity of a palladium catalyst, allowing for Pd(II)-catalyzed non-directed C–H activation of a broad range of aromatic substrates using the various arenes as the limiting reagent. The significance of this finding is demonstrated by the direct functionalization of advanced synthetic intermediates, drug molecules, and natural products that cannot be utilized in excessive quantities. The potential of this methodology to be expanded to a variety of transformations is indicated by the development of both C–H olefination and C–H carboxylation protocols. Furthermore, the site selectivity in this transformation is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C–H functionalization.
The advent of antibody-drug conjugates as pharmaceuticals has fuelled a need for reliable methods of site-selective protein modification that furnish homogeneous adducts. Although bioorthogonal methods that use engineered amino acids often provide an elegant solution to the question of selective functionalization, achieving homogeneity using native amino acids remains a challenge. Here, we explore visible-light-mediated single-electron transfer as a mechanism towards enabling site- and chemoselective bioconjugation. Specifically, we demonstrate the use of photoredox catalysis as a platform to selectivity wherein the discrepancy in oxidation potentials between internal versus C-terminal carboxylates can be exploited towards obtaining C-terminal functionalization exclusively. This oxidation potential-gated technology is amenable to endogenous peptides and has been successfully demonstrated on the protein insulin. As a fundamentally new approach to bioconjugation this methodology provides a blueprint toward the development of photoredox catalysis as a generic platform to target other redox-active side chains for native conjugation.
The enzymatic β-C–H hydroxylation of the feedstock chemical isobutytic acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transitionmetal catalyzed enantioselective β-C–H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline (MPAO) ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp3)-H bonds of one of the prochiral methyl groups. We detail the enantioselective β-arylation, -alkenylation and -alkynylation of isobutyric acid/2-amino-isobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.
L,X-Type transient directing groups (TDGs) based on a reversible imine linkage have emerged as broadly useful tools for C–H activation of ketones and free amines. However, competitive binding interactions among multiple reaction components (TDG itself, substrate, and substrate–TDG adduct) with the palladium catalyst often lead to the formation of multiple unreactive complexes, rendering ligand development extremely challenging. Herein, we report the finding of versatile 2-pyridone ligands that addresses these problems and significantly improves the γ-methylene arylation of alkyl amines, extending the coupling partners to a wide range of medicinally important heteroaryl iodides and even previously unreactive heteroaryl bromides. The combination of an appropriate transient directing group and pyridone ligand has also enabled the δ-arylation of alkyl amines. Notably, our transient directing group design reveals the importance of matching the size of the Pd-chelation with different transient directing groups and the size of palladacycles generated from γ- and δ-C–H bonds: TDGs that coordinate with Pd(II) to form a six-membered chelate are selective toward γ-C–H bonds, whereas TDGs that coordinate with Pd(II) via a five-membered chelate tend to activate δ-C–H bonds. These findings provide an avenue for developing protecting group free and selective C–H functionalization using the transient directing group strategy.
Hydroxylation of aryl carbon–hydrogen bonds with transition metal catalysts has proven challenging when oxygen is used as the oxidant. Here, we report a palladium complex bearing a bidentate pyridine/pyridone ligand that efficiently catalyzes this reaction at ring positions adjacent to carboxylic acids. Infrared, x-ray, and computational analysis support a possible role of ligand tautomerization from mono-anionic (L,X) to neutral (L,L) coordination in the catalytic cycle of aerobic carbon–hydrogen hydroxylation reaction. The conventional site selectivity dictated by heterocycles is overturned by this catalyst, thus allowing late-stage modification of compounds of pharmaceutical interest at previously inaccessible sites.
A method for the decarboxylative macrocyclization of peptides bearing N-terminal Michael acceptors has been developed. This synthetic protocol enables the efficient synthesis of γ-amino acid-containing cyclic peptides and is tolerant of functionality present in both natural and non-proteinogenic amino acids. Linear precursors ranging from 3 to 15 amino acids cyclize effectively under this photoredox protocol. To demonstrate the preparative utility of this method in the context of bioactive molecules, we have generated COR-005, a somatostatin analog currently in clinical trials.
Controlling site selectivity of C–H activation without using a directing group remains a significant challenge. While Pd(II) catalysts modulated by a mutually repulsive pyridine-type ligand have been shown to favor the relatively electron-rich carbon centers of arenes, reversing the selectivity to favor palladation at the relatively electron-deficient positions has not been possible. Herein we report the first catalytic system that effectively performs meta C–H arylation of a variety of alkoxy aromatics including 2,3-dihydrobenzofuran and chromane with exclusive meta site selectivity, thus reversing the conventional site selectivity governed by native electronic effects. The identification of an effective ligand and modified norbornene (NBE-CO2Me), as well as taking advantage of the statistics, are essential for achieving the exclusive meta selectivity.
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