Nickel-Catalyzed Radical Mechanisms: Informing Cross-Coupling for Synthesizing Non-Canonical Biomolecules.

ConspectusNickel excels at facilitating selective radical chemistry, playing a pivotal role in metalloenzyme catalysis and modern cross-coupling reactions. Radicals, being nonpolar and neutral, exhibit orthogonal reactivity to nucleophilic and basic functional groups commonly present in biomolecules. Harnessing this compatibility, we delve into the application of nickel-catalyzed radical pathways in the synthesis of noncanonical peptides and carbohydrates, critical for chemical biology studies and drug discovery.We previously characterized a sequential reduction mechanism that accounts for chemoselectivity in cross-electrophile coupling reactions. This catalytic cycle begins with nickel(I)-mediated radical generation from alkyl halides, followed by carbon radical capture by nickel(II) complexes, and concludes with reductive elimination. These steps resonate with mechanistic proposals in nickel-catalyzed cross-coupling, photoredox, and electrocatalytic reactions. Herein, we present our insights into each step involving radicals, including initiation, propagation, termination, and the nuances of kinetics, origins of selectivity, and ligand effects.Radical generation from C(sp3) electrophiles via one-electron oxidative addition with low-valent nickel radical intermediates provides the basis for stereoconvergent and cross-electrophile couplings. Our electroanalytical studies elucidate a concerted halogen atom abstraction mechanism, where electron transfer is coupled with halide dissociation. Using this pathway, we have developed a nickel-catalyzed stereoselective radical addition to dehydroalanine, facilitating the synthesis of noncanonical peptides. In this application, chiral ligands modulate the stereochemical outcome through the asymmetric protonation of a nickel-enolate intermediate.The capture of the alkyl radical by nickel(II) expands the scope of cross-coupling, promotes reductive elimination through the formation of high-valent nickel(III) species, and governs chemo- and stereoselectivity. We discovered that nickel(II)-aryl efficiently traps radicals with a barrier ranging from 7 to 9 kcal/mol, followed by fast reductive elimination. In contrast, nickel(II)-alkyl captures radicals to form a nickel(III) species, which was characterized by EPR spectroscopy. However, the subsequent slow reductive elimination resulted in minimal product formation. The observed high diastereoselectivity of radical capture inspired investigations into C-aryl and C-acyl glycosylation reactions. We developed a redox auxiliary that readily couples with natural carbohydrates and produces glycosyl radicals upon photoredox activation. Nickel-catalyzed cross-coupling of the glycosyl radical with bromoarenes and carboxylic acids leads to diverse non-natural glycosides that can facilitate drug discovery.Stoichiometric studies on well-defined d8-nickel complexes have showcased means to promote reductive elimination, including ligand association, oxidation, and oxidative addition.In the final section, we address the influence of auxiliary ligands on the electronic structure and redox activity of organonickel intermediates. Synthesis of a series of low-valent nickel radical complexes and characterization of their electronic structures led us to a postulate that ligand redox activity correlates with coordination geometry. Our data reveal that a change in ligand redox activity can shift the redox potentials of reaction intermediates, potentially altering the mechanism of catalytic reactions. Moreover, coordinating additives and solvents may stabilize nickel radicals during catalysis by adjusting ligand redox activity, which is consistent with known catalytic conditions.

Ligand Redox Activity of Organonickel Radical Complexes Governed by the Geometry.

Nickel-catalyzed cross-coupling reactions often employ bidentate π-acceptor N-ligands to facilitate radical pathways. This report presents the synthesis and characterization of a series of organonickel radical complexes supported by bidentate N-ligands, including bpy, phen, and pyrox, which are commonly proposed and observed intermediates in catalytic reactions. Through a comparison of relevant analogues, we have established an empirical rule governing the electronic structures of these nickel radical complexes. The N-ligands exhibit redox activity in four-coordinate, square-planar nickel radical complexes, leading to the observation of ligand-centered radicals. In contrast, these ligands do not display redox activity when supporting three-coordinate, trigonal planar nickel radical complexes, which are better described as nickel-centered radicals. This trend holds true irrespective of the nature of the actor ligands. These results provide insights into the beneficial effect of coordinating salt additives and solvents in stabilizing nickel radical intermediates during catalytic reactions by modulating the redox activity of the ligands. Understanding the electronic structures of these active intermediates can contribute to the development and optimization of nickel catalysts for cross-coupling reactions.

Leveraging Atropisomerism to Obtain a Selective Inhibitor of RET Kinase with Secondary Activities toward EGFR Mutants.

Unstable atropisomerism is innate in many common scaffolds in drug discovery, commonly existing as freely rotating aryl-aryl bonds. Such compounds can access the majority of dihedral conformations around the bond axis; however, most small molecules bind their target within a narrow range of these available conformations. The remaining accessible conformations can interact with other proteins leading to compound promiscuity. Herein, we leverage atropisomerism to restrict the accessible low-energy dihedral conformations available to a promiscuous kinase inhibitor and achieve highly selective and potent inhibitors of the oncogenic target rearranged during transfection (RET) kinase. We then evaluate our lead inhibitor against kinases that were predicted to bind compounds in a similar conformational window to RET, discovering a potent inhibitor of drug-resistant epidermal growth factor receptor (EGFR) mutants including L858R/T790M/C797S EGFR. Leveraging atropisomerism to restrict accessible conformational space should be a generally applicable strategy due to the prevalence of unstable atropisomerism in drug discovery.

Enantioselective Synthesis of Biaryl Atropisomers via the Addition of Thiophenols into Aryl-Naphthoquinones.

We report a cinchona alkaloid catalyzed addition of thiophenol into rapidly interconverting aryl-naphthoquinones, resulting in stable biaryl atropisomers upon reductive methylation. An array of thiophenols and naphthoquinone substrates were evaluated, and we observed selectivities up to 98.5:1.5 e.r. Control of the quinone redox properties allowed us to study the stereochemical stabilities of each oxidation state of the substrates. The resulting enantioenriched products can also be moved on via an SNAr-like reaction sequence to arrive at stable derivatives with excellent enantioretention.