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  • Title: Nickel-Catalyzed Ligand-Controlled Selective Reductive Cyclization/Cross-Couplings.
    Author: Pan Q, Ping Y, Kong W.
    Journal: Acc Chem Res; 2023 Mar 07; 56(5):515-535. PubMed ID: 36688822.
    Abstract:
    ConspectusThe use of quaternary stereocenters during lead candidate optimization continues to grow because of improved physiochemical and pharmacokinetic profiles of compounds with higher sp3 fraction. Pd-catalyzed redox-neutral alkene difunctionalization involving carbopalladation of alkenes followed by nucleophilic-trapping σ-alkyl-palladium intermediates has been developed as an efficient method to construct quaternary stereocenters. However, the low chemoselectivity and air sensitivity of organometallic nucleophiles, as well as their low availability and accessibility, limit the scope of application of this elegant strategy. Recently, Ni-catalyzed reductive cross-coupling has evolved into a privileged strategy to easily construct valuable C(sp3)-C bonds. Despite great progress, the enantioselective coupling of C(sp3) electrophiles still relies on activated or functionalized alkyl precursors, which are often unstable and require multiple steps to prepare. Therefore, Ni-catalyzed reductive difunctionalization of alkenes via selective cyclization/cross-coupling was developed. This strategy not only offers a robust and practical alternative for traditional redox-neutral alkene difunctionalization but also provides strategic complementarity for reductive cross-coupling of activated alkyl electrophiles. In this Account, we summarize the latest results from our laboratory on this topic. These findings mainly include our explorations in modulating the enantioselectivity and cyclization mode of reductive cyclization/cross-couplings.We will first discuss Ni-catalyzed enantioselective reductive cyclization/cross-coupling to construct valuable chiral heterocycles with quaternary stereocenters and focus on the effects of ligands, reductants, and additives and their roles in reductive cross-coupling. A wide range of electrophiles have been explored, including aryl halides, vinyl halides, alkynyl halides, gem-difluoroalkenes, CO2, trifluoromethyl alkenes, and cyano electrophiles. The synthetic potential of this approach has also been demonstrated in the synthesis of biologically active natural products and drug molecules. Second, we will detail how to tune the steric effects of nickel catalysts by modifying bipyridine ligands for regiodivergent cyclization/cross-couplings. Specifically, the use of bidentate ligands favors exo-selective cyclization/cross-coupling, while the use of a carboxylic acid-modified bipyridine ligand permits endo-selective cyclization/cross-coupling. We will also show how to activate the amide substrate by altering the electronic and steric properties of substituents on the nitrogen, thereby enabling the nucleophilic addition of aryl halides to amide carbonyls. Further investigation of ligand properties has led to tunable cyclization/cross-couplings (addition to the amide carbonyl vs 7-endo-cyclization) for the divergent synthesis of pharmacologically important 2-benzazepine frameworks. Finally, we serendipitously discover that modifying the ligands of nickel catalysts and changing the oxidation state of nickel can control the migratory aptitude of different groups, thus providing a switchable skeletal rearrangement strategy. This transformation is of high synthetic value because it represents a conceptually unprecedented new approach to C-C bond activation. Thus, this Account not only summarizes synthetic methods that allow the formation of valuable chiral heterocycles with quaternary stereocenters using a wide variety of electrophiles but also provides insight into the relationship between ligand structure, substrate, and cyclization selectivity.
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