New Catalytic Radical Process Involving 1,4-Hydrogen Atom Abstraction: Asymmetric Construction of Cyclobutanones

• Published in: Journal of the American Chemical Society 2021-08, Vol.143 (30), p.11670-11678
• Main Authors: Xie, Jingjing, Xu, Pan, Zhu, Yiling, Wang, Jingyi, Lee, Wan-Chen Cindy, Zhang, X. Peter
• Format: Article
• Language: English
• Subjects: Catalysis; Cobalt - chemistry; Coordination Complexes - chemistry; Cyclobutanes - chemical synthesis; Cyclobutanes - chemistry; Free Radicals - chemistry; Hydrogen - chemistry; Molecular Conformation; Stereoisomerism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.1c04968

While alkyl radicals have been well demonstrated to undergo both 1,5- and 1,6-hydrogen atom abstraction (HAA) reactions, 1,4-HAA is typically a challenging process both entropically and enthalpically. Consequently, chemical transformations based on 1,4-HAA have been scarcely developed. Guided by the general mechanistic principles of metalloradical catalysis (MRC), 1,4-HAA has been successfully incorporated as a key step, followed by 4-exo-tet radical substitution (RS), for the development of a new catalytic radical process that enables asymmetric 1,4-C–H alkylation of diazoketones for stereoselective construction of cyclobutanone structures. The key to success is the optimization of the Co­(II)-based metalloradical catalyst through judicious modulation of D 2-symmetric chiral amidoporphyrin ligand to adopt proper steric, electronic, and chiral environments that can utilize a network of noncovalent attractive interactions for effective activation of the substrate and subsequent radical intermediates. Supported by an optimal chiral ligand, the Co­(II)-based metalloradical system, which operates under mild conditions, is capable of 1,4-C–H alkylation of α-aryldiazoketones with varied electronic and steric properties to construct chiral α,β-disubstituted cyclobutanones in good to high yields with high diastereoselectivities and enantioselectivities, generating dinitrogen as the only byproduct. Combined computational and experimental studies have shed light on the mechanistic details of the new catalytic radical process, including the revelation of facile 1,4-HAA and 4-exo-tet-RS steps. The resulting enantioenriched α,β-disubstituted cyclobutanones, as showcased with several enantiospecific transformations to other types of cyclic structures, may find useful applications in stereoselective organic synthesis.