Nickel-catalyzed switchable arylative/endo-cyclization of 1,6-enynes

• Published in: Nature communications Vol. 15; no. 1; p. 2914
• Main Authors: Liu, Wenfeng, Li, Wei, Xu, Weipeng, Wang, Minyan, Kong, Wangqing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-04-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 639/638/403/933; 639/638/403/934; Alkynes; Covalent bonds; Cross coupling; Density functional theory; Fine chemicals; Humanities and Social Sciences; Ligands; multidisciplinary; Natural products; Nickel; Reaction mechanisms; Reagents; Regioselectivity; Science; Science (multidisciplinary); Selectivity; Stereoselectivity; Steric hindrance; Structural members; Substrates; Transition metals; Trapping
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47200-z

Carbo- and heterocycles are frequently used as crucial scaffolds in natural products, fine chemicals, and biologically and pharmaceutically active compounds. Transition-metal-catalyzed cyclization of 1,6-enynes has emerged as a powerful strategy for constructing functionalized carbo- and heterocycles. Despite significant progress, the regioselectivity of alkyne functionalization is entirely substrate-dependent. And only
exo
-cyclization/cross-coupling products can be obtained, while
endo
-selective cyclization/cross-coupling remains elusive and still poses a formidable challenge. In this study, we disclose a nickel-catalyzed switchable arylation/cyclization of 1,6-enynes in which the nature of the ligand dictates the regioselectivity of alkyne arylation, while the electrophilic trapping reagents determine the selectivity of the cyclization mode. Specifically, using a commercially available 1,10-phenanthroline as a ligand facilitates
trans
-arylation/cyclization to obtain seven-membered ring products, while a 2-naphthyl-substituted bisbox ligand promotes
cis
-arylation/cyclization to access six-membered ring products. Diastereoselective cyclizations have also been developed for the synthesis of enantioenriched piperidines and azepanes, which are core structural elements of pharmaceuticals and natural products possessing important biological activities. Furthermore, experimental and density functional theory studies reveal that the regioselectivity of the alkyne arylation process is entirely controlled by the steric hindrance of the ligand; the reaction mechanism involves
exo
-cyclization followed by Dowd-Beckwith-type ring expansion to form
endo
-cyclization products.
Divergent functionalizations of pi bonds allow for synthetic chemists to move from simplicity to complexity. Here, the authors report a nickel-catalyzed switchable arylation/cyclization of 1,6-enynes in which the nature of the ligand dictates the regioselectivity of alkyne arylation, while the electrophilic trapping reagents determine the selectivity of the cyclization mode.