Access to Alkenyl Cyclobutanols by Ni‐Catalyzed Regio‐ and Enantio‐Selective syn‐Hydrometalative 4‐exo‐trig Cyclization of Alkynones

• Published in: Angewandte Chemie International Edition Vol. 64; no. 3; pp. e202415164 - n/a
• Main Authors: Li, Xiao‐Lin, Deng, Jiang‐Lian, Long, Jian, Fu, Yi‐Fan, Zheng, Yu‐Qing, Liu, Wen‐Bo
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 15.01.2025; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: 4-exo-trig cyclization; Alkynes; bioisosteres; Carbonyl compounds; Carbonyls; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Cyclobutane; cyclobutanols; Enantiomers; functionalization of alkynes; nickel catalysis; Physical Sciences; Regioselectivity; Science & Technology; HYDROFUNCTIONALIZATION; ASYMMETRIC-SYNTHESIS; ENANTIOSELECTIVE SYNTHESIS; LEWIS-ACID; CYCLOBUTENES; PHOTOCATALYSIS; nickel catalysis; 4-exo-trig cyclization; HYDROAMIDATION; functionalization of alkynes; 2+2 CYCLOADDITION; bioisosteres; LIGAND; cyclobutanols; DERIVATIVES
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202415164

Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel‐catalyzed asymmetric syn‐hydrometalative 4‐exo‐trig cyclization of 1,4‐alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl‐containing rigid (spiro)carbocycle skeletons in good yields with high enantioselectivities (up to 84 % yield and 98.5 : 1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spiro molecules. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni−H species, with carbonyl‐directed hydrometalation as the key for regioselective control. This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynes and represents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres. Override the intrinsic preference of regioselectivity. An enantioselective nickel‐catalyzed syn‐hydrometalative 4‐exo‐trig cyclization of 1,4‐alkynones is reported to access alkenyl cyclobutanols. A carbonyl‐directed hydrometalation step is the key to override the intrinsic electronic effect guided regioselectivity. The products are demonstrated to readily advance to enantioenriched three‐dimensional bioisosteres.