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

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.