Copper-Catalyzed Enantioselective Intra- and Intermolecular Desymmetrization of Azetidiniums by Carbon Nucleophiles

Disclosed here is a transition-metal-catalyzed enantioselective ring-opening of azetidiniums. It also represents the first demonstration of catalytic enantioselective intramolecular desymmetrization of prochiral azetidiniums. With a cheap copper salt as the catalyst and a commercially available ferrocene-derived chiral oxazoline-phosphine as the chiral ligand, a mild borylation/cyclization cascade provided convenient access to diverse densely functionalized tetrahydropyrans and piperidine compounds bearing an α-methylene unit from readily available enone-tethered azetidinium substrates. Three new stereogenic centers and two new bonds were concomitantly constructed together with the ring formation, which also represents an unorthodox disconnection strategy in the related heterocycle synthesis. Control experiments suggested that borylation served as the enantiodetermining step. Moreover, this protocol was also extended to intermolecular C(sp³)-C(sp³) formation between azomethine ylides and azetidiniums, thereby providing expedient access to the valuable ornithine derivatives with high enantioselectivity. DFT studies also provided insights into the enantio-determining transition states.