nitrone to generate a Cu(II)-associated zwitterion intermediate, which then undergoes an enantio-determining ring-closing process to form chiral BCHep. To commence the investigation, we selected nitrone (1a) and the pyrazole amide substituted BCB (2a; Table ; see Supplementary Information for details) as standard substrates to evaluate the reaction condition. Surprisingly, of the three Earth-abundant metals tested, copper was the sole catalyst capable of yielding 2oxa-3-aza BCHep (3a) with an isolated yield of 67% (entry 1-3). Even more surprisingly, no ring-opening byproducts were observed, highlighting the high chemoselectivity of the reaction. Next, chiral ligand was employed to control enantioselectivity of the reaction. Except L5, which is known to be a negatively charged ligand in the reaction, all the other electrically neutral ligands can improve the reaction yield (entry 4-11). To our delight, Evans bisoxazoline ligand L6 presented a promising ee value of 71% (entry 9). Modification of bisoxazoline ligand revealed that one with four benzyl groups at the oxazoline ring and bridge carbon gave high ee value (89%, entry 11). Additionally, lowering the reaction temperature to -40 °C further increased the yield and enantioselectivity of the reaction (99%, 96% ee, entry 12). With optimal condition established, we then studied the substrate scope with respect to nitrone (Figure ). The nitrone substrates with methyl or trifluoromethyl group on the benzene ring of nitrones 1 all gave desired products with good yield and excellent enantioselectivity (3a-3c). The halogen substituents on the meta or para position of the benzene ring also didn't adversely affect the outcome of the reaction (3e-3i), which provides an opportunity for further cross-couplings. However, nitrone with an ortho-fluorophenyl gave lower ee value, perhaps due to the steric effect (3d). Moreover, the functional groups with potential for diverse synthetic transformation like nitro, cyano, ester, boric ester, acetoxyl, phenoxy, silyl and sulfonyl group (3j-3q) have no serious harm to the yield and enantioselectivity of the reaction. In addition, trifluoromethoxy (3r) and trifluoromethylthio (3s) groups which often show unusual bio-activities in drug molecules were compatible in the reaction. Except for substituted phenyl groups, the fused aryl rings and hetero-aryl rings in the nitrone substrates also have no negative effect, giving excellent enantioselectivity (3t-3x). Apart from the deviation of R 1 , variations in the N-protecting aryl groups of BCB, including substitutions at the meta or para positions, showed minimal influence on both yield and enantioselectivity (3y-3ab). The substrate scope with respect to BCBs was explored (Figure ). Substitutions on the benzene ring of BCB, regardless of electron donating (3ac and 3ad) or withdrawing (3ae-3ag) groups, all gave gratifying outcomes. Notably, a methylsubstituted BCB can also react with nitrone 1a to form 2-oxa-3-aza BCHep 3ah under standard conditions with high yield and enantioselectivity. To showcase the application potential of this method, we carried out mmol experiment with 1a and 2a under standard condition (Figure ). At 1 mmol scale, 3a was produced with undiminished yield and ee value, highlighting its scalability. Besides, pyrazole amide group of 3a can be readily transformed into several valuable functional groups. Firstly, the NaBH4 reduction of 3a afforded primary alcohol with quantitative yield and unharmed ee value, facilitating subsequent connection through nucleophilic substitution or Mitsunobu reaction. Hydrolysis of 3a produced carboxylic acid 5 with 81% yield and >99% enantio-specificity, granting convenience for further amidation or decarboxylative coupling . Finally, the alcoholysis of 3a converted the amide group to the ester group with 96% yield and 96% ee. In order to elucidate the reaction mechanism, control experiments were performed. Reaction of 2a in the absence of nitrone resulted in >95% recovery of starting material with no observation of ring-opening byproducts, thereby excluding the possibility of a copper-catalyzed ring-opened intermediate (Figure ). Ester substituted BCB 7 was then applied in the cycloaddition and yielded no product, revealing the chelation of bidentated pyrazole amide to copper is indispensable (Figure ). To gain a deeper insight into the activation effect of Cu(II) on pyrazole amide-substituted BCB, we perform DFT calculation to analyze the structural and electronic properties of several relevant species. As illustrated in Figure , the bridgehead carbon adjacent to the phenyl substituent of the free BCB bears a certain amount of positive charge, showing its electrophilic nature. Without the coordination of Cu(II), the strained C-C σ bond of BCB has a bond length of 1.54 Å and a Mayer bond order of 0.64, indicating a weaker bond strength than typical open chained C-C single bond. However, upon coordination with a copper catalyst bearing a bisoxazoline ligand, the strained C-C σ bond of BCB elongated to 1.63 Å with a reduced bond order of 0.49, accompanied by an increased positive charge at the bridgehead carbon. These computational results showed that the coordination of copper(II) catalyst effectively activate BCB.