Asymmetric Clicking of Alkynyl Dipolarophiles and Nitrones Catalyzed by a Well-Defined Chiral Iron Complex

The enantioselective 1,3-dipolar cycloaddition of alkynes and α-aliphatic nitrones has long been recognized as an important challenge, while considerable progress has been made for the alkenes and aromatic nitrones. We herein report an example of an earth-abundant iron-catalyzed enantioselective click-approach 1,3-dipolar cycloaddition of nonterminal alkynyl imides and α-aliphatic nitrones, and highly functionalized chiral 4-isoxazolines having a 3-alkyl-substituted stereogenic carbon center are modularly generated in up to >99% yield and 98% ee (54 examples). Although the steric bulk substituent on the nitrone plays a key role in achieving effective enantiocontrol, the challenge of steric bias differentiation between linear alkyl chain (Me, Et, etc.) and H of nitrones is also successfully overcome. The enantioface discrimination is presumably rooted in the well-defined octahedral mononuclear ferrous complex containing dual tridentate ligands (L*·Fe(OTf)2·L*, L* = (R,R)-DBFOX-Ph) and possible dual-mode σ,π-binding activation, which is evidenced by ESI-HRMS and single crystal X-ray analysis, as well as the L*/Fe ratio effect and DFT calculations. Arguably, the most interesting aspect is that the chiral iron complex can induce a superpositive nonlinear effect and the chiral bisoxazoline ligand with a low enantiopurity of 22% ee results in an 84% ee for the cycloadduct. Practicability and utility are demonstrated by the gram-scale synthesis and ready downstream functionalization based on the chiral 4-isoxazoline core and imide functional group.