Asymmetric Clicking\nof Alkynyl Dipolarophiles and\nNitrones Catalyzed by a Well-Defined Chiral Iron Complex

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