Ir(III)-Catalyzed Asymmetric C–H Activation/Annulation of Sulfoximines Assisted by the Hydrogen-Bonding Interaction

Abstract

Transition-metal-catalyzed asymmetric C–H activation reactions generally rely on the design of ligands with sterically bulky groups to create a chiral environment for enantioinduction through steric repulsion. Here we describe an Ir­(III)-catalyzed asymmetric C–H activation enabled by noncovalent interactions. A broad range of sulfur-stereogenic sulfoximines was prepared in high yields with excellent enantioselectivities via the asymmetric C–H activation/annulation of sulfoximines with diazo compounds. Desymmetrization, kinetic resolution, and parallel kinetic resolution are compatible with this protocol. Detailed DFT calculations suggested that the N–H···O hydrogen bonding interaction between sulfoximine and the chiral carboxylic acid ligand was crucial for the high enantiocontrol. Moreover, chiral iridacycle intermediates were isolated, characterized, and subjected to stoichiometric reactions. Computational and experimental studies suggested that the C–H cleavage step was the rate- and enantio-determining step.

Catalytic Enantioselective Sulfur Alkylation of Sulfenamides for the Asymmetric Synthesis of Sulfoximines

“…Sulfoximines are now established pharmacophores in medicinal chemistry, but their stereocontrolled synthesis can be challenging and limits wider implementation . While elegant chiral reagent-based and kinetic resolution approaches have been developed, the catalytic enantioselective installation of the stereogenic sulfur center is theoretically the most efficient approach for accessing enantioenriched sulfoximines . The existing catalytic enantioselective methods are primarily centered on enantioselective oxidation or amination of thioethers to afford enantioenriched sulfoxide or sulfilimine intermediates, respectively (Scheme B).…”

Recent Advances in the Synthesis of Cyclic Sulfoximines via C–H Bond Activation

“…Very recently, Hong and Shi reported an Ir(III)-catalyzed C–H activation/annulation strategy for the synthesis of chiral 1,2-benzothiazines 28 by the desymmetrization of sulfoximines 26 with diazo compounds 27 in the presence of chiral carboxylic acid 29 as ligand ( Scheme 13 ) [ 35 ]. Various electron-withdrawing groups on the diazo compounds were screened to be well tolerated and the ee value was up to 97%.…”

Synthesis of Chiral Sulfoximines via Iridium‐Catalyzed Regio‐ and Enantioselective C−H Borylation: A Remarkable Sidearm Effect of Ligand

“…[6] Therefore, several asymmetric synthetic strategies have been disclosed for these frameworks, [7] including imidation of chiral sulfoxides, [8] oxidation of enantioenriched sulfimides, [9] kinetic resolution of racemic sulfoxides or sulfoximines, [10] desymmetrization of prochiral sulfoximines, [8i, 11] and Salkylation/arylation of chiral sulfinamides. [12] Moreover, a handful of elegant catalytic asymmetric CÀ H activations enabled by Ir, [13] Rh, [10c, 11b,c] Ru, [8i, 11d] and Co [11e] catalysis have emerged as viable approaches (Scheme 1B). Yet, most of them are limited to annulation processes, [14] barring further functionalization of sulfoximine moieties.…”