Regio- and Enantioselective Catalytic δ-C–H Amidation of Dioxazolones Enabled by Open-Shell Copper-Nitrenoid Transfer

Abstract

Controlling regio- and enantioselectivity in C–H functionalization reactions is of paramount importance due to their versatile synthetic utilities. Herein, we describe a new approach for the asymmetric δ-C­(sp3)–H amidation catalysis of dioxazolones using a Cu­(I) precursor with a chiral bisoxazoline ligand to access six-membered lactams with high to excellent regio- and enantioselectivity (up to >19:1 rr and >99:1 er). Combined experimental and computational mechanistic studies unveiled that the open-shell character of the postulated Cu-nitrenoids enables the regioselective hydrogen atom abstraction and subsequent enantio-determining radical rebound of the resulting carbon radical intermediates. The synthetic utility of this asymmetric cyclization was demonstrated in the diastereoselective introduction of additional functional groups into the chiral δ-lactam skeleton as well as in the rapid access to biorelevant azacyclic compounds.

Iron-Catalyzed Asymmetric Imidation of Sulfides via Sterically Biased Nitrene Transfer

“…The use of dioxazolones as acylnitrene transfer reagents has been explored by Bolm, , Chang, − and others. − Precious metals, including Ir, Rh, and Ru, were effective promoters to decompose dioxazolones into acylnitrene species. In stark contrast, 3d transition metals have seldom been used for this purpose.…”

Catalytic, asymmetric carbon–nitrogen bond formation using metal nitrenoids: from metal–ligand complexes via metalloporphyrins to enzymes

“…5a and b). 54 By exploiting the open-shell character of the postulated copper nitrenoids, both regio- and enantioselectivity are simultaneously controlled to afford access to versatile enantioenriched δ-lactams. Not only can these intermediates undergo further diastereoselective transformations to build up ring systems with multiple stereocentres but these also provide a useful entry point to the synthesis of several biologically active alkaloids.…”

Copper/BINOL-Catalyzed Enantioselective C–H Functionalization toward Planar Chiral Ferrocenes Under Mild Conditions

“…As an earth-abundant and inexpensive 3d transition metal, copper was one of the prime contenders for this consideration . More importantly, owing to the easily accessible oxidation states ranging from 0 to +3 through both radical pathway and two-electron transfer, copper complexes might offer unique reactivity that is unavailable for precious metals. − Significant advances have been achieved in Cu-catalyzed enantioselective C–H functionalization through the outer-sphere mechanism, including asymmetric C­(sp 3 )–H insertion into copper carbenoid complexes with a chiral Box ligand, atroposelective dimerization of electron-rich arenes to construct axial chirality via the single electron transfer (SET) mechanism, the asymmetric Kharasch–Sosnovsky reaction, and the hydrogen atom transfer radical relay mechanism involving the asymmetric reaction of the carbon-centered radical with a chiral Cu center (Figure a) . However, Cu-catalyzed asymmetric C–H activation by an inner-sphere pathway, proceeding through the formation of an organometallic C–Cu intermediate, has scarcely been explored.…”