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. 2023 Dec 4;62(49):e202312829.
doi: 10.1002/anie.202312829. Epub 2023 Nov 6.

Light-Driven Enantioselective Carbene-Catalyzed Radical-Radical Coupling

Seunghwan Byun  1 , Meemie U Hwang  1 , Henry R Wise  2 , Anna V Bay  1 , Paul H-Y Cheong  2 , Karl A Scheidt  1
Affiliations

Light-Driven Enantioselective Carbene-Catalyzed Radical-Radical Coupling

Seunghwan Byun et al. Angew Chem Int Ed Engl. .

Abstract

An enantioselective carbene-catalyzed radical-radical coupling of acyl imidazoles and racemic Hantzsch esters is disclosed. This method involves the coupling of an N-heterocyclic carbene-derived ketyl radical and a secondary sp3 -carbon radical and allows access to chiral α-aryl aliphatic ketones in moderate-to-good yields and enantioselectivities without any competitive epimerization. The utility of this protocol is highlighted by the late-stage functionalization of various pharmaceutical compounds and is further demonstrated by the transformation of the enantioenriched products to biologically relevant molecules. Computational investigations reveal the N-heterocyclic carbene controls the double-facial selectivity of the ketyl radical and the alkyl radicals, respectively.

Keywords: Asymmetric Catalysis; N-Heterocyclic Carbenes; Organocatalysis; Photoredox Catalysis; Radicals.

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Figures

Figure 1.
Figure 1.
(A) Representative biologically active compounds containing α-chiral ketones. (B) Catalytic approaches for ketone synthesis. (C) Carbene-catalyzed radical-radical coupling. (D) Our strategy to build α-chiral ketones featuring enantioselective radical-radical coupling.
Figure 2.
Figure 2.
Proposed catalytic cycle.
Figure 3.
Figure 3.
(A) DFT-computed reaction coordinate diagram, computed at the PBE-D3BJ/6–31G* & LANL2DZ / SMD(CH3CN) @ 298.15 level of theory (B) Radical-radical coupling transition structures, energies in kcal/mol, distances in Å. ΔG‡CCSD(T) energies computed at the DLPNO-CCSD(T)/def2-TZVPP//PBE-D3BJ/6–31G* & LANL2DZ / SMD(CH3CN) @ 298.15 K level of theory.
Scheme 1.
Scheme 1.
Functionalization of biologically active compounds and synthetic application. [a]Reactions performed under standard conditions. See the Supporting Information for details. [b]Conditions: (a) NaBH4 (1.1 equiv), MeOH, rt, 2 h (b) ZnCl2 (0.5 equiv), ClCH2OMe, (c) BnNH2 (1.1 equiv), TiCl4 (1.0 equiv), Et3N (3.0 equiv), THF (0.2 M), NaBH(OAc)3 (10.0 equiv), AcOH (0.1 M), (d) CH2O, HCl, CHCl3, then Boc2O, CH2Cl2.
Scheme 2.
Scheme 2.
Mechanistic experiments
See this image and copyright information in PMC

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