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Review
. 2021 Jan 20;12(1):475.
doi: 10.1038/s41467-020-20770-4.

Catalytic enantioselective C(sp3)-H functionalization involving radical intermediates

Chi Zhang  1 , Zhong-Liang Li  2 , Qiang-Shuai Gu  3 , Xin-Yuan Liu  4
Affiliations
Review

Catalytic enantioselective C(sp3)-H functionalization involving radical intermediates

Chi Zhang et al. Nat Commun. .

Abstract

Recently, with the boosted development of radical chemistry, enantioselective functionalization of C(sp3)-H bonds via a radical pathway has witnessed a renaissance. In principle, two distinct catalytic modes, distinguished by the steps in which the stereochemistry is determined (the radical formation step or the radical functionalization step), can be devised. This Perspective discusses the state-of-the-art in the area of catalytic enantioselective C(sp3)-H functionalization involving radical intermediates as well as future challenges and opportunities.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. General strategies for enantioselective C(sp3)–H functionalization.
a Transition metal-catalyzed C–H activation. b Concerted metal carbenoid/nitrenoid C–H insertion. c Sequential HAA/formal HAA and functionalization of the resulting alkyl radical. HAA hydrogen atom abstraction.
Fig. 2
Fig. 2. Two catalytic modes of enantioselective C(sp3)–H functionalization reactions via radical intermediates.
a Enantiodiscriminative HAA coupled with fast stereoretentive RR. b Non-stereoselective HAA/formal HAA followed by enantioselective functionalization of the resulting prochiral/achiral radical. RR radical rebound.
Fig. 3
Fig. 3. Examples of catalytic enantioselective C(sp3)–H functionalization with enantiodiscriminative HAA.
a Mn-catalyzed enantioselective hydroxylation of secondary C(sp3)–H bonds. b Co-catalyzed enantioselective amination/alkylation of secondary C(sp3)–H bonds.
Fig. 4
Fig. 4. Examples of enantiocontrol by chiral amine catalysts in enantioselective C(sp3)–H functionalization.
a Enantioselective addition of C–H-derived chiral amine-bonded prochiral radicals to free π-acceptors. b Enantioselective homo-/heterocoupling of C–H-derived chiral amine-bonded prochiral radicals. c Enantioselective coupling of C–H-derived chiral amine-bonded prochiral radicals with another type of radicals within the solvent cage of their origin. d Enantioselective addition of C–H-derived free achiral/prochiral radicals to chiral amine-bonded π-acceptors. e Enantioselective coupling of C–H-derived free achiral/prochiral radicals with another type of chiral amine-bonded radicals. TMS trimethylsilyl, EWG electron-withdrawing group, EDA electron donor–acceptor, PET photoinduced electron transfer, MS-PCET multisite proton-coupled electron transfer, TDS thexyl-dimethylsilyl.
Fig. 5
Fig. 5. Examples of enantiocontrol by chiral Lewis/Brønsted acid catalysts in enantioselective C(sp3)–H functionalization.
a Enantioselective addition of C–H-derived free achiral/prochiral radicals to chiral Lewis acid-coordinated π-acceptors. b Enantioselective addition of C–H-derived chiral Lewis acid-coordinated prochiral radicals to free π-acceptors. c Enantioselective coupling of C–H-derived free achiral/prochiral radicals with chiral Lewis acid-coordinated radicals. d Enantioselective coupling of C–H-derived chiral Lewis acid-coordinated prochiral radicals with free radicals. e Structures of typical Lewis and Brønsted acid catalysts employed in relevant works. LA* chiral Lewis acid.
Fig. 6
Fig. 6. Examples of enantiocontrol by chiral transition metal catalysts in enantioselective C(sp3)–H functionalization.
a Enantiocontrol in enantioselective Kharasch–Sosnovsky allylic C(sp3)–H acyloxylation catalyzed by chiral copper complexes. b Enantiocontrol in enantioselective benzylic C(sp3)–H cyanation catalyzed by copper/chiral box complexes. c Enantiocontrol in enantioselective tertiary benzylic C(sp3)–H amination by copper/chiral phosphoric acid dual catalysis. d Structures of typical chiral transition metal catalysts employed in relevant works. Box bisoxazoline.
Fig. 7
Fig. 7. Ongoing major challenges for enantioselective C(sp3)–H functionalization via radical intermediates.
a Enantioselective functionalization of unactivated C(sp3)–H bonds without any directing/stabilizing remote substituent. b Enantioselective functionalization of C(sp3)–H bonds with various heteroatom-based functionalities. c Enantioconvergent functionalization of racemic tertiary C(sp3)–H bonds, ideally in an intermolecular manner.
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