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. 2021 Jul 28;143(29):11121-11129.
doi: 10.1021/jacs.1c04655. Epub 2021 Jul 20.

Asymmetric Radical Process for General Synthesis of Chiral Heteroaryl Cyclopropanes

Xiaoxu Wang  1 , Jing Ke  1 , Yiling Zhu  1 , Arghya Deb  1 , Yijie Xu  1 , X Peter Zhang  1
Affiliations

Asymmetric Radical Process for General Synthesis of Chiral Heteroaryl Cyclopropanes

Xiaoxu Wang et al. J Am Chem Soc. .

Abstract

A highly efficient catalytic method has been developed for asymmetric radical cyclopropanation of alkenes with in situ-generated α-heteroaryldiazomethanes via Co(II)-based metalloradical catalysis (MRC). Through fine-tuning the cavity-like environments of newly-synthesized D2-symmetric chiral amidoporphyrins as the supporting ligand, the optimized Co(II)-based metalloradical system is broadly applicable to α-pyridyl and other α-heteroaryldiazomethanes for asymmetric cyclopropanation of wide-ranging alkenes, including several types of challenging substrates. This new catalytic methodology provides a general access to valuable chiral heteroaryl cyclopropanes in high yields with excellent both diastereoselectivities and enantioselectivities. Combined computational and experimental studies further support the underlying stepwise radical mechanism of the Co(II)-based olefin cyclopropanation involving α- and γ-metalloalkyl radicals as the key intermediates.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1.
Scheme 1.
Working Proposal for Synthesis of Heteroaryl Cyclopropanes from Alkenes via Co(II)-Based MRC
Scheme 2.
Scheme 2.. Ligand Effect on Co(II)-Catalyzed Radical Cyclopropanation of Styrene with 2-Pyridyldiazomethanesa
aCarried out with 1a (0.10 mmol), 2a (0.15 mmol), and Cs2CO3 (0.20 mmol) using [Co(Por)] (2 mol %) in toluene (1.0 mL) at 80 °C for 16 h; Isolated yields; Diastereomeric excess (de) determined by 1H NMR of crude reaction mixture; Enantiomeric excess (ee) of the major (E)-isomer determined by chiral HPLC; Ts = 4-toluenesulfonyl.
Scheme 3.
Scheme 3.. Mechanistic Studies on Co(II)-Catalyzed Radical Olefin Cyclopropanation with Heteroaryldiazomethanesa,b,c
aDFT calculations on energetics for catalytic cyclopropanation of styrene (2a) with 2-pyridyldiazomethane (1a’) by [Co(P6)]. bTEMPO-trapping experiments for metalloradical activation of 3-pyridyl trishydrazone (1b) and 3-quinolinyl trishydrazone (1g) by [Co(P1)]. cCatalytic cyclopropanation reactions of (E)- and (Z)-β-deuterostyrenes with 2-pyridyl tosylhydrazone (1a) by [Co(P1)], [Co(P2)], and [Co(P6)].
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