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. Author manuscript; available in PMC: 2023 Sep 1.
Published in final edited form as: Trends Chem. 2022 Jul 5;4(9):850–851. doi: 10.1016/j.trechm.2022.06.003

Asymmetric radical cyclopropanation of alkenes

Wan-Chen Cindy Lee 1, X Peter Zhang 1,*
PMCID: PMC9635561  NIHMSID: NIHMS1821726  PMID: 36338602

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ORIGIN

Metalloradical catalysis (MRC), which utilizes metal-centered radicals to homolytically activate substrates for catalytic generation of metal-stabilized organic radicals as key intermediates, has emerged as a conceptually new approach for controlling both reactivity and stereoselectivity of radical reactions. As the first application of MRC, Co(II) complexes of chiral porphyrins, as stable 15e-metalloradicals, have been demonstrated as effective catalysts for asymmetric cyclopropanation of alkenes with diazo compounds via a stepwise radical mechanism.

REACTION MECHANISM

With the support of D2-symmetric chiral amidoporphyrin ligands, the Co(II)-based metalloradical system, which operates under mild conditions with low catalyst loadings, can activate various classes of diazo compounds without the need of slow addition for asymmetric cyclopropanation of diverse types of alkenes as the limiting reagents. The corresponding cyclopropanes can be synthesized in high yields with excellent control of both diastereoselectivity and enantioselectivity. The broad substrate scope and the unique catalytic profile of the Co(II)-catalyzed cyclopropanation are attributed to the underlying stepwise radical mechanism that has been established through combined experimental and computational studies. The Co(II) complexes of porphyrins as metalloradical catalysts can activate diazo compounds homolytically while translocating the original radical character from the metal center to the α-carbon atom upon releasing dinitrogen gas, resulting in the generation of α-Co(III)-alkyl radicals I. The initially generated α-Co(III)-alkyl radical intermediates I, which represent a fundamentally new class of metal-stabilized organic radicals, are kinetically competent to undergo radical addition to alkenes, leading to the generation of γ-Co(III)-alkyl radicals II while forming the first C–C bond. Since Co–C bonds are significantly weaker than C–C bonds, the resulting γ-Co(III)-alkyl radical intermediates II preferentially proceed with intramolecular radical substitution (3-exo-tet radical cyclization) over intermolecular radical addition to another alkene molecule, giving rise to selective production of the cyclopropanes by forming the second C–C bond while regenerating the Co(II)-metalloradical catalysts. Different from the well-known concerted mechanism, the Co(II)-based radical cyclopropanation controls enantioselectivity and diastereoselectivity separately during two consecutive steps of C–C bond formation.

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IMPORTANCE

As the first demonstration of MRC to harness the potential of radical chemistry for stereoselective organic synthesis, the Co(II)-based metalloradical system for radical cyclopropanation provides a fundamentally different and practically attractive method for asymmetric synthesis of chiral cyclopropanes. Due to its distinctive stepwise radical mechanism involving unprecedented α-Co(III)-alkyl radical and γ-Co(III)-alkyl radical intermediates, Co(II)-catalyzed cyclopropanation enables some long-standing problems in asymmetric cyclopropanation to be addressed.

Acknowledgments

We are grateful for financial support by the National Institutes of Health (R01-GM102554) and National Science Foundation (CHE-1900375).

Footnotes

Declaration of interests

No interests are declared.

Literature

  • 1.Lee WCC et al. (2021) Asymmetric radical cyclopropanation of dehydroaminocarboxylates: stereoselective synthesis of cyclopropyl α-amino acids. Chem 7, 1588–1601 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Wang XX et al. (2021) Asymmetric radical process for general synthesis of chiral heteroaryl cyclopropanes. J. Am. Chem. Soc 143, 11121–11129 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Ke J et al. (2022) Metalloradical activation of in situ-generated α-alkynyldiazomethanes for asymmetric radical cyclopropanation of alkenes. J. Am. Chem. Soc 144, 2368–2378 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Wang JY et al. (2022) Radical differentiation of two ester groups in unsymmetrical diazomalonates for highly asymmetric olefin cyclopropanation. Chem. Catal 2, 330–344 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Wang XX and Zhang XP (2022) Catalytic radical approach for selective carbene transfers via cobalt(II)-based metalloradical catalysis. In Transition Metal-Catalyzed Carbene Transformations, pp. 25–66, John Wiley & Sons [Google Scholar]
  • 6.Fantauzzi S et al. (2008) Asymmetric cyclopropanation of olefins catalyzed by chiral cobalt(II)-binaphthyl porphyrins. Organometallics 27, 6143–6151 [Google Scholar]
  • 7.Chirila A et al. (2018) Mechanistic investigations into the cyclopropanation of electron-deficient alkenes with ethyl diazoacetate using [Co(MeTAA)]. J. Catal 361, 347–360 [Google Scholar]
  • 8.Roy S et al. (2018) Cobalt(II)-based metalloradical activation of 2-(diazomethyl)pyridines for radical transannulation and cyclopropanation. Angew. Chem. Int. Ed 57, 2238–2243 [DOI] [PubMed] [Google Scholar]
  • 9.Doyle MP and Forbes DC (1998) Recent advances in asymmetric catalytic metal carbene transformations. Chem. Rev 98, 911–936 [DOI] [PubMed] [Google Scholar]
  • 10.Aggarwal VK et al. (2001) Application of chiral sulfides to catalytic asymmetric aziridination and cyclopropanation with in situ generation of the diazo compound. Angew. Chem. Int. Ed 40, 1433–1436 [DOI] [PubMed] [Google Scholar]

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