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Combined radical and ionic approach for the enantioselective synthesis of β-functionalized amines from alcohols


Chiral amines are among the most important organic compounds and have widespread applications. Enantioselective construction of chiral amines is a major aim in organic synthesis. Among synthetic methods, direct functionalization of omnipresent C–H bonds with common organic nitrogen compounds represents one of the most attractive strategies. However, C–H amination strategies are largely limited to constructing a specific type of N-heterocycles or amine derivatives. To maximize the synthetic potential of asymmetric C–H amination, we report here an approach that unites the complementary reactivities of radical and ionic chemistry for streamlined synthesis of functionalized chiral amines. This synthesis merges the development of an enantioselective radical process for 1,5-C(sp3)–H amination of alkoxysulfonyl azides via Co(II)-based metalloradical catalysis with an enantiospecific ionic process for ring-opening of the resulting five-membered chiral sulfamidates by nucleophiles. Given that alkoxysulfonyl azides are derived from the corresponding alcohols, this approach offers a powerful synthetic tool for enantioselective β-C–H amination of common alcohols while converting the hydroxy group to other functionalities through formal nucleophilic substitution.

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Fig. 1: Combined radical and ionic approach for enantioselective synthesis of chiral amines from alcohols.
Fig. 2: Mechanistic studies on Co(II)-catalysed radical 1,5-C–H amination of alkoxysulfonyl azides.
Fig. 3: Regioselective ring-opening of enantioenriched sulfamidates for stereospecific synthesis of β-functionalized chiral amines.
Fig. 4: Synthesis of 1,2,3-trifunctionalized cyclohexane derivatives via ring-opening of cyclohexane-fused sulfamidates.

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Data availability

Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2097080 (2l), 2097081 (2t), 2097082 (2ae), 2097083 (2e), 2097084 (2a), 2097085 (3m), 2097086 (3v), 2097087 (3i), 2097088 (N-Bn-2ad), 2097089 (2u), 2097090 (2r) and 2097091 (2c). Copies of the data can be obtained free of charge via All other data that support the findings of this study, which include experimental procedures and compound characterization, are available within the paper and its Supplementary Information.


  1. Renaud, P. & Sibi, M. P. Radicals in Organic Synthesis (Wiley-VCH, 2001).

  2. Zard, S. Z. Radical Reactions in Organic Synthesis (Oxford Univ. Press, 2003).

  3. Curran, D. P., Porter, N. A. & Giese, B. Stereochemistry of Radical Reactions: Concepts, Guidelines, and Synthetic Applications (John Wiley & Sons, 2008).

  4. Sibi, M. P., Manyem, S. & Zimmerman, J. Enantioselective radical processes. Chem. Rev. 103, 3263–3296 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Kern, N., Plesniak, M. P., McDouall, J. J. W. & Procter, D. J. Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals. Nat. Chem. 9, 1198–1204 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Li, J. et al. Site-specific allylic C–H bond functionalization with a copper-bound N-centred radical. Nature 574, 516–521 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Wang, F., Chen, P. & Liu, G. Copper-catalyzed radical relay for asymmetric radical transformations. Acc. Chem. Res. 51, 2036–2046 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Dong, X.-Y. et al. A general asymmetric copper-catalysed Sonogashira C(sp3)–C(sp) coupling. Nat. Chem. 11, 1158–1166 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Gu, Q.-S., Li, Z.-L. & Liu, X.-Y. Copper(I)-catalyzed asymmetric reactions involving radicals. Acc. Chem. Res. 53, 170–181 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Demarteau, J., Debuigne, A. & Detrembleur, C. Organocobalt complexes as sources of carbon-centered radicals for organic and polymer chemistries. Chem. Rev. 119, 6906–6955 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Nugent, W. A. & RajanBabu, T. V. Transition-metal-centered radicals in organic synthesis. Titanium(III)-induced cyclization of epoxy olefins. J. Am. Chem. Soc. 110, 8561–8562 (1988).

    Article  CAS  Google Scholar 

  12. Gansäuer, A. et al. Catalysis via homolytic substitutions with C−O and Ti−O bonds: oxidative additions and reductive eliminations in single electron steps. J. Am. Chem. Soc. 131, 16989–16999 (2009).

    Article  PubMed  CAS  Google Scholar 

  13. Yao, C., Dahmen, T., Gansäuer, A. & Norton, J. Anti-Markovnikov alcohols via epoxide hydrogenation through cooperative catalysis. Science 364, 764–767 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Ye, K.-Y., McCallum, T. & Lin, S. Bimetallic radical redox-relay catalysis for the isomerization of epoxides to allylic alcohols. J. Am. Chem. Soc. 141, 9548–9554 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. Das, S. K., Roy, S., Khatua, H. & Chattopadhyay, B. Iron-catalyzed amination of strong aliphatic C(sp3)–H bonds. J. Am. Chem. Soc. 142, 16211–16217 (2020).

    Article  CAS  PubMed  Google Scholar 

  16. Goswami, M. et al. Characterization of porphyrin-Co(III)-‘nitrene radical’ species relevant in catalytic nitrene transfer reactions. J. Am. Chem. Soc. 137, 5468–5479 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jiang, H., Lang, K., Lu, H., Wojtas, L. & Zhang, X. P. Asymmetric radical bicyclization of allyl azidoformates via cobalt(II)-based metalloradical catalysis. J. Am. Chem. Soc. 139, 9164–9167 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li, C. Q. et al. Catalytic radical process for enantioselective amination of C(sp3)–H bonds. Angew. Chem. Int. Ed. 57, 16837–16841 (2018).

    Article  CAS  Google Scholar 

  19. Bower, J. F., Rujirawanich, J. & Gallagher, T. N-Heterocycle construction via cyclic sulfamidates. Applications in synthesis. Org. Biomol. Chem. 8, 1505–1519 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Meléndez, R. E. & Lubell, W. D. Synthesis and reactivity of cyclic sulfamidites and sulfamidates. Tetrahedron 59, 2581–2616 (2003).

    Article  CAS  Google Scholar 

  21. Yin, Q., Shi, Y., Wang, J. & Zhang, X. Direct catalytic asymmetric synthesis of α-chiral primary amines. Chem. Soc. Rev. 49, 6141–6153 (2020).

    Article  PubMed  Google Scholar 

  22. Roughley, S. D. & Jordan, A. M. The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 54, 3451–3479 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    Article  CAS  PubMed  Google Scholar 

  24. Park, Y., Kim, Y. & Chang, S. Transition metal-catalyzed C–H amination: scope, mechanism, and applications. Chem. Rev. 117, 9247–9301 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Milczek, E., Boudet, N. & Blakey, S. Enantioselective C–H amination using cationic ruthenium(II)–pybox catalysts. Angew. Chem. Int. Ed. 47, 6825–6828 (2008).

    Article  CAS  Google Scholar 

  26. Zalatan, D. N. & Du Bois, J. A chiral rhodium carboxamidate catalyst for enantioselective C−H amination. J. Am. Chem. Soc. 130, 9220–9221 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Adams, C. S., Boralsky, L. A., Guzei, I. A. & Schomaker, J. M. Modular functionalization of allenes to aminated stereotriads. J. Am. Chem. Soc. 134, 10807–10810 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Alderson, J. M., Phelps, A. M., Scamp, R. J., Dolan, N. S. & Schomaker, J. M. Ligand-controlled, tunable silver-catalyzed C–H amination. J. Am. Chem. Soc. 136, 16720–16723 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Adams, C. S., Grigg, R. D. & Schomaker, J. M. Complete stereodivergence in the synthesis of 2-amino-1,3-diols from allenes. Chem. Sci. 5, 3046–3056 (2014).

    Article  CAS  Google Scholar 

  30. Miyazawa, T. et al. Chiral paddle-wheel diruthenium complexes for asymmetric catalysis. Nat. Catal. 3, 851–858 (2020).

    Article  CAS  Google Scholar 

  31. Nakafuku, K. M. et al. Enantioselective radical C–H amination for the synthesis of β-amino alcohols. Nat. Chem. 12, 697–704 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Roizen, J. L., Harvey, M. E. & Du Bois, J. Metal-catalyzed nitrogen-atom transfer methods for the oxidation of aliphatic C–H bonds. Acc. Chem. Res. 45, 911–922 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Thornton, A. R., Martin, V. I. & Blakey, S. B. π-Nucleophile traps for metallonitrene/alkyne cascade reactions: a versatile process for the synthesis of α-aminocyclopropanes and β-aminostyrenes. J. Am. Chem. Soc. 131, 2434–2435 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Burke, E. G. & Schomaker, J. M. Oxidative allene amination for the synthesis of azetidin-3-ones. Angew. Chem. Int. Ed. 54, 12097–12101 (2015).

    Article  CAS  Google Scholar 

  35. Liang, J.-L., Yuan, S.-X., Huang, J.-S., Yu, W.-Y. & Che, C.-M. Highly diastereo- and enantioselective intramolecular amidation of saturated C–H bonds catalyzed by ruthenium porphyrins. Angew. Chem. Int. Ed. 41, 3465–3468 (2002).

    Article  CAS  Google Scholar 

  36. Hu, Y. et al. Next-generation D2-symmetric chiral porphyrins for cobalt(II)-based metalloradical catalysis: catalyst engineering by distal bridging. Angew. Chem. Int. Ed. 58, 2670–2674 (2019).

    Article  CAS  Google Scholar 

  37. Ruppel, J. V. et al. A highly effective cobalt catalyst for olefin aziridination with azides: hydrogen bonding guided catalyst design. Org. Lett. 10, 1995–1998 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Chen, Y., Fields, K. B. & Zhang, X. P. Bromoporphyrins as versatile synthons for modular construction of chiral porphyrins: cobalt-catalyzed highly enantioselective and diastereoselective cyclopropanation. J. Am. Chem. Soc. 126, 14718–14719 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Xu, X. et al. Highly asymmetric intramolecular cyclopropanation of acceptor-substituted diazoacetates by Co(II)-based metalloradical catalysis: iterative approach for development of new-generation catalysts. J. Am. Chem. Soc. 133, 15292–15295 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Tian, Z., Fattahi, A., Lis, L. & Kass, S. R. Cycloalkane and cycloalkene C–H bond dissociation energies. J. Am. Chem. Soc. 128, 17087–17092 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Rousseau, J.-F., Chekroun, I., Ferey, V. & Labrosse, J. R. Concise preparation of a stable cyclic sulfamidate intermediate in the synthesis of a enantiopure chiral active diamine derivative. Org. Process Res. Dev. 19, 506–513 (2015).

    Article  CAS  Google Scholar 

  42. Diosdado, S., López, R. & Palomo, C. Ureidopeptide-based Brønsted bases: design, synthesis and application to the catalytic enantioselective synthesis of β-amino nitriles from (arylsulfonyl)acetonitriles. Chem. Eur. J. 20, 6526–6531 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Kaseda, T., Kikuchi, T. & Kibayashi, C. Enantioselective total synthesis of (+)-(S)-dihydroperiphylline. Tetrahedron Lett. 30, 4539–4542 (1989).

    Article  CAS  Google Scholar 

  44. Wolfard, J., Xu, J., Zhang, H. & Chung, C. K. Synthesis of chiral tryptamines via a regioselective indole alkylation. Org. Lett. 20, 5431–5434 (2018).

    Article  CAS  PubMed  Google Scholar 

  45. Lucet, D., Le Gall, T. & Mioskowski, C. The chemistry of vicinal diamines. Angew. Chem. Int. Ed. 37, 2580–2627 (1998).

    Article  CAS  Google Scholar 

  46. Rathi, A. K., Syed, R., Shin, H.-S. & Patel, R. V. Piperazine derivatives for therapeutic use: a patent review (2010–present). Expert Opin. Ther. Pat. 26, 777–797 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Tasso, B. et al. Synthesis, binding, and modeling studies of new cytisine derivatives, as ligands for neuronal nicotinic acetylcholine receptor subtypes. J. Med. Chem. 52, 4345–4357 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Vara, B. A. & Johnston, J. N. Enantioselective synthesis of β-fluoro amines via β-amino α-fluoro nitroalkanes and a traceless activating group strategy. J. Am. Chem. Soc. 138, 13794–13797 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ishizuka, T., Ishibuchi, S. & Kunieda, T. Chiral synthons for 2-amino alcohols. Facile preparation of optically active amino hydroxy acids of biological interest. Tetrahedron 49, 1841–1852 (1993).

    Article  CAS  Google Scholar 

  50. Muñiz, K. Imido-osmium(VIII) compounds in organic synthesis: aminohydroxylation and diamination reactions. Chem. Soc. Rev. 33, 166–174 (2004).

    Article  PubMed  Google Scholar 

  51. Cardona, F. & Goti, A. Metal-catalysed 1,2-diamination reactions. Nat. Chem. 1, 269–275 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Pendem, N. et al. Helix-forming propensity of aliphatic urea oligomers incorporating noncanonical residue substitution patterns. J. Am. Chem. Soc. 135, 4884–4892 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Jiang, H., Lang, K., Lu, H., Wojtas, L. & Zhang, X. P. Intramolecular radical aziridination of allylic sulfamoyl azides by cobalt(II)-based metalloradical catalysis: effective construction of strained heterobicyclic structures. Angew. Chem. Int. Ed. 55, 11604–11608 (2016).

    Article  CAS  Google Scholar 

  54. Reitz, A. B., Smith, G. R. & Parker, M. H. The role of sulfamide derivatives in medicinal chemistry: a patent review (2006–2008). Expert Opin. Ther. Pat. 19, 1449–1453 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Cavender, C. J. & Shiner, V. J. Trifluoromethanesulfonyl azide. Its reaction with alkyl amines to form alkyl azides. J. Org. Chem. 37, 3567–3569 (1972).

    Article  CAS  Google Scholar 

  56. Meng, G. et al. Modular click chemistry libraries for functional screens using a diazotizing reagent. Nature 574, 86–89 (2019).

    Article  CAS  PubMed  Google Scholar 

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We are grateful for financial support by the NIH (R01-GM132471) (X.P.Z.) and in part by the NSF (CHE-1900375) (X.P.Z.).

Author information

Authors and Affiliations



K.L. and Y.H. conducted the experiments. Y.H. initiated the project. K.L. completed the project. W.C.C.L. assisted the project. X.P.Z conceived the work and directed the project. K.L., Y.H. and X.P.Z. designed the experiments. K.L. and X.P.Z. wrote the manuscript.

Corresponding author

Correspondence to X. Peter Zhang.

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The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks Bas de Bruin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–6, Discussion and Table 1.

Supplementary Data 1

Crystallographic data for compound 2a, CCDC 2097084.

Supplementary Data 2

Crystallographic data for compound 2ae, CCDC 2097082.

Supplementary Data 3

Crystallographic data for compound 2c, CCDC 2097091.

Supplementary Data 4

Crystallographic data for compound 2e, CCDC 2097083.

Supplementary Data 5

Crystallographic data for compound 2l, CCDC 2097080.

Supplementary Data 6

Crystallographic data for compound 2r, CCDC 2097090.

Supplementary Data 7

Crystallographic data for compound 2t, CCDC 2097081.

Supplementary Data 8

Crystallographic data for compound 2u, CCDC 2097089.

Supplementary Data 9

Crystallographic data for compound 3i, CCDC 2097087.

Supplementary Data 10

Crystallographic data for compound 3m, CCDC 2097085.

Supplementary Data 11

Crystallographic data for compound 3v, CCDC 2097086.

Supplementary Data 12

Crystallographic data for compound NBn2ad, CCDC 2097088.

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Lang, K., Hu, Y., Lee, WC.C. et al. Combined radical and ionic approach for the enantioselective synthesis of β-functionalized amines from alcohols. Nat. Synth 1, 548–557 (2022).

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