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Controlling pyramidal nitrogen chirality by asymmetric organocatalysis

Nature volume 647, pages 897–905 (2025)Cite this article

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Abstract

Chirality is central to life, and controlling the formation of one of a pair of mirror-image molecules (enantiomers) is a central tenet of synthetic chemistry. Although controlling stereogenic carbon1,2,3, silicon4,5, phosphorus6,7 and sulfur8,9 centres is commonplace, nitrogen centres in amines are not typically stable. Limited achievements in the enantioselective construction of nitrogen chirality have primarily been established in quaternary ammonium salts10,11,12 and bridged bicyclic amines13,14,15,16,17, which have a restricted pyramidal configuration. The asymmetric synthesis of non-bridged pyramidal nitrogen-chirogenic compounds suffers from a super-stoichiometric chiral source and exhibits poor stereoselectivity18,19,20,21,22,23,24. Here we present a catalytic enantioselective strategy for construction of acyclic nitrogen stereocentres via a chiral Brønsted acid-catalysed chlorination reaction. We designed a stereospecific intramolecular reaction to overcome the structural and configurational instabilities of nitrogen-chlorinated hydroxylamines. The resulting 2-alkoxy-1,2-oxazolidines showed good enantiopurities, and density functional theory calculations confirmed successful enantiocontrol of nitrogen chirality during the chlorination process. Furthermore, this strategy has been applied successfully to synthesize the enantioselective N-chloroaziridines with a configurationally stable nitrogen stereogenic centre. Control experiments provide evidence for an SN2 pathway for the intramolecular nucleophilic substitution event.

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Fig. 1: Endeavours to control N chirality.
Fig. 2: Substrate generality of 1,2-oxazolidines bearing a N-chirogenic centre as the sole chiral element.
Fig. 3: Substrate generality exploration of 1,2-oxazolidines bearing both N- and C-chirogenic centres.
Fig. 4: Catalytic asymmetric construction of isolable and configurationally stable N-stereogenic centres.
Fig. 5: Mechanistic investigations and preliminary application attempts.
Fig. 6: DFT calculations for reaction mechanism and enantioselectivity.

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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 2330815 (20), 2405212 (32), 2405215 (ent-33′), 2330813 (34), 2330814 (45) and 2405209 (49). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. The data supporting the findings of this work are provided in Supplementary Information, including experimental procedures and characterization of new compounds.

References

  1. Quasdorf, K. W. & Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516, 181–191 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zeng, X.-P., Cao, Z.-Y., Wang, Y.-H., Zhou, F. & Zhou, J. Catalytic enantioselective desymmetrization reactions to all-carbon quaternary stereocenters. Chem. Rev. 116, 7330–7396 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Feng, J., Holmes, M. & Krische, M. J. Acyclic quaternary carbon stereocenters via enantioselective transition metal catalysis. Chem. Rev. 117, 12564–12580 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wu, Y. & Wang, P. Silicon-stereogenic monohydrosilane: synthesis and applications. Angew. Chem. Int. Ed. 61, e202205382 (2022).

    Article  ADS  CAS  Google Scholar 

  5. Xu, L.-W., Li, L., Lai, G.-Q. & Jiang, J.-X. The recent synthesis and application of silicon-stereogenic silanes: a renewed and significant challenge in asymmetric synthesis. Chem. Soc. Rev. 40, 1777–1790 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Grabulosa, A., Granell, J. & Muller, G. Preparation of optically pure P-stereogenic trivalent phosphorus compounds. Coord. Chem. Rev. 251, 25–90 (2007).

    Article  CAS  Google Scholar 

  7. Dutartre, M., Bayardon, J. & Jugé, S. Applications and stereoselective syntheses of P-chirogenic phosphorus compounds. Chem. Soc. Rev. 45, 5771–5794 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Fernández, I. & Khiar, N. Recent developments in the synthesis and utilization of chiral sulfoxides. Chem. Rev. 103, 3651–3706 (2003).

    Article  PubMed  Google Scholar 

  9. Han, J., Soloshonok, V. A., Klika, K. D., Drabowicz, J. & Wzorek, A. Chiral sulfoxides: advances in asymmetric synthesis and problems with the accurate determination of the stereochemical outcome. Chem. Soc. Rev. 47, 1307–1350 (2018).

    Article  CAS  PubMed  Google Scholar 

  10. Walsh, M. P., Phelps, J. M., Lennon, M. E., Yufit, D. S. & Kitching, M. O. Enantioselective synthesis of ammonium cations. Nature 597, 70–76 (2021).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Luo, Z. et al. Ionic hydrogen bond-assisted catalytic construction of nitrogen stereogenic center via formal desymmetrization of remote diols. Angew. Chem. Int. Ed. 63, e202404979 (2024).

    Article  CAS  Google Scholar 

  12. Bhadra, S. & Yamamoto, H. Catalytic asymmetric synthesis of N-chiral amine oxides. Angew. Chem. Int. Ed. 55, 13043–13046 (2016).

    Article  CAS  Google Scholar 

  13. Chattopadhyay, A. K. & Hanessian, S. Recent progress in the chemistry of daphniphyllum alkaloids. Chem. Rev. 117, 4104–4146 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Yuan, R. et al. The first direct synthesis of chiral Tröger’s bases catalyzed by chiral glucose-containing pyridinium ionic liquids. Chem. Eng. J. 316, 1026–1034 (2017).

    Article  CAS  Google Scholar 

  15. Huang, S. et al. Organocatalytic enantioselective construction of chiral azepine skeleton bearing multiple-stereogenic elements. Angew. Chem. Int. Ed. 60, 21486–21493 (2021).

    Article  CAS  Google Scholar 

  16. Ma, C., Sun, Y., Yang, J., Guo, H. & Zhang, J. Catalytic asymmetric synthesis of Tröger’s base analogues with nitrogen stereocenter. ACS Cent. Sci. 9, 64–71 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu, T. et al. Immobilizing stereogenic nitrogen center in doubly fused triarylamines through palladium-catalyzed asymmetric C−H activation/seven-membered-ring formation. ACS Catal. 13, 9688–9694 (2023).

    Article  CAS  Google Scholar 

  18. Annunziata, R., Fornasier, R. & Montanari, F. Compounds with molecular asymmetry due solely to a tercovalent non-bridgehead nitrogen atom: optically active N-chloro-2,2-diphenylaziridine. J. Chem. Soc. Chem. Commun. 1972, 1133–1134 (1972).

    Article  Google Scholar 

  19. Forni, A., Moretti, I., Prosyanik, A. V. & Torre, G. Optically active trifluoromethylcarbinols as chiral solvating agents for asymmetric transformations at a ring-nitrogen atom. J. Chem. Soc. Chem. Commun. 1981, 588–590 (1981).

    Article  Google Scholar 

  20. Bucciarelli, M., Forni, A., Moretti, I. & Torre, G. Optically active trifluoromethylcarbinols as chiral solvating agents for asymmetric transformations at a ring-nitrogen atom. Synthesis of optically active N-chloroaziridines and stereochemical aspects of chiral solvent-aziridine solute complexes. J. Org. Chem. 48, 2640–2644 (1983).

    Article  CAS  Google Scholar 

  21. Shustov, G. V. et al. Asymmetric nitrogen. 72. Geminal systems. 46. N-chlorooxaziridines: optical activation, absolute configuration, and chiroptical properties. J. Am. Chem. Soc. 111, 4210–4215 (1989).

    Article  ADS  CAS  Google Scholar 

  22. Montanari, F., Moretti, I. & Torre, G. Asymmetric introduction at trivalent nitrogen. Optically active 2-methyl-3,3-diphenyloxaziridine, a compound with molecular asymmetry due solely to the nitrogen atom. Chem. Commun. 1968, 1694–1695 (1968).

    Google Scholar 

  23. Boyd, D. R. Optically active oxaziridines. Tetrahedron Lett. 9, 4561–4564 (1968).

    Article  Google Scholar 

  24. Kostyanovsky, R. G., Rudchenko, V. F., Shtamburg, V. G., Chervin, I. I. & Nasibov, S. S. Asymmetrical nonbridgehead nitrogen—XXVI. Synthesis, configurational stability, and resolution of N,N-dialkoxyamines into antipodes. Tetrahedron 37, 4245–4254 (1981).

    Article  CAS  Google Scholar 

  25. Smith, O. et al. Control of stereogenic oxygen in a helically chiral oxonium ion. Nature 615, 430–435 (2023).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Porto, C. M., de Barros, G. A., Santana, L. C., Moralles, A. C. & Morgon, N. H. Ammonia quantum tunneling in cold rare-gas He and Ar clusters and factorial design approach for methodology evaluation. J. Mol. Model. 28, 293 (2022).

    Article  CAS  PubMed  Google Scholar 

  27. Adams, R. & Cairns, T. L. Attempts to prepare optically active ethyleneimine derivatives containing an asymmetric nitrogen atom. J. Am. Chem. Soc. 61, 2464–2467 (1939).

    Article  ADS  CAS  Google Scholar 

  28. Dunlop, H. G. & Tucker, S. H. Attempts to prepare optically active tervalent nitrogen compounds. Part I. Syntheses of 1:9-phenylenecarbazole and derivatives. J. Chem. Soc. 1939, 1945–1956 (1939).

    Article  Google Scholar 

  29. Brois, S. J. Aziridines. XII. Isolation of a stable nitrogen pyramid. J. Am. Chem. Soc. 90, 508–509 (1968).

    Article  ADS  CAS  Google Scholar 

  30. Rauk, A., Allen, L. C. & Mislow, K. Pyramidal inversion. Angew. Chem. Int. Ed. 9, 400–414 (1970).

    Article  CAS  Google Scholar 

  31. Zaitseva, S. & Köhler, V. Pyramidal stereogenic nitrogen centers (SNCs). Synthesis 57, 1237–1254 (2025).

    Article  CAS  Google Scholar 

  32. Shtamburg, V. G. et al. Reactions of N-chloro-N-alkoxy-tert-alkylamines with isobutylene and methanol. Russ. Chem. Bull. 40, 951–954 (1991).

    Article  Google Scholar 

  33. Rudchenko, V. F. & Kostyanovskii, R. G. Geminal oxygen–nitrogen–halogen systems. N-halohydroxylamine derivatives. Russ. Chem. Rev. 67, 179–192 (1998).

    Article  ADS  Google Scholar 

  34. Wendlandt, A. E., Vangal, P. & Jacobsen, E. N. Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction. Nature 556, 447–451 (2018).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. Singh, V. K. et al. Taming secondary benzylic cations in catalytic asymmetric SN1 reactions. Science 382, 325–329 (2023).

    Article  ADS  CAS  PubMed  Google Scholar 

  36. Zhang, X. et al. An enantioconvergent halogenophilic nucleophilic substitution (SN2X) reaction. Science 363, 400–404 (2019).

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Lovinger, G. J., Sak, M. H. & Jacobsen, E. N. Catalysis of an SN2 pathway by geometric preorganization. Nature 632, 1052–1059 (2024).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. Denmark, S. E., Kuester, W. E. & Burk, M. T. Catalytic, asymmetric halofunctionalization of alkenes—a critical perspective. Angew. Chem. Int. Ed. 51, 10938–10953 (2012).

    Article  CAS  Google Scholar 

  39. Akiyama, T., Itoh, J., Yokota, K. & Fuchibe, K. Enantioselective Mannich-type reaction catalyzed by a chiral Brønsted acid. Angew. Chem. Int. Ed. 43, 1566–1568 (2004).

    Article  CAS  Google Scholar 

  40. Uraguchi, D. & Terada, M. Chiral Brønsted acid-catalyzed direct Mannich reactions via electrophilic activation. J. Am. Chem. Soc. 126, 5356–5357 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  41. Akiyama, T. Stronger Brønsted acids. Chem. Rev. 107, 5744–5758 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Parmar, D., Sugiono, E., Raja, S. & Rueping, M. Complete field guide to asymmetric BINOL-phosphate derived Brønsted acid and metal catalysis: history and classification by mode of activation; Brønsted acidity, hydrogen bonding, ion pairing and metal phosphates. Chem. Rev. 114, 9047–9153 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Reisman, S. E., Doyle, A. G. & Jacobsen, E. N. Enantioselective thiourea-catalyzed additions to oxocarbenium ions. J. Am. Chem. Soc. 130, 7198–7199 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. Banik, S. M., Levina, A., Hyde, A. M. & Jacobsen, E. N. Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis. Science 358, 761–764 (2017).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhou, H. et al. Organocatalytic stereoselective cyanosilylation of small ketones. Nature 605, 84–89 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang, M. et al. Asymmetric hydrogenation of ketimines with minimally different alkyl groups. Nature 631, 556–562 (2024).

    Article  ADS  CAS  PubMed  Google Scholar 

  47. Frisch, M. J. et al. Gaussian 16, Revision A.03 (Gaussian, 2016).

  48. Becke, A. D. Density‐functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 98, 5648–5652 (1993).

    Article  ADS  CAS  Google Scholar 

  49. Lee, C., Yang, W. & Parr, R. G. Development of the Colle–Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B 37, 785–789 (1988).

    Article  ADS  CAS  Google Scholar 

  50. Grimme, S., Antony, J., Ehrlich, S. & Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H–Pu. J. Chem. Phys. 132, 154104 (2010).

    Article  ADS  PubMed  Google Scholar 

  51. Grimme, S., Ehrlich, S. & Goerigk, L. Effect of the damping function in dispersion corrected density functional theory. J. Comput. Chem. 32, 1456–1465 (2011).

    Article  ADS  CAS  PubMed  Google Scholar 

  52. Chai, J.-D. & Head-Gordon, M. Long-range corrected hybrid density functionals with damped atom–atom dispersion corrections. Phys. Chem. Chem. Phys. 10, 6615–6620 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Marenich, A. V., Cramer, C. J. & Truhlar, D. G. Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J. Phys. Chem. B 113, 6378–6396 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Bickelhaupt, F. M. & Houk, K. N. Analyzing reaction rates with the distortion/interaction‐activation strain model. Angew. Chem. Int. Ed. 56, 10070–10086 (2017).

    Article  CAS  Google Scholar 

  55. Duan, M. et al. Chiral phosphoric acid catalyzed conversion of epoxides into thiiranes: mechanism, stereochemical model, and new catalyst design. Angew. Chem. Int. Ed. 61, e202113204 (2022).

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (22425011 to B.T., 22231004 to B.T. and 22271135 to S.-H.X.), the National Key R&D Program of China (2022YFA1503700 to B.T.), the Guangdong Innovative Program (2019BT02Y335 to B.T.), the Guangdong Basic and Applied Basic Research Foundation (2024B1515020055 to S.-H.X.), the New Cornerstone Science Foundation through the Xplorer Prize (to B.T.), the Shenzhen Science and Technology Program (KQTD20210811090112004 to B.T.), High level of special funds (G03050K003 to B.T.) and the US National Science Foundation (CHE-2153972 to K.N.H.). We appreciate the assistance of SUSTech Core Research Facilities.

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Author notes

  1. These authors contributed equally: San Wu, Pengquan Chen, Meng Duan

Authors and Affiliations

  1. Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China

    San Wu, Pengquan Chen, Peng-Ying Jiang, Shao-Hua Xiang & Bin Tan

  2. Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA, USA

    Meng Duan, Qingyang Zhou & K. N. Houk

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Contributions

B.T. conceived of and directed the project. S.W. and P.C. designed and performed the experiments. P.-Y.J. and S.-H.X. helped with the collection of some compounds and data analysis. K.N.H. directed the DFT calculations and mechanism analysis. M.D. performed the DFT calculations. M.D. and Q.Z. conducted the mechanism analysis. B.T., S.W. and S.-H.X. wrote the paper. All authors discussed the results and commented on the paper. S.W., P.C. and M.D. contributed equally to this work.

Corresponding authors

Correspondence to K. N. Houk or Bin Tan.

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Extended data figures and tables

Extended Data Fig. 1 Research status of catalytic enantioselective construction of stereocentres and strategies to stabilize the configuration of nitrogen-chirogenic molecules.

a, Research status of catalytic asymmetric construction of various stereogenic centres. b, Conventional means to enhance the pyramidal inversion barrier of N-stereogenic centres.

Supplementary information

Supplementary Information (download PDF )

The Supplementary Information file contains Supplementary Methods, characterization details, optimized Cartesian coordinates, Supplementary Figs. 1–18, Tables 1–5 and Refs. 1–4.

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Wu, S., Chen, P., Duan, M. et al. Controlling pyramidal nitrogen chirality by asymmetric organocatalysis. Nature 647, 897–905 (2025). https://doi.org/10.1038/s41586-025-09607-6

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