Abstract
Most molecules in chemistry and biology are chiral, leading to mirror-image variants, so-called enantiomers. However, although the selective chemical synthesis of molecules in which the stereogenicity arises from a carbon atom is well-established, enantioselective approaches to nitrogen-stereogenic molecules are much less common1,2,3, and in case of acyclic, N-stereogenic amines, even unknown, because of their rapid pyramidal inversion. Here we describe the catalytic asymmetric synthesis of stable, acyclic N-stereogenic amines by the addition of enol silanes to nitronium ions that ion pair to a confined chiral anion. In the produced so-called anomeric amines, the commonly observed isomerization is slowed down by two N-oxy-substituents, which hamper nitrogen inversion. The important stereogenicity-creating step challenges previously established stereochemical descriptors of enantiodifferentiation. Computational studies provide further insight into the origin of the observed stereocontrol. Our work opens up a new avenue to investigate the fascinating and previously underexplored chemistry of enantiopure anomeric amines.
Similar content being viewed by others
Main
Despite the wealth of studies concerning enantiopure tetrahedral, C-stereogenic molecules and related structures, chiral pyramidal molecules have been less investigated. Their routine chemical synthesis can be realized only in the case of P-stereogenic phosphines1 and S-stereogenic sulfoxides2 and sulfonium salts3. Recently, one of the first asymmetric syntheses of bridged, helically chiral O-stereogenic oxonium ions4,5 has been described. By contrast, N-stereogenic, tertiary amines are generally considered configurationally unstable6 under standard laboratory conditions7 and bridging8,9 or quaternarization to the corresponding tetrahedral ammonium ions is usually required to avoid racemization by the so-called umbrella inversion10,11,12,13,14. During recent decades, marked progress has been made in synthesizing N-stereogenic cyclic amines, with or without additional stereogenic elements15,16,17,18,19,20,21,22,23,24,25.
To the best of our knowledge, however, the asymmetric synthesis of an acyclic N-stereogenic amine has not previously been accomplished and is reported here with the catalytic asymmetric addition of enol silanes to nitronium ions (Fig. 1c). Already in 1890, Hantzsch and Werner predicted that chiral trivalent amines may exist in optically active form26. However, attempts to obtain these enantiomers were unsuccessful. Later, Meisenheimer concluded that chiral amines cannot be resolved because of their rapid pyramidal inversion11. Our investigation was inspired by the realization that N-substituents have a marked effect on the inversion barrier of acyclic tertiary amines. It has been predicted that electronegative and Lewis basic N-substituents, such as oxygen, strongly enhance the pyramidal inversion barrier6. This effect is particularly pronounced in bis-oxy-substituted27,28, so-called anomeric amines, as we could confirm with initial computations29,30 (Supplementary Information). In 1980, a previous study successfully isolated anomeric amines 1a and 1b by resolution and determined their inversion energy barrier and half-life27.
a, Approaches to P-stereogenic phosphines, S-stereogenic sulfoxides and bridged O-stereogenic oxonium ions have been established. By contrast, acyclic N-stereogenic amines have not been synthesized previously. b, Examples of configurationally stabilized acyclic, tertiary amines. c, Catalytic asymmetric addition of a silyl ketene acetal to an in situ-generated silylnitronium ion (this work).
We have recently described an imidodiphosphorimidate (IDPi)-catalysed addition of silyl ketene acetals (SKA) to in situ-generated bis-silyl nitronium ions, furnishing enantiopure β3-amino acid derivatives31. The question arose whether it would be possible to add SKAs to silyl nitronium ions that are formally derived from symmetric carbonyl compounds, such that no C-stereogenic centre would be created. With two different oxygen substituents on nitrogen, the enantioselective creation of configurationally stable, only N-stereogenic amines may be realized. We describe here a catalytic asymmetric approach to enantiopure acyclic N-stereogenic amines (Fig. 1c).
Reaction development
We started our study by synthesizing alkyl nitronate 2a (ref. 32), which can be prepared from the sodium salt of 2-nitropropane and the corresponding Meerwein salt at low temperature (Supplementary Information). At the onset of our studies, we examined a series of highly acidic and confined IDPi Brønsted acid catalysts33, varying the aryl substituents (Ar) at the 3,3′-positions and the sulfur substituents (R) at the inner core, in the reaction of isopropyl nitronate 2a with tert-butyldimethylsilyl (TBS) ketene acetal 3a to give amine 1d (Fig. 2a). Chiral Brønsted acids 4a–4e, with the strongly electron-withdrawing triflyl (Tf) group were active and furnished the desired product with promising enantioselectivity. When the Tf group was replaced with a pentafluoro sulfonyl (C6F5SO2) group, catalysts 4f–4j gave even higher enantioselectivity. Among them, spiro-fluorenyl substituted catalyst 4j was found to be the best and delivered the product in 95% yield with 90:10 enantiomeric ratio (e.r.). Thus, catalyst 4j was considered for further modifications. A systematic investigation of different alkyl groups at the 7-position of the spiro-fluorenyl wing was conducted (Supplementary Information), revealing catalyst 4k as optimal, furnishing product 1d in 68% yield with excellent enantioselectivity (96.6:3.4 e.r.) (Fig. 2b). The configurational stability of amine 1d was investigated by monitoring34 the e.r. over time at 25 °C (Fig. 2c,d). The half-life (t1/2) of amine 1d was determined to be 44.4 h, corresponding to an activation free energy (ΔG‡ at 25 °C) of 25.2 kcal mol−1. Amine 1d exhibited a higher half-life than the previously reported anomeric amine 1a. Although the precise cause of this enhanced stability remains unclear, we speculate that either the presence of the silicon atom or the increased steric bulk of that substituent compared with a methoxy group may be responsible. Our observation prompted us to further explore the influence of different nitrogen substituents. In this context, we varied N-substituents in alkyl nitronates 2 and also investigated different ketene acetals 3, as summarized in Fig. 2e. Initially, a less sterically demanding nitronate derived from nitromethane was examined. Its reaction yielded product 1e in 95% yield (¹H NMR) with a good e.r. using catalyst 4 h. However, amine 1e exhibited very low chemical stability at 25 °C, and its half-life could not be reliably determined. We then turned our attention to a cyclic nitronate derived from nitrocyclohexane. Under optimized conditions, product 1f was obtained in good yield with moderate enantioselectivity. This compound showed more than three-fold lower half-life (13.3 h) compared with the model substrate 1d. This unexpected result further motivated us to systematically modify the structure at the nitrogen centre to better understand its influence on configurational stability (Fig. 2e). For example, we varied the ketene acetal component, which affects both the ester and the silyl substituent in the final product. Altering the alkyl group in the SKA from ethyl to isobutyl to benzyl (compounds 1g–1i) delivered the desired products in moderate to good e.r.s and with comparable half-lives. Replacing the nitrogen-bound ethoxy group with a methoxy group furnished product 1j in good yield and e.r., along with a notably increased half-life. Introduction of the bulky thexyldimethylsilyl (TDS) group afforded product 1k in excellent yield and enantioselectivity when using catalyst 4h. Finally, replacing the R2-alkyl substituent of the nitronates with another silyl group yielded products 1l and 1m, which were obtained in moderate yields and enantioselectivities, but showed the highest half-lives observed in this study.
a, aOptimization of the catalytic reaction was carried out as mentioned above, and the yield was determined by 1H NMR using an internal standard. b, Under the optimized condition result for product 1c. c,d, Configurational stability study of product 1d using HPLC method at 25 °C, and the obtained data were plotted as e.e. compared with time. e, Evaluation of substituent effect around the nitrogen centre of the anomeric amines. bUsing catalyst 4h. cUsing catalyst 4l. dUsing catalyst 4m. eUsing catalyst 4d. 2-Phenan, 2-Phenanthryl; TBS, tert-butyldimethylsilyl; TDS, thexyldimethylsilyl; Bn, benzyl; PhMe, toluene; ND, not determined; NP, not possible.
With the establishment of an asymmetric synthesis of an acyclic nitrogen-stereogenic amine, a particularly interesting question was how the enantiodifferentiation could be best described. The formation of a silyl nitronium cation and IDPi counteranion pair during the reaction of an SKA with a nitronate has been previously established in our amino acid ester synthesis31. In that reaction, the enantiotopic planes that are spanned by the reacting carbon atom and the groups attached to it are distinguishable as Re- and Si-faces. However, as electrophile 2a features identical substituents at the carbon atom of the nitronium ion, this formal distinction cannot be made here, although the corresponding Re and Si descriptors are fully functional with regard to the corresponding nitrogen atom. A different type of enantiodifferentiation must, therefore, be used to describe our transformation. The previously considered comprehensive nomenclature35 distinguishes three modes of enantiotopos differentiation, enantiomer differentiation (Fig. 3a), enantiofacial differentiation (Fig. 3b) and enantio(topic)-group differentiation (Fig. 3c), all of which, however, are not applicable to the current situation. Previous studies36,37 demonstrated that the addition of SKA 3a to substituted cyclic nitronates occurs in an anti-periplanar fashion such that the N-lone pair builds up anti to the newly created σ-bond. Inspired by this observation, we synthesized the unsubstituted cyclic nitronate 2n and subjected it to a reaction with SKA 3a and TBSOTf as a catalyst. As expected, this experiment resulted in the exclusive formation of cis-1n, consistent with an anti-periplanar addition pathway (Fig. 3d). An anti-periplanar mode of addition should also operate in the corresponding reactions of acyclic nitronates 2. In the key bond-forming step, electron density is transferred from the silyl ketene acetal nucleophile to the nitronium ion electrophile. The electronic movement formally occurs from the π-HOMO (highest occupied molecular orbital) of the nucleophile into the π*-LUMO (lowest unoccupied molecular orbital) of the electrophile. This particular antibonding orbital features two nodes, and identical phases of the symmetric lobes are found on the opposite planes of the C=N–π system. The transfer of electron density from the nucleophile into one π*-orbital lobe at carbon initiates not only the formation of the new C–C–σ-bond but also the breaking of the C=N–π bond and the concomitant buildup of electron density at the nitrogen atom, ultimately shaping the critical lone pair on the opposite side of the π-plane. Accordingly, distinguishing the two π* lobes at carbon determines the absolute configuration at nitrogen and thus, this unique type of enantioselectivity may be described as enantiolobal differentiation (Fig. 3e).
a, Enantiomer differentiation. b, Enantiofacial differentiation. c, Enantiogroup differentiation. d, Experimental result confirms the anti-periplanar mechanism of the reaction. e, This work: enantiolobal differentiation. aNMR yield.
With this hypothesis in mind, we calculated the transition states leading to the major enantiomer (TSmaj) and the minor enantiomer (TSmin) to gain insights into the key enantiolobal differentiation in our system with IDPi catalyst 4j. The energy difference between TSmaj and TSmin qualitatively aligns with the experimental results. For both enantiomers, as expected, the addition of the SKA to the nitronium ion builds electron density at the nitrogen atom on the opposite side of the π-plane, eventually leading to the formation of the corresponding nitrogen-centred chirality (Fig. 4a). The origin of enantioselectivity appears to arise from a finely tuned microenvironment that induces steric hindrance between the bulky silyl group and the chiral counteranion (Fig. 4b). In both cases, the nucleophile approaches in a manner that minimizes steric hindrance between the bulky silyl group and the wing of the chiral counterion. By contrast, the Si-lobe approach gains marked stabilization through non-covalent interactions between the substrates and Lewis basic functionalities in the catalytically active site, whereas the Re-lobe approach proceeds with fewer such interactions, presumably because of the silyl group on the nucleophile orienting outwards (Supplementary Fig. 2). This is further supported by a distortion-interaction analysis38 (Supplementary Table 12).
a, Visualization of the substrates in the transition states with the forming lone pairs indicated. Chiral counteranions are omitted for clarity. b, Visualization of the complexes in the transition states. Substrates are shown as sticks, and chiral counteranions are shown as spheres. The free energies were obtained at SMD(toluene)-ωB97M-V/def2-TZVPP//PBE-D4/def2-SVP level of theory.
In conclusion, we have developed a strategy for the catalytic asymmetric synthesis of configurationally stable acyclic amines with excellent enantioselectivity. Central to this achievement is the use of confined, enzyme-like IDPi catalysts, which provide a uniquely defined chiral environment capable of controlling the stereochemistry at a pyramidal nitrogen centre, long considered one of the most challenging stereochemical elements in chemical synthesis. This work establishes a new paradigm for stereocontrol at nitrogen. We anticipate that the conceptual foundation presented here will inspire further investigations, ultimately advancing the broader field of asymmetric catalysis and molecular stereochemistry.
Data availability
The experimental procedures and analytical data supporting the findings of the study are available in the paper and the Supplementary Information.
References
Baechler, R. D. & Mislow, K. Effect of structure on the rate of pyramidal inversion of acyclic phosphines. J. Am. Chem. Soc. 92, 3090–3093 (1970).
Pitchen, P., Duñach, E., Deshmukh, M. N. & Kagan, H. B. An efficient asymmetric oxidation of sulfides to sulfoxides. J. Am. Chem. Soc. 106, 8188–8193 (1984).
Andersen, K. K., Cinquini, M. & Papanikolaou, N. E. Synthesis and stereochemistry of triarylsulfonium salts. J. Org. Chem. 35, 706–710 (1970).
Meerwein, H., Hinz, G., Hofmann, P., Kroning, E. & Pfeil, E. Über tertiäre oxoniumsalze I. J. Prakt. Chem. 147, 257–285 (1937).
Smith, O. et al. Control of stereogenic oxygen in a helically chiral oxonium ion. Nature 615, 430–435 (2023).
Lehn, J. M. Nitrogen inversion: experiment and theory. Fortschr. Chem. Forsch. 15, 311–377 (1970).
Wu, Y.-T., Hayama, T., Baldridge, K. K., Linden, A. & Siegel, J. S. Synthesis of fluoranthenes and indenocorannulenes: elucidation of chiral stereoisomers on the basis of static molecular bowls. J. Am. Chem. Soc. 128, 6870–6884 (2006).
Tröger, J. Ueber einige mittelst nascirenden formaldehydes entstehende basen. J. Prakt. Chem. 36, 225–245 (1887).
Srivastava, A., Srivastava, V., Verma, S. M. & Subramanian, E. Restricted inversion of pyramidal nitrogen through π-electronic interaction in an acyclic system. J. Org. Chem. 59, 3560–3563 (1994).
Pope, W. J. & Peachey, S. J. CVIII.—the application of powerful optically active acids to the resolution of externally compensated basic substances. Resolution of tetrahydroquinaldine. J. Chem. Soc. Trans. 75, 1066–1093 (1899).
Meisenheimer, J., Andermann, L., Finn, O. & Vieweg, E. Versuche zur Darstellung optisch-aktiver Verbindungen des dreiwertigen Stickstoffs. (VI. Mitteilung) zur Stereochemie des gesättigten dreiwertigen Stickstoffs. Ber. Dtsch. Chem. Ges. 57, 1744 (1924).
Wedekind, E. Zur charaktersitik stereoisomerer Ammoniumsaize. J. Chem. Soc. 32, 3561–3569 (1899).
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).
Tayama, E. & Tanaka, H. An efficient optical resolution of nitrogen-centered chiral β-hydroxy-tetraalkylammonium salts via complexation with (R)-BINOL. Tetrahedron Lett. 48, 4183–4185 (2007).
Montanari, F., Moretti, I. & Torre, G. Asymmetric introduction at trivalent Nitrogen. Optically active 2-Methyl-3,3-didphenyloxiziridine, a compound with molecular asymmetry due solely to the nitrogen atom. Chem. Commun. 1968, 1694–1695 (1968).
Prelog, V. & Wieland, P. Über die spaltung der Tröger’schen base in optische antipoden, ein beitrag zur stereochemie des dreiwertigen stickstoffs. Helv. Chim. Acta 27, 1127–1134 (1944).
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).
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).
Maitra, U. & Bag, B. G. First asymmetric synthesis of the Troger’s base unit on a chiral template. J. Org. Chem. 57, 6979–6981 (1992).
Jameson, D. L. et al. Application of crystallization-induced asymmetric transformation to a general, scalable method for the resolution of 2,8-disubstituted Tröger’s base derivatives. J. Org. Chem. 78, 11590–11596 (2013).
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).
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).
Zaitseva, S. & Köhler, V. Pyramidal stereogenic nitrogen centers (SNCs). Synthesis 57, 1237–1254 (2025).
Kostyanovskii, R. G., Prosyanik, A. V., Markov, V. I., Zon, I. A. & Polyakov, A. E. Asymmetrical nonbridgehead nitrogen. Russ. Chem. Bull. 25, 1481–1492 (1976).
Boris, S. J. Aziridines XII. Isolation of a stable nitrogen pyramid. J. Am. Chem. Soc. 90, 508–509 (1968).
Hantzsch, A. & Werner, A. Ueber räumliche Anordnung der Atome in stickatoffhaltigen Molekülen. Ber. Dtsch. Chem. Ges. 23, 11–30 (1890).
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).
Rudchenko, V. F., Ignatov, S. M., Chervin, I. I., Nosova, V. S. & Kostyanovsky, R. G. Asymmetric nitrogen Communication 48. Geminal systems. communication 32 NH-dialkoxyamines: synthesis, hydroxy-and aminomethylation, nmr spectra, and configurational stability. Bull. Acad. Sci. USSR Div. Chem. Sci. 35, 1045–1052 (1986).
Neese, F. Software update: the ORCA program system-version 5.0. Wiley Interdiscip. Rev. Comput. Mol. Sci. 12, e1606 (2022).
Neese, F., Wennmohs, F., Becker, U. & Riplinger, C. The ORCA quantum chemistry program package. J. Chem. Phys. 152, 224108 (2020).
Das, S. et al. Harnessing the ambiphilicity of silyl nitronates in a catalytic asymmetric approach to aliphatic β3-amino acids. Nat. Catal. 4, 1043–1049 (2021).
Sato, H., Kusumi, T., Imaye, K. & Kakisawa, H. Synthesis of 4-Amino-2-hydroxybutanoic acids and its 3-methyl derivative. Bull. Chem. Soc. Jpn 49, 2815–2816 (1976).
Schreyer, L., Properzi, R. & List, B. IDPi catalysis. Angew. Chem. Int. Ed. 58, 12761–12777 (2019).
Barrett, K. T. & Miller, S. J. Regioselective derivatizations of a tribrominated atropisomeric benzamide scaffold. Org. Lett. 17, 580–583 (2015).
Izumi, Y. & Tai, A. Stereo-Differentiating Reactions (Academic Press, 1977).
Smirnov, V. O., Sidorenkov, A. S., Khomutova, Y. A., Ioffe, S L. & Tartakovsky, V. A. Five-membered cyclic nitronates in C–C coupling with 1-(tert-butyldimethylsilyloxy)-1-methoxyethylene. Eur. J. Org. Chem. 2009, 3066–3074 (2009).
New C−C coupling reaction of cyclic nitronates with carbon nucleophiles. Umpolung of the conventional reactivity of nitronates. J. Org. Chem. 69, 8485–8488 (2004).
Bickelhaupt, F. M. & Houk, K. N. Analyzing reaction rates with the distortion/interaction–activation strain model. Angew. Chem. Int. Ed. 56, 10070–10086 (2017).
Acknowledgements
We acknowledge the support from the Max Planck Society, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), under Germany’s Excellence Strategy–EXC 2033–390677874–RESOLV, and the European Research Council [Early Stage Organocatalysis] to B.L. This work was also financially supported by the Institute for Chemical Reaction Design and Discovery, which was established by the World Premier International Research Initiative, MEXT, Japan, and by the List Sustainable Digital Transformation Catalyst Collaboration Research Platform offered by Hokkaido University. Part of the computation was performed using Research Center for Computational Science, Okazaki, Japan (projects 24-IMS-C114 and 25-IMS-C115). We thank the technicians of our group and the members of our mass spectrometry and high-performance liquid chromatography service departments. We thank J. Samsonowicz-Górski for determining the absolute configuration. We also thank N. Frank for creating the graphics.
Funding
Open access funding provided by Max Planck Society.
Author information
Authors and Affiliations
Contributions
B.L. and C.K.D. designed and oversaw the project. C.K.D., C.Z. and S.D. developed and optimized the reaction. M.S.S. performed the HPLC analysis. S.J.L. and F.N. performed computational studies. N.T. performed computational studies on the transition states. B.L. wrote the original draft. B.L., C.K.D., S.D., N.T., F.N. and C.Z. reviewed and edited the paper.
Corresponding authors
Ethics declarations
Competing interests
A patent WO2017037141 (A1) filed by the Max-Planck-Institut für Kohlenforschung and B.L. covers the IDPi catalyst class and its applications in asymmetric synthesis. Furthermore, a patent on an improved synthesis of imidodiphosphoryl-derived catalysts using hexachlorophosphazonium salts has been filed by the Max-Planck-Institut für Kohlenforschung, C.K.D. and B.L. (patent no. EP 3 981 775 A1). All other authors declare no competing interests.
Peer review
Peer review information
Nature thanks Jolene Reid, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information (download PDF )
This file contains Supplementary Methods, Supplementary References, NMR spectra and HPLC chromatograms.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Zhu, C., Das, S., Sterling, M.S. et al. The asymmetric synthesis of an acyclic N-stereogenic amine. Nature 649, 621–625 (2026). https://doi.org/10.1038/s41586-025-09905-z
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41586-025-09905-z
