Metal-catalysed reactions involving ammonia gas are plagued by ammonia’s strong Lewis basicity, which leads to poor chemoselectivity and enantioselectivity. Here we introduce a strategy for preparing chiral α-amino acids directly from ammonia. By the cooperative action of copper complexes and chiral hydrogen-bond donors, enantioselective insertion of carbenes into the N–H bond of ammonia can construct C–N bonds in excellent yield and enantioselectivity. Using this method, we coupled a wide variety of diazoesters with ammonia to produce natural and non-natural chiral α-amino acids, which have a wide range of applications in pharmaceutical and biochemistry research. Our work provides a general method for asymmetric transformations involving ammonia.
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Chemoselective carbene insertion into the N−H bonds of NH3·H2O
Nature Communications Open Access 10 December 2022
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Data relating to the materials and methods, optimization studies, experimental procedures, DFT calculations, atomic coordinates, HPLC spectra and NMR spectra are available in the Supplementary Information. All data is available from the authors upon reasonable request.
Ashida, Y., Arashiba, K., Nakajima, K. & Nishibayashi, Y. Molybdenum-catalysed ammonia production with samarium diiodide and alcohols or water. Nature 568, 536–540 (2019).
Valera-Medina, A., Xiao, H., Owen-Jones, M., David, W. I. F. & Bowen, P. J. Ammonia for power. Prog. Energy Combust. Sci. 69, 63–102 (2018).
Trowbridge, A., Walton, S. M. & Gaunt, M. J. New strategies for the transition-metal catalyzed synthesis of aliphatic amines. Chem. Rev. 120, 2613–2692 (2020).
Park, Y., Kim, Y. & Chang, S. Transition metal-catalyzed C–H amination: scope, mechanism, and applications. Chem. Rev. 117, 9247–9301 (2017).
Nagano, T. & Kobayashi, S. Palladium-catalyzed allylic amination using aqueous ammonia for the synthesis of primary amines. J. Am. Chem. Soc. 131, 4200–4201 (2009).
Pouy, M. J., Stanley, L. M. & Hartwig, J. F. Enantioselective iridium-catalyzed monoallylation of ammonia. J. Am. Chem. Soc. 131, 11312–11313 (2009).
Klinkenberg, J. L. & Hartwig, J. F. Catalytic organometallic reactions of ammonia. Angew. Chem. Int. Ed. 50, 86–95 (2011).
Gallardo-Donaire, J. et al. Direct asymmetric ruthenium-catalyzed reductive amination of alkyl–aryl ketones with ammonia and hydrogen. J. Am. Chem. Soc. 140, 355–361 (2018).
McGrath, N. A., Brichacek, M. & Njardarson, J. T. A graphical journey of innovative organic architectures that have improved our lives. J. Chem. Educ. 87, 1348–1349 (2010).
Yin, Q., Shi, Y., Wang, J. & Zhang, X. Direct catalytic asymmetric synthesis of α-chiral primary amines. Chem. Soc. Rev. 49, 6141–6153 (2020).
Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications (Wiley VCH, 2010).
Bezdek, M. J., Guo, S. & Chirik, P. J. Coordination-induced weakening of ammonia, water, and hydrazine X–H bonds in a molybdenum complex. Science 354, 730–733 (2016).
Huang, L., Arndt, M., Gooßen, K., Heydt, H. & Gooßen, L. J. Late transition metal-catalyzed hydroamination and hydroamidation. Chem. Rev. 115, 2596–2697 (2015).
Gillingham, D. & Fei, N. Catalytic X–H insertion reactions based on carbenoids. Chem. Soc. Rev. 42, 4918–4931 (2013).
Brandenberg, O. F., Fasan, R. & Arnold, F. H. Exploiting and engineering hemoproteins for abiological carbene and nitrene transfer reactions. Curr. Opin. Biotechnol. 47, 102–111 (2017).
Trofimenko, S. Scorpionates: Polypyrazolylborate Ligands and Their Coordination Chemistry (Imperial College Press, 1999).
Zhu, S.-F. & Zhou, Q.-L. Transition-metal-catalyzed enantioselective heteroatom–hydrogen bond insertion reactions. Acc. Chem. Res. 45, 1365–1377 (2012).
Ford, A. et al. Modern organic synthesis with α-diazocarbonyl compounds. Chem. Rev. 115, 9981–10080 (2015).
Ren, Y.-Y., Zhu, S.-F. & Zhou, Q.-L. Chiral proton-transfer shuttle catalysts for carbene insertion reactions. Org. Biomol. Chem. 16, 3087–3094 (2018).
Li, M.-L., Yu, J.-H., Li, Y.-H., Zhu, S.-F. & Zhou, Q.-L. Highly enantioselective carbene insertion into N–H bonds of aliphatic amines. Science 366, 990–994 (2019).
Ovian, J. M. & Jacobsen, E. N. A catalytic one–two punch. Science 366, 948–949 (2019).
Zuend, S. J. & Jacobsen, E. N. Mechanism of amido-thiourea catalyzed enantioselective imine hydrocyanation: transition state stabilization via multiple non-covalent interactions. J. Am. Chem. Soc. 131, 15358–15374 (2009).
Anderson, R. J., Bendell, D., Groundwater, P. W. & Abel, E. W. Organic Spectroscopic Analysis (Royal Society of Chemistry, 2004).
Matthews, W. S. et al. Equilibrium acidities of carbon acids. VI. Establishment of an absolute scale of acidities in dimethyl sulfoxide solution. J. Am. Chem. Soc. 97, 7006–7014 (1975).
Shields, G. & Seybold, P. Computational Approaches to Predict pKa Values (CRC Press, 2013).
Tsuji, N. et al. Activation of olefins via asymmetric Brønsted acid catalysis. Science 359, 1501–1505 (2018).
Properzi, R. et al. Catalytic enantiocontrol over a non-classical carbocation. Nat. Chem. 12, 1174–1179 (2020).
Doyle, A. G. & Jacobsen, E. N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 107, 5713–5743 (2007).
Brak, K. & Jacobsen, E. N. Asymmetric ion-pairing catalysis. Angew. Chem. Int. Ed. 52, 534–561 (2013).
Anslyn, E. V. & Dougherty, D. A. Modern Physical Organic Chemistry 466 (University Science Books, 2006).
Lefebvre, C. et al. Accurately extracting the signature of intermolecular interactions present in the NCI plot of the reduced density gradient versus electron density. Phys. Chem. Chem. Phys. 19, 17928–17936 (2017).
Lu, T. & Chen, F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 33, 580–592 (2012).
Jensen, K. H. & Sigman, M. S. Evaluation of catalyst acidity and substrate electronic effects in a hydrogen bond-catalyzed enantioselective reaction. J. Org. Chem. 75, 7194–7201 (2010).
Lang, K. & Chin, J. W. Cellular incorporation of unnatural amino acids and bioorthogonal labeling of proteins. Chem. Rev. 114, 4764–4806 (2014).
Wang, Z., Xu, W., Liu, L. & Zhu, T. F. A synthetic molecular system capable of mirror-image genetic replication and transcription. Nat. Chem. 8, 698–704 (2016).
We thank the National Natural Science Foundation of China (21790332, 91956000) for financial support. We thank the Computational Chemistry Commune (http://bbs.keinsci.com/) for help with the DFT calculation.
The authors declare no competing interests.
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Extended Data Fig. 1 Optimization of reaction conditions for enantioselective carbene insertion into N–H bond of NH3.
Reaction conditions: ammonia (0.6 mmol, 0.3 M in MTBE), α-diazoester (0.2 mmol), CuI (5 mol %), Ligand (6 mol %), HBDs (6 mol %), 2 ml MTBE, 25 °C. Isolated yields were given. The ee values were determined by high-performance liquid chromatography after benzylation of products. See Supplementary tables 1–7 for details.
Extended Data Fig. 2 Different conformations of the transient states for the proton transfer catalysed by Cu-bonded HBD-1.
Extended Data Fig. 3 The independent gradient model analysis for TSRaCu-I and TSSaCu-I.
The analysis was performed with Multiwfn 3.7 program to investigate the weak interaction between the thiourea backbone of HBD-1 and the ester group of ylide in the major transition state. Graphical structures were visualized with VMD (Version 1.9.3).
Extended Data Fig. 4 Dynamic experiments.
Extended Data Fig. 5 Proposed catalytic cycle for the enantioselective carbene insertion into N–H bond of NH3.
The Tp*Cu–HBD-1 complex serves as the resting-state of the catalyst for the formation of a carbene intermediate. After nucleophilic attack of ammonia on the carbene, Tp*Cu dissociates to form an ammonium ylide intermediate, which is intercepted by the Tp*Cu–HBD-1 complex in the enantioselectivity-determining proton-transfer reaction.
Supplementary Methods, references, Figs. 1–24 and Tables 1–12.
Computational data for Cartesian coordinates of optimized structures.
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Li, ML., Pan, JB. & Zhou, QL. Enantioselective synthesis of amino acids from ammonia. Nat Catal 5, 571–577 (2022). https://doi.org/10.1038/s41929-022-00779-2
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