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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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.
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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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Nature Catalysis thanks Takashi Ohshima, Zhixiang Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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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.
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. 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.
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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
Nature Catalysis (2022)