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Enantioselective synthesis of amino acids from ammonia

Nature Catalysis volume 5, pages 571–577 (2022)Cite this article

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Abstract

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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Fig. 1: Enantioselective transformation of ammonia: challenges and strategies.
Fig. 2: Mechanistic studies.
Fig. 3: Scope of α-diazoesters in the enantioselective N–H insertion with ammonia.
Fig. 4: Synthetic applications of the reaction.

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Data availability

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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Acknowledgements

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.

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Author notes

  1. These authors contributed equally: Mao-Lin Li, Jia-Bin Pan.

Authors and Affiliations

  1. State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, China

    Mao-Lin Li, Jia-Bin Pan & Qi-Lin Zhou

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Contributions

Q.-L.Z. conceived the study. M.-L.L. and Q.-L.Z. designed the experiments and analysed the data. M.-L.L. and J.-B. P. performed the reactions and the mechanistic and DFT studies. M.-L.L., J.-B. P. and Q.-L.Z. wrote the manuscript.

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Correspondence to Qi-Lin Zhou.

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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

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.

Density functional theory calculations performed at the b3lyp-D3(BJ)/def2tzvpp (SMD-Et2O)//b3lyp-D3(BJ)/def2svp (gas) level. See Supplementary Figs. 13–19 for detailed calculation process and method.

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.

Kinetic profiles of N–H insertion reaction of diazoester and NH3. See Supplementary Figs. 20–24 for experimental details.

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 information

Supplementary Information

Supplementary Methods, references, Figs. 1–24 and Tables 1–12.

Supplementary Data

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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