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Synthesis of (+)-ribostamycin by catalytic, enantioselective hydroamination of benzene

Abstract

Aminoglycosides (AGs) represent a large group of pseudoglycoside natural products in which several different sugar moieties are harnessed to an aminocyclitol core. AGs constitute a major class of antibiotics that target the prokaryotic ribosome of many problematic pathogens. Hundreds of AGs have been isolated to date, with 1,3-diaminocyclohexanetriol, known as 2-deoxystreptamine (2-DOS), being the most abundant aglycon core. However, due to their diverse and complex architectures, all AG-based drugs are either natural substances or analogues prepared by late-stage modifications. Synthetic approaches to AGs are rare and lengthy; most studies involve semisynthetic reunion of modified fragments. Here we report a bottom-up chemical synthesis of the 2-DOS-based AG antibiotic ribostamycin, which proceeds in ten linear operations from benzene. A key enabling transformation involves a copper-catalysed, enantioselective, dearomative hydroamination, which sets the stage for the rapid and selective introduction of the remaining 2-DOS heteroatom functionality. This work demonstrates how the combination of a tailored, dearomative logic and strategic use of subsequent olefin functionalizations can provide practical and concise access to the AG class of compounds.

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Fig. 1: Aminoglycosides and synthetic considerations.
Fig. 2: Design of copper-catalysed 1,2-hydroamination of benzene.
Fig. 3: Enantioselective copper-catalysed 1,2-hydroamination of benzene.
Fig. 4: Computational studies.
Fig. 5: Synthesis of (+)-ribostamycin (2) from benzene (14).

Data availability

The experimental data as well as the characterization data for all the compounds prepared during these studies are provided in the Supplementary Information. Cartesian coordinates of all optimized geometries are provided in a separate file in the.xyz format. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2113321 (30). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures.

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Acknowledgements

Financial support for this work was provided by the University of Illinois, the University of Pittsburgh, and the NIH/National Institute of General Medical Sciences (GM122891 to D.S. and R35 GM128779 to P.L.). Bristol-Myers Squibb, Amgen, Eli Lilly and FMC are acknowledged for unrestricted research support. We thank D. Olson and L. Zhu for NMR spectroscopic assistance, D. L. Gray and A. S. Shved for X-ray crystallographic analysis assistance and F. Sun for mass spectrometric assistance. Density functional theory calculations were performed at the Center for Research Computing of the University of Pittsburgh and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the National Science Foundation. We thank S. E. Denmark and C. J. Huck for critical proofreading of this manuscript.

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Authors and Affiliations

Authors

Contributions

C.N.U. and D.S. conceived the idea, designed the experiments, analysed the data and prepared the manuscript with the input of all authors. P.G. assisted with optimization and screening efforts involving dearomative hydroamination. Y.Z. carried out the computational studies with P.L. providing guidance. S.L., K.S.L. and J.M.N. assisted with preparation of key intermediates.

Corresponding authors

Correspondence to Peng Liu or David Sarlah.

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Nature Synthesis thanks Floris Rutjes and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–15, Photographs 1 and 2, and Tables 1–5.

Supplementary Data 1

Crystal structure of intermediate compound 30 CCDC 2113321.

Supplementary Data 2

Cartesian coordinates of all optimized geometries.

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Ungarean, C.N., Galer, P., Zhang, Y. et al. Synthesis of (+)-ribostamycin by catalytic, enantioselective hydroamination of benzene. Nat. Synth 1, 542–547 (2022). https://doi.org/10.1038/s44160-022-00080-x

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