Abstract
Bioisosteric replacement has emerged as a clear strategy for drug-structure optimization. Naphthalene is the core element of many chiral pharmaceuticals and drug candidates. However, as a promising isostere of naphthalene, the chiral version of 1,2-benzazaborine has rarely been explored due to the lack of efficient synthetic methods. Here we describe a copper-catalysed enantioselective hydroboration of alkenes with 1,2-benzazaborines. The method provides a general platform for the atom-economic and efficient construction of diverse chiral 1,2-benzazaborine compounds (more than 60 examples) that bear a 2-carbon-stereogenic centre or allene skeleton in high yields and excellent enantioselectivities. Three 1,2-benzazaborine analogues of bioactive chiral naphthalene-containing molecules have been prepared, and a series of transformations around chiral 1,2-benzazaborines have also been developed. Notably, the hydroboration process of this study reveals that the identity of 1,2-benzazaborine plays an essential role in the rate-determining step and catalyst resting state.
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Data availability
The data that support the findings of this study are available within the Article and its Supplementary Information files. Crystallographic data for the structure reported in this Article has been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2245401 (3b). 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 from the National Natural Science Foundation of China (22271048 and 22001038 to K.Y.; 21931013 and 22271105 to Q.S.), the Natural Science Foundation of Fujian Province (2022J05016 to K.Y.; 2022J02009 to Q.S.), Fuzhou University (510578 to Q.S.), Guangdong Provincial Key Laboratory of Catalysis (2020B121201002 to P.Y.) and Shenzhen Science and Technology Program (KQTD20210811090112004 to P.Y.) is gratefully acknowledged. Computational work was supported by the Center for Computational Science and Engineering and the CHEM High-Performance Supercomputer Cluster (CHEM-HPC) of the Department of Chemistry, Southern University of Science and Technology.
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Q.S. and K.Y. conceived and directed the project. W.S., J.Z., X.Z. and W.Q. performed experiments. W.S. prepared the Supplementary Information. P.Y. and Y.C. performed the DFT calculations and drafted the DFT parts. Q.S., P.Y. and K.Y. wrote the paper. All authors discussed the results and commented on the manuscript.
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Nature Chemistry thanks Bi-Jie Li, Ying He and the other, anonymous, reviewers for their contribution to the peer review of this work.
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Supplementary Tables 1–13, Figs. 1–12 and starting material preparation, experimental procedures, synthetic transformations, mechanistic studies and product characterization.
Supplementary Data 1
Crystallographic data of compound 3b, CCDC reference 2245401.
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Contains the many computational structures used in this study to generate potential energy surfaces. The ‘Opt_Freq’ folder includes the key sections in the output files of structure optimizations and frequency calculations. The ‘Quasiharmonic’ folder includes the output files formed by Truhlar’s quasiharmonic correction. The ‘Solvation_SPE’ folder includes output files obtained by performing single point energy calculations using the solvation model. All these files are included in the zipped file.
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Su, W., Zhu, J., Chen, Y. et al. Copper-catalysed asymmetric hydroboration of alkenes with 1,2-benzazaborines to access chiral naphthalene isosteres. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01505-0
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DOI: https://doi.org/10.1038/s41557-024-01505-0
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