Abstract
Stereoselective functionalizations of organic molecules are of great importance to modern synthesis. A stereoselective preparation of pharmaceutically active molecules is often required to ensure the appropriate biological activity. Thereby, diastereoselective methods represent valuable tools for an efficient set-up of multiple stereocentres. In this article, highly diastereoselective Csp3 Negishi cross-couplings of various cycloalkylzinc reagents with aryl halides are reported. In all cases, the thermodynamically most-stable stereoisomer was obtained. Remarkably, this diastereoselective coupling was successful not only for 1,2-substituted cyclic systems, but also for 1,3- and 1,4-substituted cyclohexylzinc reagents. The origin of this remote stereocontrol was investigated by NMR experiments and density functional theory calculations. A detailed mechanism based on these experimental and theoretical data is proposed.
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Acknowledgements
We thank the European Research Council, the Fonds der Chemischen Industrie, the Sonderforschungsbereich 749 and the Deutsche Forschungsgemeinschaft for financial support. We also thank Evonik Degussa GmbH, BASF AG, W. C. Heraeus GmbH, Chemetall GmbH and Solvias AG for generous gifts of chemicals.
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T.T. and A.G. planned, conducted and analysed the experiments. B.H. and H.Z. planned and analysed the DFT calculations. B.H. conducted the DFT calculations. T.T., K.S., E.H. and R.M.G. planned and conducted the NMR experiments. K.S., E.H. and R.M.G. analysed the NMR experiments. P.M. performed the X-ray analysis. P.K. designed and directed the project and wrote the manuscript, with contributions from T.T., B.H. and R.M.G. All authors except P.M. contributed to discussions.
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Crystallographic data for compound 18a (CIF 17 kb)
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Crystallographic data for compound 31 (CIF 42 kb)
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Thaler, T., Haag, B., Gavryushin, A. et al. Highly diastereoselective Csp3–Csp2 Negishi cross-coupling with 1,2-, 1,3- and 1,4-substituted cycloalkylzinc compounds. Nature Chem 2, 125–130 (2010). https://doi.org/10.1038/nchem.505
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DOI: https://doi.org/10.1038/nchem.505
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