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Highly diastereoselective Csp3–Csp2 Negishi cross-coupling with 1,2-, 1,3- and 1,4-substituted cycloalkylzinc compounds

Nature Chemistry volume 2, pages 125–130 (2010)Cite this article

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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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Figure 1: Diastereoselective cross-coupling with various cycloalkylzinc reagents.
Figure 2: Mechanistic proposal for the diastereoselective cross-coupling of substituted cycloalkylzinc reagents with aryl iodides.
Figure 3: NMR studies on the transmetallation of 3-methylcyclohexylzinc chloride (17a) to give (TMPP)2PdCl2.

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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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Authors and Affiliations

  1. Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus F, München, 81377, Germany

    Tobias Thaler, Benjamin Haag, Andrei Gavryushin, Hendrik Zipse & Paul Knochel

  2. Institut für Organische Chemie, Universität Regensburg, Universitätsstrasse 31, Regensburg, 93040, Germany

    Katrin Schober, Evelyn Hartmann & Ruth M. Gschwind

  3. Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus D, München, 81377, Germany

    Peter Mayer

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Contributions

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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Correspondence to Paul Knochel.

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Crystallographic data for compound 5a (CIF 16 kb)

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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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