Catalytic asymmetric synthesis of cannabinoids and menthol from neral

Joyce A. A. Grimm, Hui Zhou, Roberta Properzi, Markus Leutzsch, Giovanni Bistoni, Johanna Nienhaus and Benjamin List ()
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Joyce A. A. Grimm: Max-Planck-Institut für Kohlenforschung
Hui Zhou: Max-Planck-Institut für Kohlenforschung
Roberta Properzi: Max-Planck-Institut für Kohlenforschung
Markus Leutzsch: Max-Planck-Institut für Kohlenforschung
Giovanni Bistoni: University of Perugia
Johanna Nienhaus: Max-Planck-Institut für Kohlenforschung
Benjamin List: Max-Planck-Institut für Kohlenforschung

Nature, 2023, vol. 615, issue 7953, 634-639

Abstract: Abstract The selective conversion of natural or synthetic neral to (1R,6S)-trans-isopiperitenol would enable and expedite sustainable routes to menthol1,2 and cannabinoids3–5. However, this reaction has been considered impossible because its product is more reactive to the required acid catalysts than its starting material, resulting in several side products6–9. We now show that an unsymmetric, strong and confined chiral acid, a highly fluorinated imino-imidodiphosphate, catalyses this process with excellent efficiency and selectivity. Expanding the method to other α,β-unsaturated aldehydes could enable access to new cannabinoids and menthol derivatives not readily accessible previously. Mechanistic studies suggest that the confined catalyst accomplishes this reaction by binding the product in an unreactive conformation, thereby preventing its decomposition. We also show how (1R,6S)-trans-isopiperitenol can be readily converted to pharmaceutically useful cannabinoids and menthol, each in the shortest and most atom-economic routes so far.

Date: 2023
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DOI: 10.1038/s41586-023-05747-9

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