One-step, stereoselective synthesis of octahydrochromanes via the Prins reaction and their cannabinoid activities

Authors: SLATER, SHUNEIZE - University Of Mississippi; LASONKAR, PRADEEP - University Of Mississippi; HAIDER, SAQLAIN - University Of Mississippi; ALQAHTANI, MONEERAH - University Of Mississippi; CHITTIBOYINA, AMAR - University Of Mississippi; KHAN, IKHLAS - University Of Mississippi

Submitted to: Tetrahedron Letters
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/16/2018
Publication Date: 1/31/2018
Citation: Slater, S., Lasonkar, P.B., Haider, S., Alqahtani, M.J., Chittiboyina, A.G., Khan, I.A. 2018. One-step, stereoselective synthesis of octahydrochromanes via the Prins reaction and their cannabinoid activities. Tetrahedron Letters. 59:807-810. https://doi.org/10.1016/j.tetlet.2018.01.040.
DOI: https://doi.org/10.1016/j.tetlet.2018.01.040

Interpretive Summary: In summary, chiral pulegols and various benzaldehydes were utilized in the Prins reaction to produce octahydrochromane compounds. The importance of the stereocenter configurations for biological activity was tested, and it was determined that the stereochemistry is not a factor in the activity of these compounds. However, the number and positions of the substituents on the aromatic ring may play a role in their activity. Determining SAR from this limited set of compounds is premature and is not the focus of the current findings. However, a focused set of compounds with better hydrophilicity will be explored to overcome solubility issues associated with these octahydrochromanes. Importantly, these one-pot reactions may serve as a starting point for new scaffolds with CB1 and/or CB2 selective agonist and antagonist activities which can be explored by varying the homoallylic alcohols and aldehydes used.

Technical Abstract: Novel, functionalized octahydrochromane derivatives were synthesized in a single step via the Prins reaction. Enantiomerically pure (+)-isopulegol was reacted with benzaldehyde to stereoselectively yield the corresponding octahydro-2H-chromen-4-ol derivative containing five stereocenters. A total of 10 compounds were synthesized by altering the enantiomer of isopulegol and the substituted benzaldehyde, and the resulting enantiopure octahydrochromanes were screened in vitro against the cannabinoid receptor isoforms CB1 and CB2. Compounds containing an olefin at the C4 position of the octahydrochromane scaffold were found to exhibit reasonable displacement of [3H] CP55, 940 from the CB receptors, whereas the corresponding hydroxy analogs had very little or no effect.