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

Abstract

Novel, functionalized octahydrochromene derivatives were synthesized in a single step the Prins reaction. Enantiomerically pure (+)-isopulegol was reacted with benzaldehyde to stereoselectively yield the corresponding octahydro-2-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 octahydrochromenes were screened against the cannabinoid receptor isoforms CB1 and CB2. Compounds containing an olefin at the C4 position [(+)-, (-)-, (-)-, (-)- and (-)-] of the octahydrochromene scaffold were found to exhibit reasonable displacement of [H] CP55,940 from the CB receptors, whereas the corresponding hydroxy analogs [(+)-, (+)-, (-)-, (-)- and (+)-] had very little or no effect.

Acid‐modified Halloysite Nanotubes as a Stereoselective Catalyst for Synthesis of 2H‐Chromene Derivatives by the Reaction of Isopulegol with Aldehydes

“…It is known that compounds with a chromene (benzopyran) scaffold have a broad spectrum of biological activity . A high pharmaceutical potential and low toxicity of these substances resulted in a considerable interest in the synthesis of new chromene derivatives . Recently, it has been shown, that in catalytic condensation of a natural allyl alcohol (−)‐isopulegol (I) with aldehydes, substituted octahydro‐2 H ‐chromen‐4‐ol (III) as 4 R ‐ and 4 S ‐diastereomers was formed along with a dehydration product IV (Scheme ).…”

“…Recently, it has been shown, that in catalytic condensation of a natural allyl alcohol (−)‐isopulegol (I) with aldehydes, substituted octahydro‐2 H ‐chromen‐4‐ol (III) as 4 R ‐ and 4 S ‐diastereomers was formed along with a dehydration product IV (Scheme ). Different catalysts such as I 2 , p ‐toluenesulfonic acid, BF 3 ⋅Et 2 O, zeolites, clays were used in this reaction . A relatively high 4 R /4 S ratio (9.0) with overall yields of 70–88 % were observed in condensation of isopulegol (obtained by cyclization of R ‐citronellal) with aromatic aldehydes at −78 °C using scandium triflate .…”

“…Some synthesized octahydro‐2 H ‐chromen‐4‐ols on the basis of isopulegol display a pronounced physiological activity . Thus, 4 R ‐diastereomer obtained by the reaction of I with thiophene‐2‐carbaldehyde on K‐10 clay exhibited in vivo prolonged analgesic effect surpassing that of Diclofenac .…”

“…Considering that stereoselectivity to chromenol formation depends on the type of aldehyde,,, condensation of isopulegol with several aldehydes was investigated in the presence of modified HNT at 20 °C to explore the reaction scope.…”

Corymbia citriodora: A Valuable Resource from Australian Flora for the Production of Fragrances, Repellents, and Bioactive Compounds

“…Drugs that act on cannabinoid receptors may be involved in targeting a number of human diseases and have been increasingly investigated as a target for organic synthesis. Octahydrochromates active on cannabinoid receptors CB1 and CB2 have recently been synthesized from 2 (Scheme 25) [140]. CB1 receptors have been shown to be active in protecting the brain from excitotoxic damage [141], relief of GI symptoms and other effects [142], whilst CB2 receptors affect the immune system and are involved in antinociceptive effects [140,143].…”