Generation and Intramolecular Cycloaddition of o-Quinonemethides in Protic Solvent. An Efficient Synthesis of (−)-trans-Hexahydrocannabinol

Abstract

A very facile and efficient synthesis of (−)-trans-hexahydrocannabinol was achieved through the intramolecular Diels-Alder reaction of an o-quinonemethide derived from 2-(1-hydroxycitronellyl)olivetol 1,3-bismethoxymethyl ether in methanol.

Stereoselective Synthesis of Pyrano[3,2-c]benzopyrans via Intramolecular Cycloaddition of o-Quinonemethides Generated from Salicylaldehydes and Unsaturated Alcohols under Very Mild Conditions

“…o- Quinonemethides 1 are very reactive intermediates in organic synthesis, and some natural products have been synthesized using [4 + 2] cycloaddition of these species as the key step (eq 1) . We have been investigating the generation and reaction of o- quinonemethides under mild conditions in order to widen the application of o- quinonemethides in organic synthesis . Previously, we reported that treatment of the phenol derivative 2 with a catalytic amount of an acid in methanol at reflux gave the tricyclic compound 3 in high yield as the sole stereoisomer (Scheme ).…”

“…o- Quinonemethides 4 were thought to be generated by elimination of methanol from 6 , which in turn, could be formed by acetal-exchange reaction between salicylaldehyde dimethyl acetal ( 7 ) and the unsaturated alcohol 8 . It is also of great interest to see whether o- quinonemethides 4 have enough reactivity toward electron-rich dienophiles or show rather weak reactivity like 6- p -methoxybenzylidene-3,4-methylenedioxy-2,4-cyclohexadien-1-one ( 9 ), 1f,3d which is known as a stable and isolable o- quinonemethide.

…”

Synthesis of a bifunctional cannabinoid ligand

“…10 Unreacted 12 was recycled. Exposure of 14 to toluene-sulfonic acid (TsOH) in MeOH at reflux 11 gave a modest yield of dihydrobenzopyran 15 accompanied by larger amounts of tetrahydrofuran 16. † The tetrahydrofuran probably results from a stepwise, ionic process.…”

“…The observed stereochemistry could not have been predicted with confidence from the outset. Cyclization to form the C9 methyl cannabinoid skeleton is known from precedent 11 to produce the C6a-C10a trans stereoisomer. Our own work 13 has shown that cyclization to form the D 9 unsaturated series produces the unnatural C6a-C10a cis stereoisomer as the exclusive product, therefore the stereochemical outcome of the cyclization is easily perturbed by minor structural changes in the seco precursor (cf.…”

Monoterpenoids

“…This self-induced non-equivalence appears to be caused by diastereoisomeric solute-solute interactions, and it is therefore possible to use NMR to determine the ee of a sample of (614) without employing a chiral shift reagent.553 Most of the (chemical) activity in this area has focused on synthesis. Citronella1 (53) reacts with phenols in refluxing quinoline to yield hexahydrocannabinoids (6 15) via intermediate quinone methides (61 6).554 Activated phenols can be A similar route has been employed in a synthesis of ( -)-trans-hexahydrocannabinol (61 7), 556 The derivative (61 8) undergoes a related intramolecular reaction to yield 9-nor-9hydroxyhexahydrocannabinol (6 1 9). j5' Apoverbenone (620) has been converted into the racemic 11nor-9-carboxy -Ag-tetrahydrocanna bin01 carboxylic acid (62 1) which is the principle human metabolite of Ag-tetrahydrocannabinol (622).…”