High-Pressure Access to the Δ9-cis- and Δ9-trans-Tetrahydrocannabinols Family

Diels-Alder reactions of a range of 1-(alkoxy/alkyl-substituted phenyl)buta-1,3-dienes with methyl vinyl ketone and methyl acrylate carried out in a green ethanolic medium under 9 kbar pressure were investigated. The use of high pressure as activating method of the Diels-Alder reactions allows the efficient and endo-diastereoselective generation of a series of cis-cyclohexenyl-benzene cycloadducts, which are selectively converted into their trans-epimers. The cis-cyclohexenyl-benzenes and trans-cyclohexenyl-benzenes produced are useful precursors for accessing substituted privileged cis-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene and trans-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene skeletons. The total syntheses of 9-cis-tetrahydrocannabinol (THC) and 9-trans-THC, through the use of selected Diels-Alder adducts, are described. Finally, a route for obtaining 9-trans-THC in both enantiomeric pure forms based on the (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP)-hydrazone method, is also reported.