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

Abstract

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 ethanol as the reaction medium under 9 kbar pressure were investigated. The use of high pressure as the activating method of the Diels-Alder reactions allows the efficient and endodiastereoselective 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 Δ(9)-cis-tetrahydrocannabinol (THC) and Δ(9)-trans-THC, through the use of selected Diels-Alder adducts, are described. Finally, a route for obtaining Δ(9)-trans-THC in both enantiomeric pure forms based on the (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP)-hydrazone method is also reported.

Synthesis of [13C4]-labeled ∆9-Tetrahydrocannabinol and 11-nor-9-Carboxy-∆9-tetrahydrocannabinol as Internal Standards for Reducing Ion Suppressing/Alteration Effects in LC/MS-MS Quantification

“…Our aim was to find an efficient synthesis of 13 C-labeled (−)-(6a R ,10a R )-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[ c ]chromen-1-ol, termed Δ 9 -THC ( 1 ), and its main urine metabolite Δ 9 -THC-COOH ( 3 ). Previously developed routes towards Δ 9 -THC ( 1 ) involve both reactions with 5-pentyl-1,3-benzenediol (olivetol) and various chiral natural derived terpenes [22,23,24,25] and asymmetric syntheses [26,27,28]. Herein, we have focused on the use of terpenes for introducing the correct stereochemistry.…”

Cannabidiol Discovery and Synthesis—a Target‐Oriented Analysis in Drug Production Processes

“…The group performed as imilar reactions equence by using ad ifferent combination of diene andd ienophile. [183] The five steps required to obtain (À)-36 provide the advanced intermediate in up to 14 %o verall yield. The major drawback of the Diels-Alder approach is the resolution of racemate 36,w hich leads to am inimum of 50 %m ass loss, and the conditions of [4+ +2] cycloaddition, which require high pressure for at least 1day.…”

“… [111] However, it is noteworthy that the authors did not test those steps. The group performed a similar reaction sequence by using a different combination of diene and dienophile [183] …”

A review on the syntheses of Dronabinol and Epidiolex as classical cannabinoids with various biological activities including those against SARS-COV2

“…Minuti et al used high pressure as the activating method of the Diels-Alder reactions for obtaining Δ 9 -cis-and Δ 9trans-THC [68]. In this method, Diels-Alder reaction was done between 3-methyl-1-(alkoxy/alkyl-substituted phenyl) buta-1,3-dienes and But-3-en-2-one(methyl vinyl ketone) under high-pressure condition (9 kbar) and then trans and cis-cyclohexenyl-benzene cycloadducts were prepared.…”