The Diels–Alder Approach to Δ⁹‐Tetrahydrocannabinol Derivatives

Abstract

We have developed an efficient strategy for the synthesis of tetrahydrocannabinol derivatives based on an unsubstituted aromatic compound. A Diels–Alder reaction of vinylchromene with an electron‐poor dienophile gave a tricycle. We describe several methods for the functionalization of this compound, e.g., alkylation, reduction, and lactonization. We also studied the hydrogenation of some of these functionalized cannabinoid compounds to give cannabinoid‐like skeletons. Of these reactions, a tetracycle containing a lactone gave the best result, with a quantitative yield using PtO2 (5 mol‐%) and an atmospheric pressure of hydrogen. These numerous reactions can be applied to substituted aromatic starting materials to obtain a facile and modular route to Δ9‐tetrahydrocannabinol, or alternatively, with different substituents, to other cannabinoid analogues.

The Diels‐Alder Approach towards Cannabinoid Derivatives and Formal Synthesis of Tetrahydrocannabinol (THC)

“…Our modular strategy is centered around vinyl chromenes 13 which can undergo Diels‐Alder reactions with a variety of dienophiles (Scheme 2). [19] These Diels‐Alder products 12 can be further derivatized, which gives the potential to synthesize a large library of cannabinoid compounds. The vinyl chromenes 13 are accessible through several steps from commercially available resorcinol derivatives 14 .…”

“…DBU, DMF, 100 °C. [18] B): Diels-Alder-concept by Gläser et al b) maleic anhydride, CH3CN, r.t., 12 h. [19]. Scheme 2.…”

“…Vinyl chromenes 13 as synthetic hub towards cannabinoids. [19] addition of N-(hydroxymethyl)phthalimide as an electrophile. A side product formed in this reaction when it was allowed to warm up before quenching and is described in the supporting information.…”

“…Access to the starting substrates 16 a/16 b is feasible by existing protocols from phenol precursors 14 a/14 b . This suggests that a large variety of analogs should be accessible by employing the respective phenol derivatives [19] . With the right substitution pattern, we could successfully synthesize a compound that has been reported as an intermediate in a THC total synthesis, thereby our protocol constitutes a formal synthesis.…”

Short and Divergent Total Synthesis of (+)‐Machaeriol B, (+)‐Machaeriol D, (+)‐Δ8‐THC, and Analogues

“…Thus far, more than 60 cannabinoids and related analogues have been identified, and some of them have found applications as psychotomimetic or other drugs 5. Owing to their great pharmacological potential, considerable efforts have been made towards the synthesis of naturally and structurally related, non‐natural cannabinoids (e.g., by the groups of Trost,6 Zhou,7 and Bräse8). Recently, Carreira et al.…”