Synthesis of cannabinoid model compounds. Part 2: (3R, 4R)‐Δ¹⁽⁶⁾‐Tetrahydrocannabinol‐5″‐oic acid and 4″(R, S)‐Methyl‐(3R, 4R)‐Δ¹⁽⁶⁾‐tetrahydrocannabinol‐5″‐oic Acid

Abstract

Two novel cannabinoid model compounds, (3 R, 4 R)-dl @)-tetrahydrocannabinol-5"-oic acid (22) and 4" (R, S)-methyl-(3 R, 4 R)-d1(6)-tetrahydrocannabinol-5"-oic acid (23) were synthesized by acid-catalyzed condensation of (+)-truns-p-mentha-2,8-dien-l-o1 (1) with the substituted resorcinols 18 and 19 obtained by a Wittig reaction between 3,5-bis (benzy1oxy)benzaldehyde (7) and methyl 4-bromobutanoate (10) or methyl 4-bromo-2 (R, 5')-methylbutanoate (11) resp. with subsequent hydrogenation. The resulting methyl esters 20 and 21 were hydrolyzed to give acids 22 and 23.In the course of our investigation of structure-activity relationships in the cannabinoid series we described the synthesis, properties and biotransformation of the non-psychotropic cannabinoid (3 R , 4 R)-d1(7)-tetrahydrocannabinol [l] [2]. We now wish to report on the synthesis of two novel cannabinoid model compounds, (3 R, 4 R)-d~f6)-tetrahydrocannabinol-5"-oic acid (22) (= ~l~(~)-THC-5"-oic acid) and 4" (R, S)-methyl-(3 R, 4 R)-Al (6)-tetrahydrocannabinol-5"-oic acid (23) ( = 4"methyl-d1 (6)-THC-5"-oic acid). Both compounds are derivatives of d1(6)-THC (3), one of the psychotropic principles of the drug hashish. Being mainly interested in acid 23 where the full aliphatic C5 side chain of the parent compound is retained, acid 22 was prepared to elaborate the synthesis of 23. Both methyl esters 20 and 21 and the acids 22 and 23 are now investigated for psychotropic activity after intraventricular injection in the cat3).The general stereospecific pathway to (3 R , 4R)-d1 @)-THC (3) and its derivatives consists according to Petrzilka et al. [3] in the acid-catalyzed reaction of (+ )-trans- ') Part 1: see [I]. 2, 3,Part of the thesis of I.F. In two double blind studies the esters 20 and 21 at doses of 10 and 20 mg resp. (spiked cigarettes, total lung delivery 2 mg 20 and 4 mg 21) could not be distinguished from placebo. 0018-019X/80/8/2508-07$01.00/0 0 1980 Schweizerische Chemische Ciesellschaft

A urinary metabolite of Δ1-tetrahydrocannabinol. The first synthesis of 4′′-hydroxy-Δ1-tetrahydrocannabinol-7-oic acid labelled with deuterium

“…This paper describes the fmt synthesis of [ZHgI-labelled 4"-hydroxy-A1-THC-7-oic acid (14). The sequence used is based on the method previously described for the synthesis of unlabelled and labelled Al-THC-7-oic acid [9, 221 and 4",5"-bisnor-A1-THC-7,3"-dioic acid [ 121, and extends the versatility of the general procedure used.…”

Total Synthesis of Brevetoxin A: Part 3: Construction of GHIJ and BCDE Ring Systems

“…Engagement of the two hydroxyl groups branching from ring D as a ketal with cyclohexanone dimethylketal and PPTS, furnished compound 74 (87 % yield) which was treated with PivCl and 4-DMAP to afford 75 (100 % yield). Cleavage of the ketal with CSA in methanol regenerated the diol system on the right side of the molecule (97 % yield), which was easily differentiated by reaction with TrCl´4-DMAP [19] [20] allowed the generation of aldehyde 80 (87 % yield), which reacted with the ylide generated from phosphonium salt Br À PPh 3 -(CH 2 ) 3 CO 2 Me [21] and KHMDS in THF to afford Z-olefin 81 (94 % yield). Exposure of 81 to LiOH cleaved the ester and acetate protecting groups, furnishing hydroxy acid 82 in high yield.…”

Asymmetric Synthesis of a Series of Chiral AB2Monomers for Dendrimer Construction

“…Concentration in vacuo yielded 7 as a colorless solid (12.0 g, 87%) which was used without further purification: mp 78-80 °C (lit. 50 79-81 °C); 1 H NMR (270 MHz, CDCl3) δ 7.33-7.42 (m, 10 H), 6.60 (d, J ) 2.2 Hz, 2H), 6.54 (t, J ) 2.2 Hz, 1H) , 5.02 (s, 4H), 4.61 (d, J ) 8.8 Hz, 2H), 1.64 (t, J ) 8.8 Hz, 1H).…”

“…Concentration of the pale yellow filtrate resulted in the precipitation of 8 (14.3 g, 94%) as colorless crystals: mp 80.5-81 °C (lit. 50…”