Hashish. X. Simple one-step synthesis of (-)-.DELTA.1-tetrahydrocannabinol (THC) from p-mentha-2,8-dien-1-ol and olivetol

Abstract

Optically pure (-j-A+THC (7) was produced in 50% yield (glc; isolated yield 31%) in a single-step synthesis from dí/rra/ií-(+)-p-mentha-2,8-dien-l-ol (1) and olivetol (2) in the presence of 1% boron trifluoride etherate and anhydrous magnesium sulfate in methylene chloride at 0°. The product was readily separated by column chromatography. The other major product formed was /r««s-A8-iso-THC (8). By the same procedure (-)-cannabidiol (3) was obtained on a preparative scale when <0.5% boron trifluoride etherate or wet ^-toluenesulfonic acid was used. A mechanistic scheme is presented for this reaction. It is shown that cannabidiols (3 and 4) are the key intermediates in this reaction and abnormal cannabidiol (4) undergoes a retro-Friedel-Crafts reaction followed by recombination to normal cannabidiol (3). This retroreaction of 4 is rationalized on steric arguments. The isolation and study of products from this reaction give a much clearer understanding of the factors which control the outcome of acid-catalyzed reactions of p-mentha-2,8-dien-l-ol and olivetol and have provided three new cannabinoids, 9,10, and 12.In this paper we report a convenient single-step synthesis of (-j-A^THC (7) in 50% yield (glc) from (+)-p-mentha-2,8-dien-l-ol (1) and olivetol (2) under controlled conditions. The reaction mixture was readily separated by column chromatography to give (-)-A^THC (7) of very high optical purity in 31 % isolated yield2 (purity by glc > 96%). The same procedure also provides experimental conditions for stopping the isomerization of the thermodynamically less stable 1double bond to the more stable 1(6) unsaturation, a problem which has hindered the synthesis of trans-A1-THC derivatives.3•4Other syntheses from (-)-verbenol6 and (+)-/> mentha-2,8-dien-1 -ol6 do not avoid this double bond isomerization but give the more thermodynamically stable ( -)-1(6)-( 5) isomer, which must be transformed to (-j-A^THC (7) by addition and elimination of hydrogen chloride. These processes thus require three steps and involve at least two very tedious and careful chromatographic separations. The one-step synthesis of (-j-A^THC that we described earlier7 was achieved from trans-(+)-2-carene oxide, but it suffered from the difficult separation of trans-A1-and m-A'-THC's, which were the major products. Of the three syntheses described above, the p-menthadienol process is presently being used for large-scale production of 7 because of the commercial availability of J 6b(1) Part X. For part IX, see R. K. Razdan, D, B. Uliss, and H. C.

Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors

“…3D), results from the transposition of the phenolic hydroxyl group and the pentyl side chain of cannabidiol. It was synthesized as described (23), and its purity was established by nuclear magnetic resonance spectroscopy, gas chromatography, and elemental analysis. Cannabinoids were dissolved in Emulphor͞ethanol͞saline, 1:1:18.…”

2‐Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal‐cannabidiol‐sensitive receptors on microglial cells

“…abn-CBD is a structural analogue of the phytocannabinoid cannabidiol (CBD) and was first synthesized in 1974 (Razdan et al, 1974). Physiological effects of abn-CBD-sensitive receptor were first reported in the cardiovascular system.…”

Medicinal Chemistry Endeavors Around the Phytocannabinoids

“…These compounds, represented here by 20, are potent but non-selective cannabinoid receptor ligands. In addition, a synthetic derivative named abnormal cannabidiol [82], (À)-4-(3,4-trans-p-mentha-1,8-dien-3-yl)olivetol (25; Fig. This observation was supported by the adamantyl-cannabinoid analogues recently described by Lu et al [77].…”