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.

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Optically active delta-3- and delta-8-tetrahydrocannabinols (THC's), cannabidiol and racemic delta-9-cis-THC, and their corresponding analogs (1b yields 4b) in which the positions of the phenolic hydroxyl group and the n-C5 side chain have been interchanged are compared in selected pharmacological tests in mice. the results indicate that the phenolic hydroxyl group in the 1 position in THC's is very important for eliciting activity and that cannabidiol and delta-9-cis-THC possess weak CNS depressant properties.

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