P-Mentha-1.5-diene

Recently the most employed method for the production of A9-THC on industrial scale is the condensation of (+)-p-mentha-2,8-dien-l-ol (5.1 in... 

The fungal bioconversion of limonene was further studied [82]. Penicillium sp. cultures were isolated from rotting orange rind that utilised limonene and converted it rapidly to a-terpineol. Bowen [83] isolated two common citrus moulds, Penicillium italicum and P. digitatum, responsible for the postharvest diseases of citrus fruits. Fermentation of P. italicum on limonene yielded cis- and frans-carveol (93) (26%) as main products, together with cis- and from-p-mentha-2,8-dien-l-ol (110) (18%), (+)-carvone (94) (6%), p-mentha-1,8-dien-4-ol (111) (4%), perillyl alcohol (100) (3%), p-menth-8-ene-1,2-diol (98) (3%), Fig. (17). Conversion by P. digitatum yielded the same products in lower yields. The two alcohols />-mentha-2,8-dien-1 -ol (110) and p-mentha-1,8-dien-4-ol (111) were not described in the transformation studies where soil Pseudomonads were used [69]. 

A mixture of 2.88 g (16.0 mmol) of olivetol, 2.45 g (16.1 mmol) of (+)-cis/trans-p-mentha-2,8-dien-l-ol, and 2 g of anhydrous magnesium sulfate was stirred with 100 mL of methylene chloride under N2 atmosphere. After cooling in an ice bath, 1 mL (8.1 mmol) of freshly distilled boron triffuoride etherate was added. The mixture was stirred for 1.5 hr at 0° C and 5 g of anhydrous sodium bicarbonate was added. The stirring was continued until the color had faded, at which time the reaction mixture was filtered and evaporated to give a colorless gum (5 g). On the basis of gas-liquid chromatography, it contained 50 percent... 

A mixture of 153 mg (0.85 mmol) of olivetol, 132 mg (0.87 mmol) of (-i-)-cjs//rans-p-mentha-2,8-dien-l-ol and 200 mg of anhydrous magnesium sulfate in 5 mL of methylene chloride was stirred and cooled to ice bath temperature. Fifty microliters of anhydrous stannic chloride (0.111 g, 0.4 mmol) was added and stirring and cooling was continued. After 10 minutes, the reaction mixture was analyzed by gas-liquid chromatography and shown to contain 30 percent of (-)-6a,10a- rans-l-hydroxy-3-n-pentyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydrodibenzo[b,d]pyran. After quenching the reaction with sodium carbonate, the desired compound can be isolated from the reaction mixture. 

Syntheses of (-)-A -THC have utilized the acid-catalyzed condensation of olivetol (9, Scheme 1) with suitable chiral monoterpenes, such as (-h)-c/5- or /ra 5-p-mentha-2,8-dien-l-ol (9,10), (+)-trans-2-czKm epoxide (11,12), p-mentha-2-ene-l,8-diol (13,14), and (-)-cis- or /ra 5-verbenol (15). Other successful approaches to A -THCs are also known (16-21), but a problem common to these methods is created by the fact that a variety of by-products results. Normal and abnormal THCs, few-adducts, open-chain intermediates, starting materials, degradation products as well as double-bond isomers complicate work-up procedures and purifications. Although an improved method has... 

Razdan and coworkers (10) have reported a modification of the Petrzilka (9) cannabinoid synthesis. Thus, condensation of olivetol with (-h)-cjs- or trans-p-mentha-2,8-dien-l-ol in the presence of boron trifluoride-etherate and anhydrous magnesium sulfate at 0°C yielded (-)-A -THC, and practically no A -iso-mer was formed (Scheme 2). This modification represents a useful direct route to (-)-A -THCs, (-)-A -tetrahydrocaimabivarins, and their regiospecifically deuterated analogs (22-24). It was recently reported that the synthesis of a (-)-A -THC derivative was accomplished without the presence of a drying agent by keeping the reaction temperature at 0°C (25). 

BFg-etherate added with ice-cooling under Ng to a stirred mixture of olivetol, (+)-c/j /rranj-p-mentha-2,8-dien-l-ol, anhydrous Mg-sulfate, and methylene chloride, stirring continued 1.5 hrs. at 0° (-)-Zl -tetrahydrocannabinol. Y 31%. R. K. 

Both geraniol and nerol have been shown to undergo cyclization to c -p-mentha-2,8-dien-l-ol on treatment with the novel tris(/ -bromophenyl)ammoniumyl radical cation, (37). The reagent X is becoming a popular choice for as a one-electron oxidant in a variety of electron-transfer reactions. The mechanism postulated involves the initial formation of a delocalized radical cation that undergoes cyclization, deprotonation, and dehydrogenation to a cyclic triene, that is protonated followed by hydration to give the product. 

A mixture of ( + )-trans-p-mentha-2,8-dien-l-ol, olivetol, and p-toluenesulfonic acid monohydrate refluxed 2 hrs. in benzene (—)-j6,l-3,4-frans-tetrahydro-cannabinol. Y 52.8%. Also from the ci s-isomer s. T. Petrzilka and G. Sikemeier, Helv. 50, 1416 (1967). 

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