B. Preparation and Use of (-)-Verbenol
(-)-verbenol is prepared by the method of (Reference 180) from levo-alpha-pinene (also written (l)- or (-)-a-pinene). The corresponding dextro-isomer ((d)- or (+)-a-pinene) is not suitable.
The required (-)-a-pinene is easily obtained by fractionally distilling commercial natural terpenes, in which it is a major constituent. "Pinene" is commercially available, but should not be used unless it is specifically designated (-)-a-pinene. This desired isomer can be distilled from turpentine of French origin, but not from American, Scandinavian, British, or German turpentines in which (due to the variety of pine from which they are prepared) the useless (+)-a-pinene occurs. Probably the most convenient source is from Oregon or Canadian Balsam (Douglas Fir Balsam), which has a variety of commercial uses and is readily available. The (-)-a-pinene is separated from the Balsam mixture by fractional distillation (collecting the fraction distilling between 155-159 deg C., at ordinary atmospheric pressure. It is freed from impurities by a second distillation after adding a little sodium metal to the distilling flask (the sodium reacts with the impurities and they remain behind as residue). During this second distillation the pure (-)-a-pinene passes over and is collected between 155-156.5 deg. C. (Reference 200)
(-)-a-Pinene is oxidized with lead tetra-acetate (see references listed in (Reference 247) for further information on the use and sources of this reagent) in benzene solution to give an intermediate compound, cis-2-acetoxypln-3-ene, which easily rearranges on standing in acetic acid to give the desired (-)-verbenol. This product is a mixture of the cis- and trans- forms, which can be used equally well.
1. Preparation of cis-2-acetoxy-pin-3-ene.
27 grams of (-)-a-pinene in 500 ml. dry benzene is warmed to 65 deg. C. and over 20 minutes there is added in portions a total of 84 grams dry lead tetra-acetate (if necessary it can be dried over phosphorus pentoxide in a desiccator). During the addition the solution is stirred and the temperature held at 60-65 deg C. After an initial bright yellow coloration, gradual precipitation of lead diacetate occurs. On completion of the addition the suspension is stirred at 60-65 deg. C. for another 30 minutes. The reaction mixture is then cooled and the solid is filtered out. The filtrate is added to water and the precipitated lead dioxide removed. The benzene layer is then separated from the aqueous portion. Probably it is sufficient to distil off the benzene and to use the crude residue in the next reaction, but if desired it can first be dried with an anhydrous salt, the benzene removed by distillation, and the crude product purified by distillation (B.p. 96-97 deg. C/ 9 mm.). The yield of pure product is about 22 grams (55%).
2. Rearrangement to (-)-Verbenol.
50 grams of the product obtained above are stirred into 250 ml. glacial acetic acid and set aside at room temperature for 30-60 minutes. Water is then added and the mixture extracted with several portions of ether. If desired the pure acetate of (-)-verbenol can be isolated by washing the ether extract with dilute sodium carbon to solution, drying, and distilling off the ether. The acetate can be purified by reduced pressure distillation (B.p. 97-98 deg C./ 9 mm. ), yield is excellent, 4.25 grams. Probably, however, the crude acetate obtained simply by distilling off the ether from the extract above can be directly subjected to hydrolysis to liberate the (-)-verbenol. Hydrolysis is carried out by adding the crude or purified acetate of (-)-verbenol to aqueous alkali solution, warming or refluxing if necessary to complete the hydrolysis, then cooling and extracting the (-)-verbenol with ether. After drying the ether solution with an anhydrous salt the ether is distilled off. The residual (-)-verbenol can be purified by distillation at reduced pressure (b.p. 91-92 deg. C./ 6 mm.). (Reference 180)
The condensation of olivetol with (-)-verbenol was carried out by Mechoulam in methylene chloride solution using either p-toluene sulphonic acid or boron trifluoride etherate as condensing agents. The first agent gave a mixture of three products "easily separated by chromatography". One of these products (4-trans-(2-olivetyl)-pinene) was then treated with "boron trifluoride etherate in methylene chloride at room temperature for 10 minutes" to convert it in 85% yield to pure THC-B. Since the intermediate was obtained in 45% yield the overall yield from olivetol is about 40% of theory.
This procedure appears to be a convenient one for obtaining pure THC in good yield. Mechoulam does not indicate the solvent to be used for developing the chromatographic column (e.g. for eluting the 3 bands). In his similar work with the citral condensation product (previous section) Taylor first poured the crude product containing reaction solution onto the chromatographic column (for techniques see both (Reference 199 and 203 - page 55)), then eluted a first portion (not the desired product) with pure hexane. The desired product containing resin was then caused to move out of the column by continuing the elution with another solvent (a mixture of hexane with ethyl ether, 95 parts to 5 parts). Because the by-products of the two reactants are different some experimentation may be needed. Other elution mixtures are given in (Reference 355). Unless facilities for experimentation are adequate, it may be desirable to use the crude reaction mixture itself, which should be satisfactory for many purposes. In this case it seems best to use the modification described by Mechoulam, in which the condensation in methylene chloride is carried out directly with boron trifluoride etherate and no p-toluene sulphonic acid is used. "THC can also be isolated directly in a 35% yield from the condensation of olivetol and (-)-verbenol when catalyzed by boron trifluoride etherate instead of p-toluene sulphonic acid". It is not clear whether chromatographic separation of the product prepared directly with boron trifluoride is more difficult than the separation of the intermediate obtained in the two stage reaction, but it is likely.
The condensation with boron trifluoride etherate is carried out as described for citral, except that one mole of (-)-verbenol (152 grams) is used instead of citral. Because Mechoulam gives no more details than indicated above for the condensation, some experiment may be needed to define the optimum conditions and reaction times. Possibly the condensation can be carried out at room temperature, but it is doubtful that higher temperatures would be desirable.
Condensation with Citral
Preparation and Use of (-)-2-Carbethoxy 5-Methylcyclohexane