L-(-)-delta-1(6)-THC
Method I
This method gives about 50% yield for THC and about 90% for the 1',1'- dimethylpentyl analog. Olivetol 4.74 g (or equimolar amount of analog), 4.03 g (+) cis or trans p-methadien (2,8)-ol-1 (the racemic compound can be used but yield will be one-half), 0.8g p-toluenesulfonic acid in 250 ml benzene; reflux two hours (or use 0.004 Moles trifluoracetic acid and reflux five hours). Cool, add ether, wash with NaHCO3 and dry, evaporate in vacuum to get about 9 g of mixture (can chromatograph on 350 g silica gel benzene elutes the THC; benzene:ether 98:2 elutes an inactive product; then benzene:ether 1:1 elutes unreacted olivetol; evaporate in vacuum to recover olivetol).
Method 2
Dissolve the olivetol or analog and p-menthadienol or p-methatriene (1,5,8) in 8 ml liquid SO2 in a bomb and fuse 70 hours at room temperature. Proceed as above to get about 20% yield. L (-)-delta-1(6)- THC. Convert (-) alpha- pinene to (-) verbenol. Add 1M(-) verbenol (racemic verbenol will give one-half yield), 1M olivetol or analog with methylene chloride as solvent. Add BF3 etherate and let stand at room temperature one-half hour to get approximately 35% yield after evaporating in vacuum or purifying as above to recover unreacted olivetol. Solvent and catalyst used in Method 1 above will probably also work. Either cis or trans verbenol can be used. The JCS paper adds 1 g BF3-etherate to a solution of 1 g olivetol and 1.1 g verbenol in 200 ml methylene chloride and let stand two hours at room temperature. JACS 94,6164(1972) recommends two hours at -10øC, then one-half hour at room temperature and the use of cis rather than trans verbenol (the latter gradually decomposes at room temperature). The reaction is also carried out under nitrogen, using twice as much verbenol as olivetol, 0.85 ml BF3 etherate and 85 ml methylene chloride/g verbenol (both freshly distilled over calcium hydride) to give ca. 50% yield. See also JACS 94,6159(1972) for the use of citral and Arzneim. Forsch. 22,1995(1972) for use of p-TSA. In the synthesis of THC with verbenol, the cis isomer is preferable to the trans since the latter decomposes at room temperature. Pinene or cawone give active THC's.
Method 3
L(-)-delta-1 and delta-1(6) THC. 1M (+)-trans-2-carene oxide (2-epoxycarene), 1M olivetol or analog, 0.05 M p-toluenesulfonic acid in 10L benzene; reflux two hours and evaporate in vacuum (or can separate the unreacted olivetol as above) to get about 30% yield THC. Olivetol can also be separated as described below. For synthesis of 2-epoxycarene (delta-4 carene oxide) from delta-4 carene (preparation given later) see p-methadieneol preparation (Method 2). 3-carene oxide gives 20% yield of delta-1(6) THC.
Method I
This method gives about 50% yield for THC and about 90% for the 1',1'- dimethylpentyl analog. Olivetol 4.74 g (or equimolar amount of analog), 4.03 g (+) cis or trans p-methadien (2,8)-ol-1 (the racemic compound can be used but yield will be one-half), 0.8g p-toluenesulfonic acid in 250 ml benzene; reflux two hours (or use 0.004 Moles trifluoracetic acid and reflux five hours). Cool, add ether, wash with NaHCO3 and dry, evaporate in vacuum to get about 9 g of mixture (can chromatograph on 350 g silica gel benzene elutes the THC; benzene:ether 98:2 elutes an inactive product; then benzene:ether 1:1 elutes unreacted olivetol; evaporate in vacuum to recover olivetol).
Method 2
Dissolve the olivetol or analog and p-menthadienol or p-methatriene (1,5,8) in 8 ml liquid SO2 in a bomb and fuse 70 hours at room temperature. Proceed as above to get about 20% yield. L (-)-delta-1(6)- THC. Convert (-) alpha- pinene to (-) verbenol. Add 1M(-) verbenol (racemic verbenol will give one-half yield), 1M olivetol or analog with methylene chloride as solvent. Add BF3 etherate and let stand at room temperature one-half hour to get approximately 35% yield after evaporating in vacuum or purifying as above to recover unreacted olivetol. Solvent and catalyst used in Method 1 above will probably also work. Either cis or trans verbenol can be used. The JCS paper adds 1 g BF3-etherate to a solution of 1 g olivetol and 1.1 g verbenol in 200 ml methylene chloride and let stand two hours at room temperature. JACS 94,6164(1972) recommends two hours at -10øC, then one-half hour at room temperature and the use of cis rather than trans verbenol (the latter gradually decomposes at room temperature). The reaction is also carried out under nitrogen, using twice as much verbenol as olivetol, 0.85 ml BF3 etherate and 85 ml methylene chloride/g verbenol (both freshly distilled over calcium hydride) to give ca. 50% yield. See also JACS 94,6159(1972) for the use of citral and Arzneim. Forsch. 22,1995(1972) for use of p-TSA. In the synthesis of THC with verbenol, the cis isomer is preferable to the trans since the latter decomposes at room temperature. Pinene or cawone give active THC's.
Method 3
L(-)-delta-1 and delta-1(6) THC. 1M (+)-trans-2-carene oxide (2-epoxycarene), 1M olivetol or analog, 0.05 M p-toluenesulfonic acid in 10L benzene; reflux two hours and evaporate in vacuum (or can separate the unreacted olivetol as above) to get about 30% yield THC. Olivetol can also be separated as described below. For synthesis of 2-epoxycarene (delta-4 carene oxide) from delta-4 carene (preparation given later) see p-methadieneol preparation (Method 2). 3-carene oxide gives 20% yield of delta-1(6) THC.