## 4 Production of Phytocannabinoids: From Biosynthesis to Synthetic Procedures
### Synthetic Procedures to Prepare Non-Psychotropic Cannabinoids CBC, CBG and (\(-\))-CBD
#### 4.2.3 Synthesis of (\(-\))-CBD  
The first synthetic routes available to synthetize (\(-\))-CBD [114; 115; 116; 117] are of scarce practical value, as they lead to (\(-\))-CBD in mediocre or even insignificant yields and the unnatural CBD isomer (Abn-CBD) (see Figure 11) was obtained in amounts considerably larger than those of (\(-\))-CBD. Despite such poor results, the procedure proposed by [PERSON] et al. in the year 1969, but using \(E\)-(+)-\(p\)-mentha-2,8-dien-1-ol in place of \(Z\)-(+)-\(p\)-mentha-2,8-dien-1-ol and olivetol in benzene in the presence of catalytic amounts of PTSA was reproduced by [PERSON] et al. in the year 2002, achieving (\(-\))-CBD in 31% yield [118]. The best route to (\(-\))-CBD described is the condensation of (+)-\(p\)-mentha-diene-l-olo with olivetol in the presence of weak acids, reported by [PERSON] et al. in the year 1974 and [PERSON] et al. the next year [117; 119]. In this case, the Abn-CBD obtained was converted to (\(-\))-CBD with BF\({}_{3}\)-etherate by a retro-Friedel-Crafts reaction, followed by recombination. However, with this reagent the reaction proceeded further causing cyclisation of (\(-\))-CBD. In the year 1985, it was reported that when BF\({}_{3}\)-etherate on alumina is used as condensing agent in the reaction of \(Z\)-(+)-\(p\)-mentha-2, 8-dien-1-ol (**1**) with olivetol (**2**), (\(-\))-CBD was obtained as the major product, in 55% yield as chromatographically pure oil, or in 41% yield as crystalline material (Scheme 14) [108]. No cyclization was observed, and side products were much more polar (14% yield) or much less polar (6% yield) than (\(-\))-CBD. Particularly, BF\({}_{3}\)-etherate was added under nitrogen to a stirred suspension of basic aluminum oxide (Al\({}_{2}\)O\({}_{3}\)) in dry DCM, and after 15 min at room temperature and 1 min at 40-41 \({}^{\circ}\)C, (+)-\(p\)-mentha-2,8-dien-l-ol and olivetol dissolved in DCM were added. The reaction was quenched within 10 s with 10% aqueous solution of sodium bicarbonate (10 mL), and after evaporation of the organic extracts, (\(-\))-CBD was obtained. In 1988, [PERSON] et al. [120] reported the reaction of (1S,2S,3R,6R)-(+)-\(E\)-car-2-ene epoxide and that of \(p\)-menthaidenol with olivetol in the presence of PTSA. Particularly, the starting material (1S,2S,3R,6R)-(+)-\(E\)-car-2-ene epoxide (**3**) was prepared starting from car-3-ene (**1**) by its treatment with potassium _tert_-butoxide to achieve the derivative **2**, which after epoxidation with \(m\)-chloroperoxybenzoic acid provided the desired compound **3** (Scheme 15). Otherwise, \(p\)-menthaidenol was prepared by citral with HCl in water or with PTSA in water/DCM (reaction not reported). The authors observed that in both cases, among other minor compounds, (\(-\))-CBD, Abn-CBD, 1-THC and 6-THC were obtained. In particular, when (1S,2S,3R,6R)-(+)-\(E\)-car-2-ene epoxide was reacted with olivetol in benzene in the presence of docosane as catalyst for 45 min at 40 \({}^{\circ}\)C, the main product which formed was \(p\)-menthaidenol with traces of (\(-\))-CBD, Abn-CBD and THC. The further reaction of the obtained \(p\)-menthaidenol with olivetol for 1h at 50 \({}^{\circ}\)C in benzene with docosane as well, afforded (\(-\))-CBD in 30% yield, together with THC (18%), \(\Delta^{8}\)-THC (6%), and Abn-CBD (13%) (Scheme 15). Rationally, the direct reaction of \(p\)-menthadienol (**1**) with olivetol in the conditions above reported afforded (\(-\))-CBD in 30% yield (last part of Scheme 15). Although in different conditions in terms of solvents, times, temperature, stereochemistry and catalysts, the reaction of \(p\)-menthadienol with olivetol was exploited by different research groups. [PERSON] et al. reacted \(E\)-(+)-\(p\)-mentha-2, 8-dien-1-ol with olivetol in toluene with PTSA for 1.5 h at 18-25 \({}^{\circ}\)C achieving (\(-\))-CBD in 20% yield [121]. Also, [PERSON] et al.