## 4 Production of Phytocannabinoids: From Biosynthesis to Synthetic Procedures
### Synthetic Procedures to Prepare Non-Psychotropic Cannabinoids CBC, CBG and (\(-\))-CBD
#### 4.2.2 Synthesis of CBG  
The oldest synthetic procedure to prepare CBG we found, not reporting the reaction yield, was described by [PERSON] et al. in the year 1964 [105]. The authors synthesized CBG by boiling geraniol (**1**) with olivetol (**2**), in decalin for 36 h (Scheme 9).  
Similarly, CBG was prepared by the condensation of geraniol and olivetol, using DCM in the presence of \(p\)-toluenesulfonic acid (PTSA) at 20\({}^{\circ}\) to achieve CBG as crystalline material in 52% yield, by [PERSON] et al. according to Scheme 10 [106].  
Starting from the same materials (geraniol and Olivetol) and using DCM as solvent and PTSA monohydrate as catalyst, [PERSON] et al. [33] prepared CBG like [PERSON] et al. [106] with the same yield, reproducing the procedure previously reported by [PERSON] et al. [107].  
The reaction was stirred at room temperature in the dark for 12 h, then added with aqueous saturated NaHCO\({}_{3}\). After evaporation of the separated organic phase, a crude residue was obtained, which was purified via flash column chromatography on silica gel, providing pure CBG as an off-white powder in 28% yield.  
In 1985, it was reported that when BF\({}_{3}\)-etherate on silica was used as condensing agent in the reaction of (+)-p-mentha-2,8-dien-l-ol (**1**) with Olivetol (**2**), CBG could be obtained as the major product, in 29% yield (Scheme 11) [108].  
Particularly, BF\({}_{3}\)-etherate was added under nitrogen to a stirred suspension of silica in dry DCM, added with \(Z\)-(+)-\(p\)-mentha-2,8-dien-l-ol and Olivetol dissolved in DCM and stirred at room temperature for 2 days. After having quenched the reaction with an aqueous solution of sodium bicarbonate followed by extraction with diethyl ether, CBG was achieved in 29% yield.  
Later, the same authors used the above-reported procedure starting from geraniol and Olivetol, as in Schemes 9 and 10, achieving CBG in 29% yield, as well [109; 110].  
A chemoenzymatic synthesis of CBG was reported by [PERSON] et al. in the year 2008 [111], which we did not discussed in the present work, because out of our scope aiming at describing only processes totally synthetic.  
In the year 2020, [PERSON] et al. reported the optimized synthesis of three phenolic natural products with unprecedented efficiency, using a new alumina-promoted regioselective aromatic allylation reaction [112]. As for CBG, it was prepared in one step from the inexpensive Olivetol and geraniol, as in the reactions implemented previously by [PERSON] et al. [33], [PERSON] et al. [106] and [PERSON] et al. [107], but using different reagents and conditions, and achieving CBG in higher yield.  
Briefly, to a solution of geraniol and Olivetol in dichloroethane (DCE), acidic alumina (Al\({}_{2}\)O\({}_{3}\)) was added, and the heterogeneous mixture was stirred at reflux temperature for 6 h. After filtration of the alumina and the removal of the organic solvent, CBG was achieved as a yellow oil, that was purified via chromatography, thus obtaining pure CBG in 62% yield.  
Like for CBC, the most recent synthetic procedures for preparing CBG have been reported in the year 2021. The group of [PERSON] et al. reported a multistep procedure based on a tandem Diels-Alder/retro-Diels-Alder cycloaddition which allowed to achieve CBG in very high yield (81%) (Scheme 12) [113].  
The group of [PERSON] [93], reproposed the procedure previously described by [PERSON] et al. in the year 1996 [110] (Scheme 13).  
Briefly, CBG was prepared reacting olivetol dissolved in dry chloroform (CHCl\({}_{3}\)) with geraniol, in the presence of PTSA for 12 h at room temperature. The crude CBG was achieved as an oil, which was purified by silica gel chromatographic column. CBG was isolated with a low 15% yield.