## 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
in the year 2022 condensed olivetol with commercially available \(Z\)-(+)-\(p\)-mentha-2, 8-dien-1-ol in the presence of 33 mol% of wet PTSA in toluene at 0 \({}^{\circ}\)C for 3 h, affording a mixture of normal (\(-\))-CBD and Abn-CBD, which were isolated in 26% and 38% yield respectively after a chromatographic column. Importantly, under these experimental conditions, no tricyclic structure was produced [122]. A different synthetic procedure was reported by [PERSON] et al. in the year 1992 [123]. The authors described a new synthesis of (\(-\))-CBD via the \(\alpha\)-arylation of camphor, achieving both (\(-\))-CBD and (\(-\))-CBD mono methyl ether as shown in Scheme 16 [123]. Particularly, the authors prepared the endo-3-(2,5-dimethoxyoxy-4-\(n\)-pentylphenyl)camphor (**2**), by reacting first olivetol dimethyl ether (**2**) dissolved in dry THF under nitrogen at \(-\)10 \({}^{\circ}\)C with _tert_-butyllithium (_tert_-BuLi) 1.7 M in hexanes for 3 h under stirring. Then the solution obtained was transferred to a solution of CuI in dry THF at 0 \({}^{\circ}\)C and the mixture was stirred for 20 min. Upon dilution with DMSO, the obtained solution was transferred dropwise to a solution of 3,9-dibromocarbon dissolved in dry THF/DMSO at 0 \({}^{\circ}\)C, and the reaction was then allowed to warm to room temperature and was stirred overnight. After the proper work-up and removal of the solvent in vacuo, the crude product was chromatographed and recrystallized from EtOH to achieve **2** in 71% yield. Compound **2** was transformed into the vinyl phosphate derivative **3**, by dissolving it in dry THF under nitrogen and titrating the obtained solution cooled to \(-\)78 \({}^{\circ}\)C with a freshly prepared 0.4 M Na-naphthalene/0.4 M tetra-ethylenediylcol dimethyl ether solution (see later) in THF until a deep green color persisted. The green mixture was then added with diethyl chlorophosphate and hexamethylfosformamide (HMPA), was allowed to warm to \(-\)20 \({}^{\circ}\)C, and opportunely treated to provide the crude product which was subjected to a short silica column obtaining the desired enol phosphate **3** as a colorless oil (89%). (\(-\))-CBD and (\(-\))-CBD monomethyl ether (**4**), were finally obtained by adding the vinyl phosphate **3** dissolved in dry THF and _tert_-butanol (_t_-BuOH) to an excess of lithium foil in methylamine (MeNH\({}_{2}\)) at \(-\)78 \({}^{\circ}\)C. When addition was complete, the reaction was allowed to stir at \(-\)10 \({}^{\circ}\)C for 1 h and treated by acidification with HCl 1M. After extraction and removal of organic solvent the crude reaction mixture was chromatographed on neutral alumina, achieving (\(-\))-CBD monomethyl ether in 43% yield. Further elution afforded (\(-\))-CBD in 35% yield. The 0.4 M Na-naphthalene/0.4 M tetra-ethylene glycol dimethyl ether solution in THF was prepared adding naphthalene in dry THF with sodium metal. The mixture was allowed to stir for 2 h, and then 2.41 mL of tetra-ethylene glycol dimethyl ether was added. The mixture was allowed to stir an additional hour at room temperature before use (Scheme not reported). Later in the year 2002, [PERSON] et al. described the synthesis of (\(-\))-CBD in 14-22% yield using \(Z\)-(+)-\(p\)-mentha-2, 8-dien-1-ol (**1**) or its acetate derivative **2** and olivetol in dichloromethane (DCM) and molybdenum catalysts (Scheme 17) [124]. According to the reported results, starting from \(Z\)-(+)-\(p\)-mentha-2, 8-dien-1-ol **(1)** and olivetol dissolved in DCM and using the molybdenum Mo (IV) triflate complex as catalyst at \(-20\)\({}^{\circ}\)C for 3 h (\(-\))-CBD was obtained in 20% yield. Similar results (22% yield) were obtained starting from \(Z\)-(+)-\(p\)-mentha-2, 8-dien-1-ol acetate (**2**), olivetol and the same cataly, and stirring the reaction mixture at \(-10\)\({}^{\circ}\)C for 30 min. On the contrary, with the bimetallic Mo (II) catalyst V, and stirring **2** and olivetol at 20 \({}^{\circ}\)C for 4 h (\(-\))-CBD was obtained in a lower yield (14%). [PERSON] et al.