## 4 Production of Phytocannabinoids: From Biosynthesis to Synthetic Procedures
### Synthetic Procedures to Prepare Non-Psychotropic Cannabinoids CBC, CBG and (\(-\))-CBD
#### 4.2.1 Syntheses of CBC  
The most recent synthetic procedures for preparing CBC were reported in the year 2021. Particularly, [PERSON] et al. [93], who reproduced synthetic procedures previously reported [94; 95; 96; 97], synthesized CBC starting from _E_-geraniol according to Scheme 3. Briefly, _E_-geraniol dissolved in dry hexane was treated with manganese dioxide (MnO\({}_{2}\)) under magnetic stirring at room temperature for about 12 h and then heated at 40 \({}^{\circ}\)C for further 3 h, to provide citral as crude product, which was purified by silica gel chromatographic column obtaining the purified aldehydes (with a yield of 75%) as an _E_/Z mixture (_E_/Z 95/5, GC-MS) of geranial (_E_-citral, 71%) and areal (_Z_-citral, 4%). Subsequently, the prepared mixture was treated with Ac\({}_{2}\)O in EtOAc in the presence of piperidine and heated at 90 \({}^{\circ}\)C for 1 h, to give an iminium salt, which was added with a solution of Olivetol in toluene and stirred at 130 \({}^{\circ}\)C for 40 h. Upon an oxa-annulation consisting of a Knoevenagel reaction providing the 1-oxatriene intermediate, followed by an oxa-electrocyclization, the crude CBC was obtained, which was then purified by chromatographic column. Pure CBC (yield 65%) and cannabicyclol (CBL, yield 10%) were finally isolated. Interestingly, [PERSON] et al. [94], and [PERSON] et al. [96], who previously employed this procedure starting from a mixture of _E_/Z-citral, and from only geranial (_E_-citral) respectively, achieved CBC with a yield lower than Seccamani (50% vs. 65%). Similar procedures starting from _E_/Z-citral and Olivetol were proposed in the same year (2021), by [PERSON], et al. [98] and by [PERSON] et al. [99], achieving CBC with yields of 50% and 35%, respectively. Particularly, the group of [PERSON] evidenced that acidic or basic conditions were determinant to redirect the reaction towards the formation of CBC rather than towards that of \(\Delta^{9}\)-THC (Scheme 4). Differently and more specifically, [PERSON] et al. reacted Olivetol and _E/Z_-citral in toluene using ethylenediamine diacetate as catalyst and heating the solution at reflux for 6 h (Scheme 5), as it was reported previously by [PERSON] et al. [100], who prepared CBC with similar yield (40% vs. 35%). The use of ethylenediamine diacetate as catalyst had been reported in the past by [PERSON] et al. in the year 1982 [101], who achieved CBC in similar yield (37%) according to a different path (Scheme 6). Briefly, geranial (**1**) was reacted with 5-pentyl-1,3-cyclohexandion (**2**) in methanol (CH\({}_{3}\)OH) with catalytic amounts of ethylenediamine diacetate at 20 \({}^{\circ}\)C, achieving the intermediate **3**, which cyclized to the crude compound **4**. A chromatographic column was necessary to purify **4**, which was isolated in 62% yield. Compound **4** was treated with lithium di-isopropyl-amide (LDA) in tetrahydrofuran (THF) at \(-\)78 \({}^{\circ}\)C and phenyl-selenyl chloride (C\({}_{6}\)H\({}_{5}\)SeCl), to afford the selenide intermediate **5**, which upon oxidation with 3-choloroperoxybenzoic acid in dichloromethane (DCM) followed by reaction with dimethoxy aniline, provided CBC in 37% yield. An analogous procedure, using \(t\)-butylamine in place of ethylenediamine diacetate, and at reflux time of 9 h in place of 6, had been reported in the years 1978 and 1982 by [PERSON] et al. [89; 102]. CBC was achieved in high yield (>60%), upon purification carried out reducing the unreacted citral with NaBH\({}_{4}\). In the 2008, the same reaction was exploited in their study by [PERSON] et al. [83]. Interestingly, CBC was prepared in very high yield (75%) by [PERSON] et al. [103], by a biomimetic green approach using water as solvent and ammonium chloride as catalyst, according to Scheme 7.