## 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 2001 reported the BF\({}_{3}\)-promoted 1,4-addition of bulky aryl groups, including dimethoxy olivetol, to an \(\alpha\)-iodo enone (**2**), prepared from the parent enone (**1**), thus affording a \(\beta\)-aryl-\(\alpha\)-iodo ketone derivative (**3**). Its subsequent reaction with EtMgBr furnished the magnesium enolate (**4**), which upon reactions with CIP(O)(OEt)\({}_{2}\) gave an enol phosphate (**5**), which was applied successfully to the synthesis of (\(-\))-CBD (Scheme 18) [125]. Particularly, the enone **1** was converted to the \(\alpha\)-iodocyclohexrenone (**2**) with I\({}_{2}\) and pyridine in CCl\({}_{4}\) with good yield. The 1,4-addition of Ar\({}_{2}\)Cu(CN)Li\({}_{2}\) to **2** promoted by BF\({}_{3}\)-OEt\({}_{2}\) furnished ketone **3** in 67% yield, after aqueous workup and purification by chromatography. Then, EtMgBr was successful used to generate the corresponding enolate **4**, which provided the enol phosphate **5** by reaction with (EtO)\({}_{2}\)P(O)Cl in 70% yield (Scheme 18). Methylation of **5** with MeMgBr in the presence of nickel (II) acetylacetonate (Ni(acac)\({}_{2}\)) afforded **6**, and its subsequent exposure to sodium ethyl thiolate (EtSn) in DMF resulted in the deprotection of the triethylsilil (TES) group and of one of the MeO groups to furnish **7**. Attempted one-step deprotection of the two MeO groups under more vigorous conditions was unsuccessful, therefore **7** was converted in (\(-\))-CBD by further exposure to EtSNa in DMF. Later in 2006, the same group reported a new reagent system for synthesizing (\(-\))-CBD and its analogues via alkenylation of cyclohexenyl diol monoacetate according to Scheme 19 [126]. Briefly, by a nickel-catalyzed allylation of 2-cyclohexene-1,4-diol monoacetate (**1**) with a new reagent consisting of (alkenyl)ZnCl/TMEDA, the SN2-type product, namely _E_-(+)_p_-mentha-2,8-dien-1-0 (**2**) was achieved with 94% reigoselectivity in good yield. Oxidation of **2** afforded the intermediate enone, which underwent isolation at the \(\alpha\) position by \(\mathrm{I}_{2}\) in the presence of 2,5-di-_tert_-butylhydroquinone (DBHQ) as a radical scavenger to produce the \(\alpha\)-iodo enone (**3**) in 63% yield (two steps). Addition of the 2,6-dimethoxy-4-pentylphenyl group of alveot (abbreviated as Ar in the first part of the Scheme) to **3** was performed with the higher-order cyanocurget derivative (Ar\({}_{2}\)Cu(CN)Li\({}_{2}\)) in turn synthesized from the Aryl (Ar) lithium anion and CuCN (not reported), obtaining compound **4**, as a 1:1 stereoisomeric mixture at the \(\alpha\) position. Compound **4** underwent reaction with EtMgBr to produce the reactive magnesium enolate **5**, which was quenched with ClP(O)(OEt)\({}_{2}\) to furnish enol phosphate **6** in 51% yield from **3**. Nickel-catalyzed coupling of **6** with MeMgCl afforded dimethyl ether **7** in good yield. Finally, (\(-\))-CBD was obtained upon demethylation of **7** using MeMgI. [PERSON] et al. in the year 2018 reported a practical synthetic approach to synthetize \(\Delta^{9}\)-THC, and (\(-\))-CBD. Particularly, (\(-\))-CBD was synthesized according to Scheme 20 [127]. Briefly, Olivetol and K\({}_{2}\)CO\({}_{3}\) in acetone were added with dimethyl sulphate (Me\({}_{2}\)SO\({}_{4}\)) in 5 min at room temperature and then the mixture was heated to 80 \({}^{\circ}\)C for 12 h under argon, achieving the crude Olivetol dimethyl ether (**1**) as an oil which was purified by column chromatography (98% yield). A yellow solution of **1** and TMEDA in anhydrous THF at \(-\)78 \({}^{\circ}\)C under argon was added with _sec_-butyllithium (_sec_-BuLi) and was stirred for 30 min at \(-\)78 \({}^{\circ}\)C and for 60 min at 0 \({}^{\circ}\)C, before being added with anhydrous DMF. The mixture was stirred at 0 \({}^{\circ}\)C for 30 min and for additional 60 min at room temperature. Upon proper work up and silica gel column chromatography the pure aldehyde derivative **2** was obtained as a yellow oil in 85% yield.