## 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
By treatment of **1** with trifluoromenthanesulfonic anhydride (Tf\({}_{2}\)O) in the presence of 2,6-lutidine at \(-\)30 to \(-\)20 \({}^{\circ}\)C in DCM using 1.5 equivalent of **1**, to prevent double triflation, afforded the triflate derivative **2**, which was isolated by silica gel column chromatography in a 78.1% yield. Compound **2** was treated with a solution of pivaloyl chloride (Piv-Cl) in DCM and a solution of DMAP in pyridine at \(-\)10 to 0 \({}^{\circ}\)C. Subsequently, the mix ture was stirred at 25 \({}^{\circ}\)C for 12 h, to obtain the O-protected derivative **3** in 95% yield after column chromatography as a yellow oil. Pentyl zinc chloride (C\({}_{5}\)H\({}_{11}\)ZnCl), was prepared in one step by the transmetalation of the correspondent Grignard C\({}_{5}\)H\({}_{11}\)MgBr. Particularly, anhydrous zinc chloride and anhydrous lithium chloride were dissolved in anhydrous THF and cooled to \(-\)10 \({}^{\circ}\)C, added with C\({}_{5}\)H\({}_{11}\)MgBr and stirred first at \(-\)10 \({}^{\circ}\)C for 15 min and then at room temperature for 1.5 h. The obtained mixture was added with a solution of **3** in THF and then with [1,1\({}^{\prime}\)-Bis(diphenylphosphino)(ferrocene)dichloropalladium(II) (Pd(dppf)Cl\({}_{2}\)), as cross-coupling agent, to provide **4** in 90% yield after stirring at 55-60 \({}^{\circ}\)C for proper time and after column chromatography. (\(-\))-CBD was finally obtained upon deprotection with MeMgBr (3 M in Et\({}_{2}\)O) in toluene at 110 \({}^{\circ}\)C for 12 h in 99% yield after silica gel column chromatography. [PERSON] et al. in the year 2021 reported an innovative and high yielding continuous approach for producing (\(-\))-CBD, strongly reducing its cyclization into THC (traces), thus achieving (\(-\))-CBD in 55% yield. Particularly, by means of flow chemistry, and following their studies concerning the use of this technology for synthesizing highly functionalized materials, the authors inserted acetyl isoperitenol and olivetol dissolved in DCM into a reservoir A, while BF\({}_{3}\):Et\({}_{2}\)O dissolved in DCM into a reservoir B. Subsequently, they pumped the two solutions simultaneously into a T-connector before passing through a 3 mL PTFE coil reactor (7 min residence time). The outgoing solution was dropped into a flask containing a stirring saturated solution of NaHCO\({}_{3}\) from which (\(-\))-CBD was extracted and purified by silica gel chromatography to provide pure (\(-\))-CBD in 55% yield (Scheme 22) [129]. The main by-products were Abn-CBD and the dialkylated cannabidiol recovered in 19 % and 4 % of yield respectively, THC was observed in traces (GC \(<\) 0.4 %) and its isolation was unfeasible. In the same year, [PERSON] et al. followed a practical approach to prepare (--)-CBD that avoided the formation of the side abnormal regio-isomers by using protected 4,6-dihalo-olivetol in coupling reaction as shown in Scheme 23 [76]. Briefly, the synthesis began by the Wittig reaction of butyl phosphonium bromide with commercially available 3,5-dimethoxybenzaldehyde (**1**), to deliver the olefin derivative **2** as mixture of \(Z\) and \(E\) isomers, which was conveniently reduced with hydrogen under pressure in presence of Pd/C as catalyst to the olivetol dimethyl ether (**3**). Regioselective electrophilic aromatic bromination of **3** using 2.3 equivalents of N-bromosuccinimide (NBS) in DCM at room temperature produced exclusively the 4,6-dibrominated product **4** in good yield. Then, the methyl ether-protecting groups were removed with boron tribromide to generate the key resorcinol intermediate **5** which was submitted to the Friedel-Craft alkylation with (1S,4R)-4-isopropyl-1-methyl-2-cyclohexen-1-ol (**6**) in DCM, in the presence of PTSA as catalyst, thus affording the adduct **7** as single diastereomer. Finally,reductive dehalogenation using sodium sulfite in the presence of triethylamine (Et\({}_{3}\)N) in a mixture of MeOH and H\({}_{2}\)O at 75 \({}^{\circ}\)C delivered the targeted cannabinoid (--)-CBD in 43% yield. [PERSON] et al.