## 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
Aldehyde **2** was converted in the emone **3** via an aldolic condensation with acetone in water using a 2.5M NaOH solution and heating the reaction mixture to 60 \({}^{\circ}\)C for 12 h (89% yield). The carbonylic group of **3** was reduced in toluene at \(-\)78 \({}^{\circ}\)C under argon, using a solution of (R)-CBS oxazaborolidine ligand (see Scheme 20) and BH\({}_{3}\bullet\)THF complex. The reaction mixture continued to stir for 30 min at \(-\)78 \({}^{\circ}\)C obtaining the crude product (\(-\))-**4** which was further purified by silica gel column chromatography achieving the pure compound (\(-\))-**4** in 94% yield (77% enantiomeric excess (e.e.)) as a clear colorless oil that solidified upon standing. An alternative to generate a product with high enantiopurity consisted of an enzymatic approach using an inexpensive and readily available enzyme. In this regard, compound **3** in the blue square was reduced with sodium borohydride (NaBH\({}_{4}\)) affording the racemic alcohol (\(\pm\))-**4**, which was acylated with vinyl butyrate in the presence of Savinase 12T thus providing the ester (\(-\))-**4.1** which was hydrolyzed with NaOH affording (\(-\))-**4** with \(>\)98% e.e. in 38% overall yield for the three steps (blue square in Scheme 20). Compound (\(-\))-**4** was converted in the carboxylate (\(-\))-**5** by its acylation with 5-methyl-5-hexencarboxylic acid in DCM in the presence of DCC and DMAP. After 1 h stirring at 0 \({}^{\circ}\)C and then overnight at room temperature, (\(-\))-**5** was achieved as crude material which was purified by column chromatography. Compound (\(-\))-**5** was treated with KHMDS in anhydrous toluene at \(-\)78 \({}^{\circ}\)C for 1 h, then a solution of anhydrous pyridine and tetramethylsilyl chloride (TMS-Cl) in anhydrous toluene was added and the mixture was stirred at \(-\)78 \({}^{\circ}\)C for 10 min and at room temperature for an additional 4 h. Upon the Ireland\(-\)Claisen rearrangement, compound (\(+\))-**6** was achieved as a white crystalline solid that could be recrystallized using hexanes in a 52% overall yield. Treatment of (\(+\))-**6** in ether at 0 \({}^{\circ}\)C with methyllithium (MeLi) and stirring overnight at room temperature led to the formation of ketone (\(+\))-**7** as colorless oil in 71.8% yield, after chromatography column. Compound (\(+\))-**7** could be cyclized and then converted into (\(-\))-CBD, via Wittig methylation and deprotection. Particularly, compound (\(+\))-**7** and Grubbs 2 nd generation catalyst in DCM were first stirred for a total of 15 h at 40 \({}^{\circ}\)C, thus achieving compound (\(-\))-**8** in 69.6% yield. Then, by reaction at room temperature of (\(-\))-**8** with bromo(methyl)triphenylphosphorane in THF, followed by the addition of potassium _tert_-butoxide and stirring at 75 \({}^{\circ}\)C for 12 h, compound (\(-\))-**9** was isolated in 82% yield. After its demethylated in anhydrous ether under argon with MeMgI and heating to 160 \({}^{\circ}\)C for 1.5 h, (\(-\))-CBD was obtained in 62% (35% on three steps) yield as a light-yellow oil. In the year 2020, [PERSON] et al. reported a novel synthetic procedure for making (\(-\))-CBD on a 10 g scale, by a late-stage diversification method, starting from commercially available phloroglucinol. First, the key intermediate (\(-\))-CBD-2 OPiv-OTf was achieved which underwent Negishi cross-coupling with the pentyl chain to give (\(-\))-CBD in 52% overall yield. By this approach using the symmetric phloroglucinol the generation of positional isomers (Abn-CBDs) was avoided (Scheme 21) [128]. Briefly, by a Friedel-Crafts alkylation of phloroglucinol with \(Z\)-(\(+\))-\(p\)-mentha-2,8-dien-1-ol in a ratio of 1:10 in presence of BF\({}_{3}\) etherate gave the desired product **1** in an excellent 80% yield.