## 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, developed a three-step concise and stereoselective synthesis route to (--)-CBD and (+)-CBD, using inexpensive and readily available starting material, such as R-(+)-limonene and S-(--)-limonene respectively. The synthesis involved the diastereoselective bi-functionalization of limonene, followed by effective elimination leading to the generation of the key chiral (+)- or (--)-\(p\)-mentha-2,8-dien-1-ols. Such dienols on coupling with olivetol under silver bis (trifluoromethylomenthanesulfonyl) imide (AgN(SO\({}_{2}\)CF\({}_{3}\))\({}_{2}\)) as catalysis provided regiospecific (--)-CBD or (+)-CBD in good yield (Scheme 24) [130]. Briefly, the present approach started with the direct generation of diastereoselective bi-functionalized 2-phenylseleninyl-\(p\)-menth-8-en-1-ol (**1**) from readily available and inexpensive starting material R-(+)-limonene. Particularly, electrophilic phenyl selenium bromide and H\({}_{2}\)O\({}_{2}\) in a mixture acetonitrile/water at \(-30\)\({}^{\circ}\)C were used, thus achieving compound **1** in 53% yield. The removal of SePh to synthesize (+)-mentha-dienedi **2** was carried out using Selectfluor in THF at room temperature for 10 h achieving optically pure (+)-\(p\)-mentha-2,8-dien-1-ol 2 in 86% yield. Compound **2** was then coupled with olivetol in DCM using AgN(SO\({}_{2}\)CF\({}_{3}\))\({}_{2}\) at room temperature for 10 h achieving (--)-CBD in 46% yield. Similarly, starting from S-(--)-limonene, (+)-CBD was synthesized. Briefly, the synthesis began from commercially available S-(--)-limonene, which was subjected to stereoselective bifunctionalization and elimination cascade to afford (--)-\(p\)-mentha-2,8-dien-1-ol. Pleasingly, (--)-\(p\)-mentha-2,8-dien-1-ol on reaction with olivetol in the presence of AgN(SO\({}_{2}\)CF\({}_{3}\))\({}_{2}\) afforded the single isomer of (+)-CBD. The last synthetic procedure we report here to obtain (--)-CBD was very recently described by [PERSON] et al. (Scheme 25) [131]. Briefly, neral (\(Z\)-citral) was cyclized to isopiperitrol using imino-imidolph phosphates (iIDP), featuring a bifunctional inner-core system with an acidic P=NHTf moiety and a basic P=O moiety, thus combining excellent reactivity and selectivity, and furnishing (1R,6S)-\(E\)-isopiperitenol (**1**) in good yield (77%) and excellent diastereo- and enantioselectivity. Interestingly, such cyclization can be performed easily on a multigram scale (>4 g) without any loss of selectivity or yield, and catalyst can be recovered in excellent yield (95%) and re-used in further cyclization reactions. Then, direct access to (--)-CBD from isopiperitenol (**1**) and olivetol was provided in 35% yield under mild conditions using PTSA as catalyst in DCM at room temperature for 5 days. It is noteworthy that no further reaction of (--)-CBD to the corresponding THC was observed. Following an overview scheme (Scheme 26) showing the synthetic procedures selected by us as the most convenient in terms of yields to obtain CBC (purple route) [103], CBD (pink route) [108] and CBG (amaranth route) [113]. Note that, while the synthetic paths leading to CBC and CBD are both one step processes shearing Olivetol as reagent, that leading to CBG is a complicate multi-step process, using reagents completely different from those leading to CBC and CBD. **Scheme 26. ** Overview scheme showing the synthetic procedures selected by us as the most convenient in terms of yields to obtain CBC (purple route), CBD (pink route) and CBG (amaranth route). In the route to CBG, each arrow represents a reaction step.