Minor Cannabinoids of Cannabis sativa L.

Fabian Thomas & Oliver Kayser

Journal of Medical Science, 2019, 88, (3), 141-149.

Doi : 10.20883/jms.367

 

ABSTRACT

Cannabinoids from Cannabis sativa L. play an important role as natural products in clinics. The major cannabinoids compromise tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA) and its decarboxylated analogs. In this review, we focus on often neglected minor cannabinoids and discuss biosynthetic and chemical degradation routes to other neglected cannabinoids in Cannabis sativa starting from THCA, CBDA and cannabichromenic acid (CBCA). Based on the literature, patents and scientific reports, essential routes for the chemical modifi cation of cannabinoids are discussed to explain chemical diversity chemical conversion and degradation by UV light, as well as temperature and pH leading to the formation of structurally unusual cannabinoids in planta called as minor cannabinoids. Based on known bioorganic reaction schemes and organic chemistry, principles for minor cannabinoid formation like [2+2] cycloaddition, Markonov condensation, radical introduction, or aromatization are discussed. Finally, the non-aqueous environment in Cannabis sativa trichomes is analyzed to clarify their role of a miniaturized bioreactors the light-induced conversion in a non-aqueous enviroment. The overall objective is to bridge from metabolic profiling via cannabinomics to structural and chemical diversity that allows the defi nition of patterns with consequences also to pharmacology and plant breeding.

Keywords : Cannabis sativa, Cannabinoids, Tetrahydrocannabinol, Cannabidiol, Cannabichromene, Cannabielsoin, Cannabitriol, Cannabinomics.

Biosynthesis of cannabinoids

Cannabinoids seem to be a unique class of natural products limited to Cannabis sativa L. only. In recent time, prenylated olivetolic acid derivates and other structurally related prenylated phenolics have also been identifi ed in various genera and species like Helichrysum umbraculigerum Less. [1] or the liverwort Radula marginata TAYLOR [2, 3]. So far, the biosynthesis of cannabinoids towards to the biogenetically hybrid derived from the mevalonate and polyketide pathway as we understand today has only been detected in Cannabis sativa L., Cannabis indica, and Cannabis ruderalis, but recently as well in the New Zealand liverwort Radula marginata TAYLOR and R. perittittonii [3]. Without going into the details of molecular biology, genetics and spatial resolution of biosynthesis (Figure 1) [4], all committed biosynthetic enzymes involved in the formation of THCA-C5, CBDA-C5 and CBCA-C5 (Figure 1), cannabidiolic acid (Figure 1) and cannabichromenic acid (Figure 1) have a common precursor in cannbigerolic acid (CBGA-C5). and all conversion products have identical masses and differ only structurally.

Major structural differences refer to the alkyl chain length of the classic THCA-C5 and the short one in cannabivarin known as THCA-C3 (Figure 2A). Interestingly, no other biosynthetically relevant gene or enzyme has been found yet that may extend on the biosynthetic pathway from above-mentioned cannabinoids on. In contrast to more than 150 found so-called minor cannabinoids [5] this observation is provoking the question if these cannabinoids, detected at very low concentrations in planta, are simply degradation products of chemical conversions induced by light, temperature or abiotic ecological factors.

Chemistry of cannabinoids

Structural diversity of cannabinoids is ruled by complex chemistry [6]. In principle, it can be distinguished between the polar carboxylated cannabinoids and the neutral lipophilic decarboxylated cannabinoids. Going deeper into structural aspects, all cannabinoids show a resorcinoyl core and mostly a side chain of three or fi ve carbons.

Flanking alkyl regions in the bicyclic region (menthyl- core) and the aliphatic chain are sensitive to oxidation [7]. Even the single double bond in position Δ9 shows poor oxidative stability during storage of dried plant material. A closer look to the isoprenyl residue (C10) that has been formerly been the C-C attached GPP moety (Figure 1), can be found in four topological arrangements [5]:

1. The simple connection via a Friedel-Crafts C-C alkylation as an electrophilic aromatic substitution towards CBG or in a second step reaction induced by UV light starting from CBCA-C5 to cannabicyclol type cannabinoids like CBL-C5 (Figure 2B). This closure of an additional carbon bond is by some authors considered to be an additional fourth topological arrangement [5].

2. Closure of the attached GPP-unit with the resorcinoyl hydroxyl group to chromenes as CBCA-C5.

3. Internal C-C reaction to a cyclohexane ring like in CBD followed by a nucleophilic reaction with one of the resorcinoyl hydroxyl groups resulting in hydrocannabinolics like THCA-C5 or canabielsoin-type cannabinoids (reaction with C5-OH) like cannabielsoin E (CBE) (reaction with C1-OH).

4. Aromatization of the cyclohexane ring from CBDA-C5 or THCA-C5 after oxidation in the positions C1, C2, C3, and C5 or C9, C10, C10a, C7, C8, respectively. Aromatization gives CBN and CBDN-type cannabinoids.

Decarboxylation of cannabinoids is a spontaneous non-enzymatical process that is highly temperature dependent. Smoking will accelerate decarboxylation at high temperatures, but during storage decarboxylation with at an estimated rate of 5–10% a year is known in dried plant material at room temperature (20–25°C) as well [8].

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