Synthesis of Cannabinoids: “In Water” and “On Water” Approaches: Influence of SDS Micelles

Abstract

We have proven that the biomimetic-like synthesis of cannabinoids from citral and the corresponding phenolic counterpart may well be carried out using water as a solvent. The influence of different additives such as surfactants was also analyzed. Rationalization of the reaction mode and regiochemistry of the processes were provided in terms of “on water” and “in water” reactions. The same reactions were conducted in organic media using Ga(III) salts as catalysts. Worthy of being underlined, an unprecedented formal [2+2+2] process was found to occur between two citral molecules and the corresponding phenolic species in both aqueous and organic environments. Computational studies were performed in order to gain a comprehensive mechanistic and energetic understanding of the different steps of this singular process. Finally, the influence of SDS micelles in the chemical behavior of olivetol and citral was also pursued using PGSE diffusion and NOESY NMR studies. These data permitted to tentatively propose the existence of a mixed micelle between olivetol and SDS assemblies.

Synthetic Strategies for Rare Cannabinoids Derived from Cannabis sativa

“…In addition, the use of EDDA also offers certain advantages in comparison to the systems piperidine/Ac 2 O or Et 3 N/AcOH, such as shortening the reaction time and simplifying the preparation of the in situ iminium salt (see the Supporting Information). The authors also tried an approach using water as solvent, which was more recently reported for an excellent yield up to 75% . However, the approach with water was not productive, as no expected product was observed (Table ; entries 7.5/6).…”

“…The authors also tried an approach using water as solvent, which was more recently reported for an excellent yield up to 75%. 40 However, the approach with water was not productive, as no expected product was observed (Table 6; entries 7.5/6).…”

“…Caprioglio et al 47 confirmed this result via a one-pot synthesis using a microwave approach. Based on the above reports, [38][39][40]47 the treatment of CBC-C 5 (7a) in the presence of several Lewis acids was re-examined by parameter screening (Table 7). The initial results showed that TFA is an appropriate catalyst for the intramolecular interaction for the chromene 7a, while all other catalysts (PTSA, FeCl 3 , BF 3 •OEt 2 , HBF 4 •OEt 2 ) yielded only poor amounts of product (Table 7; entries 8.1−6).…”

“…1 H and 13 C NMR data agree with those reported in the literature. 40 CBC-C 3 (7b). Prepared according to the general procedure using divarinol (1b) and citral (Table 6; entry 7.3-b).…”

Synthesis of Stilbenyl and Bibenzyl Cannabinoids and Analysis of Their Cannabimimetic Potential

“…Due to the structural similarity in the terpenyl structures, we revisited the intramolecular conversion of CBD-ST/CBD-BB (3a,b) into THC-ST/THC-BB (4a,b). Drawing from various recent studies, 14,25,27,28 we refined the reaction conditions by using trifluoroacetic acid (TFA) and extending the reaction time to 18 hours. In our trials, we found it challenging to separate the target compounds 4a and 4b from the initial substances 3a and 3b using normal-phase chromatography techniques.…”