Cannabichromene\n(CBC) Shows Matrix-Dependent Thermal\nConfigurational Stability

The optical purity of cannabichromene (CBC, <b>1a</b>) is\naffected by the matrix in which it is generated by thermolysis from\nits native carboxylated form (cannabichromenic acid, CBCA, <b>1b</b>). Thus, thermolysis at 130 °C <i>in planta</i> caused\na marked decrease of the enantiomeric excess (ee), while, under the\nsame conditions, only a modest decrease of optical purity was observed\nwhen thermolysis was carried out <i>in extracto</i>. To\nrationalize these puzzling observations, the kinetics of thermal (100\n°C) racemization of enantiopure cannabichromene (<b>1a</b>) was evaluated by enantioselective ultrahigh performance liquid\nchromatography in solvents (decalin and isopropyl alcohol, neat and\nacidified with TFA) and surfaces (native and silanized borosilicate\nglass) of complementary polarity. Optical stability was more than\nhalved in isopropanol compared to decalin (<i>t</i><sub>1/2</sub> 50 h vs 135 h), but acidification had no effect on racemization.\nHowever, contact with a solid surface dramatically accelerated the\nprocess, with a <i>t</i><sub>1/2</sub> of only 6 h on both\nglass surfaces. The overall extent of racemization of enantiopure\nCBC (<b>1a</b>) was compared under conditions commonly used\nfor decarboxylation (heating at 130 °C) between a decalin solution\nand a thin film on three different surfaces (native and silanized\nborosilicate glass and powdered blank cannabis biomass). In line with\nthe kinetic data, a significant erosion of enantiopurity was observed\non all solid surfaces compared to the solution. These observations\nsuggest that discrepancies in the reported enantiomeric purity of\nnatural CBC could be not only of biogenetic derivation but also be\nassociated with the decarboxylation protocol of cannabichromenic acid\n(<b>1b</b>). These findings, while relevant for the exploitation\nof the bioactivity of natural CBC for human health, should also prompt\nthe adoption of a standardized decarboxylation protocol for the studies\non the configurational status of CBC (<b>1a</b>) in cannabis\nand, in general, of cannabinochromanoids in nature.