Phytocannabinoids: Novel chemistry of Biological relevance

Phytocannabinoids are the hallmark secondary metabolites of C. sativa, a plant cogently described by Mechoulam as a “neglected pharmacological treasure trove” of bioactive compounds. Even though phytocannabinoids have been extensively investigated throughout the past decades, many aspects of their chemistry and biological profile still need clarification, and the aim of this thesis was to fill these gaps and find new avenues of exploitation for their biological potential. Seen in retrospect, a considerable section of the thesis is based on the reactivity o phytocannabinoids towards iodine, which – in different oxidation states – proved to be a remarkably enabling and versatile manoeuvre of chemical modification. The investigation of the possible generation of narcotic 9-tetrahydrocannabinols (THCs) during the pyrolysis of the non-narcotic cannabinoid cannabichromene (CBC) led to the discovery of a deconstructive annulation driven by molecular iodine that eventually led to the development of a simple one-step synthesis of cannabinol (CBN) from two simple precursors (olivetol and citral). Iodine, in the hypervalent form of SIBX, also played a central role in the oxidation of resorcinyl cannabinoids to their corresponding cannabinoquinones, a reaction of considerable relevance in medicinal chemistry owing to the ongoing clinical development of a compound of this class (VCE-004.8). The chemistry of two overlooked classes of cannabinoids, the cannabichromenoids and dimethylheptylcannabinoids was also investigated, providing the basis for the clarification of their biological potential.