Short Synthesis of Olivetolic Acid via Directed ortho-Metalation (DoM)

Cannabinoids, which are found only in Cannabis sativa, are unique secondary metabolites consisting of alkylresorcinol and monoterpene groups. More than 60 cannabinoids have been isolated from marijuana or fresh Cannabis flowers [1,2], and their pharmacological properties and biosynthetic mechanisms have been investigated extensively [3,4]. Olivetolic acid is the active form for the next biosynthetic reaction step of the cannabinoids. Olivetolic acid is the crucial intermediate in the synthesis of tetrahydrocannabinolic acid (THCA), which has valuable antiemetic properties that help to reduce the side effects of nausea and vomiting caused by cancer chemotherapeutic agents [5]. Directed ortho-metalation (DoM) is an adaptation of electrophilic aromatic substitution in which electrophiles attach themselves exclusively to the ortho position of a direct metalation group (DMG) through the intermediary of an aryllithium compound. By adopting the DoM methodology, we have successfully synthesized the Olivetolic acid in excellent yields and the full synthetic details will be presented.

Acknowledgements: The United States Department of Agriculture, Agricultural Research Service, Specific Cooperative Agreement No. 58–6408–2-0009; References: [1] Turner CE, et al. (1980)J Nat Prod 43: 169. [2] Mohamed MR, et al. (2009) J Nat Prod 72: 906. [3] Pertwee RG, et al. (2006)J Pharmacol 147: S163. [4] Taura F, et al. (2007) Chem Biodiv 4: 1649. [5] Whittle B, Javid FA, (2003) GB 2384707 A 20030806.