Development of an improved psilocybin synthesis

Abstract: Psilocybin is a hallucinogenic compound found in fungi and is currently evaluated inclinical trials for treatment of depression, anxiety and addiction. Psilocybin is aprodrug of the pharmacologically active metabolite, psilocin. The synthetic route topsilocybin relies on synthesizing psilocin from the starting material, 4-hydroxyindoleand latter converting psilocin into psilocybin by phosphorylation. The synthesis ofpsilocybin has been challenging because of the labile nature of the phosphorylationdibenzyl ester reagent and related intermediates. Several attempts to optimizepsilocybin synthesis have been published but there is still a need for furtherimprovements.The first aim of this project was to synthesize psilocybin using literature methods,while the second aim was to optimize the phosphorylation step with differentreagents and conditions.Initial studies focused on coupling the two-side chain carbon onto position three ofthe indole, this required protection of the hydroxyl group which was achieved byacylation in room temperature. With sufficient amount of dimethylamine solution, theamine addition reaction was investigated and resulted in a pure product. Thefollowing reduction with lithium aluminum hydride provided an unknown side-productinstead of psilocin.The first aim was successfully accomplished, up to psilocin, with pure intermediatesbut low yields. The second aim was not achieved due to lack of time and access tothe laboratory during covid-19 crisis. However, a literature survey of reagents andconditions for phosphorylation was performed which enables continuation of theproject.