A Novel Synthetic Route Towards Acyloxymethyl Prodrugs of Psilocin and Related Tryptamines

Acyloxymethyl (ACOM) ethers of hydroxytryptamines such as psilocin are potential prodrugs for the psychedelic treatment of mental disorders. Previous synthetic approaches suffer from insufficient selectivity and very low yields. We report a novel synthetic route towards ACOM derivatives of tryptamines, including the chemoselective installation of a carbamate protecting group at the indole nitrogen by means of a Heller-Sarpong reagent and final deprotection under extremely mild conditions. This enables delicate transformations such as the O acyloxymethylation of hydroxytryptamines or the N2-acyloxymethylation of sumatriptan. Several O-ACOM ethers of hydroxytryptamines have thus been obtained and their membrane permeability and stability in various media including human saliva and plasma were studied. The pharmacokinetic profile of the ACOM ethers is governed by the steric bulk of the acyl moiety. Short half-lives in human saliva will likely preclude the sublingual or buccal application of ACOM ethers of hydroxytryptamines, while other routes of administration may be pursued.