A urinary metabolite of Δ1-tetrahydrocannabinol. The first synthesis of 4″,5″-bisnor-Δ1-tetrahydrocannabinol-7,3″-dioic acid, and a deuterium labelled analogue

Abstract The first synthesis of unlabelled and [ 2 H 5 ]-labelled 4″,5″-bisnor- Δ 1 -THC-7,3″-dioic acid, the major dicarboxylated urinary metabolite of Δ 1 -THC in man, is presented (preliminary results of this work have been presented in part at the Melbourne Symposium on Cannabis, Australia, September 1987, Ref. 1). The synthesis of methyl 3-(3,5-dihydroxyphenyl)-[3,3- 2 H 2 ]-propanoate (8) is described in a nine step sequence from 3,5-dimethoxybenzoic acid in an overall yield of 24%. Compound 8 is condensed with a terpene synthon 9 under acidic conditions, acetylated and hydrolyzed with red HgO and HgCl 2 to afford the 1-formyl-4″,5″,7-trisnor- Δ 1 -THC-3″-oic acid derivative (11). Compound 11 is oxidized using NaClO 2 in 2-methyl-2-butene and hydrolyzed to give (±)-4″,5″-bisnor- Δ 1 -THC-7,3″-dioic acid (12). The same approach has been used to prepare both the labelled and unlabelled metabolite.