An efficient synthesis of the metabolite 11-hydroxy-Δ8-tetrahydrocannabinol (2) has been developed, based on the one-carbon homologation of 11-nor-9-ketohexahydrocannabinol (69). The ketone 69 was converted to the intermediate epoxysulphone 77 and cleaved under acid-catalysed conditions using magnesium bromide in ether to give 9β-bromo-11-oxo-hexahydrocannabinol (78b). The metabolite 11-oxo-Δ9-tetrahydrocannabinol (20) was formed as a minor byproduct of this reaction and was reduced to the metabolite 11-hydroxy-Δ9-tetrahydrocannabinol (1).
Attempts to prepare 1 by the intramolecular displacement of bromide by the phenoxide anion in 78b achieved only limited success; under standard dehydrobromination conditions, however, the metabolite 2 was furnished in 64% overall yield.
An alternative route to the metabolite 1, based on the reaction of 69 with the lithium anion of 1,3-dithiane, met with no success; unidentified products were isolated.