A concise methodology for the synthesis of (-)-Delta(9)-tetrahydrocannabinol and (-)-Delta(9)-tetrahydrocannabivarin metabolites and their regiospecifically deuterated analogs

作者：Nikas Spyros P^*; Thakur Ganesh A; Parrish Damon; Alapafuja Shakiru O; Huestis Marilyn A; Makriyannis Alexandros

来源：Tetrahedron, 2007, 63(34): 8112-8123.

DOI：10.1016/j.tet.2007.06.006

• (-)-Delta(9)-tetrahydrocannabinol
• (-)-Delta(9)-tetrahydrocannabivarin

The availability of tetrahydrocannabinols (Delta(9)-THC), tetrahydrocannabivarins (Delta(9)-THCV), and their metabolites in both their undeuterated and deuterated forms is critical for the analysis of biological and toxicological samples. We report here a concise methodology for the syntheses of (-)-Delta(9)-THC and (-)-Delta(9)-THCV metabolites in significantly improved overall yields using commercially available starting materials. Our approach allowed us to obtain the key intermediates (6aR,10aR)-9-nor-9-oxo-hexahydrocannabinols in four steps from (+)-(1R)-nopinone. This was followed by an optimized Shapiro reaction to give the (-)-11-nor-9-carboxy-metabolites, which were converted to their respective (-)-11-hydroxy analogs. The synthetic sequence involves a minimum number of steps, avoids undesirable oxidative conditions, and incorporates the costly deuterated resorcinols near the end of the synthetic sequence. This methodology enabled us to synthesize eight regiospecifically deuterated (-)-Delta(9)-THC and (-)-Delta(9)-THCV metabolites in a preparative scale and high optical purity without deuterium scrambling or loss.

• 出版日期2007-8-20
• 单位东北大学