The Synthesis and Characterization of 2-Arachidonoyl Glycerol

Cannabinoids are a structurally diverse class of compounds that act as ligands at the cannabinoid receptors, CB1 and CB2, through which the majority of the physiological effects of these compounds are mediated. Endocannabinoids (endogenous cannabinoids) are a subset of the cannabinoid family and include 2-arachidonoyl glycerol (2-AG) and N-arachidonoyl ethanolamide, and like most cannabinoids, these compounds have been shown to have anti-neoplastic effects on various cancer lines. The synthesis of 2-AG from dihydroxyacetone was selected as a research goal to try to improve yield over older published synthetic methods, to keep 2-AG in a protected form to avoid isomerization and other unwanted side reactions, and ultimately to experiment with further chemical modification of 2-AG and observe how this affects its anti-neoplastic activity. The methodology employed used the silyl ether protecting reagent t-BDPSiCl and yields up to the esterification step were excellent. Esterification with SOCl2 did not return yields on par with previous steps, but improvements in yield were seen by increasing reaction temperature. Analysis of deprotection was complicated by difficulties with the HPLC methodology, but the protecting group was found to be amenable to a single flask synthesis in DMF using SOCl2, which is a highly appealing quality to this methodology.