Synthesis Of Silicon-containing Cannabinoid Analogues

Objective:To synthesize silicon-containing cannabinoids using the principle of b loisoterism replacement of carbon with silicon.Silicon-cannabinoids are supposed to show distinct physicochemical and pharmacokinetic properties,as well as different biological activity compared to their carbon analogs.Novel cannabinoid analogues will be obtained which will enrich the compound library of synthetic cannabinoid,thus facilitating the discovery of safe and efficacious cannabinoid drugs.Methods:The coupling of silicon-containing side chains to 1-bromo-3,5-dimethoxybenzene5 followed by demethylation to form a silicon-containing resorcinol intermediate.Treatment of these intermediates with(1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol or((1R,5S)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl pivalate in the presence of boron trifluoride diethyl ether produced corresponding silicon-containing THC analogs,and their derivatives were obtained by further reduction or oxidation,respectively.In addition,1,3-dimethoxybenzene silicon-containing compound were treated with cyclopentanone,cyclohexanone or cycloheptanone respectively,and the corresponding product were subjected to dehydroxylation and demethylation conditions with BBf3 to afford silicon-containing resorcinol compounds,or the removal of a single methyl group using sodium ethanethiol to give silicon-containing phenol compounds.Results:Twelve silicon-containing cannabinoid analogues and five silicon-containing resorcinol derivatives were finally obtained.Biological activity testing on CB1 and CB2 receptor assays showed that all the compounds are potent cannabinoid receptor agonists.Conclusions:Based on the principle of bioisosterism,it is feasible to synthesize silicon-containing cannabinoids as by introducing the silicon atom into the corresponding starting materials.Synthetic silicon-cannabinoids are chemically stable and have excellent activity at cannabinoid receptors.