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Scheme 17. Synthesis of tail-modified analog 73 (95). Reagents and conditions: (a) I2, PPh3, imidazole, Et2O/CH3CN, 0 to 23°C, 1 h, 98%; (b) PPh3, CH3CN, reflux, 18 h, 90%; (c) NaHMDS, THF/HMPA, 80, -78 to 23°C, 2 h, 61%; (d) LiOH, MeOH/H2O, 23°C, 18 h, 94%; (e) oxalyl chloride, CH2Cl2, 0°C, 2 h, 100%; (f) 2-ethanolamine, CH2Cl2, 0 to 23°C.

Methyl 14-triphenylphosphoniotetradeca-(all-d,s)-5,8,11-trienoate iodide (79). To a stirred solution of triphenylphosphine (456 mg, 1.74 mmol) and imidazole (118 mg, 1.74 mmol) in Et2O:CH3CN 5:1.7, cooled to 0°C, I2 was added (441 mg, 1.74 mmol) in several portions. The resulting slurry was warmed to 25°C and stirred for 20 min. It was again cooled to 0°C, and the alcohol 78 was added slowly. The mixture was warmed to 25°C after the addition and stirred for 1 h. It was diluted with pentane:ether 80:40 and filtered through a pad of silica gel to yield the iodide as a colorless oil (562 mg, 98%). A solution of triphenylphosphine (2.25 g, 8.6 mmol) and the above iodide (2.83 g, 7.82 mmol) in acetonitrile (50 mL) was refluxed overnight. The solvent was removed under reduced pressure, and the oily residue was purified by washing and decanting with 80 mL of hexanes:benzene 50:50. The solvent was removed and the oily residue was heated in a vacuum oven overnight at 60°C to yield 79 as a yellow gum (90%), which was used in the subsequent step without further purification.

16,16-Dimethyldocosa-5,8,11,14-(all-aX)-tetraenoic acid methyl ester (81). To a stirred solution of the phosphonium salt 79 (686 mg, 1.1 mmol) in THF:hexam-ethylphosphoramide (HMPA) 6:1 cooled to -10°C was added dropwise a 1 M solution of NaHMDS in THF (1.1 mL). The mixture was stirred at 0°C for 30 min and cooled to -78°C. The aldehyde 80 (171 mg, 1.1 mmol) (88) was added dropwise in THF (1.5 mL) to the reaction mixture. The cooling bath was removed and left to warm to 25°C over 2 h. It was quenched with hexanes, and the mixture was filtered through a pad of silica gel (ethyl acetate:hexanes 20:80). The filtrate was dried over MgSO4, and the solvent was removed under reduced pressure. The oily residue was purified by flash chromatography (EtOAc:hexanes 3:97) to yield the tetraene 81 as a colorless oil (0.25 g, 61%).


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Cannabinoid Receptor Binding to Membrane Homogenates and Cannabinoid-Stimulated [35S]GTPyS Binding to Membrane Homogenates or Intact Cultured Cells

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