Enantioselective synthesis of (10S)- and (10R)-methyl-anandamides

Abstract

For the development of novel endocannabinoid templates with potential resistance to hydrolytic and oxidative metabolism, we are targeting the bis-allylic carbons of the arachidonoyl skeleton. Toward this end, we recently disclosed the synthesis and preliminary biological data for the (13S)-methyl-anandamide. We report now the total synthesis of the (10S)- and (10R)-methyl-counterparts. Our synthetic approach is stereospecific, efficient, and provides the analogs without the need for resolution. Peptide coupling, P-2 nickel partial hydrogenation, and cis-selective Wittig olefination are the key steps.

Design and synthesis of novel prostaglandin E2 ethanolamide and glycerol ester probes for the putative prostamide receptor(s)

“…As we reported earlier for the synthesis of novel anandamide analogs, the carbonyldiimidazole (CDI) activation procedure worked well and provided these compounds in excellent yields (88–92%). 29,30 The Dess–Martin periodinane/pyridine system oxidizes the 9-hydroxy back to the ketone 16 (97–98% yields). The desilylation step leading to azides 17 proved to be challenging because of the enhanced stability of the TIPS group at the 11-hydroxy position.…”

Development of Robust 17(R),18(S)-Epoxyeicosatetraenoic Acid (17,18-EEQ) Analogs as Potential Clinical Antiarrhythmic Agents

“…n -Butyllithium (2.5 M in hexanes, 3.89 mL, 9.72 mmol, 1.2 equiv) was added dropwise to a −78 °C solution of tert -butyl­(hex-5-yn-1-yloxy)­diphenylsilane ( 23 , 2.70 g, 8.10 mmol, 1 equiv) in THF (20 mL) and anhydrous hexamethylphosphoramide (HMPA, 10 mL). The reaction (blood red color) was stirred at −78 °C for 30 min and at 0 °C for 2 h. The reaction was recooled to −78 °C, and 2-(9-bromononyloxy)­tetrahydro-2 H -pyran (2.50 g, 8.10 mmol, 1 equiv) in THF (16.2 mL) was added slowly to the reaction via cannula.…”

“…Syntheses of analogues 11, 19, and 20 are summarized in Scheme 1. Alkylation of silyl protected 5-hexyn-1-ol 40 23 with 2-(9-bromononaloxy)tetrahydro-2H-pyran 41 in THF/HMPA gave 24 in good yield. Removal of the silyl protecting group, followed by semihydrogenation of the alkyne over catalytic P2nickel, and substitution of the hydroxyl group for an azide under Mitsunobu conditions provided 25.…”

“…Ethyl diazoacetate (1.60 g, 14 mmol) was added slowly under an argon atmosphere over 5 min (caution: exothermic) to give a yellow solution. After 2 days, the reaction mixture was concentrated in vacuo and the residue was purified using a Teledyne Isco Combiflash R f (40). To an oven-dried flask containing ethyl 2-(oct-7-en-1yloxy)acetate (38, 82 mg, 0.409 mmol) was added a solution of 9-BBN (0.5 M in THF, 0.614 mmol, 1.50 equiv, 1.23 mL).…”

Novel C-Ring-Hydroxy-Substituted Controlled Deactivation Cannabinergic Analogues

“…The metabolite acid 4b was prepared by alkaline hydrolysis of the ester 3b using lithium hydroxide in dioxane/water (85% yield). 27 …”