Design and Synthesis of (13S)‐Methyl‐Substituted Arachidonic Acid Analogues: Templates for Novel Endocannabinoids

Abstract

Two novel methyl-substituted arachidonic acid derivatives were prepared in an enantioselective manner from commercially available chiral building blocks, and were found to be excellent templates for the development of (13S)-methyl-substituted anandamide analogues. One of the compounds synthesized, namely, (13S,5Z,8Z,11Z,14Z)-13-methyl-eicosa-5,8,11,14-tetraenoic acid N-(2-hy-droxyethyl)amide, is an endocannabinoid analogue with remarkably high affinity for the CB1 cannabinoid receptor.

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.…”

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

“…39 Briefly, silylation of commercially available methyl ester 7 gave the TBDPS ether 8 (95% yield), which upon reduction with diisobutylaluminum hydride led to aldehyde 3 (60% yield) and alcohol 9 (38% yield). Oxidation of 9 with Dess–Martin periodinane produced 3 in 88% yield.…”

“…In this regard, we recently described the synthesis and preliminary biological evaluation of (13 S )-methyl anandamide ( Ie ). 39 With the aim of exploring all three bis-allylic positions and establishing structure–activity relationships (SAR) for the hitherto unknown, methyl-substituted arachidonoyl chain, we report here our efforts toward the total synthesis of the (10 S )- and (10 R )-methyl-anandamides. Our synthetic approach is stereospecific, efficient, and provides the analogs without the need for resolution.…”

Novel tail and head group prostamide probes

“…30,33 Our testing results (Table 1) revealed that all analogs reported here have no significant inhibitory activity exhibiting IC 50 s greater than 100 µM for all three endocannabinoid deactivating enzymes. The testing results for FAAH are consistent with those reported earlier for the endogenous prototype PGE 2 -EA.…”

“…This compound underwent a Wittig olefination reaction to yield acid 9a as a single geometrical isomer under the experimental conditions used (68% yield). 14,29 Intermediate 9a was coupled with the 2-( tert -butyldimethylsilyloxy)ethanamine 30 to give compound 10a (58% yield) which was subsequently oxidized to ketone 11a in excellent yield (89%) using Swern conditions. 31 The synthesis was completed by global desilylation of ketone 11a with hydrofluoric acid/pyridine to give the final product 12a (AM6905) in 49% yield.…”