Novel Synthesis of Lipoxine A4 Analogues. Towards Allostric Modulators for Human Cannabinoid Receptor Type 1

Abstract

The synthesis of the benzoid-based lipoxine A4 (LXA4) is the focus of this study specifically, the para substituted benzoid system. LXA4 is an endogenous agonist binding with high affinity to (ALXR) receptor that initiate it to display anti-inflammatory and antioxidant activities. Arachidonic acid is the cascade of LXA4 and its derivatives. These compounds belong to the biological active eicosanoids, which are characterized by its consistent of 20 C-atoms. Based on structure activity relationship (SAR) of LXA4, several studies postulated wide range of modification and functionalization. Benzoid based LXA4 analogues have studied by several research groups where the focus was on the O- and M-substituted benzoids. Herein, a total synthesis approach towards some structural mimics of LXA4 was conducted. Where, the target was the benzoid based LXA4. Specifically, the p-substituted benzoid suggesting that these analogues could cover the same conformational space as the native LXA4.

The project approach is based on using commercially available starting materials such as 2-deoxy-D-ribose, toluene and p-cresol to assemble the desired molecules. Important reactions in the course of the synthesis includes: C1-C8 building block: Wittig reaction, Parikh-Doering oxidation, hydrogenation of the alkene, protecting group operations. C15-C21 building block: Friedel-Craft acylation, O-alkylation, reduction by sodium borohydride. Key reaction of the synthesis is the Wittig reaction between the two coupling partners. This reaction leads to the selective formation of the trans-olefin. The formation of the lactone ring intermediates 17 and 16 during the de-protection of 1, 2-diol moiety has been studied in details with the help of computational chemistry. The last part of the thesis reveals an initial trial of another suggested approach based on “Ullmann type” reaction. The total synthetic strategy was successfully applied within 14 steps out of 17 were successfully performed obtaining intermediates 16 and 17 in a good yield. The compliment of the steps includes short reactions of lactone ring hydrolysis in basic medium in addition to reduction of the ketone moiety in intermediate 16.