Synthesis of Enantiopure 6,11‐Methylene Lipoxin B₄ Methyl Ester

Abstract

The synthesis of Lipoxin B4 analogs (LXB4) to gain access to stabilized inflammation resolving compounds is an actual field of research. Focusing on variation and stabilization of the conjugated E,Z,E,E C6–C13 tetraene moiety of natural LXB4, a methylene bridge introduced between C6 and C11 suppresses any Z/E isomerization of the C8–C9 olefin. Intending to enable prospective structure variations in connection with the C1–C5 and C14–C20 fragments, a convergent total synthesis has been developed. Optically active C1–C12 building blocks were build‐up from cycloheptatriene 1‐carbonester (C6–C11, C21) and glutaryl chloride (C1–C5) using Friedel‐Crafts‐type acylation and chiral HPLC. The C13–C20 segment had been generated via a five‐step sequence starting from heptanoyl chloride. Horner key olefination enabled the assembly of the carbon backbone. A final five‐step sequence including a chelate Cram reduction of the unsaturated ketone moiety afforded the target 6,11‐methylene LXB4 methyl ester.

A general synthesis of aromatic and heteroaromatic lipoxin B4 analogues

“…9 Since then, however, the only other examples of LXB 4 analogues have been reported by Nubbemeyer and co-workers who developed a synthesis of analogues based on a cycloheptatriene core. 16,17…”

“…9 Since then, however, the only other examples of LXB 4 analogues have been reported by Nubbemeyer and co-workers who developed a synthesis of analogues based on a cycloheptatriene core. 16,17 Given our experience with heteroaromatic analogues of LXA 4 , we aimed to develop a general synthetic route that would allow for the efficient stereoselective synthesis of a focused library of LXB 4 mimetics containing a variety of different aromatic and heteroaromatic cores. This would rapidly expand the number of LXB 4 analogues accessible and hopefully lead to better understanding of LXB 4 and the potential therapeutic applications of its stable synthetic analogues in the future.…”