Abstract
Lipoxins are an important class of pro-resolving mediators that play a crucial role
in the resolution of inflammation. Thus, the synthesis of more metabolically stable
synthetic lipoxin analogues is an area of significant interest. Herein the asymmetric
synthesis of lipoxin A4 (LXA4) mimetics is reported in which the triene core of the molecule has been replaced
by an aromatic sulfur-containing benzothiophene ring. The key steps in the synthesis
included a Friedel–Crafts acylation, a Suzuki coupling between two upper and lower
chain fragments, and a highly stereoselective Noyori transfer hydrogenation to set
the stereochemistry of the alcohol at the benzylic position. A small library of benzothiophene-containing
LXA4 analogues with further structural modifications was also successfully synthesised.
These included analogues with phenoxy, p-fluorophenoxy, and p-trifluoromethylphenoxy substituents incorporated into the lower alkyl chain with
the objective of providing enhanced metabolic stability by blocking ω-oxidation pathways.
Key words
lipoxin A
4
- benzothiophene - asymmetric synthesis - anti-inflammatory - medicinal chemistry
