Asymmetric Synthesis of Benzothiophene-Containing Lipoxin A₄ Analogues with Lower-Chain Modifications

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Herein the asymmetric synthesis of lipoxin A₄ (LXA₄) mimetics is reported in which the triene core of the molecule has been replaced by an aromatic sulfur-containing benzothiophene ring.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 A₄ - benzothiophene - asymmetric synthesis - anti-inflammatory - medicinal chemistry

Publication History

Received: 28 October 2022

Accepted after revision: 05 December 2022

Accepted Manuscript online:
05 December 2022

Article published online:
04 January 2023

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