Total synthesis of four stereoisomers of (5Z,8Z,10E,14Z)-12-hydroxy-17,18-epoxy-5,8,10,14-eicosatetraenoic acid and their anti-inflammatory activities

The four stereoisomers of novel lipid mediator 1, (5Z,8Z,10E,14Z)-12-hydroxy-17,18-epoxy-5,8,10,14-eicosatetraenoic acid, were synthesized from six simple fragments. Triyne 2 was convergently assembled through three S(N)2 alkynylation reactions and one Sonogashira coupling reaction. Two of the three alkynes of 2 were hydrogenated using Lindlar catalyst, while the third alkyne was reduced through formation of the alkyne-dicobalt hexacarbonyl complex and subsequent reductive decomplexation, producing the requisite tetraene structure in a stereoselective manner. Next, a two-step functional group manipulation at C1, followed by simultaneous deprotection and epoxide formation, gave rise to the four isomers, (12S,17R,18S)(12S,17S,18R)-lab, (12R,17R,185)-1ba and (12R,17S,18R)-1bb. The present work allowed determination of the absolute structure of naturally occurring 1 to be 1aa and 1ab, as well as biological evaluation of the two natural (1aa, 1ab) and two unnatural (1ba, 1bb) isomers. Intriguingly, natural 1aa and unnatural 1ba were found to exhibit more potent anti-inflammatory activities than lab and 1bb, indicating the greater importance of the stereochemistry of the C17,18-epoxide compared to that of the C12-hydroxy group. (C) 2015 Elsevier Ltd. All rights reserved.