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 SN2 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)-1aa, (12S,17S,18R)-1ab, (12R,17R,18S)-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 1ab and 1bb, indicating the greater importance of the stereochemistry of the C17,18-epoxide compared to that of the C12-hydroxy group.
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