Beyond Neuroprostanes: Total Synthesis and Epilipidomic Studies of a Novel Cyclopentenone Metabolite of Docosahexaenoic Acid

Abstract

Neuroprostanes (NeuroPs) are bioactive oxylipins formed in vivo from docosahexaenoic acid (DHA), the main polyunsaturated fatty acid of the human brain, by a nonenzymatic auto-oxidative process as mixtures of regio- and diastereoisomers. Thus, synthetic material is necessary to unlock their potential as oxidative stress biomarkers as well as to investigate the biological properties of individual NeuroP molecules. Despite recent advances in the field, cyclopentenone-type NeuroPs have received limited attention. Here, we present an enantioselective total synthesis of 4-A4-NeuroP-1,4-lactone and its dehydrated metabolite, 4-deoxy-Δ4,6-A4-NeuroP. The asymmetric synthesis of the chiral core relies on a robust organocatalyzed Michael addition. The assembly of the full carbon framework was accomplished via selective double olefin metathesis and Wittig olefination. The MS2 spectra of the 4-deoxy-Δ4,6-A4-NeuroP was carefully studied using molecular network and quantum chemistry software to elucidate its unique fragmentation pattern. Also, preliminary analytical studies showed for the first-time tangible amounts of 4-deoxy-Δ4,6-A4-NeuroP in trout brains.