Total Synthesis Confirms the Molecular Structure Proposed for Oxidized Levuglandin D₂

Levuglandins (LG)D₂ and LGE₂ are γ-ketoaldehyde levulinaldehyde derivatives with prostanoid side chains produced by spontaneous rearrangement of the endoperoxide intermediate PGH₂ in the biosynthesis of prostaglandins. Covalent adduction of LGs with the amyloid peptide Aβ_1-42 promotes formation of the type of oligomers that have been associated with neurotoxicity and are a pathologic hallmark of Alzheimer's disease. Within 1 min of their generation during the production of PGH₂ by cyclooxygenation of arachidonic acid, LGs are sequestered by covalent adduction to proteins. In view of this high proclivity for covalent adduction, it is understandable that free LGs have never been detected in vivo. Recently a catabolite, believed to be an oxidized derivative of LGD₂ (ox-LGD₂), a levulinic acid hydroxylactone with prostanoid side chains, was isolated from the red alga Gracilaria edulis and detected in mouse tissues and in the lysate of phorbol-12-myristate-13-acetate-treated THP-1 cells incubated with arachidonic acid. Such oxidative catabolism of LGD₂ is remarkable because it must be outstandingly efficient to prevail over adduction with proteins and because it requires a unique dehydrogenation. We now report a concise total synthesis that confirms the molecular structure proposed for ox-LGD₂. The synthesis also produces ox-LGE₂, which readily undergoes allylic rearrangement to Δ⁶-ox-LGE₂.