Approaches toward the Chemical Synthesis of Novel Arachidonic Acid Metabolites Hemiketal D2 and Hemiketal E2

Abstract

Hemiketal D2 and hemiketal E2 are eicosanoids identified by Schneider and coworkers in 2011. These novel arachidonic acid metabolites are cross-over products of the enzymes 5-LOX and COX-2, previously assumed to be operating independently in the biosynthesis of leukotrienes and prostaglandins, respectively. It was shown that the hemiketals stimulate angiogenesis of vascular endothelial cells, suggesting these compounds may be involved in inflammation and tissue repair. As the enzymatic production of these compounds is low yielding, chemical synthesis provides an attractive option for their production for further study. Thus, chapter 1 discusses the biological importance of lipid mediators and inflammation and previous synthetic approaches to these compounds. Chapter 2 details the proposed cycloisomerization/oxidation strategy to access the structurally intriguing keto-hemiketal moiety and the initial approaches toward the synthesis of hemiketal E2. Chapter 3 highlights the completion of the synthesis of hemiketal E2 and the progress toward a deuterated version of hemiketal E2. Chapter 4 discusses the progress made toward the synthesis of the related hemiketal D2.