Total Synthesis of the Delta-13-9-Isofurans: A Stereodivergent Approach

Abstract

Pulmonary arterial hypertension (PAH) is a fatal vascular disease within the lungs characterized by oxidative stress and endothelial cell proliferation. Associated with this oxidative injury is the increased production of reactive oxygen species capable of converting arachidonic acid into a number of autoxidative products, such as the isoprostanes and isofurans. Isoprostane and isofuran production diverge from a common hypothetical endoperoxide radical intermediate with isofuran production favored under increased oxygen tension. Both isofurans and isoprostanes are proposed to give an accurate assessment of oxidative damage when used comparatively. Based on unplublished work from Fessel and West, it is hypothesized that the isofurans target the orphan G-protein-coupled receptor GPR55 leading to cytoskeletal dysfunction and abnormal angiogenesis resulting in a PAH phenotype. As this autoxidative process lacks selectivity, multiple isomers of both isoprostanes and isofurans are produced, and in the case of isofurans, 8 constitutional isomers each consisting of 32 stereoisomers, for a total of 256 compounds have been proposed. In order to further investigate the physiological role of individual isofuran isomers within the context of PAH, a stereodivergent route was developed. Utilizing multi-gram quantities of common optically pure intermediates derived from tartaric acid and 2-deoxyribose, a synthetic strategy employing a series of stereospecific reactions was implemented to allow facile access to isomerically pure isofurans. In collaboration with the laboratory of Dr. James West at Vanderbilt, the biological effects of the individual isomers as well as a mixture of the isomers are proposed to be assayed to determine if there is disease association.