Stereodivergent Approach to the Total Synthesis of Selected syn trans and anti trans ∆13-9-isofurans

Abstract

Pulmonary arterial hypertension (PAH) is a fatal vascular disease within the lungs marked by oxidative stress and endothelial cell proliferation. The free radicals generated under oxidative stress conditions initiate the non-enzymatic metabolism of arachidonic acid (AA) leading to a family of compounds known as the isofurans (IsoFs). This metabolism is non-stereospecific leading to 8 constitutional isomers each consisting of 32 stereoisomers (256 total isomers). The role of these 256 IsoF’s in PAH remains unclear as their biological production is minimal, making traditional isolation methods impossible. Therefore, a stereodivergent synthesis from enantiomerically pure starting materials is being employed to produce these compounds with high enantiopurity, in sufficient amounts for biological studies. Based on unpublished work by the Fessel and West group it is hypothesized that isofurans can induce a PAH phenotype through activation of G-protein-coupled receptor 55. In this work the synthesis of four isofurans is disclosed using a stereodivergent route with 2-deoxy-L-ribose as an optically pure starting material. Then, stereospecific reactions are used to create mixtures of diastereomers which are separable. Then these separated diastereomers are taken forward separately throughout the synthetic sequence. To date this route has produced four synthetically pure diastereomers and provides the framework to access all 32 stereoisomers of the ∆13-9-isofurans.