Synthetic study of a new class of stable PGI(2) analogue, m-phenylene PGI(2) - Synthesis of beraprost sodium

Just after the discovery of PGI(2), we started to find chemically and metabolically stable PGI(2) derivatives with longer duration of action. Extensive studies led us to a new class of stable PGI(2) analogue, 5,6,7-trinor-4,8-inter-m-phenylenePGI(2) that has a phenol moiety instead of enol-ether linkage in PGI(2). In order to accomplish synthesis of the m-phenylenePGI(2), novel synthetic methods were developed, for instance, ortho-selective metal-halogen exchange reaction of bromoanisoles by means of Grignard reagent, copper-catalyzed S(N)2' cyclization to prepare dihydrocyclopenta[b]benzofuran, and regioselective and stereo-selective elongation of omega-side chain by Prins reaction. Further efforts were devoted to synthesize derivatives of m-phenylenePGI(2) with enhanced pharmacological activity and less adverse reaction. Finally, we attained to Beraprost sodium which is the first launched drug as an orally active PGI(2). This paper will focus on the study of total syntheses of m-phenylenePGI(2).