Synthesis of an Enantiomerically Pure Ring A Building Block for Tolyporphin and Tolyporphin Derivatives

Abstract

Representatives of bacteriochlorin class of compounds which are not involved in bacterial photosynthesis are the recently discovered tolyporphins. These structurally unique hydroporphyrins were found in the terrestrial cyanobacterium, Tolypothrix nodosa by Moore and his co-workers. It was demonstrated in biological experiments that tolyporphins eliminate multidrug resistance (MDR) activity in vinblastine-resistant subline of human ovarian adenocarcinoma cells. The unusual structure and important biological activity of tolyporphin makes its synthetic studies a great challenging goal. It is therefore of great interest to synthesis enantiomerically pure ring A building block which could be used for the synthesis of enantiomerically pure model compound for tolyporphins. Asymmetric synthesis was applied on bislactone using an optically active aromatic amine and this gave a pair of N-alkylated lactam-lactone diastereomers. These were separated by MPLC and debenzylated into enantiomerically pure lactam-lactone and ent-lactam-lactone respectively. The (-)-lactam-lactone was subjected to cyanation followed by thionation using Lawesson reagent and this gave cis - and trans -thiocyano lactam isomers. The suphide contraction method was applied on the cis-thiocyano lactam using the bromomalonic diester into the cis-pyrrolidine diester (ring A). This could be used as a building block for the synthesis of optically pure model compounds for tolyporphins and other hydroporphyin compounds.