Synthesis of the Dimethyl Ester of 2'‐Cyano‐8'‐formyl‐N'‐methyl‐1',1a',5a',6'‐tetrahydroacrido[4,5,5a,6‐bcd]‐Annulated 2,3‐Dihydromesoporphyrin – A Novel System with Outstanding Properties as Basis for Photodynamic Therapy in the Far‐Red Region of the Visible Spectrum

Abstract

AbstractThe sterically hindered [5‐(2'‐cyanovinyl)mesoporphyrin dimethyl ester]nickel complex 1 has been treated with N‐methylformanilide under Vilsmeier conditions. Besides the expected meso‐formylporphyrin derivatives, 22 % of a novel green compound was isolated. After removal of Ni2+ by treatment with concentrated sulfuric acid, the structure of the novel compound was elucidated by mass spectrometry and 1H and 13C NMR spectroscopy, which led to the unambiguous establishment of the unprecedented racemic dimethyl ester of 2'‐cyano‐8'‐formyl‐N'‐methyl‐1,1a,5a,6‐tetrahydroacrido[4,5,5a,6‐bcd]‐annulated 2,3‐dihydromesoporphyrin structure 5. This racemic form was efficiently separated into its two pure enantiomeric forms each of which shows the same electronic spectrum as the racemate mixture. The two optical isomers show the exact opposite circular dichroism spectra. The structure of this novel product is clearly formed after the initial attack of the carbenium ion formed from N‐methylformanilide and POCl3 at the α‐carbon atom of the appending meso‐acrylonitrile function. This processis thus far an unprecedented cyclization process underVilsmeier conditions. It is clear that in this case the aromatic system of the Vilsmeier reagent is intimately involved in this reaction. In order to further explore the reactivity of the starting material, we treated it with the Vilsmeier reagent prepared from dimethylformamide and POCl3. In this case we obtained, besides the expected formylation products, a mixture of two peri‐annulated quinoporphyrins. From the structures of the products and the starting material it could be established that in this case the attack of the Vilsmeier reagent is on the nitrogen atom of the appending acrylonitrile function. For the initial tests of 5 as the basis of a photodynamic therapy we found that in the presence of air and light it is an efficient singlet oxygen generator that is stable during the irradiation time. It shows no toxicity towards lung carcinoma cells in the dark while in the presence of air and light the compound leads to a rapid killing of the cancer cells at concentrations that are an order of magnitude lower than in the case of the quinoporphyrin systems. These are all promising properties for continued studies and further development towards a photodynamic cancer therapy. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)