Synthesis of porphyrins, chlorins and bacteriochlorins by chemical modifications of chlorophyll a

The goal of this project was to synthesize new porphyrins, chlorins and bacteriochlorins via chemical modifications of chlorophyll a so that new chemistry and applications of chlorophyll a and its related derivatives could be developed. A magnesium-free yet stable derivative of chlorophyll a, 7, isolated from the blue alga Spirulina maxima, was employed as the common intermediate in this work. As the first objective, new methods of asymmetric hydroxylation and regioselective oxidation of chlorophyll derivatives were successfully developed. Stereoselective synthesis of natural antioxidative chlorins 81, 82(S), 82(R), 83(R), 84 and 102, isolated from marine metabolites, was performed in a short and effective way. This biomimetic synthetic approach helped to elucidate the possible biogenetic evolution of these antioxidative chlorins from chlorophyll a. The second objective of this work was to design a method to convert chiorin 112 into porphyrin 114. A novel and effective acid-catalyzed tautomerization reaction was discovered and optimized, which has provided a new view on the migration of hydrogens in the saturated ring IV to the exocyclic ring V. The porphyrins so produced were used as intermediates for the further preparation of chlorophyll related petroporphyrins and regiochemically-pure benzoporphyrin derivatives (BPD5). Making use of the aforementioned tetrapyrrolic materials, the third objective of this work was to develop new photosensitizers for photodynamic therapy of tumors. New monovinylporphyrins and an [A,C]-divinylporphyrin 147 were synthesized. Diels-Alder reaction of these (di)vinylporphyrins with dimethyl acetylenedicarboxylate (DMAD) afforded new regiochemically-pure BPDs 125 and 141 and dibenzoporphyrin derivative 165. These new sensitizers have characteristics that meet or exceed the promising chemical features of benzoporphyrin derivative monoacid ring A (BPDMA), a second generation sensitizer in Phase-TI clinical trials. The final objective of this work was to exploit the nucleophilic behaviour of the bicyclic amidines, l,8-diazabicyclo[5.4.O]undec-7-ene (DBU) and 1,5-diazabicyclo- [4.3.O]non-5-ene (DBN). Two reactions were examined. Firstly, DBU acting as a difunctional nucleophile quantitatively reacted with DMAD to afford a fused tricyclic derivative 176. Secondly, 7, a weak electrophile which alone does not electrophilically react with DBU or DBN, has reacted, through catalytic activation by Lewis acids, with nucleophilic DBU and DBN to form chlorin e₆ amides 185 and 186. These results have brought about further understanding of the nucleophilicity as well as the basicity of these common organic bases. [chemical compound diagrams]Science, Faculty ofChemistry, Department ofGraduat