Synthesis of Chlorins Linked with Pyrazoline by 1,3-Dipolar Diazomethane Cycloaddition Reaction

Abstract

Chlorins and bacteriochlorins, occurred in natural systems as a class of tetrapyrrolic macrocycles, have gained much interests in recent years because of their unique optical and photochemical properties. They can be utilized as the second generation photosensitizers for photodynamic therapy (PDT) of cancer and as models for photosynthetic reaction centers. Among the chlorophyll derivatives, pheophorbide, pyropheophorbide, purpurin and N-alkylimide of purpurin18 have been reported as potent photosensitizers with significant anticancer activity. Their derivatives were usually prepared by chemical modification of peripheral functional groups, particularly the vinyl group at 3-position. Our interest in the synthesis of chlorins as potential photosensitizers for PDT led us to explore new strategies for vinyl functionalization of pheophorbide-a by 1,3-dipolar cycloaddition methodology with diazomethane. 1,3-Dipolar [3+2] cycloaddition is an effective method for the synthesis of five-membered heterocycles. It is well known that diazomethane is a reactive reagent for 1,3dipolar cycloaddition with olefin to furnish pyrazoline derivatives, which serve as useful building blocks in the synthesis of various compounds through chemical transformation and/or ring cleavage. In the present work, the novel pyrazolinyl chlorins, promising versatile starting materials for further application by chemical transformation of pyrazoline ring for constructing new structure of chlorin, were synthesized by 1,3-dipolar cycloaddition reaction with chlorin and diazomethane. It was found that the vinyl group of pheophorbide-a 1, extracted from the alga Spirulina maxima, reacts slowly over a period of 3 days with ethereal