Total Syntheses of 8-Formyl-8-demethylprotoporphyrin IX, 8-(Hydroxymethyl)-8-demethylprotoporphyrin IX, and 8-Fluoromethyl Analogues of Protoporphyrin IX

Article abstract of DOI:10.1021/jo00275a009

In connection with proposed 19F NMR studies of reconstituted fluorine-substituted heme proteins, synthetic approaches to 8-(fluoromethyl)-8-demethylprotoporphyrin IX dimethyl ester (6) and the corresponding 8-(difluoromethyl)-8-demethyl analogue 5 were investigated.After a number of preliminary investigations, the fluorinating agent (diethylamido)sulfur trifluoride (DAST) was shosen as the reagent of choice.With DAST, β-carboxypyrrole 7 gave the acyl fluoride 8, which could not be further transformed into the trifluoromethyl analogue. (2-Hydroxyethyl)pyrroles, e.g., 13, reacted with DAST to give the (2-fluoroethyl)pyrrole 14 by way of a cyclopropylpyrrolium ion; corresponding bis(2-hydroxyethyl)porphyrin 36 afforded the bis(2-fluoroethyl) compound 37, whereas the porphyrindiylbis(acetaldehyde) 34 gave the bis(2,2-difluoroethyl)porphyrin 35.Formylporphyrins (e.g., 23) gave difluoromethyl derivatives (e.g., 22) when treated with DAST, and the corresponding porphyrinyl carbinol 24 gave the fluoromethyl compound 25.Acetylporphyrins did not react with DAST, but porphyrincarboxylic acid 38 gave the acyl fluoride 39.A porphyrin (28) bearing a β-hydroxypropionate substituent was transformed into the corresponding acrylic porphyrin 29 with DAST, while the related β-keto ester porphyrin 30 gave the fluoroacrylate 31.As a synthetic approach to 5 and 6, the 8-unsubstituted porphyrin 54 was prepared by copper(II)-catalyzed 1',8'-dimethyl-a,c-biladiene cyclization; one of the byproducts from this cyclization was the required 8-formylporphyrin 42, obtained by migration of one of the terminal (1',8') carbons to the 8-position.The 8-formylporphyrin 42 was also formed from the 8-unsubstituted porphyrin 54by formylation with a hindered Vilsmeier reagent (using the copper complex 44) or by a Friedel-Crafts reaction (on the hemin 57) with tin(IV) chloride and dichloromethyl methyl ether.Vinylation of porphyrin 42 with diazabicycloundecene (after protection of the aldehyde as an acetal) gave the 8-formyl-8-demethylprotoporphyrin ester 62; sodium borohydride reduction of the formylporphyrin 42, followed by vinylation (DBU), gave the (hydroxymethyl)porphyrin 65.The iron complex free acids of these compounds have been isolated (Ator and Ortiz de Montellano J.Biol.Chem. 1987, 262, 1542) from phenylhydrazine inactivation of horseradish peroxidase.Formylporphyrin 42 was fluorinated with DAST to give the (difluoromethyl)porphyrin 59, which was vinylated (DBU) to give the required 8-(difluoromethyl)-8-demethylprotoporphyrin 5.The (hydroxymethyl)porphyrin 65 was similarly fluorinated with DAST to give 8-(fluoromethyl)-8-demethylprotoporphyrin 6, but this product was extremely easily hydrolyzed and was transformed back to the 8-(hydroxymethyl)porphyrin 65 by simple chromatography.