Synthesis of heme substituted with fluoro and perfluoroalkyl groups, and application of fluorine nuclear to NMR-probe

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Site-specific fluoro-groups(-F, -CF_3) introduction to a enzymatic reaction, coenzyme and protein has been a unique method to elucidate function-structure relationship in biological systems. Aiming at incorporation into Myoglobin, several fluorinated hemes have been synthesized and their particular physicochemical properties have been characterized by electrochemical measurement and ^<19>F NMR.The starting pyrrole β-difluoropyrrole was prepared by the improved method (ref. Henne, A.L. ; Zimmer, W.F. J.Am.Chem.Soc. 1951, 73, 1103-1104). Then, coupling reactions of β-difluoropyrrole and β-monofluoropyrrole gave rise to a new fluorinated dipyrromethene hydrobromide. Cyclization of fluorinated dipyrromethene hydrobromide and another dipyrromethene hydrobromide gave the site specific fluoroporphyrin in low yield (2,3,7-TFP:1.2%).Symmetrical bis-trifluoromethylated porphyrin (2,8-DPF) was obtained by oxidative cyclization in moderate yield (14 %).The ^<19>F NMR spectrum of 2,8-DPF was observed a single signal at δ-103.77ppm downfield from trifluoroacetic acid (TFA) as an external reference.2,8-DPF was incorporated into sperm whale apo-myoglobin. The pattern of absorption spectra of the met-, deoxy- and oxy-adduct-forms of reconstituted myoglobin with 2,8-DPF was similar to the native myoglobin. The pattern of spectral similarities among the reconstituted myoglobin with 2,8-DPF, mesohemin and native hemin indicate that the structure of these myoglobins are much the same.Thus, the ring-fluorinated heme may be useful as a mimicking prosthetic heme in the reconstitutional studies of various heme enzymes.