Effect of Meso-Substituents on the Osmium Tetraoxide Reaction and Pinacol-Pinacolone Rearrangement of the Corresponding vic-Dihydroxyporphyrins Yihui Chen, † Craig J. Medforth, ‡ Kevin M. Smith, ‡ James Alderfer, § Thomas J. Dougherty, † and Ravindra K. Pandey* ,†,| Chemistry Division, Photodynamic Therapy Center, NMR Facility, Molecular and Cellular Biophysics, and Department of Nuclear Medicine/Radiology, Roswell Park Cancer Institute, Buffalo, New York 14263, and Department of Chemistry,University of California, Davis, CA95616 ravindra.pandey@roswellpark.org Received January 4, 2001 To investigate the effects of electron-donating and electron-withdrawing substituents upon the reaction of porphyrins with osmium tetraoxide, and the pinacol-pinacolone rearrangement of the resulting diols, a series of meso-substituted porphyrins were prepared by total synthesis. Porphyrins with electron-donating substitutents at the meso-positions gave vic-dihydroxychlorins in which the adjacent pyrrole subunit was predominantly oxidized. No such selectivity was observed in a porphyrin containing a methoxycarbonyl as the electron-withdrawing group, whereas a formyl substituent again resulted in oxidation at the pyrrole unit adjacent to the meso-substituent. Under pinacol-pinacolone conditions, vic-dihydroxy chlorins containing 4-methoxyphenyl or 3,5-dimethox- yphenyl groups at the meso-position showed preferential migration of the ethyl group over the methyl group to give 8-ketochlorins, whereas the diol with an n-heptyl substituent under similar reaction conditions gave both 7- and 8-ketochlorins. In contrast, the diol containing a meso-formyl substituent produced the corresponding 7-ketochlorin exclusively. These results indicate that it is not possible to predict the reactivity of meso-substituted porphyrins in the osmium tetraoxide reaction nor the general substituent migratory aptitudes in the pinacol-pinacolone rearrangement based on simple electronic arguments, most likely because many parameters (e.g., meso--pyrrolic steric crowding and long-range electronic effects) ultimately determine the reactivity. The structural assignments of the porphyrin diols and the keto-analogues were confirmed by extensive 1 H NMR studies; some of the dihydroxychlorins and ketochlorins were found to display unusual features in their 1 H NMR spectra. Introduction In continuation of our ongoing studies, the present work describes the results of an investigation to deter- mine the effect of substituents placed regioselectively at the meso-positions of the porphyrin macrocycle to gener- ate the vic-dihydoxy- and the corresponding oxochlorins under appropriate reaction conditions. The oxo-deriva- tives of chlorins, isobacteriochlorins, and bacteriochlorins have been known for some time, 1 but their biological significance was not recognized until recently. 2 For example, the dihydroxyporphyrin structure originally proposed 3 by Barrett for heme d isolated from Aerobacter aerogenes was later reinvestigated by Timkovich et al. 4 who showed that heme d is in fact a derivative of 5,6- dihydroxyprotochlorin IX. It has also been reported by Sotiriou and Chang 5 that heme d 1 obtained from Pseu- domonas aeruginosa and Paracocis denitrificans is a dioxoisobacteriochlorin. In recent years, some of the oxochlorins, oxobacteriochlorins, dioxobacteriochlorins, and their vic-dihydroxy precursors have been investi- gated as potential photosensitizers for the treatment of cancer using photodynamic therapy (PDT). 6 Thus, due to their biological and medicinal importance, the oxo- and their corresponding vic-dihydroxy derivatives have gen- erated considerable interest. In their studies with a variety of unsymmetrical porphyrins, Chang and Sotiriou 7 showed that unsym- metrical porphyrins (e.g., deuterioporphyrin IX dimethyl ester 1, mesoporphyrin IX dimethyl ester 2) upon reaction with OsO 4 gave all the possible four (ring A, B, C, and D) vic-dihydroxychlorins 3, 4 without any pyrrole subunit selectivity (see Scheme 1). Acid-catalyzed pinacol-pina- colone rearrangement of the vic-dihydroxy compounds gave the corresponding ketones, and migratory aptitudes of hydrogen, ethyl, or alkyl groups (including the propi- * Corresponding author: Phone: (716) 845-3203, Fax: (716) 845- 8920. † Chemistry Division, Photodynamic Therapy Center, Roswell Park Cancer Institute. ‡ University of California. § NMR Facility, Molecular and Cellular Biophysics, Roswell Park Cancer Institute. | Department of Nuclear Medicine/Radiology, Roswell Park Cancer Institute. (1) (a) Bonnett, R.; Dimsdale, M. J.; Stephenson, C. F. J. Chem. Soc. (C) 1969, 564. (b) Inhoffen, H. H.; Nolte, W. Liebigs Ann. Chem. 1969, 725, 167. (c) Chang, C. K.; Sotiriou, C.; Wu, W. J. Chem. Soc., Chem. Commun. 1986, 1213. (2) Pandey, R. K.; Zheng, G. Porphyrins as photosensitizers in Photodynamic Therapy. In The Porphyrin Handbook; Kadish, Smith, and Guilard, Eds.; Academic Press: New York, 2000; Vol. 6. (3) Barrett, J. Biochem. J. 1956, 64, 626. (4) Timkovich, R.; Cork, M. S.; Gennis, R. B.; Johnson, P. Y. J. Am. Chem. Soc. 1985, 107, 6069. (5) Sotiriou, C.; Chang, C. K. J. Am. Chem. Soc. 1988, 110, 2264. (6) Kessel, D.; Smith, K. M.; Pandey, R. K.; Shiau, F.-Y.; Henderson, B. W. Photochem. Photobiol. 1993, 58, 200. (7) Chang, C. K.; Sotiriou, C. J. Heterocycl. Chem. 1985, 22, 1739. 3930 J. Org. Chem. 2001, 66, 3930-3939 10.1021/jo0100143 CCC: $20.00 © 2001 American Chemical Society Published on Web 05/02/2001