Synthetic Bacteriochlorins and Chlorins for Photomedicine and Artificial Photosynthesis

The development of tetrapyrrole chromophores that absorb in the red and near-infrared (NIR) spectral region (600--900 nm) is essential for fundamental studies and diverse applications. For photomedical applications, such as photodynamic therapy (PDT) or optical imaging, light in the NIR region affords the deepest penetration in soft tissue, thus requiring absorbers/emitters that operate in this relatively transparent window. For flow cytometry, fluorophores with narrow absorption and emission bands in the NIR region would increase diagnostic capabilities, as well as complement UV- and visible-region fluorophores. For artificial photosynthesis, the ability to capture sunlight in the red and NIR regions is essential to the overall solar-conversion efficiency because this part of the spectrum contains almost 50% of the incident solar photons. Synthetically tailorable photoactive compounds that absorb in the red/NIR region have largely been unavailable.;Chlorophylls and bacteriochlorophylls absorb strongly in the red and near-infrared spectral region, respectively. However, synthetic analogous tailored for various applications have largely been derived via semisynthesis from the natural compounds. Two significant problems with derivatives of the natural chlorins and bacteriochlorins include limited stability toward adventitious dehydrogenation and poor synthetic malleability owing to the presence of a nearly full complement of substituents about the perimeter of the macrocycle.;This work focuses on the de novo synthesis of stable tailorable bacteriochlorins and chlorins, with applications focused on photodynamic therapy (PDT) and artificial photosynthesis.;The bacteriochlorin macrocycle is prepared by the self-condensation of two molecules of a substituted dihydrodipyrrin-acetal. This work describes the development of a scalable synthesis of dihydrodipyrrin-acetals, and the identification of new mild and broadly applicable acid conditions for the self-condensation of diversely substituted dihydrodipyrrin-acetals to selectively afford the 5-methoxybacteriochlorin in up to 100-mg quantities. Desired bacteriochlorin substituents can be incorporated either by early installation via the dihydrodipyrrin-acetal or by derivatization of beta-bromobacteriochlorins.;Synthetic chlorins are prepared by the known condensation of a Western half and an Eastern half. To push the long-wavelength absorption of chlorins further into the red region, this route was extended to gain access to chlorin-13,15-dicarboximides. The new route entails (i) synthesis of a 13-bromochlorin, (ii) palladium-catalyzed carbamoylation at the 13-position, (iii) regioselective 15-bromination under acidic conditions, and (iv) one-flask palladium-mediated carbonylation and ring closure to form the imide. Indeed, the synthetic chlorin-imides absorb in the 680--715 nm region.;Similarly, the one-flask palladium-mediated carbonylation and ring closure to form the imide ring was applied to the synthetic bacteriochlorins to afford bacteriochlorin-13,15-dicarboximides. The synthetic bacteriochlorin-imides absorb far into the NIR region (790--820 nm).;The synthetic chlorins and bacteriochlorins bear a geminal dimethyl group in each reduced, pyrroline ring to prevent adventitious dehydrogenation and afford stability under routine handling on the open bench top. The long-wavelength absorption band of chlorins, chlorin--imides and bacteriochlorins prepared during this work extends far into the red/NIR region, and a set of wavelength tunable chromophores is now available spanning the red and NIR region from 600--900 nm.;Altogether, over 50 new synthetic chlorins and bacteriochlorins are described bearing diverse peripheral substituents, which not only provide tunability of the long-wavelength absorption band but also solubility in various media (including aqueous) via the hydrophilicity or overall charge. The chlorins and bacteriochlorins are being examined for PDT activity or photophysical and redox properties by collaborators at Harvard Medical School, Washington University (St. Louis), and University of California Riverside.