Synthesis of New Derivatives of Protoporphyrin IX and Chlorophyll <Emphasis Type="Italic">a</Emphasis>

The vinyl groups in protoporphyrin IX and chlorophyll a derivatives were selectively transformed into hydroxymethyl and acetoxymethyl substituents. The reactivities of β-hydroxymethyl and β-acetoxymethyl groups in porphyrins and chlorins toward nucleophilic reagents were compared for the first time using the reaction with acetylacetone as an example. Peripheral acetylacetone moieties in porphyrins and chlorins were shown to be promising as building blocks for generation of exo heterocyclic structures.     

Synthesis of hydroporphyrins based on comparative studies of palladium-catalyzed and non-catalyzed approaches

Hydroporphyrins have been synthesized using both Pd-catalyzed and non-catalyzed approaches. Comparative studies of the reaction of tetrasubstituted porphyrins with organolithium reagents in the presence of and without palladium catalysts showed that depending on reagents, the catalyst structure and reactivity of the corresponding porphyrins, chlorins (β-hydroporphyrins) and/or porphodimethenes (meso hydroporphyrins) of 5,10-type can be prepared in reasonable yields. In the absence of Pd catalysts, the formation of chlorins is predominant in the reactions with aliphatic RLi while porphodimethenes are the main products in reactions with PhLi. The use of a palladium catalyst resulted in the formation of both types of hydroporphyrins and the selective formation of either β-mono- or disubstituted chlorins. Of special interest was the reaction of octaethylporphyrin. Here, reaction with t-BuLi in the presence of Pd(PPh₃)₄/CuI proceeded with complete regioselectivity for 5,10-porphodimethenes.     

Palladium-catalyzed reactions for the synthesis of chlorins and 5,10-porphodimethenes

The palladium-catalyzed reaction of RLi with various 5,10,15,20-tetrasubstituted porphyrins offers a convenient synthetic route to chlorins and porphodimethenes (calixphyrins). The reactions utilized various Pd catalysts and CuI and yielded either 2,3-substituted chlorins or 5,10-disubstituted porphodimethenes in yields ranging from 20-40%. The reaction of octaethylporphyrin with t-BuLi in the presence of a Pd-catalyst generated the corresponding 5,10-porphodimethene in 72% yield.     

Convenient peripheral aroyloxylation reactions of porphyrins and chlorophyll-a-based chlorins with benzoyl peroxide

A practical and efficient methodology for the formation of C–O bonds on the porphyrin/chlorin periphery was developed. The aroyloxy-substituted porphyrins and chlorins related to chlorophyll-a at the β- and meso-positions, respectively, were conveniently synthesized by the free radical substitution reaction with benzoyl peroxide and its homologs.     

meso-Tetrakis(pentafluorophenyl)porphyrin-derived chromene-annulated chlorins

The synthesis of mono- and bis-chromene-annulated meso-(pentafluorophenyl)chlorins from meso-tetrakis(pentafluorophenyl)porphyrins by an OsO(4)-mediated dihydroxylation reaction, followed by an intramolecular nucleophilic aromatic substitution reaction, is described. The reaction sequence is applicable to the free base systems as well as their Zn(II), Ni(II), Pd(II), and Pt(II) complexes. The optical properties (UV-vis and fluorescence spectra) of the (metallo)chlorin-like chromophores that possess slightly red-shifted optical spectra compared to the corresponding 2,3-dihydroxychlorins are reported. Molecular modeling and (1)H-(19)F-HOESY NMR spectroscopy provide indications for the conformation of the chromene-annulated chromophores. Using (1)H-(1)H COSY and (19)F-(19)F QF-COSY NMR spectra, we interpret the (1)H and (19)F NMR spectra of the porphyrins and chlorins, thus providing a refined reference point for the use of (19)F NMR spectroscopy as a diagnostic tool in the analysis of meso-pentafluorophenyl-substituted porphyrinoids.     

Investigation of the Scope of Heterogeneous and Homogeneous Procedures for Preparing Magnesium Chelates of Porphyrins, Hydroporphyrins, and Phthalocyanines

A simple method has been developed for metalation of porphyrinic compounds under homogeneous conditions at room temperature using a stable ethereal solution of MgI(2) and N,N-diisopropylethylamine. A previously developed heterogeneous procedure employs a mixture of a magnesium halide and a nonnucleophilic amine in a noncoordinating solvent at room temperature. The scope of the heterogeneous and homogeneous magnesium insertion procedures has been investigated across a family of 19 porphyrinic compounds, including synthetic porphyrins, synthetic or naturally occurring chlorins, and organic-soluble phthalocyanines. The rate of magnesium insertion increased in the series phthalocyanines < chlorins < porphyrins, which parallels the basicity of the ligands. Though phthalocyanines have the smallest core size, the magnesium phthalocyanines were far more stable than magnesium porphyrins to acid-induced demetalation. The heterogeneous method is broadly applicable to porphyrins, chlorins, and phthalocyanines. The homogeneous method is generally slower than the heterogeneous method, though both afford rapid metalation of most porphyrins, including electron-deficient, peripherally coordinating, or facially encumbered meso-substituted tetraarylporphyrins, and the beta-substituted octaethylporphyrin. Chlorin e(6) trimethyl ester and methyl pyropheophorbide a were metalated cleanly under homogeneous but not heterogeneous conditions, while pheophytin a failed with both methods. The homogeneous method failed altogether with phthalocyanines. Several methods in magnesium chemistry have been developed that augment these procedures, including a mild synthesis of tetraphenylchlorin and a streamlined separation of porphyrin, chlorin, and bacteriochlorins based on selective formation of the magnesium chelates. Collectively, these methods should broaden the scope of model systems based on magnesium chelates of porphyrinic compounds.     

The reaction of porphyrins with organolithium reagents

Porphyrins react readily with organolithium reagents, preferentially in the meso positions. The overall reaction is a nucleophilic substitution and proceeds via initial reaction of the organic nucleophile with a meso carbon yielding an anionic species which is hydrolyzed to a porphodimethene (5,15-dihydroporphyrin), formally constituting an addition reaction to two Cm positions. Subsequent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) yields meso-substituted porphyrins. The reaction is highly versatile as it is accomplished in high, often quantitative yields with various alkyl or aryl lithium reagents. In addition, LiR can be used for reaction with a variety of metal complexes (best with NiII, but also with ZnII, CuII, and CoII) and most useful with free base porphyrins. Similarly beneficial this reaction can be used in sequence for the introduction of 1, 2, 3, or 4 (different) meso substituents giving for the first time an entry into any desired meso-substituted porphyrin. If meso-substituted porphyrins are used, reaction with LiR can be used for either the preparation of phlorins (already known reaction), porphodimethenes (5,15-dihydroporphyrins, including those with exocyclic double bonds, for example, 5(1),5(2)-didehydroporphyrins) or chlorins (2,3-dihydroporphyrins) depending on the substituent type in the reactant porphyrins. Thus, this reaction presents a generally applicable method for the facile and versatile functionalization of porphyrins.     

REGIOSELECTIVE PHOTOREDUCTION OF ZINC(II) PORPHYRINS TO GIVE CHLORINS

The ascorbic acid/organic base photoreduction of zinc(II) porphyrins was investigated. It was established that certain substituents can direct the photoreduction to the site of the macrocycle to which they are attached. For example, zinc(II) vinylporphyrins (8, 12, 16, 20) are photoreduced with cis stereochemistry on the ring bearing the vinyl group to give the corresponding chlorins. Zinc(II) acetylporphyrins (22, 24) were likewise reduced to chlorins such that cis-hydrogenation took place on the ring bearing the acetyl group. Zinc(II) formylporphyrins 33 also appear to reduce at the ring bearing the formyl group. When the zinc(II) acrylic porphyrin 28 was photoreduced, reduction did take place at the ring bearing the acrylic side chain, but migration of the acrylate double bond was very rapid, and the product isolated was the corresponding porphyrin propionate 30. Reduction of a zinc(II) porphyrin 35 bearing both a vinyl group and a nuclear carboxylic ester took place at the ring bearing the carboxylic ester. The reaction provides a general method for regioselective synthesis of chlorins from zinc(II) porphyrins without any evidence of formation of over-reduction products characteristic of many other procedures for formation of chlorins from porphyrin precursors.     

1,3-dipolar cycloaddition reactions of porphyrins with azomethine ylides

[reaction: see text] The behavior of porphyrins as dipolarophiles in 1,3-dipolar cycloadditions with azomethine ylides was studied. Depending on the nature of the substituent groups on the porphyrin macrocycles, the reaction can give monoadducts (chlorins) or bisadducts (isobacteriochlorins and bacteriochlorins). When a large excess of azomethine ylide is used, trisadducts can also be obtained. Mixed isobacteriochlorin derivatives were prepared from the reaction of azomethine ylides with the chlorin monoadducts previously obtained via Diels-Alder reactions.     

High-performance liquid chromatography/electrospray ionization tandem mass spectrometry of hydroxylated uroporphyrin and urochlorin derivatives formed by photochemical oxidation of uroporphyrinogen I

Hydroxylated uroporphyrin I and urochlorin I derivatives formed by photochemical oxidation of uroporphyrinogen I were separated by high-performance liquid chromatography and fully characterized by electrospray ionization tandem mass spectrometry. The porphyrins and chlorins were identified by analysis of their product ion spectra with each hydroxylated derivative giving a characteristic collision-induced dissociation fragmentation pattern. The porphyrins and chlorins characterized were meso-hydroxyuroporphyrin I, alpha-hydroxypropionic acid uroporphyrin I, beta-hydroxypropionic acid uroporphyrin I, hydroxyacetic acid uroporphyrin I, trans-7-hydroxy-8-spirolactoneurochlorin I, cis-7-hydroxy-8-spirolactoneurochlorin I and trans- and cis-7,8-dihydroxyurochlorins I.     

Rational synthesis of meso-substituted chlorin building blocks

Chlorins provide the basis for plant photosynthesis, but synthetic model systems have generally employed porphyrins as surrogates due to the unavailability of suitable chlorin building blocks. We have adapted a route pioneered by Battersby to gain access to chlorins that bear two meso substituents, a geminal dimethyl group to lock in the chlorin hydrogenation level, and no flanking meso and beta substituents. The synthesis involves convergent joining of an Eastern half and a Western half. A 3,3-dimethyl-2,3-dihydrodipyrrin (Western half) was synthesized in four steps from pyrrole-2-carboxaldehyde. A bromodipyrromethane carbinol (Eastern half) was prepared by sequential acylation and bromination of a 5-substituted dipyrromethane followed by reduction. Chlorin formation is achieved by a two-flask process of acid-catalyzed condensation followed by metal-mediated oxidative cyclization. The latter reaction has heretofore been performed with copper templates. Investigation of conditions for this multistep process led to copper-free conditions (zinc acetate, AgIO(3), and piperidine in toluene at 80 degrees C for 2 h). The zinc chlorin was obtained in yields of approximately 10% and could be easily demetalated to give the corresponding free base chlorin. The synthetic process is compatible with a range of meso substituents (p-tolyl, mesityl, pentafluorophenyl, 4-[2-(trimethylsilyl)ethynyl]phenyl, 4-iodophenyl). Altogether four free base and four zinc chlorins have been prepared. The chlorins exhibit typical absorption spectra, fluorescence spectra, and fluorescence quantum yields. The ease of synthetic access, presence of appropriate substituents, and characteristic spectral features make these types of chlorins well suited for incorporation in synthetic model systems.     

Cross-metathesis of the vinyl group on tetrapyrrolic macrocycles: reactivity, selectivity, and mechanism

To find a general strategy for modifying the peripheral structure of vinylchlorin and porphyrin substrates, cross-metathesis on the vinyl group of these tetrapyrrolic macrocycles was investigated. The N-heterocyclic carbene-containing ruthenium complex 3 efficiently catalyzed the cross-metathesis (CM) of vinylchlorins and vinylporphyrins with a variety of olefins in high E-stereoselectivity. Different substituents on the olefin dramatically influenced the reaction. While the chlorins were more reactive than the porphyrins (as free bases), the corresponding zinc complexes showed higher activity. The reaction mechanism was investigated, and an empirical model for selective CM was applied to our studies to direct further reactions.     

Synthesis of 1-formyldipyrromethanes

1-Formyldipyrromethanes are versatile precursors to porphyrins and chlorins. Two methods of synthesis of 1-formyldipyrromethanes have been investigated: (1) Vilsmeier formylation followed by selective removal of the unwanted 1,9-diformyldipyrromethane by dialkyltin complexation and (2) reaction with mesitylmagnesium bromide (MesMgBr) followed by formylation with phenyl formate. The two approaches are complementary (acidic versus basic conditions; statistical versus selective formylation). The latter was found to be more efficient for the preparation of 1-formyldipyrromethanes.     

Chlorins as photosensitizers in biology and medicine

The photodynamic therapy (PDT) of tumors involves illumination of the tumorous area following the administration of a tumor-localizing photodynamic sensitizer. Hematoporphyrin derivative (HPD) and Photofrin II (a purified form of HPD), the main sensitizers used clinically for PDT to date, are complex mixtures of porphyrins; furthermore, these preparations absorb light very poorly in the red region of the spectrum (wavelengths greater than 600 nm) where light penetration into mammalian tissues is greatest. Thus there is considerable interest in identifying new sensitizers that localize more effectively in tumors, absorb more strongly at longer wavelengths and can be prepared in high purity. Much of this interest has been directed towards chlorins (reduced porphyrins), which typically absorb strongly in the red. This review summarizes research that has been carried out on selected types of chlorins, some of which may have important applications as sensitizers for PDT.     

天然环状四吡咯化合物的合成研究进展

天然环状四吡咯化合物包括卟啉、卟吩、细菌卟吩、异菌卟吩以及可啉等类物质 ,其合成研究是目前有机合成领域的热点之一 .综述了上述各类物质的全合成方法及其研究进展     

Planarity of metal chlorins in n-octane solution

The geometry of porphyrins has been and continues to be a subject of vigorous research. In this work we investigated the planarity of a series of divalent metal chlorins in n-octane solutions: magnesium, zinc, copper, nickel, cobalt, manganese, tin, cadmium, strontium, lead and platinum. Room temperature electronic absorption spectra of these complexes are reported. We plotted the energy of each B band against its respective Qy origin band. Based on these results it was concluded that in these metal chlorins the configuration interaction between Qy and B states is essentially constant; the exception is the magnesium complex which deviates from the pattern produced by the other metal chlorins. This suggests that the magnesium ion is out of the plane of the chlorin skeleton; thus, it has C(S) symmetry while the other metal chlorins in this group retained C2v symmetry.     

Effect of meso-substituents on the osmium tetraoxide reaction and pinacol-pinacolone rearrangement of the corresponding vic-dihydroxyporphyrins

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-dimethoxyphenyl 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-beta-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.     

Synthesis of locked meso-beta-substituted chlorins via 1,3-dipolar cycloaddition

A novel approach toward "locked" chlorins with increased stability has been studied in detail. The chlorin skeleton is assembled in a convergent fashion from two fragments via a porphyrin forming reaction, followed by 1,3-dipolar cycloaddition of azomethine ylides, which are formed in situ. Central to the success of the process is the presence of two electron-withdrawing groups in vicinal positions at the perimeter of the porphyrin. As a result, the 1,3-dipolar cycloaddition took place regioselectively, on the bond activated by two electron-withdrawing groups. Moreover, the chlorins formed are locked and hence more stable because of the presence of two quaternary carbon atoms. Overall, in just six steps locked chlorins were constructed from easily available materials. The large array of functionalities tolerated in this approach validates it for a broad use in more advanced studies. The correlation between the results of the 1,3-dipolar cycloaddition and dipolarophile (porphyrin) LUMO energy was extensively studied. There was a definite correlation between the reaction time and the LUMO energy level, and a partial correlation between the reaction yield and the distribution of the LUMO. Additionally, various approaches toward crucial building blocks, namely 3,4-disubstituted-2,5-diformylpyrroles, were investigated.     

Fluorinated photosensitizers: synthesis, photophysical, electrochemical, intracellular localization, in vitro photosensitizing efficacy and determination of tumor-uptake by F in vivo NMR spectroscopy

For in vivo NMR studies, starting from pyrroles, a series of fluorinated porphyrins were synthesized by following the MacDonald reaction conditions. Upon reaction with osmium tetroxide, a fluorinated porphyrin containing four trifluoromethyl groups (12 fluorine units) was converted into the related chlorin and bacteriochlorin which exhibited long-wavelength absorptions at 652 and 720 nm, respectively. All compounds produced good singlet oxygen production efficiency. A comparative study of nine porphyrins with and without fluorine substituents indicated no adverse effects of the presence of fluorinated groups in the photophysical properties of the porphyrins, chlorins or bacteriochlorins. The first and second one-electron reduction potentials (vs SCE) of the investigated compounds range between −1.29 and −1.49 V and between −1.66 and −1.84 V in PhCN containing 0.1 M TBAP. UV-visible spectroelectrochemical data suggested the formation of π-anion and π-cation radicals upon the first reduction and first oxidation. The in vivo ¹⁹F MR study of a representative fluorine labeled compound with twelve equivalent fluorines confirmed the presence of the fluorine labeled sensitizer in mouse (C3H/HeJ) implanted with RIF tumors on mouse foot dorsum by inoculating 2×10⁵ cells (the studies were repeated on four tumored mice to confirm the feasibility and reproducibility). All fluorinated compounds were found to be quite effective in vitro. In a comparative intracellular localization study with Rhodamine-123 in RIF tumor cells, the most soluble porphyrin containing two propionic ester side chains was found to localize in mitochondria as well as the related chlorin and bacteriochlorin.     

Design, synthesis, and photophysical characterization of water-soluble chlorins

The use of chlorins as photosensitizers or fluorophores in a range of biological applications requires facile provisions for imparting high water solubility. Two free base chlorins have been prepared wherein each chlorin bears a geminal dimethyl group in the reduced ring and a water-solubilizing unit at the chlorin 10-position. In one design (FbC1-PO3H2), the water-solubilizing unit is a 1,5-diphosphonopent-3-yl ("swallowtail") unit, which has previously been used to good effect with porphyrins. In the other design (FbC2-PO3H2), the water-solubilizing unit is a 2,6-bis(phosphonomethoxy)phenyl unit. Two complementary routes were developed for preparing FbC2-PO3H2 that entail introduction of the protected phosphonate moieties either in the Eastern-half precursor to the chlorin or by derivatization of an intact chlorin. Water-solubilization is achieved in the last step of each synthesis upon removal of the phosphonate protecting groups. The chlorins FbC1-PO3H2 and FbC2-PO3H2 are highly water-soluble (>10 mM) as shown by 1H NMR spectroscopy (D2O) and UV-vis absorption spectroscopy. The photophysical properties of the water-soluble chlorins in phosphate-buffered saline solution (pH 7.4) at room temperature were investigated using static and time-resolved absorption and fluorescence spectroscopic techniques. Each chlorin exhibits dominant absorption bands in the blue and the red region (lambda = 398, 626 nm), a modest fluorescence yield (Phi f approximately 0.11), a long singlet excited-state lifetime (tau = 7.5 ns), and a high yield of intersystem crossing to give the triplet state (Phi isc = 0.9). The properties of the water-soluble chlorins in aqueous media are comparable to those of hydrophobic chlorins in toluene. The high aqueous solubility combined with the attractive photophysical properties make these compounds suitable for a wide range of biomedical applications.