Timothy D. Lash

Oxidation with dilute aqueous ferric chloride solutions greatly improves yields in the ‘4+1’ synthesis of sapphyrins

Abstract The use of dilute aqueous FeCl 3 as an oxidant, instead of DDQ, greatly improves the yields of sapphyrin products by the ‘4+1’ methodology; yields for carbasapphyrins were somewhat lower but also greatly benefited from this approach.

Metal Complexes of Carbaporphyrinoid Systems

The cavities of carbaporphyrinoid systems provide unique environments for the formation of organometallic species. These systems commonly act as either dianionic or trianionic ligands, and may stabilize unusual oxidation states such as silver(III). Although the metalation of N-confused porphyrins has been explored in great detail, the formation of metallo-derivatives of other carbaporphyrinoids remains far less well explored. Nevertheless, exciting advances have been made on the metalation of carbaporphyrins, azuliporphyrins, benziporphyrins and related macrocycles.

Conjugated macrocycles related to the porphyrins. Part 7.1 Tropiporphyrin: Tropylium versus porphyrinoid aromaticity

Abstract Acid catalyzed “3 + 1” condensation of 1,6-cycloheptatrienedicarboxaldehyde with a tripyrrane dicarboxylic acid, followed by neutralization with triethylamine and oxidation with DDQ, afforded the cycloheptatrienyl porphyrin analog “tropiporphyrin” in good yields this system favors porphyrin-like 18π delocalization pathways for both the free base and the related monocation.

In Vitro and In Vivo Studies of the Utility of Dimethyl and Diethyl Carbaporphyrin Ketals in Treatment of Cutaneous Leishmaniasis

ABSTRACT Carbaporphyrin ketals are porphyrinoid compounds in which a pyrrole ring of a typical porphyrin macrocycle has been replaced by a ketal-substituted indene ring. It was recently demonstrated that these compounds are effective in vitro against Leishmania tarentolae. Their in vitro effectiveness is increased when they are exposed to visible light; they act as photosensitizers capable of mediating the production of reactive oxygen species (ROS). Following on this evidence, the effectiveness and cytotoxicity of the dimethyl and diethyl carbaporphyrin ketals (CKOMe and CKOEt, respectively) were determined in vitro using pathogenic Leishmania species with and without exposure to visible light (2 and 4 h). The effectiveness against various pathogenic Leishmania species was determined to be in a micromolar range. Additionally, the effect of encapsulating the carbaporphyrin ketals in liposome formulations was tested. Liposomal delivery diminished their toxicity, while the effectiveness was enhanced upon exposure to visible light (photodynamic effect). The cytotoxicity levels for human U937 cells and hamster peritoneal macrophages were in the ranges of 0.3 to 9 μM and 7 to 330 μM, respectively. When tested in vivo, using a hamster (Mesocricetus auratus) model of cutaneous leishmaniasis, CKOMe was active even in the dark, suggesting that the compound, once metabolized in the animal tissue, produces an active ingredient that does not seem to be photosensitive. Reduction in lesion size, histopathologic analyses, and smears confirmed the in vivo effectiveness of the compound, since the parasitic load was diminished without noticeable toxic effects.

PORPHYRIN SYNTHESIS BY THE 3 + 1 METHODOLOGY : A SUPERIOR APPROACH FOR THE PREPARATION OF PORPHYRINS WITH FUSED 9,10-PHENANTHROLINE SUBUNITS

Abstract Porphyrins with fused 1,10-phenanthroline subunits have been prepared in exceptionally high yields by the acid catalyzed condensation of phenanthroline substituted tripyrranes with a 2,5-pyrroledicarboxaldehyde .

Origin of aromatic character in porphyrinoid systems

The aromatic nature of porphyrins is commonly attributed to the presence of an [18]annulene substructure. However, this viewpoint has been disputed. Drawing on a range of examples of carbaporphyrinoid systems from the authors own studies, the [18]annulene model is shown to be a self-consistent and insightful approach for considering the aromatic properties of these porphyrin analogs. Benziporphyrins provide a continuum of porphyrinoid structures that range from nonaromatic to highly aromatic species and the presence of 18π electron delocalization pathways provides an excellent explanation for the variations in their properties. The same type of analysis is applied to carbaporphyrins, tropiporphyrins, azuliporphyrins, N-confused porphyrins, pyrazoloporphyrins and dicarbaporphyrins. Nevertheless, these properties might also be explained by a 22π electron delocalization model proposed by Schleyer. The [18]annulene model gains further support from the properties of dideazaporphyrins which cannot take part in this type of 22π electron delocalization but nevertheless retain porphyrin-like aromatic properties. These results support the concept that porphyrins are bridged [18]annulenes.

Proline betaine is a highly effective osmoprotectant for Staphylococcus aureus

Proline betaine is an osmoprotectant that is at least as effective as glycine betaine, and more effective than L-proline, for various strains of Staphylococcus aureus, and Staphylococcus epidermidis and Staphylococcus saprophyticus. 13C NMR studies revealed that proline betaine accumulated to high levels in osmotically stressed S. aureus, but was also detected in organisms grown in its presence in the absence of osmotic stress. Competition experiments indicated that proline betaine was taken up by the proline transport systems of S. aureus, but not by the high affinity glycine betaine transport system.

Porphyrins with Exocyclic Rings: Part 9 [1] Synthesis of Porphyrins by the ‘3 + 1’ approach

Tripyrrane dibenzyl esters are readily available from the reaction of two equivalents of 5-acetoxymethylpyrrole-2-carboxylates with 2,5-diunsubstituted pyrroles in refluxing acetic acid-ethanol. Hydrogenolysis of the benzyl ester moieties affords the corresponding dicarboxylic acids, and subsequent condensation with 2,5-diformylpyrroles in 5% trifluoroacetic acid-dichloromethane, followed by neutralization with triethylamine and oxidation with DDQ, gives porphyrin products in good to excellent yields. The isomeric purity of these products has been rigorously demonstrated by proton and carbon-13 NMR spectroscopy. This chemistry allows the direct synthesis of porphyrin structures that would otherwise only be accessible via multistep procedures. In addition, this approach provides a convenient synthetic entry to the geochemically important tetrahydrobenzoporphyrins and cycloalkanoporphyrins. The first examples of tripyrranes with tetrahydroindole subunits are reported and their utility in the synthesis of novel cycloalkanoporphyrins is disclosed.

Porphyrins with exocyclic rings. Part 3. A reassessment on the utility of cyclopenta[b]pyrroles in the synthesis of porphyrin molecular fossils. Preparation of three type II porphyrins related to deoxophylloerythroetioporphyrin (DPEP).☆☆☆

Abstract The utility of cyclopenta[b]pyrroles in porphyrin synthesis has been reinvestigated. A 6-oxocyclopenta[b]pyrrole 18 was prepared by cyclization of the propanoyl chloride sidechain of an α-unsubstituted pyrrole 17d in the presence of tin(IV) chloride. Subsequent reduction with sodium borohydride afforded the corresponding 6-hydroxy compound 10 and further acid catalyzed condensation with α-unsubstituted pyrroles 11a and 11b gave the novel 6-pyrrolylcyclopenta[b]pyrroles 22a and 22b in excellent yields. Attempts to prepare deoxophylloerythroetioporphyrin (DPEP; 2), a widespread sedimentary porphyrin molecular fossil, from these dipyrrolic intermediates using the tripyrrene-a,c-biladiene route were unsuccessful. However, the synthesis of three related meso,β-ethanoporphyrins using the MacDonald condensation was successfully carried out in moderate to good yields. Retention of an sp3 hybridized carbon bridge at the cyclopentene ring fusion site of the intermediary open chain tetrapyrroles appears to be crucial during macrocycle formation, as this diminishes the steric repulsion between the peripheral substituents and the carbocyclic ring.

Synthesis and Reactivity of Carbachlorins and Carbaporphyrins

Acid-catalyzed condensation of 3-ethoxymethylenecyclopentene-1-carbaldehyde with a tripyrrane, followed by oxidation with aqueous ferric chloride solutions, afforded moderate yields of a carbachlorin. This porphyrinoid exhibited a porphyrin-like UV-vis spectrum with a slightly intensified peak at 650 nm. The proton NMR spectrum showed that the carbachlorin is highly diatropic, and this has been confirmed by nucleus independent chemical shift (NICS) calculations. Oxidation of the carbachlorin with DDQ gave the first example of a carbaporphyrin that is unsubstituted on the carbocyclic ring. Reaction of the carbachlorin with silver(I) acetate gave the corresponding silver(III) organometallic complex. When the carbachlorin was refluxed with methyl iodide and potassium carbonate in acetone, the 22-methyl derivative was formed. Treatment of the N-alkylation product with palladium(II) acetate afforded an unstable palladium(II) carbachlorin that was partially converted into a palladium(II) carbaporphyrin via an oxidation-methyl group migration process. Improved yields of the carbaporphyrin complex were obtained when the reaction mixture was stirred with aqueous ferric chloride solutions. These results open up the field of carbachlorin and carbaporphyrin chemistry for further study.