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Timothy D Lash

Publications and source records attributed to Timothy D Lash.

At least 19 recordsLinked to original sources
PubMed2006

Tetraphenyloxybenziporphyrin, a new organometallic ligand for silver(III) and gold(III).

[Structure: see text] Reaction of 4-hydroxyisophthalaldehyde with excess phenyl magnesium bromide gave a dicarbinol and this condensed with pyrrole and aromatic aldehydes in the presence of BF3.Et2O to afford, following oxidation with DDQ, novel tetraarylcarbaporphyrinoids in 10-24% yield. Further reaction with silver(I) acetate or gold(III) acetate gave stable organometallic derivatives that retained the aromatic characteristics of the parent macrocycle.

Journal Article↗
PubMed2006

[22]Porphyrin-(3.1.1.3), a new vinylogous expanded porphyrin system.

Acid-catalyzed condensation of a pyrrole bisacrylaldehyde with a tripyrrane, followed by oxidation with ferric chloride, gave a [22]porphyrin-(3.1.1.3). This stretched macrocycle shows a strong diamagnetic ring current by (1)H NMR spectroscopy and gives red-shifted porphyrin-like UV-vis spectra; coordination with palladium(II) induces an EZ isomerization to accommodate the metal cation while retaining highly diatropic characteristics. [structure: see text]

Journal Article↗
PubMed2005

Metabolism of pentacarboxylate porphyrinogens by highly purified human coproporphyrinogen oxidase: further evidence for the existence of an abnormal pathway for heme biosynthesis.

An abnormal series of porphyrin tetracarboxylic acids known as the isocoproporphyrins, are commonly excreted by patients suffering from the disease porphyria cutanea tarda (PCT). These porphyrins appear to arise by bacterial degradation of dehydroisocoproporphyrinogen that is generated by the premature metabolism of the normal pentacarboxylate intermediate (5dab) by coproporphyrinogen oxidase (copro'gen oxidase). This porphyrinogen can be further metabolized by uroporphyrinogen decarboxylase to give harderoporphyrinogen, one of the usual intermediates in heme biosynthesis. Therefore, it is possible that some of the heme formed under abnormal conditions may originate from the 'isocopro-type' porphyrinogen intermediate. In order to investigate the feasibility of alternative pathways for heme biosynthesis, the four type III pentacarboxylate isomeric porphyrinogens were incubated with purified, cloned human copro'gen oxidase at 37 degrees C with various substrate concentrations under initial velocity conditions. Of the four isomers, only 5dab was a substrate for copro'gen oxidase and this gave dehydroisocoproporphyrin. The structure of the related porphyrin tetramethyl ester was confirmed by proton NMR spectroscopy and mass spectrometry. The K(m) value for proto'gen-IX formation from copro'gen, an indicator of molecular recognition, was similar to the K(m) value for monovinyl product formation with 5dab, although copro'gen-III has an approximately twofold higher K(cat) value. Although 5dab is a slightly poorer substrate than copro'gen-III, these results support the hypothesis that an abnormal route for heme biosynthesis is possible in humans suffering from PCT or related syndromes such as hexachlorobenzene poisoning.

Binding Sites↗
PubMed2005

Synthesis of isomeric angularly annealed dinaphthoporphyrin systems: examination of the relative positioning and orientation of ring fusion as factors influencing the porphyrin chromophore.

Porphyrins built up from two naphtho[1,2-c]pyrrole subunits and two beta-substituted pyrroles can produce five isomeric dinaphthoporphyrin systems. To gain insights into the effects of ring fusion on extended porphyrin chromophores, all five of these systems were synthesized in isomerically pure form. In four of these syntheses, dihydronaphthopyrroles were used to introduce one or both of the naphthalene subunits, and dehydrogenation with DDQ in refluxing toluene later produced the fully conjugated systems. Naphthopyrroles were also prepared by reacting isocyanoacetate esters with 1-nitronaphthalene in the presence of a phosphazene base. These compounds proved to be less stable than their dihydronaphthopyrrolic counterparts but could still be utilized in these synthetic studies. Three isomeric adj-dinaphthoporphyrin systems were prepared using the MacDonald "2 + 2" condensation or by the cyclization of a,c-biladiene intermediates with copper(II) chloride or AgIO(3)-Zn(OAc)(2). A dinaphthoporphyrin with two naphthalene units pointing toward one another could only be obtained in low yields due to a combination of stability and steric factors, but the other two adj-difused systems were isolated in good overall yields. However, the final dehydrogenation step occurred in moderate yields (50-60%) and could only be performed when the porphyrins bore propionate ester side chains that produced sufficient solubility in organic solvents. The two related opp-dinaphthoporphyrins were synthesized by a "head-to-tail" self-condensation of a dipyrrylmethane aldehyde, or a "3 + 1" synthesis using a tripyrrane intermediate bearing two fused dihydronaphthalene moieties, in excellent yields. In both cases, a final dehydrogenation step was required, but the opp-dinaphthoporphyrins were consistently formed in virtually quantitative yields. The opp-dinaphthoporphyrin series gave UV-vis spectra with relatively strong Soret bands at 425 nm, and the visible region was dominated by an unusually strong Q-band III. The adj-dinaphthoporphyrins produced broader less intense Soret bands and four well-defined Q-bands, including a relatively strong absorption at 645 nm. However, the relative orientation of the naphthalene rings had no significant effects on these spectra. On the other hand, the dications produced in TFA-chloroform solutions showed more discrimination between the individual porphyrin systems, and the metallo derivatives also displayed significant variations in their electronic absorption spectra.

Journal Article↗
PubMed2005

Kinetic evaluation of human cloned coproporphyrinogen oxidase using a ring isomer of the natural substrate.

BACKGROUND: The enzyme coproporphyrinogen oxidase (copro'gen oxidase) converts coproporphyrinogen-III (GIII) to protoporphyrinogen-IX via an intermediary monovinyl porphyrinogen. The A ring isomer coproporphyrinogen-IV (C-IV) has previously been shown to be a substrate for copro'gen oxidase derived from avian erythrocytes. In contrast to the authentic substrate (C-III) where only a small amount of the monovinyl intermediate is detected, C-IV gives rise to a monovinyl intermediate that accumulates before being converted to an isomer of protoporphyrinogen-IX. No kinetic studies have been carried out using the purified human copro'gen oxidase to evaluate its ability to process both the authentic substrate as well as analogs. MATERIALS/METHODS: Therefore, purified, cloned human copro'gen oxidase was incubated with C-III or C-IV at 37 degrees C with various substrate concentrations (from 0.005 pM to 3.5 pM). The Km (an indication of molecular recognition) and Kcat (turnover number) values were determined. RESULTS: The Km value for total product formation was about the same with either C-III or C-IV indicating the same molecular recognition. However, the catalytic efficiency (Kcat/Km) of the enzyme for total product formation was not more than two fold higher using C-III relative to C-IV. CONCLUSIONS: Since the Km values are about the same for either substrate and the total Kcat/Km values are within two fold of each other, this could correlate with the increase of severity of porphyrias with monovinyl accumulation. The ability of the increased levels of C-IV to compete with the authentic substrate has important implications for clinical porphyrias.

Catalysis↗
PubMed2004

Synthesis of sapphyrins, heterosapphyrins, and carbasapphyrins by a "4 + 1" approach.

Sapphyrins are an important group of expanded porphyrins that show valuable anion binding characteristics. In this study, a "4 + 1" route to sapphyrin systems has been developed. Reaction of dialdehydes with a known tetrapyrrole intermediate 11b incorporating a bipyrrolic subunit afforded a wide range of sapphyrin-type products. The best conditions for these reactions involved carrying out the condensation of the dialdehydes with the tetrapyrrole in TFA-dichloromethane, followed by oxidation with dilute aqueous solutions of ferric chloride. A pyrrole dialdehyde reacted under these conditions to give sapphyrin in 50% yield, while furan and thiophene dialdehydes afforded the corresponding oxa- and thiasapphyrins in 66-90% yield. Pyrrole dialdehydes with fused phenanthrene or acenaphthylene rings also reacted with 11b to give the related phenanthro- and acenaphthosapphyrins in excellent yields. As was the case for acenaphthoporphyrins, the acenaphthosapphyrin gave longer wavelength absorptions than the corresponding phenanthrene fused structure, although the differences were not as marked as those seen in the porphyrin series. Reaction of 11b with 1,3-diformylindene gave a benzocarbasapphyrin in 38% yield, while a triformyl cyclopentadiene reacted with the tetrapyrrole to give a carbasapphyrin aldehyde in 7-12% yield. The free base carbasapphyrins were unstable but the monoprotonated hydrochloride salts could easily be isolated and characterized. Carbasapphyrins retain a strong diatropic ring current due to the presence of 22pi electron delocalization pathways. In the presence of trifluoroacetic acid, C-protonated dications are generated. Condensation of 1,3-azulenedicarbaldehyde with 11b gave an azulisapphyrin dihydrochloride salt in 35% yield, and this also showed a strong diatropic ring current. Addition of base gave the unstable free base form, while pyrrolidine formed an unstable adduct that showed an intense Soret band at 480 nm. These results demonstrate that many of the themes observed for modified porphyrins and carbaporphyrins also apply to the sapphyrin series, although in some cases reduced stability hampers these investigations.

Cyclization↗
PubMed2004

Synthesis, spectroscopy, and reactivity of meso-unsubstituted azuliporphyrins and their heteroanalogues. Oxidative ring contractions to carba-, oxacarba-, thiacarba-, and selenacarbaporphyrins.

This paper reports the first detailed study on meso-unsubstituted azuliporphyrins, an important family of porphyrin-like molecules where one of the usual pyrrole rings has been replaced by an azulene subunit. Although the azulene moiety introduces an element of cross-conjugation, zwitterionic resonance contributors with tropylium and carbaporphyrin substructures give azuliporphyrins diatropic character that falls midway between true carbaporphyrins and nonaromatic benziporphyrins. Protonation affords an aromatic dication where this type of resonance interaction is favored due to the associated charge delocalization. Two different "3 + 1" syntheses of meso-unsubstituted azuliporphyrins have been developed. Acid-catalyzed reaction of readily available tripyrrane dicarboxylic acids with 1,3-azulenedicarbaldehyde, followed by oxidation with DDQ or FeCl(3), affords good yields of azuliporphyrins. Alternatively, azulene reacted with acetoxymethylpyrroles (2 equiv) in refluxing acetic acid/2-propanol to give tripyrrane analogues, and following a deprotection step, condensation with a pyrrole dialdehyde in TFA-CH(2)Cl(2) gave the azuliporphyrin system. The latter approach was also used to prepare 23-thia- and 23-selenaazuliporphyrins. However, reaction of the azulitripyrrane with 2,5-furandicarbaldehyde produced a mixture of three oxacarbaporphyrins in moderate yield. The free base forms of thia- and selenaazuliporphyrins both showed intermediary aromatic character that was considerably enhanced upon protonation. The UV-vis spectra for azuliporphyrins and their heteroanalogues showed four bands between 350 and 500 nm and broad absorptions at higher wavelengths. Addition of TFA gave dications that showed porphyrin-like spectra with Soret bands between 460 and 500 nm. In the presence of pyrrolidine, azuliporphyrins and their heteroanalogues undergo nucleophilic attack on the seven-membered ring to give carbaporphyrin adducts. These systems also undergo oxidative rearrangements under basic conditions with t-BuOOH to give benzocarbaporphyrins. The selenaazuliporphyrin afforded two benzoselenacarbaporphyrins, a previously unknown core-modified carbaporphyrin system. The proton NMR spectra for these compounds showed strong diatropic ring currents with the internal CH resonance upfield above -5 ppm, while the meso-protons resonated downfield near 10 ppm. The UV-vis spectra were also porphyrin-like and gave strong Soret bands at ca. 440 nm.

Acids↗
PubMed2004

An effective chromatographic separation of chicken red blood cell coproporphyrinogen oxidase and uroporphyrinogen decarboxylase, two enzymes in heme biosynthesis.

Of the heme biosynthetic pathway enzymes, coproporphyrinogen oxidase is one of the least understood. Substrate recognition studies [Prepr. Biochem. Biotech.1997, 27, 47, J. Org. Chem.1999, 64, 464] have been done using chicken blood hemolysates (CBH) as the source of this enzyme. However, the enzyme uroporphyrinogen decarboxylase is also present in these preparations and separation of these two enzymes from CBH had not yet been achieved. Thus, a substrate ligand column was developed by covalently linking coproporphyrin-III to a sepharose resin following a similar procedure previously used for the purification of uroporphyrinogen decarboxylase [Int. J. Biochem.1992, 24, 105]. The ligand-resin chromatography step rapidly separates coproporphyrinogen oxidase from uroporphyrinogen decarboxylase as well as the majority of the hemoglobin.

Animals↗
PubMed2004

Tropiporphyrins, cycloheptatrienyl analogues of the porphyrins: synthesis, spectroscopy, chemistry, and structural characterization of a silver(III) derivative.

Tripyrranes were condensed with 1,3,5-cycloheptriene-1,6-dicarbaldehyde in TFA-CH(2)Cl(2) to give, following oxidation with 0.1% aqueous ferric chloride solutions, a series of tropiporphyrins 9. These cycloheptatrienyl analogues of the porphyrins show strong diatropic ring currents by proton NMR spectroscopy where the internal CH gives a resonance at -7.3 ppm, although the meso-protons are not shifted as far downfield as most aromatic porphyrinoid systems. These data indicate that the seven-membered ring distorts the porphyrinoid macrocycle and decreases the overall diatropicity in tropiporphyrins. Addition of trace amounts of TFA to solutions of 9 affords the corresponding aromatic monocations, and at higher acid concentrations a nonaromatic dication is generated. The dication has undergone C-protonation at one of the meso-bridges and has lost the plane of symmetry present in the parent system. This species shows significant downfield shifts to the cycloheptatrienyl protons, indicating that this unit has taken on tropylium character. Tropiporphyrin 9a underwent a Diels-Alder cycloaddition with dimethyl acetylenedicarboxylate in refluxing xylenes to give modest yields of the related adduct. The Diels-Alder adduct 17 showed an increased diatropic ring current where the internal proton shifted beyond -9 ppm, and this indicates that the [18]annulene substructure has flattened out compared to 9a. Diimide reduction of 9a afforded a dihydrotropiporphyrin that also showed a stronger ring current. Tropiporphyrins 9 were also shown to react with silver(I) acetate in the presence of DBU in refluxing pyridine to give the corresponding silver(III) organometallic derivatives. The meso-protons for these metal complexes give proton NMR chemical shift values similar to those for the parent tropiporphyrins, indicating that the macrocycle is still distorted, but the external olefinic protons are shifted downfield compared to 9. A diphenyl-substituted silver(III) derivative 18b was further characterized by X-ray crystallography. This shows that the cycloheptatriene unit takes on a highly twisted geometry that distorts the overall conformation of the porphyrinoid macrocycle.

Journal Article↗
PubMed2004

Oxybenziporphyrins, oxypyriporphyrins, benzocarbaporphyrins, and their 23-oxa and 23-thia analogues: synthesis, spectroscopic characterization, metalation, and structural characterization of a palladium(II) organometallic derivative.

A series of nine porphyrin analogues have been synthesized using the "3 + 1" variant on the MacDonald condensation. Tripyrrane-type systems with a centrally unsubstituted pyrrole, furan, or thiophene ring were prepared using conventional methods, and these were condensed with indene-1,3-dicarbaldehyde, 5-formylsalicylaldehyde, or 3-hydroxy-2,6-pyridinedicarbaldehyde in the presence of TFA to generate benzocarba-, oxybenzi-, and oxypyriporphyrins, respectively. The furan-containing analogues proved to be highly basic and could only be isolated as the corresponding hydrochloride salts. All nine analogue systems showed porphyrin-like UV-vis spectra with one or two Soret absorptions near 400 nm and a series of weaker bands at longer wavelengths. These systems also showed large diatropic ring currents by proton NMR spectroscopy that were comparable to true porphyrins. In the presence of trace amounts of TFA, benzocarbaporphyrin 12 formed a monocation, and in 50% TFA a C-protonated dication was generated. The 23-oxacarbaporphyrin 14 gave a monocation in chloroform, although the free base was generated in 5% Et(3)N-chloroform. In 50% TFA-CHCl(3), 14 afforded a mixture of mono- and diprotonated species. Thiacarbaporphyrin 15 also formed a monocation in the presence of TFA, but C-protonation was relatively disfavored for this system. Nonetheless, in the presence of TFA-d, 12, 14, and 15 all showed rapid exchange of the internal NH and CH protons. Carbaporphyrin 12 also showed slow exchange at the meso-positions, but this process was not observed for its heteroanalogues 14 and 15. Protonation studies were also conducted for oxybenziporphyrins and oxypyriporphyrins 16-21. Oxacarbaporphyrin 14 was shown to be a superior organometallic ligand and afforded good yields of the related nickel(II) and palladium(II) derivatives under mild conditions. A low yield of the platinum(II) complex could also be isolated. All three complexes retained their aromatic character, although the Pd(II) derivative appeared to possess a slightly larger diatropic ring current. The palladium(II) complex 27 was further characterized by X-ray crystallography. The macrocyclic core was shown to be highly planar where the dihedral angles of the component pyrrole, furan and indene rings relative to the mean [18]annulene plane were all </=2.1 degrees.

Journal Article↗
PubMed2004

New riches in carbaporphyrin chemistry: silver and gold organometallic complexes of benzocarbaporphyrins.

The NH-N-NH-N core of the porphyrin system represents one of the best studied and most versatile platforms for coordination chemistry. However, the replacement of one or more of the interior nitrogens with carbon atoms would be expected to diminish the ability of these systems to form metallo derivatives considerably. Despite this expectation, carbaporphyrinoid systems have been shown to form stable organometallic derivatives. Although azuliporphyrins and benziporphyrins act as dianionic ligands, benzocarbaporphyrins are trianionic ligands. Treatment of five different meso unsubstituted benzocarbaporphyrins and two different meso tetraarylbenzocarbaporphyrins with excess silver(I) acetate afforded 65-97% yields of the corresponding silver(III) organometallic derivatives. The insertion of silver metal was confirmed by mass spectrometry and X-ray crystallography. The UV-vis spectra showed a strong Soret band at wavelengths between 437 and 451 nm, together with a series of Q-type bands at longer wavelengths. The new metallo carbaporphyrins demonstrate the presence of a strong diatropic ring current in their proton NMR spectra, and carbon-13 NMR spectroscopy indicates that the derivatives retain a plane of symmetry. The reaction of meso tetraaryl carbaporphyrins with gold(III) acetate afforded the related gold(III) complexes, and these also showed strongly porphyrin-like aromatic characteristics. The UV-vis spectra for the gold complexes again showed a strong Soret band between 437-439 nm, but a secondary band near 400 nm is somewhat intensified for the gold species compared to the spectra for the related silver(III) meso tetrasubstituted carbaporphyrins. The ring currents observed for the gold(III) complexes by proton NMR spectroscopy were comparable to those of the silver(III) derivatives, implying that both series have similar macrocyclic conformations. Cyclic voltammetry was performed on two different carbaporphyrins, their silver(III) derivatives, and a gold(III) complex. The silver complexes display a reversible cathodic wave that is assigned to the Ag(III/II) couple. However, the gold porphyrinoid gave a value for the reductive wave that could be due to a gold(III/II) couple or a ligand-based process.

Journal Article↗
PubMed2003

Organometallic chemistry of azuliporphyrins: synthesis, spectroscopy, electrochemistry, and structural characterization of nickel(II), palladium(II), and platinum(II) complexes of azuliporphyrins.

Four azuliporphyrins, two meso-unsubstituted and two meso-tetraaryl substituted, were investigated in the synthesis of novel organometallic compounds. The meso-unsubstituted or "etio" series azuliporphyrins 8 reacted with nickel(II) acetate, palladium(II) acetate, and platinum(II) chloride in DMF to give the corresponding chelates 14-16, where the metal cation lies within the macrocyclic cavity and binds to all three nitrogens and the internal carbon atom. The newly available meso-tetraarylazuliporphyrins 13 similarly afforded the corresponding nickel(II), palladium(II), and platinum(II) complexes, 17-19, respectively. The new organometallic complexes are stable nonpolar compounds and were fully characterized spectroscopically and by mass spectrometry. The UV-vis data indicate that these complexes, in common with the parent azuliporphyrin system 8, do not possess porphyrin-type aromaticity. However, electron donation from the azulene unit can give rise to dipolar resonance contributors that provide a degree of carbaporphyrin-type aromatic character. The platinum(II) azuliporphyrins 16 gave noteworthy proton NMR spectra where the meso-protons showed satellite peaks due to transannular coupling to platinum-195. The pyrrolic protons of the platinum(II) meso-tetraarylazuliporphyrin 19b also showed similar satellite peaks due to coupling from the platinum-195 isotope. The electrochemistry of free base tetraphenylazuliporphyrin 13a and the related nickel(II) and palladium(II) complexes was investigated using cyclic voltammetry, and these data indicate that metal coordination improves the reversibility of the ligand-based oxidations. Nickel(II) azuliporphyrin 14a and palladium(II) tetrakis(4-chlorophenyl)azuliporphyrin 18b were also structurally characterized by X-ray crystallography. The macrocyclic core of the palladium(II) complex 18b was significantly more planar than the nickel(II) derivative 14b, and this difference was attributed to the better size match between the azuliporphyrin cavity and the larger palladium(II) ion. The straightforward synthesis of metalloazuliporphyrins under mild conditions, and their interesting spectroscopic, electrochemical, and structural features, demonstrates that the azuliporphyrin system holds great promise as a platform for organometallic chemistry.

Journal Article↗
PubMed2003

Regioselective oxidations of benzocarbaporphyrins with ferric chloride: a facile synthesis of bridged [18]annulene ketals with strong absorptions in the far red and an unexpected halogenation reaction at the interior carbon atom.

Benzocarbaporphyrins 4 were found to undergo regioselective oxidations with ferric chloride in methanol, ethanol, isopropyl alcohol, or ethylene glycol to give bridged benzo[18]annulene ketal derivatives 5 in excellent yields. These polar derivatives were generally isolated in a monoprotonated form and the corresponding free bases appeared to be relatively unstable. Addition of TFA resulted in the formation of spectroscopically distinct dications. The ketals 5 were highly diatropic in nature, showing the internal alkoxy substituents upfield beyond -1 ppm in their proton NMR spectra. The external meso-protons resonated near 10 ppm, confirming the presence of a strong aromatic ring current. The UV-vis spectra for 5 showed a Soret band at 422 nm, and two strong absorptions in the far red at 751 and 832 nm. A carbaporphyrin with a fused acenaphthylene ring was also oxidized with ferric chloride and this produced a ketal derivative with still further bathochromically shifted absorptions particularly for the Soret band. Also, the use of different alcohols in these reactions allows the overall polarity of these ketal products to be controlled and this could have merit in biomedical applications. Reaction of carbaporphyrin 4a with aqueous ferric chloride afforded the corresponding 21-chloro derivative 20 in good yields, and at longer reaction times a nonaromatic dione was isolated. Aqueous ferric bromide gave a 21-bromocarbaporphyrin product but in this case very poor yields (<10%) were noted. Mechanisms are proposed to explain the formation of these unusual oxidation products. The structure of 21-chlorocarbaporphyrin 20 was further demonstrated by X-ray crystallography. The presence of the interior chlorine atom was found to tilt the indene moiety by 29.59(4) degrees relative to the [18]annulene macrocyclic ring. The crystal packing for 20 shows offset face-to-face pi-stacking interactions that link the porphyrinoid molecules as closely paired dimers.

Journal Article↗
PubMed2003

Tert-butyl-substituted tripyrranes: insights into the steric and conformational factors that influence porphyrinoid ring formation in the "3 + 1" methodology.

The MacDonald "3 + 1" route for porphyrinoid synthesis involves the acid-catalyzed condensation of tripyrranes with monocyclic dialdehydes, followed by an oxidation step. In the present study, yields were found to be greatly diminished when tert-butyl substituents were introduced on to the tripyrrane unit. Analysis of the proton NMR spectra for the tripyrranes indicates that the preferred conformation in solution has been radically altered by the presence of these tert-butyl moieties. This appears to be the first time that the NMR properties of an intermediate in porphyrin or porphyrin analogue synthesis have been correlated to its effectiveness in macrocycle formation.

Journal Article↗