Stereochemical and mechanistic aspects of dioxygenase-catalysed benzylic hydroxylation of indene and chromane substrates

Toluene dioxygenase (TDO)-catalysed benzylic hydroxylation of indene substrates (8, 16 and 17), using whole cell cultures of Pseudomonas putida UV4, was found to yield inden-1-ol (14 and 22) and indan-1-one bioproducts (15 and 23). The formation of these bioproducts is consistent with the involvement of carbon-centred radical intermediates. TDO-catalysed oxidation of indenes 8 and 16 also gave cis-diols 13 and 18 respectively. TDO and naphthalene dioxygenase (NDO), used as both whole-cell preparations and as purified enzymes, were found to catalyse the benzylic hydroxylation of chromane 30, deuteriated (+/-)-chromane 30(D) and enantiomers (4S)-30(D) and (4R)-30(D) to yield (4R)- and (4S)-chroman-4-ols 31/31(D) respectively. The mechanism of benzylic hydroxylation of chromane 30/30(D) involves the stereoselective abstraction of a pro-R (with TDO) or a pro-S (with NDO) hydrogen atom at C-4 and a marked preference for retention of configuration.

Hydroisomerisation of n-alkanes over partially reduced MoO3: Promotion by CoAlPO-11 and relations to reaction mechanism and rate-determining step

The reaction mechanism and the rate-determining step (RDS) of the isomerisation of n-alkanes (C-4-C-6) over partially reduced MoO3 catalysts were studied through the effects of the addition of an alkene isomerisation catalyst (i.e. CoAlPO- 11). When an acidic CoAlPO- 11 sample was mechanically mixed with the MoO3, a decrease of the induction period and an increase of the steady-state conversion of n-butane to isobutane were observed. These data support previous assumptions that a bifunctional mechanism occurred over the partially reduced MoO3 (a complex nanoscale mixture of oxide-based phases) during n-butane isomerisation and that the RDS was the skeletal isomerisation of the linear butene intermediates. The only promotional effect of CoAlPO-11 on the activity of partially reduced MoO3 for C-5-C-6 alkane hydroisomerisation was a reduction of the induction period, as the RDS at steady-state conditions appeared to be dehydrogenation of the alkane in this case. However, lower yields of branched isomers were observed in this case, the reason of which is yet unclear. (c) 2005 Elsevier B.V. All rights reserved.

Studies on the biodegradation of fosfomycin: Growth of Rhizobium huakuii PMY1 on possible intermediates synthesised chemically

The first step of the mineralisation of fosfomycin by R. huakuii PMY1 is hydrolytic ring opening with the formation of (1R, 2R)-1,2-dihydroxypropylphosphonic acid. This phosphonic acid and its three stereoisomers were synthesised by chemical means and tested as their ammonium salts for mineralisation as evidenced by release of P-i. Only the (1R, 2R)-isomer was degraded. A number of salts of phosphonic acids such as (+/-)-1,2-epoxybutyl-, (+/-)-1,2-dihydroxyethyl-, 2-oxopropyl-, (+/-)-2-hydroxypropyl-, (+/-)-1-hydroxypropyl- and (+/-)-1-hydroxy-2-oxopropylphosphonic acid were synthesised chemically, but none supported growth. In vitro C-P bond cleavage activity was however detected with the last phosphonic acid. A mechanism involving phosphite had to be discarded as it could not be used as a phosphorus source. R. huakuii PMY1 grew well on (R)- and ( S)- lactic acid and hydroxyacetone, but less well on propionic acid and not on acetone or (R)- and (+/-)-1,2-propanediol. The Pi released from (1R, 2R)-1,2-dihydroxypropylphosphonic acid labelled with one oxygen-18 in the PO3H2 group did not stay long enough in the cells to allow complete exchange of O-18 for O-16 by enzymic turnover.

Rhodium carbenoid O-H insertion reactions with phenols; a facile method for the synthesis of trialkyl 2-aryloxyphosphonoacetates and their use in the preparation of 2-aryloxy-3-phenylpropanoates

Substituted phenols undergo a facile Rh carbenoid-mediated O-H insertion reaction with (EtO)2P(O)C(:N2)CO2R (I; R = Et, Me) to give 44-86% 2-aryloxyphosphonoacetates II (R1 = e.g., H, 4-Me, 4-Cl, 2-OH, 4-PhCH2O). Phenols contg. strongly electron withdrawing groups, bulky ortho-substituents or certain ortho-heteroatom substituents show reduced or variable yields. Catechol affords a mono-adduct which cyclizes to lactate III. Aniline inserts preferentially and exclusively over phenol in a competition reaction with I (R = Et) to give (EtO)2P(O)CH(NHPh)CO2Et. II are versatile intermediates in a prepn. of 2-aryloxy-3-phenylpropenoates IV by Wadsworth-Emmons reaction with benzaldehydes R2C6H4CHO (R2 = PhCH2O, 2-Cl, H). Dissolving Mg metal redn. provides a mild method for the conversion of propenoates IV into the corresponding propanoates.

Study of the transamidative ring expansion of N--halogenoalkyl--lactams of alkyl chain lengths 2–12 in liquid ammonia and other liquid amines: syntheses of 7-, 8- and 9-membered 1,5-diaza cyclic ketones, including routes to (±)-dihydroperiphylline and (±)-celabenzine

N-(3-Halogenopropyl)-4-phenylazetidin-2-ones undergo amination in liquid ammonia followed by transamidative ring expansion to give the eight-membered 4-phenyl -1,5-diazacyclooctan-2-one in excellent yield. Ring expansion of the amines in liquid ammonia is found to be much more effective than in hydrocarbon solvents. Formation of 7-, 8-, and 9-membered azalactams from the requisite -halogenoalkyl--lactams is an excellent synthetic process, though it is not applicable to 10membered rings. In the cases of rings of 13-, 15- and 17-members, although amination and apparent expansion takes place, the large rings appear not to be stable to ammonia and the final products are acyclic amides. N-[4-Halogenobut-2(Z)-enyl]-4-phenylazetidin-2-one satisfactorily forms a 9-membered (Z)-olefinic azalactam, but the (E)-isomer gives an acyclic amino amide. By using alkyl-substituted -lactam side-chains, C-substituted medium rings can be obtained; the relative instability of N-acyl -lactams to ammonia, however, leads to acylamino amides rather than expanded rings.Employing ethylamine in place of ammonia, it is shown that N-ethylated azalactams are formed satisfactorily, and using allylamine, N-allyl medium rings capable of further elaboration are obtained. The chemistry of these systems is discussed. Using transamidation in liquid ammonia, a short synthesis of the 9-membered spermidine alkaloid (±)-dihydroperiphylline is reported. Synthesis of key intermediates, whose transformation into the 13-membered alkaloids of the celabenzine group has already been effected, has been carried out.X-Ray single-crystal structure determinations for 4-phenyl-1,5-diazacyclononan-2-one, trans-4-phenyl-8-methyl-1,5-diazacyclooctan-2-one and (Z)-4-phenyl-1,5-diazacyclonon-7-en-2-one are reported, and comment is made on certain conformational features.

Synthesis and Reactions of Enantiopure Substituted Benzene cis-Hexahydro-1,2-diols

Enantiopure cis-dihydro-1,2-diol metabolites, obtained from toluene dioxygenase-catalysed cis-dihydroxylation of six monosubstituted benzene substrates, have been converted to their corresponding cis-hexahydro-12-diol derivatives by catalytic hydrogenation via their cis-tetrahydro-1,2-diol intermediates. Optimal reaction conditions for total catalytic hydrogenation of the cis-dihydro-1,2-diols have been established using six heterogeneous catalysts. The relative and absolute configurations of the resulting benzene cis-hexahydro-1,2-diol products have been unequivocally established by X-ray crystallography and NMR spectroscopy. Methods have been developed to obtain enantiopure cis-hexahydro-1,2-diol diastereoisomers, to desymmetrise a meso-cis-hexahydro-1,2-diol and to synthesise 2-substituted cyclohexanols. The potential of these enantiopure cyclohexanols as chiral reagents was briefly evaluated through their application in the synthesis of two enantiomerically enriched phosphine oxides from the corresponding racemic phosphine precursors.

Multiplex analysis of age-related protein and lipid modifications in human Bruch's membrane

Aging of the human retina is characterized by progressive pathology, which can lead to vision loss. This progression is believed to involve reactive metabolic intermediates reacting with constituents of Bruch's membrane, significantly altering its physiochemical nature and function. We aimed to replace a myriad of techniques following these changes with one, Raman spectroscopy. We used multiplexed Raman spectroscopy to analyze the age-related changes in 7 proteins, 3 lipids, and 8 advanced glycation/lipoxidation endproducts (AGEs/ALEs) in 63 postmortem human donors. We provided an important database for Raman spectra from a broad range of AGEs and ALEs, each with a characteristic fingerprint. Many of these adducts were shown for the first time in human Bruch's membrane and are significantly associated with aging. The study also introduced the previously unreported up-regulation of heme during aging of Bruch's membrane, which is associated with AGE/ALE formation. Selection of donors ranged from ages 32 to 92 yr. We demonstrated that Raman spectroscopy can identify and quantify age-related changes in a single nondestructive measurement, with potential to measure age-related changes in vivo. We present the first directly recorded evidence of the key role of heme in AGE/ALE formation.

Catalytic hydrogenation of tertiary amides at low temperatures and pressures using bimetallic Pt/Re-based catalysts

Hydrogenation of tertiary amides, in particular, N-methylpyrrolidin-2-one, can be efficiently facilitated by a TiO(2)-supported bimetallic Pt/Re catalyst at low temperatures and pressures. Characterisation of the catalysts and kinetic tests have shown that the close interaction between the Re and Pt is crucial to the high activity observed. DFT calculations were used to examine a range of metal combinations and show that the role of the uncoordinated Re is to activate the C=O and that of the Pt is as a hydrogenation catalyst, removing intermediates from the catalyst surface. The rate enhancement observed on the TiO(2) support is thought to be due to the presence of oxygen vacancies allowing adsorption and weakening of the C=O bond. (C) 2011 Elsevier Inc. All rights reserved.

OXOIRON(IV) PORPHYRINS DERIVED FROM CHARGED IRON(III) TETRAARYLPORPHYRINS AND CHEMICAL OXIDANTS IN AQUEOUS AND METHANOLIC SOLUTIONS

The oxidation of six charged iron(III) tetraarylporphyrins with chemical oxidants has been investigated. In aqueous solution each can be converted by tert-butyl hydroperoxide or monopersulphate into its corresponding oxoiron(IV) porphyrin, whereas in methanol only the iron(III) tetra(N-methylpyridyl)porphyrins form detectable ferryl porphyrins at ambient temperatures. On standing, the iron species revert to the parent porphyrin with a small loss due to non-reversible oxidative destruction. That the oxidised porphyrin intermediates are oxoiron(IV) species has been determined using UV-VIS, resonance Raman, H1 NMR and EPR spectroscopy.

Diabetes-related adduct formation and retinopathy

The pathogenesis of diabetic retinopathy is complex, reflecting the array of systemic and tissue-specific metabolic abnormalities. A range of pathogenic pathways are directly linked to hyperglycaemia and dyslipidaemia, and the retina appears to be exquisitely sensitive to damage. Establishing the biochemical and molecular basis for this pathology remains an important research focus. This review concentrates on the formation of a range of protein adducts that form after exposure to modifying intermediates known to be elevated during diabetes. These so-called advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs) are thought to play an important role in the initiation and progression of diabetic retinopathy, and mechanisms leading to dysfunction and death of various retinal cells are becoming understood. Perspective is provided on AGE/ALE formation in the retina and the impact that such adducts have on retinal cell function. There will be emphasis placed on the role of the receptor for AGEs and how this may modulate retinal pathology, especially in relation to oxidative stress and inflammation. The review will conclude by discussion of strategies to inhibit AGE/ALE formation or harmful receptor interactions in order to prevent disease progression from the point of diabetes diagnosis to sight-threatening proliferative diabetic retinopathy and diabetic macular oedema.

Reaction Mechanisms of Crotonaldehyde Hydrogenation on Pt(111): Density Functional Theory and Microkinetic Modeling

The microkinetics based on density function theory (DFT) calculations is utilized to investigate the reaction mechanism of crotonaldehyde hydrogenation on Pt(111) in the free energy landscape. The dominant reaction channel of each hydrogenation product is identified. Each of them begins with the first surface hydrogenation of the carbonyl oxygen of crotonaldehyde on the surface. A new mechanism, 1,4-addition mechanism generating enols (butenol), which readily tautomerize to saturated aldehydes (butanal), is identified as a primary mechanism to yield saturated aldehydes instead of the 3,4-addition via direct hydrogenation of the ethylenic bond. The calculation results also show that the full hydrogenation product, butylalcohol, mainly stems from the deep hydrogenation of surface open-shell dihydrogenation intermediates. It is found that the apparent barriers of the dominant pathways to yield three final products are similar on P(111), which makes it difficult to achieve a high selectivity to the desired crotyl alcohol (COL).

Optimised microwave-assisted synthesis of methylcarbonate salts: a convenient methodology to prepare intermediates for ionic liquid libraries

The reaction of 1-butylpyrrolidine with dimethyl carbonate to yield the ionic liquid precursor, 1-butyl-1-methylpyrrolidinium methylcarbonate, has been investigated under microwave heating conditions and the reaction parameters optimised to achieve 100% yield of the pyrrolidinium salt with no by-products in under 1 h. The reactions of tributylamine, trioctylphosphine, and 1-butylimidazole with dimethyl carbonate under comparable conditions have also been evaluated, yielding the corresponding methylcarbonate salts which can be used as intermediates for the preparation of halide-free ionic liquids without generating any undesirable salt wastes.

Kinetics and mechanism of a macrocyclic chromium(III) complex oxidation to chromium(IV) by hexacyanoferrate(III) in strongly alkaline media

Oxidation of the macrocyclic Cr(III) complex cis-[Cr(cycb)(OH)(2)](+), where cycb = rac-5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane, by an excess of the hexacyanoferrate( III) in basic solution, slowly produces Cr(V) species. These species, detected using e.p.r. spectroscopy, are stable under ambient conditions for many hours, and the hyperfine structure of the e.p.r. spectrum is consistent with the interaction of the d-electron with four equivalent nitrogen nuclei. Electro-spray ionization mass spectrometry suggests a concomitant oxidation of the macrocyclic ligand, in which double bonds and double bonded oxygen atoms have been introduced. By comparison basic chromate(III) solutions are oxidized rapidly to chromate(VI) by hexacyanoferrate(III) without any detectable generation of stable Cr(V) intermediates.

PHOTOMINERALISATION OF 4-CHLOROPHENOL SENSITIZED BY TITANIUM-DIOXIDE - A STUDY OF THE INTERMEDIATES

The photomineralisation of 4-chlorophenol (4-CP) sensitised by Degussa P25 TiO2 in O2-saturated solution represents a possible standard test system in semiconductor-sensitised photomineralisation studies. As part of a detailed examination of this photosystem, the results of the temporal variations in the concentrations of 4-CP, CO2, Cl- and the major organic intermediates, namely, 4-chlorocatechol (4-CC), hydroquinone (HQ), benzoquinone and 4-chlororesorcinol, are reported. The observed variations in [4-CP], [4-CC], [HQ] and [CO2] fit those predicted by a kinetic model which utilises kinetic equations with a Langmuir-Hinshelwood form and assumes that there are three major possible routes in which the photogenerated hydroxyl radicals can react with 4-CP, ie. 4-CP --> 4-CC, 4-CP --> HQ and 4-CP --> (unstable intermediate) --> CO2 and that these routes have the following probabilities of occurring: 48%, 10% and 42%.

Degradation of carbon disulphide (CS2) in soils and groundwater from a CS2 -contaminated site

This study is the first investigation of biodegradation of carbon disulphide (CS₂) in soil that provides estimates of degradation rates and identifies intermediate degradation products and carbon isotope signatures of degradation. Microcosm studies were undertaken under anaerobic conditions using soil and groundwater recovered from CS₂-contaminated sites. Proposed degradation mechanisms were validated using equilibrium speciation modelling of concentrations and carbon isotope ratios. A first-order degradation rate constant of 1.25 × 10-2 h-1 was obtained for biological degradation with soil. Carbonyl sulphide (COS) and hydrogen sulphide (H₂S) were found to be intermediates of degradation, but did not accumulate in vials. A 13C/12C enrichment factor of -7.5 ± 0.8 ‰ was obtained for degradation within microcosms with both soil and groundwater whereas a 13C/12C enrichment factor of -23.0 ± 2.1 ‰ was obtained for degradation with site groundwater alone. It can be concluded that biological degradation of both CS2-contaminated soil and groundwater is likely to occur in the field suggesting that natural attenuation may be an appropriate remedial tool at some sites. The presence of biodegradation by-products including COS and H₂S indicates that biodegradation of CS₂ is occurring and stable carbon isotopes are a promising tool to quantify CS₂ degradation.