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Pin1 Inhibitors: Towards Understanding the Enzymatic MechanismXu, Guoyan 11 June 2010 (has links)
An important role of Pin1 is to catalyze the cis-trans isomerization of pSer/Thr-Pro bonds; as such, it plays an important role in many cellular events through the effects of conformational change on the function of its biological substrates, including Cdc25, c-Jun, and p53. The expression of Pin1 correlates with cyclin D1 levels, which contributes to cancer cell transformation. Overexpression of Pin1 promotes tumor growth, while its inhibition causes tumor cell apoptosis. Because Pin1 is overexpressed in many human cancer tissues, including breast, prostate, and lung cancer tissues, it plays an important role in oncogenesis, making its study vital for the development of anti-cancer agents.
Many inhibitors have been discovered for Pin1, including 1) several classes of designed inhibitors such as alkene isosteres, non-peptidic, small molecular Pin1 inhibitors, and indanyl ketones, and 2) several natural products such as juglone, pepticinnamin E analogues, PiB and its derivatives obtained from a library screen. These Pin1 inhibitors show promise in the development of novel diagnostic and therapeutic anticancer drugs due to their ability to block cell cycle progression. In order to develop potent Pin1 inhibitors, the concept of transition-state analogues was used for the design of three classes of compounds: ketoamide, ketone, and reduced amide analogues.
Specifically, a convergent synthesis of α-ketoamide inhibitors of Pin1 was developed. An α-hydroxyorthothioester derivative of Ser was reacted directly with an aminyl synthon. The reaction was catalyzed by HgO and HgCl2 to form an α-hydroxyamide. Hydrolysis and coupling were combined in one step in 80% yield. Two diastereomers of a phospho-Ser-Pro α-ketoamide analogue were synthesized. The resulting IC50 values of 100 µM and 200 µM were surprisingly weak for the Pin1 peptidyl-prolyl isomerase.
Diastereomeric ketones were synthesized by coupling cyclohexenyl lithium to the serine Weinreb amide, via the Michael addition of a carboxylate synthon. The IC50 values of the two ketone diastereomers were determined to be 260 μM and 61 μM, respectively.
Five reduced amide inhibitors for Pin1 were synthesized through a selective reduction using borane. The most potent inhibitor was found to be Fmocâ pSerâ Ψ[CH2N]-Proâ tryptamine, which had an IC50 value of 6.3 µM. This represents a 4.5-fold better inhibition for Pin1 than a comparable cis-amide alkene isostere. The co-crystal structure of Acâ pSerâ Ψ[CH2N]-Proâ tryptamine bound to Pin1 was determined to 1.76 Ã resolution.
Towards understanding the two proposed mechanisms of Pin1 catalysis, nucleophilic-additition mechanism and twisted-amide mechanism, three classes of Pin1 inhibitors (ketoamide, ketone, and reduced amide analogues) involving a total of nine compounds were synthesized and evaluated. The weak inhibitory activities of ketoamide and ketone analogues do not support the nucleophilic-addition mechanism, while the twisted-amide mechanism of Pin1 catalysis is promising based on the reduced amide inhibitors with good potencies. / Ph. D.
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The acid-catalyzed self-condensation reaction of b-diketones in the presence of 2,2,2-trifluorodiazoethaneRoy, John Thomas January 1984 (has links)
A novel acid-catalyzed self-condensation reaction of 6-diketones in the presence of 2,2,2-trifluorodiazoethane (TFD) has been discovered. This reaction is of interest because not many methods are available for the preparation of cyclized products (e.g., aromatic natural products) from 6-dicarbonyl units. Acid-catalyzed reactions of 1-phenyl-1,3-butanedione and several substituted derivatives of 1- phenyl-1,3-butanedione with TFD afforded two groups of substituted biphenyl compounds. One of these groups could be an important synthon for the preparation of larger polycyclic aromatic compounds. Several cyclized products have also been obtained from the reaction of 2, 4-pentanedione with TFD. Two potential mechanisms have been suggested to describe this cyclization process. Mechanistic studies utilizing dienophiles suggest that the previously described cyclized products have originated from Michael addition reactions. Several NMR techniques have been utilized to characterize the reaction products which were obtained in this study. These techniques include ¹³C labeling, the ¹³C NMR INADEQUATE pulse experiment, and applications of lanthanide shift reagents. The results that were obtained from the lanthanide shift reagent studies illustrate that certain oxygen atoms can be converted to 2, 2, 2-trifluoroethyl ethers to prevent complexation with lanthanide shift reagents. This methodology was successfully utilized to simplify the interpretation of lanthanide shift reagent results that were obtained from polyfunctional molecules. The reactions of several additional β-diketones have also been studied to better understand the cyclization process. / Ph. D.
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Assessment of the capabilities of two polar sPC-SAFT terms through application to measured ketone-alkane phase equilibria dataCripwell, Jamie Theo 04 1900 (has links)
Thesis (MEng)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Thermodynamic models have been investigated extensively since Johannes van der Waals first
devised a mathematical relation capable of predicting both vapour and liquid phases for a mixture at
equilibrium. With the advent of modern computing power, these equations of state have gone from their
humble empirical beginnings to the comprehensive and fundamentally derived models we have today.
One such physically sound model is the Statistical Associating Fluid Theory (SAFT) family of equations,
derived from the molecular perturbation theories of the 1980’s. The relative youth of this thermodynamic
framework has meant that much work has gone into modification and optimisation of the model recently.
The variants of particular interest to this work are the simplified perturbed chain SAFT equations with the
Jog & Chapman (sPC-SAFTJC) and Gross & Vrabec (sPC-SAFTGV) polar terms.
Each of the polar terms supports one adjustable polar parameter that relates to the quantity of
polar segments in the reference fluid but not necessarily its position in the carbon chain. The strength of
polar interactions is known to decrease as the functional group moves away from the terminal methyl
group and the effects of steric hindrance increase. Thus, in question here is whether the models can
account for the change in polar interactions associated with the changing position of the polar
group, by only adjusting the values of the existing pure component parameters; that is, in lieu of
a position specific parameter. The carbonyl group in ketone molecules is one such polar group, and it is
this homologous series that is the focus of this study.
The decrease in polar interactions as the carbonyl group in a ketone molecule shifts centrally is
apparent from the lower boiling points of the isomers where the polar group is central as compared to
those where the functional group is nearer the terminal methyl group. The effect of this functional group
shift on binary phase behaviour has not previously been assessed for any system however, as the lack of
experimental data attests. Thus, experiments had to be conducted to generate phase equilibrium data for
systems comprising each structural isomer of a mid-length ketone with a common second component
with no functionality. This limitation was imposed to isolate the cause of experimentally observed
phenomena to the shifting polar group alone. The generated data could then be appropriately modelled
using the polar sPC-SAFT variants and the capabilities of each model, as outlined above, assessed. To this end, isobaric binary vapour-liquid equilibrium data were measured for 2-, 3- &
4-heptanone with three separate normal alkanes of similar length (n-octane, n-nonane & n-decane) at
40kPa. The apparatus used was a dynamic Gillespie VLE still with temperature and pressure accuracies of
0.03°C and 1.6mbar respectively. Equipment verification was achieved through the reproduction of
experimental data for the ethanol/1-butanol system at 1.013bar. The vapour and liquid samples for all
nine systems were analysed by gas chromatography with a maximum compositional error of ±0.022 mole
fraction. All reported data were found to be thermodynamically consistent using both the L/W and
McDermott-Ellis consistency tests. When paired with a common n-alkane, all three structural heptanone isomers displayed similar
qualitative trends in phase behaviour. Minimum boiling azeotropes were measured in all nine systems; in
the high alkane region for n-octane systems (~98 mole%), the equal concentration region for n-nonane
systems (34 mole% to 53 mole%) and in the very dilute n-alkane region for n-decane systems (~3 mole%).
The n-nonane systems in particular highlighted the effect of shifting functional group, with completely
separate phase envelopes away from the pure alkane composition space evident in a particularly small
temperature range.
Modelling was performed using in-house developed software, with pure component parameters
generated for each system using five different regression procedures. The first was traditional fitting of the
segment diameter (σ), segment number (m), segment energy (є/k) and the respective polar parameter (xp, np)
to DIPPR correlations of pure component saturated vapour pressure, liquid density and the heat of
vaporisation. The latter four procedures included the fixing of the polar parameter according to functional
group correlations and the three instances of including the binary VLE data set for each of the three
alkanes considered in this work. When applied to the nine binary ketone-alkane systems measured in this
work, excellent predictions of the experimental data were in evidence in most cases and only small binary
interaction parameters were necessary to correlate the data where pure predictions were poor.
The performance of the parameter sets based on the fixing of the polar parameter and the
inclusion of VLE data were consistent and of a high quality for both models, with near identical
parameters generated in all four cases for each of the nine systems. The parameter sets generated in this
fashion were shown to be applicable not only to the systems measured in this work, but also successfully
predicted the independently measured experimental data of the n-hexane/4-heptanone system. It was thus
concluded that either of these regression alternatives are viable for the generation of accurate component
parameters, and the choice of VLE data set included is trivial. The pure predictions of the sPC-SAFTGV model were generally better than its sPC-SAFTJC
counterpart, particularly in the case of the traditionally regressed parameter sets. sPC-SAFTGV displayed
constant qualitative agreement with the experimental data for each of the heptanone isomers with a given
n-alkane. The quality of the predictions of sPC-SAFTJC, however, worsened significantly as the polar
interactions diminished from 2- to 4-heptanone, with no predictions even possible for the least polar
isomer. This was attributed to the different perturbation theories used in the development of these terms,
but a more detailed study would be necessary to confirm this.
This work thus shows an apparent inability of the sPC-SAFTJC equation of state to
account for the decreasing polar interactions associated with the carbonyl group in a ketone
molecule shifting centrally, while sPC-SAFTGV produces qualitatively good fits for all three
isomers. These flaws can be overcome through the incorporation of VLE data in the regression
procedure if such data is available, or otherwise through the use of group specific correlations for fixing
the polar parameter value. / AFRIKAANSE OPSOMMING: Sedert Johannes van der Waals die eerste wiskundige verhouding ontwikkel het wat beide die
damp- en vloeibare fases van 'n mengsel by ewewig kon voorspel, is die veld van termodinamiese
modellering al deeglik ondersoek. Na die koms van die moderne rekenaars het hierdie vergelykings van
hul nederige empiriese wortels gegroei tot die omvattende, fundamentele modelle wat ons vandag het. Een
so 'n fundamenteel gebaseerde familie van vergelykings is die ‘Statistical Associating Fluid Theory’ (SAFT)
modelle, wat afgelei is vanaf molekulêre versteuringsteorieë, ontwikkel in die 1980s. Hierdie relatiewe jong
modelle het in die afgelope ruk aansienlike aanpassing en optimering ondervind. Modelvariante van
besondere belang tot hierdie werk, is die vereenvoudigde versteurde ketting of ‘simplified perturbed chain’
SAFT vergelykings, met Jog & Chapman (sPC- SAFTJC) en Gross & Vrabec (sPC- SAFTGV) polêre terme.
In die sPC-SAFT toestandsvergelyking word elkeen van die polêre terme ondersteun deur een
polêre veranderlike. Hierdie veranderlike is afhanklik van die aantal polêre segmente in die
verwysingsvloeistof, maar nie noodwendig hul posisie in die koolstofketting nie. Daarteen is dit bekend
dat die polêre interaksies tussen molekules swakker word soos die polêre groep wegbeweeg van die
terminale metielgroep, en steriese hindernis ʼn groter rol begin speel. Dus is die vraag of die model die
verandering in die polêre interaksie, as gevolg van veranderende posisie van die polêre groep, kan
voorspel deur in plek van ʼn posisie afhanklike parameter, slegs ʼn aanpassing van die polêre
waardes van die suiwer komponente te maak. Die karbonielgroep in ketoon molekules is een so 'n
polêre groep, en ʼn homoloë reeks ketone word in hierdie studie ondersoek. Die afname in die polêre interaksie soos wat die karbonielgroep in 'n ketoon molekule weg skuif
vanaf die terminale metiel groep is sigbaar deur die afname in kookpunt van die verskillende isomere.
Hierdie effek van die funksionele groepsposisie op binêre fasegedrag is nog nie voorheen vir enige stelsels
geëvalueer nie en geen eksperimentele data is vrylik beskikbaar nie. Om hierdie tekortkoming in die
literatuur aan te spreek, is eksperimentele fase ewewig data gemeet. ʼn Reeks stelsels is ondersoek wat elk
bestaan uit ʼn struktuurisomeer van ʼn mid-lengte ketoon en ʼn tweede komponent met geen funksionele
bydrae. Eksperimente is so opgestel om die effek van die skuiwende polêre groep op die fasegedrag te
isoleer en kwalitatief te ondersoek. Die gegenereerde data is dan gemodelleer met behulp van die polêre
sPC- SAFT variante, soos hierbo gespesifiseer, en die vermoëns van elke model is beoordeel.
Isobariese binêre fase ewewig data is by 40kPa gemeet vir damp-vloeistof stelsels bestaande uit 2,
3 & 4 heptanoon, gemeng met drie verskillende normaal alkane van vergelykbare kettinglengte (n-oktaan,
n-nonaan & n-dekaan). Die apparaat wat gebruik was is 'n dinamiese Gillespie VLE eenheid met
temperatuur- en drukakkuraatheid van 0,03°C en 1.6mbar, onderskeidelik. Die akkuraatheid van die
toerusting is bevestig deur eksperimentele data vir ʼn etanol/1-butanol stelsel by 1.013bar te reproduseer.
Die damp en vloeibare monsters vir al nege stelsels is ontleed deur gaschromatografie met 'n maksimum komposisionele fout van ± 0,022 (molfraksie). Alle data is as termodinamies konsekwent gevind deur van
beide die L/W en McDermott-Ellis konsekwentheidstoetse gebruik te maak.
Mengsels van die drie strukturele isomere van heptanoon met ʼn gemene n-alkaan het tydens
eksperimente soortgelyke kwalitatiewe tendense in fasegedrag getoon. Gedurende eksperimente is die lae
kookpunt asiotrope gemeet vir al nege stelsels. Die asiotrope verskyn in die hoë alkaan konsentrasies
(~98 mol%) vir n-oktaan stelsels, medium konsentrasies (34 mol% tot 53 mol%) vir n-nonaan stelsels en
baie verdunde konsentrasies (~ 3 mol%) vir n-dekaan stelsels. Die n-nonaan stelsels beeld veral die effek
van die verskuiwing van die funksionele groep uit, met diskrete fasegrense wat duidelik apart staan van die
suiwer alkaan ruimte, binne ʼn klein temperatuurverskil.
Modellering van die stelsels is uitgevoer met behulp van sagteware wat in-huis ontwikkel is.
Suiwer komponent data is gegenereer vir elke stelsel deur van vyf verskillende regressie prosedures gebruik
te maak. Die eerste is die tradisionele passing van die segment deursnee (σ), segment nommer (m), segment
energie (є/k) en die onderskeie polêre parameters (xp, np) op DIPPR korrelasies van die suiwer komponent
versadigde dampdruk, vloeistof digtheid en die hitte van verdamping. Die oorblywende vier prosedures
sluit in die bepaling van die polêre parameter deur funksionelegroep korrelasies, en drie gevalle waar die
binêre VLE data vir elk van die drie alkane ingesluit is. Deur hierdie prosedures op die modellering van die
nege binêre ketoon/alkaan stelsels toe te pas, is uitstekende passings van die eksperimentele data verkry
met slegs baie klein binêre interaksie parameters nodig waar voorspellings minder akkuraat was.
Die prestasie van die parameter stelle, gebaseer op die bepaling van die polêre parameter en die
insluiting van VLE data, is konsekwent en van 'n hoë gehalte vir albei modelle, met 'n byna identiese
parameters gegenereer in al vier gevalle vir elk van die nege stelsels. Die parameter stelle wat op hierdie
metode gegenereer is, is nie net toepaslik gevind op eksperimentele data gemeet in hierdie werk nie, maar
ook op onafhanklike data vir die n-heksaan/4-heptanoon stelsel. Daar is tot die gevolgtrekking gekom dat
beide van die regressie alternatiewe lewensvatbaar is vir die generasie van akkurate suiwer komponent
parameters, en dat die insluiting van die VLE data triviaal is. Die suiwer sPC - SAFTGV voorspelling was oor die algemeen beter as die suiwer sPC- SAFTJC
model met die voorspelling van data, veral in die geval van passings gedoen met parameters verkry vanaf
tradisionele regressie metodes. sPC- SAFTGV het ʼn voortdurende, kwalitatiewe ooreenkoms met
eksperimentele data getoon vir elk van die nege stelsels. Daarteen het voorspellings deur sPC- SAFTJC
beduidend verswak soos die polêre interaksies afgeneem het vanaf 2- na 4- heptanoon, met geen akkurate
voorspelling moontlik vir die minste polêre isomeer nie. Die verskynsel kan toegeskryf word aan die
verskil in versteuringsteorieë wat gebruik word in die ontwikkeling van die onderskeie
toestandsvergelykings, maar ʼn meer in-diepte ondersoek is nodig om hierdie teorie te bevestig.
Hierdie werk toon dus 'n skynbare onvermoë van die sPC - SAFTJC toestandsvergelyking
om die verandering in polêre interaksie, as gevolg van die veranderende posisie van die polêre
groep, vir die karbonielgroep in ʼn ketoon te voorspel, terwyl die sPC-SAFTGV toestandsvergelyking goeie kwalitatiewe passings vir al drie isomere bied. Hierdie tekortkominge
kan oorkom word deur VLE data, indien beskikbaar, in die regressie prosedure in te sluit, of deur die
gebruik van groep spesifieke korrelasies vir die aanpassing van die polêre parameter.
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Optimering i organisk syntes : betingelser, system, syntesvägarHansson, Lars January 1990 (has links)
This thesis deals with different optimization problems encountered in organic synthesis. The use of response surface, sequential simplex and PLS techniques, for simultanious optimization of yield and suppression of side reactions is investigated. This is illustrated by an example of enamine synthesis, were a side reaction was a serious problem. The problem of efficient screening to find suitable catalysts and solvents in new reactions is also investigated. Here, the use of principal properties as selection criterion, is demonstrated with a new process for the silylation of a,ß-unsaturated ketones. The extension of the new method to bis silylation of 1,2- and 1,3-diketones is demonstrated. The total synthesis of (±)-geosmin is investigated by an approach aimed to reduce the number of necessary steps involved. The suggested strategy, is to find compatible solvents through several transformations in the sequence to accomplish one-pot multistep reactions. In this context an improved method for the preparation of 1,10-dimethyl-l(9)-octalone-2 was established. Comparison with previously reported total syntheses of (±)-geosmin was done. / digitalisering@umu
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Vliv tělesné kondice dojnic na hladinu ketolátek v krviBEŇASOVÁ, Veronika January 2019 (has links)
The aim of this diploma thesis is to evaluate the data about holstein dairy cow body condition at calving and to review its effect on ketones blood level and its relation to incidence of ketosis. The monitoring took place in a selected dairy farm from October 2017 to February 2019. Body condition of 280 cows was evaluated on the day of calving by assessing the body condition score (BCS) and later on 10 days in milk the blood level of B-hydroxybutyrate was measured. Furthermore, parity, body weight in calving day, body weight on 10 days in milk, content of milk fat and protein on 10 days in milk and milk yield on 10 days in milk were monitored. Average BCS of the herd was 3,7, the maximum measured BCS value was 5, the minimum was 2. Total incidence of ketosis on herd level was 21,07 % considering ketosis if BHB 1,0 mmol.l-1. 62,7 % of that was a subclinical form of ketosis while the remaining 37,3 % was the clinical form of ketosis. Correlation analysis of the relation between parity and level of BHB in blood showed positive correlation (r=0,15, p=0,00), when cows on higher lactation had higher level of blood BHB. Positive correlation between fat/protein ratio in milk and level of BHB in blood was evaluated by correlation analysis (r=0,31 , p=0,00). The BCS at calving and BHB level on 10 days in milk showed positive correlation (r=0,14 , p=0,02). As far as negative energy balance is taken into account, the positive correlation between BCS at calving and body weight loss was confirmed (r=0,17 , p=0,00). The fact that heavier cows and cows with higher BCS mobilise more body fat reserves was confirmed by positive correlation between the body weight at calving and the body weight loss (r=0,47, p=0,00) and between the body weight at calving and the fat/protein ratio in milk (r=0,27, p=0,00). Body weight at calving had provable positive impact on the milk yield (r=0,19, p=0,00).
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Biocatalisadores de origem marinha (algas, bactérias e fungos) para redução estereosseletiva de cetonas / Biocatalysts from marine origin (algae, bacteria and fungi) for stereoselectivy reduction of ketonesMouad, Ana Maria 10 September 2009 (has links)
Neste trabalho foram realizadas reações de redução de cetonas empregando diferentes organismos marinhos como biocatalisadores (algas, fungos e bactérias). Nas triagens foram utilizados derivados de acetofenonas (o-iodoacetofenona, m-iodoacetofenona, p-iodoacetofenona, o-fluoracetofenona, o-cloroacetofenona, o-bromoacetofenona, o-nitroacetofenona) e duas cetonas 1,3-dicarboniladas: a 4,4,4-triflúor-1-(furan-2-il)butano-1,3-diona e a 4,4,4-triflúor-1-(naftalen-2-il)butano-1,3-diona. As reações com as algas marinhas Bostrychia tenella e a Bostrychia radicans levaram aos álcoois com excelentes seletividades (ee >98%), contudo, obtiveram-se baixas conversões. Foram isoladas as bactérias Bt-01 (B. tenella) e Bt-02 (B. radicans), as quais catalisaram as reduções das acetofenonas com resultados similares aos obtidos com as algas. Os fungos (Br-09, Br-23, Br-27, Br-61) isolados da alga B. radicans reduziram as acetofenonas com boas seletividades e conversões. Ainda, reações de redução das acetofenonas com quatro linhagens de fungos isolados da alga Sargassum sp (SMA2-C, SMA2-8, SMA2-58, SGPY-41) levaram a obtenção dos respectivos álcoois com diferentes conversões e seletividades. As reduções das cetonas 1,3-dicarboniladas foram realizadas com as algas B. tenella e B. radicans, e com sete linhagens de fungos marinhos (Aspergillus sydowii Ce15, Aspergillus sydowii Ce19, Aspergillus sydowii Gc12, Bionectria sp Ce5, Penicillium raistrickii Ce16, Penicillium miczynskii Gc5 e Trichoderma sp Gc1). As algas e os fungos marinhos catalisaram a redução regiosseletiva e estereosseletiva das cetonas 1,3-dicarboniladas, onde ocorreu a redução do grupo α-trifluorcarbonílico. Concluiu-se que as algas e seus microrganismos associados, e os fungos marinhos têm potencial para serem utilizados como biocatalisadores em reações de redução. Este trabalho foi o primeiro estudo realizado no país envolvendo algas marinhas e seus microrganismos associados em reações de redução de cetonas, cujos resultados são bastante promissores. / In this work, were investigated the ketone reduction reactions using several marine organisms as biocatalysts (algae, fungi and bacteria). In the screening were utilized acetophenone derivatives (o-iodoacetophenone, m-iodoacetophenone, p-iodoacetophenone, o-fluoroacetophenone, o-chloroacetophenone, o-bromoacetophenone, o-nitroacetophenone) and two 1,3-dicarbonylated compounds: 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione and 4,4,4-trifluoro-1-(naftalen-2-yl)butane-1,3-dione. The reactions with algae Bostrychia tenella and Bostrychia radicans afforded the alcohols with high selectivities (ee > 98%), however, with low conversions. The bacteria Bt-01 and Bt-02 were isolated from algae B. tenella and B. radicans, respectively, which catalyzed the reductions of acetophenones as the same as obtained with the algae. The acetophenones were reduced by several fungi (Br-09, Br-23, Br-27, Br-61) in good selectivities and conversions. These fungi were isolated from Bostrychia radicans. In addition, the acetophenone reduction reactions were screened with four strains of fungi, which were isolated from algae Sargassum sp (SMA2-C, SMA2-8, SMA2-58, SGPY-41). The alcohols were obtained with different conversions and selectivities. The reductions of 1,3-dicarbonylated compounds were carried out with the algae B. tenella and B. radicans, and marine fungi (Aspergillus sydowii Ce15, Aspergillus sydowii Ce19, Aspergillus sydowii Gc12, Bionectria sp Ce5, Penicillium raistrickii Ce16, Penicillium miczynskii Gc5 and Trichoderma sp Gc1). The algae and marine fungi catalyzed regio- and estereoselectively reductions of the 1,3-dicarbonylated compounds. The α-trifluoromethylcarbonyl group was reduced preferentially. In conclusion, the algae and associated micro-organisms and marine fungi have potential for catalyzing ketone reduction reactions. This investigation was the first study carried out in the Brazil by using algae and associated micro-organisms in the ketone reduction reactions. The obtained results here are promising and interesting.
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Palladium(II)-Catalyzed Coupling ReactionsLindh, Jonas January 2010 (has links)
Sustainable chemical processes are becoming increasingly important in all fields of synthetic chemistry. Catalysis can play an important role in developing environmentally benign chemical processes, and transition metals have an important role to play in the area of green chemistry. In particular, palladium(II) catalysis includes many key features for successful green chemistry methods, as demonstrated by a number of eco-friendly oxidation reactions catalyzed by palladium(II). The aim of the work presented in this thesis was to develop novel and greener palladium(II)-catalyzed coupling reactions. In striving to achieve this aim, the first open-vessel, room-temperature palladium(II)-catalyzed oxidative Heck reaction, using oxygen from the air as the reoxidant of palladium, was developed. In a further investigation of the palladium(II)-catalyzed oxidative Heck reaction, base-free conditions for the transformation were identified and suitable conditions for microwave-assisted oxidative Heck reactions were established. A convenient and low-cost palladium(II)-catalyzed method for the synthesis of styrene derivatives, by coupling arylboranes with vinyl acetate, was developed. The reaction mechanism was studied using ESI-MS, which enabled the detection of cationic palladium intermediates in ongoing productive reactions, and a plausible catalytic cycle was proposed. In an attempt to make the oxidative Heck and the styrene synthesis reactions more attractive from an industrial point of view, conditions for continuous flow synthesis were identified. The results were generally good and rapid synthesis of the desired products was obtained. The first palladium(II)-catalyzed C–P bond-forming Hirao-type reaction, employing arylboranes instead of the commonly used aryl halides, was developed. An ESI-MS study was performed, and a plausible catalytic pathway was suggested. Finally, a novel method for synthesizing aryl ketones from benzoic acids and nitriles, via palladium(II)-catalyzed decarboxylation of the benzoic acids, was established. Further, the reaction mechanism was studied by ESI-MS and a plausible catalytic route presented.
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Benzaldehyde Lyase Catalyzed Synthesis Of Novel AcyloinsSimsek, Ilke 01 September 2009 (has links) (PDF)
& / #945 / -Hydroxy phosphonates are versatile building blocks for the synthesis of many biologically active compounds that display antiviral, antibacterial, anticancer, pesticide activities beside their enzyme inhibitory activities such as they are the inhibitors of rennin or human immunodeficiency virus (HIV) protease and polymerase.
Benzaldehyde lyase is able to catalyze not only C-C bond formation reactions but also C-C bond breaking reactions with high enantioselectivity that brings about the development of new synthetic methodologies for the synthesis of hydroxy ketones which are the key intermediates in the synthesis of many biologically active compounds due to the versatility of stereogenic center for developing structural diversity.
There are several synthetic methodologies for the synthesis of hydroxy phoshonates however, in this work we have achieved the synthesis of hydroxy phoshonates through C-C bond forming reactions catalyzed by Benzaldehyde lyase that offers the use of green methodologies. Moreover, we have achieved the synthesis of hydroxy ketones which are versatile building blocks in the synthesis of many biologically active compounds via the immobilization of BAL enzyme on superparamagnetic solid support with high yield and high enantioselectivity.
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Studies in the asymmetric reduction of (3s)-3-amino-1-chloro-4-phenyl-2-butanone derivativesKitagawa, Kristen 04 January 2010 (has links)
This thesis focuses on the asymmetric reduction of N-protected derivatives of (3S)-3-amino-1-chloro-4-phenyl-2-butanone to their corresponding diastereomeric alcohol products, which are key intermediates in the synthesis of HIV protease inhibitors. Although the stereoselective synthesis of the (S,S) alcohol product is easily achieved, preparing the (R,S) diastereomer is much more challenging. I investigated three diastereoselective reduction processes: 1) Meerwein-Ponndorf-Verley (MPV) reduction, 2) asymmetric transfer hydrogenation, and 3) boron reducing agents. The diastereoselectivity of the MPV reduction still favored the (S,S) product; however, I discovered a significant rate enhancement when the standard catalyst (aluminum isopropoxide) was replaced with aluminum tert-butoxide. Many reaction variables were investigated in the asymmetric transfer hydrogenation reaction and the diastereoselectivity was improved to give a ratio of the desired (R,S) diastereomer to the undesired (S,S) alcohol of 9.5:1. Using chiral oxazaborolidine catalysts, an unprecedented (R,S) to (S,S) ratio of 9.5:1 was achieved. Finally, I investigated the effect of the N-protecting group on the stereoselectivity of the reduction. When the original boc-protecting group was replaced with a phthalimide group, the diastereoselectivity of the MPV reduction was reversed to favor the desired (R,S) product.
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[Alpha]-amination of ketones and protected ketones using dialkyl azodicarboxylates as a nitrogen sourceBrozell, Alec John 11 March 2014 (has links)
[Alpha]-Amino ketones can serve as important intermediates for the synthesis of biologically active molecules, and making these precursors in a practical manner has long been a challenge for organic chemists. The oxygen-carbon-carbon-nitrogen (O-C-C-N) sequence is common in natural and synthetic compounds of biological interest, due in part to their relatedness to peptides. Because of the many known carbonyl transformations, [alpha]-amino ketones have the potential to form various amine derivatives. Herein we present our research endeavors which led to several novel methods of forming this type of functionality. These endeavors culminated with the development of a two-step hydrazidation/N-N bond cleavage technique for forming [alpha]-amino ketals--which can be readily hydrolyzed to [alpha]-amino ketones. / text
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