Reactions of enantiopure cyclic diols with sulfuryl chloride

Monocyclic allylic cis-1,2-diols reacted with sulfuryl chloride at 0 °C in a regio- and stereo-selective manner to give 2-chloro-1-sulfochloridates, which were hydrolysed to yield the corresponding trans-1,2-chlorohydrins. At −78 °C, with very slow addition of sulfuryl chloride, cyclic sulfates were formed in good yields, proved to be very reactive with nucleophiles and rapidly decomposed on attempted storage. Reaction of a cyclic sulfate with sodium azide yielded a trans-azidohydrin without evidence of allylic rearrangement occurring. An enantiopure bicyclic cis-1,2-diol reacted with sulfuryl chloride to give, exclusively, a trans-1,2-dichloride enantiomer with retention of configuration at the benzylic centre and inversion at the non-benzylic centre; a mechanism is presented to rationalise the observation.

Synthesis of , of α,β-unsaturated aldehydes and nitriles via cross-metathesis reactions using Grubbs’ catalysts

A series of alpha,beta-unsaturated aldehydes and nitriles of significant interest in the fragrance industry have been prepared using Grubbs' catalysts in cross-metathesis reactions of electron-deficient olefins (i.e., acrolein, crotonaldehyde, methacrolein, and acrylonitrile) with various 1-alkenes, including 1-decene, 1-octene, 1-hexene and 2-allyloxy-6-methylheptane. The latter is of particular interest, as it has not previously being used as a substrate in cross-metathesis reactions and allows access to valuable intermediates for the synthesis of new fragrances. Most reactions gave good selectivity of the desired CM product (>= 90%). Detailed optimisation and mechanistic studies have been performed on the cross-metathesis of acrolein with 1-decene. Recycling of the catalyst has been attempted using ionic liquids. 

Quantum yield measurements for the photocatalytic oxidation of Acid Orange 7 (AO7) and reduction of 2,6-dichloroindophenol (DCIP) on transparent TiO2 films of various thickness

This work comprises the photoactivity assessment of transparent sol–gel TiO2 coatings of various thickness using two test systems. The initial rates of both photocatalytic reactions, namely the oxidative bleaching of Acid Orange 7 (AO7) and the reductive bleaching of 2,6-dichlorindophenol (DCIP) increase linearly with increasing titania film thickness as well as with increasing absorbed light flux. The latter work revealed quantum yields (QY) of 0.19% and 92% for the AO7 and DCIP test system, respectively. The low QY for the AO7 oxidation is due to the combination of a slow irreversible reduction of oxygen and also for the oxidation of AO7, thus favouring the high efficiency for electron–hole recombination that is typical for aqueous organic pollutants. In contrast, the very high QY for the photocatalysed reduction of DCIP is due to the presence of a vast excess of glycerol which traps the photogenerated holes efficiently and so allow time for the slower reduction of dye to take place. Furthermore, the oxidation of glycerol results in the generation of highly reducing R-hydroxyalkyl radicals that are able to also reduce DCIP. As a consequence of this ‘current doubling’ effect, the observed QY (92%) is much higher than the apparent theoretical value of 50%.

Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles:a stereo- and regio- selective study

The reactions of enantiopure cyclohexene epoxides and trans-1,2-bromoacetates, derived from the corresponding substituted benzene cis-dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms proposed. An initial objective was the synthesis of new 1,2-aminoalcohol enantiomers as potential chiral ligands and synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex than initially anticipated and were found to involve a combination of different reaction mechanisms. Allylic trans-1,2-azidohydrins were prepared by Lewis acid-catalysed ring-opening of cyclic vinyl epoxides with sodium azide via an S(N)2 mechanism. On heating, these trans-1,2-azidohydrins isomerized to the corresponding trans-1,4-azidohydrins via a suprafacial allyl azide [3,3]-sigmatropic rearrangement mechanism. Conversion of a 1,2-azidohydrin to a 1,2-azidoacetate moved the equilibrium position in favour of the 1,4-substitution product. Allylic trans-1,2-bromoacetates reacted with sodium azide at room temperature to give C-2 and C-4 substituted products. A clean inversion of configuration at C-2 was found, as expected, from a concerted S(N)2-pathway. However, substitution at C-4 was not stereoselective and resulted in mixtures of 1,4-cis and 1,4-trans products. This observation can be rationalized in terms of competitive S(N)2 and S(N)2 reactions allied to a [3,3]-sigmatropic rearrangement. cis-1,2-Azidohydrins and cis-1,2-azidoacetates were much more prone to rearrange than the corresponding trans-isomers. Reaction of the softer tosamide nucleophile with trans-1,2-bromoacetates resulted, predominantly, in C-4 substitution via a syn-S(N)2 mechanism. One application of the reaction of secondary amines with allylic cyclohexene epoxides, to give trans-1,2-aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an S(N)2 mechanism. Copyright (c) 2013 John Wiley & Sons, Ltd.

Convergence of products from Povarov and von Miller reactions: approaches to helquinoline

Yttrium triflate or triflic acid catalysed Povarov reaction of methyl anthranilate with ethyl vinyl ether, both as aldehyde surrogate and as alkene, gave the desired 2-methyl-4-ethoxytetrahydroquinoline diastereoisomers as the major products along with four component coupling von Miller adducts. A proton NMR-study, using yttrium triflate as catalyst, revealed that the cis-diastereoisomers were the initial major products in both the Povarov and von Miller reactions but that these isomerised to the trans-diastereoisomers under the reaction conditions. Two distinct pathways for forming von Miller adducts were uncovered with the initial Povarov products being converted to von Miller adducts under the reaction conditions. Replacement of the 4-ethoxy with a 4-methoxy group under acidic conditions gave predominantly the trans-diastereoisomer, which was subsequently converted to a cis/trans mixture of the tetrahydroquinoline antibiotic helquinoline. It was also possible to convert the von Miller products to Povarov products under acidic conditions

X=Y-ZH COMPOUNDS AS POTENTIAL 1,3-DIPOLES .43. METAL-ION CATALYZED ASYMMETRIC 1,3-DIPOLAR CYCLOADDITION REACTIONS OF IMINES AND MENTHYL ACRYLATE

Metallo-azomethine ylides, generated from imines by the action of amine bases in combination with LiBr or AgOAc, undergo cycloaddition with both 1R, 2S, 5R- and 1S, 2R, 5S-menthyl acrylate at room temperature to give homochiral pyrrolidines in excellent yield. The stronger the base the faster the cycloaddition and the greater the yield with: 2-t-butyl-1,1,3,3-tetramethylguanidine > DBU > NEt(3) X-Ray crystal structures of representative cycloadducts establish that the absolute configuration of the newly established pyrrolidine stereocentres is independent of the metal salt and the size of the pyrrolidineC(2)-substituent for a series of aryl and aliphatic imines.

On the halogenation of N(1),N(2)-di-t-Boc-5-hydroxy-piperazic acid esters and the conformational preferences of their 5-halo-piperazic acid products. The importance of A1,3 rotameric-strain in determining N(2)-acyl piperazic acid ring conformation

In this Letter, an unambiguous synthetic strategy is reported for the preparation of enantiomerically purecis-5-halo-piperazic acid derivatives in single diastereoisomer form. Contrary to the recent report by Shin and co-workers (Chem. Lett. 2001, 1172), in which it is claimed that the Ph₃P and N-chlorosuccinimide (NCS)-mediated chlorination of (3R,5S)-trans-N(1),N(2)-di-t-Boc-5-hydroxy-piperazic acid derivative 1proceeds with retention of configuration at C(5) to give 2, we now show that this and related Ph₃P-mediated halogenations all occur with S_N2 inversion at the alcohol center, as is customary for such reactions. Specifically, we demonstrate that the (3R,5S)-trans-5-Cl-piperazic acid derivative 2 claimed by Shin and co-workers (Chem. Lett. 2001, 1172) is in actual fact the chlorinated (3S,5R)-enantiomer 6, which must have been prepared from the cis-(3S,5S)-alcohol 3, a molecule whose synthesis is not formally described in the Shin paper. We further show here that the cis-(3R,5R)-5-Cl-Piz 13 claimed by Shin and co-workers inChem. Lett. 2001, 1172, is also (3S,5R)-trans-5-Cl-Piz 6. Authentic 13 has now been synthesized by us, for the very first time, here. Since Lindsley and Kennedy have recently utilized the now invalid Shin and co-workers’ retentive Ph₃P/NCS chlorination procedure on 1 in their synthetic approach to piperazimycin A (Tetrahedron Lett. 2010, 51, 2493), it follows that their claimed 5-Cl-Piz-containing dipeptide 25 probably has the alternate structure 26, where the 5-Cl-Piz residue has a 3,5-cis-configuration. The aforementioned stereochemical misassignments appear to have come from a mix-up of starting materials by Shin and co-workers (Chem. Lett. 2001, 1172), and an under-appreciation of the various steric and conformational effects that operate in N(2)-acylated piperazic acid systems, most especially rotameric A^1,3-strain. The latter has now been unambiguously delineated and defined here under the banner of the A^1,3-rotamer effect.

Action Spectra of P25 TiO2 and a visible light absorbing, carbon-modified titania in the photocatalytic degradation of stearic acid

The photonic efficiencies of films of Evonik (formerly Degussa) P25 TiO2 and carbon-modified TiO2 Kronos VLP 7000 samples are reported as a function of excitation wavelength (300–430 nm; FWHM ∼ 7.5 nm), i.e. the action spectra, for the degradation of stearic acid, a model organic for the photocatalytic destruction of solid surface organic pollutants. For each of these semiconductor photocatalysts, at 365 nm (FWHM = 18 nm), the dependence of the rate of degradation of stearic acid, upon the irradiance, I, is determined and the rate is found to be proportional to I0.65 and I0.82 for P25 and Kronos titania, respectively. Assuming this relationship holds at all wavelengths, the action spectra for two different semiconductor photocatalysts is modified by plotting, (RSA (rate of stearic acid destruction, units: molecules cm−2 s−1)/Iθ) vs. wavelength of excitation (λexcit), and both differ noticeably from those of the original (unmodified) action spectra, which are plots of (RSA/I = photonic efficiency, ξ) vs. λexcit. The shape of the modified action spectrum for P25 TiO2 is consistent with that reported by others for other organic mineralisation reactions and correlates well with diffuse reflectance data for P25 TiO2 (Kubelka–Munk plot), although there is some evidence that the active phase, in the photodegradation of stearic acid, is the anatase form present in P25. The unmodified and modified action spectra of the beige Kronos VLP 7000 TiO2 compound exhibits little or no activity in the visible i.e. (λexcit > 400 nm) and a peak at 350 nm. The Kronos powder contains a yellow/brown conjugated, extractable, organic sensitiser which has been identified by others as the species responsible for its reported photocatalytic visible light activity. But, irradiation of the Kronos powder film, with and without a stearic acid coating, in air, using UVA or visible light, bleaches rapidly (<60 min) most, if not all, of the little colour exhibited by the original Kronos powder. The photobleached form of the Kronos has a similar action spectrum to that of the unbleached form, which, in turn, appears very similar to that of P25 titania, at wavelengths >350 nm. It is proposed that the difference between the Kronos and P25 powder films at wavelengths <350 nm is due to a photodegradation-resistant, previously unidentified (but extractable using MeCN) UV-absorbing organic species in the former which screens the titania particles at these lower wavelengths. The implications of these observations are discussed briefly.

Generation, Release, and Uptake of the NAD Precursor Nicotinic Acid Riboside by Human Cells

NAD is essential for cellular metabolism and has a key role in various signaling pathways in human cells. To ensure proper control of vital reactions, NAD must be permanently resynthesized. Nicotinamide and nicotinic acid as well as nicotinamide riboside (NR) and nicotinic acid riboside (NAR) are the major precursors for NAD biosynthesis in humans. In this study, we explored whether the ribosides NR and NAR can be generated in human cells. We demonstrate that purified, recombinant human cytosolic 5'-nucleotidases (5'-NTs) CN-II and CN-III, but not CN-IA, can dephosphorylate the mononucleotides nicotinamide mononucleotide and nicotinic acid mononucleotide (NAMN) and thus catalyze NR and NAR formation in vitro. Similar to their counterpart from yeast, Sdt1, the human 5'-NTs require high (millimolar) concentrations of nicotinamide mononucleotide or NAMN for efficient catalysis. Overexpression of FLAG-tagged CN-II and CN-III in HEK293 and HepG2 cells resulted in the formation and release of NAR. However, NAR accumulation in the culture medium of these cells was only detectable under conditions that led to increased NAMN production from nicotinic acid. The amount of NAR released from cells engineered for increased NAMN production was sufficient to maintain viability of surrounding cells unable to use any other NAD precursor. Moreover, we found that untransfected HeLa cells produce and release sufficient amounts of NAR and NR under normal culture conditions. Collectively, our results indicate that cytosolic 5'-NTs participate in the conversion of NAD precursors and establish NR and NAR as integral constituents of human NAD metabolism. In addition, they point to the possibility that different cell types might facilitate each other's NAD supply by providing alternative precursors.

Synthesis and biological activities of polyphenolic hybrids - evaluation of anti-cancer, anti-inflammatory and antioxidant activities

Os compostos polifenólicos constituem uma classe de metabolitos secundários de plantas, mas existe também uma enorme quantidade de derivados sintéticos ou semi-sintéticos contendo múltiplas unidades fenólicas. Estes compostos apresentam importantes características biológicas, que dependem das suas estruturas básicas. Certos derivados desta família de compostos, tais como flavonoides, cromonas e cumarinas contribuem para os benefícios da dieta humana, e partilham o núcleo de benzopiran-(2 e 4)-ona ou benzofuran-3-ona. A presente dissertação inclui uma introdução geral e três capítulos que descrevem as novas rotas sintéticas estabelecidas para a preparação de novos híbridos de diversos compostos polifenólicos, assim como a sua elucidação estrutural e termina com a presentação dos resultados da avaliação biológica desses mesmos compostos. No segundo capítulo discute-se a preparação de híbridos de pirimidina- e imidazolidina-polifenóis, especialmente a síntese diastereoseletiva de novos híbridos benzofuran-3-ona-hidantoína e derivados de uracilo. A rota sintética envolve a ação de carbodiimidas sobre os ácidos cromona-(2- e 3)-carboxílicos num só passo ou em dois passos sequenciais, catalisada por uma base orgânica ou inorgânica. O terceiro capítulo descreve reações do tipo adições conjugadas 1,4 - hetero-ciclisações em cascata de compostos 1,3-dicarbonílicos em ácido cromona-3-carboxílico catalisadas por uma base orgânica, que originaram novas cromonas, cromanonas e flavonas polissubstituídas. As bispiranonas [bispiran-2 e 4)-onas] foram elaboradas numa reacção de acoplamento da 4-hidroxicumarina ou da lactona do ácido triacético com o ácido cromona-3-carboxílico ou precursores formil-funcionalizados (ω-formil-2’-hydroxy acetofenonas e cromona-3-carbaldeídos) utilizando organocatálise básica. Finalmente, alargou-se o estudo das adições conjugadas 1,4 para uma variedade de 4-hidroxipiran-2-onas e cetonas α,β-insaturadas para originar novos análogos de warfarina. Obteve-se uma variedade de estruturas complexas por hibridação das unidades de 4-hidroxicumarina ou da lactona do ácido triacético com os novos derivados de cromonas polissubstituídas. Todos as reações foram executadas em condições suaves e ambientalmente favoráveis, utilizando a 4-pirrolidinopiridina como organocatalisador básico. As estruturas dos novos híbridos polifenólicos foram caracterizados por técnicas espectroscópicas de alta resolução, incluindo espectroscopia de ressonância magnética nuclear (1D e 2D) e por difractometria de raios-X, que nos permitiram resolver o complexidade estrutural dos compostos sintetizados. O quarto capítulo apresenta os resultados da avaliação biológica obtidos com os híbridos polifenólicos sintetizados neste trabalho, mostrando a possibilidade de seu envolvimento na terapia do cancro. A maioria dos compostos foram avaliados quanto ao seu efeito sobre a citotoxicidade e proliferação de células leucémicas e ao seu envolvimento na regulação de via pró-inflamatória NF-kB, na qual, os híbridos de biscumarinas exibiram actividades elevadas (IC50 = 6-19 μM para inibição de NF-kB depois de 8 horas de incubação e IC50 = 15-39 μM para efeitos citotóxicos em células cancerosas, após 24 horas de incubação). Uma inibição moderada das enzimas HDAC e Cdc25 foi induzida pelos derivados de benzofuran-3-ona-hidantoína. Catorze dos novos derivados polifenólicos polissubstituídos, tendo como estrutura básica a benzopiran-4-ona, foram avaliados pela sua actividade quimiopreventiva do cancro mediada pela indução de sinalização citoprotectora Nrf2 (fator 2 relacionado com o fator nuclear da proteína E2) e capacidade para inibir a proliferação das células de cancro da mama. Os derivados da classe das cromanonas foram identificados como os indutores mais potentes da actividade Nrf2. As concentrações necessárias para aumentar a actividade de luciferase em 10 vezes (C10) foram de 2,8-21,3 μM. Todos os novos híbridos polifenólicos que apresentam atividade citotóxica e anti-proliferativa não afectam o crescimento de células saudáveis periféricas do sangue (PBMC) (IC50 > 50 μM), indicando a sua seletividade para as células cancerosas e sugerindo que alguns deles são estruturalmente interessantes para posteriores análises. A avaliação da atividade antioxidante utilizando os testes do radical livre DPPH e o poder redutor do ião férrico FRAP foram realizados em algumas estruturas híbridas polifenólicas.

Catalytic routes to convert saccharides to furanic aldehydes

The conversion of plant biomass-derived carbohydrates (preferably non-edible) into added-value products is envisaged to be at the core of the future biorefineries. Carbohydrates are the most abundant natural organic polymers on Earth. This work deals with the chemical valorisation of plant biomass, focusing on the acid-catalysed conversion of carbohydrates (mono and polysaccharides) to furanic aldehydes, namely 2-furaldehyde (Fur) and 5-hydroxymethyl-2-furaldehyde (Hmf), which are valuable platform chemicals that have the potential to replace a variety of oil derived chemicals and materials. The investigated reaction systems can be divided into two types depending on the solvent used to dissolve the carbohydrates in the reaction medium: water or ionic liquid-based systems. The reaction temperatures were greater than 150 ºC when the solvent was water, and lower than 150 º C in the cases of the ionic liquid-based catalytic systems. As alternatives to liquid acids (typically used in the industrial production of Fur), solid acid catalysts were investigated in these reaction systems. Aiming at the identification of (soluble and insoluble) reaction products, complementary characterisation techniques were used namely, FT-IR spectroscopy, liquid and solid state NMR spectroscopy, TGA, DSC and GC´GC-ToFMS analyses. Complex mixtures of soluble reaction products were obtained and different types of side reactions may occur. The requirements to be put on the catalysts for these reaction systems partly depend on the type of carbohydrates to be converted and the reaction conditions used. The thermal stability is important due to the fact that formation of humins and catalyst coking phenomena are characteristically inherent to these types of reactions systems leading to the need to regenerate the catalyst which can be effectively accomplished by calcination. Special attention was given to fully inorganic nanoporous solid acids, amorphous or crystalline, and consisting of nano to micro-size particles. The investigated catalysts were silicoaluminophosphates, aluminosilicates and zirconium-tungsten mixed oxides which are versatile catalysts in that their physicochemical properties can be fine-tuned to improve the catalytic performances in the conversion of different substrates (e.g. introduction of mesoporosity and modification of the acid properties). The catalytic systems consisting of aluminosilicates as solid acids and water as solvent seem to be more effective in converting pentoses and related polysaccharides into Fur, than hexoses and related polysaccharides into Hmf. The investigated solid acids exhibited fairly good hydrothermal stabilities. On the other hand, ionic liquid-based catalytic systems can allow reaching simultaneously high Fur and Hmf yields, particularly when Hmf is obtained from D-fructose and related polysaccharides; however, catalyst deactivation occurs and the catalytic reactions take place in homogeneous phase. As pointed out in a review of the state of the art on this topic, the development of truly heterogeneous ionic liquid-based catalytic systems for producing Fur and Hmf in high yields remains a challenge.

Piezoelectricity and ferroelectricity in amino acid glycine

Bioorganic ferroelectrics and piezoelectrics are becoming increasingly important in view of their intrinsic compatibility with biological environment and biofunctionality combined with strong piezoelectric effect and switchable polarization at room temperature. Here we study piezoelectricity and ferroelectricity in the smallest amino acid glycine, representing a broad class of non-centrosymmetric amino acids. Glycine is one of the basic and important elements in biology, as it serves as a building block for proteins. Three polymorphic forms with different physical properties are possible in glycine (α, β and γ), Of special interest for various applications are non-centrosymmetric polymorphs: β-glycine and γ-glycine. The most useful β-polymorph being ferroelectric took much less attention than the other due to its instability under ambient conditions. In this work, we could grow stable microcrystals of β-glycine by the evaporation of aqueous solution on a (111)Pt/Ti/SiO2/Si substrate as a template. The effects of the solution concentration and Pt-assisted nucleation on the crystal growth and phase evolution were characterized by X-ray diffraction analysis and Raman spectroscopy. In addition, spin-coating technique was used for the fabrication of highly aligned nano-islands of β-glycine with regular orientation of the crystallographic axes relative the underlying substrate (Pt). Further we study both as-grown and tip-induced domain structures and polarization switching in the β-glycine molecular systems by Piezoresponse Force Microscopy (PFM) and compare the results with molecular modeling and computer simulations. We show that β-glycine is indeed a room-temperature ferroelectric and polarization can be switched by applying a bias to non-polar cuts via a conducting tip of atomic force microscope (AFM). Dynamics of these in-plane domains is studied as a function of applied voltage and pulse duration. The domain shape is dictated by both internal and external polarization screening mediated by defects and topographic features. Thermodynamic theory is applied to explain the domain propagation induced by the AFM tip. Our findings suggest that β-glycine is a uniaxial ferroelectric with the properties controlled by the charged domain walls which in turn can be manipulated by external bias. Besides, nonlinear optical properties of β-glycine were investigated by a second harmonic generation (SHG) method. SHG method confirmed that the 2-fold symmetry is preserved in as-grown crystals, thus reflecting the expected P21 symmetry of the β-phase. Spontaneous polarization direction is found to be parallel to the monoclinic [010] axis and directed along the crystal length. These data are confirmed by computational molecular modeling. Optical measurements revealed also relatively high values of the nonlinear optical susceptibility (50% greater than in the z-cut quartz). The potential of using stable β-glycine crystals in various applications are discussed in this work.

Growth conditions, omega - 3 fatty acid concentrations and gene expression of fatty acid desaturases in Portulaca oleracea leaves

Tese de dout., Ciências Biotecnológicas (Biotecnologia Vegetal), Univ. do Algarve, 2009

Boronic acids as partners in multicomponent reactions

Tese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2014

Gallium compounds forthe design of (nano)radiophamarceuticals

Tese de doutoramento, Química (Química Inorgânica), Universidade de Lisboa, Faculdade de Ciências, 2014