Rapid synthesis of carbohydrate derivatives, including mimetics of c-linked disaccharides and c-Linked aza disaccharides, using the Hetero-Diels−Alder Reaction

In this work we demonstrate the value of performing a Hetero Diels-Alder reaction (HDAR) between Danishefsky’s diene and a range of aldehydes or imines, under microwave irradiation. By using a range of aldehydes and imines, including those derived from carbohydrates, access to functionalised 2,3-dihydro-4H-pyran-4-ones or 2,3-dihydro-4-pyridinones in good to excellent synthetic yields is possible. A particular strength of the methodology is its ability to access mimetics of C-linked disaccharides and C-linked aza disaccharides, targets of current therapeutic interest, in a rapid, convenient and diastereoselective manner. The effect of high pressure on the HDARs involving carbohydrate derived aldehydes and imines is also explored, with enhancement in yields occurring for the aldehyde substrates. Finally, HDARs using carbohydrate derived ketones, enones and enals are described under a range of conditions. Optimum results were obtained under high pressure conditions, with highly functionalized carbohydrate derivatives being afforded, in good yields, in this way.

Formal total synthesis of (±)-conduramine E utilising the Bryce-Smith-Gilbert photoamination reaction

Utilising a Bryce-Smith-Gilbert photoamination of benzene as a key step, a synthesis of ()-conduramine E was carried out. A highly regioselective dihydroxylation of a cyclic diene was effected utilising Sharpless AD-mix-b.

Metabolism of Maillard reaction products by the human gut microbiota - implications for health

The human colonic microbiota imparts metabolic versatility on the colon, interacts at many levels in healthy intestinal and systemic metabolism, and plays protective roles in chronic disease and acute infection. Colonic bacterial metabolism is largely dependant on dietary residues from the upper gut. Carbohydrates, resistant to digestion, drive colonic bacterial fermentation and the resulting end products are considered beneficial. Many colonic species ferment proteins but the end products are not always beneficial and include toxic compounds, such as amines and phenols. Most components of a typical Western diet are heat processed. The Maillard reaction, involving food protein and sugar, is a complex network of reactions occurring during thermal processing. The resultant modified protein resists digestion in the small intestine but is available for colonic bacterial fermentation. Little is known about the fate of the modified protein but some Maillard reaction products (MRP) are biologically active by, e.g. altering bacterial population levels within the colon or, upon absorption, interacting with human disease mechanisms by induction of inflammatory responses. This review presents current understanding of the interactions between MRP and intestinal bacteria. Recent scientific advances offering the possibility of elucidating the consequences of microbe-MRP interactions within the gut are discussed.

Functional coupling of the human dopamine D-2 receptor with G alpha(i1), G alpha(i2), G alpha(i3) and G alpha(o) G proteins: evidence for agonist regulation of G protein selectivity

1 The human dopamine D-2long (D-2L) receptor was expressed with four different G proteins in Sf9 cells using the baculovirus expression system. When co-expressed with G(i)/G(o) G proteins (G(i1)alpha, G(i2)alpha, G(i3)alpha, or G(o)alpha, plus Gbeta(1) and Ggamma(2)) the receptor displayed a high-affinity binding site for the agonists (dopamine and NPA), which was sensitive to GTP (100 mum), demonstrating interaction between the receptor and the different G proteins. 2 The receptor to G protein ratio (R: G ratio) was evaluated using [H-3]-spiperone saturation binding (R) and [S-35]-GTPgammaS saturation binding (G). R: G ratios of 1: 12, 1: 3, 1: 14 and 1: 5 were found for G(i1), G(i2), G(i3), and Go preparations, respectively. However, when R:G ratios of 1:2 and 1: 12 were compared for G(i2) and G(o), no difference was found for the stimulation of [S-35]-GTPgammaS binding. 3 Several agonists were tested for their ability to stimulate [S-35]-GTPgammaS binding to membranes co-expressing the receptor and various G proteins. All the compounds tested showed agonist activity in preparations expressing G(i3) and G(o). However, for G(i2) and G(i1) preparations, compounds such as S-(-)-3-PPP and p-tyramine were unable to stimulate [S-35]-GTPyS binding. 4 Most of the compounds showed higher relative efficacies (compared to dopamine) and higher potencies in the preparation expressing G(o). Comparison of the effects of different agonists in the different preparations showed that each agonist differentially activates the four G proteins. 5 We conclude that the degree of selectivity of G protein activation by the D-2L receptor can depend on the conformation of the receptor stabilised by an agonist.

Surprisingly slow reaction of dimethylsilylene with dimethylgermane: time-resolved kinetic studies and related quantum chemical calculations

Time-resolved studies of silylene, SiH2, and dimethylsilylene, SiMe2, generated by the 193 nm laser flash photolysis of appropriate precursor molecules have been carried out to obtain rate constants for their bimolecular reactions with dimethylgermane, Me2GeH2, in the gas phase. SiMe2 + Me2GeH2 was studied at five temperatures in the range 299-555 K. Problems of substrate UV absorption at 193 nm at temperatures above 400 K meant that only three temperatures could be used reliably for rate constant measurement. These rate constants gave the Arrhenius parameters log(A/cm(3) molecule(-1) s(-1)) = -13.25 +/- 0.16 and E-a = -(5.01 +/- 1.01) kJ mol(-1). Only room temperature studies of SiH2 were carried out. These gave values of (4.05 +/- 0.06) x 10(-10) cm(3) molecule(-1) s(-1) (SiH2 + Me2GeH2 at 295 K) and also (4.41 +/- 0.07) x 10(-10) cm(3) molecule(-1) s(-1) (SiH2 + MeGeH3 at 296 K). Rate constant comparisons show the surprising result that SiMe2 reacts 12.5 times slower with Me2GeH2 than with Me2SiH2. Quantum chemical calculations (G2(MP2,SVP)//B3LYP level) of the model Si-H and Ge-H insertion processes of SiMe2 with SiH4/MeSiH3 and GeH4/MeGeH3 support these findings and show that the lower reactivity of SiMe2 with Ge-H bonds is caused by a higher secondary barrier for rearrangement of the initially formed complexes. Full details of the structures of intermediate complexes and the discussion of their stabilities are given in the paper. Other, related, comparisons of silylene reactivity are also presented.

An investigation of the germylene addition reaction, GeH2+C2H2: Time-resolved gas-phase kinetic studies and quantum chemical calculations of the reaction energy surface

Time resolved studies of germylene, GeH2, generated by laser flash photolysis of 3,4-dimethylgermacyclopentene-3, have been carried out to obtain rate constants for its bimolecular reaction with acetylene, C2H2. The reaction was studied in the gas-phase over the pressure range 1-100 Tort, with SF6 as bath gas, at 5 temperatures in the range 297-553 K. The reaction showed a very slight pressure dependence at higher temperatures. The high pressure rate constants (obtained by extrapolation at the three higher temperatures) gave the Arrhenius equation: log(k(infinity)/cm(3) molecule(-1) s(-1)) (-10.94 +/- 0.05) + (6.10 +/- 0.36 kJ mol(-1))/RTln10. These Arrhenius parameters are consistent with a fast reaction occurring at approximately 30% of the collision rate at 298 K. Quantum chemical calculations (both DFT and ab initio G2//B3LYP and G2//QCISD) of the GeC2H4 potential energy surface (PES), show that GeH2 + C2H2 react initially to form germirene which can isomerise to vinylgermylene with a relatively low barrier. RRKM modelling, based on a loose association transition state, but assuming vinylgermylene is the end product (used in combination with a weak collisional deactivation model) predicts a strong pressure dependence using the calculated energies, in conflict with the experimental evidence. The detailed GeC2H4 PES shows considerable complexity with ten other accessible stable minima (B3LYP level), the three most stable of which are all germylenes. Routes through this complex surface were examined in detail. The only product combination which appears capable of satisfying the (P-3) + C2H4.C2H4 was confirmed as a product by GC observed lack of a strong pressure dependence is Ge(P-3) + C2H4. C2H4 was confirmed as a product by GC analysis. Although the formation of these products are shown to be possible by singlet-triplet curve crossing during dissociation of 1-germiranylidene (1-germacyclopropylidene), it seems more likely (on thermochernical grounds) that the triplet biradical, (GeCH2CH2.)-Ge-., is the immediate product precursor. Comparisons are made with the reaction of SiH2 with C2H2.

Time-resolved gas-phase kinetic and quantum chemical studies of the reaction of silylene with nitric oxide

Time-resolved kinetic studies of the reaction of silylene, SiH2, generated by laser flash photolysis of phenylsilane, have been carried out to obtain rate constants for its bimolecular reaction with NO. The reaction was studied in the gas phase over the pressure range 1-100 Torr in SF6 bath gas at five temperatures in the range 299-592 K. The second-order rate constants at 10 Torr fitted the Arrhenius equation log(k/cm(3) molecule(-1) s(-1)) = (- 11.66 +/- 0.01) + (6.20 +/- 0.10 kJ mol(-1))IRT In 10 The rate constants showed a variation with pressure of a factor of ca. 2 over the available range, almost independent of temperature. The data could not be fitted by RRKM calculations to a simple third body assisted association reaction alone. However, a mechanistic model with an additional (pressure independent) side channel gave a reasonable fit to the data. Ab initio calculations at the G3 level supported a mechanism in which the initial adduct, bent H2SiNO, can ring close to form cyclo-H2SiNO, which is partially collisionally stabilized. In addition, bent H2SiNO can undergo a low barrier isomerization reaction leading, via a sequence of steps, ultimately to dissociation products of which the lowest energy pair are NH2 + SiO. The rate controlling barrier for this latter pathway is only 16 kJ mol(-1) below the energy of SiH2 + NO. This is consistent with the kinetic findings. A particular outcome of this work is that, despite the pressure dependence and the effects of the secondary barrier (in the side reaction), the initial encounter of SiH2 with NO occurs at the collision rate. Thus, silylene can be as reactive with odd electron molecules as with many even electron species. Some comparisons are drawn with the reactions of CH2 + NO and SiCl2 + NO.

The addition reaction between silylene and ethyne: further isotope studies, pressure dependence studies, and quantum chemical calculations

Time-resolved kinetic studies of the reaction of dideutero-silylene, SiD2, generated by laser flash photolysis of phenylsilane-d(3), have been carried out to obtain rate constants for its bimolecular reaction with C2H2. The reaction was studied in the gas phase over the pressure range 1-100 Torr in SF6 bath gas, at five temperatures in the range 297-600 K. The second-order rate constants obtained by extrapolation to the high-pressure limits at each temperature fitted the Arrhenius equation log(k(infinity)/cm(3) molecule(-1) s(-1)) = (-10.05 +/- 0.05) + (3.43 +/- 0.36 kJ mol(-1))/RT ln 10. The rate constants were used to obtain a comprehensive set of isotope effects by comparison with earlier obtained rate constants for the reactions of SiH2 with C2H2 and C2D2. Additionally, pressure-dependent rate constants for the reaction of SiH2 with C2H2 in the presence of He (1-100 Tort) were obtained at 300, 399, and 613 K. Quantum chemical (ab initio) calculations of the SiC2H4 reaction system at the G3 level support the initial formation of silirene, which rapidly isomerizes to ethynylsilane as the major pathway. Reversible formation of vinylsilylene is also an important process. The calculations also indicate the involvement of several other intermediates, not previously suggested in the mechanism. RRKM calculations are in semiquantitative agreement with the pressure dependences and isotope effects suggested by the ab initio calculations, but residual discrepancies suggest the possible involvement of the minor reaction channel, SiH2 + C2H2 - SWPO + C2H4. The results are compared and contrasted with previous studies of this reaction system.

Investigation of the prototype silylene reaction, SiH2+H2O(and D2O): time-resolved gas-phase kinetic studies, isotope effects, RRKM calculations, and quantum chemical calculations of the reaction energy surface

Time-resolved kinetic studies of the reaction of silylene, SiH2, with H2O and with D2O have been carried out in the gas phase at 296 and at 339 K, using laser flash photolysis to generate and monitor SiH2. The reaction was studied over the pressure range 10-200 Torr with SF6 as bath gas. The second-order rate constants obtained were pressure dependent, indicating that the reaction is a third-body assisted association process. Rate constants at 339 K were about half those at 296 K. Isotope effects, k(H)/k(D), were small averaging 1.076 0.080, suggesting no involvement of H- (or D-) atom transfer in the rate determining step. RRKM modeling was undertaken based on a transition state appropriate to formation of the expected zwitterionic donoracceptor complex, H2Si...OH2. Because the reaction is close to the low pressure (third order) region, it is difficult to be definitive about the activated complex structure. Various structures were tried, both with and without the incorporation of rotational modes, leading to values for the high-pressure limiting (i.e., true secondorder) rate constant in the range 9.5 x 10(-11) to 5 x 10(-10) cm(3) molecule' s(-1). The RRKM modeling and mechanistic interpretation is supported by ab initio quantum calculations carried out at the G2 and G3 levels. The results are compared and contrasted with the previous studies.

Experimental and theoretical evidence for homogeneous catalysis in the gas-phase reaction of SiH2 with H2O (and D2O): a combined kinetic and quantum chemical study

Time-resolved kinetic studies of the reaction of silylene, SiH2, with H2O and with D2O have been carried out in the gas phase at 297 K and at 345 K, using laser flash photolysis to generate and monitor SiH2. The reaction was studied independently as a function of H2O (or D2O) and SF6 (bath gas) pressures. At a fixed pressure of SF6 (5 Torr), [SiH2] decay constants, k(obs), showed a quadratic dependence on [H2O] or [D2O]. At a fixed pressure of H2O or D2O, k(obs) Values were strongly dependent on [SF6]. The combined rate expression is consistent with a mechanism involving the reversible formation of a vibrationally excited zwitterionic donor-acceptor complex, H2Si...OH2 (or H2Si...OD2). This complex can then either be stabilized by SF6 or it reacts with a further molecule of H2O (or D2O) in the rate-determining step. Isotope effects are in the range 1.0-1.5 and are broadly consistent with this mechanism. The mechanism is further supported by RRKM theory, which shows the association reaction to be close to its third-order region of pressure (SF6) dependence. Ab initio quantum calculations, carried out at the G3 level, support the existence of a hydrated zwitterion H2Si...(OH2)(2), which can rearrange to hydrated silanol, with an energy barrier below the reaction energy threshold. This is the first example of a gas-phase-catalyzed silylene reaction.

Anion-directed synthesis of metal-organic frameworks based on 2-picolinate Cu(II) complexes: a ferromagnetic alternating chain and two unprecedented ferromagnetic fish backbone chains

Three new polynuclear copper(II) complexes of 2-picolinic acid (Hpic), {[Cu-2(pic)(3)(H2O)]ClO4}(n) (1), {[Cu-2(pic)(3)(H2O)]BF4}(n) (2), and [Cu-2(pic)3(H2O)(2)(NO3)](n) (3), have been synthesized by reaction of the "metalloligand" [Cu-(pic)(2)] with the corresponding copper(II) salts. The compounds are characterized by single-crystal X-ray diffraction analyses and variable-temperature magnetic measurements. Compounds 1 and 2 are isomorphous and crystallize in the triclinic system with space group P (1) over bar, while 3 crystallizes in the monoclinic system with space group P2(1)/n. The structural analyses reveal that complexes 1 and 2 are constructed by "fish backbone" chains through syn-anti (equatorial-equatorial) carboxylate bridges, which are linked to one another by syn-anti (equatorial-axial) carboxylate bridges, giving rise to a rectangular grid-like two-dimensional net. Complex 3 is formed by alternating chains of syn-anti carboxylate-bridged copper(II) atoms, which are linked together by strong H bonds involving coordinated nitrate ions and water molecules and uncoordinated oxygen atoms from carboxylate groups. The different coordination ability of the anions along with their involvement in the H-bonding network seems to be responsible for the difference in the final polymeric structures. Variable-temperature (2-300 K) magnetic susceptibility measurement shows the presence of weak ferromagnetic coupling for all three complexes that have been fitted with a fish backbone model developed for 1 and 2 (J = 1.74 and 0.99 cm(-1); J' = 0.19 and 0.25 cm(-1), respectively) and an alternating chain model for 3 (J = 1.19 cm(-1) and J' = 1.19 cm(-1)).

Chemoselective catalytic hydrogenation of acrolein on Ag(111): effect of molecular orientation on reaction selectivity

The adsorption and hydrogenation of acrolein on the Ag(111) surface has been investigated by high resolution synchrotron XPS, NEXAFS, and temperature programmed reaction. The molecule adsorbs intact at all coverages and its adsorption geometry is critically important in determining chemoselectivity toward the formation of allyl alcohol, the desired but thermodynamically disfavored product. In the absence of hydrogen adatoms (H(a)), acrolein lies almost parallel to the metal surface; high coverages force the C=C bond to tilt markedly, likely rendering it less vulnerable toward reaction with hydrogen adatoms. Reaction with coadsorbed H(a) yields allyl alcohol, propionaldehyde, and propanol, consistent with the behavior of practical dispersed Ag catalysts operated at atmospheric pressure: formation of all three hydrogenation products is surface reaction rate limited. Overall chemoselectivity is strongly influenced by secondary reactions of allyl alcohol. At low H(a) coverages, the C=C bond in the newly formed allyl alcohol molecule is strongly tilted with respect to the surface, rendering it immune to attack by H(a) and leading to desorption of the unsaturated alcohol. In contrast with this, at high H(a) coverages, the C=C bond in allyl alcohol lies almost parallel to the surface, undergoes hydrogenation by H(a), and the saturated alcohol (propanol) desorbs.