Catalytic Deoxygenation of Xylitol to Renewable Chemicals: Advances on Catalyst Design and Mechanistic Studies.

Xylitol is commonly known as one of the top platform intermediates for biomass conversion. Catalytic deoxygenation of xylitol provides an atomic and energetic efficient way to produce a variety of renewable chemicals including ethylene glycol, 1,2-propanediol, lactic acid and 1,4-anhydroxylitol. Despite a few initial attempts in converting xylitol into those products, improving catalyst selectivity towards C-O and C-C cleavage reactions remains a grand challenge in this area. To our best knowledge, there is lack of comprehensive review to summarize the most recent advances on catalyst design and mechanisms in deoxygenation of xylitol, offering important perspective into future development of xylitol transformation technologies. Therefore, in this mini-review, we have critically discussed the conversion routes involved in xylitol deoxygenation over solid catalyst materials, the nanostructures of supported metal catalysts for C-H, C-C and C-O bond cleavage reactions, and mechanistic investigation for xylitol conversion. The outcome of this work provides new insights into rational design of effective deoxygenation catalyst materials for upgrading of xylitol and future process development in converting hemicellulosic biomass.

Novel N-acetyl-Glycol-split heparin biotin-conjugates endowed with anti-heparanase activity.

Heparanase is regarded as a promising target for anticancer drugs and Ronepastat is one of the most promising heparanase inhibitors insert in clinical study for Multiple Myeloma Therapy. To improve its pharmacokinetic/pharmacodynamic profile, as well to have an antidote able to neutralize its activity in case of over dosages or intolerance, a new class of its derivatives was obtained inserting non-carbohydrate moieties of different length between the polysaccharide chain and biotin or its derivatives. In vitro these novel derivatives maintain the anti-heparanase activity without induced toxicity. The newly synthesized compounds retained the ability to attenuate the growth of CAG myeloma tumors in mice with potency similar, or in one case even higher than that of the reference compound Roneparstat as well as inhibited metastatic dissemination (lung colonization) of murine B16-F10 melanoma cells in vivo.

Catalytic Enantioselective Pinacol and Meinwald Rearrangements for the Construction of Quaternary Stereocenters.

The development of enantioselective pinacol rearrangement is extremely challenging due to the likelihood involvement of the carbenium intermediate that renders the stereochemical communication between catalyst and substrate difficult to achieve. Herein, we report chiral N-triflyl phosphoramide-catalyzed enantioselective pinacol rearrangement of 1,2-tertiary diols and mechanistically related Meinwald rearrangement of tetrasubstituted epoxides for the synthesis of enantioenriched 2-alkynyl-2-arylcyclohexanones and 2,2-diarylcyclohexanones, respectively. Total synthesis of (+)-mesembrane featuring the catalytic enantioselective pinacol rearrangement as a key strategic step is also documented.

New catalytic strategies for α,ω-diols production from lignocellulosic biomass.

Catalytic strategies for the synthesis of 1,5-pentanediol (PDO) with 69% yield from hemicellulose and the synthesis of 1,6-hexanediol (HDO) with 28% yield from cellulose are presented. Fractionation of lignocellulosic biomass (white birch wood chips) in gamma-valerolactone (GVL)/H2O generates a pure cellulose solid and a liquid stream containing hemicellulose and lignin, which is further dehydrated to furfural with 85% yield. Furfural is converted to PDO with sequential dehydration, hydration, ring-opening tautomerization, and hydrogenation reactions. Acid-catalyzed cellulose dehydration in tetrahydrofuran (THF)/H2O produces a mixture of levoglucosenone (LGO) and 5-hydroxymethylfurfural (HMF), which are converted with hydrogen to tetrahydrofuran-dimethanol (THFDM). HDO is then obtained from hydrogenolysis of THFDM. Techno-economic analysis demonstrates that this approach can produce HDO and PDO at a minimum selling price of $4090 per ton.

Synthesis and Characterization of Diol-Based Unsaturated Polyesters: Poly(diol fumarate) and Poly(diol fumarate-co-succinate).

In this work, we describe the synthesis and characterization of variants of poly(diol fumarate) and poly(diol fumarate-co-succinate). Through a Fischer esterification, α,ω-diols and dicarboxylic acids were polymerized to form aliphatic polyester comacromers. Because of the carbon-carbon double bond of fumaric acid, incorporating it into the macromer backbone structure resulted in unsaturated chains. By choosing α,ω-diols of different lengths (1,6-hexanediol, 1,8-octanediol, and 1,10-decanediol) and controlling the amount of fumaric acid in the dicarboxylic acid monomer feed (33, 50, and 100 mol %), nine diol-based macromer variants were synthesized and characterized for molecular weight, number of unsaturated bonds per chain, and thermal properties. Degradation and in vitro cytotoxicity were also measured in a subset of macromers. As proof-of-principle, macromer networks were photo-cross-linked to demonstrate the ability to perform free radical addition using the unsaturated macromer backbone. Cross-linked macromer networks were also characterized for physicochemical properties (swelling, sol fraction, compressive modulus) based on diol length and amount of unsaturated bonds. A statistical model was built using data generated from these diol-based macromers and macromer networks to evaluate the impact of monomer inputs on final macromer and macromer network properties. With the ability to be modified by free radical addition, biodegradable unsaturated polyesters serve as important macromers in the design of devices such as drug delivery vehicles and tissue scaffolds. Given the ability to extensively control final macromer properties based on monomer input parameters, poly(diol fumarate) and poly(diol fumarate-co-succinate) represent an exciting new class of macromers.

New Strategy to Access Dual-Stimuli-Responsive Triple-Shape-Memory Effect in a Non-overlapping Pattern.

Multistimuli-responsive shape-memory polymers are highly desirable in various applications, and numerous modes have been developed in recent years. However, most of them need to reprogram before they are ready to respond to another stimulus while one is triggered. Here, a new strategy is developed to achieve dual-stimuli-responsive triple-shape memory with non-overlapping effect in one programming cycle. Here, a series of poly(l-lactide)-poly(tetramethylene oxide) glycol copolymers (PLA-PTMEG-A) is prepared by selected dangling photoresponsive anthracene moieties on the crystalline PTMEG backbone. The architectures of the copolymers are well-controlled in order to keep a good balance between the crystallinity of the soft segment and the mobility of the anthracene moieties. Thus, PLA-PTMEG-A's can respond to heat and light with non-overlapping effect. The thermally-induced shape-memory effect (TSME) is realized by the crystallization-melting transition of PTMEG soft segments, while the light-induced shape-memory effect (LSME) is achieved by the reversible photodimerization of anthracene groups. In view of the non-overlapping effect of TSME and LSME in the copolymers, a triple-shape-memory effect triggered by dual-stimuli is realized in one programming and recovery cycle.

Synthesis and intramolecular glycosylation of sialyl mono-esters of o-xylylene glycol. The importance of donor configuration and nitrogen protecting groups on cyclization yield and selectivity; isolation and characterization of a N-sialyl acetamide indicative of participation by acetonitrile.

The synthesis and cyclization reactions, leading to spirocyclic medium ring-sized diolides, of o-(hydroxymethyl)xylylene monoesters of sialyl thioglycosides is described. Cyclization yields and stereoselectivities are found to vary as a function of the anomeric stereochemistry of the thioglycoside and of the N5 protecting group, and these effects are discussed in terms of the reaction mechanism. Cyclization in the presence of acetonitrile results in the isolation and characterization of a Ritter-type N-sialyl acetamide, which affords strong evidence for the participation of acetonitrile in the form of sialyl nitrilium ions.

High-specificity synthesis of novel monomers by remodeled alcohol hydroxylase.

BACKGROUND: Diols are important monomers for the production of plastics and polyurethanes, which are widely used in our daily life. The medium-chain diols with one hydroxyl group at its subterminal end are able to confer more flexibility upon the synthesized materials. But unfortunately, this type of diols has not been synthesized so far. The strong need for advanced materials impelled us to develop a new strategy for the production of these novel diols. In this study, we use the remodeled P450BM3 for high-specificity production of 1,7-decanediol. RESULTS: The native P450BM3 was capable of converting medium-chain alcohols into corresponding α, ω1-, α, ω2- and α, ω3-diols, with each of them accounting for about one third of the total diols, but it exhibited a little or no activity on the short-chain alcohols. Greatly improved regiospecificity of alcohol hydroxylation was obtained by laboratory evolution of P450BM3. After substitution of 12 amino acid residues (J2-F87A), the ratio of 1,7-decanediol (ω-3 hydroxylation) to total decanediols increased to 86.8 % from 34.0 %. Structure modeling and site-directed mutagenesis demonstrated that the heme end residues such as Ala(78), Phe(87) and Arg(255) play a key role in controlling the regioselectivity of the alcohol hydroxylation, while the residues at the mouth of substrate binding site is not responsible for the regioselectivity. CONCLUSIONS: Herein we employ an engineered P450BM3 for the first time to enable the high-specificity biosynthesis of 1,7-decanediol, which is a promising monomer for the development of advanced materials. Several key amino acid residues that control the regioselectivity of alcohol hydroxylation were identified, providing some new insights into how to improve the regiospecificity of alcohol hydroxylation. This report not only provides a good strategy for the biosynthesis of 1,7-decanediol, but also gives a promising approach for the production of other useful diols.

Asymmetric synthesis of (+)-17-epi-methoxy-kauran-3-one through tandem oxidative polycyclization-pinacol process.

A synthesis of (+)-17-epi-methoxy-kauran-3-one, an O-methylated isomer of the natural diterpene 17-hydroxy-kauran-3-one, has been achieved. The strategy is based on a diastereoselective oxidative polycyclization-pinacol tandem process consisting of transforming a functionalized phenol into a compact and complex tetracycle, which represents the main core of kaurane family members. The synthesis also includes an enantioselective Yamamoto's allylation, a diastereoselective Ru-catalyzed hydrocyanation, a ring-closing metathesis and a reductive isomerization process as key steps. The structure of our synthetic substrate was determined through comparison with an O-methylated derivative of the natural compound.

Synthesis, properties and applications of biodegradable polymers derived from diols and dicarboxylic acids: from polyesters to poly(ester amide)s.

Poly(alkylene dicarboxylate)s constitute a family of biodegradable polymers with increasing interest for both commodity and speciality applications. Most of these polymers can be prepared from biobased diols and dicarboxylic acids such as 1,4-butanediol, succinic acid and carbohydrates. This review provides a current status report concerning synthesis, biodegradation and applications of a series of polymers that cover a wide range of properties, namely, materials from elastomeric to rigid characteristics that are suitable for applications such as hydrogels, soft tissue engineering, drug delivery systems and liquid crystals. Finally, the incorporation of aromatic units and α-amino acids is considered since stiffness of molecular chains and intermolecular interactions can be drastically changed. In fact, poly(ester amide)s derived from naturally occurring amino acids offer great possibilities as biodegradable materials for biomedical applications which are also extensively discussed.

Synthesis of ethynylbenzene-substituted glycol as a versatile probe for labeling oligonucleotides.

Positron emission tomography (PET) is a highly sensitive quantitative imaging technique for studying molecular pathways and interactions in vivo. This imaging technique plays a key role in drug discovery, pharmacokinetics, pharmacodynamics, and assessing in vivo distribution. In this study, we designed an ethynylbenzene-substituted glycol (M(E)) as a versatile probe for PET labeling of oligonucleotides through a click reaction.

Direct synthesis of 1,6-hexanediol from HMF over a heterogeneous Pd/ZrP catalyst using formic acid as hydrogen source.

A new approach is developed for hydrogenolytic ring opening of biobased 5-hydroxymethylfurfural (HMF), dehydration product of hexoses, towards 1,6-hexanediol (HDO) under atmospheric pressure. The highest yield of HDO, 43%, is achieved over reusable Pd/zirconium phosphate (ZrP) catalyst at 413 K in the presence of formic acid as hydrogen source. In comparison with various Brønsted and/or Lewis acidic supports, the specific Brønsted acidity on ZrP support effectively accelerated the cleavage of C-O bond in a furan ring.

First total synthesis of (+)-apotrisporin E and (+)-apotrientriols A-B: a cyclization approach to apocarotenoids.

The first total synthesis of the natural apocarotenoids (+)-apotrisporin E (1) and (+)-apotrientriols A and B (2-3) has been accomplished. The structure, relative stereochemistry and the assignation of the absolute configuration have been confirmed. This is a fast and easy access to this family of natural products whose key steps are a diastereoselective cyclization and a HWE olefination to attach the dienic side chain. This work also opens the door to the synthesis of other apocarotenoids such as trisporols and trisporic acids.

(2S,3S)-2,6-dimethylheptane-1,3-diol, the oxygenated side chain of 22(S)-hydroxycholestrol, and its synthetic precursor (R)-4-benzyl-3-[(2R,3S)-3-hydroxy-2,6-dimethylheptanoyl]-1,3-oxazolidin-2-one.

(2S,3S)-2,6-dimethylheptane-1,3-diol, C9H20O2, (I), was synthesized from the ketone (R)-4-benzyl-3-[(2R,3S)-3-hydroxy-2,6-dimethylheptanoyl]-1,3-oxazolidin-2-one, C19H27NO4, (II), containing C atoms of known chirality. In both structures, strong hydrogen bonds between the hydroxy groups form tape motifs. The contribution from weaker C-H···O hydrogen bonds is much more evident in the structure of (II), which furthermore contains an example of a direct short Osp(3)···Csp(2) contact that represents a usually unrecognized type of intermolecular interaction.

Structure, stereochemistry and synthesis of enantiopure cyclohexenone cis-diol bacterial metabolites derived from phenols.

Biotransformation of 3-substituted and 2,5-disubstituted phenols, using whole cells of P. putida UV4, yielded cyclohexenone cis-diols as single enantiomers; their structures and absolute configurations have been determined by NMR and ECD spectroscopy, X-ray crystallography, and stereochemical correlation involving a four step chemoenzymatic synthesis from the corresponding cis-dihydrodiol metabolites. An active site model has been proposed, to account for the formation of enantiopure cyclohexenone cis-diols with opposite absolute configurations.

Covalent layer-by-layer assembly of hyperbranched polyether and polyethyleneimine: multilayer films providing possibilities for surface functionalization and local drug delivery.

A convenient and simple route to multifunctional surface coatings via the alternating covalent layer-by-layer (LBL) assembly of p-nitrophenyloxycarbonyl group-terminated hyperbranched polyether (HBPO-NO(2)) and polyethylenimine (PEI) is described. The in situ chemical reaction between HBPO-NO(2) and PEI onto aminolyzed substrates was rapid and mild. Results from ellipsometry measurements, contact angle measurements, and ATR-FTIR spectra confirmed the successful LBL assembly of the building blocks, and the surface reactivity of the multilayer films with HBPO-NO(2) as the outmost layer was demonstrated by the immobilization of an amine-functionalized fluorophore. Furthermore, a biomimetic surface was achieved by surface functionalization of the multilayer films with extracellular matrix protein collagen to promote the adhesion and growth of cells. The studies on the drug loading and in vitro release behaviors of the multilayer films demonstrated their application potentials in local delivery of hydrophilic and hydrophobic therapeutic agents.

Synthetic versatility in C-H oxidation: a rapid approach to differentiated diols and pyrans from simple olefins.

Conventionally, C-H oxidation reactions are used to install functional groups. The use of C-H oxidation to transform simple starting materials into highly versatile intermediates, which enable rapid access to a range of complex target structures, is a new area with tremendous potential in synthesis. Herein we report a Pd(II)/sulfoxide-catalyzed allylic C-H oxidation to form anti-1,4-dioxan-2-ones from homoallylic oxygenates. These versatile building blocks are rapidly elaborated to differentiated syn-1,2-diols, stereodefined amino-polyols, and syn-pyrans, structures ubiquitous in medicinally important complex molecules found in Nature. We also demonstrate that a C-H oxidation approach to the synthesis of these motifs is orthogonal and complementary to other state-of-the-art methods.

The effect of systematic structural modifications on the antibacterial activity of novel oxazolidinones.

A novel series of tetraethylene glycol (TEG) triazolyl and squaramide containing oxazolidinones were synthesized and tested for their antibacterial activity against a selected panel of Gram-positive and Gram-negative bacteria. The 4-TEG-triazolyl derivatives were prepared by 'click reaction'. The introduction of the TEG and squaramide groups did not favor antibacterial activity. The three nucleoside-containing oxazolidinones were also prepared by 'click' methodology resulted in weak antibacterial activity.

Synthesis and properties of the simplified nucleic acid glycol nucleic acid.

The nucleosides of glycol nucleic acid (GNA), with the backbone comprising just the three carbons and one stereocenter of propylene glycol (1,2-propanediol), probably constitute the simplest possible building blocks for a chemically stable nucleic acid that contains phosphodiester bonds. However, it was not until 2005 that the astonishing duplex formation properties of GNA homoduplexes were discovered in our laboratory. The R- and S-enantiomers of GNA, (R)-GNA and (S)-GNA, pair in like-symmetric combinations to form highly stable antiparallel duplexes in a Watson-Crick fashion, with thermal and thermodynamic stabilities exceeding those of analogous duplexes of DNA and RNA. Interestingly, (R)-GNA and (S)-GNA do not significantly cross-pair with each other, either in a parallel or antiparallel fashion. GNA discriminates strongly in favor of the Watson-Crick base-pairing scheme, with only slightly lower fidelity than DNA. Two (S)-GNA homoduplex structures recently determined by X-ray crystallography, one a brominated 6-mer duplex and the other an 8-mer duplex containing two copper(II) ions, reveal that the overall GNA double helix is distinct from canonical A- and B-form nucleic acids. The structure is perhaps best described as a helical ribbon loosely wrapped around the helix axis. Within the backbone, the propylene glycol nucleotides adopt two different conformations, gauche and anti, with respect to the torsional angles between the vicinal C3'-O and C2'-O bonds. A strikingly large backbone-base inclination results in extensive zipper-like interstrand and reduced intrastrand base-base interactions. This strong backbone-base inclination might explain the observation that neither the R- nor S-enantiomer of GNA cross-pairs with DNA, whereas (S)-GNA can interact with RNA strands that are devoid of G:C base pairs. Given the combination of structural simplicity, straightforward synthetic accessibility, and high duplex stability of GNA duplexes, GNA affords a promising nucleic acid scaffold for biotechnology and nanotechnology. Along these lines, we describe the functionalization of GNA duplexes through the incorporation of metal-ion-mediated base pairs. Finally, the properties of GNA discussed here reinforce its candidacy as one of the initial genetic molecules formed during the origins of life on Earth.

Mecanismos celulares e moleculares de ação dos glicocorticóides endógenos sobre a mobilização de neutrófilos / Cellular and molecular mechanisms of action of endogenous glucocorticoids on the neutrophil mobilization

Temos mostrado que os glicocorticóides endógenos (GE) modulam o rolling e a aderência de neutrófilos in vivo, mediando a expressão de moléculas de adesão no leucócito e no endotélio. Adicionalmente, os GE controlam a maturação neutrofílica na medula e a sua mobilização para o sangue periférico. O presente trabalho visou investigar os mecanismos moleculares e celulares envolvidos na modulação exercida pelos GE neste processo. Utilizando ratos Wistar submetidos à adrenalectomia bilateral, tratados com RU 38486 ou controles (falso-operados, tratados com veículo ou não manipulados), foi demonstrado que: 1) os GE controlam, negativamente, a expressão de L-selectina em neutrófilos circulantes e ICAM-1, VCAM-1, PECAM-1, VAP-1 na célula endotelial e, positivamente, a expressão de L-selectina em granulócitos da medula óssea via seu receptor citosólico (GCR); 2) o mecanismo envolvido no controle dos GE sobre a expressão de L-selectina é independente de ação sobre sua expressão gênica ou da atividade de NFkB, mas dependente da expressão de anexina-A1, como verificado em camundongos knockouts (KO) para esta proteína 3) o controle da expressão de moléculas de adesão endotelial é dependente de ações sobre a expressão gênica, via translocação nuclear do NFkB; 4) a neutrofilia detectada em animais adrenalectomizados (ADR) é mediada pelo GCR, e dependente de anexina- A1; 5) a neutrofilia parece ser dependente da ação da anexina-A1 sobre a secreção de SDF-1 na medula óssea e expressão de CXCR-4 em neutrófilos circulantes e da medula; 6) concentrações circulantes elevadas de GE induzidas pela administração de ACTH confirmaram o controle dos GE, via anexina A-1, sobre o tráfego de neutrófilos da medula óssea para o sangue, mas sugerem um controle diferencial dos GE e anexina A-1 sobre a expressão de L-selectina em células da medula e do sangue circulante. Estes dados mostram mecanismos inéditos do controle dos GE sobre o tráfego de neutrófilos, que diferem em cada microambiente...

We have shown that endogenous glucocorticoids (GE) modulate the rolling and adhesion of neutrophils in vivo, mediating the expression of adhesion molecules on leukocytes and the endothelium. Additionally, the GE control neutrophil maturation in bone marrow and mobilization to peripheral blood. This work aimed to investigate the molecular and cellular mechanisms involved in the modulation exerted by GE in this process. Using male Wistar rats, submitted to bilateral adrenalectomy, treatment with RU 38 486 or controls (sham operated, vehicle or non manipulated), it was shown that: 1) GE control, negatively, L-selectin expression on circulating neutrophils and ICAM-1, VCAM-1, PECAM-1, VAP-1 on endothelial cell and, positively, L-selectin expression on bone marrow granulocytes via their cytosolic receptor (GCR); 2) the mechanism involved in the control of GE on the L-selectin expression is independent of its action on gene expression or NFkB activity, but dependent on the expression of anexina-A1, as observed in mice knockouts for this protein; 3) the control of endothelial adhesion molecules is dependent on gene expression, via NFkB translocation; 4) the neutrophilia detected in adrenalectomized animals (ADR) is mediated by GCR, and dependent on anexina-A1; 5) the neutrophilia seems to be dependent on the action of annexin A-1 on SDF-1á secretion in bone marrow and expression of CXCR-4 in peripheral blood and bone marrow; 6) high circulating concentrations of GE induced by administration of ACTH confirmed the control of GE, via the annexin-1, on the traffic of neutrophils from the bone marrow to the blood, but suggest a differential control of GE and annexin A-1 on the L-selectin expression in the bone marrow and circulating blood. These data indicate unpublished mechanisms of control of GE on the traffic of neutrophils, which differ in each microenvironment and cell type involved in this complex phenomenon.