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Versatile Technique to Produce a Hierarchical Design in Nanoporous Gold

The potential to generate variable pore sizes, simplistic surface modification, and a breadth of commercial uses in the fields of biosensors, actuators, ...

Saint Louis University

The main focus of this review is to describe accomplishments made in the stereoselective synthesis of β-linked mannosides functionalized with carboxyls or amines/amides. These ManNAc, ManA and ManNAcA residues found in many glycoconjugates, bacterial polysaccharides, and alginates have consistently captured interest of the glycoscience community both due to synthetic challenge and therapeutic potential.

Recent Advances in Stereocontrolled Mannosylation: Focus on Glycans Comprising Acidic and/or Amino Sugars.

Presented herein is an improved synthesis of a common 3-OH glycosyl acceptor. This compound is a building block that is routinely synthesized by many research groups to be used in glycosylation refinement studies. The only known direct synthesis by Koto lacks regioselectivity and relies on chromatography separation using hazardous solvents. Our improved synthetic approach relies on Koto's selective benzylation protocol, but it is followed by acylation-purification-deacylation sequence. Although this approach involves additional manipulations, it provides consistent results and is superior to other indirect strategies. Also obtained, albeit in minor quantities, is 4-OH acceptor, another common building block.

Streamlined access to carbohydrate building blocks: Methyl 2,4,6-tri-O-benzyl-α-d-glucopyranoside.

A method for direct, highly stereoselective synthesis of glycans containing β-linked d-mannosaminuronic acid (ManNAcA) residues is reported herein, among which is the capsular polysaccharide of  type 8. Previous chemical syntheses of this glycan relied on indirect methods comprising glucosylation followed by a multistep epimerization and oxidation sequence. The high β-stereocontrol with direct glycosidation of 3--picoloylated ManNAcA donors was achieved using the H-bond-mediated aglycone delivery (HAD) reaction. A method to achieve complete α-ManNAcA stereoselectivity with 3--benzoylated donors is also reported.

Direct Synthesis of Glycans Containing Challenging ManNAcA Residues.

Thioglycosides are among the most common glycosyl donors that find broad application in the synthesis of glycans and glycoconjugates. However, the requirement for toxic and/or large access of activators needed for common glycosylations with thioglycosides remains a notable drawback. Due to the increased awareness of the chemical waste impact on the environment, synthetic studies have been driven by the goal of finding non-toxic reagents. The main focus of this review is to highlight recent methods for thioglycoside activation that rely on transition metal catalysis.

Transition-Metal-Mediated Glycosylation with Thioglycosides.

As the 21 century unfolds with rapid changes, new challenges in research and development emerge. These new challenges prompted us to repurpose our HPLC-A platform that was previously used in solid phase glycan synthesis to a solution phase batch synthesis described herein. The modular character of HPLC allows for implementing new attachments. To enable sequential synthesis of multiple oligosaccharides with the single press of a button, we supplemented our system with a four-way split valve and an automated fraction collector. This enabled the operator to load all reagents and all reactants in the autosampler, press the button to start the repetitive automation sequence, leave the lab, and upon return find products of multiple reactions ready for purification, analysis, and subsequent application.

HPLC-Based Automated Synthesis of Glycans in Solution.

Sepsis is a serious medical condition characterized by bacterial infection and a subsequent massive systemic inflammatory response. In an effort to identify compounds that block lipopolysaccharide (LPS)-induced inflammation reported herein is the development of simple Lipid-A analogues that lack a disaccharide core yet still possess potent antagonistic activity against LPS. The structure of the new lead compound was developed based on predictive computational experiments. LPS antagonism by the lead compound was not straightforward, and a biphasic effect was observed suggesting a possibility of more than one binding site. An IC value of 13 nM for the new compound was determined for the possible high affinity site. The combination of computational, synthetic, and biological studies revealed new structural determinants of these simplified analogues. It is expected that the acquired information will aid future design of LPS targeting glycopharmaceuticals.

Development of a Simple and Effective Lipid-A Antagonist Based on Computational Prediction.

Advances in synthetic carbohydrate chemistry have dramatically improved access to common glycans. However, many novel methods still fail to adequately address challenges associated with chemical glycosylation and glycan synthesis. Since a challenge of glycosylation has remained, scientists have been frequently returning to the traditional glycosyl donors. This review is dedicated to glycosyl halides that have played crucial roles in shaping the field of glycosciences and continue to pave the way toward our understanding of chemical glycosylation.

Synthesis and Glycosidation of Anomeric Halides: Evolution from Early Studies to Modern Methods of the 21st Century.

The reverse orthogonal strategy was invented in 2011 in an attempt to address drawbacks of other strategies for glycan assembly. Different from the classical orthogonal approach that relies on the orthogonality of leaving groups, the reverse strategy is based on orthogonal protecting groups that could be removed during the glycosylation step. This strategy remained largely unexplored due to only one combination of orthogonal protecting groups that would fit into this concept. Reported herein are new orthogonal combinations of leaving and protecting groups that help to streamline the glycan assembly. Also reported is further refinement of the previously reported reaction conditions.

Broadening the Scope of the Reverse Orthogonal Strategy for Oligosaccharide Synthesis.

Recently, we reported that silver(I) oxide mediated Koenigs-Knorr glycosylation reaction can be dramatically accelerated in the presence of catalytic acid additives. We have also investigated how well this reaction works in application to differentially protected galactosyl bromides. Reported herein is the stereoselective synthesis of α-galactosides with galactosyl chlorides as glycosyl donors. Chlorides are easily accessible, stable, and can be efficiently activated for glycosylation. In this application, the most favorable reactions conditions comprised cooperative AgSO and Bi(OTf) promoter system.

Expanding the scope of stereoselective α-galactosylation using glycosyl chlorides.

Presented herein is a streamlined synthesis of building blocks of a rare sugar D-altrosamine. Also investigated was the glycosylation of different glycosyl acceptors with differentially protected altrosamine donors. High facial stereoselectivity was achieved with 3--picoloyl donors and reactive glycosyl acceptors  the H-bond-mediated aglycone delivery (HAD) pathway. In contrast, glycosidations of the altrosamine donor equipped with the 3--benzoyl group were poorly stereoselective.

Synthesis and glycosidation of building blocks of D-altrosamine.

While studying indolylthio glycosides, previously we determined their activation profile that required large excess of activators. This drawback was partially addressed in the present study of N-alkylated SInR derivatives. The activation process was studied by NMR and the increased understanding of the mechanism led to a discovery of different activation pathways taking place with SIn versus SInR derivatives. Also investigated was orthogonality of the SInR leaving groups versus thioglycosides and selective activation of thioimidates over SInR glycosides.

N-Alkylated Analogues of Indolylthio Glycosides as Glycosyl Donors with Enhanced Activation Profile.

Reported herein is a new protocol for glycosidation of alkyl and aryl thioglycosides in the presence of copper(II) bromide. While the activation with CuBr alone was proven suitable for reactive glycosyl donors, the activation of less reactive donors was more efficient in the presence of triflic acid as an additive. A variety of thioglycoside donors in reactions with different glycosyl acceptors were investigated to determine the initial scope of this reaction.

Activation of Thioglycosides with Copper(II) Bromide.

Nanoporous gold (NPG) is one of the most extensively investigated nanomaterials owing to its tunable pore size, ease of surface modification, and range of applications from catalysis, actuation, and molecular release to the development of electrochemical sensors. In an effort to improve the usefulness of NPG, a simple and robust method for the fabrication of hierarchical and bimodal nanoporous gold electrodes (hb-NPG) containing both macro-and mesopores is reported using electrochemical alloying and dealloying processes to engineer a bicontinuous solid/void morphology. Scanning electron microscopy (color SEM) images depict the hierarchical pore structure created after the multistep synthesis with an ensemble of tiny pores below 100 nm in size located in ligaments spanning larger pores of several hundred nanometers. Smaller-sized pores are exploited for surface modification, and the network of larger pores aids in molecular transport. Cyclic voltammetry (CV) was used to compare the electrochemically active surface area of the hierarchical bimodal structure with that of the regular unimodal NPG with an emphasis on the critical role of both dealloying and annealing in creating the desired structure. The adsorption of different proteins was followed using UV-vis absorbance measurements of solution depletion revealing the high loading capacity of hb-NPG. The surface coverage of lipoic acid on the hb-NPG was analyzed using thermogravimetric analysis (TGA) and reductive desorption. The roughness factor determinations suggest that the fabricated hb-NPG electrode has tremendous potential for biosensor development by changing the scaling relations between volume and surface area which may lead to improved analytical performance. We have chosen to take advantage of the surface architectures of hb-NPG due to the presence of a large specific surface area for functionalization and rapid transport pathways for faster response. It is shown that the hb-NPG electrode has a higher sensitivity for the amperometric detection of glucose than does an NPG electrode of the same geometric surface area.

Alexei V. Demchenko

Department of Chemistry

Saint Louis University

Versatile Technique to Produce a Hierarchical Design in Nanoporous Gold

Alexei V. Demchenko

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Chemistry

Saint Louis University

Versatile Technique to Produce a Hierarchical Design in Nanoporous Gold

Department of Chemistry