Superparamagnetic core-shell nanoparticles as solid supports for peptide synthesis

Functional superparamagnetic core-shell nanoparticles are synthesized by a microwave assisted route and can be used as colloidal supports for peptide synthesis in "quasi solution".     

Microwave reactions under continuous flow conditions

Microwave chemistry has already impacted significantly on the everyday synthesis of organic molecules. The adoption and integration of this liberating technology has permitted a resurrection of many synthetic transformations that were previously considered too extreme in their conditions (temperatures, pressures, reaction times) to be synthetically useful. Furthermore, whole arrays of additional chemical transformations have been devised under microwave heating that allow access to more diverse chemical architectures via more expedient routes. Continuous flow processing of chemical intermediates taking advantage of the unique heating mechanism and characteristics of microwave irradiation will certainly be the next evolutionary step forward in this area. The synergistic combination afforded by the simultaneous application of these two core processing tools will enhance still further the synthetic capabilities of tomorrow's chemists. This short review aims to highlight the current developments and future potential offered by continuous flow microwave mediated synthesis.     

Bartoli indole synthesis on solid supports

[reaction: see text] Bartoli indole synthesis has been performed for the first time on solid supports. Starting from Merrifield resin, immobilization of five nitro benzoic acids was performed. Addition of four different alkenyl Grignard reagents and basic cleavage leads to substituted methyl indole carboxylates in excellent purities. Features of this reaction are the stability of halide groups, ester moieties, and tolerance of o,o'-unsubstituted nitro resins. Heck and Sonogashira reactions are also possible with immobilized indoles.     

Manganese triazacyclononane oxidation catalysts grafted under reaction conditions on solid cocatalytic supports

Manganese complexes of 1,4,7-trimethyl-1,4,7-triazacyclononane (tmtacn) are highly active and selective alkene oxidation catalysts with aqueous H(2)O(2). Here, carboxylic acid-functionalized SiO(2) simultaneously immobilizes and activates these complexes under oxidation reaction conditions. H(2)O(2) and the functionalized support are both necessary to transform the inactive [(tmtacn)Mn(IV)(μ-O)(3)Mn(IV)(tmtacn)](2+) into the active, dicarboxylate-bridged [(tmtacn)Mn(III)(μ-O)(μ-RCOO)(2)Mn(III)(tmtacn)](2+). This transformation is assigned on the basis of comparison of diffuse reflectance UV-visible spectra to known soluble models, assignment of oxidation state by Mn K-edge X-ray absorption near-edge spectroscopy, the dependence of rates on the acid/Mn ratios, and comparison of the surface structures derived from density functional theory with extended X-ray absorption fine structure. Productivity in cis-cyclooctene oxidation to epoxide and cis-diol with 2-10 equiv of solid cocatalytic supports is superior to that obtained with analogous soluble valeric acid cocatalysts, which require 1000-fold excess to reach similar levels at comparable times. Cyclooctene oxidation rates are near first order in H(2)O(2) and near zero order in all other species, including H(2)O. These observations are consistent with a mechanism of substrate oxidation following rate-limiting H(2)O(2) activation on the hydrated, supported complex. This general mechanism and the observed alkene oxidation activation energy of 38 ± 6 kJ/mol are comparable to H(2)O(2) activation by related soluble catalysts. Undesired decomposition of H(2)O(2) is not a limiting factor for these solid catalysts, and as such, productivity remains high up to 25 °C and initial H(2)O(2) concentration of 0.5 M, increasing reactor throughput. These results show that immobilized carboxylic acids can be utilized and understood like traditional carboxylic acids to activate non-heme oxidation catalysts while enabling higher throughput and providing the separation and handling benefits of a solid catalyst.     

Oriented immobilization of peptide ligands on solid supports.

A synthetic procedure was developed for the direct immobilization on preactivated affinity supports of peptidic ligands requiring free alpha-amino groups to recognize their targets properly. The peptidic ligand is assembled by solid-phase peptide synthesis on an octa-branched heptalysine core through a polyglycine spacer, similar to the method developed for the production of multiple antigenic peptides. After deblocking from the resin, peptide is dialysed, lyophylized and used directly for coupling to preactivated supports. Following immobilization, only a limited number of peptide chains are covalently linked to the solid phase, leaving the remainder facing the mobile phase and sufficiently spaced to interact properly. This procedure was applied successfully to the design, synthesis and oriented immobilization of a multimeric tripeptide ligand (Met-Tyr-Phe) for affinity purification of bovine neurophysin.     

Palladium-catalyzed synthesis of uridines on polystyrene-based solid supports

In this paper, the solid-phase synthesis of various substituted pyrimidine nucleosides is described starting from 2'-deoxyuridine, which has been attached through a base labile linker to polystyrene resins. The utility of the Pd(0) cross-coupling to functionalized pyrimidine nucleosides is expanded herein to include reactions of resin-supported 5-iodo-2'-deoxyuridine under Sonogashira, Stille, Heck, and Suzuki conditions. Upon cleavage with MeONa, a library of 5-substituted pyrimidine nucleosides was obtained in good (under Sonogashira and Stille conditions) to moderate (under Heck or Suzuki conditions) yields and high purity. Except the Suzuki-type reactions, the presented methods exhibit a significant improvement and facilitate the synthetic procedure with respect to purification and yields (determined after filtration over silica gel).     

Protease-catalyzed peptide synthesis on solid support

The direct enzymatic synthesis of peptides from amino acids is widely used as a useful alternative to chemical synthesis. However, good yields of such enzyme-catalyzed reactions require altered reaction conditions to overcome the bias for hydrolysis in aqueous medium. We argue that the synthesis/hydrolysis equilibrium can be shifted toward synthesis in aqueous medium by immobilizing the amine on solid support. In this report, we show the first examples of solid-phase peptide synthesis catalyzed by a protease in bulk aqueous buffer.     

Comparison of CIM discs and CPG glass as solid supports for bioanalytical columns used in allergen detection

This work presents a comparison of convective interaction media (CIM) and controlled pore glass (CPG) as solid supports for immunoglobulin antibodies used in bioanalytical detection of allergens in foodstuffs. A flow-injection manifold with highly sensitive thermal lens spectrometric detection was used for this purpose. Using beta-lactoglobulin, a milk allergen, as a model analyte, CIM disc supports had a higher linear range (0.2–3.5 μg L⁻¹), better reproducibility (intra-day RSD = 1%, inter-day RSD = 10%), lower consumption of reagents, and better immunocolumn stability (1 month, over 240 injections of substrate), while providing comparable LODs (0.1 μg L⁻¹). Application of CIM discs as solid supports in immunocolumns for allergen detection enables fast and sensitive screening of allergens in foodstuffs with sample throughput of up to eight samples per hour.     

Novel non-PEG derived polyethers as solid supports. 2. Solid-phase synthesis studies

Novel non-PEG derived polyether resins, coined SLURPS (Superior Liquid Uptake Resins for Polymer-supported Synthesis), were studied for their performance in solid-phase synthesis. Novel amino functional resins, SLURPS-NH2, were prepared with a loading of up to 8.5 mmol/g and employed successfully in the solid-phase synthesis of Leu-Enkephalin. The peptide was obtained with the same purity when compared to its synthesis with commercial standard poly(dimethyl acrylamide) resins. Furthermore we show loading and cleavage of aromatic carboxylic acids in excellent yield. The advantageous solvent compatibility of our support was demonstrated through the biphasic dihydroxylation of alkenes with OsO4 in t-BuOH/water mixtures producing bound 1,2-diols and synthesis and removal of a bound oxime using ethanol/water mixtures both in excellent yields. Reactions were easily monitored by gel-phase NMR and FTIR. These results show that SLURPS are very well suited for organic transformations using highly polar solvent mixtures and reagents and at much higher loading levels than standard amphiphilic resins of similar solvent compatibility.     

N-Terminal peptide aldehydes as electrophiles in combinatorial solid phase synthesis of novel peptide isosteres

N-Terminal peptide aldehydes were synthesized on a solid support and utilized as electrophiles in nucleophilic reactions in order to furnish novel and diverse peptide isosteres. The aldehyde moiety of the peptide was synthesized by coupling a protected aldehyde building block to the peptide and deprotecting it quantitatively in less than 3 min. It was found that protection of the two succeeding amide nitrogens was necessary in order to avoid reaction between the aldehyde and backbone amides. The N-terminal peptide aldehydes were successfully reacted in the following way: (a) reductive amination with a large variety of amines, leading to N-alkyl-gamma-aminobutyric peptide isosteres positioned centrally in the peptide; (b) reductive amination with amino esters, leading to N-terminal 2,5-diketopiperazine peptides; (c) Horner-Wadsworth-Emmons olefination, leading to unsaturated peptide isosteres positioned centrally in the peptide; and (d) Pictet-Spengler condensations, leading to tetrahydro-beta-carbolines either positioned centrally in a peptide or fused with a diketopiperazine ring in the N-terminus of the peptide.     

Reaction of Grignard reagents with carbonyl compounds under continuous flow conditions

This contribution details how a continuous flow reactor was used to react carbonyl compounds with Grignard reagents at room temperature in an efficient and safe manner. Flow rate, residence time and temperature were optimized for the preparation of a small collection of secondary and tertiary alcohols. Excellent yields and general applicability were observed using the set-up protocol. The procedure was also applied for the preparation of Tramadol, an analgesic drug belonging to the opioid group. The developed conditions allowed the selective addition of Grignard reagents to aldehydes and ketones in the presence of a nitrile function.     

Development of new acid-functionalized resins for combinatorial synthesis on solid supports

New methods for the synthesis of acid-functionalized polystyrene and TentaGel resins are described; these methods serve to overcome problems with currently available resins and will be instrumental in spurring the use of carboxylic acid resins in solid phase chemistry.     

Hydrothermal treatment of microcrystalline cellulose under mild conditions: characterization of solid and liquid-phase products

Microcrystalline cellulose (MCC) particles were subjected to hydrothermal treatment using an autoclave with temperatures ranging from 200 to 250 °C and reaction times ranging from 20 to 100 min. The structure and chemical composition of the reacted solid phase was analyzed by X-ray diffraction, thermo-gravimetric analysis, FTIR spectroscopy and ¹³C-NMR spectroscopy. The relative composition of the water-soluble products was determined by one-dimensional ¹H-NMR and two-dimensional homo and hetero-nuclear NMR spectroscopy. Within the experimental temperature and treatment time ranges, the crystallinity of the reacted solid phase was found to be mostly dependent on the treatment temperature while the aqueous solution was found to change with both temperature and treatment time. At the maximum temperature employed in this study (250 °C), the solid products are similar to amorphous oxidized carbon with glucose as the main water-soluble product. At lower temperatures the particles are unconverted MCC and the liquid products are primarily levulinic acid, formic acid and acetic acid with smaller quantities of 5-hydroxymethyl-furfural and glucose. Heterogeneous and liquid phase reaction-schemes are proposed to explain the observed solid and water-soluble products as a function of temperature and treatment time.     

Nanocrystalline magnesium oxide as a solid base catalyst promoted one pot synthesis of gem-dichloroaziridine derivatives under thermal conditions

In this study, efficient and mild synthesis of gem-dichloroaziridines from Schiff bases in the presence of nanocrystalline magnesium oxide/chloroform as a novel source of dichlorocarbene intermediate under thermal conditions have been described. The reaction is dramatically enhanced in the presence of nanocrystalline magnesium oxide, and any byproducts were detected during or after the reaction. The corresponding products have been obtained in excellent yields, high purity and short reaction times.     

An efficient green procedure for the synthesis of chalcones using C-200 as solid support under grinding conditions

Abstract

A simple, rapid, efficient and environmentally benign procedure for the synthesis of chalcones has been achieved by grinding aryl aldehydes and acetophenones with anhydrous barium hydroxide (C-200) in the absence of any solvent. The use of organic solvent for extraction of compound is also avoided. This present method is highly useful for the synthesis of 2′-hydroxy chalcones, required intermediates for the synthesis of flavanoids.     

Structurally defined imidazolium-type ionic oligomers as soluble/solid support for peptide synthesis

Structurally defined ionic liquid-type imidazolium oligomers have been synthesized in multigram scales. These imidazolium salts have been applied to synthesize peptides efficiently in gram scale. The assembly of oligopeptides was conducted in homogeneous solution phase without the need of much excess reagents and capping as in the case of solid-phase peptide synthesis. Importantly, this approach made efficient peptide block couplings possible.