para-Selective C-H amidation of simple arenes with nitriles

A para-selective C-H amidation of simple arenes with nitriles has been developed. By increasing the amount of arenes, a further meta-selective C-H arylation of the produced amides occurred. Both steric and electronic effects are utilized to control the selectivity, resulting in only para-selective amidation products. The readily available nitriles as amidation reagents instead of amides makes the synthesis of N-arylamides more accessible

End-group functionalization of poly(2-oxazoline)s using methyl bromoacetate as initiator followed by direct amidation

Poly(2-alkyl/aryl-2-oxazoline)s (PAOx) are an alluring class of polymers for many applications due to the broad chemical diversity that is accessible for these polymers by simply changing the initiator, terminating agent and the monomer(s) used in their synthesis. Additional functionalities (that are not compatible with the cationic ring-opening polymerization) can be introduced to the polymers via orthogonal post-polymerization modifications. In this work, we expand this chemical diversity and demonstrate an easy and straightforward way to introduce a wide variety of functional end-groups to the PAOx, by making use of methyl bromoacetate (MeBrAc) as a functional initiator. A kinetic study for the polymerization of 2-ethyl-2-oxazoline (EtOx) in acetonitrile (CH3CN) at 140 degrees C revealed relatively slow initiation and slower polymerization than the commonly used initiator, methyl tosylate (MeOTs). Nonetheless, well-defined polymers could be obtained with MeBrAc as initiator, yielding polymers with near-quantitative methyl ester end-group functionality. Next, the post-polymerization modification of the methyl ester end-group with different amines was explored by introducing a range of functionalities, i.e. hydroxyl, amino, allyl and propargyl end-groups. The lower critical solution temperature (LCST) behavior of the resulting poly(2-ethyl-2-oxazoline)s was found to vary substantially in function of the end-group introduced, whereby the hydroxyl group resulted in a large reduction of the cloud point transition temperature of poly(2-ethyl-2-oxazoline), ascribed to hydrogen bonding with the polymer amide groups. In conclusion, this paper describes an easy and fast modular approach for the preparation of end-group functionalized PAOx

Functional poly(2-oxazoline)s by direct amidation of methyl ester side chains

Poly(2-alkyl/aryl-2-oxazoline)s (PAOx) are biocompatible pseudopolypeptides that have received significant interest for biomedical applications in recent years. The growing popularity of PAOx in recent years is driven by its much higher chemical versatility compared with the gold standard in this field, poly(ethylene glycol) (PEG), while having similar beneficial properties, such as stealth behavior and biocompatibility. We further expand the PAOx chemical toolbox by demonstrating a novel straightforward and highly versatile postpolymerization modification platform for the introduction of side-chain functionalities. PAOx having side chain methyl ester functionalities is demonstrated to undergo facile uncatalyzed amidation reactions with a wide range of amines, yielding the corresponding PAOx with side-chain secondary amide groups containing short aliphatic linkers as well as a range of side-chain functionalities including acid, amine, alcohol, hydrazide, and propargyl groups. The PAOx with side-chain methyl ester groups can be prepared by either partial hydrolysis of a PAOx followed by the introduction of the methyl ester via modification of the secondary amine groups with methyl succinyl chloride or by the direct copolymerization of a nonfunctional 2-oxazoline monomer with a 2-methoxycarbonylethyl-2-oxazoline. Thus, this novel synthetic platform enables direct access to a wide range of side-chain functionalities from the same methyl-ester-functionalized poly(2-oxazoline) scaffold

Evaluation of alternative solvents in common amide coupling reactions : replacement of dichloromethane and N,N-dimethylformamide

A range of alternative solvents have been evaluated within amidation reactions employing common coupling reagents with a view to identifying suitable replacements for dichloromethane and N,N-dimethylformamid

Identification of the growth hormone-releasing hormone analogue [Pro1, Val14]-hGHRH with an incomplete C-term amidation in a confiscated product

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Genome sequencing analysis of Streptomyces coelicolor mutants that overcome the phosphate-depending vancomycin lethal effect

Abstract Background Glycopeptide antibiotics inhibit bacterial cell-wall synthesis, and are important for the treatment of infections caused by multi drug-resistant strains of enterococci, streptococci and staphylococci. The main mechanism by which bacteria resist the action of glycopeptides is by producing a modified cell-wall in which the dipeptide D-Alanine-D-Alanine is substituted by D-Alanine-D-Lactate or D-Alanine-D-Serine. Recently, it has been shown that inorganic phosphate (Pi) induces hypersensitivity to vancomycin in Streptomyces coelicolor (which is highly resistant to the antibiotic in low-Pi media). This finding was surprising because the bacterium possesses the entire set of genes responsible for vancomycin resistance (VR); including those coding for the histidine kinase/response regulator pair VanS/VanR that activates the system. Results This work shows that high Pi amounts in the medium hamper the activation of the van promoters and consequently inhibit VR in S. coelicolor; i.e. the repression effect being stronger when basic or acidic forms of the nutrient are used. In addition, this work shows that lysozyme resistance is also highly regulated by the Pi concentration in the medium. At least five different mutations contribute to the overcoming of this repression effect over VR (but not over lysozyme resistance). Therefore, the interconnection of VR and lysozyme resistance mechanisms might be inexistent or complex. In particular, two kinds of mutant in which Pi control of VR has been lost (one class expresses the van genes in a constitutive manner; the other retains inducibility by vancomycin) have been isolated and further characterized in this study. Sequencing revealed that the first class of mutation conferred a single amino acid substitution in the second transmembrane helix of the VanS protein; whereas the other class hampered the expression or activity of a putative homolog (SCO1213) to the staphylococcal GatD protein. Complementation, phenotypic and bioinformatics analyses identified SCO1213, and its upstream gene (i.e. murT), as relevant genetic determinants involved with VR in S. coelicolor. Conclusion The genomic approach of this study together with other genetic and phenotypic analyses has allowed the identification of the uncharacterized murT-gatD Streptomyces genes and the characterization of their involvement with the Pi control of VR in S. coelicolor

Exploring the scope of DBU-promoted amidations of 7-carboxymethyl-pterin

Pteridines are an important heterocycle often used in the development of pharmaceutically relevant compounds, and in the field of supramolecular chemistry. Their synthetic use is often hampered by the notorious insolubility of pterins, slowing the development of novel pteridine derivatives. Reactions which expedite the rapid development of new pterins are thus of great importance. Through a dual role of diazabicycloundecene (DBU), 7-carboxymethyl-pterin is converted to the soluble DBU salt, with additional DBU promoting an ester-to-amide transformation. We have explored this reaction to assess its scope and identify structural features in the amines which significantly affect success, monitored the reaction using pseudo-first order kinetics, and further adapted the reaction conditions to allow for product formation in as little as 5 min, with yields often \u3e80%

The neuropeptide transcriptome of a model echinoderm, the sea urchin Strongylocentrotus purpuratus

The work reported here was supported by a grant from the University of London Central Research Fun