Rapid Mechanochemical Synthesis of Amides with Uronium-Based Coupling Reagents, a Method for Hexa-amidation of Biotin[6]uril

<p>Solid-state reactions using mechanochemical activation have emerged as solvent-free atom-efficient strategies for sustainable chemistry. Herein we report a new mechanochemical approach for the amide coupling of carboxylic acids and amines, mediated by combination of (1-сyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU) or <i>N</i>,<i>N</i>,<i>N</i>′,<i>N</i>′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and K₂HPO₄. The method delivers a range of amides in high 70–96% yields and fast reaction rates. The reaction protocol is mild, maintains the integrity of the adjacent to carbonyl stereocenters, and streamlines isolation procedure for solid amide products. Minimal waste is generated due to the absence of bulk solvent. We show that K₂HPO₄ plays a dual role, acting as a base and a precursor of reactive acyl phosphate species. Amide bonds from hindered carboxylic acids and low-nucleophilic amines can be assembled within 90 min by using TCFH in combination with K₂HPO₄ or <i>N</i>-methylimidazole. The developed mechanochemical liquid-assisted amidation protocols were successfully applied to the challenging couplings of all six carboxylate functions of biotin[6]uril macrocycle with phenylalanine methyl ester, resulting in an 80% yield of highly pure hexa-amide-biotin[6]uril. In addition, fast and high-yielding synthesis of peptides and versatile amide compounds can be performed in a safe and environmentally benign manner, as verified by green metrics.<b></b></p>

Rapid Mechanochemical Synthesis of Amides with Uronium-Based Coupling Reagents, a Method for Hexa-amidation of Biotin[6]uril

<p>Solid-state reactions using mechanochemical activation have emerged as solvent-free atom-efficient strategies for sustainable chemistry. Herein we report a new mechanochemical approach for the amide coupling of carboxylic acids and amines, mediated by combination of (1-сyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU) or <i>N</i>,<i>N</i>,<i>N</i>′,<i>N</i>′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and K₂HPO₄. The method delivers a range of amides in high 70–96% yields and fast reaction rates. The reaction protocol is mild, maintains the integrity of the adjacent to carbonyl stereocenters, and streamlines isolation procedure for solid amide products. Minimal waste is generated due to the absence of bulk solvent. We show that K₂HPO₄ plays a dual role, acting as a base and a precursor of reactive acyl phosphate species. Amide bonds from hindered carboxylic acids and low-nucleophilic amines can be assembled within 90 min by using TCFH in combination with K₂HPO₄ or <i>N</i>-methylimidazole. The developed mechanochemical liquid-assisted amidation protocols were successfully applied to the challenging couplings of all six carboxylate functions of biotin[6]uril macrocycle with phenylalanine methyl ester, resulting in an 80% yield of highly pure hexa-amide-biotin[6]uril. In addition, fast and high-yielding synthesis of peptides and versatile amide compounds can be performed in a safe and environmentally benign manner, as verified by green metrics.<b></b></p>

Synthesis and Preliminary Biological Activity Evaluation of New N- Substituted Phthalimide Derivatives

A A new series of bases of Schiff (H2-H4) derived from phthalic anhydrideweresynthesized. These Schiff bases were prepared by the reaction of different amines (tyrosine methyl ester, phenylalanine methyl ester, and isoniazid) with the phthalimide derived aldehyde with the aid of glacial acetic acid or triethylamine ascatalysts. All the synthesized compounds were characterized by (FT-IR and 1HNMR) analyses and were in vitro evaluated for their antimicrobial activity against six various kinds of microorganisms. All the synthesized compounds had been screened for their antimicrobial activity against two Gram-positive bacteria “Staph. Aureus, and Bacillus subtilis”, two Gram-negative bacteria “Escherichia coli, and Klebsiella pneumoniae”, and two fungi species “Candida tropicalis and Candida albicans” using concentrations of 62.5, 125 and 250 µg\mLof derivative in dimethyl sulfoxide(DMSO). All the synthesized compounds showed no activity at all against Gram-positive bacteria, for Gram-negative bacteria and fungi they showed moderate or no activity except compound H1revealedhigh antifungal activityagainstCandida tropicalisat concentrations 125 and 250 µg\ mL. Keywords: Schiff base, phthalic anhydride, antimicrobial.

Copper(II) and Zinc(II) Complexes of Mono- and Bis-1,2,3-Triazolesubstituted Heterocyclic Ligands

Chelating 1,4-disubstituted mono- (8a−8d) and bis-1,2,3-triazole-based (9a−11a) ligands were prepared by regioselective copper(I)-catalysed 1,3-dipolar cycloaddition of terminal alkynes with aromatic azides, together with bioconjugate 13a synthesized by amide coupling of L-phenylalanine methyl ester to 11a. Cu(II) and Zn(II) complexes were prepared and single crystal structures were determined for complexes 8aCu, 8dCu, 9cCu and 10cCu, as well as the free ligands 10a and 10c. The in situ prepared Zn(II) complexes were studied by NMR spectroscopy, while the stoichiometry of the Cu(II) complexes in solution was determined by UV-Vis titrations and confirmed by the electronic structure DFT calculations at the (SMD)/M05-2X/6-31+G(d)/LanL2DZ + ECP level of theory.

Copper(II) and Zinc(II) Complexes of Mono- and Bis-1,2,3-Triazolesubstituted Heterocyclic Ligands

Chelating 1,4-disubstituted mono- (8a−8d) and bis-1,2,3-triazole-based (9a−11a) ligands were prepared by regioselective copper(I)-catalysed 1,3-dipolar cycloaddition of terminal alkynes with aromatic azides, together with bioconjugate 13a synthesized by amide coupling of L-phenylalanine methyl ester to 11a. Cu(II) and Zn(II) complexes were prepared and single crystal structures were determined for complexes 8aCu, 8dCu, 9cCu and 10cCu, as well as the free ligands 10a and 10c. The in situ prepared Zn(II) complexes were studied by NMR spectroscopy, while the stoichiometry of the Cu(II) complexes in solution was determined by UV-Vis titrations and confirmed by the electronic structure DFT calculations at the (SMD)/M05-2X/6-31+G(d)/LanL2DZ + ECP level of theory.

Mechanistic Insights into Aspartame-induced Immune Dysregulation

Background & Objective: Aspartame, (L-aspartyl-L-phenylalanine methyl ester) is a widely used artificial sweetener but studies raise safety concerns regarding the use of aspartame metabolites especially methanol. In this review, we aimed to provide mechanistic insights that may explain aspartame-induced immune dysregulation. Findings: While evidence is limited, from the available literature, possible mechanisms for immune dysfunction associated with aspartame include (1) alterations in bidirectional communication between neuro-immune-endocrine responses (2) disruption of the brain-gut-microbiota-immune axis (3) induction of oxidative stress in immune cells and organs and lastly (4) the immune-activation effect of methanol. Conclusion: Further studies are needed to confirm above proposed mechanisms that may explain aspartame- induce immune dysregulation.

Synthesis and Complexation Studies of Optically Active Aza- and Diazacrown Ethers Containing a Pyrene Fluorophore Unit

Novel enantiopure azacrown [(R,R)-1 and (S,S)-1] and diazacrown [(R,R)-2–(R,R)-4 and (S,S)-2–(S,S)-4] ethers containing a pyrene fluorophore unit and two phenyl groups at their chiral centers were obtained in multistep syntheses. The action of these chemosensors is based on the photoinduced electron transfer (PET) process, thus they show fluorescence enhancement in the presence of protonated primary amines and amino acid esters. Their recognition abilities toward the enantiomers of 1-phenylethylamine hydrogen perchlorate (PEA), 1-(1-naphthyl) ethylamine hydrogen perchlorate (NEA), phenylglycine methyl ester hydrogen perchlorate (PGME), and phenylalanine methyl ester hydrogen perchlorate (PAME) were examined in acetonitrile using fluorescence spectroscopy.