2224-52-4Relevant articles and documents
Ring opening polymerization of α-amino acid N-carboxyanhydrides catalyzed by rare earth catalysts: Polymerization characteristics and mechanism
Peng, Hui,Ling, Jun,Shen, Zhiquan
, p. 1076 - 1085 (2012)
Five rare earth complexes are first introduced to catalyze ring opening polymerizations (ROPs) of γ-benzyl-L-glutamate N-carboxyanhydride (BLG NCA) and L-alanine NCA (ALA NCA) including rare earth isopropoxide (RE(OiPr)3), rare earth tris(2,6-di-tert-butyl-4-methylphenolate) (RE(OAr)3), rare earth tris(borohydride) (RE(BH4) 3(THF)3), rare earth tris[bis(trimethylsilyl)amide] (RE(NTMS)3), and rare earth trifluoromethanesulfonate. The first four catalysts exhibit high activities in ROPs producing polypeptides with quantitative yields (>90%) and moderate molecular weight (MW) distributions ranging from 1.2 to 1.6. In RE(BH4)3(THF)3 and RE(NTMS)3 catalytic systems, MWs of the produced polypeptides can be controlled by feeding ratios of monomer to catalyst, which is in contrast to the systems of RE(OiPr)3 and RE(OAr)3 with little controllability over the MWs. End groups of the polypeptides are analyzed by MALDI-TOF MS and polymerization mechanisms are proposed accordingly. With ligands of significant steric hindrance in RE(OiPr)3 and RE(OAr) 3, deprotonation of 3-NH of NCA is the only initiation mode producing a N-rare earth metallated NCA (i) responsible for further chain growth, resulting in α-carboxylic-I-aminotelechelic polypeptides after termination. In the case of RE(BH4)3(THF)3 with small ligands, another initiation mode at 5-CO position of NCA takes place simultaneously, resulting in α-hydroxyl-I-aminotelechelic polypeptides. In RE(NTMS)3 system, the protonated ligand hexamethyldisilazane (HMDS) initiates the polymerization and produces α-amide-I-aminotelechelic polypeptides.
Self-assembly of a model peptide incorporating a hexa-histidine sequence attached to an Oligo-Alanine sequence, and binding to gold NTA/nickel nanoparticles
Hamley, Ian W.,Kirkham, Steven,Dehsorkhi, Ashkan,Castelletto, Valeria,Adamcik, Jozef,Mezzenga, Raffaele,Ruokolainen, Janne,Mazzuca, Claudia,Gatto, Emanuela,Venanzi, Mariano,Placidi, Ernesto,Bilalis, Panayiotis,Iatrou, Hermis
, p. 3412 - 3420 (2014)
Amyloid fibrils are formed by a model surfactant-like peptide (Ala)10-(His)6 containing a hexa-histidine tag. This peptide undergoes a remarkable two-step self-assembly process with two distinct critical aggregation concentrations (cac's), probed by fluorescence techniques. A micromolar range cac is ascribed to the formation of prefibrillar structures, whereas a millimolar range cac is associated with the formation of well-defined but more compact fibrils. We examine the labeling of these model tagged amyloid fibrils using Ni-NTA functionalized gold nanoparticles (Nanogold). Successful labeling is demonstrated via electron microscopy imaging. The specificity of tagging does not disrupt the β-sheet structure of the peptide fibrils. Binding of fibrils and Nanogold is found to influence the circular dichroism associated with the gold nanoparticle plasmon absorption band. These results highlight a new approach to the fabrication of functionalized amyloid fibrils and the creation of peptide/nanoparticle hybrid materials.
Synthesis of α-Amino Acid N-Carboxyanhydrides
Laconde, Guillaume,Amblard, Muriel,Martinez, Jean
supporting information, p. 6412 - 6416 (2021/08/30)
A simple phosgene- and halogen-free method for synthesizing α-amino acid N-carboxyanhydrides (NCAs) is described. The reaction between Boc-protected α-amino acids and T3P reagent gave the corresponding NCA derivatives in good yield and purity with no detectable epimerization. The process is safe, is easy-to-operate, and does not require any specific installation. It generates nontoxic, easy to remove byproducts. It can apply to the preparation of NCAs for the on-demand on-site production of either little or large quantities.
Improved Scale-up Synthesis and Purification of Clinical Asthma Candidate MIDD0301
Arnold, Leggy A.,Cook, James M.,Knutson, Daniel E.,Mian, Md Yeunus,Roni, M. S. Rashid,Stafford, Douglas C.
, p. 1467 - 1476 (2020/11/23)
We report an improved and scalable synthesis of MIDD0301, a positive GABAA receptor modulator that is under development as oral and inhaled treatments for asthma. In contrast to other benzodiazepines in clinical use, MIDD0301 is a chiral compound that has limited brain absorption. The starting material to generate MIDD0301 is 2-amino-5-bromo-2′-fluorobenzophenone, which has a nonbasic nitrogen due to electron-withdrawing substituents in the ortho and para positions, reducing its reactivity toward activated carboxylic acids. Investigations of peptide coupling reagents on a multigram scale resulted in moderate yields due to incomplete conversions. Second, the basic conditions used for the formation of the seven-membered 1,4-diazepine ring resulted in racemization of the chiral center. We found that neutral conditions comparable to the pKa of the primary amine were sufficient to support the formation of the intramolecular imine but did not enable the simultaneous removal of the protecting group. Both difficulties were overcome with the application of the N-carboxyanhydride of d-alanine. Activated in the presence of an acid, this compound reacted with nonbasic 2-amino-5-bromo-2′-fluorobenzophenone and formed the 1,4-diazepine upon neutralization with triethylamine. Carefully designed workup procedures and divergent solubility of the synthesic intermediates in solvents and solvent combinations were utilized to eliminate the need for column chromatography. To improve compatibility with large-scale reactors, temperature-controlled slow addition of reagents generated the imidazodiazepine at -20 °C. All intermediates were isolated with a purity of >97% and impurities were identified and quantified. After the final hydrolysis step, MIDD0301 was isolated in a 44% overall yield and a purity of 98.9% after recrystallization. The enantiomeric excess was greater than 99.0%.
METHOD OF SYNTHESIZING N-CARBOXYANHYDRIDE USING FLOW REACTOR
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Paragraph 0092-0096; 0119-0120, (2020/03/26)
PROBLEM TO BE SOLVED: To provide a synthesis method that allows high-yield continuous production of a compound of interest in synthesis and production of N-carboxyanhydride (NCA) and the like using a flow reactor. SOLUTION: In a synthesis method using a flow reactor 100, a basic solution adjusted in advance to a pH of 7-14 becomes acidic with a pH of 0-7, or an acidic solution adjusted in advance to a pH of 0-7 becomes basic with a pH of 7-14, within 60 seconds after the start of mixture of at least two ingredient solutions. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2020,JPOandINPIT
