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SYNTHESIS OF TWO LINEAR OCTAPEPTIDE FRAGMENTS OF CYCLOSPORIN BY STEPWISE AND FRAGMENT CONDENSATION STRATEGIES

The octapeptide Z-(Me)Leu-Val-(Me)Leu-Ala-D-Ala-(Me)Leu-(Me)Leu-(Me)Val-O(t-Bu) was prepared by stepwise elongation starting from H-(Me)Val-O(t-Bu).Diphenylphosphinic mixed anhydrides were preferentially used throughout as they gave high yields of optically homogeneous products in this extensively N-methylated peptide.The above peptide and the octapeptide Z-Ala-D-Ala-(Me)Leu-(Me)Leu-(Me)Val-(Me)Thr(t-Bu)-Abu-Sar-O(t-Bu) were also prepared by the fragment condensation approach employing a variety of coupling methods.Ultimately, it was clear that the stepwise assembly gave the highest yield, and most homogeneous product.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N2628 – PubChem

 

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TOTAL SYNTHESIS OF GALANTIN I. REVISION OF THE ORIGINAL STRUCTURE

The proposed structure of galantin I, isolated as a mixture of homologs (1a/1b = 9/1), was shown to be incorrect by total synthesis and was revised twice to finally give 5a and 5c, respectively, by total synthesis.

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A facile and simple method for the reduction of N-protected amino acids and peptides to the corresponding alcohols

A practical and chemoselective method for the reduction of N-protected amino acids and peptides including carboxylic acids to their corresponding alcohols is outlined.

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Simple and efficient preparation of (R)- and (S)-enantiomers of alpha-carbon deuterium-labelled alpha-amino acids

A procedure for the synthesis of (R)- and (S)-enantiomers of alpha-carbon deuterium-labelled alpha-amino acids, exemplified for (R)- and (S)-[2-2H1]-Leu is described. Starting from the respective (S)- or (R)-enantiomer or from the racemic mixture of an alpha-amino acid the selective proton exchange at the alpha-carbon is carried out by racemization via a Schiff base in monodeuterated acetic acid as solvent which serves as deuterium source. After N-protection the racemic mixture is liquid chromatographically separated into the individual (R)- and (S)-enantiomers on preparative scale employing a chiral anion exchanger based on carbamoylated quinine as chiral selector. After deprotection the enantiomerically pure products can be obtained in good yields.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N2699 – PubChem

 

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An efficient approach to chiral C8/C9-piperazino-substituted 1,4-benzodiazepin-2-ones as peptidomimetic scaffolds

(Chemical Equation Presented) A promising way to interfere with biological processes is through the modulation of protein-protein interactions by means of small molecules acting as peptidomimetics. The 1,4-benzodiazepine scaffold has been widely reported as a peptide-mimicking, pharmacogenic system. While several synthetic pathways to C6-8 substituted benzodiazepines have been disclosed, few 1,4-benzodiazepines substituted at C9 have been reported. Herein, we describe a versatile approach to introduce cyclic, protonatable functionality at C8/C9. Introduction of the piperazine system at C8 and C9 gave access to a unique functionalization of the versatile benzodiazepine skeleton, broadening tailoring options on the benzofused side of the molecule, and the possibility of discovering novel peptidomimetics potentially able to modulate protein-protein interactions. Coupling of activated amino acids with poorly reactive anilines under mild conditions, while avoiding racemization, gave easy access to these compounds. Efficient amino acid activation was obtained by exploiting the rapid formation of acid chlorides under low temperature and acid/base free conditions, using triphenylphosphine and hexachloroacetone. This procedure successfully resulted in high reaction yields, did not produce racemization (ee > 98%, as demonstrated by using chiral solvating agents), and was compatible with the acid sensitive protecting groups present in the substrates.

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Pyridazine – Wikipedia,
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Depsipeptide methodology for solid-phase peptide synthesis: Circumventing side reactions and development of an automated technique via depsidipeptide units

The depsipeptide technique is a recently developed method for peptide synthesis which is applicable to difficult sequences when the synthetic difficulty arises because of aggregation phenomena. In the present work, application of the depsipeptide method to extremely difficult sequences has been demonstrated and a serious side reaction involving diketopiperazine formation uncovered and subsequently avoided by the appropriate use of the Bsmoc protecting group. Many other aspects of the technique have been investigated, such as the stability of the depsi units during assembly and workup procedures, the completeness of the O-acylation step, the occurrence of epimerization of the amino acid activated during O-acylation, and the nature of side products formed. In addition, the method was modified so as to allow for completely automated syntheses of long-chain depsipeptides without the need for any interruption by manual esterification procedures. Finally, the synthesis efficiency of the new depsipeptide technique was shown to be comparable to that of the well-known pseudoproline technique.

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Highly enantioselective phase-transfer-catalyzed alkylation of protected alpha-amino acid amides toward practical asymmetric synthesis of vicinal diamines, alpha-amino ketones, and alpha-amino alcohols

Highly enantioselective alkylation of protected glycine diphenylmethyl (Dpm) amide 1 and Weinreb amide 10 has been realized under phase-transfer conditions by the successful utilization of designer chiral quaternary ammonium salts of type 4 as catalyst. Particularly, remarkable reactivity of the chiral ammonium enolate derived from 1b and 4c allowed the reaction with less reactive simple secondary alkyl halides with high efficiency and enantioselectivity. An additional unique feature of this chiral ammonium enolate is its ability to recognize the chirality of beta-branched primary alkyl halides, which provides impressive levels of kinetic resolution and double stereodifferentiation during the alkylation, allowing for two alpha- and gamma-stereocenters to be controlled. Combined with the subsequent reduction using LiAlH4 in cyclopentyl methyl ether (CPME), this system offers a facile access to structurally diverse optically active vicinal diamines. Furthermore, the optically active alpha-amino acid Weinreb amide 11 can be efficiently converted to the corresponding amino ketone by a simple treatment with Grignard reagents. In addition, reduction and alkylation of the optically active alpha-amino ketone into both syn and anti alpha-amino alcohols with almost complete relative and absolute stereochemical control have been achieved. With (S,S)- and (R,R)-4 in hand, the present approach renders both enantiomers of alpha-amino amides including Weinreb amides readily available with enormous structural variation and also establishes a general and practical route to vicinal diamines, alpha-amino ketones, and alpha-amino alcohols with the desired stereochemistry.

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Tetramethyl Orthosilicate (TMOS) as a Reagent for Direct Amidation of Carboxylic Acids

Tetramethyl orthosilicate (TMOS) is shown to be an effective reagent for direct amidation of aliphatic and aromatic carboxylic acids with amines and anilines. The amide products are obtained in good to quantitative yields in pure form directly after workup without the need for any further purification. A silyl ester as the putative activated intermediate is observed by NMR methods. Amidations on a 1 mol scale are demonstrated with a favorable process mass intensity.

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Pyridazine – Wikipedia,
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Inhibition of 125I-labeled ristocetin binding to Micrococcus luteus cells by the peptides related to bacterial cell wall mucopeptide precursors: Quantitative structure-activity relationships

Quantitative structure-activity relationships (QSAR) of N-Ac amino acids, N-Ac dipeptides, and N-Ac tripeptides in inhibition of 125I-labeled ristocetin binding to Micrococcus luteus cell wall have been developed to probe the details of the binding between ristocetin and N-acetylated peptides. The correlation equations indicate that (1) the binding is stronger for peptides in which the side chain of the C-terminal amino acid has a large molar refractivity (MR) value, (2) the binding is weaker for peptides with polar than for those with nonpolar C-terminal side chains, (3) the N-terminal amino acid in N-Ac dipeptides contributes 12 times that of the C-terminal amino acid to binding affinity, and (4) the interactions between ristocetin and the N-terminal amino acid of N-acetyl tripeptides appear to be much weaker than those with the first two amino acids.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N2672 – PubChem

 

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Compositions and methods of inhibiting N-acylethanolamine-hydrolyzing acid amidase

Compounds and pharmaceutical compositions are contemplated that inhibit N-acyl-ethanolamine-hydrolyzing acid amidase (NAAA) to so increase the concentration of the substrate of NAAA, palmitoylethanolamide (PEA). NAAA inhibition is contemplated to be effective to alleviate conditions associated with a reduced concentration of PEA. Among other uses, various NAAA inhibitors are especially contemplated as therapeutic agents in the treatment of inflammatory diseases.

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Pyridazine – Wikipedia,
Pyridazine | C4H4N2577 – PubChem