Amino acids hydrazides

The 1,3,4-oxadiazole moiety, in analogy to the 1,2,4-oxadiazole discussed in Section 11.2.5.1, has been used extensively as an ester or amide bioisostere, but also has only recently been applied as an amide replacement in actual peptide segments.1104-1071 The synthesis of the peptide surrogate 1,3,4-oxadiazole derivative 60 is shown in Scheme 18.11021 The N-protected amino acid Boc-Ala-OH (56) was coupled with ethanol to form the ester 57 which was subsequently reacted with hydrazine to form the amino acid hydrazide 58.11(1X1 The hydrazide 58 was reacted with ethyl oxalyl chloride at — 30 °C to room temperature to provide the diacylhydrazide 59. This intermediate was subsequently dehydrated with thionyl chloride in refluxing toluene to form the desired 1,3,4-oxadiazole 60 in >95% ee. Although the overall yields are only moderate, the reported enantioselectivities of the final compounds are very good (Table 4).11021... 

Solid-phase syntheses of triazines (Table 15.32) include the cyclocondensation of polystyrene-bound isothiuronium salts with /V-(cyano)iminodithiocarbonates and the cyclization with simultaneous cleavage from the support of derivatives of a-amino acid hydrazides (Table 15.32). (Benzylthio)triazines, such as those listed in Table 15.32 (Entries 1 and 2), have been cleaved from a support by oxidation to sulfoxides or sul-fones with N-benzenesulfonyl-3-phenyloxaziridine, followed by nucleophilic cleavage with primary or secondary aliphatic amines or with electron-rich anilines (see Section 3.8). 

Chemical methods for carboxyl end-group determination are considerably less satisfactory. Treatment of the peptide with anhydrous hydrazine at 100°C results in conversion of all the amino acid residues to amino acid hydrazides except for the carboxyl-terminal residue, which remains as the free amino acid and can be isolated and identified chro-matographically. Alternatively, the polypeptide can be subjected to limited breakdown (proteolysis) with the enzyme carboxypeptidase. This results in release of the carboxyl-terminal amino acid as the major free amino acid reaction product. The amino acid type can then be identified chroma-tographically. 

Resolution of Carboxylic Acids. A variety of racemic monofunctional carboxylic acids have been resolved with chiral a-amino acid hydrazides, including L-1Vr-NHNH2 andL-leucine hydrazide, which produce mandelic acid analogs with greater than 99% ee. Other examples of resolutions of simple carboxylic acids have appeared in the patent literature (eq 1). ... 

Peptide analysis. In the Akabori method for determination of the C-terminal amino acid, the peptide is heated with anhydrous hydrazine at 100-120° for about 8 hrs. to convert internal units into amino acid hydrazides and liberate the free acid from the terminal unit. Unfortunately several amino acids are decomposed under... 

The work of Zeller et al. (116) on the amino acid hydrazides thus demonstrated several interesting points the need for considering susceptibility to... 

Numerous methods were proposed for this purpose, but only few withstood the test of time. A reliable procedure is hydrazinolysis (Akabori et al. 1952) which involves the heating of a solution of the peptide in ca. 97 % hydrazine in a sealed tube at 100 °C for 12 hours. The peptide bonds are cleaved by hydrazine and the amino acid constituents thus converted to amino acid hydrazides except the C-terminal residue which is merely hberated in the process. Its separation is faciUtated by dinitrophenylation of the mixture with 2,4-dinitrofluorobenzene. The DNP-amino acid hydrazides as neutral substances are extracted from the aqueous, bicarbonate containing mixture with an organic solvent while the sodium salt of the DNP-derivative of the C-terminal amino acid remains dissolved ... 

In thQ hydrazine method, all the amino acid residues except the carboxyl terminal residue are converted into amino acid hydrazides ... 

Amino-2-oxazolidinones 821 have been prepared by treating Cbz-protected amino acid hydrazides 820 with sodium nitrite/HCl in glacial acetic acid [607]. 

Peptide and amino acid hydrazides and hydrazones may easily be differentiated from other compounds on thin-layer chromatograms by treatment of the plates with ferric chloride followed by potassium ferri-cyanideU a royal blue color is obtained. Likewise, the p-nitrophenyl moiety may be detected by addition of base to obtain the bright yellow-color due to the p-nitrophenolate anion. 

Hybrid dynamic proteoids, containing alternating imine and acylhydrazone linkages, have been obtained by polycondensation of amphiphilic dialdehydes with amino acid hydrazides. The polymerization displays nucleation-elongation behavior driven by hydrophobic effects, resulting in the formation of globular particles reminiscent of folded proteins (Fig. 6) [89]. 

The C-terminal amino acid is then separated from the amino acid hydrazides, e. g., by a cation exchange resin, and identified. It is possible to mark the C-terminal amino acid through selective titration via oxazolinone ... 

This reaction forms the basis of one method of terminal residue analysis A peptide is treated with excess hydrazine in order to cleave all the peptide linkages One of the terminal amino acids is cleaved as the free amino acid and identified all the other ammo acid residues are converted to acyl hydrazides Which amino acid is identified by hydrazmolysis the N terminus or the C terminus ... 

Claisen ester condensation, 6, 279 Thiazolecarboxylic acid chlorides reactions, 6, 279-280 Thiazolecarboxylic acid hydrazides synthesis, 6, 280 Thiazolecarboxylic acids acidity, 6, 279 decarboxylation, 6, 279 reactions, S, 92 6, 274 Thiazole-2-carboxylic acids decarboxylation, S, 92 Thiazole-4-carboxylic acids stability, S, 92 Thiazole-5-carboxylic acids decarboxylation, S, 92 Thiazole-4,5-dicarboxylic acid, 2-amino-diethyl ester reduction, 6, 279 Thiazole-4,5-dicarboxylic acids diethyl ester saponification, 6, 279 Thiazolediones diazo coupling, 5, 59 Thiazoles, 6, 235-331 ab initio calculations, 6, 236 acidity, S, 49 acylation, 6, 256 alkylation, S, 58, 73 6, 253, 256 analytical uses, 6, 328 antifogging agents... 

Sulfobenzyl esters were prepared (cesium salt or dicyclohexylammonium salt, Na03SC6H4CH2Br, DMF, 37-95% yield) from A -protected amino acids. They are cleaved by hydrogenolysis (H2/Pd), or hydrolysis (NaOH, dioxane/water). Treatment with ammonia-or hydrazine results in formation of the amide or hydrazide. The ester is stable to 2 M HBr/AcOH and to CF3SO3H in CF3CO2H. The relative rates of hydrolysis and hydrazinolysis for different esters are as follows ... 

CN 4-pyridinecarboxylic acid 2-[3-oxo-3-[(phenylmethyl)amino]propyl]hydrazide... 

RN 2066-89-9 MF C7H7NO3 C,H,N30 MW 290.28 EINECS 218-183-2 CN 4-pyridinecarboxylic acid hydrazide mono(4-amino-2-hydroxybenzoate)... 

Much more important than these reactions, however, are the reactions of CDI and its analogues with carboxylic acids, leading to AAacylazoles, from which (by acyl transfer) esters, amides, peptides, hydrazides, hydroxamic acids, as well as anhydrides and various C-acylation products may be obtained. The potential of these and other reactions will be shown in the following chapters. In most of these reactions it is not necessary to isolate the intermediate AAacylazoles. Instead, in the normal procedure the appropriate nucleophile reactant (an alcohol in the ester synthesis, or an amino acid in the peptide synthesis) is added to a solution of an AAacylimidazole, formed by reaction of a carboxylic acid with CDI. Thus, CDI and its analogues offer an especially convenient vehicle for activation of... 

If the reactions are carried out with hydrazides like Z-NHNH2 or Z-Gly-NHNH2 instead of A-protected amino acids, the reaction products are called azapeptides [43]... 

The unsubstituted phthalic acid hydrazide and several nonaromatic cyclic hydrazides such as maleic acid hydrazide or succinic acid hydrazide are either nonchemiluminescent or show extremely weak CL. However, the 6-amino isomer of luminol, which is called isoluminol, is chemiluminescent to about the same extent as is luminol. Isoluminol has been used in many chemiluminescent studies, and because the amino group is less sterically hindered than that of luminol, it is probably derivatized for chemiluminescent labeling far more often than is luminol (Fig. 3). 

Acyl azides (see Section 2.13) The acyl-azide method of coupling is unique for two reasons. First, it is the only case in which the immediate precursor of the activated form of the peptide is not the parent acid. The starting material is the peptide ester that is obtained from the amino acid ester by usual chain assembly (Figure 2.25, path A). Second, it is the only method that just about guarantees production of a peptide that is enantiomerically pure, provided scrupulous attention is paid to details of procedure. There is no danger for loss of chirality during conversion of the ester to the hydrazide and then the azide, but care must be taken to avoid contact of... 

K Hofmann, A Lindenmann, MZ Magee, NH Khan. Studies on polypeptides III. Novel routes to a-amino acid and peptide hydrazides. (protected hydrazides). J Am... 

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