Amino acid amide formation

A further strategy used to prepare amides on insoluble supports is based on the Ugi reaction (Figure 13.8). Simple mixing of an amine, an aldehyde, an acid, and an isonitrile can lead to the formation of a-amino acid amides. The mechanism of this remarkable reaction is outlined in Figure 13.8. Sometimes, the amine is first condensed with the aldehyde to form an imine, which is then combined with the acid and the isonitrile. 

G values for the destruction of amino acids and formation of amide-like nitrogen were calculated from the initial slopes of linear plots of yield-dose data. For doses up to 1 Mrad in 0.1% solution, these were straight lines. 

The mechanism of retention on chiral phases that is based on multiple hydrogen bonding formation involves the formation of base pairs and triple hydrogen bonds between the solutes and the chiral stationary phase 95 Fundamental work in this area has been done by Hara and Dobashi,96 97 using amino acid amide and tartaric acid amide phases. In addition, N,N -2,6-pyridinediyl bis(alkanamides) chemically bonded to silica gel have been described for the resolution of barbiturates 95... 

The solubilizing capacity of the choline residue is so pronounced that even substrates combining two hydrophobic amino acids are homogeneously soluble in aqueous buffer without any additional cosolvent. These favorable physical properties were also used in the enzymatic formation of peptide bonds. The amino acid choline ester 38 acts as the carboxyl component in kinetically controlled peptide syntheses with the amino acid amides 39 and 40 [52] (Fig. 11). The fully protected peptides 41 and 42 were built up by means of chymotrypsin in good yields. Other proteases like papain accept choline esters as substrates also, and even butyrylcholine esterase itself is able to generate peptides from these electrophiles. 

The second group of hydroxy compound derivatization reactions includes acylation of OH groups with the formation of esters. The most important are listed below (for the table of physicochemical and gas chromatographic constants of acylation reagents refer to the entry Derivatization of Amines, Amino Acids, Amides, and Imides for GC Analysis). 

The basis of the process leading to the enantiomerically pure acid is essentially the same as that for a-H-a-amino acids. However, in this case, a ketone is used as the starting material which undergoes a Strecker reaction, followed by hydrolysis of the resulting aminonitrile to form the racemic a-alkyl-a-amino acid amide. Enzymatic hydrolysis results in the formation of the L-a-alkyl-a-amino acid (Fig. 12.2-2). 

The reactions of ferrocenylphosphines and tris(diethylamino)phosphine with iodine lead to the formation of iodotri(organo)phosphonium iodides. The related chlorophosphonium chloride obtained from the reaction of tris(dimethyl-amino)phosphine with phosgene has been used as a dehydrating agent for the preparation of A-protected amino-acid amides. ... 

The well known specificity of proteinases implies the use of specific amino acids (amides, esters) as acyl donors and—seldom—specific amino acid (derivatives) as acceptors in enzymatic peptide bond formation, since the same structural features of RCONHR that influence the rate of hydrolytic cleavage are also involved in the synthesis. Accordingly trypsin is well suited to the formation of a new -Arg-X or -Lys-X bond. As an example the transformation of the -Lys-AlaOH terminus of the B-chain of porcine insulin into -LysThrOBu of human insuhn may be mentioned. C-terminal Ala was removed by means of car-boxypeptidase A, trypsin-catalyzed condensation of the des-alanine peptide with threonine tert. butylester gave 73% of the ester of human insulin [33] (see also... 

In each of the initiation steps the strongest nucleophile present reacts with the lactam cation. When strong anhydrous Bronsted acids initiate the polymerizations, the free lactams are acylated first with the formation of aminoacyllactams. When the polymerizations are initiated by amine salts, the initial steps are conversions of the amines to the amino acid amides. On the other hand, hydrolytic polymerizations start formations of unsubstituted amino acids [122] ... 

S) Amino Acid Amide Transaminases. Mention was made previously (see Amidases) of the observations by Greenstein and co-workers that the addition of pyruvic and other a-keto acids to liver extracts accelerated the formation of ammonia from glutamine and asparagine. This reaction has been shown by Meister and co-workers to involve a transamination reaction different in several respects from those previously discussed. The reaction for glutamine may be formulated as follows ... 

Recently, it was foimd that kojic add-tripeptide amides showed similar tyrosinase inhibitoiy activities to those of kojic add-tripeptide free adds but exhibited superior storage stability than those of kojic acid and kojic add-trip>eptide free acids (Noh, 2007). To find further kojic acid derivatives with higher tyrosinase inhibitory activity, stability, and synthetic effidency, a library of kojic add-amino acid amides (KA-AA-NH2) prepared and screened for their tyrosinase inhibitoiy activities. It was also confirmed that the kojic add-phenylalanine amides reduced the amount of dopachrome production during the melanin formation. It was suggested that a tyrosinase inhibition mechanism of KA-AA-NH2 based on the possible hydrophobic interadions between the side chain of KA-AA-NH2 and tyrosinase active site by a docking program (Noh, 2009 Kim, 2004). 

On this basis the extent to which an enzyme-catalyzed transamidation will occur will depend on the relative concentration of water and the replacement reagent, and the relative affinity of the replacement agent for the ES-complex. Durell and Fruton (51) have studied papain-catalyzed hydroxamic acid formation from o-benzoyl-L-argininamide. Their calculations show that hydroxylamine is about 420 times more efficient in its reaction with the enzyme-substrate complex than is water. Preliminary observations suggest that when amino acid amides or peptides are the attacking molecule the efficiency is even greater. Moreover, papain is a much more effective catalyst for transamidation than trypsin. 

Lipase Amino acid surfactants Formation of amide bond between c-amine group of lysine and fatty acyl group Gardossi et al., 1991 Monlet et al., 1990 Soo et al., 2003... 

Classical enzymes employed for peptide coupling of the serine hydrolase family are chymotrypsin, trypsin, and subtilisin. Chymotrypsin and trypsin are secreted in the mammalian gut as inactive precursors, which are activated by autoproteolysis and structural reorganization. The use of chymotrypsin for peptide synthesis has been reported since the 1930s [50]. Most early examples concern peptide s)mthesis using amides or (m)ethyl esters as acyl donors and free amino acids and their amides, short peptides, or short peptide amides as nucleophilic acyl acceptors [3]. These studies revealed that a high pH, high nucleophile concentration, and low product solubility stimulate the formation of synthetic product. Ethyl esters appeared suitable acyl donors in kinetically controlled conversions, and amino acid amides act better as nucleophilic acyl acceptors than the free amino acids [4]. Furthermore, tripeptides often performed better than dipeptides or amino acids as acyl acceptors. 

Although every resolution process is intrinsically hampered by a maximum yield of 50%, racemization of the unwanted isomer can lead to 100% yield. For the aminoamidase process this can easily be done via racemization of the benzaldehyde Schiff base of the D-amide under basic conditions (Scheme 4) [17]. Since the separation of the L-acid and the D-amide proceeds via Schiff base formation of the amide, racemization can be performed without any additional step. Evidently, if the required products are D-amino acid (amides), the L-acid can of course also be recycled via this route (after formation of the L-amide). 

Esterification, Amidation, and Acid Chloride Formation. Amino acids undergo these common reactions of the carboxyl group with due regard for the need for A/-protection. 

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