Carboxylic acid imides peptides

In solution-phase peptide synthesis, acylation of amino acids or peptides with N-protected azetidine-2-carboxylic acid is performed via the active esters, e.g. A-hydroxysuccin-imide 100 111-112 or pentachlorophenyl ester, m 117 as well as by the mixed anhydride 101114 or carbodiimide 118 methods. An attempt to prepare the A-carbonic acid anhydride by cycli-zation of A-(chloroformyl)azetidine-2-carboxylic acid with silver oxide in acetone or by addition of triethylamine in situ failed, presumably due to steric hindrance. 111 In SPPS, activation of the Fmoc-protected imino acid by HBTU 119,120 is reported. In solution-phase peptide synthesis, coupling of N-protected amino acids or peptides to C-protected azetidine-2-carboxylic acid or related peptides may be performed by active esters, 100 118 121 mixed anhydrides, 95 or similar methods. It may be worth mentioning that the probability of pip-erazine-2,5-dione formation from azetidine-2-carboxylic acid dipeptides is significantly reduced compared to proline dipeptides. 111 ... 

The observation that carboxyl ate ions react at a much faster rate than amines with nitrilium ions and that they give Z-O-acylisoamides only, has led to the development of a new method for the synthesis of peptides (13). Imide halide 4 on dissolution in a polar solvent undergoes rapid unimolecular ionization to the nitrilium ion 42 which reacts with the carboxylate ion to give the Z-O-acylisoamide 43 which in turn reacts with the amine to give the amide product 44. The formation of the amide (or peptide) can be carried out by adding the halide 41 to a solution containing both the amine and the carboxylic acid. The initial reaction (41 42 43) is best carried out at pH=6 and when the pH is adjusted to =8, formation of the amide (43 44)... 

Ester links between threonine and the terminal carboxyl of a peptide chain forming a lactone have been found in actinomycin (Bullock and Johnson, 1957), while Dekker et al. (1949) have found an imide link in the form of a pyrrolidonyl ring involving the N-terminal glutamic acid residue in a peptide isolated from algae. In teichoic acids (polymers present in... 

Amino acids have a much more diverse set of functional groups than nucleotides. The functional groups of the side chains of the amino acids include carboxylate, carboxamide, imide, hydroxy, thiol, and primary and secondary amines. These functional groups are responsible for the numerous interactions in peptides and proteins. When they are part of large proteins, they display three-dimensional structures. The repertoire may be even larger by forming special active sites. 

Deamidation. The side chain of amide linkage in a Gin or Asn residue is hydrolysed to form a free carboxylic acid that gives mixtures of peptides in which the polypeptide backbone is attached via an alpha-carboxyl linkage (Asp/Glu) or is attached via beta carboxyl linkage (iso-Asp/Glu) [4]. The key step in the reaction is the formation of a five- or six-membered cyclic imide structure [5], and this degradative reaction most often occurs at a higher rate at the sequence Asn-Gly. 

The polymeric imide could then be reacted with primary amines or ammonia to form ammonium salts for a subsequent reactions with a carboxylic acid in the presence of a coupling reagent. It could then be converted to amides or functionalized as a uranium salt for use as polymer-supported peptide coupling. In addition, the anhydride was also reacted with di(2-pyrldyl)methylamine and formed a recoverable palladium catalyst for cross-coupling reactions that could take place in water. 

Amidation. A number of other various amidation reactions have been conducted using BOP. Such preparations include A) O-dimethyl hydroxamates of amino acids and peptides (precursors of chiral peptidyl aldehydes), heterocyclic amide fragments in the synthesis of macrolide and porphyrin models, dan-sylglycine anhydride as a mixed sulfonic-carboxylic imide by dehydration-cyclization of dansylglycine, and selective monoacylation of heterocyclic diamine in carbohydrate series (eq 9). ... 

Peptide synthesis requires the use of selective protecting groups. An N-protected amino acid with a free carboxyl group is coupled to an O-protected amino acid with a free amino group in the presence of dicydohexvlcarbodi-imide (DCC). Amide formation occurs, the protecting groups are removed, and the sequence is repeated. Amines are usually protected as their teit-butoxy-carbonyl (Boc) derivatives, and acids are protected as esters. This synthetic sequence is often carried out by the Merrifield solid-phase method, in which the peptide is esterified to an insoluble polymeric support. 

Another competing cyclisation during peptide synthesis is the formation of aspartimides from aspartic acid residues [15]. This problem is common with the aspartic acid-glycine sequence in the peptide backbone and can take place under both acidic and basic conditions (Fig. 9). In the acid-catalysed aspartimide formation, subsequent hydrolysis of the imide-containing peptide leads to a mixture of the desired peptide and a (3-peptide. The side-chain carboxyl group of this (3-peptide will become a part of the new peptide backbone. In the base-catalysed aspartimide formation, the presence of piperidine used during Fmoc group deprotection results in the formation of peptide piperidines. 

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