Peptide synthesis specific

We now turn from the general problems of peptide synthesis to specific problems connected with three currently important procedures, namely ... 

To illustrate the specific operations involved, the scheme below shows the first steps and the final detachment reaction of a peptide synthesis starting from the carboxyl terminal. N-Boc-glycine is attached to chloromethylated styrene-divinylbenzene copolymer resin. This polymer swells in organic solvents but is completely insoluble. ) Treatment with HCl in acetic acid removes the fert-butoxycarbonyl (Boc) group as isobutene and carbon dioxide. The resulting amine hydrochloride is neutralized with triethylamine in DMF. 

With its structure known, the synthesis of a peptide can then be undertaken— perhaps to obtain a larger amount for biological evaluation. A simple amide might be formed by treating an amine and a carboxylic acid with dicyclo-hexylcarbodiimide (DCC Section 21.7), but peptide synthesis is a more difficult problem because many different amide bonds must be formed in a specific order rather than at random. 

Developments of protection strategies in peptide synthesis have led to the introduction of a wider variety of protecting groups for different functionalities and provide orthogonal protection to specific side chains (Table 1). 

M Bodanszky, A Bodanszky. Racemization in peptide synthesis. Mechanism specific models, (nitrophenyl esters) Chem Commun 591-593, 1967. 

Solid-phase peptide synthesis offers a fast and convenient route for many peptides when isotope-enriched compounds are not required. Classical synthesis additionally permits the use of non-natural amino acids and allows site-specific isotope labeling. Although Fmoc protected 15N-labeled amino adds are commercially available, the cost of such synthesis is usually prohibitive, and the peptides from chemical synthesis require perdeuterated detergents and unfortunately exclude investigation of internal dynamics through measurement of 15N relaxation. 

Faith A. Akdis CA. Akdis M, Joss A, Wymann D. Blaser K An altered peptide ligand specifically inhibits Th2 cytokine synthesis by abrogating TCR signaling. J Immunol 1999 162 1836-1842. 

A possibility to overcome the time-consuming solution-phase peptide synthesis, but avoiding specific synthetic problems that cannot be addressed on tbe solid support, is to follow a combined solution-/solid-pbase approach. In such an approach the majority of the peptide sequence is typically assembled on solid support, but critical steps are performed in solution. Below, some exemplary peptides are discussed. 

DKPs may be produced without any difficulties and may form without particular activation of the carboxyl function of the dipeptide precursor. However, the cyclization reaction may be a slow process, justifying the need for specific activation of the carboxyl moiety. Kopple stated that there is no single perfect method for the cyclization of all peptides, only guidelines aiding in the judicious choice of combinations of procedures to limit the generation of unwanted by-products of peptide synthesis. 

Since the first chemical studies into the preparation of simple phosphoserine-peptides in 1959, several synthetic approaches have been investigated for the solution or solid-phase synthesis of phosphorylated peptides containing phosphoserine Ser(P), phosphothreonine Thr(P), and phosphotyrosine Tyr(P) residues. This section outlines two main methods for the synthesis of phosphorylated peptides which involve (1) the specific incorporation of protected phosphoamino acids in Boc or Fmoc peptide synthesis or (2) the post-assembly phosphorylation of Ser-, Thr- or Tyr-containing peptide-resins. For comprehensive recent reviews on the synthesis of phosphorylated peptides, the reader is directed to refs[141142l... 

Several applications of photoreactive peptides require the presence of a radionuclide to allow specific and sensitive detection of the photo-cross-linked conjugates. In several cases, radioiodination of tyrosyl moieties and radiolabeled Bolton-Hunter reagents have been used. However, the presence of a radiolabel within the benzophenone photophore is desirable, particularly when the objective is to identify the site of photo-insertion of benzophenone. To this end some radiolabeled, benzophenone-based compounds have been developed and used in peptide synthesis, in particular tritiated Phe(4-Bz) (Scheme 24)J2161 [1-14C-carboxy]-4-benzoylbenzoic acid,1221 and 4-benzoyl-(2,3-3H2)-dihydrocinnamic acid.[154l In addition, 4-(4-hydroxybenzoyl)phenylalanine (Scheme 25) has been directly radioiodinated with Na125I and Chloramine-T)151 ... 

A distinct group of synthetic depsipeptides comprises of compounds that do not originate from natural product biodiversity several artificial substrates of peptidases and esterases belong to this group, as well as polydepsipeptides that are considered as potentially biodegradable polymeric materials. A specific feature of depsipeptide synthesis is the necessity to acylate a hydroxy acid component, which requires stronger activation of the amino acid component in comparison to normal peptide synthesis. Otherwise, the main principles of depsipeptide synthesis are similar to those of peptides. Frequently, formation of the ester... 

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