Protected peptide fragments chains

Fig. l The use of the 2-chlorotrityl chloride resin for the preparation of protected peptides and proteins. Either amino acids (a) or fully protected peptide fragments (b) are condensed to the growing peptide chain on the resin. 

The hydroxyl version of the Rink amide linker, known as the Rink acid resin (25), was developed as a tool for the preparation of protected peptide fragments [13]. The peptide-linker ester bond is labile to extremely weak acids, such as HOBt or acetic acid, allowing peptides bearing t-butyl-based side-chain protection to be cleaved intact. Conversion of the hydroxyl group into chloride [66] or trifluoroacetyl [67] provides linkers that have been used for immobilization of various nucleophiles, including alcohols, N-protected hydroxylamines, phenols, purines, amines, anilines and thiols [66-68], The stability of the cation derived from this tinker is such that even thiols and amines can be cleaved from this tinker with TFA (Figure 14.12). 

Many other handles exist that are cleavable by orthogonal mechanisms for the synthesis of protected peptide fragments these are also summarized in Table 5. A novel strategy for the synthesis of cyclic peptides on resin is to attach the peptide to the resin by a backbone nitrogen rather that the C -carboxyl. The N-and C-termini then remain free for further functionalization such as cyclization, esterification, or thioester formation. This backbone amide linker (BAL) is listed in Table 5. Other strategies such as attaching the peptide to the resin via the side chain of trifunctional amino acids and more comprehensive listings of linkers and handles are covered in References 9,12, and 109-111. 

These methodologies have been reviewed (22). In both methods, synthesis involves assembly of protected peptide chains, deprotection, purification, and characterization. However, the soHd-phase method, pioneered by Merrifield, dominates the field of peptide chemistry (23). In SPPS, the C-terminal amino acid of the desired peptide is attached to a polymeric soHd support. The addition of amino acids (qv) requires a number of relatively simple steps that are easily automated. Therefore, SPPS contains a number of advantages compared to the solution approach, including fewer solubiUty problems, use of less specialized chemistry, potential for automation, and requirement of relatively less skilled operators (22). Additionally, intermediates are not isolated and purified, and therefore the steps can be carried out more rapidly. Moreover, the SPPS method has been shown to proceed without racemization, whereas in fragment synthesis there is always a potential for racemization. Solution synthesis provides peptides of relatively higher purity however, the addition of hplc methodologies allows for pure peptide products from SPPS as well. 

Synthesis of octreotide and derivative thereof can be carried out by two methods. The first method is synthesized initially by fragment condensation solution phase procedures. The synthetic process of octreotide has been described by Bauer et al. (1). The second method is the synthese by solid-phase procedures. Edward et al. (2) isolated side chain protected octreotide with a total yield of 14% by cleaving the protected peptide from the resin with threoninol. Arano et al. (3) carried out another solid phase method for octreotide, and produced it in overall 31.8% yield based on the starting Fmoc-Thr(tBu)-ol-resin. The basic difference from the other procedures already described is that the introduction of the threoninol is carried out upon the protected peptidic structure (resin-free), which, when appropriately activated, leads quantitatively and without needing to make temporary protections upon the threoninol, to the protected precursor of octreotide, which in turn, with a simple acid treatment leads to octreotide with very high yields. 

TFA at higher temperatures,or TFA/thioanisole where the push-pull mechanism remarkably increases the rate of acidolysis,f l liquid HF/pyridine,t °l BBrj/CHaQa, or BBrj/TFA for longer peptide fragments.By these procedures also the benzyl-type side-chain protection is cleaved as well as Arg(Tos). Additionally, numerous sulfonic acids were shown to efficiently remove the Z group, such as methanesulfonic acid, trifluoromethanesulfonic acid, or fluorosulfonic acid mainly in CH2CI2 or Since the acidolytic removal of the... 

In order to prepare Asp- or Glu-containing peptide fragments, in which side-chain carboxy groups are unblocked, one method is to introduce aspartic or glutamic acid into the peptide through its A-carboxyanhydride. Another method is to introduce aspartic or glutamic acid with the side chain protected as the benzyl ester and then to remove the benzyl ester by YiJ Pd and finally convert the C-terminal methyl ester into the corresponding hydrazide. 

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