Peptides backbone protection

This group is used for peptide backbone protection. The acetoxy group makes it stable to TFA that is used to cleave the BOC group during peptide synthesis. 

The dimethoxybenzyl group was used for backbone protection of the pseudopeptides of the form Xaai/r(CH2N)Gly (Xaa = amino acid). It is introduced by reductive alkylation with the aldehyde and NaCNBH3. Acidolysis with TFMSA in TFA/thioanisole is used to remove it from the amine, but the efficiency is dependent upon the peptide sequence. ... 

Enantiopure N,N -hnked oligoureas were originally described in 1995 by Burgess and coworkers as novel peptide backbone mimetics [271, 272]. Several synthetic approaches have been reported, all of which involve sequential acylation and amine deprotection cycles using appropriately protected carbonyl synthons [83, 271, 272, 274, 286-288]. Although elongation can be performed in solution, most of the synthetic procedures are elaborated on solid supports starting from Rink s... 

Poor peptide solubility has been identified as a major obstacle to efficient segment assembly of peptides on a solid phase particularly for fully protected strategies. 1,5,6 Backbone protection directly addresses this problem and is the basis for a general route to the synthesis of small proteins. 7,8 However, the inclusion of backbone protection in a synthesis is not yet automated or routine and requires careful planning. 

The insolubility of peptides is not limited to the solution phase and can occur during peptide synthesis on the solid phase where it manifests itself as the difficult sequence problem. On-resin peptide aggregation and poor peptide segment solubility are due to the formation of (3-sheet-like structures. Difficult sequences contain predominantly hydrophobic residues that consistently show incomplete acylation and a characteristic shrinkage of the peptide-resin during synthesis.111 Reversible backbone protection was introduced into Fmoc/ tBu SPPS after the study of synthesis failure during the assembly of difficult sequences1121 and is now routinely used to circumvent synthesis failure in SPPS. 

O-Acylated Hmb is stable to acidolysis by TFA giving a useful additional feature to Hmb-containing peptides. Side-chain protection and the V -protection, if it is first replaced with Boc before Hmb O-acetylation, can be removed and backbone protection retained. After deacetylation of Hmb with aqueous hydrazine the peptide can be further purified before removal of the Hmb groups, useful when the product is poorly soluble. This feature is also useful for the purification of large polypeptides as the presence of backbone protection on the side-chain deprotected peptide prevents the formation of relatively stable folded structures that can complicate HPLC purification.1 11... 

The aims of inserting a thiazolidine-4-carboxylic acid (4-thiaproline, Thz, 11) residue into peptide chains are similar to those discussed for the 4-oxaproline analogue in Section 9.2.3.4.I. Thiazolidine-4-carboxylic acid (11), particularly when disubstituted at the C5 position of the proline ring, can act as a cysteine precursor and concomitantly as an amide backbone protecting group (see Section 23.2.4). Its solubilizing properties derive from its preference for the cis configuration of the Xaa-Thz bond. 169-172 ... 

Recently, two moderately active (V-hydroxyamide) analogues of the HIV protease substrate have been prepared in two different ways, with O-benzyl protection of the TV-hydroxy-a-amino acid residue.150 Boc-Phet >[CO-N(OH)]Gly-Ile-Phe-OMe is constructed by the mixed anhydride procedure in a step-by-step elongation of the peptide backbone. In contrast, Boc-Phei i[CO-N(OH)]Phe-Ile-Phe-OMe 49 is prepared by fragment condensation (Scheme 15). 

A crucial step in the chemical synthesis of glycopeptides is the incorporation of the saccharide into the peptide. Two approaches can be considered to accomplish this the direct glycosylation of a properly protected full-length peptide and the use of a preformed glycosylated amino acid building block for the stepwise synthesis of the peptide backbone (Scheme 1). 

The convergent approach to N-glycopeptides was first demonstrated by Peter Lansbury et al. (Scheme 11.4) [52, 53], Condensation of an oligosaccharyl amine with the Asp side chain of a suitably protected peptide was examined in solution phase but can also be carried out in solid phase. However, the drawback of this method is that the Asp unit meant to be coupled to an oligosaccharyl amine is prone to cyclic aspartimide formation with the amide nitrogen atom of the peptide backbone. Samuel Danishefsky and coworkers examined several conditions to overcome... 

Key Words Acidolytic cleavage backbone amide linkage bioconjugate chemical ligation combinatorial chemistry handle linker peptide alcohol peptide aldehyde peptide ester peptide thioester protecting group solid support. 

In principle, C-terminal glycine units of a peptide chain 250 can be deprotonated selectively by strong lithium bases such as LiHMDS or LDA, without affecting other a-CH groups in the peptide backbone, because these units are protected by deprotonation of the adjacent amide NHs (251). Treatment of 251 with an electrophile (EX), followed by hydrolysis, leads to the peptide chain 252, a-substituted at the C-terminal glycine unit (equation 65). 

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