Protected peptides synthesis

E. Gross and J. Meinenhofer, Eds., The Peptides Analysis. Synthesis, Biology Vol. 3 Protection of Functional Groups in Peptide Synthesis, Academic Press, New York, 1981. 

M Jaouadi, C Selve, JR Dormoy, B Castro, J Martinez. Isopropenyl chloroformate in the chemistry of amino acids and peptides. III. Synthesis of active esters of A-protected amino acids. Tetrahedron Lett 26, 1721, 1985. 

The commercial availability of protected /V-methyl amino acids [(Me)Xaa] of many proteinogenic amino acids (as well as other V-alkyl amino acids), the availability of procedures for the synthesis of protected V-alkyl analogues of all the protein amino acids, and the availability of synthetic procedures for site-selective alkylation during SPPS (see Section 10.1.2.1) allows the alkylation of nearly all peptide bonds in a given parent peptide. The synthesis of a series of V-alkyl peptide analogues based on the sequence of a given bioactive peptide (linear or cyclic) in which each peptide bond is successively alkylated and evaluation of the biological activity of this series will be called herein A-alkyl-scan (for example Me-scan, Et-scan, etc.)... 

Only one method has been used to prepare various peptidyl diazomethyl ketones. A protected amino acid or peptide acid is activated as the mixed anhydride and reacted with ethereal diazomethane at low temperature. Generally a peptide with the desired sequence is prepared first and then converted into the diazomethyl ketone in the final step of the synthesis. Since the diazomethyl ketone functional group is stable to alkali but unstable to acid, acidic conditions used to deprotect many peptide protecting groups must be avoided. 

Fujii, N., Otaka, A., Funakoshi, S., Bessho, K., and Yajima, H. (1987) Studies on peptides. CLI. Synthesis of cystine-peptides by oxidation of S-protected cysteine-peptides with thallium(III) trifluoroacetate. Chem. Pharm. Bull. 35, 2339-2347. 

Fig. 3 (29—32). A minor disadvantage of this method is that it produces protected cyclized peptide, which must be purified, deprotected, and then purified again. The backbone amide and side-chain attachment strategies alleviate this, as synthesis on resin is followed by a combined deprotection/cleavage step. However, these strategies produce the cyclic peptide in solution as a complex mixture with scavengers and cleaved protecting groups (Fig, 4). As a consequence, all these methods require a significant effort to be spent on purifying the cyclic peptide after synthesis.

Figure 4 Protected fragments of peptide and synthesis scheme for GIP.

However, in the cases examined so far, the molar solubility in DMF has not increased significantly. The 1-adamantyloxycarbonyl (1-Adoc) group could potentially improve the solubility of amino acids and peptides protected by 1-Adoc in organic solvents due to its strong hydrophobicity.P Lys(l-Adoc) was successfully employed in the synthesis of peptide histidine isoleucine (PHI) (Scheme 9)P9 and in the synthesis of a peptide fragment of a lysozyme.P l... 

In the synthesis of sulfur-free peptides, protecting groups removable by catalytic hydrogenation, such as Arg(N02), Asp(OBzl), or Glu(OBzl), can be used. Boissonnas et al. employed this procedure for the synthesis of bradykinin in 1960,and Arakawa and Bumpus utilized this method in the synthesis of angiotensin II in 1961.0 ... 

Section 23.9 Strategy of Peptide Bond Synthesis N-Protection and C-Activation... 

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