A rapid and efficient method for the synthesis of selectively S-Trt or S-Mmt protected Cys-containing peptides

Abstract

Selective removal of protecting groups under different cleavage mechanisms could be an asset in peptide synthesis, since it provides the feasibility to incorporate different functional groups in similar reactive centres. However, selective protection/deprotection of orthogonal protecting groups in peptides is still challenging, especially for Cys-containing peptides, where protection of the cysteine side-chain is mandatory since the nucleophilic thiol can be otherwise alkylated, acylated or oxidized. Herein, we established a protocol for the synthesis of Cys-selective S-Trt or S-Mmt protected Cys-containing peptides, in a rapid way. This was achieved by, simply fine-tuning the carbocation scavenger in the final acidolytic release of the peptide from the solid support in the classic SPPS.

Unveiling and tackling guanidinium peptide coupling reagent side reactions towards the development of peptide-drug conjugates

“…Among the most classically utilized guanidinium reagents are HATU (N-[(dimethylamino)-1H-1,2,3-triazo [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexauorophosphate-N-oxide) (1), and HBTU (N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium hexauorophosphate-Noxide) (2). [1][2][3][4][5][6] Based on their structure, HBTU and HATU were originally classied as O-uronium salts; later were revised to N-guanidinium salts (Fig. 1).…”

Synthesis and Applications of Synthetic Peptides

“…Because each amino acid contains different groups in its side chains, the protecting groups which prevent these groups from reacting vary according to the amino acid and used methodology (Fmoc or Boc chemistry). Some amino acids have not any functional groups to react in the side groups; only alpha-amino groups of these amino acids are protected by Fmoc or Boc [23][24][25][26][27][28][29][30][31][32][33].…”

Regioselective Formation of Multiple Disulfide Bonds with the Aid of Postsynthetic S-Tritylation

“…The former is achieved by postsynthetic modification using Trt–OH in hexafluoro-2-propanol (HFIP) to selectively promote S-tritylation in the presence of peptide functionalities . In the latter case, the Trt cation generated during TFA cleavage is trapped again in Cys by changing the carbocation scavengers in TFA acidolysis cocktails from TIS/thiols to 1,3-dimethoxybenzene (DMB) since DMB is a less effective Trt cation scavenger than the Cys sulfhydryl group due to steric hindrance …”