S_N 1 and S_N 2 mechanisms for the deprotection of synthetic peptides by hydrogen fluoride

Abstract

Studies on the side reaction leading to ring alkylation during HF deprotection of tyrosine revealed that under SN 1 conditions the formation of by‐product can be reduced by using protecting groups that either provide only weakly electrophilic carbocations or give rise to an intermediate that deactivates the tyrosine ring and allows scavengers to suppress the formation of 3‐alkyltyrosine. The effectiveness of the scavenger can be qualitatively predicted by its pKa value. A new reagent (HF: dimethylsulfide, 1:3, v/v) provides an SN 2 cleavage mechanism that removes the danger of carbocation formation and suppresses the electrophilic alkylation side reaction.

Methods, setup and safe handling for anhydrous hydrogen fluoride cleavage in Boc solid-phase peptide synthesis

“…For the synthesis of peptides containing long-chain acids, glutamyl and Cys residues, the use of a 50:50 mixture of p-cresol and p-thiocresol has been recommended (e.g., 9 ml HF, 500 µl of p-cresol and 500 µl of p-thiocresol). p-Cresol is highly effective in preventing aspartimide formation and Tyr ring benzylation during HF cleavage 34,35 , whereas p-thiocresol improves cation scavenging and increases deprotection rates of the protected forms of Trp, Arg or Cys residues 32,35-37 .…”

α-Helix peptides designed from EBV-gH protein display higher antigenicity and induction of monocyte apoptosis than the native peptide

“…The theoretical helical content calculated for peptide 11438 in pH 7.0, ionic strength 0.1 and at 278°K temperature was 0.83% by using the approach developed by Serrano’s group (AGADIR analysis) (Bax and Davis 1985; Houghten 1985; Rance et al 1983; Tam et al 1983). N-terminal or C-terminal truncated peptides were analyzed by the same approach for determining the ability of each amino acid from peptide 11438 sequence to stabilize or distort the α-helix structure.…”

Detection of the Sm31 antigen in sera of Schistosoma mansoni– infected patients from a low endemic area

“…The selected linear segments were synthesized by a manual t‐Boc strategy developed by Merrifield (33) and modified by Houghten (23) and Tam et al. (34). Extra N‐terminal Cys–Gly and C‐terminal Gly–Cys dipeptides were added to favour polymerization under oxidative (air) conditions.…”

“…An additional criterion for selection was to select those Sm31 segments that are distant from regions probably involved with the active site. The selected linear segments were synthesized by a manual t-Boc strategy developed by Merrifield (33) and modified by Houghten (23) and Tam et al (34). Extra N-terminal Cys-Gly and C-terminal Gly-Cys dipeptides were added to favour polymerization under oxidative (air) conditions.…”