Chapter 3 - Peptide Global Deprotection/Scavenger-Induced Side Reactions

Abstract

Successful assembly of target peptide chains on solid supports does not necessarily indicate the final triumph of SPPS. The following detachment of immobilized peptides from solid supports (peptide cleavage) and the deblocking of the side chain protecting groups (global deprotection) are also extremely decisive for the success of the concerned peptide synthesis. HF and TFA are routinely utilized as acid for the purpose of peptide cleavage, and global deprotection in the scope of Boc- and Fmoc-chemistry, respectively. The cleaved protecting groups exist in the reaction systems in the form of carbocations, sulfonyl cations, or other derivatives prequenching by the corresponding scavenger. These reactive electrophilic species can nevertheless react with the liberated nucleophilic functional groups on the side chains of the peptides, e.g., thioether group on Met, phenolic group on Tyr, indolyl on Trp, hydroxyl on Ser/Thr, sulfhydryl on Cys, and guanidino on Arg, in either reversible or irreversible manner, and give rise to diverse adduct side products. In order to prevent or minimize the occurrence of such side reactions, appropriate nucleophiles are supposed to be concomitantly charged into TFA or HF cleavage solutions in order to protect peptide global deprotection reactions by in situ entrapping the degraded carbocations, sulfonyl cations, and other reactive species. By this means the homogeneities of the functional groups from the target peptides are assured of in the process of peptide cleavage, and global deprotection. Nonetheless, even though the liberated functional groups from the target peptide products are protected by the shielding effect of the added scavengers at the step of peptide cleavage and global deprotection: diverse side reactions could still unavoidably take place, and corresponding impurities are generated. The core content of this chapter will be focused on the behavior, mechanism, and potential solution for these side reactions invoked in the process of peptide cleavage and global deprotection.