Linkers peptide thioester formation

In order to facilitate the generation of peptide thioesters, several groupst have developed generalized versions of the thioester linker pioneered by Hojo and Aimoto.f A 3-sulfanylpropanoic acid residue is generated on an acid-labile linker such as Boc-Leu-PAM-resin or Boc-Leu-MBHA-resin. It is important to have a one-residue spacer between the MBHA linker and the thiol for optimal acid stability of the amide bond.f All twenty Boc-protected amino acids can be coupled to this thiol on the solid support to generate the thioester.Despite the potential reactivity of the thioester to the amino terminus, the formation of a dioxopiperazine is not generally observed when using in situ neutralization protocols. However, when the sequence was Leu-Tyr-Arg-Ala-Pro, 20% of a dipeptide deletion product, Leu-Tyr-Arg, was observed. It is likely that sequences such as C-terminal Pro-Gly would also be subject to this side reaction.t ... 

Many other handles exist that are cleavable by orthogonal mechanisms for the synthesis of protected peptide fragments these are also summarized in Table 5. A novel strategy for the synthesis of cyclic peptides on resin is to attach the peptide to the resin by a backbone nitrogen rather that the C -carboxyl. The N-and C-termini then remain free for further functionalization such as cyclization, esterification, or thioester formation. This backbone amide linker (BAL) is listed in Table 5. Other strategies such as attaching the peptide to the resin via the side chain of trifunctional amino acids and more comprehensive listings of linkers and handles are covered in References 9,12, and 109-111. 

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