Abstract
Peptide thioester synthesis by N→S acyl transfer is being intensively explored by many research groups the world over. Reasons for this likely include the often straightforward method of precursor assembly using Fmoc-based chemistry and the fundamentally interesting acyl migration process. In this review we introduce recent advances in this exciting area and discuss, in more detail, our own efforts towards the synthesis of peptide thioesters through N→S acyl transfer in native peptide sequences. We have found that several peptide thioesters can be readily prepared and, what’s more, there appears to be ample opportunity for further development and discovery.
Highlights
The importance of peptides and proteins in biology and medicine has inspired chemists to consider methods that bring about their synthesis for over a century.[1]
When the peptide was resynthesized with the internal cysteine residue Acm protected, we found that the reaction was capable of proceeding as originally proposed, to form the Ala thioester
Was more than 1 : 1. in this study the difference in rates of thioester formation between carboxyl- and carboxamide-terminated peptides was not considered, the results clearly indicated that competing Native Chemical Ligation (NCL) occurs under the reaction conditions, but only becomes significant when d-Cys is added in large excess
Summary
The importance of peptides and proteins in biology and medicine has inspired chemists to consider methods that bring about their synthesis for over a century.[1]. When the sample was heated we found that an alternative major product, 2, emerged which corresponded to the Gly–MPA thioester, where the peptide had undergone thiolysis at the internal cysteine site This result was initially surprising since we were unaware of any solely chemical method reported to bring about selective peptide or protein backbone cleavage with concomitant thioester formation. The fact that the reaction occurs at all is presumably because the N!S acyl shift is facilitated by enhanced protonation of the liberated amino group below pH 7.[16] Further model reactions confirmed that thioester formation could be selective, across Gly–Cys, His–Cys, and Cys–Cys junctions, and that in these cases the products do not appear to undergo epimerization of the C-terminal residue (Table 1). The simplicity with which the precursors can be prepared has propelled us forward to investigate satisfactory solutions to the current limitations, since they do not appear overtly intractable
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