Chemoselective Peptide Ligation–Desulfurization at Aspartate

Abstract

Nützlicher Rest: Ein synthetischer β‐Mercapto‐Aspartatrest vereinfacht die schnelle Ligation an eine Reihe von Peptidthioestern. Nach der Ligationsreaktion (und ohne Aufreinigung) ergibt die chemoselektive Desulfurierung der β‐Mercapto‐Einheit in Gegenwart ungeschützter Cysteinreste native Peptidprodukte.

Modern Extensions of Native Chemical Ligation for Chemical Protein Synthesis

“…Notably, the authors of this report utilize the β-epimer of the thiol Asp derivative previously employed for the ligation-based assembly of CXCR4 [122]. In contrast to the rate differential observed with epimeric β-thiol Leu derivatives 91 [109], these results confirm that configuration at the β-position does not have a large impact on the efficiency of ligation reactions at β-thiol Asp residues [122,123].…”

“…Tan and coworkers subsequently reported the 7-step synthesis of a modified β-thiol Asp derivative 98 and the application of this building block in the total synthesis of the 60-amino acid neuropeptide human galanin-like peptide (hGALP) using ligation-desulfurization chemistry [123]. Notably, the authors of this report utilize the β-epimer of the thiol Asp derivative previously employed for the ligation-based assembly of CXCR4 [122]. In contrast to the rate differential observed with epimeric β-thiol Leu derivatives 91 [109], these results confirm that configuration at the β-position does not have a large impact on the efficiency of ligation reactions at β-thiol Asp residues [122,123].…”

“…Very recently, the application of the β-thiol Asp derivative 97 [122] has been reported in the one-pot, three-component total synthesis of madanin-1 123 (Scheme 30), a small, Cys-free thrombin inhibitory protein derived from the hard tick H. longicornis [124]. In this study, the target 60-amino acid protein 123 was disconnected at Asp and Ala ligation junctions using ligation-desulfurization chemistry mediated by β-thiol Asp and Cys, respectively.…”

“…A concise, three-step synthesis of β-thiol Asp derivative 97 (Scheme 23) was developed in 2013 by Thompson et al from commercially available Boc-Asp (OtBu)-OH by employing a key sulfenylation reaction to install the requisite protected-thiol moiety [122]. Building block 97 was shown to facilitate the highyielding synthesis of native peptides through ligation-desulfurization chemistry, and ligation reactions were found to proceed with equal efficiency, regardless of the configuration at the β-position.…”

“…The utility of the ligation-chemoselective desulfurization protocol was demonstrated through an efficient, one-pot synthesis of the N-terminal, extracellular domain of the chemokine receptor CXCR4. The target CXCR4(1-38) fragment contained a native Cys residue (although at an intractable Pro-Cys junction) and two post-translational modifications -an Nlinked glycan and Tyr O-sulfation [122]. Tan and coworkers subsequently reported the 7-step synthesis of a modified β-thiol Asp derivative 98 and the application of this building block in the total synthesis of the 60-amino acid neuropeptide human galanin-like peptide (hGALP) using ligation-desulfurization chemistry [123].…”