Sulfanylmethyldimethylaminopyridine as a Useful Thiol Additive for Ligation Chemistry in Peptide/Protein Synthesis

Abstract

Sulfanylmethyl-installed dimethylaminopyridine, 2-sulfanylmethyl-4dimethylaminopyridine (2), has an acidic thiol group comparable to that in aryl thiols due to the formation of a zwitterion consisting of a thiolate anion and a pyridinium cation. It can be used as an additive for native chemical ligation. The alkyl thiol in 2 allows it to be used for the one-pot native chemical ligation−desulfurization protocol in peptide synthesis. The utility of 2 in the synthesis of cyclic peptides is demonstrated.

Cysteine protecting groups: applications in peptide and protein science

“…239 Aside from Pd, Cu complexes can also be used to deprotect Thz. 139,240 Thz is removed by CuSO 4 in the presence of sodium ascorbate (critical for avoiding oxidation by-products), in 5 M GdnÁHCl in HEPPS buffer (pH 7.0, 1 h, 37 1C). This was demonstrated in the synthesis of CXCL14 (Fig.…”

Enabling Cysteine‐Free Native Chemical Ligation at Challenging Junctions with a Ligation Auxiliary Capable of Base Catalysis

“…In a follow‐up paper, Otaka et al. described the use of 2‐mercaptomethyl‐4‐dimethylaminopyridine as a thiol additive for NCL chemistry [18] . Though not used as a cleavable ligation auxiliary, the 2‐mercaptomethyl‐DMAP systems from Kanai et al.…”

“…[17] In afollow-up paper, Otaka et al described the use of 2-mercaptomethyl-4-dimethylaminopyridine as athiol additive for NCL chemistry. [18] Though not used as acleavable ligation auxiliary,t he 2-mercaptomethyl-DMAP systems from Kanai et al and Otaka et al share ak ey feature with our MPyE auxiliary,t hat is,t he 2-mercaptomethylpyridine structure.Kanai and Otaka explained the beneficial effect of the 2-mercaptomethyl-DMAP systems with an increased acidity of the thiol group which would in turn increase the reactivity of the acyl component of the thioester intermediate formed upon thiol exchange.C onsidering that even NCL reactions on seleno-modified auxiliaries can stop before rearrangement, [10] we think that activation of the acyl component cannot account for the high ligation rates observed with the MPyE auxiliary.…”

Ein zur Basenkatalyse befähigtes Ligationsauxiliar ermöglicht die cysteinfreie native chemische Ligation an anspruchsvollen Verknüpfungsstellen

“…In einer Folgearbeit beschrieben Otaka et al. die Verwendung von 2‐Mercaptomethyl‐4‐dimethylaminopyridin als Thiol‐Additiv für die NCL‐Chemie [18] . Obwohl dieses nicht als spaltbares Ligationsauxiliar verwendet wurde, teilen die 2‐Mercaptomethyl‐DMAP‐Systeme von Kanai et al.…”

“…[17] In einer Folgearbeit beschrieben Otaka et al die Verwendung von 2-Mercaptomethyl-4-dimethylaminopyridin als Thiol-Additiv fürd ie NCL-Chemie. [18] Obwohl dieses nicht als spaltbares Ligationsauxiliar verwendet wurde,t eilen In Anbetracht der Tatsache,d ass selbst NCL-Reaktionen an selenomodifizierten Auxiliaren vor der Umlagerung abbrechen kçnnen, [10] denken wir, dass die Aktivierung der Acylkomponente nicht fürd ie hohen Ligationsraten verantwortlich sein kann, die mit dem MPyE-Auxiliar beobachtet wurden.…”