Peptide Bond Formation Mediated by 4,5-Dimethoxy-2-mercaptobenzylamine after Periodate Oxidation of the N-Terminal Serine Residue

Abstract

[reaction in text] A thiol linker-attached peptide was prepared from a nonprotected peptide via an N(alpha)()-alpha-oxoacyl peptide. Selective oxidation of the N-terminal serine with sodium periodate gave the N(alpha)-glyoxyloyl peptide, reductive amination of which with 4,5-dimethoxy-2-(triphenylmethylthio)benzylamine gave an N(alpha)-4,5-dimethoxy-2-mercaptobenzyl glycyl peptide after removal of the trityl group. The N(alpha)-4,5-dimethoxy-2-mercaptobenzyl peptide can be condensed with a peptide thioester, and the linker is removable. This strategy provides a useful method for the synthesis of peptides using recombinant proteins.

Progress in Chemical Synthesis of Peptides and Proteins

“…Two peptides are linked together by the help of the auxiliaries in a manner similar to NCL, and acyl transfer occurs via a six-membered ring intermediate. Removal of the auxiliaries can be conducted under acidic conditions [76,77]. The third class of auxiliaries, N a -(1-phenyl-2-mercaptoethyl) group bearing a nucleophilic alkyl thiol, can enhance transthioesterification during capture step and mediate acyl transfer via a five-membered ring intermediate [78].…”

Modern Extensions of Native Chemical Ligation for Chemical Protein Synthesis

“…A third class of auxiliaries probed for use in ligation reactions employed the 2-mercaptobenzyl motif (e.g., 30-33, Scheme 5d) [44][45][46][47]. The rationale for this tethered thiophenol-based scaffold was to exploit the rate enhancement observed in the presence of aryl thiol additives [15].…”

“…Furthermore, substitution of the aromatic ring could be used to modulate the nucleophilicity of the thiol or enhance the lability of the auxiliary [44]. For example, increasing substitution of the aromatic ring with electrondonating functionalities (e.g., methoxy groups) was shown to enhance greatly the acid lability of the auxiliaries, with the 4,5-dimethoxy-2-mercaptobenzyl auxiliary 32 [45,46] cleaved upon treatment with strongly acidic trifluoromethane sulfonic acid (TFMSA) or bromotrimethylsilane (TMSBr) and the more electron-rich 4,5,6-trimethoxy-2-mercaptobenzyl derivative 33 effectively removed in the presence of TFA [47]. Notably, the comparatively mild conditions for removal of trimethoxybenzyl (Tmb) auxiliary 33 enabled its application in the synthesis of glycopeptides [48], including fragments derived from human erythropoietin (EPO) bearing complex O-and N-linked glycans [49,50].…”

‘100 years of peptide synthesis’: ligation methods for peptide and protein synthesis with applications to β‐peptide assemblies*

“…Several groups have shown that the N‐terminal cysteine can also be replaced by a 2‐mercaptobenzylamine linker (Fig. 30) (65–67). In this case, the intramolecular acyl shift proceeds through a six‐membered ring with the linker subsequently removed by treatment with an acid such as trifluoromethanesulfonic acid (TFMSA).…”