Synthesis and application of an auxiliary group for chemical ligation at the X-gly site

Vizzavona, Jean; Dick, Fritz; Vorherr, Thomas

doi:10.1016/s0960-894x(02)00319-0

Cited by 38 publications

(19 citation statements)

References 10 publications

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“…We sought to i) improve ligation rates by avoiding steric bulk at the ligation site and ii) prevent cleavage of the formed N ‐alkyl amides by getting around the acidic cleavage conditions that typically induce S→N acyl shift reactions. This analysis guided us to the development of new auxiliary scaffolds such as the 2‐mercapto‐2‐phenethyl (MPE) auxiliary, which is the first auxiliary that escapes the need for glycine at the ligation junction and permits auxiliary removal under mild basic conditions when S→N acyl shifts are favored over N→S acyl shifts. Previous reports stressed the importance of native chemical ligation‐type reactions proceeding through 5‐membered ring transition states .…”

Section: Introductionmentioning

confidence: 99%

Features of Auxiliaries That Enable Native Chemical Ligation beyond Glycine and Cleavage via Radical Fragmentation

Loibl

Dallmann

Hennig

et al. 2018

Chemistry A European J

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Native chemical ligation (NCL) is an invaluable tool in the total chemical synthesis of proteins. Ligation auxiliaries overcome the requirement for cysteine. However, the reported auxiliaries remained limited to glycine-containing ligation sites and the acidic conditions applied for cleavage of the typically applied N-benzyl-type linkages promote side reactions. With the aim to improve upon both ligation and cleavage, we systematically investigated alternative ligation scaffolds that challenge the N-benzyl dogma. The study revealed that auxiliary-mediated peptide couplings are fastest when the ligation proceeds via 5-membered rather than 6-membered rings. Substituents in α-position of the amine shall be avoided. We observed, perhaps surprisingly, that additional β-substituents accelerated the ligation conferred by the β-mercaptoethyl scaffold. We also describe a potentially general means to remove ligation auxiliaries by treatment with an aqueous solution of triscarboxyethylphosphine (TCEP) and morpholine at pH 8.5. NMR analysis of a C-labeled auxiliary showed that cleavage most likely proceeds through a radical-triggered oxidative fragmentation. High ligation rates provided by β-substituted 2-mercaptoethyl scaffolds, their facile introduction as well as the mildness of the cleavage reaction are attractive features for protein synthesis beyond cysteine and glycine ligation sites.

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Section: Introductionmentioning

confidence: 99%

Features of Auxiliaries That Enable Native Chemical Ligation beyond Glycine and Cleavage via Radical Fragmentation

Loibl

Dallmann

Hennig

et al. 2018

Chemistry A European J

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“…Vorherr et al beobachteten den N!S-Acyltransfer als Nebenreaktion, wenn die Dmmb-Gruppe als Verknüpfungsauxiliar an N-terminalem Glycin verwendet wurde. [29] Dieser Befund begründete die Dmmb-vermittelte Synthese von Peptidthioestern (Schema 7 a). [30] Nach Entschützen der tritylgeschützten Mercaptogruppe in 28 führt ein säureindu-zierter N!S-Acyltransfer zur partiellen Bildung eines Peptidthioesters, der durch ein externes Thiol wie MesNa abgefangen wird.…”

Section: Methoden Auf Basis Eines N!s-acyltransfersunclassified

9‐Fluorenylmethyloxycarbonyl‐basierte Festphasensynthese von α‐Peptidthioestern

Mende

Seitz

2010

Angewandte Chemie

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Peptidthioester sind Schlüsselverbindungen in der konvergenten Proteinsynthese, wie es die native chemische Verknüpfung, die spurlose Staudinger‐Verknüpfung und die Ag+‐vermittelte Thioesterverknüpfung beispielhaft belegen. Den zuverlässigsten Zugang zu Peptidthioestern bietet die Boc‐basierte Festphasensynthese. Die Säurelabilität vieler Peptidmodifikationen und die technische Ausstattung der meisten Parallelpeptidsyntheseautomaten erhöhen jedoch die Nachfrage nach der milderen Fmoc‐Synthesechemie. Die Fmoc‐basierte Peptidthioestersynthese ist oftmals mühevoll und verläuft in wesentlich geringeren Ausbeuten als die Synthese von Peptidsäuren und ‐amiden. Der Erfolg der nativen chemischen Verknüpfung und verwandter Techniken hat allerdings die Entwicklung neuer Synthesestrategien vorangetrieben. Gegenstand dieses Aufsatzes ist es, die neueren Entwicklungen auf diesem schnell expandierenden Forschungsgebiet aufzuzeigen.

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“…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].…”

Section: N-terminal Ligation Auxiliariesmentioning

confidence: 99%

Modern Extensions of Native Chemical Ligation for Chemical Protein Synthesis

Malins

Payne

2014

Protein Ligation and Total Synthesis I

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Over the past 20 years, native chemical ligation has facilitated the synthesis of numerous complex peptide and protein targets, with and without post-translational modifications, as well as the design and construction of a variety of engineered protein variants. This powerful methodology has also served as a platform for the development of related chemoselective ligation technologies which have greatly expanded the scope and flexibility of ligation chemistry. This chapter details a number of important extensions of the original native chemical ligation manifold, with particular focus on the application of new methods in the total chemical synthesis of proteins. Topics covered include the development of auxiliary-based ligation methods, the post-ligation manipulation of Cys residues, and the synthesis and utility of unnatural amino acid building blocks (bearing reactive thiol or selenol functionalities) in chemoselective ligation chemistry. Contemporary applications of these techniques to the total chemical synthesis of peptides and proteins are described.

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Synthesis and application of an auxiliary group for chemical ligation at the X-gly site

Cited by 38 publications

References 10 publications

Features of Auxiliaries That Enable Native Chemical Ligation beyond Glycine and Cleavage via Radical Fragmentation

Features of Auxiliaries That Enable Native Chemical Ligation beyond Glycine and Cleavage via Radical Fragmentation

9‐Fluorenylmethyloxycarbonyl‐basierte Festphasensynthese von α‐Peptidthioestern

Modern Extensions of Native Chemical Ligation for Chemical Protein Synthesis

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