Fmoc Solid‐Phase Synthesis of C‐Terminal Peptide Thioesters by Formation of a Backbone Pyroglutamyl Imide Moiety

Tofteng, A. Pernille; Sørensen, Kasper K.; Conde‐Frieboes, Kilian; Høeg-Jensen, Thomas; Jensen, Knud J.

doi:10.1002/anie.200903710

Cited by 76 publications

(34 citation statements)

References 20 publications

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“…Originally thioesters were reported to be synthesized using Boc/Bzl chemistry. 21,22 The progress in the synthesis of this class of molecules has recently been reviewed, including different methods compatible with Fmoc-SPPS. 23 A popular method is application of the sulfonamide "safety catch" linker, which after activation can be converted to thioesters by nucleophilic cleavage.…”

Section: Resultsmentioning

confidence: 99%

C-Terminally modified peptides via cleavage of the HMBA linker by O-, N- or S-nucleophiles

2016

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A large variety of C-terminally modified peptides was obtained by nucleophilic cleavage of the ester bond in solid phase linked peptide esters of 4-hydroxymethyl benzamide (HMBA). The developed methods provided peptides, C-terminally functionalized as esters, amides and thioesters, with high purity directly from the resin in a single reaction step. A comprehensive screening of the reaction conditions and scope for nucleophilic cleavage of peptides from the HMBA linker was performed.

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Section: Resultsmentioning

confidence: 99%

C-Terminally modified peptides via cleavage of the HMBA linker by O-, N- or S-nucleophiles

2016

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“…[55] Dem Aufbau des Peptids an der festen Phase folgt die selektive Acidolyse des Phenylisopropylesters in 58. Die Aktivierung der Seitenketten-Carboxygruppe mit PyBrOP unter basischen Bedingungen und Mikrowellenbestrahlung führt zum Pyroglutamylimid 59.…”

Section: Rückgrat-pyroglutamylimide Als Vorstufen Für A-peptidthioesterunclassified

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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“…However, they can be activated by sulfonamide N ‐alkylation to yield an N ‐substituted sulfonamide and the subsequent “catch” reaction using a thiol nucleophile in an intermolecular S N 2 substitution reaction leads to a thioester, generally under basic conditions. Variations of the “safety catch” approach include the hydrazide,7 pyroglutamyl imide,8 and N ‐acylurea methods 9…”

Section: Introductionmentioning

confidence: 99%

Selective Bi‐directional Amide Bond Cleavage ofN‐Methylcysteinyl Peptide

2014

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A selective bi‐directional peptide bond cleavage mediated by N‐methylcysteine (MeCys) in Xaa‐MeCys‐Yaa peptides (Xaa and Yaa, non‐cysteine residues) leading to thioesters and thiolactones is described. Rate and product analyses showed that an Nα‐amide bond cleavage occurred at the Xaa‐MeCys bond by an N–S acyl shift to generate an Xaa‐S‐(MeCys‐Yaa) thioester at pH 1–5, whereas under strongly acidic conditions of H0 = –5, the MeCys‐Yaa bond underwent a Cα‐amide bond cleavage via an oxazolone intermediate, which was trapped by thiocresol (TC) as an Xaa‐MeCys‐TC thioester. This thioester was then transformed into an Xaa‐MeCys‐β‐thiolactone at pH 4–5. Replacing MeCys by a Cys residue did not result in significant bi‐directional peptide bond cleavage, which suggests that N‐methylation in a MeCys residue is important for the N–S acyl shift reaction and formation of oxazolone. The isomerization of amides and thioesters was successfully used to prepare cyclic peptides.

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Fmoc Solid‐Phase Synthesis of C‐Terminal Peptide Thioesters by Formation of a Backbone Pyroglutamyl Imide Moiety

Cited by 76 publications

References 20 publications

C-Terminally modified peptides via cleavage of the HMBA linker by O-, N- or S-nucleophiles

C-Terminally modified peptides via cleavage of the HMBA linker by O-, N- or S-nucleophiles

9‐Fluorenylmethyloxycarbonyl‐basierte Festphasensynthese von α‐Peptidthioestern

Selective Bi‐directional Amide Bond Cleavage ofN‐Methylcysteinyl Peptide

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