HF-free Boc synthesis of peptide thioesters for ligation and cyclization

Richard Raz; Fabienne Burlina; Mohamed Ismail; Julian Downward; Jiejin Li; Stephen J Smerdon; Martin Quibell; Peter D White; John Offer

doi:10.1002/anie.201607657

HF-free Boc synthesis of peptide thioesters for ligation and cyclization

Richard Raz, Fabienne Burlina, Mohamed Ismail, Julian Downward, Jiejin Li, Stephen J Smerdon, Martin Quibell, Peter D White, John Offer

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

We have developed a convenient method for the direct synthesis of peptide thioesters, versatile intermediates for peptide ligation and cyclic peptide synthesis. The technology uses a modified Boc SPPS strategy that avoids the use of anhydrous HF. Boc in situ neutralization protocols are used in combination with Merrifield hydroxymethyl resin and TFA/TMSBr cleavage. Avoiding HF extends the scope of Boc SPPS to post-translational modifications that are compatible with the milder cleavage conditions, demonstrated here with the synthesis of the phosphorylated protein CHK2. Peptide thioesters give easy, direct, access to cyclic peptides, illustrated by the synthesis of cyclorasin, a KRAS inhibitor.

Original language	English
Pages (from-to)	13174-13179
Number of pages	6
Journal	Angewandte Chemie (International Edition)
Volume	55
Issue number	42
Early online date	6 Oct 2016
DOIs	https://doi.org/10.1002/anie.201607657
Publication status	Published - 10 Oct 2016

Bibliographical note

Keywords

Cyclization
Esters/chemistry
Formic Acid Esters/chemical synthesis
Molecular Structure
Peptides/chemistry
Sulfhydryl Compounds/chemistry

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Raz_et_al_HF_free_Boc_synthesis_of_peptide_thioesters_for_ligation_and_cyclization_Angewandte_Chemie_2016
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Cite this

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title = "HF-free Boc synthesis of peptide thioesters for ligation and cyclization",

abstract = "We have developed a convenient method for the direct synthesis of peptide thioesters, versatile intermediates for peptide ligation and cyclic peptide synthesis. The technology uses a modified Boc SPPS strategy that avoids the use of anhydrous HF. Boc in situ neutralization protocols are used in combination with Merrifield hydroxymethyl resin and TFA/TMSBr cleavage. Avoiding HF extends the scope of Boc SPPS to post-translational modifications that are compatible with the milder cleavage conditions, demonstrated here with the synthesis of the phosphorylated protein CHK2. Peptide thioesters give easy, direct, access to cyclic peptides, illustrated by the synthesis of cyclorasin, a KRAS inhibitor.",

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AU - Raz, Richard

AU - Burlina, Fabienne

AU - Ismail, Mohamed

AU - Downward, Julian

AU - Li, Jiejin

AU - Smerdon, Stephen J

AU - Quibell, Martin

AU - White, Peter D

AU - Offer, John

PY - 2016/10/10

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AB - We have developed a convenient method for the direct synthesis of peptide thioesters, versatile intermediates for peptide ligation and cyclic peptide synthesis. The technology uses a modified Boc SPPS strategy that avoids the use of anhydrous HF. Boc in situ neutralization protocols are used in combination with Merrifield hydroxymethyl resin and TFA/TMSBr cleavage. Avoiding HF extends the scope of Boc SPPS to post-translational modifications that are compatible with the milder cleavage conditions, demonstrated here with the synthesis of the phosphorylated protein CHK2. Peptide thioesters give easy, direct, access to cyclic peptides, illustrated by the synthesis of cyclorasin, a KRAS inhibitor.

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KW - Esters/chemistry

KW - Formic Acid Esters/chemical synthesis

KW - Molecular Structure

KW - Peptides/chemistry

KW - Sulfhydryl Compounds/chemistry

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HF-free Boc synthesis of peptide thioesters for ligation and cyclization

Abstract

Bibliographical note

Keywords

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