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

Research output: Contribution to journalArticle

Authors

  • Richard Raz
  • Fabienne Burlina
  • Mohamed Ismail
  • Julian Downward
  • Jiejin Li
  • Martin Quibell
  • Peter D White
  • John Offer

Colleges, School and Institutes

External organisations

  • Structural Biology Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
  • Département de Chimie, ENS, PSL Research University, UPMC, Univ Paris 06, CNRS, LBM, Paris, France.
  • Merck Chemicals, Padge Road, Beeston, Notts, NG9 2JR, UK.
  • The Francis Crick Institute, 1 Midland road, London, NW1 1AT, UK. john.offer@francis.crick.ac.uk.

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.

Bibliographic note

© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Details

Original languageEnglish
Pages (from-to)13174-13179
Number of pages6
JournalAngewandte Chemie (International Edition)
Volume55
Issue number42
Early online date6 Oct 2016
Publication statusPublished - 10 Oct 2016

Keywords

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