HF-Free Boc Synthesis of Peptide Thioesters for Ligation and Cyclization

Angew Chem Int Ed Engl. 2016 Oct 10;55(42):13174-13179. doi: 10.1002/anie.201607657.

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.

Keywords: Boc-SPPS; cyclic peptide; peptide ligation; peptide thioester; post-translational modification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Esters
  • Formic Acid Esters
  • Peptides
  • Sulfhydryl Compounds
  • t-butyloxycarbonyl group