Steric effects in release of amides from linkers in solid-phase synthesis. Molecular mechanics modeling of key step in peptide and combinatorial chemistry

Per-Ola Norrby, Knud Jørgen Jensen

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Acidolytic release of an amide from a solid support by C-N bond cleavage is all ubiquitous and crucial step in many solid-phase syntheses. We have used molecular modeling of a pseudo-equilibrium to explore substituent and steric effects in the release of peptides. The high acid-lability of the backbone amide linkage (BAL), which releases sec. amides, compared to C-terminal amide anchoring, which releases primary amides, was rationalized by steric relief upon cleavage. Thus, the relative stability of the carbenium ion formed from the linker in the acidolytic release is an insufficient measure of the lability of a linkage. In addition, predictions indicated that steric effects from the C-alpha-substituent in a BAL anchored amino acid residue should accelerate the acidolytic release. The finding that steric crowding leads to increased acid-lability will be important for further development and use of handles.
Original languageEnglish
JournalInternational Journal of Peptide Research and Therapeutics
Volume12
Issue number4
Pages (from-to)335-339
ISSN1573-3149
Publication statusPublished - 2006

Keywords

  • BAL
  • peptide
  • backbone amide linker
  • solid-phase synthesis

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