Backbone amide linker (BAL) strategy for solid-phase synthesis of C- terminal-modified and cyclic peptides

Knud J. Jensen, Jordi Alsina, Michael F. Songster, Josef Vágner, Fernando Albericio, George Barany

Research output: Contribution to journalArticle

283 Scopus citations

Abstract

Peptide targets for synthesis are often desired with C-terminal end groups other than the more usual acid and amide functionalities. Relatively few routes exist for synthesis of C-terminal-modified peptides-including cyclic peptides-by either solution or solid-phase methods, and known routes are often limited in terms of ease and generality. We describe here a novel Backbone Amide Linker (BAL) approach, whereby the growing peptide is anchored through a backbone nitrogen, thus allowing considerable flexibility in management of the termini. Initial efforts on BAL have adapted the chemistry of the tris(alkoxy)benzylamide system exploited previously with PAL anchors. Aldehyde precursors to PAL, e.g. 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid, were reductively coupled to the α-amine of the prospective C-terminal amino acid, which was blocked as a tertbutyl, allyl, or methyl ester, or to the appropriately protected C-terminal-modified amino acid derivative. These reductive aminations were carried out either in solution or on the solid phase, and occurred without racemization. The secondary amine intermediates resulting from solution amination were converted to the 9- fluorenylmethoxycarbonyl (Fmoc)-protected preformed handle derivatives, which were then attached to poly(ethylene glycol)-polystyrene (PEG-PS) graft or copoly(styrene-1% divinylbenzene) (PS) supports and used to assemble peptides by standard Fmoc solid-phase chemistry. Alternatively, BAL anchors formed by onresin reductive amination were applied directly. Conditions were optimized to achieve near-quantitative acylafion at the difficult step to introduce the penultimate residue, and a side reaction involving diketopiperazine formation under some circumstances was prevented by a modified protocol for N(α)- protection of the second residue/introduction of the third residue. Examples are provided for the syntheses in high yields and purifies of representative peptide acids, alcohols, N,N-dialkylamides, aldehydes, esters, and head-to- tall cyclic peptides. These methodologies avoid postsynthetic solution-phase transformations and are ripe for further extension.

Original languageEnglish (US)
Pages (from-to)5441-5452
Number of pages12
JournalJournal of the American Chemical Society
Volume120
Issue number22
DOIs
StatePublished - Jun 10 1998
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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