Peptide cyclization and cyclodimerization by Cu I-mediated azide-alkyne cycloaddition

Reshma Jagasia, Justin M. Holub, Markus Bollinger, Kent Kirshenbaum, M. G. Finn

Research output: Contribution to journalArticle

Abstract

Head-to-tail cyclodimerization of resin-bound oligopeptides bearing azide and alkyne groups occurs readily by 1,3-dipolar cycloaddition upon treatment with Cu I. The process was found to be independent of peptide sequence, sensitive to the proximity of the alkyne to the resin, sensitive to solvent composition, facile for a- and β-peptides but not for γ-peptides, and inhibited by the inclusion of tertiary amide linkages. Peptides shorter than hexamers were predominantly converted to cyclic monomers. Oligoglycine and oligo(β-alanine) chains underwent oligomerization by 1,3-dipolar cycloaddition in the absence of a copper catalyst. These results suggest that cyclodimerization depends on the ability of the azido-alkyne peptide to form in-frame hydrogen bonds between chains in order to place the reacting groups in close proximity and lower the entropic penalty for dimerization. The properties of the resin and solvent are crucial, giving rise to a productive balance between swelling and interstrand H-bonding. These findings allow for the design of optimal substrates for triazole-forming ring closure and for the course of the reaction to be controlled by the choice of conditions.

Original languageEnglish (US)
Pages (from-to)2964-2974
Number of pages11
JournalJournal of Organic Chemistry
Volume74
Issue number8
DOIs
StatePublished - Apr 17 2009

Fingerprint

Alkynes
Azides
Cycloaddition
Cyclization
Peptides
Resins
Bearings (structural)
Oligopeptides
Oligomerization
Triazoles
Dimerization
Amides
Alanine
Swelling
Copper
Hydrogen bonds
Monomers
Catalysts
Substrates
Chemical analysis

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Peptide cyclization and cyclodimerization by Cu I-mediated azide-alkyne cycloaddition. / Jagasia, Reshma; Holub, Justin M.; Bollinger, Markus; Kirshenbaum, Kent; Finn, M. G.

In: Journal of Organic Chemistry, Vol. 74, No. 8, 17.04.2009, p. 2964-2974.

Research output: Contribution to journalArticle

Jagasia, Reshma ; Holub, Justin M. ; Bollinger, Markus ; Kirshenbaum, Kent ; Finn, M. G. / Peptide cyclization and cyclodimerization by Cu I-mediated azide-alkyne cycloaddition. In: Journal of Organic Chemistry. 2009 ; Vol. 74, No. 8. pp. 2964-2974.
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