Electrochemical cyclization of dipeptides toward novel bicyclic, reverse-turn peptidomimetics. 1. Synthesis and conformational analysis of 7,5-bicyclic systems

Fabrice Cornille, Urszula Slomczynska, Mark L. Smythe, Denise D. Beusen, Kevin D. Moeller, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Novel, highly constrained, 7,5-bicyclic dipeptides (1-aza-6-oxa-2-oxobicyclo[5.3.0]decanering skeletons, 3Sa and 7Sa) have been synthesized on a 40 mmol scale in ∼50% yield by a one-step electrochemical cyclization from the dipeptides Boc-L-homoserine-L-proline-OMe (Boc-Hse-Pro-OMe) and Boc-Hse-D-Pro-OMe. The reaction involved a selective anodic amide oxidation which was highly diastereoselective, generating a new chiral center having an S configuration from both precursors. In terms of conformation, the bicyclic system restricts two (ψ2 and φ3) of the four torsion angles that characterize a reverse turn. Conformational analysis of these molecules and analogs having an R configuration at the ring fusion revealed some families of minimum energy conformations with torsion angles close to those of classical β-turns, a secondary structural feature found in many bioactive peptides. This new ring skeleton was stable to trifluoroacetic acid, dilute base, and anhydrous hydrofluoric acid, making it compatible with standard solid phase peptide synthesis methodologies.

Original languageEnglish
Pages (from-to)909-917
Number of pages9
JournalJournal of the American Chemical Society
Volume117
Issue number3
DOIs
StatePublished - Jan 25 1995

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