Electrochemical cyclization of dipeptides to form novel bicyclic, reverse-turn peptidomimetics. 2. Synthesis and conformational analysis of 6,5-bicyclic systems

David K. Chalmers, Mark L. Smythe

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Novel, highly constrained, 6,5-bicyclic dipeptides (1-aza-5-oxa-2-oxobicyclo[4.3.0]nonane ring skeletons, 2) have been synthesized by a one-step electrochemical cyclization from the dipeptides Boc-(S)-serine-(S)-proline-OMe (Boc-(S)-Ser-(S)-Pro-OMe, 3) and Boc-(R,S)-α-methylserine-(S)proline-OMe (Boc-(R,S)-α-MeS-(S)-Pro-OMe, 12) in yields of 10-25% and 41%, respectively. The one-pot reaction uses selective anodic amide oxidation to generate an N-acyliminium cation which is trapped by an intramolecular hydroxyl group. The cyclization of Boc-(S)-Ser-(S)-Pro-OMe (3) to the 6,5-bicyclic skeleton 4 was highly diastereoselective, generating a new chiral center with an S configuration. This bicyclic compound was sufficiently stable to trifluoroacetic acid and anhydrous hydrofluoric acid for use in standard solid phase peptide synthesis methodologies. Oxidation of Boc-(R,S)-MeS-(S)-Pro-OMe (12) gave different results for each diastereoisomer. Cyclization only occurred for the S,S-diastereoisomer with very low stereoselectivity (6:4 ratio of diastereomers) at the newly-formed ring fusion. In terms of conformation, the 6,5-bicyclic system restricts two (ψ2 and ∅3) of the four torsion angles that characterize a reverse turn. Conformational analyses of tetrapeptides containing the 6,5-bicyclic system were performed using Monte Carlo conformational searches and molecular dynamics simulations. All of the eight possible diastereomers arising from the three stereogenic centers (Ser Cα, Pro Cα, and newly formed bridgehead) were considered. These studies revealed that the 3S,7S,10S and 3R,7R,10R configurations are effective turn inducers although the torsion angles of the backbone do not exactly mimic those of classical β-turns. Other diastereomers were found to stabilize the peptide backbone in an extended conformation.

Original languageEnglish
Pages (from-to)1198-1204
Number of pages7
JournalThe Journal of Organic Chemistry
Issue number4
Publication statusPublished - 23 Feb 1996
Externally publishedYes

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