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

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 st...