Electrochemical Cyclization of Dipeptides toward Novel Bicyclic, Reverse-Turn Peptidomimetics. 1. Synthesis and Conformational Analysis of 7,5-Bicyclic Systems

Novel, highly constrained, 6,5-bicyclic dipeptides (1-aza-5-oxa-2-oxoibicyclo[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)-alpha-methylserine-(S)-proline-OMe (Boc-(R,S)-alpha-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 (psi(2) and phi(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. AU of the eight possible diastereomers arising from the three stereogenic centers (Ser C alpha, Pro C alpha, 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 beta-turns. Other diastereomers were found to stabilize the peptide backbone in an extended conformation

Local elevation: A method for improving the searching properties of molecular dynamics simulation

The concept of memory has been introduced into a molecular dynamics algorithm. This was done so as to persuade a molecular system to visit new areas of conformational space rather than be confined to a small number of low-energy regions. The method is demonstrated on a simple model system and the 11-residue cyclic peptide cyclosporin A. For comparison, calculations were also performed using simulated temperature annealing and a potential energy annealing scheme. Although the method can only be applied to systems with a small number of degrees of freedom, it offers the chance to generate a multitude of different low-energy structures, where other methods only give a single one or few. This is clearly important in problems such as drug design, where one is interested in the conformational spread of a system. © 1994 ESCOM Science Publishers B.V