ELECTROCHEMICAL CYCLIZATION OF DIPEPTIDES TOWARD NOVEL BICYCLIC, REVERSE-TURN PEPTIDOMIMETICS .1. SYNTHESIS AND CONFORMATIONAL-ANALYSIS OF 7,5-BICYCLIC SYSTEMS

Novel, highly constrained, 7,5-bicyclic dipeptides (1-aza-6-oxa-2-oxob icyclo[5.3.0]decane ring skeletons, 3Sa and 7Sa) have been synthesized on a 40 mmol scale in similar to 50% yield by a one-step electrochemi cal cyclization from the dipeptides Boc-L-homoserine-L-proline-OMe (Bo c-Hse-Pro-OMe) and Boc-Hse-D-Pro-OMe. The reaction involved a selectiv e anodic amide oxidation which was highly diastereoselective, generati ng a new chiral center having an S configuration from both precursors. In terms of conformation, the bicyclic system restricts two (psi 2 an d phi 3) of the four torsion angles that characterize a reverse turn. Conformational analysis of these molecules and analogs having an R con figuration at the ring fusion revealed some families of minimum energy conformations with torsion angles close to those of classical beta-tu rns, 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.