Design, synthesis, structure and properties of an alpha-helix cap templatederived from N-[(2S)-2-chloropropionyl]-(2S)-Pro-(2R)-Ala-(2S,4S)-4-thioPro-OMe which initiates alpha-helical structures.

A strategy based upon removing the requirement for all of the carbonyl dipo les to align at the same time in the transition state leading to the cyclis ation of N-[(2S)-2-chloropropionyl]-(2S) -Pro-(2R)-Ala-(2S,4S)-4-thioPro-OM e to a Zimm-Bragg type a-helix peptide intitator template was successful. E ach amide bond of the 12-membered macrocyclic template existed in the trans -rotomeric form. Derivatives of the template were prepared by extending the C-terminus and these were characterised by NMR spectroscopy and restrained simulated annealing. In deuterochloroform solution at low temperature, sep arate sets of NMR signals were observed for two rapidly interconverting hel ical conformational isomers of the thioether macrocycle which possessed an appended trialkylammonium ion. A similar time-averaged conformation was als o observed in aqueous solution. Ar -80 degrees C in d(2)-dichloromethane th e rate of conformational exchange was slowed sufficiently to obtain resonan ce assignments and NOE data separately for each isomer. In the minor isomer (40%), the four carbonyl oxygen hydrogen-bond accepters of the template ar e aligned in an a-helical conformation and in the major conformer the Pro(2 ) carbonyl dipole was anti-aligned with the other three dipoles. Thus, the conformers differ in the orientation of one carbonyl group. Molecular model ling calculations showed that the minor isomer was stabilised by coulombic interactions between the trialkylammonium salt and the carbonyl group dipol e moments. (C) 1998 Elsevier Science Ltd. All rights reserved.