Spiro beta-lactams as beta-turn mimetics. Design, synthesis, and NMR conformational analysis.
Molecular modeling calculations using high-level ab initio methods (MP2/6-31+G) of a new type of spiro beta-lactams predict that these systems could adopt a beta-turn secondary structure in solution. Strong intramolecular hydrogen bonds stabilize the beta-turn conformation with a geometry that is very close to the ideal type II beta-turns. The synthesis of the spiro beta-lactams is achieved by Staudinger reaction of a cyclic ketene derived from N-bencyloxycarbonyl-L-proline acid chloride with an imine. This reaction allows the formation of the spiranic backbone in a single-step with high diastereoselectivity and good yields. The new spiro beta-lactams obtained are the core for the preparation of different types of peptidomimetics using well-established peptide chemistry. The NMR conformational analysis shows that these compounds adopt beta-turn conformation as predicted by the theoretical studies.
Alonso
E
E
Departamento de Química Orgánica e Inorgánica Universidad de Oviedo, 33071 Oviedo, Spain.
López-Ortiz
F
F
del Pozo
C
C
Peralta
E
E
Macías
A
A
González
J
J
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000737:chemistry
D000900:Anti-Bacterial Agents; D010455:Peptides; D047090:beta-Lactams