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Spiro beta-lactams as beta-turn mimetics. Design, synthesis, and NMR conformational analysis

J Org Chem. 2001 Sep 21;66(19):6333-8. doi: 10.1021/jo015714m.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Drug Design
  • Magnetic Resonance Spectroscopy
  • Models, Chemical
  • Molecular Conformation
  • Molecular Mimicry
  • Peptides / chemical synthesis
  • beta-Lactams / chemical synthesis*
  • beta-Lactams / chemistry

Substances

  • Anti-Bacterial Agents
  • Peptides
  • beta-Lactams