Spiro β-lactams as β-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 U-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.