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

Molecular modeling calculations using high-level ab initio methods (MP2/6-3 1+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 ve ry 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 a llows the formation of the spiranic backbone in a single-step with high dia stereoselectivity and good yields. The new spiro beta -lactams obtained are the core for the preparation of different types of peptidomimetics using w ell-established peptide chemistry. The NMR conformational analysis shows th at these compounds adopt beta -turn conformation as predicted by the theore tical studies.