A TRICYCLIC TEMPLATE DERIVED FROM (2S,4R)-4-HYDROXYPROLINE FOR THE SYNTHESIS OF PROTEIN LOOP MIMETICS

A tricyclic diketopiperazine, formally derived by coupling (2S,4S)-4-a minoproline (Pro(NH2)) and (2S,4R)-4-(carboxymethyl)proline (Pro(CH2CO OH)), is synthesized starting From readily available (2S,4R)-4-hydroxy proline. The resulting tricyclic template has carboxy and amino groups to which a peptide chain may be attached. The Fmoc-protected template 5 is incorporated into the cyclic molecule lo(-Ala(1)-Asn(2)-Pro(3)-A sn(4)-Ala(5)-Ala(6)(sic) Pro(NH2)(7) = Pro(CH2COOH)(8)(sic) (6) where Pro(NH2)(7) = Pro(CH2COOH)(8) represents the template, using solid-pha se peptide synthesis with cyclization in solution. The molecule is sho wn by NMR and dynamic simulated annealing methods to adopt a preferred conformation in aqueous solution, which includes an extended backbone at the residues Asn(2)-Pro(3)-Asn(4), and a type-I beta-turn at Asn(4 )-Ala(5)-Ala(6)(sic) Pro(NH2)(7). These studies show that this novel t emplate may be used in the synthesis of cyclic peptide and protein mim etics having defined secondary structure in aqueous environments.