| Abstract
| - Two general solid-phase methods for the synthesis of a new class of 2,5-diketopiperazines (DKPs)containing the trans-4-hydroxy-l-proline amino acid residue (Hyp) have been developed. AnN-protected hydroxyproline methyl ester was linked through the hydroxyl function to the Ellmanresin. The synthesis procedures were conceived to enable a sequence of Hyp alkylation, HypN-acylation, cyclization, and amide bond alkylation. Up to three different centers of moleculardiversity were introduced around the DKP scaffold. Highly functionalized bicyclic compounds wereobtained in good yield and purity. The alkylation of hydroxyproline αCH was performed withoutcontrol of the diastereoselectivity. During the final alkylation of the backbone, amide bondepimerization at the α-carbon atoms of the two amino acid residues was observed. The structuresof representative DKPs were elucidated with multidimensional NMR experiments. The describedreaction pathways can be applied to the identification of heterocyclic molecule inhibitors to diverseenzyme targets.
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