A. Bianco et al., Solid-phase synthesis and structural characterization of highly substituted hydroxyproline-based 2,5-diketopiperazines, J ORG CHEM, 65(7), 2000, pp. 2179-2187
Two general solid-phase methods for the synthesis of a new class of 2,5-dik
etopiperazines (DKPs) containing the trans-4-hydroxy-L-proline amino acid r
esidue (Hyp) have been developed. An N-protected hydroxyproline methyl este
r was linked through the hydroxyl function to the Ellman resin. The synthes
is procedures were conceived to enable a sequence of Hyp alkylation, Hyp N-
acylation, cyclization, and amide bond alkylation. Up to three different ce
nters of molecular diversity were introduced around the DKP scaffold. Highl
y functionalized bicyclic compounds were obtained in good yield and purity.
The alkylation of hydroxyproline (CH)-C-alpha was performed without contro
l of the diastereoselectivity. During the final alkylation of the backbone,
amide bond epimerization at the alpha-carbon atoms of the two amino acid r
esidues was observed. The structures of representative DKPs were elucidated
with multidimensional NMR experiments. The described reaction pathways can
be applied to the identification of heterocyclic molecule inhibitors to di
verse enzyme targets.