Design and synthesis of glucose-templated proline-lysine chimera: polyfunctional amino acid chimera with high prolyl cis amide rotamer population.

We describe the synthesis of two glucose-templated proline-lysine chimeras (GlcTProLysCs) that differ in the stereochemistry of the hydroxymethyl substituent at the C-5' position of the pyrrolidine ring. The key synthetic steps involve C-glycosylation of an exocyclic glucose-based epoxide with allyltributylstannane, which affords functionalized C-ketosides containing an alpha-hydroxy ester moiety; introduction of an amino group at C-2 through stereoselective reductive amination; and regioselective installation of the azide group at C-6 on the glucose scaffold. Incorporation of these chimeras into the model peptides Ac-GlcTProLysC-NHMe and Ac-GlcTProLysC-OMe demonstrates that the stereochemistry of the hydroxymethyl substituent at the C-5' position has a profound effect on the equilibrium constant of prolyl amide cis/trans isomerization. The equilibrium constant K(c/t) for the peptide mimic Ac-GlcTProLysC-NHMe with C-5'(R) stereochemistry was determined to be 3.03+/-0.04, while the K(t/c) for the C-5'(S) diastereoisomer was 0.56+/-0.04 in D(2)O. Temperature coefficient experiments indicate that the origin of these effects is derived from two critical hydrogen bonds involving the C-5' hydroxymethyl substituent: one to the N-terminal amide carbonyl group, and the other to the primary amino group in the glucose moiety.