Our goal is to generate a convergent synthetic approach to alkene-peptide isosteres. Isosteres are molecules that mimic the size and geometry of the targeted molecule but lack an electronic component (such as a H-Bond donor or acceptor). A useful isostere of the amide bond is a trans-alkene. In emulating the convergent method in which peptides are generated in the lab and in nature, our retrosynthesis would involve formation of the alkene carbon-carbon bond. As a powerful reaction for alkene synthesis, olefin cross-metathesis was chosen to investigate the formation of peptide isosteres.

Our initial target is the peptide sequence D-Ala-D-Ala, (present on bacterial cell walls). This peptide sequence is implicated in the recognition of Vancomycin (a potent antibiotic) to the bacteria. By replacing the amide bond with a trans-olefin, information about the nature of this interaction can be probed by asking, "How much is an H-bond worth?"

We have successfully completed the synthesis of the D-Ala-D-Ala isostere target in 9 linear steps from commerically available starting materials. The isostere was tested for its binding to Vancomycin (See: R.K. Quinn, A.L. Cianci, J.A. Beaudoin and B.R. Sculimbrene, Bioorg. Med. Chem. Lett. 2010, 20, 4382-4385). The study showed that the replaced amide is important for recognition but that vancomycin-resistant strains of bacteria rely on a mutation that does more then disrupt H-bonding.

We are currently investigating the selectivity of the key cross metathesis step and will apply these findings to the synthesis of other peptide isosteres with different functional groups.