Fluoroolefin Isosteres

Replacement of the amide bond in the peptide backbone can improve the activity, stability, or bioavailability of the resultant unnatural peptide (1 ). Amide bond surrogates cannot only impart peptidase resistance, but can also facilitate conformational control of the target peptide. Although the alkene ψ[C=C] isostere is an accurate mimic of the steric demand, bond lengths, and bond angles of the amide bond (2 –6 ), it also permits construction of both the (E ) and (Z ) cis - and trans -) isomers independently. Unlike the amide bond, which has some degree of flexibility, the ψ[C=C] isostere is conformational fixed (7 –8 ). The ψ[CF=C] isostere retains these attributes, but accurately mimics the electronic features of the amide bond (9 –11 ) to include dipole moment, charge distribution, and electrostatic potential.