Expedient Synthesis of 1,3-Substituted Benzene Peptidomimetics

A synthetic route for replacing the central amino acid in the tripeptide Thr-Ala-Val (TAV) with a 1,3-substituted benzene ring was developed. L-Threonine was introduced into the benzene ring by a Grignard reaction with protected L-threoninal, where the nature of the side-chain protecting group was found to be of utmost importance. Subsequently, L-valine was introduced by a copper-mediated amination. Overall, the tripeptide analogue was obtained in six steps with an overall yield of 18%. An orthogonal protecting group strategy allowed attachment of the tripeptide analogue to a solid support and subsequent preparation of the corresponding pentapeptide analogue. Both compounds were tested in a plasma stability assay, showing improved stability compared to their peptide counterparts.