Expedient Synthesis of 1,3-Substituted
Benzene Peptidomimetics

Anders Bach; Kristian Strømgaard

doi:10.1055/s-0030-1258425

PAPER

Expedient Synthesis of 1,3-Substituted Benzene Peptidomimetics

Anders Bach, Kristian Strømgaard*
Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Fax: +4535336041; e-Mail: krst@farma.ku.dk;

Abstract

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Abstract

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.

Key words

amino acids - peptides - Grignard reaction - nucleophilic aromatic substitution - copper

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