Synthesis of the Novel Amino Acid 4-Amino-3-(aminomethyl)benzoic Acid (AmAbz) and Its Protected Derivatives as Building Blocks for Pseudopeptide Synthesis

Abstract

4‐Amino‐3‐(aminomethyl)benzoic acid (1) (AmAbz) is a novel unnatural amino acid with promise in applications as a building block for the synthesis of peptidomimetics and as a scaffold for combinatorial chemistry. It was efficiently synthesized in three steps (63% overall yield) from 4‐aminobenzoic acid, by means of regioselective amidomethylation with hydroxymethylphthalimide. AmAbz (1) contains three distinct functionalities which could be discriminated from one another. Firstly, Boc2O or Fmoc−OSu reacted selectively with the benzylamino group to give the monoprotected derivatives AmAbz(Boc) (8a) or AmAbz(Fmoc) (8b), respectively. The absence of acylation at the arylamino group was also noticed in coupling experiments using the BOP reagent and building block 8b. This made protection of the arylamino group unnecessary either for peptide bond formation at the carboxyl group, or for subsequent elongation of a peptide chain at the benzylamino group. Finally, the arylamino group could be acylated under base‐free, carbodiimide‐mediated coupling conditions. These properties are illustrated by the solid‐phase synthesis of the AmAbz‐containing branched pseudopeptide Fmoc−Ala−Phe−AmAbz(H−Lys−Leu)−Val−Gly−NH2 (15). The synthesis of Fmoc−AmAbz(Boc) (10) is also described.