Convenient route to Fmoc-homotyrosine via metallaphotoredox catalysis and its use in the total synthesis of anabaenopeptin cyclic peptides

Abstract

Herein, we report the first solid-phase total synthesis of the natural cyclic peptide anabaenopeptin F and the use of metallaphotoredox catalysis to overcome the key challenges associated with the preparation of the non-proteinogenic amino acid homotyrosine contained in these peptides. Starting from L-homoserine, enantiopure Fmoc-protected homotyrosine was prepared in a straightforward manner by metallaphotoredox catalysis with N-Fmoc-(S)-2-amino-4-bromobutanoic acid and 4-tert-butoxybromobenzene partners. The prepared protected amino acid was used in solid-phase peptide synthesis to achieve the total synthesis of anabaenopeptin F and establish the stereochemistry of the isoleucine residue. Protease inhibition studies with the synthesized anabaenopeptin F showed inhibitory activities against carboxypeptidase B in the low nanomolar range. The high convergency of the synthetic methodologies paves the way for the rapid access to N-Fmoc-protected non-proteinogenic and unnatural amino acids and the total synthesis of complex bioactive peptides containing these amino acids.