SEARCH

SEARCH BY CITATION

Keywords:

  • cross-coupling;
  • Knochel–Grignard;
  • peptidomimetics;
  • protein–protein interactions;
  • pyridine-based 1,4-teraryls

Abstract

One of the most common protein–protein interactions (PPI) is the interaction of the α-helix of one protein with the surface of the second one. Terphenylic scaffolds are bioinspired motifs in the inhibition of PPIs and have been identified as suitable α-helix mimetics. One of the challenging aspects of this strategy is the poor solubility of terphenyls under physiological conditions. In the literature pyrrolopyrimidine-, pyrimidine- or pyridazine-based mimetics have been reported to show improved solubility. We present a new convergent strategy for the synthesis of linear pyridine-type teraryls based on a phenylic core unit. A general approach for the synthesis of 3,5-disubstituted pyridine-based boronic acid pinacol esters with amino acid side chains in the 3-position (representing Phe, Leu, Ile, Lys, Asp, Asn) is presented and exploits the functional group tolerance of the Knochel–Grignard reagents. The building blocks have been used in a convergent in situ two-step synthesis of teraryl α-helix mimetics.