Design and synthesis of chiral aminophosphonates: from biomimetic catalysis to phosphapeptides

Aminophosphonates are interesting compounds due to their analogy with amino acids and their derived peptides. Phosphapeptides are designed to contain an aminophosphonate residue in short Aib-based peptide helices. A number of peptides comprising achiral a,a-disubstituted amino acid residues have been synthesized using standard solution phase peptide coupling reagents. The synthesis of these sterically encumbered amino acid residues afforded moderate yields compared to typical couplings involving more traditional proteinogenic residues. Studies aimed at determining the detailed structures of the peptides are underway by NMR together with computational chemistry. In parallel, we are focusing our efforts on using an induced preference for a particular helical handedness to preferentially generate a single enantiomer in a catalytic reaction, taking place at a remote location from the binding site of the chiral phosphonate amino acid.

Aminophosphonates are interesting compounds due to their analogy with amino acids and their derived peptides. They could interfere in biological mechanisms through their hydroxyphosphonyl group approximating the enzymatic reactive tetrahedral intermediate . We aim at creating a new basis for the investigation of aminophosphonates as amino acid mimics. In the research focus is the practical, efficient and enantioselective methodologies for the synthesis of aminophosphonates. Chiral ammonium salts that are p hase-transfer catalysts will be evaluated in preparation of such aminophosphonates. Phosphapeptides will be prepared by incorporating an aminophosphonate residue in short peptides, and will be studied using NMR together with computational chemistry as too ls to gain insight into changes in their conformations, dynamics and type of aggregates.