Synthesis of Ψ[CH(RF)NH]Gly-peptides: The dramatic effect of a single fluorine atom on the diastereocontrol of the key aza-Michael reaction

We describe in full-detail the synthesis of new ψ[CH(RF)NH]-peptidomimetics, having different fluoroalkyl groups RF, as peptide bond surrogates. A key step in the synthesis is a stereoselective aza-Michael addition of chiral α-amino acid esters to β-fluoroalkyl-α-nitroethenes. The diastereoselection of the process was influenced by the electronegativity, rather than by the steric bulk, of the fluorinated residue RF in the β-position of the nitroalkene acceptors. Replacement of a single F atom of RF by a hydrogen or methyl group brings about a dramatic drop of stereocontrol, whereas Br, Cl and CF3, albeit bulkier than F, provide inferior results in terms of stereocontrol. A mechanistic hypothesis is provided.

Graphical abstractWe describe in full-detail the synthesis of new ψ[CH(RF)NH]-peptidomimetics, having different fluoroalkyl groups RF, as peptide bond surrogates. A key step in the synthesis is a stereoselective aza-Michael addition of chiral α-amino acid esters to β-fluoroalkyl-α-nitroethenes. The diastereoselection of the process was influenced by the electronegativity, rather than by the steric bulk, of the fluorinated residue RF in the β-position of the nitroalkene acceptors. Replacement of a single F atom of RF by a hydrogen or methyl group brings about a dramatic drop of stereocontrol, whereas Br, Cl and CF3, albeit bulkier than F, provide inferior results in terms of stereocontrol. A mechanistic hypothesis is provided.Figure optionsDownload full-size imageDownload as PowerPoint slide