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 Psi[CH(R-F)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 alpha-amino acid esters to beta-fluoroalkyl-alpha-nitroethenes. The diastereoselection of the process was influenced by the electronegativity, rather than by the steric bulk, of the fluorinated residue R-F in the beta-position of the nitroalkene acceptors. Replacement of a single F atom of R-F 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. (c) 2008 Elsevier B.V. All rights reserved.