The Influence of Fluoroalkyl-Group Electronegativity on Stereocontrol in the Synthesis of Ψ[CH(R_F)NH]Gly Peptides

Abstract

New peptidomimetics featuring CH(R_F)NH units, having different degree of fluorination, as peptide-bond surrogates have been synthesized. The key step in the synthesis consists of 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 R_F in β-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 poorer results in terms of stereocontrol.

Key words

peptidomimetics - fluorine - electronegativity - peptide bond surrogate - fluoroalkyl

References and Notes

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12

The stereochemistry of the diastereoisomers was assessed by X-ray diffraction of a Michael adduct and on the basis of their spectroscopic and analytical features. Full details will be given in a full paper.