Ψ[CH(CF3)NH]Gly-peptides: synthesis and conformation analysis

Abstract

Psi[CH(CF(3))NH]Gly peptides, a conceptually new class of peptidomimetics having a stereogenic trifluoroethylamine group as a natural peptide-bond surrogate, have been synthesized by stereoselective addition of alpha-amino acid esters to trans-3,3,3-trifluoro-1-nitropropene. Long range nuclear Overhauser effects, detected via ROESY experiments, provided evidence that model Psi[CH(CF(3))NH]Gly-tetrapeptides incorporating a trifluoroethylamine mimic of the dipeptide loop Pro-Gly can be represented by an ensemble of unfolded and folded conformations. The latter are driven by the formation of a hydrogen bond between a carbonyl group and the aminic proton of the trifluoroethylamine unit. MD calculations indicate a population of conformers which adopt folded beta turn structures for all the L-peptides; on the other hand, a D-stereochemistry at the Pro residue induces a natural folding towards a beta hairpin conformation driven by the formation of a second hydrogen bond, regardless of the stereochemistry of the stereogenic peptide bond surrogate.

Enantioselective Organocatalytic Reduction of β‐Trifluoromethyl Nitroalkenes: An Efficient Strategy for the Synthesis of Chiral β‐Trifluoromethyl Amines

“…Fluorinated nitroalkenes represent an obvious entry for the synthesis of β‐trifluoromethylamino derivatives. They have been widely used in combination with a chiral reactant partner to diastereoisomerically produce β‐nitro‐trifluoromethylated products; typical examples include the synthesis of trifluoromethylated peptide analogues, using enantiopure α‐amino acids as nucleophiles 9. Fluorinated nitroolefines have been also employed in organocatalytic Michael reactions with aldehydes,10 intermolecular oxa‐Michael addition of oximes,11 and 3‐alkylidene oxindoles,12 and in the addition of indole13 and β‐dicarbonyl compounds 14…”

The Influence of Bioisosteres in Drug Design: Tactical Applications to Address Developability Problems

“…The electron-withdrawing properties of the CF 3 and CHF 2 deployed β- to an amine reduce basicity to an extent that these functionalities have found application as amide mimics, an isosteric relationship furthered by the similarity of dipoles and the geometry of the N-C-CF 3 and N-C-CF 2 , which approximates the 120° associated with an amide moiety, as illustrated in Fig. 29 [ 251 – 254 ]. Although this bioisostere was originally conceived to replace the amide bonds of peptide derivatives, it has begun to find a similar application in drug design, with the most prominent example being the cathepsin K inhibitor odanacatib ( 170 ) which has completed phase 3 clinical trials for the treatment of osteoporosis.…”

Trifluoromethyl aldimines: an overview in the last ten years

“…63 Performing a four multi-component Ugi (U-4 MC) condensation directly with trifluoroacetaldehyde methyl hemiacetal, benzylamine, CF 3 COOH, and tert-butyl isocyanide the expected product was formed in 21% yield, instead when the MCR was carried out in the presence of 4 Å MS the target compound can be obtained in 52% yield. Only starting from preformed aldimine 3a and always in the presence of strong acids a significant increase of yields was obtained performed the Ugi-type reaction in CH 2 Cl 2 as solvent ( Obviously, all compounds were isolated in good yields but as a mixture of diastereomers (∼1:1).…”