Heterochiral Ala/(αMe)Aze sequential oligopeptides: Synthesis and conformational study.

α-Amino acid residues with a ϕ,ψ constrained conformation are known to significantly bias the peptide backbone 3D structure. An intriguing member of this class of compounds is (αMe)Aze, characterized by an N -alkylated four-membered ring and C -methylation. We have already reported that (S)-(αMe)Aze, when followed by (S)-Ala in the homochiral dipeptide sequential motif -(S)-(αMe)Aze-(S)-Ala-, tends to generate the unprecedented γ-bend ribbon conformation, as formation of a regular, fully intramolecularly H-bonded γ-helix is precluded, due to the occurrence of a tertiary amide bond every two residues.

A novel peptide conformation: the γ-bend ribbon.

Unlike the extensively investigated relationship between the peptide β-bend ribbon and its prototypical 310-helix conformation, the corresponding relationship between the narrower γ-bend ribbon and its regular γ-helix counterpart still remains to be studied, as the latter 3D-structures have not yet been experimentally authenticated. In this paper, we describe the results of the first characterization, both in the crystal state and in solution, of the γ-bend ribbon conformation using X-ray diffraction and FT-IR absorption, electronic CD and 2D-NMR spectroscopies applied to an appropriate set of synthetic, homo-chiral, sequential dipeptide oligomers based on (S)-Ala and the known γ-bend inducer, Cα-tetrasubstituted, N-alkylated α-amino acid residue (S)-Cα-methyl-azetidine-carboxylic acid.

A one carbon staple for orthogonal copper-catalyzed azide-alkyne cycloadditions.

We describe herein the use of α-hydroxy-β-azidotetrazoles, easily prepared in one step from α,β-epoxynitriles, as new scaffolds for orthogonal CuAAC reactions performed on the same carbon atom. After a first ligation involving an alkyne with the β-azido moiety, treatment with EDC smoothly releases an alkyne from the remaining α-hydroxytetrazole, ready for a second CuAAC reaction. This "double click" process can be performed iteratively, leading to triazolamers.

Competitive Ring Expansion of Azetidines into Pyrrolidines and/or Azepanes.

Azetidines fitted with a 3-hydroxypropyl side chain at the 2-position undergo intramolecular N-alkylation after activation of the primary alcohol, and the produced 1-azonia-bicyclo[3.2.0]heptane is opened by different nucleophiles (cyanide, azide, or acetate anions) to produce mixtures of ring expanded pyrrolidines and azepanes, or a unique type of compound.

N-Arylazetidines: Preparation through Anionic Ring Closure.

We report herein an efficient synthesis of diversely substituted N-aryl-2-cyanoazetidines based on an anionic ring-closure reaction. These compounds can be prepared from β-amino alcohols in enantiomerically pure form through a three-step sequence involving (i) copper-catalyzed N-arylation, (ii) N-cyanomethylation of the secondary aniline, and (iii) one-pot mesylation followed by ring closure induced by a base. This high-yielding sequence gives access to azetidines with a predictable and adjustable substitution pattern and also with predictable diastereoselectivity.