Direct Transformation of N-Protected α,ß-Unsaturated γ-Amino Amides into γ-Lactams through a Base-Mediated Molecular Rearrangement.

Here, we are reporting a single-step transformation of N-protected α,ß-unsaturated γ-amino amides into 5,5-disubstituted γ-lactams through a base-mediated new molecular rearrangement. In contrast to the known N- to C(O) cyclization of saturated γ-amino acids into corresponding γ-lactams, the new rearrangement involves the cyclization between N-terminal Cγ- to C-terminal amide N. The cyclization process was initiated by the migration of double bond from α,ß â†’ ß,γ position. The enamine-imine tautomerization of the new ß,γ-double bond and subsequent 5-exo-trig cyclization of terminal amide leads to the formation of N-protected 5,5-disubstituted γ-lactam. The structures of various γ-lactams obtained from the rearrangement were studied in single crystals. Overall, the results reported here demonstrate the facile and single-step transformation of N-protected α,ß-unsaturated γ-amino amides into γ-lactams and provided an excellent opportunity to construct small-molecule peptidomimetics.

Impact of substituent effects on the design of ß-sheet mimetics and ß-double helices from (E)-vinylogous γ-amino acid oligomers.

Here we report the design, single crystal conformations, impact of the substituents and structural differences of two structurally important motifs, ß-sheets and ß-double helices. Though ß-sheets are common structural motifs in protein structures, ß-double helices are not common in proteins and peptides. We found that both ß-sheet mimetics and ß-double helices can be constructed from the homooligomers of α,ß-unsaturated γ-amino acids. Results suggested that introducing gem-dialkyl substitutions at the γ-carbon of the homooligomer of α,ß-unsaturated γ-amino acids resulted in the ß-double helix conformation, while the same oligomer with monosubstitution at the γ-carbon displayed a ß-sheet structure.

Design of Helical Peptide Foldamers through α,ß â†’ ß,γ Double-Bond Migration.

The direct transformation of nonhelical α,γ-hybrid peptides composed of alternating α- and E-vinylogous amino acids into 12-helical structures through a base-mediated α,ß â†’ ß,γ double-bond migration is reported. The conformations of double-bond-migrated new 12-helices were studied in single crystals and in solution. Instructively, the 12-helices reported here were found to be acid labile, and they completely break down into the corresponding amino acid derivatives upon treatment with acids.

Structural Dimorphism of Achiral α,γ-Hybrid Peptide Foldamers: Coexistence of 12- and 15/17-Helices.

Here, novel 12-helices in α,γ-hybrid peptides composed of achiral α-aminoisobutyric acid (Aib) and 4-aminoisocaproic acid (Aic, doubly homologated Aib) monomers in 1:1 alternation are reported. The 12-helices were indicated by solution and crystal structural analyses of tetra- and heptapeptides. Surprisingly, single crystals of the longer nonapeptide displayed two different helix types: the novel 12-helix and an unprecedented 15/17-helix. Quantum chemical calculations on both helix types in a series of continuously lengthened Aib/Aic-hybrid peptides confirm that the 12-helix is more stable than the 15/17-helix in shorter peptides, whereas the 15/17-helix is more stable in longer sequences. Thus, the coexistence of both helix types can be expected within a definite range of sequence lengths. The novel 15/17- and 12-helices in α,γ-hybrid peptides with 5→1 and 4→1 hydrogen-bonding patterns, respectively, can be viewed as backbone-expanded analogues of native α- and 310 -helices.

Non-classical Helices with cis Carbon-Carbon Double Bonds in the Backbone: Structural Features of α,γ-Hybrid Peptide Foldamers.

The impact of geometrically constrained cis α,ß-unsaturated γ-amino acids on the folding of α,γ-hybrid peptides was investigated. Structure analysis in single crystals and in solution revealed that the cis carbon-carbon double bonds can be accommodated into the 12-helix without deviation from the overall helical conformation. The helical structures are stabilized by 4→1 hydrogen bonding in a similar manner to the 12-helices of ß-peptides and the 310 helices of α-peptides. These results show that functional cis carbon-carbon double bonds can be accommodated into the backbone of helical peptides.