Local constraints that restrict rotation about bond angles in a single amino acid or between two amino acids in a dipeptide can have significant consequences on the global conformation of the entire peptide (Figure 3). For example, natural proline favors turn geometry and can order the alignment of amide bonds of distant amino acid residues in the peptide chain to form hairpin and β-sheet conformations. Studying various analogs of proline and its homolog pipecolic acid, we have employed the steric and electronic interactions of ring substituents to favour specific ring puckering and dihedral angle geometry. For example, 5-tert-butylproline was conceived to favour prolyl cis-amide isomers and shown to stabilize type VI β-turns in model peptides. Aza-pipecolic acid analogs are also being used as cis-amide surrogates, and have been employed to create mimics of the second mitochondria-derived activator of caspases (Smac) with potential anti-cancer activity.
In contrast to the proline heterocycle which possesses a covalent bridge between the nitrogen and α-carbon of the same amino acid, a so-called “Freidinger-Veber” amino lactam ring joins the α-carbon of one amino acid to the nitrogen of its C-terminal residue. Pioneering the applications of 5- and 6-membered cyclic sulfamidate electrophiles to make β- and γ-substituted amino acids, we have developed methods for introducing α- and β-amino γ-lactams, as well as α-amino β-hydroxy γ-lactams into peptides, and are currently exploring the impact of their configuration and substitution patterns on conformation and biology. Studying aza variants of amino lactams in cyclic urea analogs, methods are being innovated for the introduction of side chains onto the heterocycle and the scanning of peptide structures. Conformational analysis of N-amino-imidazolidin-2-one model peptides has illustrated dynamic chirality about the α-nitrogen enabling mimicry of both type II and II’ conformers.
Azabicyclo[X.Y.0]alkanone amino acids are constrained dipeptides in which the central amide nitrogen is bridged to the α-carbons of both its N- and C-terminal amino acid residues. Combining the attributes of proline and α-amino lactam structures described above, azabicycloalkanone amino acids can control peptide folding and serve as rigid platforms for orienting pharmacophores. Innovating synthetic methods to access these heterocycles with control of ring size, stereochemistry and ring substituents, we have conceived a stereo-controlled ring-closure metathesis–transannular lactam cyclization strategy that gives functionalized azabicyclo[X.Y.0]alkanone amino acids possessing different heterocycle ring sizes (e.g., 5,5-, 5,6-, 6,4-, 6,5-, 6,6-, and 7,5-fused systems) from their 8–10-membered dipeptide lactam precursors. This approach is currently being employed to constrain the backbone and side chain geometry of various peptides.
Figure 3. 5-tert-butylprolyl, azapipecolyl, α-amino γ-lactam, α-amino β-hydroxy γ-lactam, hydroxyl indolizidinone and hydroxyl pyrrolizidinone residue targets.