Water-Stable Helical Structure of Tertiary Amides of Bicyclic β-Amino Acid Bearing 7-Azabicyclo[2.2.1]heptane. Full Control of Amide Cis−Trans Equilibrium by Bridgehead Substitution

Abstract

Helical structures of oligomers of non-natural β-amino acids are significantly stabilized by intramolecular hydrogen bonding between main-chain amide moieties in many cases, but the structures are generally susceptible to the environment; that is, helices may unfold in protic solvents such as water. For the generation of non-hydrogen-bonded ordered structures of amides (tertiary amides in most cases), control of cis-trans isomerization is crucial, even though there is only a small sterical difference with respect to cis and trans orientations. We have established methods for synthesis of conformationally constrained β-proline mimics, that is, bridgehead-substituted 7-azabicyclo[2.2.1]heptane-2-endo-carboxylic acids. Our crystallographic, 1D- and 2D-NMR, and CD spectroscopic studies in solution revealed that a bridgehead methoxymethyl substituent completely biased the cis-trans equilibrium to the cis-amide structure along the main chain, and helical structures based on the cis-amide linkage were generated independently of the number of residues, from the minimalist dimer through the tetramer, hexamer, and up to the octamer, and irrespective of the solvent (e.g., water, alcohol, halogenated solvents, and cyclohexane). Generality of the control of the amide equilibrium by bridgehead substitution was also examined.

Bicyclic β-amino acids

“…141 Helical structures analogous to that shown in Figure 18b were generated independently of the number of residues in the oligomers of the amino acid 333 (Figure 18c) (from the dimer up to the octamer), and irrespective of the solvent (from water to cyclohexane). Notably, relative stability of these structures was also independent of number of residues in the oligomers.…”

Visible‐Light‐Triggered Release of Nitric Oxide from N‐Pyramidal Nitrosamines

“…[18]. DMSO (4.5 mL, 63.36 mmol) at À78 8C was added to a solution of oxalyl chloride (3.6 mL, 42.54 mmol) in CH 2 Cl 2 (220 mL).…”

“…A comparison of the Abstract: Although many organic/inorganic compounds that release nitric oxide (NO) upon photoirradiation (phototriggered caged-NOs) have been reported, their photoabsorption wavelengths mostly lie in the UV region, because XÀNO bonds (X = heteroatom and metal) generally have rather strong p-bond character. Thus, it is intrinsically difficult to generate organic compounds that release NO under visi-UV/Vis spectra of these bicyclic nitrosamines (1-15, e.g., 3) with those of the monocyclic derivatives (16)(17)(18), e.g., 16) showed significant bathochromic shifts, and the absorption tails into the visible light region (up to 500 nm) in the case of the bicyclic nitrosamines. The absorption peaks at around 300-450 nm can be attributed to HOMO (n)-to-LUMO (p*) transitions ( Figure 2).…”

Non-naturally Occurring Helical Molecules Can Interfere with p53–MDM2 and p53–MDMX Protein–Protein Interactions

“…β-Peptides form orderly secondary structures, as do α-peptides, and their resistance to proteolysis is advantageous, e.g., for the development of peptide drugs, including β-peptide-based antibiotics. 1,2) The enhanced molecular flexibility of β-peptides results in great structural diversity, 3) but conversely leads to difficulties in forming constrained conformations, and especially in controlling amide cis-trans isomerization.…”