Exploring a ß-Amino Acid with a Seven-Membered Ring Constraint as a Foldamer Building Block for Nontraditional Helices.

We explored trans- and cis-2-aminocycloheptanecarboxylic acid (ACHpC) as potential building blocks for helical foldamers. trans-ACHpC does not show sufficient folding propensity in unnatural peptides. cis-ACHpC promotes nontraditional helices of two unnatural peptide backbones: the 11/9-helix for 1:1 α/ß-peptides and the 12/10-helix for ß-peptides with interconvertible handedness. The two opposite-handed 12/10-helices rapidly interconvert in solution by pseudorotation of the two twist chair forms of the cycloheptane moiety in each cis-ACHpC residue.

Altering the binding affinities of tetraruthenocycles for polycyclic aromatic hydrocarbons by post-assembly modification.

We developed a strategy for manipulating the binding strength of polycyclic aromatic hydrocarbons (PAHs) via covalent post-assembly modification (PAM) of tetranuclear ruthenium macrocycles containing s-tetrazine ligands. The macrocycles act as efficient receptors for various PAHs. Inverse electron demand Diels-Alder (IEDDA) reaction of the macrocycles was applied to reduce the binding ability significantly.

Effect of a cis-4-aminopiperidine-3-carboxylic acid (cis-APiC) residue on mixed-helical folding of unnatural peptides.

The α/ß-peptide 11/9-helix and the ß-peptide 12/10-helix belong to "mixed" helices, in which two types of hydrogen bonds with opposite directionality alternate along the helical axis. cis-2-Aminocyclohexanecarboxylic acid (cis-ACHC) is known to promote these mixed helices and stabilize the helical propensity more than other acyclic ß-residues. Application of a mixed-helical backbone still requires sufficient solubility in aqueous solution. In this regard, we chose cis-4-aminopiperidine-3-carboxylic acid (cis-APiC) as a foldamer building block that can provide both sufficient aqueous solubility and mixed-helical propensity. Conformational analyses of α/ß- and ß-peptides containing a cis-APiC residue by circular dichroism spectroscopy and single-crystal X-ray crystallography suggest that the incorporation of cis-APiC instead of cis-ACHC can enhance the aqueous solubility of the mixed-helical peptides without any adverse effect on helical folding. In addition, the ratio between right- and left-handed 12/10-helices of ß-peptides can be rationalized by relative energies between the local conformations of the cis-APiC residue.

Helical Structures of Nylon-Like Oligomers Consisting of 1,2-Diamine and 1,2-Dicarboxylic Acid Building Blocks Containing a Five-Membered Ring Constraint.

A series of nylon-like oligomers was synthesized, which consisted of alternating cyclic 1,2-diamine and 1,2-dicarboxylic acid building blocks with a five-membered ring constraint. The nylon 2 4 oligomers are symmetric and display helical structures similar to the ß-peptide 12-helix with intramolecular 12-membered ring hydrogen bonds. The cyclopentane moiety allows each building block to promote 12-helical folding. In addition, a tartaric acid derivative with the acetonide moiety increases the solubility of oligomers in common organic solvents and promotes helical folding.

Metal-Ion Tuning in Triple-Stranded Helicate-Based Metallosupramolecules.

Effective incorporation of multiple types of ligands in a given coordination structure provides structural complexity and functional diversity to the resultant coordination-driven assembly. One of the most widely used synthetic approaches is the utilization of the molecular symmetry principle to combine multiple ligands and specific metallic centers in a preferred manner. The variation of metal ions can be helpful to understand the importance of symmetry for the generation of structurally hierarchical supramolecular platforms. We describe the synthesis and characterization of isostructural supramolecular helicates, [M8 (PDA)6 (AIP)3 (DMF)6-x (H2 O)x ] (M=Ni (1), Co (2), and Mn (3); PDA=2,6-pyridinedicarboxylate; AIP=5-aminoisophthalate; x=0 for 1, and x=4 for 2 and 3). The effect of metal variation on the formation of supramolecular helicates and their solid-state crystal packing are discussed. Despite the disparity in the ionic radii and distinct coordination-geometry preferences of Co2+ , Ni2+ , and Mn2+ , all metal centers engaged in the assembly with the heteroleptic ligands in the same manner to form isostructural supramolecular helicates.

Triazole-bearing calixpyrroles: strong halide binding affinities through multiple N-H and C-H hydrogen bonds.

Triazole-bearing calixpyrroles (TCPs) were synthesized as artificial anion binding receptors. The additional C-HX hydrogen bonding interaction induced strong binding affinity towards halide ions. Using this strong binding affinity, Cl- was successfully extracted from the aqueous to organic phase.

Cage-like crystal packing through metallocavitands within a cobalt cluster-based supramolecular assembly.

A cobalt (Co) supramolecular triple-stranded helicate, [Co8(PDA)6(Br-PTA)3(DMF)4(H2O)2] (1) (PDA = 2,6-pyridinedicarboxylate, Br-PTA = 5-bromoisophthalate, DMF = dimethylformamide), is successfully synthesized and fully characterized. The solid-state structure of 1 shows that four cobalt atoms are coordinated by three PDA ligands to form a tetranuclear cobalt cluster with three extension points and the ditopic Br-PTA ligands interlink two basic assembly units. In crystal packing, the bromo group is surrounded by the cavity-like tetranuclear cobalt cluster, which acts as a metallocavitand, to generate a unique cage-like crystal packing geometry. The isomorphous molecular cage, which exhibits a similar crystal-packing geometry as observed in 1, is also successfully isolated. This is an unusual example of a highly symmetric cage-like crystal packing architecture, resulting from the interaction among metallocavitands of in situ generated supramolecular modules.

Side chain-specific 11/9-helix propensity of α/ß-peptides with alternating residue types.

The 11/9-helix is among the most stable and non-traditional helical structures for α/ß-peptides with alternating residue types. The effect of side chain groups of α-residues and ß3-residues on the 11/9-helix propensity was examined under various solvent conditions. An α-amino acid residue with one of the four representative side chain groups was incorporated into the central position of an α/ß-pentapeptide backbone. A ß-branched valine residue did not show any destabilizing effect. α,α-Dimethylsubstituted Aib residue was tolerated under nonpolar conditions, but did not promote 11/9-helical folding. The oligomer with a glycine residue did not show 11/9-helical folding under polar solvent conditions. The single unmatched stereochemistry of d-alanine was deleterious to 11/9-helical folding. Replacement of a cyclic ß-residue with an acyclic ß3-residue in the 11/9-helical structure had a slight destabilizing effect, which could be compensated by a longer peptide sequence with more cyclic ß-residues. These results provide a guidance for incorporating functional groups into an 11/9-helical α/ß-peptide backbone to design functional oligomers.

Aromatic Hybrid Foldamer with a Hydrophilic Helical Cavity Capable of Encapsulating Glucose.

An indolocarbazole-naphthyridine hybrid oligomer capable of adopting a stable helical conformation was prepared, and its folding properties were thoroughly studied in the solid state and in solution. As a result of folding, a hydrophilic cavity was generated inside the helix wherein monosaccharides were able to be encapsulated in the order of glucose (9.6 × 104 M-1) > galactose (1.0 × 104 M-1) ≫ mannose (∼0) in 10% (v/v) DMSO/CH2Cl2.

Stereospecific control of the helical orientation of indolocarbazole-pyridine hybrid foldamers by rational modification of terminal chiral appendages.

The helical handedness excess of an indolocarbazole-pyridine hybrid oligomer capable of folding into a stable helical structure was achieved up to 96% by rational modification of terminal chiral residues.

A Cobalt Supramolecular Triple-Stranded Helicate-based Discrete Molecular Cage.

We report a strategy to achieve a discrete cage molecule featuring a high level of structural hierarchy through a multiple-assembly process. A cobalt (Co) supramolecular triple-stranded helicate (Co-TSH)-based discrete molecular cage (1) is successfully synthesized and fully characterized. The solid-state structure of 1 shows that it is composed of six triple-stranded helicates interconnected by four linking cobalt species. This is an unusual example of a highly symmetric cage architecture resulting from the coordination-driven assembly of metallosupramolecular modules. The molecular cage 1 shows much higher CO2 uptake properties and selectivity compared with the separate supramolecular modules (Co-TSH, complex 2) and other molecular platforms.

Helical α/ß-depsipeptides with alternating residue types: conformational change from the 11-helix to the 14/15-helix.

Short α/ß-peptides that consist of alternating l-α-amino acids and trans-2-aminocyclopentanecarboxylic acid are known to adopt both 11- and 14/15-helical conformations in solution. We report short α/ß-depsipeptides containing (S)-lactic acid as the third residue from the N-terminus. The α/ß-depsipeptide pentamers and heptamers adopt 14/15-helical conformations analogous to the α-helix in the crystal state and display 14/15-helical conformations predominantly in solution.

Helical Aromatic Foldamers Functioning as a Fluorescence Turn-on Probe for Anions.

Indolocarbazole-pyridine hybrid foldamers are strongly fluorescent in an extended random conformation, but the fluorescence is completely quenched upon folding to a helical conformation due to the compact stacking between aryl planes in the backbone. Anion binding disturbs the helical conformation, thus regenerating the fluorescence of the foldamers. This unique property has been utilized to develop a fluorescence turn-on probe for anions such as sulfate and fluoride.

Anion induced structural transformation in silver-(3,6-dimethoxy-1,2,4,5-tetrazine) coordination polymers under mechanochemical conditions.

Mechanochemical reactions of 3,6-dimethoxy-s-tetrazine (dmotz) with AgCF3SO3 and AgClO4 afforded the 1D linear polymer [Ag(dmotz)(CF3SO3)]n (1) and the 2D grid polymer {[Ag(dmotz)2](ClO4)}n (2), respectively. Mechanochemical processes convert 1 to 2 in the presence of an equivalent of [ClO4](-) and dmotz; even on using excess [CF3SO3](-), conversion from 2 to 1 was not observed.

Stabilization of 11/9-helical α/ß-peptide foldamers in protic solvents.

α/ß-Peptides with alternating α-amino acid and cis-2-aminocyclohexanecarboxylic acid (cis-ACHC) residues adopt 11/9-helical conformations, the folding propensity of which decreases as the solvent polarity increases. We report a new cis-ACHC analogue, cis-2-amino-cis-4-methylcyclohexanecarboxylic acid, which significantly stabilizes the 11/9-helix propensity in protic solvents.

Folding-Generated Molecular Tubes Containing One-Dimensional Water Chains.

A series of indolocarbazole-pyridine (IP) oligomers were prepared that fold into helical conformations, and their folding features in solution and in the solid state were revealed. Helical folding of these IP foldamers is induced by dipolar interactions through the ethynyl bond and π-stacking between two repeating units. Upon helical folding, (1)H NMR signals of aromatic protons were significantly shifted upfield by Δδ = 0.5-2.2 ppm. In addition, hypochromic shifts and fluorescence quenching were observed in the absorption and emission spectra. X-ray crystal structures clearly demonstrated that IP foldamers folded to helical structures with cylindrical internal cavities wherein 3 or 5 water molecules were occupied by hydrogen-bonding interactions in a 1-D array, reminiscent of transmembrane water channels, called aquaporins.

Synthesis of cobalt cluster-based supramolecular triple-stranded helicates.

A cobalt cluster-based triple-stranded helicate, Co8(PDA)6(PTA)3(DMF)3(H2O)3 () (PDA = 2,6-pyridinedicarboxylate, PTA = benzene-1,3-dicarboxylate, DMF = dimethylformamide) was successfully synthesized and fully characterized. Complex can be used as a supramolecular building block in constructing a higher-order helix-of-helix structure, [Co8(PDA)6(PTA)3(DMF)2(H2O)4-0.51(Co(OHn)2)] (n = 1 or 2) ().

Modulation of Axial-Ligand Binding and Releasing Processes onto the Triazole-Bearing Nickel(II) Picket-Fence Porphyrins: Steric Repulsion versus Hydrogen-Bonding Effects.

N-(p-Methoxycarbonylbenzyl) triazole (BTz) substituents have been introduced to Ni(II) porphyrins (NiPs), in which their modulated axial-coordination processes have been investigated. For this study, the two types of ligands, neutral pyridine versus anionic cyanide, were employed to investigate an effect of BTz substituents. The unique microenvironments given by the BTz substituents provided two different effects on the axial-coordination processes of NiPs on the ground and excited states: (1) steric shielding and (2) donation of hydrogen-bonding sites. The steric shielding diminished the binding affinity of pyridine, while the cooperation of hydrogen bonds extraordinarily strengthened the binding affinity of CN(-). Interestingly, it was observed that the binding of CN(-) with the supporting of BTz substituents accompanied nonplanar distortion of NiPs. Such conformational change perturbed the electronic structure of NiPs, which gave rise to the modulation of coordination processes of NiPs in the excited state. As a consequence, photoinudced ligand binding and releasing processes of four- and six-coordinated NiPs were changed into the dominant photoinduced ligand releasing process.

Synthetic K⁺/Cl⁻-selective symporter across a phospholipid membrane.

Synthetic molecules which selectively transport sodium or potassium chloride across a lipid membrane have been prepared. The salt carriers consist of two heteroditopic binding sites, an anion-binding cavity with three hydrogen bond donors and an azacrown ether for binding an alkali metal cation. The association constants between the carriers and chloride ion have been enhanced by 1 order of the magnitude in the presence of sodium or potassium ion in 10% (v/v) CD3OH/CD3CN, due to the formation of a contact ion-pair between the bound cation and chloride as demonstrated by the single-crystal X-ray structure of a sodium chloride complex. A series of transport experiments have demonstrated that the synthetic molecule functions as a mobile carrier of transporting salts via M(+)/Cl(-) symport. Among alkali metal chlorides, the carrier with an 18-azacrown-6 exhibits a strong selectivity toward potassium chloride, while the carrier with a 15-azacrown-5 displays a moderate selectivity for sodium chloride.

Helical folding of α/ß-peptides containing ß-amino acids with an eight-membered ring constraint.

αßα-Tripeptide that contains a cyclic ß-amino acid with an eight-membered ring, a cis-2-aminocyclooct-5-enecarboxylic acid (cis-ACOE) or a cis-2-aminocyclooctanecarboxylic acid (cis-ACOC) displayed an 11/9-helical turn in the crystal state. The related α/ß-peptide oligomers were shown to adopt 11/9-helical conformations in solution.