Chiral induction in phenanthroline-derived oligoamide foldamers: an acid- and base-controllable switch in helical molecular strands

A series of phenanthroline-derived oligoamides bearing a chiral (R)-phenethylamino end group were synthesized that displayed chiral helical induction and subsequently formed one-hand helical foldamers in solution. Moreover, an acid- and base-controllable switch in the helical molecular strands was observed, which has been demonstrated by NMR, UV-vis, and circular dichroism spectroscopy.     

Aromatic δ-peptides: design, synthesis and structural studies of helical, quinoline-derived oligoamide foldamers

Oligoamides of 8-amino-4-isobutoxy-2-quinolinecarboxylic acid were designed and synthesized, and their helical structures were characterized in the solid state by single crystal X-ray diffraction, and in solution by ¹H NMR. The monomer methyl 4-isobutoxy-8-nitro-2-quinolinecarboxylate is easily prepared in three steps from 2-nitroaninile and dimethyl acetylene dicarboxylate. Successive hydrogenations of nitro groups, saponifications of esters and couplings of amines and acids via the acid chlorides gave a dimer, tetramer, hexamer, octamer, and decamer in a convergent fashion. The oligomers were shown to adopt a bent conformation stabilized by intramolecular hydrogen bonds between amide hydrogens and adjacent quinoline nitrogens. In the solid, the dimer adopts a planar crescent shape and the octamer a helical conformation. All NMR data are consistent with similar conformations in solution. The helices are apparently remarkably stable. Some of them remain helical even at 120°C in deuterated DMSO. The structural studies confirm the predictions made by computer and demonstrate the high potency of the design principles.     

Assessing the folding propensity of aliphatic units within helical aromatic oligoamide foldamers

Great attention is devoted to hybrid foldamers composed of more than one type of monomers. The folding of such hybrids requires units that may possess very different structures to be compatible. A method to assess this compatibility consists in studying the behavior of a monomer of one type within a sequence of another type of monomer. We have prepared and investigated the structure of flexible aliphatic monomers in the context of the rigid helices of quinoline-carboxamides. NMR and X-ray crystallography show that the rigid helical backbones may impart defined conformation into otherwise flexible units and that compatible folding modes exist between very different monomers.     

Solution structure of quinoline- and pyridine-derived oligoamide foldamers

The unambiguous elucidation of a new folded structure in solution may prove to be a very challenging task. The NMR protocols developed for solving the solution structures of alpha-peptides have been applied to aliphatic beta- and gamma-peptides but are not directly applicable to aromatic oligomers. In particular, the string of spin systems in an aromatic sequence cannot be reconstituted solely from correlations between protons. For aromatic oligomers, it is shown that the assignment of a large part of the 13C NMR spectrum through HMBC and HSQC experiments allows to unambiguously assign proton NMR spectra and in turn to interpret NOE correlations. This has been implemented both with quinoline- and pyridine-derived oligoamide foldamers, and should be applicable to a wide range of oligomers including various combinations of monomers. The NOE correlations allow the unambiguous solution structure elucidation of helical conformations of oligoamides derived from pyridine and quinoline monomers showing that, in these series, the solution structures correspond very well to the structures observed in the solid state.     

Phenanthroline dicarboxamide-based helical foldamers: stable helical structures in methanol

A series of new aromatic oligoamides 2-5 based on 1,10-phenanthroline diacid and o-phenylenediamine have been synthesized through a convergent segment coupling strategy. These oligomers can fold into well-defined helical structures in solution through intramolecular hydrogen bonds and aromatic stacking interactions, which has been established by 1H NMR, fluorescence, and UV/vis spectra. In particular, it was found that the oligomers were more favorable to fold into stable helical structures in methanol than in chloroform and dichloromethane. The helical foldamers formed in the solid state have been characterized by single-crystal X-ray diffraction analysis. The results showed that the high curvature of the strands led to one and a half turns for both 2 and 21, three turns for 4, and nearly four turns for 5.     

Absolute control of helicity at the C-termini in quinoline oligoamide foldamers by chiral oxazolylaniline moieties

Absolute one-handed chiral quinoline tetramers andoctamers containing different oxazolylanilines at the C-terminus have been synthesized.The absolute one-handed sense and diastereomeric excess values were valued by^1H NMR.X-ray crystal diffractionand CD studies reveal that the S-oxazolylaniline always induces a P-handed helicity and the absolute helicity is driven by the stable three-center hydrogen bonding between protons in the amide and N atoms in oxazolylaniline and adjacent quinoline ring.CPL investigations demonstrated that S-CQn-a-d are CPL active and its g(lum)values are dependent on its length.Interestingly,the sizes of the substituents in the chiral centers are different,howeve r,they exert no effect on the dissymmetric factors g(abs)and g(lum)of quinoline oligoamide foldamers.     

Absolute control of helical handedness in quinoline oligoamides

The synthesis of quinoline-derived helically folded aromatic oligoamides functionalized by various chiral functions at their N-terminus is reported. When a (1S)-(-)-camphanyl moiety was introduced, it was found that helix handedness was completely shifted to right-handed helicity (de > 99%), in both protic and nonprotic solvents. The absolute helical sense and the de values were unambiguously characterized by using (1)H NMR, circular dichroism (CD), and X-ray crystallography. The crystal structure of these compounds allowed us to propose a rationale for the efficiency of helix handedness induction based on a combination of steric factors and intramolecular hydrogen bonding.     

Hydrogen bonding-induced aromatic oligoamide foldamers as spherand analogues to accelerate the hydrolysis of nitro-substituted anisole in aqueous media

Four intramolecular hydrogen bonding-driven aromatic amide foldamers 2-5 have been designed and synthesized in which a 2-methoxy-3-nitrobenzamide unit was incorporated at the end of the backbone. Kinetic studies in dioxane-water (4:1, v/v) at 60-90 degrees C have revealed that the folded backbone of the oligomers was, like the rigidified spherand, able to complex Li+, Na+, and K+ and, consequently, accelerated the hydrolysis of the nitro-appended anisole unit of the foldamers. Generally, longer foldamers displayed an increased accelerating effect, and LiOH displayed the highest reactivity probably due to the most efficient complexation by the folded oligomers. Addition of excessive potassium chloride substantially reduced the complexing interaction, and the hydrolysis of the longer oligomers became slower than that of the shorter ones due to an increased steric effect. The results indicate that, even in a hot aqueous medium of high polarity, intramolecular hydrogen bonding is still able to induce structurally matched oligomers to generate a preorganized rigidified conformation.     

Solid phase synthesis of aromatic oligoamides: application to helical water-soluble foldamers

Synthetic helical aromatic amide foldamers and in particular those based on quinolines have recently attracted much interest due to their capacity to adopt bioinspired folded conformations that are highly stable and predictable. Additionally, the introduction of water-solubilizing side chains has allowed to evidence promising biological activities. It has also created the need for methods that may allow the parallel synthesis and screening of oligomers. Here, we describe the application of solid phase synthesis to speed up oligomer preparation and allow the introduction of various side chains. The synthesis of quinoline-based monomers bearing protected side chains is described along with conditions for activation, coupling, and deprotection on solid phase, followed by resin cleavage, side-chain deprotection, and HPLC purification. Oligomers having up to 8 units were thus synthesized. We found that solid phase synthesis is notably improved upon reducing resin loading and by applying microwave irradiation. We also demonstrate that the introduction of monomers bearing benzylic amines such as 6-aminomethyl-2-pyridinecarboxylic acid within the sequences of oligoquinolines make it possible to achieve couplings using a standard peptide coupling agent and constitute an interesting alternative to the use of acid chloride activation required by quinoline residues. The synthesis of a tetradecameric sequence was thus smoothly carried out. NMR solution structural studies show that these alternate aminomethyl-pyridine residues do not perturb the canonical helix folding of quinoline monomers in protic solvents, contrary to what was previously observed in nonprotic solvents.     

Naphthyridine-based helical foldamers and macrocycles: synthesis, cation binding, and supramolecular assemblies

Unraveling the factors that control the conformation of molecular chains is of great interest both for understanding the shape of biological molecular strands and for designing artificial ones that adopt desired forms. Thus, a variety of artificial folding codons have been identified that enforce the formation, among others, of helices, strands, and loops, the major emphasis being on the shape of the foldamer. We report herein the synthesis and study of a family of foldamers and macrocycles based on the 1,8-naphthyridine and pyrimidine units, whose internal cavity is large enough to accommodate ionic substrates, and focus on the impact of guest binding within a cylindrical environment. Interestingly, the binding event within these large oligomers is translated to the outside of the receptors and affects the interaction of the overall complexes with the outside world. For instance, alkali cations bind to the one-turn helices and macrocycles to promote fibril formation and aggregation. Also, polyammonium substrates are able to tune the length of the overall helix assemblies and the rigidity of long oligomers. The reported data on one-turn, two-turn helices and macrocycles not only allows one to devise a model for the ion-controlled supramolecular assembly of such systems but also provides evidence that such controlled scaffolds bear promise in the design of complex systems.     

Solvophobic and steric effects of side groups on polymer folding: molecular modeling studies of amine-functionalized m-poly(phenyleneethynylene) foldamers in aqueous solution

The folding behavior of five different amine-functionalized m-poly(phenyleneethynylene) (m-PPE) oligomers containing 24 phenyl rings (12 residues, where a residue includes 2 phenyl rings) in water was examined by using a combination of molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulation techniques. The REMD method employed the highly parallelized GROMACS MD software and a modified OPLS-AA force field to simulate 44 replicas of each solvated system in parallel, with temperatures ranging from 300 to 577 K. Our results showed that the REMD method was more effective in predicting the helical conformation of the m-PPE in water, from an extended structure, than canonical MD methods in the same simulation time. Furthermore, we observed from canonical MD simulations of the explicitly solvated helical m-PPEs at 300 K that the radius of gyration, average helix inner diameter, and average helix pitch of the helical structure all pass through a minima when the side group is R = OC(2)H(5) as R is changed from R = H through OC(4)H(9).     

Computing handedness: quantized and superposed switch and dynamic memory of helical polysilylene.

Two new conjugating helical polymers comprising a rodlike silicon backbone and enantiopure chiral pendants, poly[(R)-3,7-dimethyloctyl-(S)-3-methylpentylsilylene] (PS-1) and its diastereomeric poly[(S)-3,7-dimethyloctyl-(S)-3-methylpentylsilylene] (PS-2), were prepared. Molecular mechanics calculations of PS-1 and PS-2 model oligomers indicated a double well potential energy curve corresponding to almost enantiomeric helices with dihedral angles of 150-160 degrees (P-motif, global minimum) and 200-210 degrees (M-motif), regardless of their tacticity. Experimentally, it was found that PS-1 in dilute isooctane revealed switchable ambidextrous helicity on application of a thermal energy bias. Although PS-1 featured three distinct switching regions, viz. "region 1, between -80 and -10 degrees C", "region 2, between -10 and +10 degrees C", and "region 3, between +10 degrees C and +80 degrees C", the switching properties were interpreted as the result of superposed P- and M-helicities, undergoing dynamic pseudo-racemization or oscillation. Oscillating helicity in region 2 was roughly estimated to be about 13 cm(-)(1). The superposed helicity in region 2 was critical since it afforded molecular recognition ability with a dynamic memory function that was highly susceptible to solvent molecular topology and volume fraction. This could lead to potential as a molecular information processor to serve as a gauge of chemical properties. On the other hand, PS-2 could not switch its preferential screw-sense in the range of -80 to +80 degrees C. This may be related to greater differences the potential energy curve between P- and M-motifs.     

Flaws in foldamers: conformational uniformity and signal decay in achiral helical peptide oligomers

Although foldamers, by definition, are extended molecular structures with a well-defined conformation, minor conformers must be populated at least to some extent in solution. We present a quantitative analysis of these minor conformers for a series of helical oligomers built from achiral but helicogenic α-amino acids. By measuring the chain length dependence or chain position dependence of NMR or CD quantities that measure screw-sense preference in a helical oligomer, we quantify values for the decay constant of a conformational signal as it passes through the molecular structure. This conformational signal is a perturbation of the racemic mixture of M and P helices that such oligomers typically adopt by the inclusion of an N or C terminal chiral inducer. We show that decay constants may be very low (<1% signal loss per residue) in non-polar solvents, and we evaluate the increase in decay constant that results in polar solvents, at higher temperatures, and with more conformationally flexible residues such as Gly. Decay constants are independent of whether the signal originates from the N or the C terminus. By interpreting the decay constant in terms of the probability with which conformations containing a screw-sense reversal are populated, we quantify the populations of these alternative minor conformers within the overall ensemble of secondary structures adopted by the foldamer. We deduce helical persistence lengths for Aib polymers that allow us to show that in a non-polar solvent a peptide helix, even in the absence of chiral residues, may continue with the same screw sense for approximately 200 residues.     

New helical foldamers: heterogeneous backbones with 1:2 and 2:1 alpha:beta-amino acid residue patterns

Foldamers, oligomers with strong folding propensities, are subjects of growing interest because such compounds offer unique scaffolds for the development of molecular function. We report two new foldamer classes, oligopeptides with regular 1:2 or 2:1 patterns of alpha- and beta-amino acid residues. Two distinct helical conformations are detected via 2D NMR in methanol for each backbone. One of the helices for each backbone is characterized via X-ray crystallography.     

Isolation and handedness of helical coiled cellulosic thickenings from plant petiole tracheary elements

Leaf stalks (petioles) are critical components of the vascular system that conducts water from the roots to the photosynthetic apparatus of most green plants. Helical coiled cellulosic microfibrils that reinforce the tracheary elements in plant leaf petioles were isolated by a gentle treatment with alkali and acid chlorite from celery and from a number of tree species, including sugar maple, London plane, horse chestnut, tulip tree, paulownia and ginko. Analysis of the hydrolysate of celery coils gave glucose as the main product, but significant quantities of xylose and other sugars were also detected. Polarized light microscopy was used to determine the location, dimensions and handedness of the coils. The coils were made up of single or multiple parallel strands in contact, ranging up to 35 μm in diameter and several cm in length. The strand structure was chiral; significantly, only left-handed helices were observed. An attempt is made to rationalize the left-handed structure by comparison with the spontaneous handedness observed in vitro for cellulose nanocrystals suspensions. The ubiquitous presence of coiled thickenings in petiole vascular elements indicates their importance in plant functions.     

Chiral direction and interconnection of helical three-connected networks in metal-organic frameworks

The control of the interpenetration and chirality of a family of metal-organic frameworks is discussed. These systems contain two- (A) and four-fold (B) interpenetration of helical three-connected networks generated by binding the 1,3,5-benzenetricarboxylate (btc) ligand to a metal center. These frameworks have the general formula Ni(3)(btc)(2)X(m)Y(n).solvent (where X = pyridine or 4-picoline, Y = ethylene glycol, 1,2-propanediol, 1,4-butanediol, meso-2,3-butanediol, 1,2,6-hexanetriol, glycerol). The structural and chemical effects of modifying the alcohol and aromatic amine ligands bound to the metal center include controlling the thermal stability and the degree of interpenetration. Covalent linking of the four interpenetrating networks in the A family and the switching of diol binding from mono- to bidentate are demonstrated. Recognition of chiral diols by the hand of the network helices is investigated by binding an alcohol ligand with two chiral centers of opposite sense to the same helix. This reveals the subtle nature of the helix-ligand interaction.     

Impact of steric interactions on the helical transition in assemblies of discotic molecules

We investigate theoretically the effect of excluded-volume interactions on the helical configurational transition of supramolecular assemblies in solutions of chiral disklike molecules. To this end, we set up a second-virial theory within the context of the helical self-assembly of rodlike objects. We find that interaggregate interactions shift both the helical-transition point and the sharpness of the transition. For realistic values of the model parameters, the helical-transition temperature shifts by several degrees, and the more so the higher the concentration of assembling material. The mean aggregation number is also affected by the interactions, albeit only by a modest amount, unless the solution becomes very concentrated.     

Polymeric stabilized emulsions: steric effects and deformation in soft systems

Polymeric stabilizers are used in a broad range of processes and products, from pharmaceuticals and engine lubricants to formulated foods and shampoos. In rigid particulate systems, the stabilization mechanism is attributed to the repulsive force that arises from the compression of the polymer coating or "steric brush" on the interacting particles. This mechanism has dictated polymer design and selection for more than thirty years. Here we show, through direct measurement of the repulsive interactions between immobilized drops with adsorbed polymers layers in aqueous electrolyte solutions, that the interaction is a result of both steric stabilization and drop deformation. Drops driven together at slow collision speeds, where hydrodynamic drainage effects are negligible, show a strong dependence on drop deformation instead of brush compression. When drops are driven together at higher collision speeds where hydrodynamic drainage affects the interaction force, simple continuum modeling suggests that the film drainage is sensitive to flow through the polymer brush. These data suggest, for drop sizes where drop deformation is appreciable, that the stability of emulsion drops is less sensitive to the molecular weight or size of the adsorbed polymer layer than for rigid particulate systems.     

Origins of steric effects in general-base-catalyzed enolization: solvation and electrostatic attraction

Br?nsted plots for general-base-catalyzed enolization of aldehydes and ketones show significant negative deviations for the rates of proton removal by sterically hindered amine bases. The origins of the deviations are not apparent from considerations of interactions at the site of the proton transfer. Contrasting behavior is observed in general-base-catalyzed proton removal from an iminium derivative, N1'-methyl-2-(1-hydroxybenzyl)thiamin (NMHBnT), which shows no deviations from the Br?nsted correlation for sterically hindered amine bases. The difference in behavior for these two systems suggests that the steric effects arise from disruption of solvation of the enolate enforced by the electrostatic requirements of the overall process. This interpretation also can account for reduced steric effects for enolization in the presence of metal ions.