Engineering Chiral Induction in Centrally Functionalized o-Phenylenes.

Work on foldamers, nonbiological oligomers that mimic the hierarchical structure of biomacromolecules, continues to yield new architectures of ever increasing complexity. o-Phenylenes, a class of helical aromatic foldamers, are well-suited to this area because of their structural simplicity and the straightforward characterization of their folding in solution. However, control of structure requires, by definition, control over folding handedness. Control over o-phenylene twist sense is currently lacking. While chiral induction from groups at o-phenylene termini has been demonstrated, it would be useful to instead direct twisting from internal positions to leave the ends free. Here, we explore chiral induction in a series of o-phenylenes with chiral imides at their centers. Conformational behavior has been studied by nuclear magnetic resonance and circular dichroism spectroscopies and density functional theory calculations. Chiral induction in otherwise unfunctionalized o-phenylenes is generally poor. However, strategic functionalization of the helix surface with trifluoromethyl or methyl groups allows it to better interact with the imide groups, greatly increasing diastereomeric excesses. The sense of chiral induction is consistent with computational models that suggest that it primarily arises from a steric effect.

Guest-Driven Control of Folding in a Crown-Ether-Functionalized ortho-Phenylene.

A crown-ether-functionalized o-phenylene tetramer has been synthesized and coassembled with monotopic and ditopic, achiral and chiral secondary ammonium ion guests. NMR spectroscopy shows that the o-phenylene forms both 1:1 and 1:2 complexes with monotopic guests while remaining well-folded. Binding of an elongated ditopic guest, however, forces the o-phenylene to misfold by pulling the terminal rings apart. A chiral ditopic guest biases the o-phenylene twist sense.

Fluorine Labeling of ortho-Phenylenes to Facilitate Conformational Analysis.

1H NMR spectroscopy is a powerful tool for the conformational analysis of ortho-phenylene foldamers in solution. However, as o-phenylenes are integrated into ever more complex systems, we are reaching the limits of what can be analyzed by 1H- and 13C-based NMR techniques. Here, we explore fluorine labeling of o-phenylene oligomers for analysis by 19F NMR spectroscopy. Two series of fluorinated oligomers have been synthesized. Optimization of monomers for Suzuki coupling enables an efficient stepwise oligomer synthesis. The oligomers all adopt well-folded geometries in solution, as determined by 1H NMR spectroscopy and X-ray crystallography. 19F NMR experiments complement these methods well. The resolved singlets of one-dimensional 19F{1H} spectra are very useful for determining relative conformer populations. The additional information from two-dimensional 19F NMR spectra is also clearly valuable when making 1H assignments. The comparison of 19F isotropic shielding predictions to experimental chemical shifts is not, however, currently sufficient by itself to establish o-phenylene geometries.

Biomedically Relevant Applications of Bolaamphiphiles and Bolaamphiphile-Containing Materials.

Bolaamphiphiles (BAs) are structurally segmented molecules with rich assembly characteristics and diverse physical properties. Interest in BAs as standalone active agents or as constituents of more complex therapeutic formulations has increased substantially in recent years. The preorganized amphiphilicity of BAs allows for a range of biological activities including applications that rely on multivalency. This review summarizes BA-related research in biomedically relevant areas. In particular, we review BA-related literature in four areas: gene delivery, antimicrobial materials, hydrogels, and prodrugs. We also discuss several distinguishing characteristics of BAs that impact their utility as biomedically relevant compounds.

Twist sense control in terminally functionalized ortho-phenylenes.

Many abiotic foldamers are based on achiral repeat units but adopt chiral geometries, especially helices. In these systems, there is no inherent preference for one handedness of the fold; however, it is well-established that the point chirality of substituents can be communicated to the helix. This capability represents a basic level of control over folding that is necessary for applications in molecular recognition and in the assembly of higher-order structures. The ortho-phenylenes are a structurally simple class of aromatic foldamers that fold into helices driven by arene-arene stacking interactions. Although their folding is now reasonably well-understood, access to o-phenylenes enriched in one twist sense has been limited to resolution, yielding conformationally dynamic samples that racemize over the course of minutes to hours. Here, we report a detailed structure-property study of chiral induction from o-phenylene termini using a combination of NMR spectroscopy, CD spectroscopy, and computational chemistry. We uncover mechanistic details of chiral induction and show that the same substituents can give effective twist sense control in opposite directions in mixtures of interconverting conformers; that is, they are "ambidextrous". This behavior should be general and can be rationalized using a simple model based on sterics, noting that arene-arene stacking is, to a first approximation, unaffected by flipping either partner. We demonstrate control over this mechanism by showing that chiral groups can be chosen such that they both favor one orientation and provide effective chiral induction.

Solvent effects on the folding of o-phenylene oligomers.

ortho-Phenylene oligomers fold into compact helical conformations in solution, and have therefore recently emerged as a class of foldamers. Previous work has shown that their folding is controlled by arene-arene stacking interactions parallel to the helical axis. Such interactions might reasonably be expected to be sensitive to solvent, but little is known of solvent effects in this system. Here, we report on the behavior of a representative set of o-phenylene oligomers in solvents ranging from non-polar (benzene) to polar and protic (methanol and water). The oligomers have been synthesized using post-oligomerization functionalization by click chemistry. Their folding is good in all solvents studied, but becomes measurably worse as the dielectric constant of the solvent increases. Thus, in contrast to the behavior of many other classes of aromatic foldamers, the folding propensity of o-phenylenes does not appear to be strongly affected by the solvophobic effect. Instead, the greater polarity of "frayed end" states governs their behavior.