Foldamers Stabilized by Aliphatic Units

It is difficult to use aliphatic solvophobes to construct well defined structures for several reasons. First, their association generally does not have highly preferred orientations as in that of aromatic groups and, hence, puts little geometrical con straint on the process of aggregation. The aggregates often vary greatly both in terms of number of molecules and their relative arrangement within in the structure. Second, the most widely used aliphatic solvophobes are flexible hydrocarbon chains. Geometrical manipulation of such objects is not as straightforward as in flat aromatic hydrocarbons. Third, without a well defined shape, precise arrangement of solvophobic and solvophilic groups and creation of amphiphilic pattern (to control aggregation) in aliphatic solvophobes are challenging. Fourth, aliphatic-aliphatic interactions originate from solvophobic interactions and dispersive forces, but aromatic-aromatic interactions have additional contributions such as electrostatic and quadrupolar interactions.

Zhao and co-workers recently described oligomeric cholates derived from cholic acid 35 [133]. Cholic acid has a unique structure. As a metabolite of cholesterol, it is quite rigid with four fused rings. Its rigid backbone is very attractive from the standpoint of geometrical manipulation. It has built-in amphiphilicity with the hydroxylated a face and the hydrocarbon-containing b face. With a distinctive shape and facial amphiphilicity, its aggregation is much more selective compared to most aliphatic amphiphiles. Unlike conventional head-tail surfactants, sodium cholate tends to form dimers at early stages of aggregation and form large aggregates mostly at relatively high concentrations in water [134]. Another distinguishing feature of cholic acid is its size. The distance between the carboxyl tail and the hydroxyl group at C-3 is about 1.4 nm. A large monomer unit will not only improve the efficiency of synthesis dramatically, but also provide a strong solvophobic driving force, as the strength of solvophobic interaction is directly proportional to the buried solvophobic area. Therefore, most of the problems mentioned above for aliphatic solvophobes are absent in this natural product.

35, Cholic acid

Scheme 3.20

Most of the methods employed in the characterization of aromatic foldamers including hypochromism, excimer formation, and upfield-shifted proton signals could not be used in aliphatic foldamers. NOE techniques were also excluded due to signal overlapping in the 1H NMR spectroscopy. Fluorescence spectroscopy turned out particularly useful. In a mostly nonpolar mixture (e.g. CCl4 or hexane/ethyl acetate) containing a small amount of polar solvent (e.g. methanol

Fig. 3.9 Space-filling molecular models of the unfolded and folded cholate hexamer.

or DMSO), polar solvents were enriched near the fluorophore in 36n. In addition, quenching of the emission of 36n by a hydrophilic quencher 37 became more efficient with an increase in the chain length in the above (mostly nonpolar) solvent mixtures, but was independent of chain length in more polar solvents or by the hydrophobic quencher. The results were consistent with folding of the oligocho-lates to create a helix with a nanometer-sized internal hydrophilic cavity where polar solvents or polar molecules such as 37 could be bound (Fig. 3.9). Folding was confirmed also by fluorescence resonance energy transfer (FRET), a method (essentially a long-ranged version of NOE) widely used in the conformational characterization of proteins and [135-137]. In fact, for foldamers resembling molten-globular proteins, FRET represents a more powerful method than NOE for characterizing conformations. The most interesting result from FRET was that the hexamer (394) had a closer end-to-end distance than either the pentamer

Scheme 3.21

(393) or the heptamer (395) under folding conditions, as expected from a helix with three monomer units per turn. The data fit well to a two-state transition model, in agreement with the helix-coil transition. The conformational change was extremely sensitive to solvents and could easily detect <0.5% change in solvent composition. High sensitivity toward solvent change was probably due to lack of any other intramolecular interactions besides solvophobic forces. More recently, this highly sensitive, cooperative conformational change was employed to tune the binding affinity between mercury ions and a cholate hexamer with two methionine units incorporated. Simple solvent changes could alter the binding constant over five orders of magnitude [138]. Importantly, the methionine-containing hexamer could fold as well as (actually slightly better than) the parent cholate hexamer. Thus, as expected, functionalized solvophobic foldamers do not deviate (significantly) in foldability from their parent, unfunctionalized versions.

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