Allosteric Recognition of Homomeric and Heteromeric Pairs of Monosaccharides by a Foldamer Capsule.

The recognition of either homomeric or heteromeric pairs of pentoses in an aromatic oligoamide double helical foldamer capsule was evidenced by circular dichroism (CD), NMR spectroscopy, and X-ray crystallography. The cavity of the host was predicted to be large enough to accommodate simultaneously two xylose molecules and to form a 1:2 complex (one container, two saccharides). Solution and solid-state data revealed the selective recognition of the α-4 C1 -d-xylopyranose tautomer, which is bound at two identical sites in the foldamer cavity. A step further was achieved by sequestering a heteromeric pair of pentoses, that is, one molecule of α-4 C1 -d-xylopyranose and one molecule of ß-1 C4 -d-arabinopyranose despite the symmetrical nature of the host and despite the similarity of the guests. Subtle induced-fit and allosteric effects are responsible for the outstanding selectivities observed.

Citric acid encapsulation by a double helical foldamer in competitive solvents.

A new double helical aromatic oligoamide capsule able to bind to citric acid in polar and protic solvents was prepared. Aromatic amino acids in the sequence encode both structural (strand curvature and double helix formation) and functional features (recognition pattern) of the assembled capsule.

Polar solvent effects on tartaric acid binding by aromatic oligoamide foldamer capsules.

Aromatic oligoamide sequences able to fold into single helical capsules were functionalized with two types of side chains to make them soluble in various solvents such as chloroform, methanol or water and their propensity to recognize tartaric acid was evaluated. The binding affinities to tartaric acid and binding thermodynamics in different media were investigated by variable temperature (1)H NMR and ITC experiments, the two methods giving consistent results. We show that tartaric acid binding mainly rests on enthalpically favourable polar interactions that were found to be sufficiently strong to be effective in the presence of a polar aprotic solvent (DMSO) and even in pure methanol. Binding in water was very weak. The stronger binding interactions were found to be more susceptible to the effect of competitive solvents and compensated by unfavourable entropic effects. Thus, the best host in a less polar medium eventually was found to be the worst host in protic solvents. An interesting case of entropically driven binding was evidenced in methanol.

Iterative design of a helically folded aromatic oligoamide sequence for the selective encapsulation of fructose.

The ab initio design of synthetic molecular receptors for a specific biomolecular guest remains an elusive objective, particularly for targets such as monosaccharides, which have very close structural analogues. Here we report a powerful approach to produce receptors with very high selectivity for specific monosaccharides and, as a demonstration, we develop a foldamer that selectively encapsulates fructose. The approach uses an iterative design process that exploits the modular structure of folded synthetic oligomer sequences in conjunction with molecular modelling and structural characterization to inform subsequent refinements. Starting from a first-principles design taking size, shape and hydrogen-bonding ability into account and using the high predictability of aromatic oligoamide foldamer conformations and their propensity to crystallize, a sequence that binds to ß-D-fructopyranose in organic solvents with atomic-scale complementarity was obtained in just a few iterative modifications. This scheme, which mimics the adaptable construction of biopolymers from a limited number of monomer units, provides a general protocol for the development of selective receptors.

Structure elucidation of host-guest complexes of tartaric and malic acids by quasi-racemic crystallography.

Racemic on the outside, but not inside: Aromatic-foldamer hosts are enantiomers and as such prefer to co-crystallize even though the guests (e.g. L-tartaric acid, see picture) in each host are not present as enantiomers. This behavior allows a one-step structure elucidation of diastereomeric and quasi-racemic structures in the solid state.

Identification of a foldaxane kinetic byproduct during guest-induced single to double helix conversion.

An aromatic oligoamide sequence was designed and synthesized to fold in a single helix having a large cavity and to behave as a host for a dumbbell-shaped guest derived from tartaric acid. NMR, molecular modeling, and circular dichroism (CD) evidence demonstrated the rapid formation of this 1:1 host-guest complex and induction of the helix handedness of the host by the guest. This complex was found to be a long-lived kinetic supramolecular byproduct, as it slowly transformed into a 2:2 host-guest complex with two guest molecules bound at the extremities of a double helix formed by the host, as shown by NMR and CD spectroscopy and a solid-state structure. The guest also induced the handedness of the double helical host, but with an opposite bias. The chiroptical properties of the system were thus found to revert with time as the 1:1 complex formed first, followed by the 2:2 complex.

Long-range effects on the capture and release of a chiral guest by a helical molecular capsule.

Helically folded molecular capsules based on oligoamide sequences of aromatic amino acids which are capable of binding tartaric acid in organic solvents with high affinity and diastereoselectivity have been synthesized, and their structures and binding properties investigated by (1)H NMR, X-ray crystallography, circular dichroism, and molecular modeling. We found that elongating the helices at their extremities by adding monomers remote from the tartaric binding site results in a strong increase of the overall helix stability, but it does not influence the host-guest complex stability. The effect of this elongation on the binding and release rates of the guest molecules follows an unexpected non-monotonous trend. Three independent observations (direct monitoring of exchange over time, 2D-EXSY NMR, and molecular modeling) concur and show that guest exchange rates tend to first increase upon increasing helix length and then decrease when helix length is increased further. This investigation thus reveals the complex effects of adding monomers in a helically folded sequence on a binding event that occurs at a remote site and sheds light on possible binding and release mechanisms.

Free radical 5-exo-dig cyclization as the key step in the synthesis of bis-butyrolactone natural products: experimental and theoretical studies.

Radical cyclization reactions were performed by 5-exo-dig mode to yield cis-fused bicyclic systems, leading to the synthesis of bis-butyrolactone class of natural products. The study was aimed at understanding the impact of alkyl side chains of furanoside ring systems in L-ara configuration on the radical cyclization. It was amply demonstrated by experimental studies that the increase in the length of the alkyl side chain has an effect on the cyclization: while efficient cyclization reactions could be realized with methyl and ethyl side chains, the yields were significantly reduced in the case of n-pentyl side chain. Theoretical studies using DFT and (RO)MP2 methods were carried out to analyze the influence of the substitution pattern on the cyclization barriers.

The design of α/ß-peptides: study on three-residue turn motifs and the influence of achiral glycine on helix and turn.

Novel three-residue helix-turn secondary structures, nucleated by a helix at the N terminus, were generated in peptides that have 'ß-Caa-L-Ala-L-Ala,' 'ß-Caa-L-Ala-γ-Caa,' and 'ß-Caa-L-Ala-δ-Caa' (in which ß-Caa is C-linked carbo-ß-amino acid, γ-Caa is C-linked carbo-γ-amino acid, and δ-Caa is C-linked carbo-δ-amino acid) at the C terminus. These turn structures are stabilized by 12-, 14-, and 15-membered (mr) hydrogen bonding between NH(i)/CO(i+2) (i+2 is the last residue in the peptide) along with a 7-mr hydrogen bond between CO(i)/NH(i+2). In addition, a series of α/ß-peptides were designed and synthesized with alternating glycine (Gly) and (S)-ß-Caa to study the influence of an achiral α-residue on the helix and helix-turn structures. In contrast to previous results, the three 'ß-α-ß' residues at the C terminus (α-residue being Gly) are stabilized by only a 13-mr forward hydrogen bond, which resembles an α-turn. Extensive NMR spectroscopic and molecular dynamics (MD) studies were performed to support these observations. The influence of chirality and side chain is also discussed.

Hybrid helices: motifs for secondary structure scaffolds in foldamers.

The concept of "hybrid helices" as a new motif for foldamers is presented. Hybrid helices can be realized by a combination of two or more different types of homologous and hybrid peptides, for example, beta-peptides and alpha/beta- and alpha/gamma-hybrid peptides, within the same oligomer. The different helix types of the various peptide foldamer classes are maintained and form a regular helix along the sequence of the oligomer. The transition from one helix type to another was found to be rather smooth with high compatibility of the different helix types. Such hybrid helices represent novel motifs of secondary structure scaffolds. They open up the possibility to change the direction of helix propagation in a subtle manner. Hybrid helices enrich the arsenal of defined foldamer structures for a structural and functional mimicry of native peptides and proteins.

Three-residue turns in alpha/beta-peptides and their application in the design of tertiary structures.

A new three-residue turn was serendipitously discovered in alpha/beta hybrid peptides derived from alternating C-linked carbo-beta-amino acids (beta-Caa) and L-Ala residues. The three-residue beta-alpha-beta turn at the C termini, nucleated by a helix at the N termini, resulted in helix-turn (HT) supersecondary structures in these peptides. The turn in the HT motif is stabilized by two H bonds-CO(i-2)-NH(i), with a seven-membered pseudoring (gamma turn) in the backward direction, and NH(i-2)-CO(i), with a 13-membered pseudoring in the forward direction (i being the last residue)--at the C termini. The study was extended to generalize the new three-residue turn (beta-alpha-beta) by using different alpha- and beta-amino acids. Furthermore, the HT motifs were efficiently converted, by an extension with helical oligomers at the C termini, into peptides with novel helix-turn-helix (HTH) tertiary structures. However, this resulted in the destabilization of the beta-alpha-beta turn with the concomitant nucleation of another three-residue turn, alpha-beta-beta, which is stabilized by 11- and 15-membered bifurcated H bonds. Extensive NMR spectroscopic studies were carried out to delineate the secondary and tertiary structures in these peptides, which are further supported by molecular dynamics (MD) investigations.