The meso Helix: Symmetry and Symmetry-Breaking in Dynamic Oligourea Foldamers with Reversible Hydrogen-Bond Polarity.

Oligoureas (up to n=6) of meso cyclohexane-1,2-diamine were synthesized by chain extension with an enzymatically desymmetrized monomer 2. Despite being achiral, the meso oligomers adopt chiral canonical 2.5-helical conformations, the equally populated enantiomeric screw-sense conformers of which are in slow exchange on the NMR timescale, with a barrier to screw-sense inversion of about 70 kJ mol(-1) . Screw-sense inversion in these helical foldamers is coupled with cyclohexane ring-flipping, and results in a reversal of the directionality of the hydrogen bonding in the helix. The termini of the meso oligomers are enantiotopic, and desymmetrized analogues of the oligoureas with differentially and enantioselectively protected termini display moderate screw-sense preferences. A screw-sense preference may furthermore be induced in the achiral, meso oligoureas by formation of a 1:1 hydrogen-bonded complex with the carboxylate anion of Boc-d-proline. The meso oligoureas are the first examples of hydrogen-bonded foldamers with reversible hydrogen-bond directionality.

Huge electro-/photo-/acidoinduced second-order nonlinear contrasts from multiaddressable indolinooxazolodine.

In this work, linear and nonlinear optical properties of electro-/acido-/photoswitchable indolino[2,1-b]oxazolidine derivatives were investigated. The linear optical properties of the closed and open forms have been characterized by UV-visible and IR spectroscopies associated with DFT calculations. Nonlinear optical properties of the compounds have been obtained by ex situ and in situ hyper-Rayleigh experiments in solution. We show that protonated, oxidized, and irradiated open forms exhibit the same visible absorption and NLO features. In particular, the closed and open forms exhibit a huge contrast of the first hyperpolarizability with an enhancement factor of 40-45. Additionally, we have designed an original electrochemical cell that allows to monitor in situ the hyper-Rayleigh response upon electrical stimulus. We report notably a partial but good and reversible NLO contrast in situ during oxidation/reduction cycles. Thereby, indolinooxazolidine moieties are versatile trimodal switchable units which are very promising for applications in devices.

Unambiguous Determination of the Absolute Configuration of Dimeric Stilbene Glucosides from the Rhizomes of Gnetum africanum.

Dimeric stilbene glucosides 1-3 [two diastereomers of (-)-gnemonoside A (1a and 1b), (-)-gnemonoside C (2), and (-)-gnemonoside D (3)] as well as a mixture of the two enantiomers of gnetin C (4) were isolated from the rhizomes of Gnetum africanum. The two enantiomers of gnetin C, (+)-4 and (-)-4, were obtained from the aglycones of 1a and 1b, respectively. The configurations of these stilbenoids were investigated by NMR and vibrational circular dichroism (VCD) experiments. The absolute configurations of (-)-1a, (-)-2, (-)-3, and (-)-4 were established as 7aS,8aS by VCD spectroscopy in combination with density functional theory calculations. The antiamyloidogenic activity of the isolated stilbenes was also evaluated versus beta-amyloid fibrils. The four glucosides of gnetin C (1a, 1b, 2, and 3) were found to be the most active compounds, with inhibition percentages of 56, 56, 58, and 54 at 10 µM, respectively.

Chiroptical properties of nona- and dodecamethoxy cryptophanes.

Enantiopure cryptophane derivatives bearing nine (2, 3) and 12 (4) methoxy substituents attached on the six aromatic rings were separated by HPLC using chiral stationary phases. The chiroptical properties of compounds 2-4 were determined from polarimetry, electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) experiments and were compared to those of cryptophane-A (1) derivative. ECD spectra of 1 and 4 were calculated by time-dependent density functional theory (TDDFT) to determine the absolute configuration (AC) of cryptophane derivatives. The (+)-PP absolute configuration was thus established for the anti-cryptophane-A (1) and its congeners 2 and 4. VCD experiments associated with DFT calculations confirmed the (+)-PP configuration of anti-compounds 2 and 4 and established the (+)-PM configuration of the syn-3 compound as well. This study revealed the preferential all-trans (TTT) conformation of the three ethylenedioxy linkers for the CHCl3@1, CHCl3@3, and CHCl3@4 complexes, whereas the GTT conformation was found the most favorable for the CHCl3@2 complex.

Raman optical activity of enantiopure cryptophanes.

Raman optical activity (ROA) and density functional theory (DFT) calculations were used to determine the absolute configuration of enantiopure cryptophane molecules and to obtain conformational information about their three ethylenedioxy linkers. ROA spectra recorded in chloroform solution for the two resolved enantiomers of cryptophanes derivatives bearing five (2), six (1), nine (3 and 4), and 12 (5) methoxy substituents are presented for the first time. The number of methoxy substituents (cryptophanes 1, 3, and 5) and the arrangement of the three linkers (anti for 3 and syn for 4) are two important parameters that significantly affect the ROA spectra. DFT calculations, at the B3PW91/6-31G** level, for cryptophane bearing six methoxy substituents establish, besides the absolute configuration, the preferential all-trans conformation of the ethylenedioxy linkers of the chloroform-cryptophane complex. This study shows that the ROA/DFT approach exhibits a higher selectivity for the conformation of the linkers than vibrational circular dichroism (VCD) associated with theoretical calculations.

Formation of a hydrogen-bonded barbiturate [2]-rotaxane.

Interlocked structures containing the classic Hamilton barbiturate binding motif comprising two 2,6-diamidopyridine units are reported for the first time. Stable [2]-rotaxanes can be accessed either through hydrogen-bonded preorganization by a barbiturate thread followed by a Cu(+)-catalyzed "click" stoppering reaction or by a Cu(2+)-mediated Glaser homocoupling reaction.

Influence of the cavity size of water-soluble cryptophanes on their binding properties for cesium and thallium cations.

The binding properties of water-soluble cryptophane 1 toward cesium and thallium cations, in basic solution, have recently been reported. In this Article, we show that water-soluble cryptophane-222 (2), cryptophane-223 (3), and cryptophane-233 (4), bearing zero, one, and two propylenedioxy linkers, respectively, also efficiently bind these two cations under similar experimental conditions. Their binding properties are thoroughly studied by (133)Cs and (205)Tl NMR spectroscopy, while the binding constants are determined by isothermal titration calorimetry (ITC) experiments under various experimental conditions. Complexation of cesium and thallium is also evidenced by electronic circular dichroism (ECD) using the enantiopure MM-2 compound. This study reveals that the cavity size of the cryptophane is not the main parameter to observe efficient binding. In contrast, the number of phenolate moieties surrounding the cryptophane backbone seems to be pivotal for the complexation of these two cations. These results are important in the field of detoxification.

Organocatalyzed aldol reaction between pyridine-2-carbaldehydes and α-ketoacids: a straightforward route towards indolizidines and isotetronic acids.

Enantioselective aldol reactions between substituted pyridine carbaldehydes and α-ketoacids were shown to provide isotetronic acids or their corresponding pyridinium salts, depending on the nature of the substituents on the pyridine ring. The pyridinium salts were generated through nucleophilic attack of the pyridine nitrogen atom onto the reactive keto functional group. Moderate-to-good yields of both compounds were typically obtained and high levels of enantioselectivity were observed by using benzimidazole pyrrolidine I as a catalyst. Hydrogenation of the resulting pyridinium salts led to new indolizidines with high ee values and diastereocontrol. X-ray diffraction studies allowed the determination of the relative configuration of the products. Finally, DFT calculations were performed to rationalize the divergent pathway as a function of the pyridine substituents.

Reversible control over molecular recognition in surface-bound photoswitchable hydrogen-bonding receptors: towards read-write-erase molecular printboards.

The synthesis of an anthracene-bearing photoactive barbituric acid receptor and its subsequent grafting onto azide-terminated alkanethiol/Au self-assembled monolayers by using an Cu(I) -catalyzed azide-alkyne reaction is reported. Monolayer characterization using contact-angle measurements, electrochemistry, and spectroscopic ellipsometry indicate that the monolayer conversion is fast and complete. Irradiation of the receptor leads to photodimerization of the anthracenes, which induces the open-to-closed gating of the receptor by blocking access to the binding site. The process is thermally reversible, and polarization-modulated IR reflection-absorption spectroscopy indicates that photochemical closure and thermal opening of the surface-bound receptors occur in 70 and 100 % conversion, respectively. Affinity of the open and closed surface-bound receptor was characterized by using force spectroscopy with a barbituric-acid-modified atomic force microscope tip.

Conformational equilibria of bridled chiroporphyrins in solution investigated by vibrational circular dichroism.

A series of bridled chiroporphyrins (BCP) and their metal complexes were prepared, in which two n-methylene straps connect adjacent meso substituents by ester linkages. These compounds can exist as four atropisomers (αααα, αßαß, αααß, or ααßß) depending on the position of the meso groups relative to the macrocycle (α when above and ß when below). We characterized the conformation of these chiral porphyrins and their metal (Zn, Ni, Mn) complexes by vibrational circular dichroism (VCD) associated with ab initio calculations. VCD spectra of the three metalloporphyrins were recorded in CDCl3 and benzene solutions and ab initio calculations of their four atropoisomers were performed at the Density Functional Theory (DFT) level. The bridled chiroporphyrin with the longer straps (9 CH2) and its nickel(II) complex can be isolated as the αßαß atropisomer in the solid state and were found with the same conformation in CDCl3 and benzene solutions. The bridled chiroporphyrin with the shortest straps (8 CH2) and its zinc(II) complex can be isolated as the αααα atropisomer in the solid state, but in solution they are subject to atropisomeric equilibria, resulting in atropisomer distributions that are strongly solvent-dependent. Comparison of the experimental VCD spectra with the predicted spectra of the four atropisomers allowed the quantification of these distributions. Finally, the manganese(III) complex also exhibits an atropisomeric equilibria in solution which is slightly solvent-dependent.

Synthesis of highly substituted cryptophane derivatives.

We report the synthesis of new cryptophane derivatives 1-4 bearing nine (1, 2) and twelve (3, 4) methoxy substituents. These compounds represent the first examples of cryptophane derivatives bearing more than six substituents attached on the benzene rings. The preparation of these highly substituted cryptophanes was achieved due to the synthesis of a new cyclotrisyringyl derivative obtained from the reaction of a protected syringyl alcohol in the presence of a catalytic amount of scandium triflate Sc(OTf)3. This reaction also provides the protected cyclotetrasyringyl derivative in low yield (7%), which was fully characterized by (1)H NMR, IR, and X-ray crystallography. In contrast to what is observed for the cryptophane-A congener, the synthesis of these highly substituted cryptophanes gives rise to the two anti- and syn-diastereomers. These compounds have been fully characterized, and their X-ray structures have been obtained to ascertain the stereochemistry of these new cryptophane derivatives.

Helix-forming propensity of aliphatic urea oligomers incorporating noncanonical residue substitution patterns.

Aliphatic N,N'-linked oligoureas are peptidomimetic foldamers that adopt a well-defined helical secondary structure stabilized by a collection of remote three-center H-bonds closing 12- and 14-membered pseudorings. Delineating the rules that govern helix formation depending on the nature of constituent units is of practical utility if one aims to utilize this helical fold to place side chains in a given arrangement and elaborate functional helices. In this work, we tested whether the helix geometry is compatible with alternative substitution patterns. The central -NH-CH(R)-CH2-NH-CO- residue in a model oligourea pentamer sequence was replaced by guest units bearing various substitution patterns [e.g., -NH-CH2-CH2-NH-CO-, -NH-CH2-CH(R)-NH-CO-, and -NH-CH(R(1))-CH(R(2))-NH-CO-], levels of preorganization (cyclic vs acyclic residues), and stereochemistries, and the helix formation was systematically assessed. The extent of helix perturbation or stabilization was primarily monitored in solution by Fourier transform IR, NMR, and electronic circular dichroism spectroscopies. Our results indicate that although three new substitution patterns were accommodated in the 2.5-helix, the helical urea backbone in short oligomers is particularly sensitive to variations in the residue substitution pattern (position and stereochemistry). For example, the trans-1,2-diaminocyclohexane unit was experimentally found to break the helix nucleation, but the corresponding cis unit did not. Theoretical calculations helped to rationalize these results. The conformational preferences in this series of oligoureas were also studied at high resolution by X-ray structure analyses of a representative set of modified oligomers.

Water-soluble molecular capsule for the complexation of cesium and thallium cations.

Binding properties of cesium and thallium cations by an enantiopure cryptophane derivative PP-1 have been investigated in water under basic conditions. The binding process has been evidenced using electronic circular dichroism (ECD), and binding constants of the Cs(+)@PP-1 and Tl(+)@PP-1 complexes have been determined from isothermal titration calorimetry (ITC) experiments in LiOH/H(2)O, NaOH/H(2)O, and KOH/H(2)O solutions. In addition, Tl(+)@PP-1 complex has been characterized for the first time by (205)Tl NMR spectroscopy. Cryptophane 1 exhibits an exceptionally high affinity for thallium and cesium cations in a large range of experimental conditions (nature, concentration of the counterion, and temperature). For example, binding constants as high as 2.9 × 10(9) M(-1) and 5.3 × 10(8) M(-1) have been measured by ITC at 298 K in NaOH/H(2)O (0.1 M) solution, for the Tl(+)@PP-1 and Cs(+)@PP-1 complexes, respectively. The high affinity of cryptophane 1 for Cs(+) and Tl(+) cations is preserved at higher LiOH, NaOH, and KOH concentrations and under extreme basic conditions, revealing the stability and the great selectivity of this supramolecular system toward Li(+), Na(+), and K(+) cations.

Synthetic studies toward C-glucosidic ellagitannins: a biomimetic total synthesis of 5-O-desgalloylepipunicacortein†A.

C-glucosidic ellagitannins constitute a subclass of bioactive polyphenolic natural products with strong antioxidant properties, as well as promising antitumoral and antiviral activities that are related to their capacity to interact with both functional and structural proteins. To date, most synthetic efforts toward ellagitannins have concerned glucopyranosic species. The development of a synthetic strategy to access C-glucosidic ellagitannins, whose characteristic structural feature includes an atropoisomeric hexahydroxydiphenoyl (HHDP) or a nonahydroxyterphenoyl (NHTP) unit that is linked to an open-chain glucose core by a C-aryl glucosidic bond, is described herein. The total synthesis of the biarylic HHDP-containing 5-O-desgalloylepipunicacortein A (1 ß) was achieved by either using the natural ellagic acid bis-lactone as a precursor of the requested HHDP unit or by implementing an atroposelective intramolecular oxidative biarylic coupling to forge this HHDP unit. Both routes converged in the penultimate step of this synthesis to enable a biomimetic formation of the key C-aryl glucosidic bond in the title compound.

High affinity of water-soluble cryptophanes for cesium cations.

Exceptionally high affinity for cesium cations was achieved in aqueous solution using two enantiopure cryptophanes. Complexation of cesium was evidenced by (133)Cs NMR spectroscopy and by electronic circular dichroism (ECD). Binding constants as high as 6 × 10(9) M(-1) have been measured by isothermal titration calorimetry (ITC). Very strong complexation of rubidium cations (K ~10(6) M(-1)) has also been measured. Chiral hosts allowed the detection of the two cations at low concentrations (µM) using ECD.

Influence of the chemical structure of water-soluble cryptophanes on their overall chiroptical and binding properties.

The synthesis and the chiroptical properties of the two enantiomers of the hexacarboxylic acid cryptophane-A derivative, 1, are described in this article. The chiroptical and binding properties of 1 toward achiral and chiral guests have been investigated in water under basic conditions by polarimetry, electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and (1)H NMR spectroscopy. These experiments reveal that the (1)H NMR spectra of 1 are very sensitive to the nature of the guest trapped in its cavity whereas ECD and VCD spectra remain unchanged. We also show that the two enantiomers of 1 are able to distinguish between the two enantiomers of a series of small chiral epoxides. The enantiodiscrimination increases with the size of the chiral guest whereas the corresponding binding constants decrease. In contrast to what was observed for other water-soluble cryptophanes, the molecular recognition process is found independent of the nature of the counterions surrounding host 1, shedding light on the importance of the chemical structure of cryptophanes on their binding and chiroptical properties.

Ab initio calculations of proline vibrations with and without water: consequences on the infrared spectra of proline-rich proteins.

The infrared spectra of proline-rich proteins display a strong band in the 1450 cm(-1) region. In the literature, this band has been assigned either to the deformation modes of the CH(2) and CH(3) groups or to the CN stretching mode of proline residues. In order to establish the correct assignment of this band, the impact of proline vibrations in a polypeptide chain is studied and ab initio calculations are performed for a model molecule (I) containing a repeat unit of polyproline. A strong band is effectively calculated in the 1450 cm(-1) region and mostly assigned to CN stretching, whereas, due to the absence of the N-H bond, there is no amide II band. These results are in good agreement with the spectral features observed in the Fourier transform infrared (FT-IR) spectra of gliadins. Moreover, the spectral shifts calculated when a water molecule is complexed with (I) are consistent with the hydration effect observed in the experimental data.

Enantioselective complexation of chiral propylene oxide by an enantiopure water-soluble cryptophane.

ECD and NMR experiments show that the complexation of propylene oxide (PrO) within the cavity of an enantiopure water-soluble cryptophane 1 in NaOH solution is enantioselective and that the (R)-PrO@PP-1 diastereomer is more stable than the (S)-PrO@PP-1 diastereomer with a free energy difference of 1.7 kJ/mol. This result has been confirmed by molecular dynamics (MD) and ab initio calculations. The enantioselectivity is preserved in LiOH and KOH solutions even though the binding constants decrease, whereas PrO is not complexed in CsOH solution.

Experimental and theoretical study of the vibrational spectra of oligoureas: helical versus ß-sheet-type secondary structures.

Ab initio calculations of two oligoureas stabilized in helix and sheet organization have been performed. The hydrogen bond distances were found to be almost the same for both structures. The vibrational assignment of the two oligourea structures and the direction of the transition moment of each vibration have been determined. From these results, and using the experimental isotropic optical index determined for one oligourea, we have established the anisotropic infrared optical files for the two structures. Interestingly, most urea absorptions vibrate in only one principal direction. Also, the shift of the carbonyl band is weaker and inverse to what was reported for corresponding protein secondary structures. Finally, simulations of the Polarization Modulation Infrared Reflection Absorption Spectroscopy (PMIRRAS) and Attenuated Reflection Spectroscopy (ATR) infrared spectra demonstrate the possibility to determine the orientation of the oligoureas in thin or ultrathin films, even if in some cases it may be difficult to unambiguously assign their secondary structure.

Conformational effects induced by guest encapsulation in an enantiopure water-soluble cryptophane.

A new water-soluble cryptophane 1 derivative (penta-hydroxyl cryptophane-A) has been synthesized from cryptophanol-A and the chiroptical properties of its two enantiomers MM-1 and PP-1 have been studied by polarimetry, electronic circular dichroism (ECD), and vibrational circular dichroism (VCD). Cryptophane 1 shows specific circular dichroism responses upon complexation that depend on the size of the guest and on the nature of the counterion (Li(+), Na(+), K(+), Cs(+)) present in the solution. In LiOH and NaOH solutions, chiroptical changes induced by the encapsulation of guests and by the presence of cations in the vicinity of hosts can be interpreted from molecular dynamics (MD) and ab initio calculations by subtle conformational changes of the bridges. In KOH solution, the exchange dynamics is dependent on the size of the guest molecules, whereas in CsOH solution no encapsulation effect is observed whatever the size of the guest molecule. This last behavior comes from the fact that host 1 exhibits a very high affinity for cesium cations.