Synthesis and NMR Analysis in Solution of Oligo(3‐hydroxyalkanoic acid) Derivatives with the Side Chains of Alanine,Valine, and Leucine (β‐Depsides): Coming Full Circle from PHB to β‐Peptides to PHB

Oligomers of 3‐hydroxyalkanoic acids that contain two, three, and six residues with and without O‐terminal (tBu)Ph₂Si and C‐terminal PhCH₂ protection have been synthesized in such a way that the side chains on the oligoester backbone were those of the proteinogenic amino acids Ala (Me), Val (CHMe₂), and Leu (CH₂CHMe₂). The enantiomerically pure 3‐hydroxyalkanoates were obtained by Noyori hydrogenation of the corresponding 3‐oxo‐alkanoates with [Ru((R)‐binap)Cl₂](binap=2,2′bis(diphenylphosphanyl)‐1,1′‐binaphthalene)/H₂ (Scheme 1), and the coupling was achieved under the conditions (pyridine/(COCl)₂, CH₂Cl₂, −78°) previously employed for the synthesis of various oligo(3‐hydroxybutanoic acids) (Schemes 2 and 3). The Cotton effects in the CD spectra of the new oligoesters provided no hints about chiral conformation (cf. a helix) in MeOH, MeCN, octan‐1‐ol, or CF₃CH₂OH solutions (Figs. 1 and 2). Detailed NMR investigations in CDCl₃ solution (Figs. 3–6, and Tables 1–5) of the hexa(3‐hydroxyalkanoic acid) with the side chains of Val (HC), Ala (HB), Leu (HH), Val, Ala, Leu (from O‐ to C‐terminus; 3 ) gave, on the NMR time‐scale, no evidence for the presence of any significant amount of a 2₁‐ or a 3₁‐helical conformation, comparable to those identified in stretched fibers of poly[(R)‐3‐hydroxybutanoic acid], or in lamellar crystallites and in single crystals of linear and cyclic oligo[(R)‐3‐hydroxybutanoic acids], or in the corresponding β‐peptide(s) (the oligo(3‐aminoalkanoic acid) analogs; 1 – 3 ). Thus, the extremely high flexibility (averaged or ‘random‐coil' conformation) of the polyester chain (CO−O rotational barrier ca. 13 kcal/mol; no hydrogen bonding), as compared to polyamide chains (CO−NH barrier ca. 18 kcal/mol; hydrogen bonding) has been demonstrated once again. The possible importance of this structural flexibility, which goes along with amphiphilic properties, for the role of PHB in biology, in evolution, and in prebiotic chemistry is discussed. Structural similarities of natural potassium‐channeling proteins and complexes of oligo(3‐hydroxybutanoates) with Na⁺, K⁺, or Ba²⁺ are alluded to (Figs. 7–9).     

Synthesis of macromonomers bearing hydrolyzable segments derived from α‐hydroxyalkanoic acids

Methacrylic macromonomers bearing hydrolyzable oligoester segments are prepared by derivatization of oligo(α‐hydroxyalkanoic acids) (obtained by thermal polycondensation) with methacrylic acid and copolymerized with tert‐butyl acrylate.     

A Novel Route to α,ω‐Bis(acrylamidopeptide)‐Terminated Oligo(ethylene oxide) and Hydrogels

A new family of α,ω‐bis(acrylamidopeptide)‐terminated macromonomers were prepared via the ring‐opening addition of 4,4‐dimethyl‐2‐vinyl‐ and 2‐isopropenyl‐4,4‐dimethyl‐oxazol‐5‐on to α,ω‐diamine‐terminated poly(ethylene oxide). These macromonomers were used to produce hydrogels by means of thermally induced free‐radical polymerization. Swelling behavior and mechanical properties of the resulting hydrogels were influenced by the macromonomer type and the crosslinking density, as reflected by the equilibrium water uptake.     

Conformational Dynamics of the Single Lipopolysaccharide O‐Antigen in Solution

The O‐antigen is the most variable and highly immunogenic part of the lipopolysaccharide molecule that covers the surface of Gram‐negative bacteria and makes up the first line of cellular defense. To provide insight into the details of the O‐antigen arrangement on the membrane surface, we simulated its behavior in solution by molecular dynamics. We developed the energetically favorable O‐antigen conformation by analyzing free‐energy distributions for its disaccharide fragments. Starting from this conformation, we simulated the behavior of the O‐antigen chain on long timescales. Depending on the force field and temperature, the single molecule can undergo reversible or irreversible coil‐to‐globule transitions. The mechanism of these transitions is related either to the rotation of the carbohydrate residues around O‐glycosidic bonds or to flips of the pyranose rings. We found that the presence of rhamnose in the O‐antigen chain crucially increases its conformational mobility.     

A Combined QM/MM Molecular Dynamics Simulations Study of Nitrate Anion (NO3‐) in Aqueous Solution.

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On the Solution Structure of PHB: Preparation and NMR Analysis of Isotopically Labeled Oligo[(R)‐3‐hydroxybutanoic Acids] (OHBs)

While the chain conformation of poly‐ and oligo[(R)‐3‐hydroxybutanoate] (PHB, OHB) is known to be 2₁‐ and 3₁‐helical in stretched fibers and in the crystalline state, respectively (Fig. 2), the structure in solution is unknown. To be able to determine the NMR‐solution structure, specifically labeled linear oligomers have been prepared: a 16‐mer consisting of alternating pairs of fully ¹³C‐labeled and non‐labeled residues ( 1 ) and a 20‐mer containing an O‐¹³CH(¹³CH₂D)‐¹³CHD^Si‐¹³CO residue in position 9 (from the O‐terminus) and a fully ¹³C‐labeled residue in position 12 ( 2 ), both with (t‐Bu)Ph₂Si protection at the O‐ and Bn protection at the C‐terminus. The labeled (R)‐3‐hydroxybutanoic acid building blocks were prepared by Noyori hydrogenation of the ethyl ester of fully ¹³C‐labeled acetoacetic acid, and the D‐atoms were incorporated by D₂/Pd‐C reduction of a previously reported dibromo‐1,3‐dioxinone 8 (Scheme 1). The oligomers were obtained by a series of fragment couplings (Schemes 2 and 3). 600‐MHz NMR COSY, HSQC, ROESY, and cross‐correlated relaxation measurements (Figs. 4 – 6, 9, and 12, and Tables 1 – 3) at different temperatures and interpretations thereof led to assignments of all resonances, including those from the diastereotopic C(2)H₂ protons, and to determination of the conformationally averaged dihedral angles ϕ₂ and ϕ₃ (Figs. 2, 7, and 8) in the chain of the oligoester. The conclusions are: all but five or six terminal residues adopt the same conformation; the 2₁ helix is not the predominant secondary structure; the structure of the HB chain is averaged, even at –30°. Our investigation confirms the high flexibility of the polyester chain, a property that has been deduced previously from biological studies of PHB in membranes, in ion channels, and as appendage of proteins.     

Berberine/γ‐Cyclodextrin Inclusion Structure Studied by 1H‐NMR Spectroscopy and Molecular‐Dynamics Calculations

To understand the increased solubility and decreased bitter taste of berberine, a clinically important isoquinoline alkaloid, in the presence of cyclodextrins, the interaction with γ‐cyclodextrin (γ‐CD) in aqueous solution was studied by a combination of ¹H‐NMR analyses and molecular‐dynamics calculations. The proposed complexation mode of berberine by γ‐CD could explain the increased solubility in water. No difference in germicidal activity between berberine alone and its inclusion complex with γ‐ or β‐CD was observed, which is important to further develop the pharmacological application of berberine.     

Conformational Preferences of a β‐Octapeptide as Function of Solvent and Force‐Field Parameters

The ability to design properly folded β‐peptides with specific biological activities requires detailed insight into the relationship between the amino acid sequence and the secondary and/or tertiary structure of the peptide. One of the most frequently used spectroscopic techniques for resolving the structure of a biomolecule is NMR spectroscopy. Because only signal intensities and frequencies are recorded in the experiment, a conformational interpretation of the recorded data is not straightforward, especially for flexible molecules. The occurrence of conformational and/or time averaging, and the limited amount and accuracy of experimental data hamper the precise conformational determination of a biomolecule. In addition, the relation between experimental observables with the underlying conformational ensemble is often only approximately known, thereby aggravating the difficulty of structure determination of biomolecules. The problematic aspects of structure refinement based on NMR nuclear Overhauser effect (NOE) intensities and ³J‐coupling data are illustrated by simulating a β‐octapeptide in explicit MeOH and H₂O as solvents using three different force fields. NMR Data indicated that this peptide would fold into a 3₁₄‐helix in MeOH and into a hairpin in H₂O. Our analysis focused on the conformational space visited by the peptide, on structural properties of the peptide, and on agreement of the MD trajectories with available NMR data. We conclude that 1) although the 3₁₄‐helical structure is present when the peptide is solvated in MeOH, it is not the only relevant conformation, and that 2) the NMR data set available for the peptide, when solvated in H₂O, does not provide sufficient information to derive a single secondary structure, but rather a multitude of folds that fulfill the NOE data set.     

Crystalline morphology and thermal properties for random copolyesters of (R)‐3‐hydroxybutyric acid with different hydroxyalkanoic groups

The solid‐state structures and thermal properties of melt‐crystallized films of random copolymers of (R)‐3‐hydroxybutyric acid (3HB) with different hydroxyalkanoic acids such as (R)‐3‐hydroxypentanoic acid (3HV), (R)‐3‐hydroxyhexanoic acid (3HH), medium‐chain‐length (R)‐3‐hydroxyalkanoic acids (mcl‐3HA; C8‐C12), 4‐hydroxybutyric acid (4HB), and 6‐hydroxyhexanoic acid (6HH) were characterized by means of small‐angle X‐ray scattering, differential scanning calorimetry, and optical microscopy. The randomly distributed second monomer units except for 3HV in copolyesters act as defects of P(3HB) crystal and are excluded from the P(3HB) crystalline lamellae. The lamellar thickness of copolymers decreased with an increase in either the main‐chain or the side‐chain carbon numbers of second monomer units. In addition, the growth rate of spherulites decreased with an increase in the carbon numbers of second monomer units for copolymers with an identical comonomer composition. These results indicate that the steric bulkiness of second monomer unit affects on the crystallization of 3HB segments in random copolyesters.     

Conformational Polymorphism in N‐(4′‐methoxyphenyl)‐ 3‐bromothiobenzamide

Three conformational polymorphs of N‐(4′‐methoxyphenyl)‐3‐bromothiobenzamide, yellow α, orange β, and yellow γ, have been identified by single‐crystal X‐ray diffraction. The properties and structure of the polymorphs were examined with FT Raman, FTIR (ATR), and UV/Vis spectroscopy, as well as differential scanning calorimetry. Computational data on rotational barriers in the isolated gas‐phase molecule indicate that the molecular conformation found in the α form is energetically preferred, but only by around 2 kJ mol^?1 over the γ conformation. The planar molecular structure found in the β form is destabilized by 10–14 kJ mol^?1, depending on the calculation method. However, experimental evidence suggests that the β polymorph is the most stable crystalline phase at room temperature. This is attributed to the relative planarity of this structure, which allows more and stronger intermolecular interactions, that is, more energetically effective packing. Calculated electronic‐absorption maxima were in agreement with experimental spectra.     

Temperature‐Responsive Chiral (A)6B Supramolecular Cages Based on Conformational Preferences

Two chiral (A)₆B‐typed supramolecular cages were constructed from hydrogen‐bonded C₆‐symmetric zinc porphyrin hexamers and chiral C₃‐symmetric pyridyl hexadentates with a core of 1,3,5‐triphenylbenzene. Circular dichroism and molecular simulations revealed that the symmetry of the supramolecular cages switched from pseudo‐C_3v to C₃ with the rotational confinement of the biphenyl backbones at low temperatures, which generated conformationally chiral transfer and amplification. This unique phenomenon suggests a new strategy to develop smart materials with high sensitivity and excellent reversibility.     

Poly(2‐vinylpyridine)‐block ‐Poly(ϵ‐caprolactone) Single Crystals in Micellar Solution

Self‐assembly of poly(2‐vinylpyridine)‐block‐poly(ϵ‐caprolactone) (P2VP‐b‐PCL) diblock copolymer in the presence of a selective solvent is investigated by transmission electron microscopy and atomic force microscopy. Addition of water into a P2VP‐b‐PCL solution in N,N‐dimethylformamide at 20 °C produces elongated truncated lozenge shaped single crystals of uniform size and shape in large quantities. The single crystals are composed of PCL single‐crystal layer sandwiched between two P2VP layers tethered on the top and bottom basal surfaces. The formation of the single crystals is found to depend on the temperature. These findings provide a facile approach to the preparation of uniform single crystals in large quantities.

     

A Conformational Study of Cyclohexane‐1,3,5‐tricarbonitrile Derivatives

Cyclohexane‐1,3,5‐tricarbonitrile reached equilibrium having 1,3‐cis‐1,5‐cis and 1,3‐cis‐1,5‐trans isomers in a ratio of 3:7. The cis, cis‐isomer preferred the conformation with three equatorial cyano groups, where as the cis, trans‐isomer displayed two cyano groups on equatorial positions and another cyano group on axial position. Condensation of cis, cis‐cyclohexane‐1,3,5‐tricarbonitrile with L‐(S)‐valinol by the catalysis of ZnCl₂ in refluxing 1,2‐dichlorobenzene afforded two isomeric cyclohexane‐1,3,5‐trioxazolines in favor of the 1,3‐cis‐1,5‐trans isomer. Metalation of cis, cis‐cyclohexane‐1,3,5‐tricarbonitrile, followed by alkylations with dimethyl sulfate, benzyl bromide or allyl bromide, gave the cor responding trialkylation products with predominance of 1,3‐cis‐1,5‐trans isomers. The cis, trans‐isomer showed two cyano groups on axial positions and another cyano group on equatorial position, where as the cis, cis‐isomer exhibited three axial cyano groups. Treatment of trimethyl cis, cis‐cyclohexane‐1,3,5‐tricarboxylate with lithium diisopropylamide and dimethyl sulfate afforded mainly the trimethyl ester of Kemp's triacid, which showed three axial carboxylate groups. Two competitive factors, i.e. the steric effect of in coming electrophiles and the dipole‐dipole inter actions of the cyano or carboxylate groups, might inter play to give different stereoselectivities in these reaction systems.     

Inherent Conformational Preferences of Ac‐Gln‐Gln‐NHBn: Sidechain Hydrogen Bonding Supports a β‐Turn in the Gas Phase

Gas‐phase single‐conformation spectroscopy is used to study Ac‐Gln‐Gln‐NHBn in order to probe the interplay between sidechain hydrogen bonding and backbone conformational preferences. This small, amide‐rich peptide offers many possibilities for backbone–backbone, sidechain–backbone, and sidechain–sidechain interactions. The major conformer observed experimentally features a type‐I β‐turn with a canonical 10‐membered ring C=O—H?N hydrogen bond between backbone amide groups. In addition, the C=O group of each Gln sidechain participates in a seven‐membered ring hydrogen bond with the backbone NH of the same residue. Thus, sidechain hydrogen‐bonding potential is satisfied in a manner that is consistent with and stabilizes the β‐turn secondary structure. This turn‐forming propensity may be relevant to pathogenic amyloid formation by polyglutamine segments in human proteins.     

Folding and Aggregation of Cationic Oligo(aryl‐triazole)s in Aqueous Solution

Cationic aryl triazole oligomers have been synthesized through “click chemistry”. The results show that cationic aryl triazole oligomers adopt a helical conformation in water or in a mixture of water and methanol, but prevail as a random‐coiled conformation in methanol. Importantly, circular dichroism spectroscopy and dynamic light scattering experiments revealed that cationic oligomers aggregated intermolecularly to form higher order architectures with a helical sense opposite to that of the individual helix, which eventually led to the formation of aggregates with sizes in the range 100–500 nm. The aggregation of cationic oligomers was governed by the concentration and polarity of the environment. More interestingly, cationic foldamers were able to recognize chloride and fluoride anions in aqueous solution. The recognition consequently destabilized intermolecular aggregation.     

Behavior of 3(2‐pyridinylmethylene)‐5‐aryl‐2(3H)‐furanones and 3(3‐pyridinylmethylene)‐5‐aryl‐2(3H)‐furanones as alkylating agents: A comparative study

3(2‐pyridinylmethylene)‐5‐aryl‐2(3H)‐furanones and 3(3‐pyridinylmethylene)‐5‐aryl‐2(3H)‐furanones were prepared as a mixture of (E) and (Z) stereoisomers by condensing pyridine‐2‐carboxaldehyde and pyridine‐3‐carboxaldehyde with 3‐aroylpropionic acids. The reaction of the furanones 6 and 7 with anhydrous aluminium chloride in benzene led to the formation of 4,4‐diaryl‐1‐(2‐pyridinyl)but‐1,3‐diene ( 8 ) and 4,4‐diaryl‐1‐(3‐pyridinyl)but‐1,3‐diene ( 9 ) as mixtures of geometrical (E,E‐ and E,Z‐) stereoisomers via an intermolecular alkylation mode. When the reaction was carried out in tetrachloroethane as a solvent, the reaction of 6 gave 5‐arylquinoline‐7‐carboxylic acid via intramolecular alkylation mode. This may be considered as a novel method for the synthesis of quinoline derivatives. J. Heterocyclic Chem., (2011).     

A Structural Study of the Solid Solution Eu2(Mo1‐xWx)3O12

A structural study by means of X‐ray and electron diffraction of intermediate oxides between Eu₂Mo₃O₁₂ and Eu₂W₃O₁₂ shows the existence of a new Eu₂(Mo_1?xW_x)₃O₁₂ solid solution with the scheelite structural type. The essential feature of the x = 1/3 and x = 2/3 compounds is the presence of isolated oxygen tetrahedra, in which, according to X‐ray and electron diffraction data, W and Mo are randomly distributed. Eu atoms occupy distorted square antiprisms sites.