Dual, Photo-Responsive and Redox-Active Supramolecular Foldamers.

We report on dual, light-responsive and redox-active foldamers that demonstrate reversible and robust stimuli-induced behaviour. Herein, UV/Vis, 1H NMR and circular dichroism (CD) spectroscopy and cyclic voltammetry have been used to establish the reversibility and highly robust nature of the light- and redox-driven behaviour of these new foldamers with minimal levels of fatigue observed even upon multiple cyclic treatments with irradiative/non-irradiative and oxidative/reductive conditions. This proof-of-concept work paves the way towards the creation of novel stimuli-responsive foldamers of increasing sophistication capable of demonstrating reversible and robust responses to multiple distinct stimuli.

Temperature-Induced Sign Inversion of Circularly Polarized Luminescence of Binaphthyl-Bridged Tetrathiapyrenophanes.

D2-symmetric (R)-binaphthyl-bridged pyrenophanes containing thioether bonds were synthesized. The pyrenophanes exhibited the temperature-induced sign inversion of circularly polarized luminescence (CPL) while maintaining the emission wavelength and reversibility. The Δglum value reached 0.02, and the FL quenching by heat was negligible. The sign inversion of CPL originates from the inversion of intramolecular excimer chirality associated with excitation dynamics. The two pyrenes form a kinetically trapped left-handed twist excimer at low temperatures, while they form a thermodynamically favored right-handed twist excimer at high temperatures. The thioether linkers can impart flexibility suitable for the inversion of chirality of the excimers.

Going Viral: An Investigation into the Chameleonic Behaviour of Antiviral Compounds.

The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d6 ) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as "partial molecular chameleons" and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption.

The Fluorescent Enzyme Cascade Detects Low Abundance Protein Modifications Suitable for the Assembly of Functionally Annotated Modificatome Databases.

Pathophysiological functions of proteins critically depend on both their chemical composition, including post-translational modifications, and their three-dimensional structure, commonly referred to as structure-activity relationship. Current analytical methods, like capillary electrophoresis or mass spectrometry, suffer from limitations, such as the detection of unexpected modifications at low abundance and their insensitivity to conformational changes. Building on previous enzyme-based analytical methods, we here introduce a fluorescence-based enzyme cascade (fEC), which can detect diverse chemical and conformational variations in protein samples and assemble them into digital databases. Together with complementary analytical methods an automated fEC analysis established unique modification-function relationships, which can be expanded to a proteome-wide scale, i. e. a functionally annotated modificatome. The fEC offers diverse applications, including hypersensitive biomarker detection in complex samples.

Synthesis, Structure, and Dynamics of Chiral Eight-Membered Cyclic Molecules with Thienylene and Cyclopropylene Units Alternately Connected.

A rhodium(II)-catalyzed asymmetric cyclooligomerization of bifunctional monomers possessing triazolyl and vinyl groups at 2,3- and 3,4-positions on the thiophene ring is studied. Structurally interesting cyclic dimers in which thienylene and cyclopropylene units are alternately connected are obtained as the major components. The eight-membered rings in the center are non-planar and adopt a tub-shaped conformation. We also observe the phenomenon of racemization caused by a tub-to-tub ring-flipping, the activation energy of which is determined as 108 kJ mol-1 by electronic circular dichroism spectra measurement.

α-Amino-iso-Butyric Acid Foldamers Terminated with Rhodium(I) N-Heterocyclic Carbene Catalysts.

To investigate how remotely induced changes in ligand folding might affect catalysis by organometallic complexes, dynamic α-amino-iso-butyric acid (Aib) peptide foldamers bearing rhodium(I) N-heterocyclic carbene (NHC) complexes have been synthesized and studied. X-ray crystallography of a foldamer with an N-terminal azide and a C-terminal Rh(NHC)(Cl)(diene) complex showed a racemate with a chiral axis in the Rh(NHC) complex and a distorted 310 helical body. Replacing the azide with either one or two chiral L-α-methylvaline (L-αMeVal) residues gave diastereoisomeric foldamers that each possessed point, helical and axial chirality. NMR spectroscopy revealed an unequal ratio of diastereoisomers for some foldamers, indicating that the chiral conformational preference of the N-terminal residue(s) was relayed down the 1 nm helical body to the axially chiral Rh(NHC) complex. Although the remote chiral residue(s) did not affect the stereoselectivity of hydrosilylation reactions catalysed by these foldamers, these studies suggest a potential pathway towards remote conformational control of organometallic catalysts.

Ruthenium Complexes Bearing Axially Chiral Bipyridyls: The Mismatched Diastereomer Showed Red Circularly Polarized Phosphorescence.

RutheniumII complexes bearing three axially chiral bipyridyl ligands were synthesized as a new family of chiral complex dyes, and Δ-(S)- and Λ-(S)-diastereomers were obtained. The X-ray crystal structure analyses, spectroscopy, and DFT calculations suggested that all the bipyridyls maintained chirality in both the ground and excited states, and the Δ-(S)- and Λ-(S)-isomers are the matched (more relaxed) and mismatched (more constrained) pairs, respectively. The mismatched Λ-(S)-isomer exhibited red circularly polarized phosphorescence (CPP) both in solution and in the solid state. The solution state CPP is the most intense of ruthenium complexes, while the solid state CPP is the first example of them. It is supposed that, for the Λ-(S)-isomer, the six cumulative CH/π interactions suppress further distortion in the T1 state.

Synthesis, Structures, and Properties of Helically Fused Anthraquinones with Unusually Close Carbonyl-Carbonyl Contacts.

Electron-deficient aromatic ketones consisting of three fused anthraquinone units were synthesized by oxidation of the corresponding fused anthracenes. X-ray analysis revealed that these compounds had nonplanar helical structures with unusual contacts, C=O⋅⋅⋅C=O 2.467 Å, between the inner carbonyl groups. The role of n⋅⋅⋅π* interactions in the short contacts was evaluated using a noncovalent interaction plot and natural bond orbital analysis. The dynamic process involving helical inversion was observed by the variable temperature 1 H NMR measurement of a derivative with 2,4,6-trimethylphenyl groups, and the barrier was estimated to be 77 kJ mol-1 . DFT calculations indicated that the helical inversion proceeded via a multistep mechanism. The characteristic spectroscopic and electrochemical data due to the electron-deficient anthraquinone units and the sterically congested carbonyl groups are discussed with the aid of DFT calculations.

Characterization of Asx Turn Types and Their Connate Relationship with ß-Turns.

Models of asparagine-containing dipeptides specifically designed to favor intrinsic folding into an Asx turn were characterized both theoretically, by using quantum chemistry, and experimentally, by using laser spectroscopy in the gas phase. Both approaches provided evidence for the spontaneous folding of both the Asn-Ala and Asn-Gly dipeptide models into the most stable Asx turn, a conformation stabilized by a C10 H-bond that was very similar to a type II' ß-turn. In parallel, analysis of Asx turns implicating asparagine in crystallized protein structures in the Protein Data Bank revealed a sequence-dependent behavior. In Asn-Ala sequences, the Asx turn was found in conjunction with a type I ß-turn for which the first of the four defining residues was Asn. The observation that the Asx turn in these structures is mostly of type II' (i. e., its most stable innate structure) suggests that this motif might foster the formation and/or enhance the stability of the backbone ß-turn. In contrast, the Asx turns observed in Asn-Gly sequences extensively adopted a type II Asx-turn structure, thus suggesting that their formation should be ascribed to other factors, such as hydration. The fact that the Asx turn in a Asn-Gly sequence is also often found in combination with a hydrated ß-bulge supports the premise that a Asn-Gly sequence might efficiently promote the formation of the ß-bulge secondary structure.

The Use of Bridging Ligand Substituents to Bias the Population of Localized and Delocalized Mixed-Valence Conformers in Solution.

The electronic structure and associated spectroscopic properties of ligand-bridged, bimetallic 'mixed-valence' complexes of the general form {M}(µ-B){M+ } are dictated by the electronic couplings, and hence orbital overlaps, between the metal centers mediated by the bridge. In the case of complexes such as [{Cp*(dppe)Ru}(µ-C≡CC6 H4 C≡C){Ru(dppe)Cp*}]+ , the low barrier to rotation of the half-sandwich metal fragments and the arylene bridge around the acetylene moieties results in population of many energy minima across the conformational energy landscape. Since orbital overlap is also sensitive to the particular mutual orientations of the metal fragment(s) and arylene bridge through a Karplus-like relationship, the different members of the population range exemplify electronic structures ranging from strongly localized (weakly coupled Robin-Day Class II) to completely delocalized (Robin-Day Class III). Here, we use electronic structure calculations with the hybrid density functional BLYP35-D3 and a continuum solvent model in combination with UV-vis-NIR and IR spectroelectrochemical studies to show that the conformational population in complexes [{Cp*(dppe)Ru}(µ-C≡CArC≡C){Ru(dppe)Cp*]+ , and hence the dominant electronic structure, can be biased through the steric and electronic properties of the diethynylarylene (Ar) moiety (Ar=1,4-C6 H4 , 1,4-C6 F4 , 1,4-C6 H2 -2,5-Me2 , 1,4-C6 H2 -2,5-(CF3 )2 , 1,4-C6 H2 -2,5-i Pr2 ).

Exhaustive Conformational Search for Sialyl Cation Reveals Possibility of Remote Participation of Acyl Groups.

Finding convenient ways for the stereoselective α-sialylation is important due to the high practical significance of α-sialic acid-containing glycans and neoglycoconjugates. It was proposed that sialylation stereoselectivity is determined by the structure of the sialyl cation (also known in biochemistry as "sialosyl cation"), a supposed intermediate in this reaction. Here we design a new approach for studying the conformational space of highly flexible sialyl cation and find 1625 unique conformers including those stabilized by covalent remote participation (also known as long-range participation) of 4-O-acetyl (4-OAc), 5-N-trifluoroacetyl (5-NTFA), as well as 7,8,9-OAc from both α and ß sides. The most energetically stable sialyl cation conformers are featured by 4-OAc participation, closely followed by 5-NTFA- and 7-OAc-stabilized conformers; unstabilized sialyl cation conformers are ∼10 kcal mol-1 less stable than the 4-OAc-stabilized ones. Analysis of all the obtained conformers by means of substituents positions, side chain conformations and ring puckering led us to a new "eight-conformer hypothesis" which describes interconversions among the most important sialyl cation conformers and predicts that stronger remote participation of acyl groups favors ß-anomers. Thus, selective synthesis of the desired α-sialosides requires minimization of acyl groups participation.

Design and synthesis of fluorinated peptides for analysis of fluorous effects on the interconversion of polyproline helices.

The unique interaction between fluorine atoms has been exploited to alter protein structures and to develop synthetic and analytical applications. To expand such fluorous interaction for novel applications, polyproline peptides represent an excellent molecular nanoscaffold for controlling the presentation of perfluoroalkyl groups on their unique secondary structure. We develop approaches to synthesis fluorinated peptides to systematically investigate how the number, location and types of the fluorous groups on polyproline affect the conformation by monitoring the transition between the two major polyproline structures PPI and PPII. This work provides valuable information on how fluorous interaction affects the peptide structure and also benefits the design of functional fluorous molecules.

Sulfur-Doped Quintuple [9]Helicene with Azacorannulene as Core.

Herein, a hetero(S,N)-quintuple [9]helicene (SNQ9H) molecule with an azacorannulene core was synthesized, currently representing the highest hetero-helicene reported in the field of multiple [n]helicenes. X-ray crystallography indicated that SNQ9H includes not only a propeller-shaped conformer SNQ9H-1, but also an unforeseen quasi-propeller-shaped conformer SNQ9H-2. Different conformers were observed for the first time in multiple [n≥9]helicenes, likely owing to the doping of heteroatomic sulfurs in the helical skeletons. Remarkably, the ratio of SNQ9H-1 to SNQ9H-2 can be regulated in situ by the reaction temperature. Experimental studies on the photophysical and redox properties of SNQ9H and theoretical calculations clearly demonstrated that the electronic structures of SNQ9H depend on their molecular conformations. The strategy of introducing heteroatomic sulfurs into the helical skeleton may be useful in constructing various conformers of higher multiple [n]helicenes in the future.

Binaphthyl-Bridged Pyrenophanes: Intense Circularly Polarized Luminescence Based on a D2 Symmetry Strategy.

A series of D2 -symmetric macrocycles composed of alternately linked pyrene and binaphthyl moieties (binaphthyl-bridged pyrenophanes) have been synthesized. Among them, a pyrenophane possessing ether linkers at the 2,7-positions of the pyrenes exhibited intense circularly polarized luminescence (CPL) with a |glum | value of 0.053. This value is by far the highest for excimers and was not sensitive to temperature, solvent, or concentration. The CPL originated from a twisting pyrene excimer, with the (R)-binaphthyl moieties producing a left-handed twist excimer, which exhibited (-)-CPL. The electric and magnetic transition dipole moments are perfectly parallel, which is the best relationship for strong CPL.

A Rapid and Mild Sulfation Strategy Reveals Conformational Preferences in Therapeutically Relevant Sulfated Xylooligosaccharides.

Although sulfated xylooligosaccharides are promising therapeutic leads for a multitude of afflictions, the structural complexity and heterogeneity of commercially deployed forms (e. g. Pentosan polysulfate 1) complicates their path to further clinical development. We describe herein the synthesis of the largest homogeneous persulfated xylooligomers prepared to date, comprising up to eight xylose residues, as standards for biological studies. Near quantitative sulfation was accomplished using a remarkably mild and operationally simple protocol which avoids the need for high temperatures and a large excess of the sulfating reagent. Moreover, the sulfated xylooligomer standards so obtained enabled definitive identification of a pyridinium contaminant in a sample of a commercially prepared Pentosan drug and provided significant insights into the conformational preferences of the constituent persulfated monosaccharide residues. As the spatial distribution of sulfates is a key determinant of the binding of sulfated oligosaccharides to endogenous targets, these findings have broad implications for the advancement of Pentosan-based treatments.

Oligo-Quinolylene-Vinylene Foldamers.

Quinoline based aromatic amide foldamers are known to adopt stable folded conformations. We have developed a synthetic approach to produce similar oligomers where all amide bonds, or part of them, have been replaced by an isosteric vinylene group. The results of solution and solid state structural studies show that oligomers exclusively containing vinylene linkages are not well folded, and adopt predominantly flat conformations. In contrast, a vinylene segment flanked by helical oligoamides also folds in a helix, albeit with a slightly lower curvature. The presence of vinylene functions also result in an extension of π-conjugation across the oligomer that may change charge transport properties. Altogether, these results pave the way to foldamers in which both structural control and specific electronic properties may be engineered.

Five Step Total Synthesis of Lythranidine.

A concise synthesis of the alkaloid lythranidine is reported. The strategy exploits the target's local C2 symmetry by adopting a two directional synthetic approach, first in an acyclic environment, then in a cyclic system and finally in a bridged macrocyclic domain. The latter phase of the synthesis, which installs all four stereocenters, involves a thermodynamically controlled, twofold intermolecular/transannular aza-Michael addition and a twofold hydride reduction. The synthesis is one third of the length of the most step-economic previous approach, providing access to gram quantities of the natural product. The broad-spectrum nature of the synthesis is demonstrated through the preparation of three diastereomeric analogues of the natural product.

Dynamics of Meso-Chiral Interconversion in a Butterfly-Shape Overcrowded Alkene Rotor Tunable by Solvent Properties.

Elucidation of dynamics of molecular rotational motion is an essential part and challenging area of research. We demonstrate reversible diastereomeric interconversion of a molecular rotor composed of overcrowded butterfly-shape alkene (FDF). Its inherent dual rotatory motion (two rotors, one stator) with interconversion between two diastereomers, chiral trans-FDF and meso cis-FDF forms, has been examined in detail upon varying temperatures and solvents. The free energy profile of 180° revolution of one rotor part has a bimodal shape with unevenly positioned maxima (transition states). FDF in aromatic solvents adopts preferentially meso cis-conformation, while in non-aromatic solvents a chiral trans-conformation is more abundant owing to the solvent interactions with peripheral hexyl chains (solvophobic effect). Moderate correlations between the trans-FDF/cis-FDF ratio and solvent parameters, such as refractive index, polarizability, and viscosity were found.

Circularly Polarized Luminescence Liquids Based on Siloxybinaphthyls: Best Binaphthyl Dihedral Angle in the Excited State.

A series of axially chiral 1,1'-binaphthyls with trialkylsiloxy (OSiR3 ) groups were synthesized. Among them, 1 a-c possessing OSiR3 groups at the 7,7'-positions and methyl groups at the 2,2'-positions were liquids at room temperature, and the neat liquids showed circularly polarized luminescence (CPL) (R=Bu; Φfl,liquid =0.21, |glum,liquid |=1.6×10-3 ). The |glum,liquid | value is the highest of pure liquids. These compounds remained liquid over a broad range of temperatures, down to -50 °C. Time-dependent DFT calculations indicated that in the excited state, the binaphthyls adopt a transoid conformation with a small angle between the electric and magnetic transition dipole moments (θµ,m =77°), which is a key factor in their CPL activity. The best binaphthyl dihedral angle in the excited state is approximately 110°.

Isoindoline-Based Nitroxides as Bioresistant Spin Labels for Protein Labeling through Cysteines and Alkyne-Bearing Noncanonical Amino Acids.

Electron paramagnetic resonance (EPR) spectroscopy in combination with site-directed spin labeling (SDSL) is a powerful tool in protein structural research. Nitroxides are highly suitable spin labeling reagents, but suffer from limited stability, particularly in the cellular environment. Herein we present the synthesis of a maleimide- and an azide-modified tetraethyl-shielded isoindoline-based nitroxide (M- and Az-TEIO) for labeling of cysteines or the noncanonical amino acid para-ethynyl-l-phenylalanine (pENF). We demonstrate the high stability of TEIO site-specifically attached to the protein thioredoxin (TRX) against reduction in prokaryotic and eukaryotic environments, and conduct double electron-electron resonance (DEER) measurements. We further generate a rotamer library for the new residue pENF-Az-TEIO that affords a distance distribution that is in agreement with the measured distribution.