4C1 Conformation Research Articles

Methyl Internal Rotation in Fruit Esters: Chain-Length Effect Observed in the Microwave Spectrum of Methyl Hexanoate.

The gas-phase structures of the fruit ester methyl hexanoate, CH3-O-(C=O)-C5H11, have been determined using a combination of molecular jet Fourier-transform microwave spectroscopy and quantum chemistry. The microwave spectrum was measured in the frequency range of 3 to 23 GHz. Two conformers were assigned, one with Cs symmetry and the other with C1 symmetry where the γ-carbon atom of the hexyl chain is in a gauche orientation in relation to the carbonyl bond. Splittings of all rotational lines into doublets were observed due to internal rotation of the methoxy methyl group CH3-O, from which torsional barriers of 417 cm−1 and 415 cm−1, respectively, could be deduced. Rotational constants obtained from geometry optimizations at various levels of theory were compared to the experimental values, confirming the soft degree of freedom of the (C=O)-C bond observed for the C1 conformer of shorter methyl alkynoates like methyl butyrate and methyl valerate. Comparison of the barriers to methyl internal rotation of methyl hexanoate to those of other CH3-O-(C=O)-R molecules leads to the conclusion that though the barrier height is relatively constant at about 420 cm−1, it decreases in molecules with longer R.

Multimeric structure enables the acceleration of KaiB-KaiC complex formation induced by ADP/ATP exchange inhibition.

Circadian clocks tick a rhythm with a nearly 24-hour period in a variety of organisms. In the clock proteins of cyanobacteria, KaiA, KaiB, and KaiC, known as a minimum circadian clock, the slow KaiB-KaiC complex formation is essential in determining the clock period. This complex formation, occurring when the C1 domain of KaiC hexamer binds ADP molecules produced by the ATPase activity of C1, is considered to be promoted by accumulating ADP molecules in C1 through inhibiting the ADP/ATP exchange (ADP release) rather than activating the ATP hydrolysis (ADP production). Significantly, this ADP/ATP exchange inhibition accelerates the complex formation together with its promotion, implying a potential role in the period robustness under environmental perturbations. However, the molecular mechanism of this simultaneous promotion and acceleration remains elusive because inhibition of a backward process generally slows down the whole process. In this article, to investigate the mechanism, we build several reaction models of the complex formation with the pre-binding process concerning the ATPase activity. In these models, six KaiB monomers cooperatively and rapidly bind to C1 when C1 binds ADP molecules more than a given threshold while stabilizing the binding-competent conformation of C1. Through comparison among the models proposed here, we then extract three requirements for the simultaneous promotion and acceleration: the stabilization of the binding-competent C1 by KaiB binding, slow ADP/ATP exchange in the binding-competent C1, and relatively fast ADP/ATP exchange occurring in the binding-incompetent C1 in the presence of KaiB. The last two requirements oblige KaiC to form a multimer. Moreover, as a natural consequence, the present models can also explain why the binding of KaiB to C1 reduces the ATPase activity of C1.

SYNTHESIS, CHARACTERIZATION, IN SILICO OPTIMIZATION, AND CONFORMATIONAL STUDIES OF METHYL 4-O-PIVALOYL-α-L-RHAMNOPYRANOSIDES

Considering promising biological activities of natural and synthetic rhamnopyranoside esters, we have synthesized several methyl 4-O-pivaloyl-α-L-rhamnopyranosides via selective 2,3-O-acetonide protection of methyl α-L-rhamnopyranoside (4) followed by C-4 pivaloylation, and deprotection. The synthesized 4-O-pivaloate 7 and its 2,3-di-O-esters 8a-e are characterized by spectroscopy and are optimized by using density functional theory (DFT). The free energy and bond angles thus calculated are used to establish the probable conformation(s). The 2,3-O-acetonide protected rhamnopyranosides 5-6 are found to be slightly distorted from the regular 1C4 conformation, and exist between the chair and twist-boat (skew) conformation while other pivaloyl esters 7-8a-e exist in regular 1C4 chair conformation.

Confirmation of gaseous methanediol from state-of-the-art theoretical rovibrational characterization.

High-level rovibrational characterization of methanediol, the simplest geminal diol, using state-of-the-art, purely ab initio techniques unequivocally confirms previously reported gas phase preparation of this simplest geminal diol in its C2 conformation. The F12-TZ-cCR and F12-DZ-cCR quartic force fields (QFFs) utilized in this work are among the largest coupled cluster-based anharmonic frequencies computed to date, and they match the experimental band origins of the spectral features in the 980-1100 cm-1 range to within 3 cm-1, representing a significant improvement over previous studies. The simulated spectrum also matches the experimental spectrum in the strong Q branch feature and qualitative shape of the 980-1100 cm-1 region. Additionally, the full set of rotational constants, anharmonic vibrational frequencies, and quartic and sextic distortion constants are provided for both the lowest energy C2 conformer as well as the slightly higher Cs conformer. Several vibrational modes have intensities of 60 km mol-1 or higher, facilitating potential astronomical or atmospheric detection of methanediol or further identification in laboratory work especially now that gas phase synthesis of this molecule has been established.

π-Expanded triple [5]helicenes bearing dibenzocoronene monoimide subunits.

Two novel π-expanded triple [5]helicenes containing three dibenzocoronene monoimide subunits have been synthesized and characterized. The helicenes exhibit low-energy conformational interconversions, as supported by NMR spectra. The single-crystal X-ray analysis reveals a C1 conformation in the solid state. Furthermore, the helicenes exhibit ambipolar transport characteristics in thin film transistors.

Pyranose Ring Puckering Thermodynamics for Glycan Monosaccharides Associated with Vertebrate Proteins.

The conformational properties of carbohydrates can contribute to protein structure directly through covalent conjugation in the cases of glycoproteins and proteoglycans and indirectly in the case of transmembrane proteins embedded in glycolipid-containing bilayers. However, there continue to be significant challenges associated with experimental structural biology of such carbohydrate-containing systems. All-atom explicit-solvent molecular dynamics simulations provide a direct atomic resolution view of biomolecular dynamics and thermodynamics, but the accuracy of the results depends on the quality of the force field parametrization used in the simulations. A key determinant of the conformational properties of carbohydrates is ring puckering. Here, we applied extended system adaptive biasing force (eABF) all-atom explicit-solvent molecular dynamics simulations to characterize the ring puckering thermodynamics of the ten common pyranose monosaccharides found in vertebrate biology (as represented by the CHARMM carbohydrate force field). The results, along with those for idose, demonstrate that the CHARMM force field reliably models ring puckering across this diverse set of molecules, including accurately capturing the subtle balance between 4C1 and 1C4 chair conformations in the cases of iduronate and of idose. This suggests the broad applicability of the force field for accurate modeling of carbohydrate-containing vertebrate biomolecules such as glycoproteins, proteoglycans, and glycolipids.

Synthesis, conformational analysis and glycosidase inhibition of bicyclic nojirimycin C-glycosides based on an octahydrofuro[3,2-b]pyridine motif

A set of bicyclic iminosugar C-glycosides, based on an octahydrofuro[3,2-b]pyridine motif, has been synthesized from a C-allyl iminosugar exploiting a debenzylative iodocycloetherification and an iodine nucleophilic displacement as the key steps. The halogen allowed the introduction of a range of aglycon moieties of different sizes bearing several functionalities such as alcohol, amine, amide and triazole. In these carbohydrate mimics the fused THF ring forces the piperidine to adopt a flattened 4C1 conformation according to NMR and DFT calculations studies. In their deprotected form, these bicycles were assayed on a panel of 23 glycosidases. The iminosugars displaying hydrophobic aglycon moieties proved to be superior glycosidase inhibitors, leading to a low micromolar inhibition of human lysosome β-glucosidase (compound 11; IC50 = 2.7 μM) and rice α-glucosidase (compound 10; IC50 = 7.7 μM). Finally, the loose structural analogy of these derivatives with Thiamet G, a potent OGA bicyclic inhibitor, was illustrated by the weak OGA inhibitory activity (Ki = 140 μM) of iminosugar 5.

Synthesis, crystal structure, spectroscopic, antidiabetic, antioxidant and computational investigations of Ethyl 5-hydroxy-1-isonicotinoyl-3-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate

In this work, a novel pyrazole derivative, ethyl 5-hydroxy-1-isonicotinoyl-3-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate (EIMPC) has been synthesized by condensation of ethyl 2,4-dioxopentanoate with isoniazid. Its molecular structure was characterized by FT-IR, 1H NMR, 13C NMR and ESI-MS spectroscopies and by single crystal X-ray diffraction (XRD). The experimental structure shows the presence of both enantiomeric forms and of a most stable C2 conformer while the optimized theoretical structures in gas phase and aqueous solution by functional hybrid B3LYP/6–311++G** level of theory evidence two stable C1 and C2 conformers. Both differ in the position of side chains containing the carboxylate groups. Higher repulsions between the most electronegative O atoms of side chains together with the higher volume and low dipole moment value probably justify why C1 cannot exist in the solid phase. Hydrations of acceptors and donors groups of C2 by water molecules could explain the shifting of bands assigned to those groups toward lower wavenumbers and, also, its higher solvation energy. Frontier orbitals studies support the higher reactivity of C2 in both media, as compared with C1. Comparisons between theoretical and experimental IR and NMR spectra show good correlations among them. 1H and 13C NMR chemical shifts predicted for both forms of (EIMPC) in aqueous solution suggest that C1 could also be present in this medium, as suggested by NBO and AIM calculations. 3D Hirshfeld surface and 2D fingerprint plot are carried to define the contribution of non-covalent interactions in EIMPC crystal. EIMPC was also evaluated in vitro for their α-glucosidase and α-amylase inhibition, and antioxidant activities. Thus, molecular docking analyses of the title compound were performed within the active site of α-glucosidase (PDB ID:4XP0), α-amylase (PDB ID:2QPU), oxidase (PDB ID:6I95) to analyze the binding conformation and interactions responsible for their activities.

Chemical Reactivity Descriptors and Molecular Docking Studies of Octyl 6-O-hexanoyl-β-D-glucopyranosides

The present study describes different chemical reactivity predictions of 6-O-hexanoylation of octyl β-D-glucopyranosides prepared from octyl β-D-glucopyranoside (OBG). Also, molecular docking of the OBGs was conducted against SARS-CoV-2 main protease (6LU7), urate oxidase (Aspergillus flavus; 1R51) and glucoamylase (Aspergillus niger; 1KUL). DFT optimization indicated that glucoside 1 and its ester derivatives 2-7 exist in 4C1 conformation with C1 symmetry. Interestingly, the addition of ester group(s) decreased the HOMO-LUMO gap (Δԑ) of glucosides indicating their good chemical reactivities, whereas the other chemical reactivity descriptors indicated their moderate reactive nature. This fact of moderate reactivity was confirmed by their molecular docking with 6LU7, 1R51 and 1KUL. All the esters showed a moderate binding affinity with these three proteins. More importantly, incorporation of the ester group(s) increased binding affinity with 6LU7 and 1R51, whereas decreased with 1KUL as compared to non-ester OBG 1.

Pure rotational spectrum and structural determination of 1,1-difluoro-1-silacyclopentane

The ground state, pure rotational spectrum of 1,1-difluoro-1-silacyclopentane has been studied using chirped-pulse, Fourier transform microwave (CP-FTMW) spectroscopy and observed in the 6-20.3 GHz region of the electromagnetic spectrum. This spectrum was acquired leveraging the deep averaging capability of the technique. The parent species, 13C, 29Si, and 30Si singly substituted isotopologues were observed in natural abundance and are reported. Only one conformer, the C2 conformer (half-chair), was observed. This is confirmed with a determined CCCC dihedral angle of -48.1(11)°. The spectrum is comprised of entirely a-type transitions in accordance with quantum chemical calculations. Multiple split transitions are present in the spectrum which have been attributed to a ring-twisting of the carbon atoms attached to the silicon atom in the ring. This motion has the carbons crossing the a-axis in the bc-plane leading to an inversion potential. Potential energy surfaces for the ring-twisting motion were undertaken and the experimentally determined energy level difference observed in comparison to these surfaces is reasonable. A Kraitchman analysis of the experimentally determined, singly substituted isotopologues is in agreement with the optimized, twisted (nonplanar) equilibrium structure. This structure has been compared to other similar silicon-containing ring molecules using second moment arguments and these comparisons are discussed.

De novo synthesis of an l-lemonose thioglycoside donor from d-Threonine

A short de novo synthesis of an l-lemonose thioglycoside donor is described starting from d-threonine. The synthesis leverages a Dieckmann condensation and Stork-Danheiser transposition to arrive at a key vinylogous ester intermediate on gram scale. Ensuing 1,2-addition diastereoselectively establishes the C3 tetra-substituted center and subsequent glycal hydration allows for anomeric functionalization to the thioglycoside. 1H and NOESY NMR analyses reveal that the major α-anomer of the thioglycoside deviates from the expected 1C4 conformation.

Oxidative Addition of α‐Glycosyl Halides to a Platinum(0) Olefin Complex: Stereochemistry of Pt−C Bond Formation

AbstractThe oxidative addition of α‐glucosyl and α‐galactosyl halides to the platinum(0) complex [Pt(2,9‐dimethyl‐1,10‐phenanthroline)(ethene)] has been investigated. In all cases the main reaction product is the five‐coordinate Pt(II) complex containing in axial position an α‐glycosyl fragment in the unusual 1C4 conformation. In the case of glucose, a minor product could be identified as the β isomer, which retains the typical 4C1 chair. The single crystal structures of two diastereomers are compared. The outcome of the reaction does not depend on the nature of the halide and is only slightly affected by the solvent. The addition mechanism is discussed, also in the light of literature data. Experimental data, along with DFT calculations, point towards a radical chain mechanism.

An Ultrahigh-Affinity Complement C4b-Specific Nanobody Inhibits In Vivo Assembly of the Classical Pathway Proconvertase.

The classical and lectin pathways of the complement system are important for the elimination of pathogens and apoptotic cells and stimulation of the adaptive immune system. Upon activation of these pathways, complement component C4 is proteolytically cleaved, and the major product C4b is deposited on the activator, enabling assembly of a C3 convertase and downstream alternative pathway amplification. Although excessive activation of the lectin and classical pathways contributes to multiple autoimmune and inflammatory diseases and overexpression of a C4 isoform has recently been linked to schizophrenia, a C4 inhibitor and structural characterization of the convertase formed by C4b is lacking. In this study, we present the nanobody hC4Nb8 that binds with picomolar affinity to human C4b and potently inhibits in vitro complement C3 deposition through the classical and lectin pathways in human serum and in mouse serum. The crystal structure of the C4b:hC4Nb8 complex and a three-dimensional reconstruction of the C4bC2 proconvertase obtained by electron microscopy together rationalize how hC4Nb8 prevents proconvertase assembly through recognition of a neoepitope exposed in C4b and reveals a unique C2 conformation compared with the alternative pathway proconvertase. On human induced pluripotent stem cell-derived neurons, the nanobody prevents C3 deposition through the classical pathway. Furthermore, hC4Nb8 inhibits the classical pathway-mediated immune complex delivery to follicular dendritic cells in vivo. The hC4Nb8 represents a novel ultrahigh-affinity inhibitor of the classical and lectin pathways of the complement cascade under both in vitro and in vivo conditions.

Synthesis, crystal structure, spectroscopic studies, NBO, AIM and SQMFF calculations of new pyridazinone derivative

A new pyridazinone derivative, (E)-ethyl 2-(5-(4-methylbenzyl)-6-oxo-3-styrylpyridazin-1(6H)-yl)acetate (2) has been synthesized and characterized by FT-IR, 1H- and 13C-NMR, ESI-MS. The (E)-configuration was confirmed by single-crystal X-ray diffraction. Theoretical B3LYP/6-31G* calculations have evidenced two stable C1 and C2 conformers where the structure of C2 form is in agreement with the corresponding experimental one. The difference in the energy values between both forms is 33.32 kJ/mol. The higher stability of C2 against C1 could probably be attributed to most negative NPA and Mulliken charges predicted on the O4 and O44 atoms of acetate groups of C2 form, as compared with C1.The calculated harmonic vibrational frequencies for C2 are consistent with their experimental ATR spectrum in the solid phase. The complete vibrational assignment of 153 vibration modes expected for C2 were performed by using the SQMFF methodology and a set of scaled force constants were also reported. C2 has revealed a higher reactivity than (E)-N'-4-methoxybenzylidene-5-methyl-1H-pyrazole-3-carbohydrazide. The Raman spectrum of both C1 and C2 forms of (2) in gas phase by using the B3LYP/6-31G* method were also predicted. Reasonable correlations are observed between the experimental and predicted 1H and 13C NMR and UV-Vis spectra. The intermolecular interactions in the crystal structure were analysed using Hirshfeld surface analysis and two-dimensional fingerprint plots.

Internal Rotation of the Acetyl Methyl Group in Methyl Alkyl Ketones: The Microwave Spectrum of Octan-2-one.

Methyl n-alkyl ketones form a class of molecules with interesting internal dynamics in the gas-phase. They contain two methyl groups undergoing internal rotations, the acetyl methyl group and the methyl group at the end of the alkyl chain. The torsional barrier of the acetyl methyl group is of special importance, since it allows for the discrimination of the conformational structures. As part of the series, the microwave spectrum of octan-2-one was recorded in the frequency range from 2 to 40 GHz, revealing two conformers, one with C1 and one with Cs symmetry. The barriers to internal rotation of the acetyl methyl group were determined to be 233.340(28) cm-1 and 185.3490(81) cm-1 , respectively, confirming the link between conformations and barrier heights already established for other methyl alkyl ketones. Extensive comparisons to molecules in the literature were carried out, and a small overview of general trends and rules concerning the acetyl methyl torsion is given. For the hexyl methyl group, the barrier height is 973.17(60) cm-1 for the C1 conformer and 979.62(69) cm-1 for the Cs conformer.

Partition Coefficients (logP) of Hydrolysable Tannins.

The partition coefficients (logP) between n-octanol and water of 47 purified and characterized hydrolysable tannins were measured with the shake flask method utilizing UPLC and HPLC with UV detection. Results show that galloyl glucoses and gallotannins are clearly more hydrophobic than ellagitannins but the differences in hydrophobicity within ellagitannins are more varied than within galloyl glucoses or gallotannins. Most notable structural features that were found to influence the hydrophobicity of ellagitannins were the number of free galloyl groups, acyclic versus cyclic polyol, substitution of the anomeric position of glucose and 4C1 versus 1C4 conformation of the glucopyranose core.

The conformation of the idopyranose ring revisited: How subtle O-substituent induced changes can be deduced from vicinal 1H-NMR coupling constants

The idopyranose ring plays a pivotal role in the conformational, dynamical, and intermolecular binding aspects of glycosaminoglycans like heparin and dermatan sulfate and it was early on assigned a role in the Sugar Code governing biological recognition processes. There is consensus that next to the two canonical 1C4 and 4C1 chair conformations, the conformational space accessible to the idopyranose ring entails a 2SO skew-boat conformation, but the equilibrium between these three ring puckers has evaded satisfactory quantification. In this study a meta-analysis of X-ray solid-state data and vicinal NMR coupling constants is presented, based on the Truncated Fourier Puckering (TFP) formalism and the generalized Karplus (CAGPLUS) equation. This approach yields a model-free, granular and consistent reckoning of 159 idopyranose solution puckering equilibria studied by NMR and allows us to reproduce the involved 636 NMR vicinal couplings with an overall residual RMS(Jobs-Jcalc) of 0.184 Hz. Our analyses show that for all ring systems examined, the idopyranosyl chair conformations take up the same ring pucker irrespective of the ring substituent pattern or a vast variety in experimental conditions. Instead, it is the (skew-)boat conformation that adapts to the substitution pattern of the idopyranose ring or a specific sulfation pattern of neighboring saccharides. All idopyranose rings are involved in conformational equilibria that subsume the aforementioned conformers which turn out to differ only a few kJ/mole in conformational energy. Thus, the plasticity and flexibility of idopyranose remains intact under practically all circumstances and, as the glycosidic linkages in heparin are considered to be relatively stiff, the iduronic moiety functions as the linchpin of heparin flexibility thereby being rather a “space(r)” than a “letter” in the alleged Sugar Code alphabet.

The Conformational Landscape, Internal Rotation, and Structure of 1,3,5-Trisilapentane using Broadband Rotational Spectroscopy and Quantum Chemical Calculations.

The rotational spectrum of 1,3,5-trisilapentane was observed on a chirped-pulse Fourier transform microwave spectrometer and is reported. During assignment, multiple conformations of the molecule were identified in the molecular beam. Prior quantum-chemical calculations performed on the molecule show that the identified spectra correspond to the lowest three calculated energetic structures. These structures are of C2 (Conf.1), C2v (Conf.2), and C1 (Conf.3) symmetry, with relative energy ordering of Conf.1 < Conf.3 < Conf.2, which is in stark contrast to n-pentane and all known silicon-substituted n-pentane derivatives. This is found to most likely arise from the elongation of the Si-C bond and the size of the silicon atoms providing for the C2 and C1 structures relieving steric hindrance in comparison to that of the C2v. In the C2v and C1 conformers, splitting in the spectra due to internal rotation of the -SiH3 end groups of 1,3,5-trisilapentane was observed and determined. The C2v equivalent V3 values are 368.46(33) cm-1, and the C1V3 values are 347.78(21) and 360.18(88) cm-1, respectively. These barriers are compared to similar species in order to help verify their veracity and are determined to be accurate based on similar molecular silyl rotors.

Synthesis, Conformational Analysis, and Complexation Study of an Iminosugar-Aza-Crown, a Sweet Chiral Cyclam Analog.

A new family of chiral C2 symmetric tetraazamacrocycles, coined ISAC for IminoSugar Aza-Crown, incorporating two iminosugars adopting a 4C1 conformation is disclosed. Multinuclear NMR experiments on the corresponding Cd2+ complex show that the ISAC is a strong chelator in water and its tetramine cavity adopts a conformation similar to that of the parent Cd–cyclam complex. Similar behavior is observed with Cu2+ in solution, with enhanced stability compared to the Cu–cyclam complex.

Theoretical design and rotational conformation analysis of molecular bevel gear with triptycene as rotator

A molecular bevel gear with triptycene as the rotator and naphtha[2,1,8-def]isoquinoline as the stator was designed, and the rotational process and conformational transformation of the gear were calculated and analyzed by density functional theory. To be specific, the rotational potential energy surface was investigated via scanning the dihedral angle θ (H71‒N67‒C1‒C5). The geometry optimization was performed at the M06-2X level in conjunction with def-TZVP basis set. According to the correlation between the two rotors, the rotation mode of gear can be defined as gear rotation and gear slippage. And the rotational energy barrier indicated that the gear rotation was easier than gear slippage. For transition-state and ground-state structures, the single-point energy and thermodynamic correction were calculated at M06-2X/def2-TZVP levels. The C2 conformations in ground state achieved its stable structure owing to intramolecular hydrogen bonding, C‒H···π, and π···π stacking interactions. In order to gain insight into the intramolecular interaction, the noncovalent interactions based on the reduced density gradient method and Bader’s atoms in molecules theory were analyzed in detail.