Conformational Diversity in Partially Fluorinated N-Alkyl Pipecolic Acid Amide Derivatives

The molecular and crystal structures of 19 N-alkyl-substituted pipecolamide derivatives with partial fluorination of N-propyl and N-butyl groups are presented. Fluorination patterns include one F-atom at internal or terminal locations, two F-atoms in geminal or vicinal arrangements at various positions, as well as terminal trifluoromethylation. Due to the presence of the carboxamide side chain in pipecolamide derivatives, enantiomeric fluorination patterns in the N-alkyl group result in diastereomeric compounds, which exhibit dramatically different crystal and molecular structures. An extraordinary conformational diversity is diagnosed for the various N-alkylpiperidine units. Structural comparisons and theoretical assessments based on extensive force field calculations provide insight into consistent conformational patterns that point to intramolecular factors as well as intermolecular modulations due to crystal packing effects.     

Synthesis,Structures, and Properties of Highly Strained Cyclophenylene–Ethynylenes with Axial and Helical Chirality

Single and double cyclophenylene–ethynylenes (CPEs) with axial and helical chirality have been synthesized by the Sonogashira cross‐coupling of di‐ and tetraethynyl biphenyls with a U‐shaped prearomatic diiodoparaphenylene followed by reductive aromatization. X‐ray crystallographic analyses and DFT calculations revealed that the CPEs possess highly twisted bent structures. Bend angles on the edge of the paraphenylene units were close to the value of [5]cycloparaphenylene (CPP)—the smallest CPP to date. The double and single CPEs possessed stable chirality despite flexible biphenyl structures because of the high strain in the diethynyl–paraphenylene moiety. In both the single and double CPEs, orbital interactions along the biphenyl axis were observed by DFT calculations in LUMO and LUMO+2 of the single CPE and LUMO+1 of the double CPE, which likely cause lowering of these orbital energies. Concerning chiroptical properties: boosting of the g_abs value was observed in the biphenyl‐based double CPE, as well as the binaphthyl‐based single CPE, compared to the biphenyl‐based single CPE.     

Use of Trifluoromethyl Groups for Catalytic Benzylation and Alkylation with Subsequent Hydrodefluorination

The electrophilic organofluorophosphonium catalyst [(C₆F₅)₃PF][B(C₆F₅)₄] is shown to effect benzylation or alkylation by aryl and alkyl CF₃ groups with subsequent hydrodefluorination, thus resulting in a net transformation of CF₃ into CH₂–aryl fragments. In the case of alkyl CF₃ groups, Friedel–Crafts alkylation by the difluorocarbocation proceeded without cation rearrangement, in contrast to the corresponding reactions of alkyl monofluorides.     

Conformational energy penalties of protein-bound ligands

The conformational energies required for ligands to adopt their bioactive conformations were calculated for 33 ligand–protein complexes including 28 different ligands. In order to monitor the force field dependence of the results, two force fields, MM3 and AMBER, were employed for the calculations. Conformational analyses were performed in vacuo and in aqueous solution by using the generalized Born/solvent accessible surface (GB/SA) solvation model. The protein-bound conformations were relaxed by using flat-bottomed Cartesian constraints. For about 70% of the ligand–protein complexes studied, the conformational energies of the bioactive conformations were calculated to be 3 kcal/mol. It is demonstrated that the aqueous conformational ensemble for the unbound ligand must be used as a reference state in this type of calculations. The calculations for the ligand–protein complexes with conformational energy penalties of the ligand calculated to be larger than 3 kcal/mol suffer from uncertainties in the interpretation of the experimental data or limitations of the computational methods. For example, in the case of long-chain flexible ligands (e.g. fatty acids), it is demonstrated that several conformations may be found which are very similar to the conformation determined by X-ray crystallography and which display significantly lower conformational energy penalties for binding than obtained by using the experimental conformation. For strongly polar molecules, e.g. amino acids, the results indicate that further developments of the force fields and of the dielectric continuum solvation model are required for reliable calculations on the conformational properties of this type of compounds.     

Structural analysis of the microporous semiconductor K-SBC-1 during its reversible sorption of water

The reversible sorption of water molecules in the crystalline microporous semiconductor K-SBC-1 was investigated using temperature-resolved single-crystal XRD analysis. Three crystallographic sites of adsorbed water molecules, differing in adsorption strength, were discovered in the pores of K-SBC-1. The least tightly bound is located at the centre of the {Sb₁₂O₁₈} tube and begins to desorb around 50 °C. Above 200 °C the more strongly bound water molecules rearrange from their potassium-coordinating positions to the centre of the tube, thus obtaining the characteristics of the loosely bound water, and desorb thereafter. At 240 °C approximately 10% of the water has desorbed, leaving the host framework of K-SBC-1 intact. Upon re-adsorption of water at room temperature the molecules preferentially adsorb at sites in the centre of the {Sb₁₂O₁₈} tube. This shows that a heat treatment of 240–300 °C activates K-SBC-1 for sorption and explains the observed facile desorption of water from activated samples.     

Preparation and Electric Property of Polysilsesquioxane Thin Films Incorporating Carbazole Groups

New silsesquioxane incorporating a carbazole groups (PCTSQ) has been synthesized by a click thiol–ene reaction and a subsequent sol–gel reaction. To evaluate the electric property of this hybrid, diode devices have been fabricated by using PCTSQ thin film by spin‐coating onto n‐type ZnO film prepared by the electrodeposition method. The thin film hybrid devices showed good electric characteristics and high rectification ratio, as well as worked as a rectifier.     

Autoassembly of cage structures

The molecular structure of 1,4-dimethyl-2,5-dioxabicyclo[2.2.2]octane-3,6-dione (1) has been determined by X-ray diffraction analysis. The skeleton of dilactone1 has a synchro(+,+,+)-twist conformation with dihedral angles =4.0° for the hydrocarbon bridge bonds and =4.4, 4.6° for the lactone bridge bonds.For the previous paper in the series see Ref. 1.Translated fromIzyestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1965–1968, November, 1994.This work was supported by the International Science Foundation (MCO 000), the Russian Foundation for Basic Research (project code 94-03-08730), and NATO (LG 921193).     

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 β 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 β-anomers. Thus, selective synthesis of the desired α-sialosides requires minimization of acyl groups participation.     

Effect of Axial Ligands on the Molecular Configurations,Stability, Reactivity,and Photodynamic Activities of Silicon Phthalocyanines

To demonstrate the effect of axial ligands on the structure–activity relationship, a series of axially substituted silicon phthalocyanines (SiPcs) have been synthesized with changes to the axial ligands. The reactivity of the axial ligand upon shielding by the phthalocyanine ring current, along with their stability, photophysical, and photodynamic therapy (PDT) activities were compared and evaluated for the first time. As revealed by single‐crystal XRD analysis, rotation of the axial ? OMe ligands was observed in SiPc 3 , which resulted in two molecular configurations coexisting synchronously in both the solid and solution states and causing a split of the phthalocyanine α protons in the ¹H NMR spectra that is significantly different from all SiPcs reported so far. The remarkable photostability, good singlet oxygen quantum yield, and efficient in vitro photodynamic activity synergistically show that compound 3 is one of the most promising photosensitizers for PDT.     

Solid-state structure and conformation of (Z)-2-(phenylbenzylidene)-3-quinuclidinone,an intermediate in the synthesis of quinuclidine derivatives

(Z)-2-(2-phenylbenzylidene)-3-quinuclidinone, C₂₀H₁₉NO,M _r =300.47D crystallizes in the monoclinicP2₁/c space group witha = 6.9809(2) Å,b=19.0523(2) Å,c = 11.7733(1) Å,=100.92(2)°,V=1537.5(3) ų,Z=4,D _c = 1.298 g/cm³,D _x =1.29 g/cm³ (flotation). Diffractometric data, using CuK radiation,=1.54178 Å, were collected on plate-like crystals. The structure, solved by direct methods was refined to a final R value of 0.037 for the 2645 observed reflections withF _o >3.0(F _o ). The molecule shows a trans conformation around the double bond. The quinuclidine and the diphenyl moieties present deformations in their geometric and conformational parameters due to the need of releasing intramolecular strains and/or nonbonded interactions.     

Fluorinated Musk Fragrances: The CF2 Group as a Conformational Bias Influencing the Odour of Civetone and (R)‐Muscone

The difluoromethylene (CF₂) group has a strong tendency to adopt corner over edge locations in aliphatic macrocycles. In this study, the CF₂ group has been introduced into musk relevant macrocyclic ketones. Nine civetone and five muscone analogues have been prepared by synthesis for structure and odour comparisons. X‐ray studies indeed show that the CF₂ groups influence ring structure and they give some insight into the preferred ring conformations, triggering a musk odour as determined in a professional perfumery environment. The historical conformational model of Bersuker and co‐workers for musk fragrance generally holds, and structures that become distorted from this consensus, by the particular placement of the CF₂ groups, lose their musk fragrance and become less pleasant.     

Synthesis and Antimicrobial Properties of the Novel Fluonnated Bis-ammonium Salts with Two Primary Amine Groups

In order to resolve the increasing resistance phenomena of the Gram-negative bacteria against single chain quaternary ammonium salts (QAS), lysine with a pedant fluorinated bis-ammonium salts was synthesized and its antimicrobial properties were evaluated in this work. The novel fluorinated bis-ammonium salts shows similar activity with conventional single chain quaternary ammonium salts against Gram-positive bacteria but stronger activity against Gram-negative bacteria and yeast compared with the single chained counterpart.     

Structural Features of [(CpPPh2AuCl)2ZrCl2]: Exploring the Limits of Aurophilic Interactions

The reaction of [(CpPPh₂)₂ZrCl₂] ( 1 a ) with two molar equivalents of (Me₂S)AuCl gave the trimetallic complex [(CpPPh₂AuCl)₂ZrCl₂] ( 6 ). Crystalline complex 6 shows a conformational structure that features both P? Au? Cl vectors oriented toward the open front side of the bent metallocene wedge. Quantum‐chemical calculations rationalized the absence of an aurophilic Au???Au interaction in 6 by showing that a combination of noncovalent forces overcompensates any possible attractive Au???Au interaction.     

Janus‐Like Squaramide‐Based Hosts: Dual Mode of Binding and Conformational Transitions Driven by Ion‐Pair Recognition

New tripodal squaramide‐based hosts have been synthesised and structurally characterised by spectroscopic methods. In 2.5 % (v/v) [D₆]DMSO in CDCl₃, compound 4 formed dimeric assemblies [log K_dim=3.68(8)] as demonstrated by ¹H NMR spectroscopy and UV dilution experiments. AFM and SEM analyses revealed the formation of a network of bundled fibres, which indicates a preferential mechanism for aggregation. These C₃‐symmetric tripodal hosts exhibited two different and mutually exclusive modes of binding, each one easily accessible by simultaneous reorientation of the squaramide groups. In the first, a convergent disposition of the NH squaramide protons allowed the formation of an array of N? H???X^? hydrogen bonds with anions. In the second mode, reorientation of carbonyl squaramide groups allowed multiple C?O???H interactions with ammonium cations. The titration of 4 with different tetraalkylammonium iodides persistently showed the formation of 1:1 complexes, as well as 1:2 and 1:3 complexes. The corresponding stoichiometries and binding affinities of the complexes were evaluated by multi‐regression analysis. The formation of high‐order complexes, supported by ROESY, NOESY and mass spectrometry experiments, has been attributed to the insertion of NR₄I ion pairs between the carbonyl and NH protons of the squaramide groups located in adjacent arms of 4 . The observed effects reflect the induction of significant conformational changes in the hosts, mainly in relation to the relative orientation of the squaramide groups adapting their geometries to incoming ion‐pair complementary substrates. The results presented herein identify and fully describe two different modes of ion‐pair recognition aimed at directing conformational transitions in the host, therefore establishing a base for controlling more elaborate movements of molecular devices through ion‐pair recognition.     

The Bis(pentafluoroethyl)germylene Trimethylphosphane Adduct (C2F5)2Ge⋅PMe3: Characterization,Ligand Properties,and Reactivity

The synthesis of the germylene phosphane adduct (C₂F₅)₂Ge?PMe₃ is described. Starting from (C₂F₅)₃GeH in an excess of PMe₃, heating was applied, whereupon reductive elimination of C₂F₅H occurred. The molecular structure was ascertained by X‐ray diffraction and compared with information obtained by quantum chemical methods. The ligand properties were derived by studying the IR spectrum of the nickel(0) complex [Ni(CO)₃{Ge(C₂F₅)₂(PMe₃)}] in the CO region. (C₂F₅)₂Ge?PMe₃ turned out to be a π‐accepting ligand comparable to PMe₃, in terms of Tolman's electronic parameter. Furthermore a [2+4] cycloaddition reaction with 2,3‐dimethyl‐1,3‐butadiene, and σ‐bond insertion reactions were recorded. Activation of the C?Cl bond in dichloromethane gives rise to the formation of the phosphonium ylide complex [(C₂F₅)₂Cl₂Ge‐CH₂PMe₃], which was fully characterized by X‐ray diffraction.     

Combined Inhibitor Free‐Energy Landscape and Structural Analysis Reports on the Mannosidase Conformational Coordinate

Mannosidases catalyze the hydrolysis of a diverse range of polysaccharides and glycoconjugates, and the various sequence‐based mannosidase families have evolved ingenious strategies to overcome the stereoelectronic challenges of mannoside chemistry. Using a combination of computational chemistry, inhibitor design and synthesis, and X‐ray crystallography of inhibitor/enzyme complexes, it is demonstrated that mannoimidazole‐type inhibitors are energetically poised to report faithfully on mannosidase transition‐state conformation, and provide direct evidence for the conformational itinerary used by diverse mannosidases, including β‐mannanases from families GH26 and GH113. Isofagomine‐type inhibitors are poor mimics of transition‐state conformation, owing to the high energy barriers that must be crossed to attain mechanistically relevant conformations, however, these sugar‐shaped heterocycles allow the acquisition of ternary complexes that span the active site, thus providing valuable insight into active‐site residues involved in substrate recognition.     

Siamese‐Twin Porphyrin Origami: Oxidative Fusing and Folding

Oxidation of a nonaromatic Siamese‐twin porphyrin, a pyrazole‐containing expanded porphyrin with two porphyrinlike binding pockets, with a stoichiometric amount of the two‐electron, two‐proton oxidizing agent 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzochinone led to the formation of a single N^pz‐C^o‐Ph linkage between the pyrazole unit with a neighboring meso‐phenyl group, forming a pyrazolo‐ [1,5‐a]indole moiety. Repeated treatment with a second equivalent of the oxidant yielded a doubly N‐fused species, involving the second pyrazole moiety. The conversion products were characterized by variable‐temperature and multinuclear 1D and 2D NMR spectroscopy. The fusions strongly alter the conformation of the macrocycles, as shown by X‐ray diffraction analyses of all three compounds, eventually leading to a folded structure. UV/Vis and NMR‐spectroscopic investigations indicated the presence of highly delocalized but nonmacrocycle‐aromatic π systems. This behavior of the Siamese‐twin porphyrin in response to oxidation is in contrast to the behavior of related all‐pyrrole‐based expanded macrocycles that switch, by redox processes and protonation, between Hückel and Möbius aromatic states.     

Simultaneous Assessment of Kinetic,Site‐Specific,and Structural Aspects of Enzymatic Protein Phosphorylation

Protein phosphorylation is a widespread process forming the mechanistic basis of cellular signaling. Up to now, different aspects, for example, site‐specificity, kinetics, role of co‐factors, and structure–function relationships have been typically investigated by multiple techniques that are incompatible with one another. The approach introduced here maximizes the amount of information gained on protein (complex) phosphorylation while minimizing sample handling. Using high‐resolution native mass spectrometry on intact protein (assemblies) up to 150 kDa we track the sequential incorporation of phosphate groups and map their localization by peptide LC‐MS/MS. On two model systems, the protein kinase G and the interplay between Aurora kinase A and Bora, we demonstrate the simultaneous monitoring of various aspects of the phosphorylation process, namely the effect of different cofactors on PKG autophosphorylation and the interaction of AurA and Bora as both an enzyme–substrate pair and physical binding partners.