Conformational Analysis of Biphenyl-2,2′-Diacetate

Conformational analysis of biphenyl-2,2′-diacetate by dynamic NMR and UV spectra and by plots of enzyme activity vs temperature plots is described. From dynamic NMR spectra of the biphenyl-2,2′-diacetate with a chiral shift reagent, the coalescence temperature (T_c), the Gibbs energy of activation (ΔG^≠), and the rate coefficient (k) of bipbenyl-2,2′-diacetate were ?5 °C, 59.5 kJ/mol, and 13.3 s^?1, respectively. From analysis of the conformational break in the UV spectra and the discontinuity in the plots of enzyme activity vs temperature, the racemerization temperature of bipbenyl-2,2′-diacetate is about 5°C.     

Conformational Analysis of Biphenyl Derivatives. I. A Novel Steric Constant from the Internal Rotation Rate of 2,2′‐Bis‐(N‐Substituted Carbamoylmethyl)Biphenyl by Means of Dynamic NMR

A novel scale of steric substituent constant E_s^D is defined from the correlation of the logarithms of the internal rotation rate (k_r) at 393 K with Hancock (E_s^c) steric constant by means of dynamic NMR. In the inhibition of Pseudomona species lipase by 2,2′‐bis‐(N‐substituted carbamoylmethyl)biphenyls (1‐8), the logarithms of bimolecular rate constants are multiply correlated with both the Taft substituent constant σ* and E_s^D.     

A Mild Approach to the Synthesis of sn‐Glycerol 1,2‐Di‐γ‐linolenate 3‐Palmitate

A synthetic approach comprising several studied modifications was applied to the preparation of sn‐glycerol 1,2‐di‐γ‐linolenate 3‐palmitate ( 4 ). Thereby, a convenient and mild synthetic method was elaborated, affording 4 from 1,2‐O‐isopropylidene‐sn‐glycerol ( 1 ) in an average yield of 65 – 75% and analytically acceptable purity.     

First Synthesis of 3‐O‐Functionalized Cellulose Ethers via 2,6‐Di‐O‐Protected Silyl Cellulose

The present paper describes the synthesis of 2,6‐di‐O‐thexyldimethylsilyl cellulose as a novel 2,6‐di‐O‐protected cellulose derivative. This material was obtained by reacting cellulose in N,N‐dimethylacetamide/LiCl solution with thexyldimethylchlorosilane and imidazole for 24 h at 100°C. In a typical subsequent reaction the residual OH‐group in position 3 could be completely etherified without loss of any protecting groups. Treatment with tetrabutylammonium fluoride leads to the novel compounds 3‐O‐allyl and 3‐O‐methyl cellulose. The structures of all polymers are revealed by means of one‐ (¹H and ¹³C) and two‐dimensional (COSY and HMQC) NMR techniques.     

3‐Fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐Oxides as Rigid Acetylcholine Mimetics: Conformational Analysis and Direct Evidence of the Anomeric Effect

Conformational analyses of the P(3)‐axially and P(3)‐equatorially F‐substituted (±)‐cis‐ and (±)‐trans‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐oxides (3‐fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides) were performed. The results are based on independent studies in both solution and the solid state by ¹H‐ and ³¹P‐NMR experiments and computational and X‐ray crystallographic data. As expected, the axial epimers adopt neat double‐chair conformations in solution and in the crystal. Due to the anomeric effect of the electron withdrawing F‐substituent, the 2,4‐dioxa‐3‐phospha moiety in the equatorial epimers adopts a mixture of conformations in solution, mainly chair and twist‐boat; whereas a neat twist‐boat (trans‐isomer) and the unusual envelope conformation (cis‐isomer) were detected in the solid state. This is the first report of a straight visualization of these conformations and the impact of the anomeric effect in such systems.     

1,2:5,6‐Di‐O‐Cyclohexylidene‐d‐Mannitol and Its Bis(Trimethylsilyl) Ether in the Dithiophosphorylation Reactions

The reaction of 2,4‐diaryl 1,3,2,4‐dithiadiphosphetane‐2,4‐disulfide with diketonide of d ‐mannitol has been found to give optically active bisaryldithiophosphonic acids transformed into the corresponding diammonium salts by the treatment of n‐hexadecylamine. O,O‐Bis(trimethylsilyl) ether of d ‐mannitol ketonide reacts with 2,4‐diaryl 1,3,2,4‐dithiadiphosphetane‐2,4‐disulfide to form chiral S,S‐disilylbisaryldithiophosphonate. Diammonium bisaryldithiophosphonate possesses antibacterial activity against Staphylococcus aureus ATCC 6538‐P.     

Experimental and Theoretical Conformational Analysis of 5‐Benzylimidazolidin‐4‐one Derivatives – a ‘Playground’ for Studying Dispersion Interactions and a ‘Windshield‐Wiper’ Effect in Organocatalysis

The PF₆ salts of 5‐benzyl‐1‐isopropylidene‐ and 5‐benzyl‐1‐cinnamylidene‐3‐methylimidazolidin‐4‐ones 1 (Scheme) with various substituents in the 2‐position have been prepared, and single crystals suitable for X‐ray structure determination have been obtained of 14 such compounds, i.e., 2 – 10 and 12 – 16 (Figs. 2–5). In nine of the structures, the Ph ring of the benzyl group resides above the heterocycle, in contact with the cis‐substituent at C(2) (staggered conformation A ; Figs. 1–3); in three structures, the Ph ring lies above the iminium π‐plane (staggered conformation B ; Figs. 1 and 4); in two structures, the benzylic C? C bond has an eclipsing conformation ( C ; Figs. 1 and 5) which places the Ph ring simultaneously at a maximum distance with its neighbors, the CO group, the N?C‐π‐system, and the cis‐substituent at C(2) of the heterocycle. It is suggested by a qualitative conformational analysis (Fig. 6) that the three staggered conformations of the benzylic C? C bond are all subject to unfavorable steric interactions, so that the eclipsing conformation may be a kind of ‘escape’. State‐of‐the‐art quantum‐chemical methods, with large AO basic sets (near the limit) for the single‐point calculations, were used to compute the structures of seven of the 14 iminium ions, i.e., 3, 4 / 12, 5 – 7, 13 , and 16 (Table) in the two staggered conformations, A and B , with the benzylic Ph group above the ring and above the iminium π‐system, respectively. In all cases, the more stable computed conformer (‘isolated‐molecule’ structure) corresponds to the one present in the crystal (overlay in Fig. 7). The energy differences are small (≤2 kcal/mol) which, together with the result of a potential‐curve calculation for the rotation around the benzylic C? C bond of one of the structures, 16 (Fig. 8), suggests that the benzyl group is more or less freely rotating at ambident temperatures. The importance of intramolecular London dispersion (benzene ring in ‘contact’ with the cis‐substituent in conformation A ) for DFT and other quantum‐chemical computations is demonstrated; the benzyl‐imidazolidinones 1 appear to be ideal systems for detecting dispersion contributions between a benzene ring and alkyl or aryl CH groups. Enylidene ions of the type studied herein are the reactive intermediates of enantioselective organocatalytic conjugate additions, Diels–Alder reactions, and many other transformations involving α,β‐unsaturated carbonyl compounds. Our experimental and theoretical results are discussed in view of the performance of 5‐benzyl‐imidazolidinones as enantioselective catalysts.     

Conformational Analysis of Epiquinine and Epiquinidine

The conformational potential energy surfaces for the epiquinine and epiquinidine molecules were analyzed in gas phase and water solution using semiempirical and ab initio levels of theory. The results obtained showed that the main conformation of the nonactive threo epimers is distinct from those observed for the active parent compounds quinine and quinidine. This result might be used, on a qualitative way, to understand the loss of activity of the threo epimers and allow selecting important conformations to be considered in molecular modeling quantitative studies addressing the drug–receptor interactions.     

On the Reaction of Glycerol Dehydratase with But‐3‐ene‐1,2‐diol

Intriguing inactivation : Calculations suggest that the ability of relatively high‐energy radical intermediates to inactivate glycerol dehydratase (GDH) may reflect a general and hitherto unidentified inactivation mechanism in the reaction of coenzyme B₁₂‐dependent enzymes and 3‐unsaturated 1,2‐diols (see scheme; AdoCbl: adenosylcobalamin or coenzyme B₁₂).

     

Regioselective Benzoylation of 6‐O‐Protected and 4,6‐O‐Diprotected Hexopyranosides as Promoted by Chiral and Achiral Ditertiary 1,2‐Diamines

Monobenzoylation of triols (6‐O‐silylated glycopyranosides) or diols (4,6‐O‐benzylidenated glycopyranosides) with benzoyl chloride and triethylamine at ?60° to 23° is promoted by catalytic amounts of ditertiary 1,2‐diamines. The regioselectivity depends mostly on the structure of the alcohols; it is modulated by the configuration and constitution of the diamines, as shown by comparing the effect of Oriyama's catalyst ((S)‐ 1 and (R)‐ 1 ), N,N,N′,N′‐tetramethylethylenediamine (TMEDA), N,N,N′,N′‐tetraethylethylenediamine (TEEDA), Et₃N, and EtNMe₂. The effect of the catalysts on the reactivity is impaired by their steric hindrance. In agreement with the modest enantioselectivity of the mono‐ and dibenzoylation of rac‐cyclohexane‐1,2‐diol in the presence of Oriyama's catalyst, the influence of these diamines on the regioselectivity is rather limited. While associated with procedural simplicity, these catalysts lead, in a few cases, to higher yields of a single benzoate than established methods, viz. in the preparation of the 3‐O‐benzoyl β‐D ‐glucopyranoside 4 , the 2‐O‐benzoyl α‐D ‐galactopyranoside 22 , the 3‐O‐benzoyl α‐D ‐galactopyranoside 23 , and the benzylidenated 2‐O‐benzoyl α‐D ‐galactopyranoside 44 . The regioselective benzoylation of the benzylidenated β‐D ‐mannopyranoside 47 , leading to 48 , appears to be new.     

Conformational analysis of 1,2-dichloroethane adsorbed in metal-organic frameworks

This paper describes the conformational analysis of 1,2-dichloroethane adsorbed into three different metal-organic frameworks, MIL-53(Al), MIL-68(In), MIL-53-NH₂(Al), by using FT-Raman spectroscopy in combination with powder XRD and TGA. For non-polar frameworks, the main guest-host interactions are van der Waal interactions between the CH bonds of 1,2-dichloroethane (DCE) and the π system of terephthalate ligands. The polar framework of MIL-53-NH₂ is able to stabilize the gauche conformation of DCE at room temperature. The conformational enthalpy of each system was determined through variable temperature FT-Raman spectroscopy. Furthermore, the line-width of the Raman bands provides information regarding the molecular motion of the halocarbons at various temperatures inside the framework.     

sp2‐Iminosugar O‐, S‐, and N‐Glycosides as Conformational Mimics of α‐Linked Disaccharides; Implications for Glycosidase Inhibition

The synthesis of mimics of the α(1→6)‐ and α(1→4)‐linked disaccharides isomaltose and maltose featuring a bicyclic sp²‐iminosugar nonreducing moiety O‐, S‐, or N‐linked to a glucopyranoside residue is reported. The strong generalized anomeric effect operating in sp²‐iminosugars determines the α‐stereochemical outcome of the glycosylation reactions, independent of the presence or not of participating protecting groups and of the nature of the heteroatom. It also imparts chemical stability to the resulting aminoacetal, aminothioacetal, or gem‐diamine functionalities. All the three isomaltose mimics behave as potent and very selective inhibitors of isomaltase and maltase, two α‐glucosidases that bind the parent disaccharides either as substrate or inhibitor. In contrast, large differences in the inhibitory properties were observed among the maltose mimics, with the O‐linked derivative being a more potent inhibitor than the N‐linked analogue; the S‐linked pseudodisaccharide did not inhibit either of the two target enzymes. A comparative conformational analysis based on NMR and molecular modelling revealed remarkable differences in the flexibility about the glycosidic linkage as a function of the nature of the linking atom in this series. Thus, the N‐pseudodisaccharide is more rigid than the O‐linked derivative, which exhibits conformational properties very similar to those of the natural maltose. The analogous pseudothiomaltoside is much more flexible than the N‐ or O‐linked derivatives, and can access a broader area of the conformational space, which probably implies a strong entropic penalty upon binding to the enzymes. Together, the present results illustrate the importance of taking conformational aspects into consideration in the design of functional oligosaccharide mimetics.     

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.     

2,7‐Di‐tert‐butylnaphtho[1,8‐cd][1,2]dithiole 1,2‐dioxides: Thermally Stable,Photochemically Active vic‐Disulfoxides

Bulking up: The thermal barrier to rearrangement of a vic‐disulfoxide is significantly increased through steric buttressing about the (O)S? S(O) bond. Whereas the title compounds represent the most thermally stable vic‐disulfoxides known to date, they also undergo a novel photomediated epimerization at room temperature (see scheme).

     

Water‐mediated intermolecular interactions in 1,2‐O‐cyclohexylidene‐myo‐inositol: a quantitative analysis

The syntheses of new myo‐inositol derivatives have received much attention due to their important biological activities. 1,2‐O‐Cyclohexylidene‐myo‐inositol is an important intermediate formed during the syntheses of certain myo‐inositol derivatives. We report herein the crystal structure of 1,2‐O‐cyclohexylidene‐myo‐inositol dihydrate, C₁₂H₂₀O₆·2H₂O, which is an intermediate formed during the syntheses of myo‐inositol phosphate derivatives, to demonstrate the participation of water molecules and hydroxy groups in the formation of several intermolecular O—H…O interactions, and to determine a low‐energy conformation. The title myo‐inositol derivative crystallizes with two water molecules in the asymmetric unit in the space group C 2/c , with Z = 8. The water molecules facilitate the formation of an extensive O—H…O hydrogen‐bonding network that assists in the formation of a dense crystal packing. Furthermore, geometrical optimization and frequency analysis was carried out using density functional theory (DFT) calculations with B3LYP hybrid functionals and 6‐31G(d), 6‐31G(d,p) and 6‐311G(d,p) basis sets. The theoretical and experimental structures were found to be very similar, with only slight deviations. The intermolecular interactions were quantitatively analysed using Hirshfeld surface analysis and 2D (two‐dimensional) fingerplot plots, and the total lattice energy was calculated.