Benzenesulfonylcarbonitrile oxide. 5. Face selectivity of cycloaddition to chiral terminal alkenes

The diastereomer ratio for cycloaddition of benzenesulfonylcarbonitrile oxide (BSNO) to a series of (S)-vinylglycine-derived alkenes varied from 30:70 to 66:34 depending on the substitutents at the chiral center. Isomer ratios were routinely determined by ¹H-NMR; isolation confirmed the results in several cases. Isomer assignment was based on comparison to acivicin where the absolute configuration has been determined by X-ray analysis. The results are interpreted as consistent with competitive cycloaddition to the alkene oriented in two differing conformations.     

Helical conformations of isotactic polyacetaldehyde and other isotactic polytrihaloacetaldehydes

Minimum potential energy helical conformations for a family of four isotactic polyacetaldehydes have been determined. Our results indicate that all of the polymers form irrational helices. Comparisons have been made with the reported structures for two of these stereoregular polymers based on earlier X-ray diffraction data. c-Axis values associated with the pitch of the helix for polyacetaldehyde and for polytrichloroacetaldehyde (polychloral) were experimentally measured to be 0.48 and 0.51 nm, respectively. Our calculated conformations afforded values for a helix pitch of 0.47 and 0.52 nm, respectively, which derive from a 3.9/1 helix for polyacetaldehyde and a 3.7/1 helix for polychloral. The structure for polytribromoacetaldehyde (polybromal) was predicted to be similar to that for polychloral. For polytrifluoroacetaldehyde (polyfluoral) and polyacetaldehyde, a number of helical conformations with similar energies were found. All of these conformations could be related to the polychloral helical structure. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 1855–1860, 1998     

Pattern recognition in the prediction of protein structure. III. An importance-sampling minimization procedure

A procedure that generates random conformations of a protein chain, and then applies energy minimization to find the structure of lowest energy, is described. Single-residue conformations are represented in terms of four conformational states, α, ?, α*, and ?*. Each state corresponds to a rectangular region in the ?, ψ map. The conformation of an entire chain is then represented by a sequence of single-residue conformational states. The distinct “chain-states” in this representation correspond to multidimensional rectangular regions in the conformational space of the whole protein. A set of highly-probable chain-states can be predicted from the amino acid sequence using the pattern recognition procedure developed in the first two articles of this series. The importance-sampling minimization procedure of the present article is then used to explore the regions of conformational space corresponding to each of these chain-states. The importance-sampling procedure generates a number of random conformations within a particular multidimensional rectangular region, sampling most densely from the most probable, or “important,” sections of the ?, ψ map. All values of ? and ψ are allowed, but the less-probable values are sampled less often. To achieve this, the random values of ? and Φ are generated from bivariate gaussian distributions that are determined from known X-ray structures. Separate gaussian distributions are used for proline residues in the α and ? states, for glycine residues in the α, ?, α*, and ?* states, and for ordinary residues involved in 29 different tripeptide conformations. Energy minimization is then applied to the randomly-generated structures to optimize interactions and to improve packing. The final energy values are used to select the best structures. The importance-sampling minimization procedure is tested on the avian pancreatic polypeptide, using chain-states predicted from the amino acid sequence. The conformation having the lowest energy is very similar to the X-ray conformation.     

Molecular modelling prediction of ligand binding site flexibility

We have investigated the efficacy of generating multiple sidechain conformations using a rotamer library in order to find the experimentally observed ligand binding site conformation of a protein in the presence of a bound ligand. We made use of a recently published algorithm that performs an exhaustive conformational search using a rotamer library to enumerate all possible sidechain conformations in a binding site. This approach was applied to a dataset of proteins whose structures were determined by X-ray and NMR methods. All chosen proteins had two or more structures, generally involving different bound ligands. By taking one of these structures as a reference, we were able in most cases to successfully reproduce the experimentally determined conformations of the other structures, as well as to suggest alternative low-energy conformations of the binding site. In those few cases where this procedure failed, we observed that the bound ligand had induced a high-energy conformation of the binding site. These results suggest that for most proteins that exhibit limited backbone motion, ligands tend to bind to low energy conformations of their binding sites. Our results also reveal that it is possible in most cases to use a rotamer search-based approach to predict alternative low-energy protein binding site conformations that can be used by different ligands. This opens the possibility of incorporating alternative binding site conformations to improve the efficacy of docking and structure-based drug design algorithms.     

Crystal structure-reactivity correlation in single-crystalline photochromism of 1,2-bis(2-methyl-5-phenyl-3-thienyl)perfluorocyclopentene

Single-crystalline photochromism of 1,2-bis(2-methyl-5-phenyl-3-thienyl)perfluorocyclopentene 1a was followed in situ by X-ray crystallographic analysis. The crystal of 1a has two molecules with different conformations in the crystallographic asymmetric unit. The X-ray analysis of the photoirradiated crystal showed that the photocyclization reaction of the molecule with the shorter distance between the reactive carbons prevails over the reaction of the other molecule. The mechanism has been discussed based on the calculation of the electronic transitions of the two molecules in the different conformations. The photocyclization quantum yield was determined to be 1 (100%) in the crystal.     

Elucidation of the methyl transfer mechanism catalyzed by chalcone O-methyltransferase: a density functional study

The mechanism of the methyl transfer catalyzed by chalcone O-methyltransferase has been computationally investigated by employing the hybrid functional B3LYP. Two models are constructed based on the two conformations of the substrate isoliquiritigenin in the X-ray structure. Our calculations show that the overall reaction is divided into two elementary steps: the water-assisted deprotonation of the substrate by His278 as a catalytic base, followed by the methyl transfer from S-adenosyl-L-methionine (SAM) to the substrate. The calculated rate-limiting barriers for the methyl-transfer step indicate that the catalytic reactions are energetically feasible for both conformations adopted by the substrate.     

Enantioselective catalysis. Part 133: Conformational analysis of amides of 9-amino(9-deoxy)epicinchonine

Amides of 9-amino(9-deoxy)epicinchonine have been used as chiral base catalysts to induce asymmetry in enantioselective decarboxylation reactions. To understand the reaction mechanism and to optimize the bases by variation of the amide substituents, a detailed knowledge of their preferred conformation is necessary. The conformations were investigated by ¹H NMR spectroscopy, X-ray analysis and semi-empirical molecular orbital calculations. Principally, cinchona alkaloids may adopt four different conformations (Fig. 1

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Figure 1. Schematic drawings illustrating the two closed and open conformations of 9-amino(9-deoxy)epicinchonine derivatives

), of which open b and open b′ are preferred by 2-ethoxy-N-(9-deoxyepicinchonine-9-yl)benzamide 2 in solution. AM1 Calculations confirm these results, and the small energy barrier between the two open conformations explains their simultaneous existence in solution. Crystal structure analyses of various amides show open conformations in the solid state. Local minimum energy conformations were found for open conformations of the compound 2 protonated at the quinuclidine system, which is the active species in the enantioselective decarboxylation reaction.     

A Dynamic Study of the Stereoisomerization of Pentaphenylethane by Molecular Mechanics Methods

Two conformations, 1 and 2 , of pentaphenylethane are compared. The ground state conformation 2 results from an earlier computational work by force fields procedures [1], whereas 1 has been more recently observed in the crystalline state by X-ray diffraction methods. The strain energy of 1 minimizes very close to the value computed for 2 . These conformations belong to two distinct minima of the potential energy surface and are at the most separated by a barrier of about 7 kcal/mol. The pathway converting 1 into its enantiomer is shown to run over a barrier of only 1.5 kcal/mol.     

A conformational study of bis-, tris- and tetrakis-pyrazolylmethane. Crystallography, L.S.R., dipole moments and theoretical calculations

Theoretical calculations (MM2 and MNDO) have been carried out on several conformations of bis-, tris- and tetrakispyrazolylmethane. The potential surface thus obtained has been compared with experimental results both in solution (lanthanide shift reagents, dipole moments) and in the solid state (crystallography). The structure of tetrakispyrazolylmethane (3) was determined by X-ray diffraction. The compound crystallizes in the C2/c space group, with a cell of dimensions 29.5117(14), 6.9815(2), 13.8903(4) Å and 105.237(3)°. The molecule presents an approximate S₄( ) axis such as N12, N22, N32 and N42 form a distorted tetrahedron. The calculated conformations of minimum energy are consistent with dielectric measurements. The structure of 3 in the solid state lies 5.0 kcal.mol-1 above the minimum as a result of the crystal field. To explain the LSR results, a coordination with two pyrazole nuclei has to be assumed. The presence of a metal (LSR, organometallic complexes) strongly modifies the conformation: in these conditions, bidentated and tridentated structures are observed.     

Structures and conformational dynamics of gold(I) halide complexes of resorcinarene tetraphosphinite ligands

Gold(I) halide derivatives of several tetrakis(diphenylphosphinite) tetraester resorcinarene compounds have been prepared. The complexes are shown to exist in boat conformations, and two different boat conformations were characterized by X-ray structure determinations; the structural characterization of both boat conformations of the same parent resorcinarene is unprecedented. Intramolecular Au.Au interactions were observed in the solid state for both boat conformers and could cause twisting of the resorcinarene skeleton. Several of the complexes exist in solution as an equilibrium mixture of the two different boat conformers, and the equilibrium and dynamics of exchange were studied by variable-temperature NMR.     

Anti and gauche conformers of an inorganic butane analogue, NH3BH2NH2BH3

The crystal structures of an inorganic butane analogue, NH(3)BH(2)NH(2)BH(3) (DDAB), were determined using single crystal X-ray diffraction, revealing both anti and gauche conformations. The anti conformation is stabilized by intermolecular dihydrogen bonds in the crystal whereas two gauche conformations of DDAB observed in its 18-crown-6 adducts are stabilized by an intramolecular dihydrogen bond. The two gauche conformations show rotational isomerization but whether they are a pair of enantiomers is yet to be defined.     

Conformational studies by dynamic NMR. 88.(1) stereomutation processes in the diastereoisomers of a representative amino alcohol and related amide precursors

The barriers for three internal motions (i.e., phenyl and tert-butyl rotation as well as N-inversion) have been determined by dynamic NMR spectroscopy in the two diastereoisomeric forms of a typical amino alcohol [dimethylamino-2,4,4-trimethyl-3-phenyl-3-pentanol, Me(2)NCH(2)CHMeC(OH)PhBu(t)]. The two structures were assigned by connection with those of the corresponding amide precursors determined by single-crystal X-ray diffraction. These amides (C=O in place of CH(2)) too were found to undertake internal motions amenable to NMR observation, i.e., phenyl, tert-butyl, and N-CO rotations: the corresponding barriers were also measured. Ab initio computations indicate that H-bonding makes all these molecules adopt six-membered cyclic conformations, a conclusion which agrees well with the X-ray crystal structure determined for the amide precursors.     

Conformational variability in a new terpenoid-like bischalcone: Structure and theoretical studies

A new terpenoid-like bischalcone (1E,4E)-1-(4-nitrophenyl)-5-(2,6,6-trimethylcyclohex-1-enyl)-penta-1,4-dien-3-one was synthesized from a β-ionone and 4-nitrobenzaldehyde by Claisen-Schmidt condensation reaction and its structure was determined by single crystal X-ray diffraction analysis. Additionally, this compound was featured by powder X-ray diffraction, ¹H, ¹³C NMR and IR spectroscopy techniques. The molecule in the asymmetric unit showed disordered occupancy sites over two positions for the trimethylcyclohexene atoms. These two conformations were related by a rotation of about 180° around the axis of the C-C bond linking the six-membered ring and the olefin carbons. Single-molecule calculations using the DFT method have strengthened this structural finding, since our theoretical approaches also suggest two well-defined conformations of similar energies which resemble the molecular geometries determined by X-ray diffraction. Furthermore, the inspection of the crystal packing revealed that the hydrogen bonding patterns are different for each conformation of the compound reported here.     

Conformational Analysis of Free and Bound Retinoic Acid

The conformational profiles of unbound all-trans and 9-cis retinoic acid (RA) have been determined using classical and quantum mechanical calculations. Sixty-six all-trans-RA (ATRA) and forty-eight 9-cis-RA energy minimum conformers were identified via HF/6-31G* geometry optimizations in vacuo. Their relative conformational energies were estimated utilizing the M06, M06-2x and MP2 methods combined with the 6-311+G(d,p), aug-cc-pVDZ and aug-cc-pVTZ basis sets, as well as complete basis set MP2 extrapolations using the latter two basis sets. Single-point energy calculations performed with the M06-2x density functional were found to yield similar results to MP2/CBS for the low-energy retinoic acid conformations. Not unexpectedly, the conformational propensities of retinoic acid were governed by the orientation and arrangement of the torsion angles associated with the polyene tail. We also used previously reported QM/MM X-ray refinement results on four ATRA-protein crystal structures plus one newly refined 9-cis-RA complex (PDB ID 1XDK) in order to investigate the conformational preferences of bound retinoic acid. In the re-refined RA conformers the conjugated double bonds are nearly coplanar, which is consistent with the global minimum identified by the Omega/QM method rather than the corresponding crystallographically determined conformations given in the PDB. Consequently, a 91.3% average reduction of the local strain energy in the gas phase, as well as 92.1% in PCM solvent, was observed using the QM/MM refined structures versus the PDB deposited RA conformations. These results thus demonstrate that our QM/MM X-ray refinement approach can significantly enhance the quality of X-ray crystal structures refined by conventional refinement protocols, thereby providing reliable drug-target structural information for use in structure-based drug discovery applications.     

How to use a very simple microcomputing system for a dynamical conformational analysis of versatile molecules. The case of some anticancer inorganic ring systems

A very simple use of a suitable microcomputing system allows discrimination of a set of X-ray structures of anticancer drugs which (i) are the “natural” preferred conformations and (ii) are the direct relationships logically linking these conformations together. Such an approach appears the main interest for a deep understanding of the relative antitumour activities of drugs, whatever the target may be.     

Synthesis, structure, magnetic properties and molecular mechanics study on the dinuclear copper (II) with biradical

Dinuclear copper complex with biradicals [Cu(hfac)2]2PhBNM(PhBNM = 2,5-bimethyl-1,4-bis(4,4,5,5-tetramethyllimidazoline-1-oxyl-3-oxide)phenyl,hfac=hexafluoroacetylacetonate) has been synthesized and characterized. It crystallized in the monoclinic system, with space group C2/c, a=1.9012(4), b=1.3718(3), c=2.1620(4) nm, β=97.55(3)°, Z=4. The X-ray structure analysis shows that the molecular structure consists of two kinds of conformations. The ratio of them is 7:3. The energy of two conformations, calculated with molecular mechanics, are different, E1=740 kJ/mol, and E2=771 kJ · mol-1. The CNDO/k results on the complex indicate that the orbital energy of low spin state is lower than that of high spin state, which correspond with the results of magnetic measurement.     

Expanding cavitand chemistry: the preparation and characterization of [n]cavitands with n>=4

The preparation of cavitands composed of 4, 5, 6, and 7 aromatic subunits ([n]cavitands, n=4-7) is described. The simple, two-step synthetic procedure utilized readily available starting materials (2-methylresorcinol and diethoxymethane). The two cavitand products having 4 and 5 aromatic subunits exhibited highly symmetric cone conformations, while the larger cavitands (n = 6 and 7) adopt conformations of lower symmetry. 1H NMR spectroscopic studies of [6]cavitand and [7]cavitand revealed that these hosts undergo exchange between equivalent conformations at room temperature. The departure of these two cavitands from cone conformations is related to steric crowding on their Ar-O-CH2-OAr bridges and is predicted by simple molecular mechanics calculations (MM2 force field). X-ray diffraction studies on single crystals of the [4]cavitand, [5]cavitand, and [6]cavitand hosts afforded additional experimental support for these conclusions.     

Conformational analysis: crystallographic,NMR, and molecular mechanics studies of flexible sulfonic esters

Two novel X-ray structures of the sulfonic ester derivatives 2-(6-iodo-1,3-benzodioxol-5-yl)ethyl 4-nitrobenzenesulfonate, 3, and 2-(6-iodo-1,3-benzodioxol-5-yl)ethyl 4-methylbenzenesulfonate, 4, have been obtained in a study aimed at analyzing the structures and conformations of sulfonic ester derivatives that are routinely used in alkaloid syntheses. The crystal structure of 4 is highly unusual, containing four independent molecules that belong to two distinct conformational types: (1) a hairpin conformation (stabilized mainly by intramolecular pi-stacking) and (2) a stepped conformation (stabilized mainly by intermolecular pi-stacking). Compound 3, on the other hand, crystallizes exclusively as the hairpin conformer. New MM+ force field parameters for sulfonic esters have been developed using the X-ray data, empirical rules, and DFT calculations to estimate the bond dipole parameters. Grid searches of conformational space for 3 and 4 using MM methods show that there are several gas-phase conformations within 5 kcal/mol of the global minimum and that the lowest energy conformations (by approximately 4.6 kcal/mol) are of the hairpin type. Analysis of the MM conformational energies suggests that the dominant intramolecular interaction stabilizing the hairpin conformations of 3 and 4 is van der Waals attraction. Moreover, the lattice energies for packing the hairpin conformations of 3 and 4 are approximately 4 kcal/mol more favorable than for the stepped conformations. Various intermolecular interactions contribute to the complexity of the observed crystal structures of 3 and 4, including electrostatic attraction between O and I atoms in neighboring molecules. Langevin dynamics (LD) simulations at several temperatures (6.0 ns, friction coefficient = 2.5 ps(-1)) indicate that the conformational exchange rates are approximately 10(10)-10(11) s(-1) over the temperature range 213-400 K, accounting for the temperature-independent (1)H NMR spectra of 3 and 4.     

Hydrolysis of glutaric anhydride to glutaric acid in the presence of β-cyclodextrin. Crystallographic and NMR study

Crystallization of glutaric anhydride in the presence of β-cyclodextrin (βCD) from aqueous solution resulted in crystals of the glutaric acid/βCD inclusion complex. The result was verified by NMR spectroscopic experiments, which moreover showed that βCD does not protect glutaric anhydride from hydrolysis. The structure determination by X-ray crystallography revealed a host:guest ratio of 1:1 and crystal packing identical to that of natural βCD, i.e., herring bone packing, as is common for guest molecules of small size. Glutaric acid has partial occupancy in the complex and it is disordered in three positions and conformations inside the cavity. All three conformations are stabilised by: (a) Interactions among its carboxyl groups and the host’s primary side hydroxyls pointing towards the cavity, thus justifying the conformations of the latter and (b) by two water molecules located on either side of the cavity, as well as hydroxyl groups of neighbouring hosts. In all conformations the guest is not extended, oxygen atoms between the two carboxyl groups being within H-bond distance.