Anisotropic and hydrogen bonding effects in phenylglyoxamides and mandelamides: theoretical and NMR conformational evaluation

Interesting anisotropic effects were observed for phenylglyoxamides and their respective mandelamides. Such effects were observed in experimental (1)H and (13)C NMR (in CDCl(3), CD(3)OD, and DMSO-d(6) solvents) and in some cases with good correlation to theoretical (1)H and (13)C NMR DFT-GIAO (B3LYP/6-311++G**//B3LYP/6-31G*) calculations. A systematic conformational analysis of these compounds was performed in a two-step methodology, using PM3 and DFT (B3LYP/6-31G*) calculations; with good accomplishment and computational time economy. It was observed that intramolecular hydrogen bonding plays a significant role in the conformation of such compounds. Finally, a geminal nonequivalence of an N-CH(2) moiety, in one of the alkyl side chain (R1 = R2), was found for the tertiary mandelamides studied.     

Conformational analysis and the binding sites of nitrilotriacetamide: A computational study

The conformational analysis of nitrilotriacetamide has been carried out computationally, at both the semi‐empirical AM1 and density functional theory (DFT) (B3LYP/6‐31+G*) levels of theory. The lowest‐energy conformation predicted with the Monte Carlo search method, using the AM1 model, has two amide functionalities aligned on the same side; however, the DFT calculations at B3LYP/6‐31+G* predicted the global minimum with all three acetamide functionalities on the same side in the gas phase. In the aqueous phase, the DFT results predicted the orientations of amides similar to that of the reported crystal structure. The rotation barriers to transition to different low‐energy conformers of nitrilotriacetamide are lower in energy (5.0 kcal/mol) in water. The molecular electrostatic isopotentials (MESP) generated for the selected conformers at DFT level show that the nitrilotriacetamide could interact more effectively with the sodium chloride surface than that of its monomeric unit nitrilomonoacetamide. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

Motuporamines, anti-invasion and anti-angiogenic alkaloids from the marine sponge Xestospongia exigua (Kirkpatrick): isolation, structure elucidation, analogue synthesis, and conformational analysis.

Extracts of the sponge Xestospongia exigua collected in Papua New Guinea were positive in a new assay for anti-invasion activity. Bioassay-guided fractionation led to the identification of the three known motuporamines A (1), B (2), and C (3) along with the new motuporamines D (4), E (5), and F (6) and a mixture of G, H, and I (15). Motuporamines A (1), B (2), and C (3) and the mixture of G, H, and I (15) were responsible for the anti-invasion activity of the crude extract. Motuporamine C (3) has also been found to be anti-angiogenic. A series of analogues of the motuporamines have been synthesized and evaluated for anti-invasive activity. These SAR results revealed that a saturated 15-membered cyclic amine fused to the natural motuporamine diamine side chain (13) represented the optimal structure for anti-invasive activity in this family. Single-crystal X-ray diffraction analysis of one of the analogues 20 showed that in the solid state its 16-membered macrocyclic amine fragment adopted the [4444] quadrangular conformation predicted by calculations to be the lowest energy conformation for the corresponding cycloalkane, cyclohexadecane. These data along with literature X-ray data and conformational analysis for derivatives of azacyclotridecane have been used as precedents for predicting the lowest energy ring conformations of other motuporamines. The SAR data from the natural and synthetic motuporamines have been combined with the conformational analyses to provide an outline of the functionality and shape required for activity in this family of alkaloids and to design a new analogue 49 that showed good anti-invasion activity.     

Langmuir monolayers of an inclusion complex formed by a new calixarene derivative and fullerene

The design of new molecules with directed interactions to functional molecules as complementary building blocks is one of the main goals of supramolecular chemistry. A new p-tert-butylcalix[6]arene monosubstituted derivative bearing only one alkyl chain with an acid group (C6A3C) has been synthesized. The C6A3C has been successfully used for building Langmuir monolayers at the air-water interface. The C6A3C molecule adopts a flatlike orientation with respect to the air-water interface. The molecular structure gives the molecule amphiphilic character, while allowing the control of both the dissociation degree and the molecular conformation at the air-water interface. The C63AC has been combined with pristine fullerene (C60) to form the supramolecular complex C6A3C:C60 in 2:1 molar ratio (CFC). The CFC complex retains the ability of C6A3C to form Langmuir monolayers at the air/water interface. The interfacial molecular arrangement of the CFC complex has been convincingly described by in situ UV-vis reflection spectroscopy and synchrotron X-ray reflectivity measurements. Computer simulations complement the experimental data, confirming a perpendicular orientation of the calixarene units of CFC with respect to the air-water interface. This orientation is stabilized by the formation of intermolecular H-bonds. The interfacial monolayer of the CFC supramolecular complex is proposed as a useful model for the well-defined self-assembly of recognition and functional building blocks.     

Synthesis and Crystal Structure of α-(N-Protected amino) β-lactam Derivative of 1,5-Benzothiazepine

The crystal of the title compound C, C30H30N2O3S has been prepared by reaction of 1,5-benzothiazepine with N-protected glycine and determined by X-ray single crystal diffraction. Crystal data: Mr=498.62, triclinic with P space group, a=10.880(2), b=13.955(3), c=9.537(2)(A), α=99.34(3)°, β=110.43(3)°, γ=88.56(3)°, V=1338.2(5)(A)3, F(000)=528, λ(MoKα)=0.71073(A), Z=2, Dc=1.237g/cm3, μ=0.154mm-1. Final R=0.0453, wR=0.1256 for 3491 observed reflections [I>2σ(I)]. Structure analysis reveals that the substituents at C(23) and C(7) in four-membered ring are located on the same side. The conformation of seven-membered ring is chair-like.     

Polyphenyl macrocyclic oligophenylenes

The Diels-Alder reaction of tribenzohexadehydro[12]annulene (12) and 3,4-diphenyl-2,5-dimethylcyclopentadienone (13) at 300 degrees C gave the triple adduct 2,3,10,11,18,19-hexaphenyl-1,4,9,12,17,20-hexamethylhexa-o-phenylene (6b) in 13% yield. NMR and X-ray analysis indicated that 6b adopts a screw conformation (C2) rather than a crown conformation (C3), and computational studies seem to rule out any interconversion of the two. Palladium-catalyzed coupling of 1,2-bis(4-bromophenyl)-3,4,5,6-tetraphenylbenzene (17) and the corresponding bis(boronic acid) 18 gave a mixture of linear and cyclic oligomers of hexaphenylbenzene containing two to six hexaphenylbenzene subunits. A macrocyclic tetramer was isolated from this mixture in 5% yield, and X-ray analysis showed it to be the "supertetraphenylene" 7 (C168H112) that contains a large central cavity and packs to form highly solvated, porous crystals. The difficulties encountered in the purification of 7 led to the development of alternative, more highly selective syntheses that give the pure macrocycle more easily but in essentially the same overall yield.     

Effect of peracylation of beta-cyclodextrin on the molecular structure and on the formation of inclusion complexes: an X-ray study.

The molecular structures of peracylated beta-cyclodextrins (CDs)--heptakis(2,3,6-tri-O-acetyl)-beta-CD (TA), heptakis(2,3,6-tri-O-propanoyl)-beta-CD (TP), and heptakis(2,3,6-tri-O-butanoyl)-beta-CD (TB)--have been determined by single crystal X-ray structure analysis. Due to the lack of O2...O3' hydrogen bonds between adjacent glucose units of the peracylated CDs, the macrocycles are elliptically distorted into nonplanar boat-shaped structures. The glucose units are tilted with respect to the O4 plane to relieve steric hindrance between adjacent acyl chains. In TB, all glucose units adopt the common (4)C(1)-chair conformation and one butanoyl chain intramolecularly penetrates the cavity, whereas, in TA and TP, one glucose unit each occurs in (O)S(2)-skew-boat conformation and one acyl chain closes the O6 side like a lid. In each of the three homologous molecules the intramolecular self-inclusion and lidlike orientation of acyl chains forces the associated O5-C5-C6-O6 torsion angle into a trans-conformation never observed before for unsubstituted CD; the inclusion behavior of TA, TP, and TB in solution has been studied by circular dichroism spectroscopy with the drug molsidomine and several organic compounds. No inclusion complexes are formed, which is attributed to the intramolecular closure of the molecular cavity by one of the acyl chains.     

Design of Peptides with α,β-Dehydro Residues: Synthesis,Crystal Structure and Molecular Conformation of a Peptide N-Boc-Phe-ΔPhe-Ile-OCH<Subscript>3</Subscript>

To develop a complete set of design rules with α,β-dehydro residues, a tripeptide N-Boc-Phe-ΔPhe-Ile-OCH₃ was synthesized. The synthesis was carried out in solution phase using azlactone procedure. The three-dimensional structure of the peptide was determined by X-ray diffraction method and refined to an R-factor of 0.085. The structure contains three peptide molecules in the asymmetric unit. In all the three crystallographically independent molecules ΔPhe residue adopts one of the three conformations that have been reported for a ΔPhe residue. The overall conformations of three peptide molecules in the asymmetric unit are not similar. Two out of three crystallographically independent molecules adopt type II β-turn conformations whereas the third molecule is found having the characteristic S-shaped conformation in which the values of dihedral angles φ, ψ have opposite signs alternately. One of these two types of conformations has been observed when a ΔPhe is introduced at (i+2) position of a tetrapeptide. The β-turn conformation is stabilized by a 4→1 hydrogen bond where the hydrophobic side chains of residues at (i+1) and (i+3) positions stabilized the unfolded conformation with van der Waals interactions. The three independent molecules are locked together by three hydrogen bonds between molecules A and B and two hydrogen bonds between molecules B and C.     

Parallel assembly of dipolar columns composed of a stacked cyclic tri-beta-peptide

A novel cyclic trimer of a beta-amino acid, trans-2-aminocyclohexylcarboxylic acid, was synthesized and its conformation and ability to form assemblies investigated. FT-IR and NMR measurements and computational calculations showed that this cyclic tri-beta-peptide has a C3-symmetric conformation with trans amide groups. A notable feature of the conformation is a vertical and parallel orientation of the three amide groups to the cyclic skeleton. The cyclic tri-beta-peptide was crystallized from a solution in trifluoroacetic acid-methanol (or trifluoroacetic acid-water) to yield a rod-shaped molecular assembly, as observed by TEM. The electron crystallography of the rod-shaped assembly both in suspension and in ultrathin cross-section revealed that the cyclic tri-beta-peptides were stacked up to form molecular columns, and that a two-fold screw symmetry operation along the column direction was present in the unit cell, which contained two cyclic tri-beta-peptides. This indicates that all the amide groups are oriented in the same direction. Since any two molecular columns are staggered by a quarter of a c-axis length and aligned parallel to each other, the dipole moments of the columns are aligned to enhance the strength additively in the whole assembly.     

Conformational analysis of a model synthetic prodiginine

A conformational analysis of a synthetic model prodiginine was carried out. In solution this compound showed a strong preference for the β conformation, in which all the heterocycles are mutually cis. This conformation provided an ideal alignment of the three N-H groups for interacting with anions when the molecule is protonated. A different conformation was also detected in d(6)-DMSO for the mesylate salt, assigned to the α conformation, in which the C ring is engaged in an intramolecular hydrogen bond with the OMe group. The formation of a homodimer was observed in concentrated CDCl(3) solutions of the neutral free base form of this prodiginine derivative. DFT calculations and the solid state structures of the hydrochloric and methanesulfonic acid salts were in good agreement with the results observed in solution. A complete study of the relative energies of different tautomers, isomers, and supramolecular complexes supported the preference for the β conformation both in water and in the gas phase.     

Hartree-Fock and density functional theory study of alpha-cyclodextrin conformers

Herein, we report the geometry optimization of four conformers of alpha-cyclodextrin (alpha-CD) by means of PM3, HF/STO-3G, HF/3-21G, HF/6-31G(d), B3LYP/6-31G(d), and X3LYP/6-31G(d) calculations. The analysis of several geometrical parameters indicates that all conformers possess bond lengths, angles, and dihedrals that agree fairly well with the crystalline structure of alpha-CD. However, only three of them (1-3) resemble the polar character of CDs and show intramolecular hydrogen-bonding patterns that agree with experimental NMR data. Among them, conformer 3 appears to be the most stable species both in the gas phase and in solution; therefore, it is expected to be the most suitable representative structure for alpha-CD conformation. The purpose of selecting such a species is to identify an appropriate structure to be employed as a starting point for reliable computational studies on complexation phenomena. Our results indicate that the choice of a particular alpha-CD conformer should affect the results of ab initio computational studies on the inclusion complexation with this cyclodextrin since both the direction and the magnitude of the dipole moment depend strongly on the conformation of alpha-CD.     

(C‐rac‐5,5,7,12,12,14‐Hexamethyl‐1,4,8,11‐tetraazacyclotetradecane‐κ4N)(nicotinato‐O,O′)nickel(II) perchlorate

In the title compound, [Ni(C₆H₄NO₂)(C₁₆H₃₆N₄)]ClO₄, the macrocyclic unit adopts a folded conformation, allowing the two carboxyl O atoms to occupy two neighbouring coordination sites and thus form an additional four‐membered chelate ring. The less crowded side of the macrocycle (that with the two asymmetric C—H groups) is directed towards the nicotinate anion and the asymmetric C—CH₃ groups are directed away from it. The macrocyclic NH groups neighbouring the C—CH₃ groups are also directed away from the nicotinate anion, while those NH groups which are near to the geminal methyl groups are directed towards the nicotinate anion. Although the complex does not include water mol­ecules, three types of hydrogen bond were found, involving NH groups of the macrocyclic ligand, pyridine N atoms and O atoms of the perchlorate anions.     

紫杉醚与αβ微管蛋白的分子对接

采用Insight II/Affinity对紫杉醚与αβ微管蛋白进行分子对接, 共得到10个对接构象. 应用密度泛函B3LYP/6-31G 方法计算对接口袋构象的结合能, 筛选出结合能达-190.53 kJ·mol-1的最优对接构象5. 通过构象分析建立紫杉醚与受体结合的作用模型, 结果表明, 在活性口袋的底部紫杉醚与受体间的作用主要是疏水作用, 而在活性口袋的顶部两者间主要是氢键作用. 氢键作用位置可分为A和B两个作用区, 其中A区有3个氢键, 由C13侧链分别与受体的ASP26和ARG369作用形成; B区也有3个氢键, 是由紫杉醚母环上的极性基团分别与受体的THR276、ARG278和GLN282作用产生的. 紫杉醚与αβ微管蛋白间形成的6个氢键可以有效地将紫杉醚固定在活性口袋中.     

A theoretical rationalization of the asymmetric induction in sulfinyl-directed [5C + 2C] intramolecular cycloadditions

A computational DFT examination (B3LYP/6-31G and B3LYP/6-311+G//B3LYP/6-31G) of the thermal [5C + 2C] cycloaddditions of 6-acetoxy-3-pyranones and 3-silyloxy-4-pyrones with tethered alkenyl sulfoxides confirms that the high level of diastereofacial selectivity obtained is ultimately due to the preference of the alkenesulfinyl group to adopt a well-defined conformation in the transition state of the reaction. This conformation, which is different from that found in the ground state, is most probably dictated by dipolar interaction effects between the sulfoxide and the oxidopyrylium ylide intermediate.     

Hydrogen-bonding directed cocrystallization of flexible piperazine with hydroxybenzoic acid derivatives: Structural diversity and synthon prediction

Four hydroxybenzoic acid building blocks,m-hydroxybenzoic acid,2,4-dihydroxybenzoic acid,2,5-dihydroxyterephthalic acid,and 5-hydroxyisophthalic acid,have been synthesized as robust cocrystallizing agents and employed in reactions with piperazine,including [(C4H12N22+).(C7H5O3)2 ](1),[(C4H12N22+).(C 7H5O4)2 ](2),[(C4H12N22+).(C8H5O62)](3),and [(C4H12N22+)1/2.(C8H5O5)].2H2O(4).Hydrogen-bonded directed assemblies of four salts were validated by single-crystal X-ray diffraction analysis.In compounds 1-4,hydroxybenzoic acids are all deprotonated and piperazine molecules are all protonated to form piperazine dications and keep the chair conformation.Thermal stability of these compounds has been investigated.     

Electrophilic substitution reaction of indole,part XXIV: Synthesis,characterization, and crystal structure of a novel heterocyclic compound

The reaction of indole with cyclohexanone in the presence of the Lewis acid, boron trifluoride diethyl etherate, resulted in the synthesis of a novel and interesting product ( 1 ) in addition to the bis(indolyl)methane system ( 2 ). The structure of this novel compound has been determined by NMR (¹H and ¹³C) and X‐ray crystal structure analysis. Compound 1 is a (1:2) addition reaction product of indole with cyclohexanone. The spiro six‐membered ring is in the classic chair conformation. An epoxide bridge at C‐4a/C‐10b and the two hydroxyl groups at C‐5a, C‐10a are all on the same side of the central five membered ring. J. Heterocyclic Chem., (2011).     

Peptide backbone folding induced by the C(alpha)-tetrasubstituted cyclic alpha-amino acids 4-amino-1,2-dithiolane-4-carboxylic acid (Adt) and 1-aminocyclopentane-1-carboxylic acid (Ac5c). A joint computational and experimental study

The conformational study of a new group of synthetic peptides containing 4-amino-1,2-dithiolane-4-carboxylic acid (Adt), a cysteine-related achiral residue, has been carried out through a joint application of computational and experimental methodologies. Molecular Dynamics simulations clearly suggest the tendency of this molecule to adopt a gamma-turn conformation in vacuum and help in analyzing the complex and crucial conformational behaviour of the dithiolane ring which appears to preferentially adopt a C(S)-like structure. Electronic structure calculations carried out in solution using the Density Functional Theory also indicate the preservation of the gamma-like folding in apolar solvents and the helix-like one in more polar solvents. A comparison with the achiral 1-aminocycloalkane-1-carboxylic acid (Ac5c) has been carried out using the same computational tools. NMR and IR data on dipeptide derivatives containing the Adt or Ac5c residue show that in chloroform solution all the models prefer a gamma-turn structure, centered at the cyclic residue, stabilized by an intramolecular H-bond, whereas in a more polar solvent, i.e. dimethyl sulfoxide, this folding is not maintained. The experimental conformational studies, extended to N-Boc protected tripeptides, clearly indicate the remarkable tendency of both the five-membered C(alpha)-tetrasubstituted cyclic amino acids Adt and Ac5c to induce the gamma-turn structure also in models able to adopt the beta-bend conformation.     

Ab initio study of the (5R)- and (5S)-TT pyrimidine h5(6-4) pyrimidone photoproducts. Implications on the design of new biologically relevant analogues

A computational study of a series of N(1)- and/or C(6)-alkyl-5,6-dihydrothymine diastereomers at theory levels up to MP4(SDTQ)/6-31G//HF/6-31G and MP2/6-311G//HF/6-31G has demonstrated the respective importance of the substituents at positions 1, 5, and 6 on the energetically favored conformation of each isomer. Results obtained both in the gas and condensed phase indicate that unsubstitution of the N(1)-position favors a half-chair conformation with the C(5) -and C(6)-substituents in the equatorial position. On the other hand, in the case of the (6S)-1,6-dimethyl-5,6-dihydrothymine, the C(6)-substituent adopts the axial position to minimize its van der Waals interactions with the N(1)-substituent. Furthermore, if the configuration at the C(5)-dihydrothymine position has no resultant influence on the total molecular free energy, when a pyrimidone substituent is introduced at the dihydrothymine C(6)-position, additional repulsive forces between the C(5)- and C(6)-substituents make the diaxially substituted half-chair conformation the most energetically favorable one. These results indicate that the observed C(6)-axially substituted conformation of the thymine-thymine pyrimidine h(5)(6-4) pyrimidone photoproducts is not necessarily induced by the macrocyclic structure. They also nicely explain the formation mechanism of these photoproduct derivatives, and allow the prediction of the conformation of new analogues.     

Use of the tubulin bound paclitaxel conformation for structure-based rational drug design

A new computational docking protocol has been developed and used in combination with conformational information inferred from REDOR-NMR experiments on microtubule bound 2-(p-fluorobenzoyl)paclitaxel to delineate a unique tubulin binding structure of paclitaxel. A conformationally constrained macrocyclic taxoid bearing a linker between the C-14 and C-3'N positions has been designed and synthesized to enforce this "REDOR-taxol" conformation. The novel taxoid SB-T-2053 inhibits the growth of MCF-7 and LCC-6 human breast cancer cells (wild-type and drug resistant) on the same order of magnitude as paclitaxel. Moreover, SB-T-2053 induces in vitro tubulin polymerization at least as well as paclitaxel, which directly validates our drug design process. These results open a new avenue for drug design of next generation taxoids and other microtubule-stabilizing agents based on the refined structural information of drug-tubulin complexes, in accordance with typical enzyme-inhibitor medicinal chemistry precepts.     

The reactions of alkylamino substituted phosphines with I2 and (Ph2Se2I2)2: structural features of alkylamino phosphonium cations

The reactions of the tris-dialkylamino phosphines (Et2N)3P and (nPr2N)3P, and the pyrrolidinyl substituted phosphines (C4H8N)3P and tBuP(NC4H8)2, with I2 and (Ph2Se2I2)2, have been reported. The reactions with diiodine lead to the formation of [R3PI]I adducts, which are essentially ionic, but show a tendency to display long, soft-soft, II interactions in the solid state. The crystal structures of [(Et2N)3PI]I, (1), [(nPr2N)3PI]I, (2), and [(C4H8N)3PI]I, (3), have all been determined, and display II interactions varying between 3.5170(6) and 3.6389(14) A. The analogous reactions with (Ph2Se2I2)2 lead to the formation of phenylseleno-phosphonium salts, [R3PSePh]I. The structures of [(C4H8N)3PSePh]I, (6) and [(C4H8N)2tBuPSePh] I, (7), have been determined and do not display any soft-soft interactions between the selenium and iodine atoms. All of the phosphonium salts represent examples of structures containing tris-dialkylamino phosphine fragments which show no special nitrogen atom, i.e. all three nitrogen atoms are planar. This type of arrangement is usually observed when a C3 symmetric conformation is observed, (which is the case for 1 and 2), but not for the (C4H8N)3P adducts 3 and 6, where the conformation is closer to Cs, although the nitrogen atoms are still essentially planar. The P-N bonds in all the compounds reported herein are short, ranging between 1.599(12) A and 1.643(12) A, and are consistent with the previously reported short P-N bonds in phosphonium salts featuring tris-dialkylamino substituted phosphines.