Tetrahydrofuran Calpha-tetrasubstituted amino acids: two consecutive beta-turns in a crystalline linear tripeptide

The synthesis of tetrahydrofuran Calpha-tetrasubstituted amino acids (TAAs) and their effect on the conformation in small peptides are reported. The synthesis starts from the protein amino acid methionine, which is protected at the C and N terminus and converted into the corresponding sulfonium salt by alkylation. Simple base treatment in the presence of an aryl aldehyde leads to the formation of tetrahydrofuran tetrasubstituted Calpha-amino acids in a highly diastereoselective (trans/cis ratio up to 97:3) reaction with moderate to good yields (35-78%) depending on the aldehyde used. Palladium-catalyzed coupling reactions allow a subsequent further functionalization of the TAA. The R,S,S-TAA-Ala dipeptide amide adopts a beta-turn type I conformation, whereas its S,R,S isomer does not. The R,S,S-Gly-TAA-Ala tripeptide amide shows in the solid state and in solution a conformation of two consecutive beta-turn type III structures, stabilized by i+3-->i intramolecular hydrogen bonds.     

Conformational aspects of glutathione tripeptide: electron density topological & natural bond orbital analyses

Glutathione tripeptide (γ-glutamyl-cysteinyl-glycine) is a flexible molecule and its conformational energy landscape is strongly influenced by forming intramolecular hydrogen bond, its charge and the environment. This study employs DFT-B3LYP method with the 6-31+G (d,p) basis set to carry out conformational analysis of neutral, zwitterionic, cationic, and anionic forms of glutathione. In analyzing the structural characteristics of these structures, intramolecular hydrogen bonds were identified and characterized in details by topological parameters such as electron density ρ(r) and Laplacian of electron density $ \nabla^{2} $ ρ(r) from Bader’s atom in molecules theory. Charge transfer energies based on natural bond orbital analysis are also considered to interpret these intramolecular hydrogen bonds. Our results show that these hydrogen bonds are partially electrostatic and partially covalent in nature, in which the covalent contribution increases as the stabilization energy of hydrogen bond increases. Furthermore, the back bone and side chain (Ramachandran map) orientations of various ionic forms of glutathione have been studied and conformation of each constitution of glutathione tripeptide (i.e., Glu, Cys, and Gly moieties) was determined. In most species side chain conformation were found to be hindered gauche–gauche orientation by intramolecular hydrogen bonds.     

Interactions of glutathione tripeptide with gold cluster: influence of intramolecular hydrogen bond on complexation behavior

Understanding the nature of the interaction between metal nanoparticles and biomolecules has been important in the development and design of sensors. In this paper, structural, electronic, and bonding properties of the neutral and anionic forms of glutathione tripeptide (GSH) complexes with a Au(3) cluster were studied using the DFT-B3LYP with 6-31+G**-LANL2DZ mixed basis set. Binding of glutathione with the gold cluster is governed by two different kinds of interactions: Au-X (X = N, O, and S) anchoring bond and Au···H-X nonconventional hydrogen bonding. The influence of the intramolecular hydrogen bonding of glutathione on the interaction of this peptide with the gold cluster has been investigated. To gain insight on the role of intramolecular hydrogen bonding on Au-GSH interaction, we compared interaction energies of Au-GSH complexes with those of cystein and glycine components. Our results demonstrated that, in spite of the ability of cystein to form highly stable metal-sulfide interaction, complexation behavior of glutathione is governed by its intramolecular backbone hydrogen bonding. The quantum theory of atom in molecule (QTAIM) and natural bond orbital analysis (NBO) have also been applied to interpret the nature of interactions in Au-GSH complexes. Finally, conformational flexibility of glutathione during complexation with the Au(3) cluster was investigated by means of monitoring Ramachandran angles.     

Influence of N(1) protonation on the orientation of the N(6) substituent in hypermodified nucleic acid base N6-(N-glycylcarbonyl) adenine

The influence of protonation at N(1) on the conformational preferences of the N(6) substituent in the modified nucleic acid base N⁶-(N-glycylcarbonyl) adenine, gc⁶Ade, was investigated by the quantum chemical perturbative configuration interaction using localized orbitals (PCILO) method. The preferred orientation of the glycylcarbonyl substituent changes on the protonation of N(1). In the preferred conformation, the carbonyl oxygen O(10) is placed on the same side as N(1)H and provides stabilization through intramolecular hydrogen bonding of O(10) with HN(1). The amino acid component is so oriented that the carboxyl oxygen O(13b) is aligned closely with the N(6)H direction. Thus, the preferred molecular orientation is further stabilized by intramolecular hydrogen bonding involving HN(6) with O(13b). The alternative conformation has 0.5 kcal/mol higher energy than has the preferred conformation. The preferred conformation is about 1 kcal/mol more stable than is the conformation obtained by the flipping of torsion angle β alone, from the favored orientation for the unprotonated gc⁶Ade. © 1997 John Wiley & Sons, Inc. Int J Quant Chem 62: 551–556, 1997     

Enforcing solution phase nanoscopic aggregation in a palindromic tripeptide

C-terminal dimerization of a tripeptide palindrome afforded fibrillation in solution through an assembly probably driven by hydrogen bonding and hydrophobic contributions; such an approach provides an expeditious entry into fabrication of fibrillating peptides from non-fibrillating peptide sequences.     

A new class of linear tetrapyrroles: acetylenic 10,10a-didehydro-10a-homobilirubins

Novel bilirubin analogues with dipyrrinones conjoined to an acetylene rather than a methylene group were synthesized and examined spectroscopically. Despite the increased separation of the dipyrrinones forced by replacing a -CH(2)- by a -C(triple bond)C- unit, molecular dynamics calculations show that, like bilirubin, they may still engage in intramolecular hydrogen bonding to carboxylic acid groups when the propionic acid chains are slightly lengthened, e.g., butanoic acids. Unlike bilirubin, however, which is bent in the middle and has a ridge-tile shape, the acetylene orients the attached dipyrrinones along a linear path, and intramolecular hydrogen bonding preserves a twisted linear molecular shape. The extended planes of the dipyrrinones intersect along the -C(triple bond)C- axis at an angle of 136 degrees for the conformation stabilized by intramolecular hydrogen bonding in the bis-butyric acid rubin (1b). With shorter acid chains (propionic), only one CO(2)H can engage an opposing dipyrrinone in intramolecular hydrogen bonding, and in this energy-minimum conformation of the linear pigment 1a, the intersection of the extended planes of the dipyrrinones has an angle of 171 degrees. Spectroscopic evidence for such linearized and twisted structures was found in the pigments' NMR spectral data and their exciton UV-vis and induced circular dichroism spectra.     

The fixed conformation of the leucyl side-chain in a tripeptide

The complete analysis of the ¹H NMR spectrum of the leucyl side-chain of a tripeptide allows the deduction of the conformation of this side-chain. In the peptide, in contrast to the free amino acid, the side-chain is in a single fixed conformation.     

Oligo(p-phenyleneethynylene)s with hydrogen-bonded coplanar conformation

A series of monodispersed oligo( p-phenyleneethynylene)s were synthesized bearing intramolecular hydrogen bonds between side chains of adjacent phenylene units in the backbone. Thus, all repeating units of the molecules are constrained in a coplanar orientation. Such planarized conformation is considered favorable for single-molecule conductance. Photophysical characterization results show narrowed bandgaps and extended conjugation lengths, consistent with a rigid, planar backbone framework as a result of intramolecular hydrogen bonding.     

A novel intramolecular hydrogen bonding between a side-chain pyridine ring and an amide hydrogen of the peptide backbone in tripeptides containing the new amino acid, alpha,alpha-di(2-pyridyl)glycine

Four tripeptides (Z-AA1-2Dpy-AA3-OMe; AA1, AA3 = Gly, Aib) containing a novel amino acid, alpha, alpha-di(2-pyridyl)glycine (2Dpy), were synthesized by the modified Ugi reaction. NMR analysis clearly indicated that the 2Dpy-containing tripeptides except the peptide in which AA1, AA3 = Aib, adopt a unique conformation with two intramolecular hydrogen bonds between 2Dpy-NH and a pyridine nitrogen and between AA3-NH and another pyridine nitrogen. This conformation has so far not been reported. On the other hand, the peptide Z-Aib-2Dpy-Aib-OMe probably adopts a beta-turn structure which is stabilized by two intramolecular hydrogen bonds between 2Dpy-NH and a pyridine nitrogen and between AA3-NH and the C=O of the Z group.     

Intramolecular hydrogen bonding in disubstituted ethanes. A comparison of NH...O- and OH...O- Hydrogen bonding through conformational analysis of 4-amino-4-oxobutanoate (succinamate) and monohydrogen 1,4-butanoate (monohydrogen succinate) anions

Relative strengths of amide NH...O- and carboxyl OH...O- hydrogen bonds were investigated via conformational analysis of succinamate and monohydrogen succinate anions with the aid of vicinal proton-proton NMR couplings and B3LYP DFT quantum mechanical calculations for a variety of solvents. New experimental results for succinamate are compared with those obtained from previous studies of monohydrogen succinate. While some computational results for monohydrogen succinate were published previously, the results contained herein are the product of a more powerful methodology than that used earlier. The experimental results clearly show that intramolecular hydrogen-bond formation is more favored in aprotic solvents than in protic solvents for both molecules. Furthermore, the preference of the succinate monoanion for the gauche conformation is much stronger in aprotic solvents than that of succinamate, indicating that the OH...O- hydrogen bond is substantially stronger than its NH...O- counterpart, despite the approximately 5 kcal cost for formation of the E configuration of the carboxyl group needed to make an intramolecular hydrogen bond. The actual energy differences between formation of internal hydrogen bonds for monohydrogen succinate and succinamate anion were estimated by comparison of the relative values of K1 of the respective acids in water and DMSO by a procedure first developed by Westheimer. Recent theoretical work with succinamate highlights the necessity of considering substituent orientational degrees of freedom to understand the conformational equilibria of the central CH2-CH2 torsions in disubstituted ethanes. Similar methodology is applied here to succinic acid monoanion, by mapping potential-energy surfaces with respect to the CH2-CH2 torsional, carboxyl-substituent rotational, and carboxyl-proton E/Z isomeric degrees of freedom. Boltzmann populations were compared with gauche populations estimated from the experimentally determined coupling constants. The quantum mechanical results for succinamate show a much weaker tendency toward hydrogen bonding than for the succinic acid monoanion. However, the theoretical methods employed appear to substantially overestimate contributions from intramolecularly hydrogen-bonded structures for the succinic acid monoanion when compared with experimental results. Natural bond orbital analysis, applied to the quantum mechanical wave functions of fully optimized gauche and trans structures, showed a strong correlation between the population of amide sigma*(N-H) and carboxyl sigma*(O-H) antibonding orbitals and apparent hydrogen-bonding behavior.     

Toward an amphiphilic bilirubin: the crystal structure of a bilirubin e-isomer

A new bilirubinoid analog (1) with two methoxy beta-substituents on the lactam ring of each dipyrrinone was synthesized and examined spectroscopically. It is more soluble in CH3OH and CHCl3 than bilirubin, which is insoluble in CH3OH but soluble in CHCl3. The solubility of 1 is approximately 10 microg/mL in CH3OH (vs < or =1 microg/mL for bilirubin) and approximately 3 mg/mL in CHCl3 (vs approximately 0.6 mg/mL for bilirubin). Vapor pressure osmometry indicates that 1, like bilirubin, is monomeric in CHCl3, and NMR studies show that the most stable structure has the syn-4Z,syn-15Z configuration, with the pigment's dipyrrinones engaged in intramolecular hydrogen bonding to the propionic acid carboxyl groups. And, like bilirubin, Z,Z-1 adopts a conformation that is bent in the middle into a ridge-tile shape. For the first time, a crystal structure of a bilirubin E-isomer has been obtained. Crystallization of 1 under dim room lighting gave an X-ray quality crystal of the anti-4E,syn-15Z-(photo) isomer, in which only the Z-dipyrrinone half is engaged in intramolecular hydrogen bonding to a propionic acid. Hydrogen bonding is nearly completely disengaged in the E-dipyrrinone half; yet, the ridge-tile conformation persists.     

Anion detection driven by a surprising internal hydrogen-bonding association in a dinuclear rhenium(I) complex

A neutral dinuclear rhenium(I) bipyridinetricarbonyl bromide complex has been investigated with a range of anions, giving a remarkable binding affinity for dihydrogenphosphate. These studies highlight that anion sensing can be achieved with structurally simple species provided that the compound adopts an unconventional conformation, through, for example, intramolecular hydrogen bonding in solution.     

Thermal polymorphic transformation of p-tert-Butylcalix

Studies were made on the polymorphism of p-tert-butylcalix[4]arene derivatives having amino acid groups on the lower rim to stabilize their hydrophilic pseudocavity by circular intramolecular hydrogen bonding. The calixarenes exhibit a polymorphic transformation upon heating in the solid state. This transformation is controlled by the thermal history of solids, accompanying the change on the conformation of the calixarene skeleton and also the change of hydrogen bonding in the hydrophilic pseudocavity.     

A nonpeptidic reverse-turn scaffold stabilized by urea-based dual intramolecular hydrogen bonding

A novel nonpeptidic reverse-turn scaffold containing urea fragments that are connected by a conformationally constrained D-prolyl-cis-1,2-diaminocyclohexane (D-Pro-DACH) linker is reported. The scaffold adopts a well-defined reverse-turn conformation that is stabilized by dual intramolecular hydrogen bonding in both solution and solid states.     

Structure and dynamics of pyrimidine-based macrocycles in solution

The conformational structure of macrocycles obtained from two thiopyrimidine and uracil nucleic acids linked by polymethylene spacers is determined by the length of the spacers, intramolecular NH bonding, pH and solvent. In CDCl₃, NH-OC hydrogen bonding can impact the overall stabilization of the folded conformation, however spatial preorganization to such hydrogen bonding is a prerequisite. Protonation leads to disruption of intramolecular hydrogen bonds, destabilization of the folded conformation and to strong counterion assisted self-aggregation of macrocyles which can be destroyed in polar solvents.     

Effect of Anchimeric Assistance in the Reaction of Triphenylphosphine with α,β‐Unsaturated Carboxylic Acids

Quaternization of triphenylphosphine with maleic and cis‐aconitic acids is strongly accelerated by participation of the cis‐carboxyl group in stabilization of the phosphonium zwitterion intermediate by intramolecular hydrogen bonding, in spite of steric hindrance by the acid's reaction center. A similar effect for trans‐isomeric acids is not observed, which can be rationalized on the basis of spatial structures of the generated zwitterions, implying an electrostatic interaction between the phosphonium center and carbonyl oxygen atom. The effect of anchimeric assistance decreases when the intramolecular hydrogen bonding disfavors attack of the phosphine on the sterically less hindered carbon atom of the C=C bond, as observed for cis‐aconitic acid.     

Solid-state conformation of a hybrid tripeptide between beta-amino acid; 8-aminocyclooct-4-enecarboxylic acid and 2-aminoisobutyric acid

An eight-membered cyclic beta-amino acid, 8-aminocyclooct-4-enecarboxylic acid, was designed as a conformationally restricted non-proteinogenic amino acid. A hybrid tripeptide containing this eight-membered cyclic beta-amino acid and 2-aminoisobutyric acids was synthesized by conventional solution methods. The conformation of the tripeptide was studied using X-ray analysis and was shown to form an eleven-membered hydrogen-bonded turn (3(11)-helical structure) in the solid state.     

Evidence of Hydrogen Bonding in Stabilizing the Cone Conformation of a Monoalkylated Calix[4]arene. X-ray Structure of 25-[2-(ethoxy-1-p-toluene-sulfonate)phenyl]-26,27,28-trihydroxy calix[4]arene

The synthesis of25-[2-(ethoxy-1-p-toluene-sulfonate)phenyl]-26,27,28-trihydroxy calix[4]arene3 as a byproduct of the preparation of 1,3-dialkylated25,27-di-[2-(ethoxy-1p-toluene-sulfonate)phenyl]-26,28-dihydroxy calix[4]arene 2 is reported. Compound 3 is a monoalkylatedcalix[4]arene in the cone conformation. The X-ray structure of 3 showed that this conformation is stabilized by intramolecular hydrogen bonding.     

Chiral Bisphosphoric Acids and Their Applications in Asymmetric Catalysis

Asymmetric Brønsted acid catalysis has been recognized as a powerful concept for asymmetric synthesis. In the process of pursuing more robust and highly effective chiral Brønsted acid catalysts, chiral bisphosphoric acids have received much attention in the last two decades. Their unique catalytic properties are mainly attributed to the inherent intramolecular hydrogen bonding interactions that could increase the overall acidity and tune the conformation property. Integrating hydrogen bonding into the catalyst design, quite a few structurally unique and effective bisphosphoric acids have been synthesized, which frequently exhibited superior selectivity in a broad range of asymmetric transformations. This review summarizes the status quo of chiral bisphosphoric acid catalysts and their applications in catalyzing asymmetric transformations.     

Intramolecular Hydrogen-Bonding in a C(10)-Exploded Bilirubinoid

Summary. A new linear tetrapyrrole, with two dipyrrinones connected by a string of 5 carbons, was synthesized from two equivalents of a 9H-dipyrrinone and one of glutaryl dichloride. Unlike typical dipyrrinones, which are intermolecularly hydrogen bonded in the crystal and in CHCl₃ solution, 1,3-bis-[2,3,7,8-tetraethyl-(10H)-dipyrrin-9-carbonyl]propane is a monomer in CHCl₃, as determined by vapor phase osmometry (VPO) measurements. Its crystal structure determination revealed a folded conformation with a novel type of dipyrrinone to dipyrrinone intramolecular hydrogen bonding. Unexpectedly, the same conformation apparently persists in CHCl₃ solution, as shown by ¹H NMR spectroscopy.