An investigation of site-selective gas-phase reactions of amino alcohols with dimethyl ether ions

The reactions of dimethyl ether ions with neutral amino alcohols were examined in both a quadrupole ion trap mass spectrometer and a triple quadrupole mass spectrometer. These ion-molecule reactions produced two types of ions: the protonated species [M+l]⁺ and a more complex product at [M+13]⁺. The abundance of the [M+13]⁺ ions relative to that of the [M+1]⁺ ions decreases with increasing formal interfunctional distance. Multistage collision-activated dissociation techniques were used to characterize the [M+13]⁺ product ions, their reactivities, and the mechanisms for their formation and dissociation. In addition, molecular semiempirical calculation methods were used to probe the thermochemistry of these reactions. Reaction at the amino alcohol nitrogen site is favored, and the resulting [M+13]⁺ addition products may cyclize for additional stabilization. Comparisons were made among the behavior of related compounds, such as alcohols, diols, amines, and diamines. The alcohols reacted only to form the protonated species, but the diols, amines, and diamines all formed significant amounts of [M+13]⁺ ions or related dissociation products.     

Supramolecular chirogenesis in zinc porphyrins: interaction with bidentate ligands,formation of tweezer structures,and the origin of enhanced optical activity

The complexation behavior, binding properties, and spectral parameters of supramolecular chirality induction in the achiral host molecule, syn (face-to-face conformation) ethane-bridged bis(zinc porphyrin), upon interaction with chiral bidentate guests (diamines and amino alcohols) have been studied by means of UV-vis, CD, fluorescence, (1)H NMR, and ESI MS techniques. It was found that the guest structure plays a decisive role in the chirogenesis pathway. The majority of bidentate ligands (except those geometrically unsuitable) exhibit two major equilibria steps: the first guest ligation leading to formation of the 1:1 host-guest tweezer structure (K(1)) and the second guest molecule ligation (K(2)) forming the anti bis-ligated species (1:2). The second ligation is much weaker (K(1) > K(2)) due to the optimal geometry and stability of the 1:1 tweezer complex. The enhanced conformational stability of the tweezer complex ensures an efficient chirality transfer from the chiral guest to the achiral host, consequently inducing a remarkably high optical activity in the bis-porphyrin.     

Noncovalent interactions: defining cooperativity. Ligand binding aided by reduced dynamic behavior of receptors. Binding of bacterial cell wall analogues to ristocetin A

Changes in the relative populations of the monomer and asymmetric dimer forms of ristocetin A, upon binding of two molecules of ligand, suggest that ligand binding is negatively cooperative with respect to dimerization. However, strong hydrogen bonds formed in the binding sites of the ligands are reinforced in the dimer relative to the monomer, and the barrier to dissociation of the dimer is increased upon binding of the ligands. It is concluded that the interactions which are common in the binding of both ligands are made with positive cooperativity with respect to those involved in dimerization. The conclusions are relevant to the binding of ligands to proteins, where ligand binding energy can be derived from stabilization of the protein in its ligand-bound form.     

Preparation of novel multifunctional amino alcohols from nitroparaffins and α,β-unsaturated aldehydes

A series of novel multifunctional amino alcohols were prepared by tandem Michael–Henry reaction by reacting nitroalkanes such as 2-nitropropane with readily available α,β-unsaturated aldehydes. The dinitro compounds were further reduced by catalytic hydrogenation to obtain respective diamines. This synthetic route provides a very convenient method of preparing multifunctional amino alcohols.     

Selective mono protection of diols, diamines, and amino alcohols using cesium bases

Efficient synthetic methods were developed for the synthesis of mono xanthates, as well as mono dithiocarbamates of diamines and amino alcohols. This protocol utilizes the three component coupling of diols, diamines, and amino alcohols using alkyl bromides and carbon disulfide in the presence of a cesium base and tetrabutylammonium iodide (TBAI).     

Quantifying Protein-Ligand Binding Constants using Electrospray Ionization Mass Spectrometry: A Systematic Binding Affinity Study of a Series of Hydrophobically Modified Trypsin Inhibitors

NanoESI-MS is used for determining binding strengths of trypsin in complex with two different series of five congeneric inhibitors, whose binding affinity in solution depends on the size of the P3 substituent. The ligands of the first series contain a 4-amidinobenzylamide as P1 residue, and form a tight complex with trypsin. The inhibitors of the second series have a 2-aminomethyl-5-chloro-benzylamide as P1 group, and represent a model system for weak binders. The five different inhibitors of each group are based on the same scaffold and differ only in the length of the hydrophobic side chain of their P3 residue, which modulates the interactions in the S3/4 binding pocket of trypsin. The dissociation constants (K_D) for high affinity ligands investigated by nanoESI-MS ranges from 15?nM to 450?nM and decreases with larger hydrophobic P3 side chains. Collision-induced dissociation (CID) experiments of five trypsin and benzamidine-based complexes show a correlation between trends in K_D and gas-phase stability. For the second inhibitor series we could show that the effect of imidazole, a small stabilizing additive, can avoid the dissociation of the complex ions and as a result increases the relative abundance of weakly bound complexes. Here the K_D values ranging from 2.9 to 17.6???M, some 1?C2 orders of magnitude lower than the first series. For both ligand series, the dissociation constants (K_D) measured via nanoESI-MS were compared with kinetic inhibition constants (K_i) in solution.     

Determination of affinity constants and response factors of the noncovalent dimer of gramicidin by electrospray ionization mass spectrometry and mathematical modeling

The dimerization of gramicidin, a 15-residue membrane peptide, in solution can be viewed as a model for protein-protein interactions. We reported previously that the dimer can be observed when electrosprayed from organic solvents and that the abundances of the dimer depends on the dielectric constant of the solvent. Here, we report an effort to determine an affinity constant for the dimerization of gramicidin by using gas-phase abundance. Two issues affecting the determination are the electrospray-induced dissociation of the dimer and discrimination in the electrospray of the dimer compared with the monomer. Other methods developed for the purpose of determining affinity from mass spectral abundance do not address the dissociation of the complex in the gas phase or can not be applied for cases of low affinity constant, K(a). We present a mathematical model that uses the ratio of the signal intensities of the dimer and the monomer during a titration. The model also incorporates the dissociation and an electrospray ionization-response factor of the dimer for extracting the affinity constant for the dimerization of gramicidin. The dimerization constants from the new method agree within a factor of two with values reported in the literature.     

Origins of cooperative noncovalent host-guest chemistry in mixed valence complexes

The electronic effects resulting from noncovalent host-guest interactions between calix[6]arene and a ruthenium dimer, [Ru3O(OAc)6(CO)(ppy)]2-mu-pz (ppy=4-phenyl pyridine, pz=pyrazine), are presented. The noncovalent interaction is between the calix[6]arene and the ppy ligands of the dimer. The dimer can bind 2 equiv of calix[6]arene. The complex [Ru3O(OAc)6(CO)(ppy)]2-mu-pz forms a highly stable mixed valence ion with strong electronic coupling between the two Ru3 clusters. The strength of the electronic interaction is found to be moderated by calix[6]arene binding. Addition of calix[6]arene to the mixed valence ion causes the electronic coupling to decrease. The binding of calix[6]arene is found to be cooperative. The origins of cooperative binding are developed in terms of the potential energy surfaces associated with the symmetric and asymmetric mixed valence ion. In particular, it is found that symmetry breaking (through the binding of a single calix[6]arene) destabilizes the mixed valence state. Restoration of symmetry (through the binding of a second calix[6]arene) increases the stability of the mixed valence ion and provides an additional driving force for the binding of the second calix[6]arene.     

Investigations of bivalent antibody binding on fluid-supported phospholipid membranes: the effect of hapten density

Investigations of ligand-receptor binding between bivalent antibodies and membrane-bound ligands are presented. The purpose of these studies was to explore binding as a function of hapten density in a two-dimensionally fluid environment. A novel microfluidic strategy in conjunction with total internal reflection fluorescence microscopy was designed to achieve this. The method allowed binding curves to be acquired with excellent signal-to-noise ratios while using only minute quantities of protein solution. The specific system investigated was the interaction between anti-DNP antibodies and phospholipid membranes containing DNP-conjugated lipids. Binding curves for ligand densities ranging from 0.1 to 5.0 mol % were obtained. Two individual dissociation constants could be extracted from the data corresponding to the two sequential binding events. The first dissociation constant, K(D1), was 2.46 x 10(-)(5) M, while the second was K(D2) = 1.37 x 10(-)(8) mol/m(2). This corresponded to a positively cooperative binding effect with an entropic difference between the two events of 62.3 +/- 2.7 J/(mol.K). Furthermore, the percentage of monovalently and bivalently bound protein was determined at each ligand density.     

Modification of polymers in the melt

The kinetics of polymer‐analogue reactions in the melt are discussed with the example of conversions of styrene copolymers including anhydride or nitrile groups in the side chain and additives with amino and hydroxyl groups. Poly(styrene‐co‐maleic anhydride) has been modified with primary alcohols and amines, secondary amines, diamines, amino acids and amino alcohols. Poly(styrene‐co‐acrylonitrile) has been modified with various amino alcohols.     

Highly Regio‐ and Stereodivergent Access to 1,2‐Amino Alcohols or 1,4‐Fluoro Alcohols by NHC‐Catalyzed Ring Opening of Epoxy enals

Described is an unprecedented NHC‐catalyzed (NHC=N‐heterocyclic carbene), stereoselective ring opening of epoxy and cyclopropyl enals to deliver valuable compounds bearing multiple stereocenters. A straightforward three‐step procedure involving two catalytic enantioselective transformations has been developed and leads to a regio‐ and stereodivergent synthesis of either 1,2‐amino alcohols/diamines or 1,4‐fluoro alcohols with excellent diastereo‐ and enantiopurity.     

Study of alkaloids of the Siberian and Altai flora. 9. Synthesis of amino derivatives of elatidine

New secondary-tertiary diamines were prepared from elatidal imines with primary amino alcohols, derivatives of natural amino acids of the S-series. N-Methylation of the diamines yielded bi-tertiary diamines unable to undergo quaternization with MeI due to steric hindrance.     

Protein-aptamer binding studies using microchip affinity capillary electrophoresis

The use of traditional CE to detect weak binding complexes is problematic due to the fast-off rate resulting in the dissociation of the complex during the separation process. Additionally, proteins involved in binding interactions often nonspecifically stick to the bare-silica capillary walls, which further complicates the binding analysis. Microchip CE allows flexibly positioning the detector along the separation channel and conveniently adjusting the separation length. A short separation length plus a high electric field enables rapid separations thus reducing both the dissociation of the complex and the amount of protein loss due to nonspecific adsorption during the separation process. Thrombin and a selective thrombin-binding aptamer were used to demonstrate the capability of microchip CE for the study of relatively weak binding systems that have inherent limitations when using the migration shift method or other CE methods. The rapid separation of the thrombin-aptamer complex from the free aptamer was achieved in less than 10 s on a single-cross glass microchip with a relatively short detection length (1.0 cm) and a high electric field (670 V/cm). The dissociation constant was determined to be 43 nM, consistent with reported results. In addition, aptamer probes were used for the quantitation of standard thrombin samples by constructing a calibration curve, which showed good linearity over two orders of magnitude with an LOD for thrombin of 5 nM at a three-fold S/N.     

Last ten years (2008–2018) of chiral ligand‐exchange chromatography in HPLC: An updated review

Chiral ligand‐exchange chromatography is one of the elective strategies for the direct enantioresolution of small chelating compounds: amino acids, diamines, amino alcohols, diols, small peptides, etc. Unlike other methods, the interaction between chiral selector and analyte enantiomers is mediated by a cation, thus producing diastereomeric ternary complexes. Two main approaches are conventionally applied in chiral ligand‐exchange chromatography. The first relies upon chiral stationary phases where the chiral selector is either covalently immobilized or physically adsorbed onto suitable packing materials (coated phases). In the second approach, chiral molecules are added to the eluent, thus generating chiral eluent systems. Among the advantages of chiral ligand‐exchange chromatography, the generation of UV/vis‐active metal complexes, and the use of commercially available or easy‐to‐synthesize chiral selectors, in combination to rather inexpensive achiral columns for coated phases and chiral eluents, are noteworthy. Besides amino acids and amino alcohols, other species have proven suitable for chiral ligand‐exchange chromatography applications. Recently, the use of either chiral ionic liquids or micellar liquid chromatography systems as well as the successful off‐column formation of diastereomeric complexes have expanded the selectivity profiles and application fields. All of these issues are touched in the review, shedding light to the contributions appeared in the last decade.     

Solvent effect on regioselectivity of epoxide ring opening in styrene oxide by O- and N-nucleophiles in neutral and basic media

The results of ring opening in styrene oxide by alcohols, amines, amino alcohols, and diamines were generalized. On low polarizing ability of the solvent, the main direction of the process is the formation of normal α-substituted products. The solvent effect on regioselectivity of the reaction was studied for N,N-diethylethylenediamine. The ratio of products correlates well with the value of dielectric constant for mixed aqueous-organic solvents and with the parameters of polarity E _T and AN for neat solvents.     

A comparative study of reactivity and selectivity of chiral diamines and structurally analogous amino alcohol ligands in enantioselective alkylations with diethylzinc

A series of chiral δ‐diamines and structurally analogous δ‐amino alcohols derived from natural tartaric acid were synthesized and a comparative study of their activity and selectivity in the enantioselective alkylation of aromatic aldehydes was carried out. Our results show that in general the δ‐diamines were found to be better chiral inducers than the corresponding δ‐amino alcohols. The highest selectivity was observed when benzaldehyde was alkylated in the presence of the benzylic diamine, giving (R)‐1‐phenylpropanol with an ee of 42%. Copyright © 2008 John Wiley & Sons, Ltd.     

A Mild and Efficient Method for Selective Acetylation of Amines

Primary and secondary amines were acetylated under mild conditions by means of 3-acetyl-1,3-thiazolidine-2-thione [ATT(1)]. The reaction was successfully applied to selective acetylation of a primary amino group of diamines containing a primary and a secondary amino groups or exclusive N-acetylation of amino alcohols.     

Stable gas-phase radical cations of dimeric tryptophan and tyrosine derivatives

Stable radical cations of dimeric amino acid derivatives of tryptophan and tyrosine were generated by collision-induced dissociation of [Cu(II)(diethylenetriamine)(amino acid derivative)2]*2+. The yields of the dimer radical cations were dependent on both the auxiliary ligand and the tryptophan or tyrosine derivatives used. Amino acid derivatives with an unmodified carboxylic acid group did not generate dimer radical cations. For the amino acid derivatives Ac-Trp-OMe and Ac-Trp-NH2 (Ac is N-acetyl; OMe and NH2 are the methyl ester and amide modifications of the C-terminal carboxylic group), no auxiliary ligand was required for generating the dimer radical cations. Collision-induced dissociation of the [Cu(II)(amino acid derivative)4]*2+ precursor generated the dimer radical cation [(amino acid derivative)2]*+. Stabilizing interactions, most likely involving hydrogen bonding, between the two amino acid derivatives are proposed to account for observation of the dimer radical cations. Dissociation of these ions yields protonated or radical cationic amino acid derivatives; these observations are consistent with the expectation of proton competition between monomeric units, whose proton affinities were calculated using density functional theory.     

Minimalist protein design: a beta-hairpin peptide that binds ssDNA

A 28-residue beta-hairpin dimer (WKWK)2 with two Trp and two Lys residues on one face of each beta-sheet was shown to form a complex with single-stranded oligonucleotides at low micromolar concentrations. Each beta-hairpin of the dimer contains a cross-strand Trp-Trp pair in a diagonal orientation which has previously been shown to create a cleft for the intercalation of aromatic guests such as adenine (J. Am. Chem. Soc. 2003, 125, 9580). The beta-hairpin dimer binds 5-residue ssDNA sequences 5'-AAAAA-3', 5'-TTTTT-3', and 5'-CCCCC-3' in water with dissociation constants in the range of 12-30 muM. A weak energetic preference for binding to sequence 5'-AAAAA-3' was observed, which is believed to result from stronger stacking interactions between Trp and the adenine base. The interaction of 5'-AAAAA-3' with the Lys and Trp residues of the peptide was evident by NMR, and a 1:1 association was demonstrated. The recognition of an 11-residue ssDNA sequence occurred with a dissociation constant of 3 muM under near-physiological ionic strength and pH, demonstrating that the beta-hairpin dimer binds ssDNA as strongly as many naturally occurring proteins. The salt dependence of the interaction of the 11-residue oligonucleotide with the peptide dimer indicates that Trp-nucleobase stacking interactions contribute about -4 kcal/mol to recognition, which is much greater than the contribution of nonionic interactions in unstructured peptides containing Trp. Moreover, recognition of the ssDNA demonstrated reduced salt dependence relative to the corresponding duplex, resulting in selectivity for ssDNA under high salt conditions. Peptide (WKWK)2 is a relevant mimic of OB-fold (oligonucleotide/oligosaccharide-binding) proteins which bind ssDNA on the surface of a beta-sheet.