Novel chiral solvating agents derived from natural amino acid: enantiodiscrimination for chiral α-arylalkylamines

Two benzo[de]isoquinoline 1,3-dione amino acids 1 and 2 were readily prepared, and their enantiodiscriminating ability were investigated by ¹H NMR spectroscopy. It was found that 1 exhibited an excellent chiral recognition ability toward chiral α-phenylethylamine and some of its derivatives, leading to clear baseline separation of the multiplet of the probe groups in two enantiomers. The stoichiometric ratio and association constants of some host-guest complexes were determined. The interactions between the hosts and guest 3 were further studied by intermolecular NOE experiment and ESI-MS.     

Thermochemical study of the reactions of acid–base interaction in an aqueous solution of α-aminobutyric acid

The heat effects of the interaction between a solution of α-aminobutyric acid and solutions of HNO₃ and KОН are measured by means of calorimetry in different ranges of рН at 298.15 K and values of ionic strength of 0.25, 0.5, and 0.75 (KNO₃). The heat effects of the stepwise dissociation of the amino acid are determined. Standard thermodynamic characteristics (Δ_r H ⁰, Δ_r G ⁰, and Δ_r S ⁰) of the reactions of acid–base interaction in aqueous solutions of α-aminobutyric acid are calculated. The connection between the thermodynamic characteristics of the dissociation of the amino acid and the structure of this compound is considered.     

Towards an atomistic model for ORMOCER?-I: application of forcefield methods

ORMOCER^?s are an outstanding class of hybrid materials due to their tuneable properties, e.g. hardness, resistivity and refractive index. These materials are well-characterized with regard to their macroscopic properties, but understanding the system at the atomistic level still remains challenging. Understanding the material formation process at this level becomes especially important when three-dimensional nanoscale patterns are generated employing processes as laser-based multi-photon polymerization. We have developed an atomistic model based on the COMPASS forcefield to simulate the reference system ORMOCER^?-I. We chose representative compositions for the condensation reaction product as well as for the organically cross-linked polymerized product. In the first part of the study, the results of forcefield validation experiments and the development of the atomistic model for ORMOCER^?s are presented. The second part contains the results from molecular dynamics simulations at room temperature and under periodic boundary conditions, performed in order to test the feasibility of our model. The densities of the simulated materials are in very good agreement with experimentally determined densities for the unpolymerized as well as for the polymerized state, respectively.     

Microwave activation of an asymmetric Michael reaction: unexpected behaviour of chiral α-alkoxy imines

While it has been previously established that chiral α-alkoxy imines undergo thermal rearrangement at temperatures above 50°C, the microwave activation of the Michael addition between chiral imine 3b and methyl acrylate at 100°C led cleanly to the corresponding Michael adduct 5b without the formation of any rearranged product and with the same regio- and stereoselectivity as the corresponding thermal condensation at 40°C (ee 95%).     

A stereoselective synthesis of an α-substituted α-amino acid as a substructure for the construction of myriocin

A synthetic route to the protected quaternary α-amino acid 2 with a hydroxylated side chain has been achieved. The key transformations are the diastereoselective substrate-controlled epoxidation of allylic alcohol 4; a highly stereoselective oxidation–reduction protocol, and the excellent regioselective isomerization of the oxazolidinone ring to give an oxazinanone skeleton in derivative 3. The carboxylic acid 2 obtained represents the polar substructure, which is present in myriocin 1.     

Conformational studies on peptides containing α,α-disubstituted α-amino acids: chiral cyclic α,α-disubstituted α-amino acid as an α-helical inducer

Four types of α,α-disubstituted amino acids {i.e., α-aminoisobutyric acid (Aib), 1-aminocyclopentanecarboxylic acid (Ac(5)c), (3S,4S)-1-amino-(3,4-dimethoxy)cyclopentanecarboxylic acid [(S,S)-Ac(5)c(dOM)] and its enantiomer (R,R)-Ac(5)c(dOM)} were introduced into l-leucine-based hexapeptides and nonapeptides. The dominant conformations of eight peptides: Cbz-(L-Leu-L-Leu-dAA)(2)-OMe [dAA = 1: Aib; 2: Ac(5)c; 3: (S,S)-Ac(5)c(dOM); 4: (R,R)-Ac(5)c(dOM)] and Boc-(L-Leu-L-Leu-dAA)(3)-OMe [dAA = 5: Aib; 6: Ac(5)c; 7: (S,S)-Ac(5)c(dOM); 8: (R,R)-Ac(5)c(dOM)], were investigated by IR, CD spectra and X-ray crystallographic analysis. The CD spectra revealed that Aib hexapeptide 1 and Ac(5)c hexapeptide 2 formed right-handed (P) 3(10)-helices, while Ac(5)c(dOM) hexapeptides 3 and 4 formed a mixture of (P) 3(10)- and α-helices. The Aib nonapeptide 5 formed a (P) 3(10)-helix, the Ac(5)c nonapeptide 6 formed a mixture of (P) 3(10)- and α-helices, and the Ac(5)c(dOM) nonapeptides 7 and 8 formed (P) α-helices. X-Ray crystallographic analysis revealed that the Aib hexapeptide 1 formed a (P) 3(10)-helix, while (S,S)-Ac(5)c(dOM) hexapeptide 3 formed a (P) α-helix. In addition, the Ac(5)c nonapeptide 6 and (R,R)-Ac(5)c(dOM) nonapeptide 8 formed (P) α-helices. The Aib and achiral Ac(5)c residues have the propensity to form 3(10)-helices in short peptides, whereas the chiral Ac(5)c(dOM) residues have a penchant for forming α-helices.     

New chiral iodooxazoline catalysts for the I(III)-mediated α-tosyloxylation of ketones: refining the stereoinduction model

A new family of iodooxazoline catalysts, derived from widely available chiral ketones (menthone and camphor), was developed to promote the iodine(III)-mediated α-tosyloxylation of ketone derivatives. The reaction conditions to achieve the direct formation of the oxazoline moieties from the corresponding aminoalcohols and an aldehyde were explored and optimized. These catalysts were tested for the α-tosyloxylation of propiophenone and led to new information on the stereoinduction process. The results demonstrate that modulation of the steric hindrance around the iodane center is critical to obtain good activity. Additionally, from the selectivities observed, a preliminary predictive model is proposed.     

Highly enantioselective electrophilic α-bromination of enecarbamates: chiral phosphoric acid and calcium phosphate salt catalysts

Metal-free chiral phosphoric acids and chiral calcium phosphates both catalyze highly enantio- and diastereoselective electrophilic α-bromination of enecarbamates to provide an atom-economical synthesis of enantioenriched vicinal haloamines. Either enantiomer can be formed in good yield with excellent diastereo- and enantioselectivity simply by switching the catalyst from a phosphoric acid to its calcium salt.     

Theoretical study of Lewis acid activation models for hypervalent fluoroiodane reagent: The generality of “F-coordination” activation model

The bench-stable cyclic hypervalent fluoroiodane reagent (1) is receiving increasing attention in fluorine chemistry because of its completely new reactivity. Fluorination mediated by reagent 1 generally requires activation by an exogenous Lewis acid. A more complete understanding of the Lewis acid activation model is thus paramount for the development of new strategies involving this reagent. Density functional theory (DFT) calculations herein demonstrate the generality of the “F-coordination” activation mechanism for reagent 1 that we recently showed to be favored over the commonly accepted “O-coordination” activation mechanism.     

Carbon-based solid acid: an efficient and reusable catalyst for the diastereoselective ring opening reaction of α-epoxyketones

Carbon-based solid acid efficiently catalyzes diastereoselective ring opening of α-epoxyketones in the presence of methanol to produce the corresponding α-hydroxy-β-methoxyketones in excellent yield.     

A pinene-based chiral auxiliary for α-alkylation and aldol reactions: an unexpected effect of the base on the stereoselectivity

While the use of LDA as the base in the kinetic deprotonation step of the pinene-based ester 3 led to moderate diastereoselectivities in α-alkylation and aldol reactions, the use of LICA and LTMP resulted in a reduction in the anti/syn ratios and π-facial selectivities.     

Strategies for determination of insulin with tandem electrospray mass spectrometry: implications for other analyte proteins?

Using human insulin (MW 5808 Da) as a model compound, the possible strategies towards optimization of sensitivity and selectivity of measurement by electrospray ionization with a standard triple quadrupole mass spectrometer were investigated. For measurement in selected ion-monitoring (SIM) mode, these strategies involved systematic variation of instrumental parameters and spray pH. In this investigation four different operating modes were used corresponding to positive/negative ionization modes with acidic/basic sprays and pH reversed (hereafter termed 'wrong-way-round' operation); the cone voltage was optimized for each mode of operation. When collision-activated dissociation (CAD) is employed, two additional operation modes are possible: namely, low collision energies (10-35 eV, CAD-l) for the generation of sequence-specific fragments and high collision energies (>80 eV, CAD-h) for the generation of nonspecific fragments. Overall, this results in twelve different modes of operation. Loop-injection of aqueous insulin standards were run for each of the twelve operating modes and measurements made for five different charge states (n = 2-6) observable with our instrument that has an upper mass limit of m/z 4000. The signal/noise (S/N) ratio was optimized for each charge state, resulting in 60 measurements. The best S/N ratios (20 000) were achieved under positive SIM conditions with charge state 6 (m/z 969) and under 'wrong-way-round' negative SIM conditions with charge state 3 (m/z 1935). Lower S/N ratios were observed under positive CAD-h conditions with charge state 5 (m/z 1163, S/N 15 000) and positive CAD-l conditions with charge state 6 (m/z 969, S/N 10 000). All other operating modes gave maximum S/N ratios of 4000. For measurement of insulin standards, the results obtained show SIM to give the best S/N ratio. However, for samples in complex matrices, our general experience suggests CAD to be the preferable operating mode. Consequently, for the development of a quantitative method for proteins in general, it might be advocated that all of the twelve operating modes and all relevant charge states be investigated to find the optimum S/N ratio.     

C2-symmetric recyclable organocatalyst for enantioselective Strecker reaction for the synthesis of α-amino acid and chiral diamine--an intermediate for APN inhibitor

Recyclable chiral amide-based organocatalyst 5 efficiently catalyzed asymmetric Strecker reaction of various aromatic and aliphatic N-benzhydrylimines with ethyl cyanoformate as cyanide source at -10 °C to give a high yield (95%) of α-aminonitriles with excellent chiral induction (ee, up to 99%) with the added advantage of recyclability. Based on experimental observations a probable mechanism was proposed for this reaction. This protocol with catalyst 5 was extended for the synthesis of (R)-phenylalanine and pharmaceutically important drug intermediate (R)-3-phenylpropane-1,2-diamine in high yield with high enantioselectivity.     

Communication: Use of an α-Haloether for the Acetonation of Carbohydrates.

Cyclic acetals are important and commonly used protective groups for polyhydroxy compounds, e.g., carbohydrates. The formation of cyclic acetals has been thoroughly investigated and much is now known about the factors that influence the outcome of these reactions. Several reviews have been written on this subject.^1,2,3     

Is spin-component scaled second-order Møller-Plesset perturbation theory an appropriate method for the study of noncovalent interactions in molecules?

Testing of the spin-component scaled second-order M?ller-Plesset (SCS-MP2) method for the computation of noncovalent interaction energies is done with a database of 165 biologically relevant complexes. The effects of the spin-scaling procedure (i.e., MP2 vs SCS-MP2), the basis set size, and the corrections for basis set superposition error (BSSE) are systematically examined. When using two-point basis set extrapolations for the correlation energy, augmentation of the atomic orbital basis with computationally costly diffuse functions is found to be obsolete. In general, SCS-MP2 also improves results for noncovalent interactions statistically on MP2, and significant outliers are removed. Moreover, it is shown that effects of BSSE and one-particle basis set incompleteness almost cancel each other in the case of triple-zeta sets (SCS-MP2/TZVPP or SCS-MP2/cc-pVTZ without counterpoise correction), which opens a practical route to efficient computations for large systems. We recommend SCS-MP2 as the preferred quantum chemical wave function based method for the noncovalent interactions in large biologically relevant systems when reasonable coupled-cluster with single and double and perturbative triple excitations (CCSD(T)) calculations cannot be performed anymore. A comparison to MP2 and CCSD(T) interaction energies for n-alkane dimers, however, indicates (and this also holds to a lesser extent for hydrogen-bonded systems) limitations of SCS-MP2 when treating chemically "saturated" interactions. The different behavior of second-order perturbation theory for saturated and for stacked pi-systems is discussed.     

Site specificity of OH α-H abstraction reaction for a β-hairpin peptide: an ab initio study

A β-hairpin peptide (PDB ID 1UAO) was modeled to explore the backbone oxidation of a protein by an OH radical to abstract one α-H atom with ab initio calculation at the B3LYB/6-31G(d) without any constraint. Three glycine residues located at three different sites in 1UAO were used to examine the possible site specificity of this backbone oxidation. The pre- and post-reactive complexes along with their associated transition states were located and verified by the intrinsic reaction coordinate method. The reaction profile of these α-H abstraction reactions was constructed. The effects of the aqueous solution were estimated by the conductor-like polarizable continuum model (CPCM) model. Rate constants were calculated with transition state theory. The reaction rate of the OH α-H abstraction varies among these three different sites. The differences among these three sites were rationalized in terms of the molecular and electronic structures of the reactive complexes along the reaction pathway. The explicit solvation effect was estimated through the similar abstraction of a zwitterionic glycine with the combination of microsolvation and a CPCM model. Our results indicate that the α-H abstraction at certain sites requires explicit salvation to obtain accurate results. A replica exchange molecular dynamics simulation was performed to demonstrate the structural change due to this type of abstraction.     

Feasibility study: fast liquid chromatography–mass spectrometry for the quantification of aspartic acid in an aspartate drug

We have studied the feasibility of fast high-performance liquid chromatography coupled to electrospray ionization mass spectrometry in the selected ion monitoring mode for the quantitative determination of aspartic acid in an aspartate drug. Internal standardization was required, but mass spectrometric detection allowed for very short retention times of approximately 0.5 min for the analyte and the internal standard without chromatographic separation. The analytical system was found stable, as demonstrated by multiple injections giving a coefficient of variation of 4% for the peak area ratio of aspartic acid and glutamic acid. Calibrations were linear between 0.5 ng and 150 ng aspartic acid injected, with accuracies between 99.8% and 102% found for the back-calculated amounts. Investigation of several drug batches gave reasonable results. Therefore, the method appeared feasible for the determination of aspartic acid in an aspartate drug from 0.3 wt% to 100 wt% aspartic acid.Abbreviations CV coefficient of variation - ESI electrospray ionization - HPLC high-performance liquid chromatography - HSGC headspace gas chromatography - KaFi Karl Fischer titration - MS mass spectrometry - MSD mass-selective detector - % m/m percentage by weight - PAR peak area ratio - r² coefficient of determination - RP reversed-phase - SIM selected ion monitoringThis work was originally presented as a poster at the Conference of the German Society for Mass Spectrometry, 9–12 March 2003, in Münster, Germany     

Stability of Au 2 2+ : metastability through an excited state?

We discuss the stability of doubly charged Auclusters. From a calculation using semi-empirical linear combination of atomic-orbitals (LCAO) method, we conclude that Au ₂ ²⁺ in an excited state (³Σ _u ⁺ or¹Σ _u ⁺ ) is metastable with an energy barrier of about 0.3 eV. In the ground state (¹Σ _g ⁺ ) Au ₂ ²⁺ is unstable, except for small values of Δ(=ε _s ?ε _d ) (difference between thes andd atomic energy levels of Au), when a very shallow minimum appears in the binding energy curve. These results are critically discussed and compared with those obtained by different calculations.     

Chemoenzymatic synthesis of each enantiomer of orthogonally protected 4,4-difluoroglutamic acid: a candidate monomer for chiral Brønsted acid peptide-based catalysts

We have accomplished an asymmetric synthesis of each enantiomer of 4,4-difluoroglutamic acid. This α-amino acid has been of interest in medicinal chemistry circles. Key features of the synthesis include highly scalable procedures, a Reformatsky-based coupling reaction, and straightforward functional group manipulations to make the parent amino acid. Enantioenrichment derives from an enzymatic resolution of the synthetic material. Conversion of the optically enriched compounds to orthogonally protected forms allows for the selective formation of peptide bonds. 4,4-Difluoroglutamic acid, in a suitably protected form, is also shown to exhibit enhanced catalytic activity in both an oxidation reaction and a reduction reaction, in comparison to the analogous glutamic acid derivative.     

Diastereoselective amidoallylation of glyoxylic acid with chiral tert-butanesulfinamide and allylboronic acid pinacol esters: efficient synthesis of optically active γ,δ-unsaturated α-amino acids

A convenient synthesis of δ,γ-unsaturated amino acids has been developed. After a mixture of (R)-tert-butanesulfinamide and glyoxylic acid with molecular sieves in CH₂Cl₂ was stirred for 42 h at room temperature, allylboronic acid pinacol ester was added to the mixture to give (R)-2-((R)-tert-butanesulfinamido)pent-4-enoic acid with high diastereoselectivity. The corresponding reaction of (Z)-crotylboronic acid pinacol ester produced no product; however, that of (E)-crotylboronic acid pinacol ester produced (2R,3S)-2-((R)-tert-butylsulfinamido)-3-methylpent-4-enoic acid with excellent diastereoselectivity.