Enantiomer discrimination of peptides by tandem mass spectrometry: influence of the peptide sequence on chiral recognition

The enantiomer discrimination of peptides by electrospray ionization tandem mass spectrometry is described. A cinchona alkaloid derivative, tert-butylcarbamoylquinine, is used as chiral selector. The chiral selector forms diastereomeric complexes with the peptide enantiomers in the liquid phase (methanolic solution), which are then transferred to the gas phase, where their dissociation behaviour is studied in an ion-trap mass spectrometer. Different degrees of dissociation of the diastereomeric complexes allow for the discrimination of the peptide enantiomers. The influence of the peptide sequence on enantiomer discrimination is discussed and molecular recognition information is derived by comparing the results obtained for related peptides. For dipeptides, small amino acid residues at the N-terminus and bulky side chains at the C-terminus were found to enhance chiral recognition, while for tripeptides the effects were rather irregular.     

Switchable Stereoselectivity in Bromoaminocyclization of Olefins: Using Brønsted Acids of Anionic Chiral Cobalt(III) Complexes

Brønsted acids of anionic chiral Co^III complexes act as bifunctional phase‐transfer catalysts to shuttle the substrates across the solvent interface and control stereoselectivity. The diastereomeric chiral Co^III‐templated Brønsted acids, with the same chiral ligands, enabled a switch in the enantioselective bromoaminocyclization of olefins to afford the two enantiomers of 2‐substituted pyrrolidines with high enantioselectivities (up to 99:1 e.r.).     

Chiral recognition mass spectrometry: remarkable effects observed from the relative ion abundances of ternary diastereomeric complexes using electrospray ionization

The relative abundances of ternary diastereomeric complexes (composed each from a cinchonane-type chiral selector, a model chiral acid, and an alkali cation) are shown to change remarkably and fortuitously with variation in concentration and type of alkali metal using electrospray ionization-mass spectrometry and competitive binding analysis.     

Induced-fit in the gas phase: conformational effects on the enantioselectivity of chiral tetra-amide macrocycles

The structure, stability, and reactivity of proton-bound diastereomeric [M x H x A]+ complexes between some amino acid derivatives (A) and several chiral tetra-amide macrocycles (M) have been investigated in the gas phase by ESI-FT-ICR and ESI-ITMS-CID mass spectrometry. The displacement of the A guest from the diastereomeric [M x H x A]+ complexes by reaction with the 2-aminobutane enantiomers (B) exhibits a distinct enantioselectivity with regards to the leaving amino acid A and, to a minor extent, to the amine reactant B. The emerging selectivity picture, discussed in the light of molecular mechanics calculations, provides compelling evidence that the most stable conformers of the selected chiral tetra-amide macrocycles M may acquire in the gas phase a different conformation by induced fit on complexation with some representative amino acid derivatives A. This leads to the coexistence in the gas phase of stable diastereomeric [M x H x A]+ eq-eq and ax-ax structures, in proportions depending on the configuration of A and M and characterized by different stability and reactivity toward the 2-aminobutane enantiomers. The enantioselectivity of the gas-phase A-to-B displacement in the diastereomeric [M x H x A]+ complexes essentially reflects the free energy gap between the homo- and heterochiral [M x H x A]+ complexes, except when the tetra-amidic host presents an additional macrocycle generated by a decamethylene chain. In this case, the measured enantioselectivity mostly reflects the stability difference between the relevant diastereomeric transition structures.     

Enantiopure O-substituted phenylphosphonothioic acids: chiral recognition ability during salt crystallization and chiral recognition mechanism

[structure: see text] The chiral recognition ability of enantiopure O-methyl, O-ethyl, O-propyl, and O-phenyl phenylphosphonothioic acids (1a-d) for various kinds of racemic amines during salt crystallization and the chiral recognition mechanism were thoroughly investigated. The chiral recognition abilities of enantiopure 1a-d for a wide variety of racemic amines varied in a range of 6 to >99% enantiomeric selectivity. Deposited less-soluble diastereomeric salts were classified into two categories, prism- and needle-type crystals; the prism-type crystals were composed of a globular molecular cluster, while there existed a 2(1) column in the needle-type crystals. In contrast to a general observation of a similar 2(1) column in the less-soluble diastereomeric salt crystals of chiral primary amines with chiral carboxylic acids, the globular molecular cluster is a very unique hydrogen-bonding motif that has never been constructed in diastereomeric salt crystals. Excellent chiral recognition was always achieved when the less-soluble diastereomeric salts were prism-type crystals. Significant correlations were found between the degree of the chiral recognition with 1a-d, the crystal shape of the less-soluble diastereomeric salts, and the hydrogen-bonding motif (molecular cluster/2(1) column). The chiral recognition mechanisms via the molecular cluster and the 2(1) column formations are discussed in detail on the basis of X-ray crystallographic analyses.     

Highly stereoselective addition of silylphosphines to chiral aldehydes

The reaction between diphenyl(trimethylsilyl)phosphine and chiral aldehydes proceeds with high stereoselectivity to give diastereomerically pure tertiary α-trimethylsiloxyalkylphosphines. The diastereomeric purity of the addition products was 90-100%. The products were purified via the formation of borane-phosphine complexes. The reaction of bis(trimethylsilyl)phenylphosphine with acetonide (R)-glyceraldehyde provides tertiary bis(glyceryl)phosphines.     

Chiral recognition by resorcin[4]arene receptors: intrinsic kinetics and dynamics

Molecular recognition of representative amino acids (A) by a chiral amido[4]resorcinarene receptor (1(L)) was investigated in the gas phase by ESI-FT-ICR mass spectrometry. The ligand displacement reaction between noncovalent diastereomeric [1(L).H.A](+) complexes and the 2-aminobutane enantiomers (B) exhibits a distinct enantioselectivity with regard to both the leaving amino acid A and the amine reactant B. The emerging selectivity picture, discussed in the light of molecular mechanics and molecular dynamics calculations, points to chiral recognition by 1(L), as determined by the effects of the host asymmetric frame on the structure, stability, and rearrangement dynamics of the diastereomeric [1(L).H.A](+) complexes and the orientation of the amine reactant B in encounters with [1(L).H.A](+). The results contribute to the development of a dynamic model of chiral recognition of biomolecules by enzyme mimics in the unsolvated state.     

Exceptional gas-phase enantioselectivity of chiral tetramide macrocycles

Diastereomeric proton-bound complexes between some phenylalanine derivatives (A) and chiral tetramide macrocycles (M) exhibit an uncommon enantioselectivity when reacting with the enantiomers of 2-aminobutanes in the gas phase (B). The measured enantioselectivity depends mainly on two distinct factors: (i) the configuration of the A guest; and (ii) the structure and the relative stability of isomeric [MHA]+ complexes. No significant effects of the B configuration are observed. The diastereomeric [MHA]+ complexes with A = 1-naphthylalanine ethyl ester exhibit the largest enantioselectivity factor ever measured in the gas phase (khomo/khetero = 0.046). The origin of such an exceptional enantioselectivity is mainly attributed to the relative stability of the diastereomeric [MHA]+ complexes, as demonstrated by the comparison of the kinetic results with those from collision-induced dissociation of the trimeric [M2HA]+ adducts and with computational evidence.     

Enantioselective decarboxylation of beta-keto esters with Pd/amino alcohol systems: successive metal catalysis and organocatalysis

The kinetics and mechanisms of one-pot cascade reactions of racemic beta-keto esters to give chiral ketones in the presence of Pd/C-chiral amino alcohol catalyst systems were studied. Transformation of 2-methyl-1-tetralone-2-carboxylic acid benzyl ester (1) into 2-methyl-1-tetralone (4) in the presence of Pd/C and cinchona alkaloids or ephedrine was chosen as a model reaction. After the first reaction step, the Pd-catalysed debenzylation of 1 to afford the corresponding beta-keto acid (2), there are two possible reaction routes that may be catalysed by the chiral amino alcohol in solution or by Pd(0) sites on the metal surface in cooperation with the adsorbed amino alcohol. The reaction intermediate 2 was synthesized, and the kinetics of decarboxylation were followed by NMR, UV and IR spectroscopy. The studies revealed that the role of Pd is to trigger the reaction series by deprotection of 1. The subsequent dominant reaction route from the racemic beta-keto acid 2 to the chiral ketone 4 is catalysed by the chiral amino alcohol in the liquid phase. It is shown that kinetic resolution of the diastereomeric salt of rac-2 and the chiral amino alcohol plays a key role in the enantioselection. High enantioselectivity necessitates an amino alcohol/rac-2 ratio of at least 2. A high ratio favours the formation of 1:1 amino alcohol/acid diastereomeric complexes, and the second amino alcohol molecule may be responsible for the enantioselective protonation of 2 in the diastereomeric complex.     

Stereoselective recognition of vicinal diamines with a Zn(II) complex

Zn(II) complex of L (N,N'-bis(2-pyridylmethyl)-N,N'-dimethyl-trans-1,2-diaminocyclohexane) binds chiral vicinal diamines (1,2-diphenylethylenediamine (dpen) and 1,2-diaminocyclohexane (dach)) stereoselectively. Crystallographic studies reveal that the ternary complex has the C2 symmetric cis-alpha topology. 1H NMR shows that the R,R form of the tetradentate zinc complex binds rapidly and reversibly to the R,R form of the diamine over the S,S form with a stereoselectivity of about 5:1. Although the diamine exchange rate is rapid it is slower than the NMR time scale, and distinct signals for the diastereomeric complexes are observed when racemic mixtures of the host and guest molecules are mixed. Origin of stereoselectivity is discussed in terms of steric effects.     

Formation and emission of tetraalkylammonium salt molecular ions sputtered from a gelatin matrix

A gelatin matrix was simultaneously doped with nine equimolar, homologous, tetraalkylammonium salts ranging in mass from 210 to 700 Da. Bombardment of the sample with kiloelectronvolt ions resulted in a nonidentical distribution of relative cation intensities with a maximum at m/z 242 for samples with a total salt concentration of 0.004 g of salt/g of gelatin. A rapid increase in relative intensities with increasing mass is observed for the low mass salts and is believed to be linked to changes in the ionization efficiencies. The changes in ionization efficiencies are likely related to decreasing coulombic attractive forces between the organic cation and the counterion. Disappearance cross-sections, determined from decay curves, indicate that sputter-induced damage increases with increasing mass of the cation. Fragment-to-intact cation ratios also suggest that damage accumulates fastest in the heaviest salts. These observations indicate that desorption yields of the organic salts in a gelatin matrix decrease with increasing mass. In addition, suppression of lower mass tetraalkylammonium salt intact cation intensities was observed for salt-in-gelatin concentrations greater than 10⁻³ g/g.     

Steric and electronic effects in the resolution of enantiomeric amides on a commercially available Pirkle-type high-performance liquid chromatographic chiral stationary phase

The steric and electronic effects in the resolution of enantiomeric amides on a commercially available (R)-N-(3,5-dinitrobenzoyl)phenylglycine chiral stationary phase (CSP) have been investigated. Several homologous series of enantiomeric amides were synthesized from alkyl and aromatic amines and from alkyl and aromatic acids. The results of the study indicate that chiral recognition is based on the formation of diastereomeric solute-CSP complexes that are due to attractive interactions located on a single bond in both the solute and CSP and on steric interactions within the complexes. The magnitude of the chiral resolution appears to depend on the steric bulk at the chiral center. In addition, when the amides synthesized from chiral amines were chromatographed, the (R)-enantiomers eluted first, whereas the opposite elution order was found for the amides synthesized from enantiomeric carboxylic acids. Thus, the amide moiety not only provides the sites of attractive interaction between the solute and CSP, but also influences the spatial orientation of the two molecules, thereby affecting the relative stabilities of the two diastereomeric complexes and determining the enantiomeric elution order.     

Stereoselective synthesis of 3,4-diaryl β-lactams

Novel 3,4-diaryl β-lactams were prepared with high stereoselectivity in an efficient manner by a palladium-catalyzed [2+2] carbonylative cycloaddition of benzyl halides with heteroarylidene amines. The type of alkyl group linked to the nitrogen atom influences the reaction’s stereoselectivity. Moreover, using chiral imines, separable diastereomeric mixtures of chiral 3,4-diaryl-β-lactams were isolated with good yields and high trans diastereoselections.     

A new atropisomeric P,N ligand for rhodium-catalyzed asymmetric hydroboration

A new optically active and large dihedral angle atropisomeric P,N ligand, pyphos, which contains a tertiary phosphine and pyridine moiety, was prepared and resolved through diastereomeric complexation with chiral palladium amine complexes. The hexafluorophosphate salt of the diastereomers were found to be separable by fractional recyrstallization, while the corresponding chloride salt did not. [Rh(COD)pyphos]PF(6) complex was synthesized by metalation of pyphos with [Rh(COD)Cl](2) followed by anion exchange with NH(4)PF(6) in excellent yield, and the target rhodium complex was characterized by single-crystal X-ray crystallography. The chiral cationic rhodium complex was utilized in the enantioselective hydroboration of vinylarenes. Excellent regioselectivity and good enantioselectivity were observed, and the ee values were found to be dependent on the electronic properties of para-substituted styrenes.     

Phase diagrams of diastereomeric pairs in inclusion resolution

In the development and understanding of the resolution of diastereomeric salts, phase diagrams are of great importance. This study constitutes the first example of phase diagrams of diastereomeric complexes formed from simple chiral compounds, as used in inclusion resolutions. Simple melting diagrams and DSC thermograms could not be used, because of the decomposition of the complex caused by the escape of the guest from the inclusion complex upon heating. A ternary solution phase diagram was constructed from the diastereomeric inclusion complexes of phenethylamine with a taddol. Solid solution behavior was found and confirmed by powder diffraction and X-ray studies. The limited scope of inclusion resolutions, as already indicated by our earlier studies, was confirmed by these results.     

A new class of versatile chiral-bridged atropisomeric diphosphine ligands: remarkably efficient ligand syntheses and their applications in highly enantioselective hydrogenation reactions

A series of chiral diphosphine ligands denoted as PQ-Phos was prepared by atropdiastereoselective Ullmann coupling and ring-closure reactions. The Ullmann coupling reaction of the biaryl diphosphine dioxides is featured by highly efficient central-to-axial chirality transfer with diastereomeric excess >99%. This substrate-directed diastereomeric biaryl coupling reaction is unprecedented for the preparation of chiral diphosphine dioxides, and our method precludes the tedious resolution procedures usually required for preparing enantiomerically pure diphosphine ligands. The effect of chiral recognition was also revealed in a relevant asymmetric ring-closure reaction. The chiral tether bridging the two aryl units creates a conformationally rigid scaffold essential for enantiofacial differentiation; fine-tuning of the ligand scaffold (e.g., dihedral angles) can be achieved by varying the chain length of the chiral tether. The enantiomerically pure Ru- and Ir-PQ-Phos complexes have been prepared and applied to the catalytic enantioselective hydrogenations of alpha- and beta-ketoesters (C=O bond reduction), 2-(6'-methoxy-2'-naphthyl)propenoic acid, alkyl-substituted beta-dehydroamino acids (C=C bond reduction), and N-heteroaromatic compounds (C=N bond reduction). An excellent level of enantioselection (up to 99.9% ee) has been attained for the catalytic reactions. In addition, the significant ligand dihedral angle effects on the Ir-catalyzed asymmetric hydrogenation of N-heteroaromatic compounds were also revealed.     

Cyclic amino acid salts as catalysts for the asymmetric Michael reaction

Different chiral cyclic amino acid alkali metal and ammonium salts were used as catalysts for the asymmetric Michael addition of aldehydes to nitrostyrene. The reaction yield and stereoselectivity depend slightly on the salt cation. The highest yield of the reaction (up to 100%) was obtained with (S)-morpholine-3-carboxylic acid salts, which gave moderate to good enantioselectivities (up to 72% ee) and diastereoselectivities (dr up to 89:11) whereas the highest selectivity was obtained with proline sodium salt (ee 88%).     

"Chiral perturbation factor" approach reveals importance of entropy term in stereocontrol of the 2,4-pentanediol-tethered reaction

The stereocontrol mechanism of the 2,4-pentanediol (PD)-tethered reaction was studied in detail using a reaction system consisting of phenyl and rhodium carbenoid moieties. Different tethers were examined to analyze the effects of the methyl groups on the PD tether. Among the reactions with these tethers, the PD tether achieves an unmeasurably high stereoselectivity in a diastereomeric ratio of >500. Another tether showing a high but measurable stereoselectivity in a ratio of 41 is mostly controlled by the entropy term. To clarify the role of the methyl groups on the chiral tethers, which are the origin of the stereocontrol, the "chiral perturbation factor" is introduced. This parameter is defined as the rate of a chiral reaction relative to that of an achiral reference reaction. By analyzing the temperature dependence of the chiral perturbation factors for different chiral-tethered reactions, high potentials of the PD-tethered reaction in its stereocontrol are concluded to be due to the entropy term.     

Lanthanum-pyBOX complexes as catalysts for the enantioselective conjugate addition of malonate esters to β,γ-unsaturated α-ketimino esters

Abstract

In this paper, we report the application of chiral complexes of La(III) with pyBOX ligands as Lewis acid catalysts in the conjugate addition of malonic esters to N-tosyl imines derived from β,γ-unsaturated α-keto esters to give the corresponding chiral α,β-dehydroamino esters. pyBOX complexes with La(III), Yb(III), Sc(III), and In(III) triflates were assessed in this reaction but only La(III) showed good activity and enantioselectivity, while Yb(III) provided the expected product with low yield and stereoselectivity, and the Sc(III) and In(III) complexes were completely inactive. The complex of La(OTf)₃ with the diphenyl-pyBOX ligand prepared in situ provided the best results and allowed obtaining chiral α,β-dehydroamino esters 3 with excellent yields, E:Z diastereomeric ratios (29:71–99:1) and high enantiomeric excesses (20–95%). The reaction could be applied to imines having a substituted aromatic ring or a heterocycle attached to the double bond, although the presence of electron-withdrawing groups on the aromatic ring was detrimental for stereoselectivity. The reaction products were obtained with the S configuration at the stereogenic center and the Z configuration at the enamine double bond as determined by NOESY experiments and X-ray analysis. Based on the experimental results a stereochemical model involving a nine-coordinate La(III) species has been proposed.     

Synthesis of fluorinated pseudopeptides: metal mediated reversal of stereochemistry in diastereoselective addition of organometallic reagents to N-(tert-butanesulfinyl)-α-fluoroenimines

The addition reaction of organometallic reagents to N-(tert-butanesulfinyl)-α-fluoroenimines was studied. Depending of the nature of the organometallic species (Grignard reagents or zincate complexes), we were able to control the configuration of the newly created stereogenic centers in high yields with good to high diastereomeric ratios. The chiral β-fluoro allylamines are key synthons toward the synthesis of fluorinated pseudopeptides bearing a fluoroolefin moiety as a peptide bond mimic.