Diastereomeric Host-guest Complex Research Articles

Enantioselective Molecular Recognition in a Flexible Self-Folding Cavitand.

We report a chiral deep cavitand receptor based on calix[5]arene stabilized by a cooperative network of hydrogen bonds and having a highly flexible structure. The cavitand displays enantioselective molecular recognition with a series of chiral quaternary ammonium salts, providing unprecedented stability ratios between the corresponding diastereomeric host-guest complexes. Molecular dynamics simulations corroborate the higher flexibility of the new host and the emergence of superior induced-fit behavior with regards to resorcin[4]arene derived self-folding cavitands.

Metalloporphyrin Dimers Bridged by a Peptoid Helix: Host-Guest Interaction and Chiral Recognition.

Co-facial porphyrins have been designed to construct porphyrin tweezers with versatile molecular recognition capabilities. In this study, we synthesized metalloporphyrin–peptoid conjugates (MPPCs) displaying two metalloporphyrins on a peptoid scaffold with either achiral unfolded (1) or helical (2 and 3) secondary structures. Host–guest complexation of MPPCs was realized with various guests of different lengths and basicities, and the extent of complexation was measured by UV-vis and circular dichroism (CD) spectroscopic titration. Intermolecular and intramolecular chirality induction were observed on achiral and chiral peptoid backbones, respectively. Spectroscopic data indicated that a broad scope of achiral guests can be recognized by chiral 2; in particular, longer and more flexible guests were seen to bind more tightly on 2. In addition, chiral 2 provided a distinct CD couplet with dl-, d-, or l-Lys-OMe, which was a result of the diastereomeric host–guest complex formation. Our results indicated that MPPCs can recognize, contrast, and analyze various achiral, chiral, or racemic molecules. Based on co-facial metalloporphyrins present on peptoid scaffolds, we developed a novel class of porphyrin tweezers, which can be further utilized in asymmetric catalysis, molecular sensing, and drug delivery.

Host–guest complexation of omeprazole, pantoprazole and rabeprazole sodium salts with cyclodextrins: an NMR study on solution structures and enantiodiscrimination power

The application of different cyclodextrins (CDs) as NMR chiral solvating agents (CSAs) for the sodium salts of the proton-pump inhibitors omeprazole, pantoprazole (sesquihydrate) and rabeprazole was investigated. It was proved that the formation of diastereomeric host–guest complexes in D2O solution between the CDs and those substrates permitted the direct 1H NMR discrimination of the enantiomers of the sodium salts of these compounds without the need of previous working-up. Rotating frame nuclear overhauser effect spectroscopy (ROESY) was used to ascertain the solution geometries of the host–guest complexes. The results suggested a preferential binding of the benzimidazole moiety of the guest molecules within the macrocyclic cavity of α-CD, whereas the higher dimensions of β- and γ-CD also permitted the inclusion of the highly substituted pyridine moieties. Moreover, the solution stoichiometries and the binding constants of the complexes formed with pantoprazole at room temperature were determined by 1H and 19F NMR titration. Diffusion-filtered Spectroscopy was applied to obtain clean spectra without the interference of the HOD signal.

A facile circular dichroism protocol for rapid determination of enantiomeric excess and concentration of chiral primary amines.

A protocol for the rapid determination of the absolute configuration and enantiomeric excess (ee) of alpha-chiral primary amines with potential applications in asymmetric reaction discovery has been developed. The protocol requires derivatization of alpha-chiral primary amines through condensation with pyridine carboxaldehyde to quantitatively yield the corresponding imine. The Cu(I) complex with 2,2'-bis (diphenylphosphino)-1,1'-dinaphthyl (BINAP--Cu(I)) with the imine yields a metal-to-ligand charge-transfer (MLCT) band in the visible region of the circular dichroism (CD) spectrum upon binding. Diastereomeric host-guest complexes give CD signals of the same signs but different amplitudes, allowing for differentiation of enantiomers. Processing the primary optical data from the CD spectrum with linear discriminant analysis (LDA) allows for the determination of the absolute configuration and identification of the amines, and processing with a supervised multilayer perceptron artificial neural network (MLP-ANN) allows for the simultaneous determination of the ee and concentration. The primary optical data necessary to determine the ee of unknown samples is obtained in two minutes per sample. To demonstrate the utility of the protocol in asymmetric reaction discovery, the ee values and concentrations for an asymmetric metal-catalyzed reaction are determined. The potential of the application of this protocol in high-throughput screening (HTS) of ee is discussed.

Use of (S)‐BINOL as NMR chiral solvating agent for the enantiodiscrimination of omeprazole and its analogs

The application of (S)-1,1'-binaphthyl-2,2'-diol as NMR chiral solvating agent (CSA) for omeprazole, and three of its analogs (lanso-, panto-, and rabe-prazole) was investigated. The formation of diastereomeric host-guest complexes in solution between the CSA and the racemic substrates produced sufficient NMR signal splitting for the determination of enantiomeric excesses by (1)H- or (19)F-NMR spectroscopy. Using of hydrophobic deuterated solvents was mandatory for obtaining good enantiodiscrimination, thus suggesting the importance of intermolecular hydrogen bonds in the stabilization of the complexes. The method was applied to the fast quantification of the enantiomeric purity of in-process samples of S-omeprazole.

Nuclear Magnetic Resonance Signaling of Molecular Chiral Information Using an Achiral Reagent

Until now NMR spectroscopic detection of guest chirality using an achiral host has not been possible in the absence of a chiral medium or auxiliary since chiral discrimination is principally based on chiral discrimination by host and/or diastereomeric host-guest complex formation. In this paper, we demonstrate that an achiral oxoporphyrinogen works as a host capable of signaling chiral information of alpha-hydroxycarboxylic acids in (1)H NMR spectroscopy. In particular, enantiomeric excess (ee) can be determined by observing the splitting of (1)H NMR resonances of the achiral host. This differs from the case of chiral hosts (shift reagents) where % ee is generally determined from the ratio of peak areas due to diastereomeric host-guest complexes. UV/vis, CD, FT-IR, and NMR spectroscopic investigations suggest that the unusual phenomenon reported here is based on formation of a complex with 1:2 stoichiometry in concert with a protonation-driven tautomerization of the host.

Simultaneously bound guests and chiral recognition: a chiral self-assembled supramolecular host encapsulates hydrophobic guests

Driven by the hydrophobic effect, a water-soluble, chiral, self-assembled supramolecular host is able to encapsulate hydrophobic organic guests in aqueous solution. Small aromatics can be encapsulated in the supramolecular assembly, and the simultaneous encapsulation of multiple species is observed in many cases. The molecular host assembly is able to recognize different substitutional isomers of disubstituted benzenes with ortho substitution leading to the encapsulation of two guests, but meta or para substitution leading to the encapsulation of only one guest. The scope of hydrophobic guest encapsulation is further explored with chiral natural products. Upon encapsulation of chiral molecules into the racemic host, diastereomeric host–guest complexes are formed with observed diastereoselectivities of up to 78:22 in the case of fenchone.

Direct Assignment of Enantiofacial Discrimination on Single Heterocyclic Substrates by Self‐induced CD

The first direct assignment of highly dynamic enantiofacial discrimination acting on a single heterocyclic substrate has been achieved by a combination of experimental and theoretical CD spectroscopy. The interaction of chirally modified hosts based on triphenylene ketals with appropriate prochiral guests can lead to the preferential formation of one diastereomeric host-guest complex. This reversible stereoselective binding transmits the chiral information from remote chiral groups in the host to the strongly absorbing triphenylene chromophore, which gives rise to self-induced CD. This effect was exploited for the determination of the enantiofacial recognition in various host-guest systems. Inversion of the steric demand either of the chiral substituents at the host or of the prochiral guest leads to almost complete inversion of the resulting CD spectra. For the assignment of the absolute stereochemistry of the complexes, a combined molecular dynamics/quantum-chemical approach was successfully employed. Despite the size and the highly dynamic character of the supramolecular systems, fundamental properties of the systems and details of the spectra were simulated accurately, providing access to fast and reliable assignment of the enantiofacial preference. The results are highly consistent with available X-ray data.

Matrix Effects on the Chiral Recognition Determined by the Relative Peak Intensity of Diastereomeric Host-Guest Complex Ions Using the FAB Mass Spectrometry/Enantiomer Labeled Guest Method.

The FAB mass spectrometry (MS)/enantiomer labeled (EL) guest method is one of the useful technique to easily evaluate chiral discrimination ability of a chiral host (H) toward chiral guests (GR+, GS-dn+). In this paper, the matrix dependency of the relative peak intensity (IRIS) of the diastereomeric host-guest complex ions [(H+GR)+ and (H+GS-dn)+] was investigated (host, MeFruNys; guest, Phe-O-iPr+). The IRIS values of spectra measured using NBA, NPOE, and DTDE matrices agreed almost with the ratio of concentrations of the complex ions calculated from the association constants (KR and KS) in chloroform at 298 K. While, the IRIS values of spectra using glycerol matrix reached almost unity. It was assumed that the IRIS values depend upon the matrices used since the difference of solvation ability of the matrices affects the actual concentration of the guest concerning in the complexation. And then, it was recommended that NBA is the best matrix for chiral recognition mass spectrometry studies.

定量的キラル認識マススペクトロメトリーの進歩

The developments of our quantitative chiral recognition studies in the host-guest complexations between chiral crown ethers and chiral amino acid esters by FAB, ESI, and MALDI mass spectrometry have been described. Both the enantiomer labeled (EL)-guest method and the EL-host method, which had been previously proposed by us, were successfully advanced. The relative peak intensity (IRIS) values of the diastereomeric host-guest complex ions appeared in mass spectra were especially noted, and their use to chiral recognition was illustrated. Generally, the former method was used to chiral recognition ability-determination of a given host, and the latter one was used to enantiomeric excess (e.e.)-determination of a given guest. Through the manuscript, emphasis has been put on the finding that one can detect correctly the concentration ratio of the two diastereomeric host-guest complex ions formed in a matrix solution by FAB mass spectrometry and then, that FABMS is a powerful tool for detecting chiral host-guest interactions in the host-guest complexation systems. Recent ,e.e.-determination methods by ESI mass spectrometry etc. were also summarized.

Chiral Recognizable Host-Guest Interactions Detected by Fast-Atom Bombardment Mass Spectrometry: Application to the Enantiomeric Excess Determination of Primary Amines

The enantiomeric excess ( ee) of organic amine compounds has been determined using fast-atom bombardment (FAB) mass spectrometry based on the chiral host–guest complexation systems. The method uses a 1:1 mixture of the given chiral crown ether hosts (HRRRR and HSSSS-dn), one of whose enantiomers is isotopically labeled, for the ee-determination of a given amine salt guest (G+). The peak intensity ratio { I[(HRRRR + G)+] / I[(HSSSS-dn + G)+] = IRIS} of the two diastereomeric host–guest complex ions clearly changes with the change in the ee of the guest. The intensity excess ( Ie) of the two complex ion peaks is newly defined as Ie = ( IRIS −1) / ( IRIS + 1). The two sets of mass spectrometrically obtained Ie values vs a set of ee values of phenylalanine methyl ester and leucine methyl ester hydrochlorides show excellent linear relationships through the zero point ( R2 = 0.9989 and R2 = 0.9970, respectively). This indicates the potential utility of the present ee-determination method to within ± 3% ee. Furthermore, based on the solution equilibrium distributions of the complex ions, the linearity is mathematically justified. Therefore, the ee-determination can be simplified as ee (%) = (| Ie| / | Ie(100)|) × 100: here, Ie(100) is the corresponding Ie value obtained using an enantiomerically pure (100% ee) guest as a reference. The present chiral dimethoxyphenyl crown ether host pairs employed are effective ( IRIS ≥ 1.5) for the ee-determination of most α-amino acid esters, but not effective ( IRIS ≈ 1.0) for most simple alkylamines.

Electrospray Ionisation Mass Spectrometry (ESI-MS): a powerful tool for the evaluation of chiral recognition in host-guest complexation

The chiral recognition properties of a series of synthetic crown ethers or cryptands (1-10) incorporating a chiral spiroacetal moiety in the polyether chain toward ammonium enantiomeric pairs (G1 or G2) have been evaluated by Electrospray Ionisation Mass Spectrometry (ESI-MS). Isotopic-labelling has been used to distinguish one diastereomeric host-guest complex ion from the other. The reliability of this method has also been tested by studying the stability of the labelling and the influence of the labelling on the degree of chiral recognition. Various degrees of chiral recognition have emerged from this study.

アミノ糖類の立体異性体識別 エナンチオマー標識ホスト法を用いるキラル認識ＦＡＢマススペクトロメトリー

FAB mass spectrometry coupled with the host-guest complexation method was used to distinguish some amino sugars (1-8) including glucosamine, galactosamine, and mannosamine, etc. The method characteristically used a 1:1 mixture of the chiral crown ether host whose enantiomer was isotopically labeled. Diastereomer differentiation of a given amino sugar salt (G+) was simply measured with a given host pair (A or B) (HRRRR:HSSSS-d6=1:1) from the peak intensity ratio of the two diastereomeric host-guest complex ions as I[(HRRRR+G)+]/I[(HSSSS-d6+G)+]≡IRIS (abbreviation). The stereoisomer differentiation was performed by the IRIS values in the range from 0.4 to 2.0 (for the use of the host pair A) and from 0.4 to 3.4 (for the use of the host pair B). The five underivatized amino sugar hydrochloride salts (1-5) were successfully differentiated using the present chiral recognition FAB mass spectrometry. The stereoisomer-(13C)-labeled guest method was also presensed to evaluate their relative complexation abilities.

Determination of enantiomeric excess for organic primary amine compounds by chiral recognition fast-atom bombardment mass spectrometry

Enantiomeric excess (ee) of organic primary amine compounds such as phenylglycine methyl ester hydrochloride ( 2) has been determined by fast-atom bombardment (FAB) mass spectrometry (NBA matrix). Chiral recognition in host–guest complexation systems between crown ethers [H] and amino acid ester ammonium ions [G] has been extended to the ee determination. The method characteristically uses a 1/1 mixture of a pair of enantiomeric hosts whose enantiomer is isotopically labeled [(RRRR)- 1 and (SSSS)- 1-d 6]. Chiral recognition of a given guest is simply measured with the given host–pair reagent from the relative peak intensities of the two corresponding diastereomeric host–guest complex ions in I[(H RRRR · G) +]/ I[(H SSSS-d 6 · G) + = I R/ I S-d 6 , so called IRIS value. The IRIS value varies in a linear fashion with the ee quantitiy of 2 and produces a symmetric linear V-shaped plot, indicating that in the case of a primary amine guest (such as 2) with unknown ee, one can determine the ee by this type of chiral recognition FAB mass spectometry. Further, based on the observed concentration effects on the IRIS values, it is suggested that the present IRIS value reflects the concentration ratio of the diastereomeric complex ions formed in the matrix.

Chiral amino acid recognition detected by electrospray ionization (ESI) and fast atom bombardment (FAB) mass spectrometry (MS) coupled with the enantiomer-labelled (EL) guest method

Chiral recognition of crown ethers toward amino acids and their esters is detected both by electrospray ionization (ESI) and by fast atom bombardment (FAB) mass spectrometry (MS) and then compared as a series of host (H)–guest (G) pairs. A racemic guest (GR+∶[2Hn]GS+ = 1∶1, of which one enantiomer is deuterium-labelled), is mixed with the target host. The chiral amino acid recognition of the host is determined from the relative peak intensities of the corresponding diastereomeric host–guest complex ions, [eqn. (a)]: I[(H·GR)+]/I[(H·[2Hn]GS)+] = IRIS. (a) For the complexation between chiral host 1 and guest MetOMe+, FABMS gives IRIS = 5.0 (NBA matrix), which is practically equal to the corresponding equilibrium constant ratio (KR/KS) in solution. However, ESIMS gives IRIS = 1.5 for the same complexation (MeOH), which is a remarkable decrease in the IRIS value. Another complex between chiral host 8 and guest MetOMe+, gives IRIS = 2.0 by FABMS but IRIS = 1.2 by ESIMS. Moreover, in a much simpler system, the amino ester ion selectivity, LeutOMe+/MetOMe+, of host 18-crown-6 is depressed to such an extent that we must conclude that ammonium ion selectivity cannot be evaluated by ESIMS, but the metal ion selectivity, K+/Na+, of the same host 18-crown-6 gives a good qualitative evaluation of the relative concentrations of the corresponding H–G complex ions in solution. It is demonstrated that the IRIS values from the FABMS coupled with the enantiomer-labelled (EL) amino ester guest method are the most reliable and generally useful of the measures considered for the chiral amino acid recognition.

Capillary zone electrophoretic separation of the enantiomers of dipeptides based on host-guest complexation with a chiral crown ether

The enantiomeric separation of racemic glycyldipeptides and diastereomeric dipeptides by using capillary zone electrophoresis and (+)-18-crown-6-tetracarboxylic acid (18C6H 4) as a chiral selector added to the electrolyte is described. The separation of dipeptides with two stereogenic centres into four peaks by using capillary zone electrophoresis is reported for the first time. Chiral discrimination is attributed to the formation of a diastereomeric host-guest complex which leads to different interactions for each enantiomer. Owing to the differences in stability of the complexes, the four optical isomers elute at different migration times, allowing the chiral separation. The influence of buffer composition, crown ether concentration and the addition of organic modifiers was studied. All glycyldipeptides were resolved and for most of the diastereomeric dipeptides four baseline-separated peaks were observed.

Chiral separations by host-guest complexation with cyclodextrin and crown ether in capillary zone electrophoresis

Capillary zone electrophoresis using cyclodextrins and a chiral crown ether as buffer constituents was studied for the enantiomeric separation of drugs and amino acids. Based on results obtained from separation of racemic α-amino acids both chiral selectors are compared with respect to resolution, efficiency and retention time. For (±)-Quinagolide effects of buffer composition and temperature are examined using β-cyclodextrin as chiral agent. Optimum conditions were pH 2.5 at 30 mmol L−1 β-cyclodextrin. A linear dependence of retention on β-cyclodextrin concentration allowed calculation of formation constants of the host-guest complexes. Buffer concentration and temperature also influence resolution. The application of a chiral crown ether to the separation of optical isomers in capillary zone electrophoresis is described for the first time. Chiral recognition of solutes depends on the formation of protonated alkyl amines and separation is attributed to the formation of diastereomeric host-guest complexes with different interactions for each enantiomer. The effects of crown ether concentration on resolution are presented.

Diastereomeric host-guest complex formation by an optically active paracyclophane in water

The first synthesis of a water-soluble cyclophane possessing a chiral hydrophobic cavity, and the formation of diastereomeric inclusion complexes with chiral hydrophobic guests in water are described.