Formation Of Diastereomeric Complexes Research Articles

Selector‐Induced Dynamic Deracemization of a Selectand‐Modified Tropos BIPHEPO‐Ligand: Application in the Organocatalyzed Asymmetric Double‐Aldol‐Reaction

Stereolabile interconverting catalysts open up the possibility of directing enantioselectivity in asymmetric synthesis by formation of diastereomeric complexes with chiral auxiliaries and deracemization. However, the stoichiometrically used auxilliaries can significantly limit the potential applications of such systems. We synthesized a new BIPHEPO tropos ligand containing achiral selectands in the backbone, which forms transient diastereomeric associates with amylose-tris-3,5-dimethylphenyl carbamate as a selector and thus deracemizes. The enantiomerically enriched BIPHEPO obtained was successfully used in the organocatalytic asymmetric double aldol addition of substituted methyl ketones to form benzaldehyde. This strategy combines an on-column deracemization with the high stereoinduction of chiral biarylphosphineoxides and opens up new possibilities in the field of self-amplified asymmetric syntheses.

Aromatic Amide and Hydrazide Foldamer-Based Responsive Host–Guest Systems

CONSPECTUS: In host-guest chemistry, a larger host molecule selectively and noncovalently binds to a smaller guest molecule or ion. Early studies of host-guest chemistry focused on the recognition of spherical metal or ammonium ions by macrocyclic hosts, such as cyclic crown ethers. In these systems, preorganization enables their binding sites to cooperatively contact and attract a guest. Although some open-chain crown ether analogues possess similar, but generally lower, binding affinities, the design of acyclic molecular recognition hosts has remained challenging. One of the most successful examples was rigid molecular tweezers, acyclic covalently bonded preorganized host molecules with open cavities that bind tightly as they stiffen. Depending on the length of the atomic backbones, hydrogen bonding-driven aromatic amide foldamers can form open or closed cavities. Through rational design of the backbones and the introduction of added functional groups, researchers can regulate the shape and size of the cavity. The directionality of hydrogen bonding and the inherent rigidity of aromatic amide units allow researchers to predict both the shape and size of the cavity of an aromatic amide foldamer. Therefore, researchers can then design guest molecules with structure that matches the cavity shape, size, and binding sites of the foldamer host. In addition, because hydrogen bonds are dynamic, researchers can design structures that can adapt to outside stimuli to produce responsive supramolecular architectures. In this Account, we discuss how aromatic amide and hydrazide foldamers induced by hydrogen bonding can produce responsive host-guest systems, based on research by our group and others. First we highlight the helical chirality induced as binding occurs in solution, which includes the induction of helicity by chiral guests in oligomeric and polymeric foldamers, the formation of diastereomeric complexes between chiral foldamer hosts and guests, and the induction of helical chirality by chiral guests into inherently flexible backbones. In addition, molecular or ion-pair guests can produce supramolecular helical chirality in the organogel state. Such structures exhibit remarkable time-dependence and a "Sergeants and Soldiers" effect that are not observed for other two-component organogels that have been reported. We further illustrate that the reversible folding behavior of an aromatic amide foldamer segment can modulate the switching behavior of donor-acceptor interaction-based [2]rotaxanes. Finally we show that a folded oligomer can induce folding in one or two attached intrinsically flexible oligomers, an example of a solvent-responsive intramolecular host-guest system.

Surface Diastereomeric Complexes Formed by Methyl Benzoylformate and (R)-1-(1-Naphthyl)ethylamine on Pt(111)

The formation of diastereomeric complexes between methyl benzoylformate (MBF) and (R)-1-(1-naphthyl)ethylamine, (R)-NEA, on Pt(111) was studied using scanning tunneling microscopy. We observe several distinct geometries formed by 1:1 and 2:1 MBF/(R)-NEA complexes. The complexation patterns are compared with our previous data for 2,2,2-trifluoroacetophenone, (TFAP)/(R)-NEA, and methyl-3,3,3 trifluoropyruvate, (MTFP)/(R)-NEA, complexes on Pt(111). Steric hindrance due to the phenyl group forces MBF to form complexes that are inverted relative to those formed by MTFP. Compared to TFAP, the addition of the ester group, permitting intermolecular bonding through either the ester or the keto-carbonyl or both, increases the number of complexation geometries that the substrate can adopt. In particular, the ketoester group permits the phenyl group to be placed distant from (R)-NEA at several positions while also permitting NH···OC bonding. Overall, this leads to a decrease of the prochiral selectivity relative to TFAP/(R)-NEA complexes.

Resolution of 1-n-propoxy-3-methyl-3-phospholene 1-oxide by diastereomeric complex formation using TADDOL derivatives and calcium salts of O,O′-dibenzoyl-(2R,3R)- or O,O′-di-p-toluoyl-(2R,3R)-tartaric acid

1-n-Propoxy-3-methyl-3-phospholene 1-oxide was prepared in optically active form by extending resolution methods applying (−)-(4R,5R)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane (‘TADDOL’) and (−)-(2R,3R)-α,α,α′,α′-tetraphenyl-1,4-dioxaspiro[4.5]decan-2,3-dimethanol (‘spiro-TADDOL’), as well as the acidic and neutral Ca2+ salts of (−)-O,O′-dibenzoyl- and (−)-O,O′-di-p-toluoyl-(2R,3R)-tartaric acid. In one case, the diastereomeric complex could be identified by single crystal X-ray analysis. The absolute P-configuration of the enantiomers of the phospholene oxide was also determined by CD spectroscopy.

Reductive Labilization of a Cyclometalating Ligand Applied to Auxiliary-Mediated Asymmetric Coordination Chemistry

(4S)-4-Isopropyl-2-(3-nitrophenyl)-4,5-dihydrooxazole ((S)-Phox) is introduced as a novel chiral auxiliary for the asymmetric synthesis of ruthenium polypyridyl complexes. A simply accessible (S)-Phox-bearing precursor serves as the starting point for diastereoselective coordination chemistry: The stereogenic carbon atom of the cyclometalating auxiliary controls the spatial arrangement of incoming 1,10-phenanthrolines during ligand substitution reactions (ratio Λ:Δ up to 14:1), and further precipitation affords diastereopure compounds. In the following key step, the labilization of the auxiliary ligand is achieved by reduction, thus permitting its replacement against a third polypyridyl ligand with complete retention of the configuration at the metal center (er > 99:1) under mildly acidic conditions, in contrast with previously developed systems that require strong acid. On the basis of results of NMR experiments and X-ray analysis obtained for intermediate compounds, mechanistic considerations for the formation of diastereomeric complexes were made, revealing a Δ → Λ isomerization as the reason for the observed limitations in selectivity optimization. This work expands the pool of methods available for the asymmetric synthesis of tris-heteroleptic ruthenium polypyridyl complexes and additionally may serve as an inspiration for the synthesis of other nonracemic octahedral chiral-at-metal compounds.

Complex formation of fenchone with α-cyclodextrin: NMR titrations.

13C NMR titration studies of inclusion complexes of bicyclic terpenoid, fenchone enantiomers with α-cyclodextrin revealed their 1:2 guest–host stoichiometry. Sequential binding constants were determined indicating a strong binding cooperativity of two α-cyclodextrin to fenchone. The overall association constants were used to calculate the Gibbs free energies of diastereomeric complex formation, which might be used as a measure of chiral recognition of fenchone by α-cyclodextrin. These results were compared with corresponding data derived for camphor, which is an isomeric bicyclic terpenoid.Electronic supplementary materialThe online version of this article (doi:10.1007/s10847-013-0356-4) contains supplementary material, which is available to authorized users.

NMR spectroscopic detection of chirality and enantiopurity in referenced systems without formation of diastereomers.

Enantiomeric excess of chiral compounds is a key parameter that determines their activity or therapeutic action. The current paradigm for rapid measurement of enantiomeric excess using NMR is based on the formation of diastereomeric complexes between the chiral analyte and a chiral resolving agent, leading to (at least) two species with no symmetry relationship. Here we report an effective method of enantiomeric excess determination using a symmetrical achiral molecule as the resolving agent, which is based on the complexation with analyte (in the fast exchange regime) without the formation of diastereomers. The use of N,N′-disubstituted oxoporphyrinogen as the resolving agent makes this novel method extremely versatile, and appropriate for various chiral analytes including carboxylic acids, esters, alcohols and protected amino acids using the same achiral molecule. The model of sensing mechanism exhibits a fundamental linear response between enantiomeric excess and the observed magnitude of induced chemical shift non-equivalence in the 1H NMR spectra.

Stereodirection of an α-Ketoester at Sub-molecular Sites on Chirally Modified Pt(111): Heterogeneous Asymmetric Catalysis

Chirally modified Pt catalysts are used in the heterogeneous asymmetric hydrogenation of α-ketoesters. Stereoinduction is believed to occur through the formation of chemisorbed modifier-substrate complexes. In this study, the formation of diastereomeric complexes by coadsorbed methyl 3,3,3-trifluoropyruvate, MTFP, and (R)-(+)-1-(1-naphthyl)ethylamine, (R)-NEA, on Pt(111) was studied using scanning tunneling microscopy and density functional theory methods. Individual complexes were imaged with sub-molecular resolution at 260 K and at room temperature. The calculations find that the most stable complex isolated in room-temperature experiments is formed by the minority rotamer of (R)-NEA and pro-S MTFP. The stereodirecting forces in this complex are identified as a combination of site-specific chemisorption of MTFP and multiple non-covalent attractive interactions between the carbonyl groups of MTFP and the amine and aromatic groups of (R)-NEA.

Surface-Induced Diastereomeric Complex Formation of a Nucleoside at the Liquid/Solid Interface: Stereoselective Recognition and Preferential Adsorption

With the aim of achieving surface-mediated enantioselective adsorption, the self-assembly of chiral oligo(p-phenylenevinylene) (OPV3T) with nucleosides is investigated at the liquid/solid interface by means of scanning tunneling microscopy and molecular modeling. OPV3T enantiomers form mirror related hexameric rosette patterns. The DNA nucleoside, thymidine, does not self-assemble into stable adlayers but coadsorbs with OPV3T on the surface, leading to a pattern transformation of OPV3T from rosettes to dimers, and a change in chiral expression as well. Diastereoselective recognition between OPV3T and thymidine enantiomers can be used to resolve thymidine enantiomers at an achiral surface with an OPV3T enantiomer as the resolving agent. The impact of molar ratio and concentration on the self-assembly and chiral resolution is systematically investigated. Because there is no interaction between OPV3T and thymidine in solution, the liquid/solid interface acts as the platform for the chiral resolution of thymidine enantiomers.

Novel optically active methacrylic polymers containing side-chain porphyrin moieties for chiral recognition

Novel optically active methacrylic homopolymers bearing in the side chain one or more chiral groups of one single configuration ( l-lactic acid residue) linked to tetraphenylporphyrin have been successfully synthesized and fully characterized. These intrinsically chiral polymers exhibit remarkable thermal stability, with glass transition temperature in the range 250–315 °C and decomposition temperatures in the range 360–390 °C. Spectroscopic, thermal and chiroptical characterizations indicate the occurrence of dipolar interactions among the side chain moieties and the presence of chiral helix conformation at least for chain segments of the macromolecules. The macromolecular Zinc-porphyrin material resulted capable to bind optically active α,ω-diamine guests through nitrogen/zinc coordination to form complexes exhibiting exciton-coupled bisignate Circular Dichroism (CD) spectra with signs related to the absolute configuration of the guest compound. This behavior is due to the formation of diastereomeric complexes which lead to a preferred porphyrin helicity, at least for chain segments. The method turns out to be very sensitive, requiring only few micrograms of guest compound.

Chiral sensing system based on the formation of diastereomeric metal complex on a homocysteine monolayer using field effect transistor

A self-assembled monolayer (SAM) of l-homocysteine ( l-Hcy) formed on the surface of a gold-deposited gate of a field effect transistor (FET) was used to differentiate between enantiomers of amino acids, for which the formation of diastereomeric metal complexes is fundamental for chiral discrimination. Here, we focus our attention on the dependence of the FET response on the analyte amino acids, the central metal ions involved in complex formation, and the solution pH. Using the l-Hcy SAM-modified gate with added Cu(II), notable negative FET responses were enantioselectively observed for the l-enantiomers of alanine (Ala), phenylalanine, and tryptophan, whereas differences in the FET responses between enantiomers were negligible for asparagine and aspartic acid. Regarding the enantioselectivity for Ala, the addition of Cu(II) was demonstrated to show higher selectivity as compared to other metal ions such as Co(II) and Ni(II). Moreover, for the addition of l-Ala and Cu(II), a particularly strong negative FET response was observed at pH 5.5.

Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids

Efficient use of the readily accessible chiral C 2-symmetric acyclic diamines (1–2) as well as macrocyclic amines (3–5) containing trans-1,2-diaminocyclohexyl moiety as chiral solvating agents (CSA) for the determination of enantiomeric excess of representative carboxylic acids (6–7) and an amino acid derivative (8) is illustrated. The enantiomeric composition of different carboxylic acids estimated here by the 1H NMR method, based on the integration of the corresponding methine proton signals are in good correlation with that determined using HPLC method. The data are in accordance with the formation of multimolecular diastereomeric complexes in solution, which render good splitting of NMR signals for the enantiomers of representative carboxylic acids as well as for N-Ts-phenylglycine (up to ΔΔδ = 0.295 ppm, 118 Hz).

Chiral discrimination between alanine enantiomers by field effect transistor with a homocysteine monolayer-modified gate

Abstract The application of field effect transistor (FET) to chiral discrimination was investigated. An Au film vapor-deposited on a self-assembled monolayer (SAM) of (3-mercaptopropyl)trimethoxysilane, which was formed on the SiO2 gate of FET as an adhesive and insulating layer, stabilizes the drain current–gate voltage (Id–Vg) property of FET. The modification by homocysteine (Hcy) SAM on the surface of Au-coated gate makes it possible for the FET to distinguish between the enantiomers of alanine (Ala). Namely, after the sequential addition of Ala and Cu(II) to a K2SO4 solution in this system, it was confirmed that the lateral shift of Id–Vg curves for the FET corresponded to the chirality of Ala. With the l -Hcy SAM-modified gate, a notable negative shift was observed for l -Ala, whereas the shift observed with d -Ala was much smaller. In contrast, opposite results were obtained with d -Hcy SAM. Results of quartz crystal microbalance measurement suggested that such an FET response was originated from the enantioselective formation of diastereomeric Cu complexes with Ala molecules on the Hcy SAM. This system was demonstrated to respond quantitatively to one enantiomeric form of Ala in mixed solutions of two enantiomers as well as in pure enantiomeric solutions.

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.

Multicomponent analyses of chiral samples by use of regression analysis of UV–visible spectra of cyclodextrin guest–host complexes

We report the first combined use of analytical spectroscopy, guest-host chemistry, and multivariate regression analysis for determination of enantiometric composition of multicomponent samples of chiral analytes. Sample solutions containing multicomponent analytes of ephedrine, tryptophan, propranolol, and proline of varying enantiomeric composition with beta-cyclodextrin (BCD) or methyl-beta-cyclodextrin (Me-BCD) as chiral host molecules were investigated using ultraviolet (UV)-visible spectroscopy. The interactions of enantiomers of chiral analytes with chiral hosts resulted in the formation of transient diastereomeric inclusion complexes with varying spectral properties. Multivariate analysis using partial-least-square (PLS) regression was used to correlate subtle changes in the UV-visible spectra of the guest-host complexes with the enantiomeric composition of the calibration samples. These PLS regressions were carefully optimized and then used to predict the enantiomeric composition of multicomponent chiral analytes of validation samples. The results of these validation studies demonstrate the predictive ability of the regression models for determination of future enantiomeric composition of samples. The accuracy of the models to correctly predict the enantiomeric composition of samples, evaluated by use of the root mean square percent relative error (RMS%RE) was analyte and chiral host dependent. In general, better prediction of enantiomeric composition of samples and low RMS%RE values were obtained when Me-BCD was used as the chiral host. The analyses procedure reported here is simple, rapid, and inexpensive. In addition, this approach does not require prior separation of chiral analytes, thus reducing analysis time and eliminating the need for expensive chiral columns.

On the Resolution of Secondary Phosphine Oxides via Diastereomeric Complex Formation: The Case of tert-Butylphenylphosphine Oxide

The secondary phosphine oxide, t-BuPhHP=O, the most prominent chiral member of this compound class, has been resolved in high yield and with excellent ee. This resolution discloses an efficient route to enantiopure phosphorus compounds.

Electrochemical Chiral Sensors and Biosensors

AbstractChiral molecular recognition depends on difference in stability constants of diastereomeric complexes with applied selectors, different migration of enantiomers based on the formation and dissociation of diastereomeric complexes, and on a different interaction rate of enantiomers with selector. Selected examples of electrochemical enantioselective sensors and biosensors based on different mechanisms of molecular recognition are reviewed. Chemical chiral sensors can be based on plasticized membranes incorporating a chiral ionophore, on differences of Gibbs free energy for interphase electron transfer, or on the use of molecularly imprinted polymers and electrodeposited conducting polymers doped with chiral ions. Reported chiral biosensors include enzymatic devices and immunosensors. Especially pronounced enantioselectivity of enzymatic biosensors can be employed practically, e.g., in food control, showing chiral discrimination better that two orders of magnitude. Developed, so far, chemical sensors show enantioselectivity usually not exceeding two orders magnitude and require further investigation for any practical analytical applications.

Separation of the Enantiomers of p-Chiral Cyclic Phosphorus Compounds

The antipodes of 1-aryl-, 1-alkyl- and 1-alkoxy-3-methyl-3-phospholene 1-oxides 1a-h were separated in good yields and in high enantiomeric excesses (up to 99% ee) by resolution via formation of diastereomeric complexes with (–)-(4R,5R)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane (–)-2 (TADDOL) or (–)-(2R,3R)-?,?,?’,?’-tetraphenyl-1,4-dioxaspiro[4.5]decan-2,3-dimethanol (–)-3. The resolution process of 1 with (–)-3 was further examined in various mixture of solvents. Stereostructure of the supramolecular formations and absolute configuration of the resulting 3-phospholene oxides (–)-1a, (+)-1e, (+)-1f were elucidated by single crystal X-ray crystallography.1-4 The method extended to the resolution of the 1-phenyl-3-methyl-3-phospholene 1-sulfide2 4, 6-diethylamino-dibenzo[c.e][5,6]oxaphosphorine 6-oxide 5, 1-[(1’R,2’S,5’R)-(–)-menthyl]-3-methyl-3-phospholene 1-oxide 6 and 3- and 5-methyl-1-phenyl-4-chloro-1,2-dihydro-phosphinine 1-oxide 7, suggesting that our novel procedure may be of general value.

Resolution of racemic trans-1,2-cyclohexanediol with tartaric acid

A simple method for the resolution of racemic trans-1,2-cyclohexanediol enantiomers is presented in this paper. The chiral discrimination was performed by tartaric acid via diastereomeric complex formation. The diastereomeric complexes were formed by adding the resolving agent to the racemic diol in a 0.5:1 molar ratio. The (2 R,3 R)-(+)-tartaric acid forms stable diastereomeric complex with (1 R,2 R)-(−)-cyclohexanediol. Supercritical carbon dioxide extraction was applied to the separation of the mixture of diastereomeric complexes and uncomplexed diol enantiomers. We found unexpected optimal conditions according to the 3 2 factorial design on the resolution efficiency within the studied range of the extraction pressure and temperature. In the best cases, the (1 S,2 S)- and (1 R,2 R)-diol enantiomers were obtained with ee (1 S,2 S) = 62% and ee (1 R,2 R) = 93% enantiomeric excess in one equilibrium stage, respectively.