Resolution of sertraline with (R)-mandelic acid: chiral discrimination mechanism study

The chiral discrimination mechanism in the resolution of sertraline with mandelic acid was investigated by examining the weak intermolecular interactions (such as hydrogen bond, CH/π, and van der Waals interactions) and molecular packing difference in crystal structures of the resulting diastereomeric salts. A new one-dimensional chain-like hydrogen-bonding network and unique supramolecular packing mode are disclosed. The investigation demonstrated that stable hydrogen-bonding pattern, herringbone-like arrangement of aromatic rings, and planar boundary surface in the hydrophobic region are the three most important structural characteristics expected in less soluble diastereomeric salts. The existence and magnitude of hydrogen bond, CH/π interaction, and van der Waals interaction related to three characteristic structures, determine the stability of diastereomeric salt. The hydrogen bond is not necessarily the dominant factor while the synergy and optimization of all weak intermolecular interactions attribute to the chiral recognition.     

Synthesis, absolute configuration, and application of enantiopure trans-1-aminobenz[f]indan-2-ol

Both novel enantiopure trans-1-aminobenz[f]indan-2-ols (4) were obtained from the racemate by the diastereomeric salt formation with (+)- and (-)-dibenzoyltartaric acids (8), respectively, and the absolute configuration of the enantiomer 4 in the less-soluble diastereomeric salt of racemic 4 with (+)-8 was determined to be (1S,2S) by an X-ray crystallographic analysis. The chiral recognition ability of the enantiopure amino alcohol was examined for the enantioseparation of racemic 2-arylalkanoic acids by the diastereomeric salt formation. The role of the naphthylene group of the amino alcohol was found to be closely associated with the stabilization of the crystal by CH/pi interactions on the basis of an X-ray crystallographic study.     

MalphaNP acid, a powerful chiral molecular tool for preparation of enantiopure alcohols by resolution and determination of their absolute configurations by the (1)H NMR anisotropy method

A novel methodology using a chiral molecular tool of MalphaNP acid (1), 2-methoxy-2-(1-naphthyl)propionic acid, useful for preparation of enantiopure secondary alcohols and determination of their absolute configurations by the (1)H NMR anisotropy method was developed; racemic MalphaNP acid (1) was enantioresolved with (-)-menthol, and the enantiopure MalphaNP acid (S)-(+)-(1) obtained was allowed to react with racemic alcohol, yielding a mixture of diastereomeric esters, which was clearly separated by HPLC on silica gel. By applying the sector rule of (1)H NMR anisotropy effect, the absolute configuration of the first-eluted MalphaNP ester was unambiguously determined. Solvolysis or reduction of the first-eluted MalphaNP esters yielded enantiopure alcohols.     

Practical enantioresolution of alcohols with 2-methoxy-2-(1-naphthyl)propionic acid and determination of their absolute configurations by the (1)H NMR anisotropy method.

The enantioresolution of racemic alcohols as esters of 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid 1) and the determination of their absolute configurations on the basis of (1)H NMR anisotropy effect are described. The enantiopure MalphaNP acid (S)-(+)-1 was allowed to react with racemic 2-alkanols and 1-octyn-3-ol, yielding diastereomeric mixtures of esters, which were easily separated by HPLC on silica gel. To determine the absolute configurations of the first-eluted diastereomeric esters by the (1)H NMR anisotropy method, the general scheme was proposed. Separated esters were reduced with LiAlH(4) or hydrolyzed with KOH/EtOH to recover enantiopure alcohols.     

Enantiopure O‐Ethyl Phenylphosphonothioic Acid: A Solvating Agent for the Determination of Enantiomeric Excesses

An improved method, which is highly reproducible, was developed for the enantioseparation of racemic O‐ethyl phenylphosphonothioic acid ( 1a ) with brucine by introducing seeding to a supersaturated solution of the diastereomeric salt mixture. The present method gave both diastereomeric salts in high yields with a diastereomeric ratio of >99.5:0.5 upon choosing the crystallization solvent (MeOH for the ( (R)-1a salt and MeOH/H₂O for the ( (S)-1a salt). The enantiopure acid (R)-1a , (S)-1a showed a good chirality recognition ability for not only strong bases, such as amines and amino alcohols, but also weakly basic alcohols and was applicable as a solvating agent to the ¹H NMR determination of the enantiomeric excess of chiral amines, amino alcohols, and alcohols, including aliphatic substrates. Chirality 26:614–619, 2014. © 2014 Wiley Periodicals, Inc.     

Stereoisomeric flavour compounds LXVII. 2-, 3-, and 4-Alkyl-branched acids,part 1: General approach to the synthesis of the enantiopure acids

A general approach to the synthesis of 2-, 3-, and 4-alkyl-branched acids of high enantiomeric purity is described. The enantiopure 2-alkyl-branched acids are prepared via liquid chromatographic resolution of diastereomeric phenylglycinol amides and their absolute configuration is deduced from the ¹H-NMR data of the separated diastereomers. Chain elongation methods, by Arndt–Eistert synthesis, via 2-alkylated alkyl carbonitrile or by malonic ester synthesis, are used to prepare 3- and 4-alkyl-branched acids of high configurational purity and known absolute configuration starting from the enantiomeric 2-alkyl-branched acids. © 1994 Wiley-Liss, Inc.     

Crystal and molecular structures of new enantiopure quinuclidines

X-ray crystal structure analysis was performed on single crystals of two diastereomeric enantiopure quinuclidines, (3R,8R)-3-vinyl-8-hydroxymethyl-quinuclidine (quincoridine, QCD) and (3R,8S)-3-vinyl-8-hydroxymethyl-quinuclidine (quincorine, QCI) as their salts with tartaric and p-toluenesulphonate anions, respectively. The molecules of these quinuclidine derivatives are considered here as fragments of the Cinchona alkaloids, quinidine and quinine. A comparison of the conformational features of QCD, QCI, and Cinchona alkaloids in the crystalline state shows that the molecular geometry of the title compounds is similar to that of threo-alkaloids (e.g., R,R isomer of epicinchonine) rather than to quinidine and quinine. The packing of the molecules in both structures is dominated by intermolecular hydrogen bonds.     

Density functional theory study of N-H...O, O-H...O and C-H...O hydrogen-bonding effects on the 14N and 2H nuclear quadrupole coupling tensors of N-acetyl-valine

Hydrogen-bonding effects in the crystalline structure of N-acetyl-valine, NAV, were studied using the (14)N and (2)H quadrupole coupling tensors via density functional theory. The calculations were carried out at the B3LYP level with the 6-311++G(d,p) and 6-311+G(d) basis sets. The theoretical quadrupole coupling components and their relative orientation in the molecular frame axes at the nitrogen site are compared to experimental values. This nucleus is involved in a rather strong intermolecular O=CNH...O=CNH hydrogen bond, r(N-H...O(1))=2.04 A and angleN-H...O(1)=171.53 degrees. A reasonably good agreement between the experimentally obtained (2)H quadrupole coupling tensors and the B3LYP/6-311++G(d,p) calculations is achievable only in molecular model where a complete hydrogen-bonding network is considered.     

Stereoconvergent approach for synthesizing enantiopure 5, 6-dialkylpipecolic acids

Investigating a general route for synthesizing pipecolic acid ) piperidine-2-carboxylic acid ( derivatives with substituents at the 3-, 4-, 5- and 6-position, we discovered a stereoconvergent process that provides an effective means for making 5, 6-dialkyl-epsilonpipecolate (Scheme 1, PhF = 9-phenylfluoren-9-yl). Hydrogenation of diastereomeric mixtures of gamma-oxo gamma-hydroxy and gamma-acetoxy alpha-N-(PhF)amino tert-butyl esters causes the eventual loss of the gamma-substituent to furnish an azadiene intermediate that can reduce diastereoselectively to 5, 6-dialkylpipecolate having the all cis relative stereoconfiguration. Five enantiopure (>94% ee) 5,6-dialkylpipecolic acids were synthesized, employing aspartic acid as an inexpensive chiral educt in this process.     

Resolution of 2-chloromandelic acid with (R)-(+)-N-benzyl-1-phenylethylamine: chiral discrimination mechanism

During the resolution of 2-chloromandelic acid with (R)-(+)-N-benzyl-1-phenylethylamine, the crystals of the less soluble salt were grown, and their structure were determined and presented. The chiral discrimination mechanism was investigated by examining the weak intermolecular interactions (such as hydrogen bond, CH/π, and van der Waals interactions) and molecular packing mode in crystal structure of the less soluble diastereomeric salt. A one-dimensional double-chain hydrogen-bonding network and a "lock-and-key" supramolecular packing mode are disclosed. The investigation demonstrates that hydrophobic layers with corrugated surfaces can fit into the grooves of one another to realize a compact packing, when the molecular structure of resolving agent is much larger than that of the racemate. This "lock-and-key" assembly is recognized to be another characteristic of molecular packing contributing to the chiral discrimination, in addition to the well-known sandwich-like packing by hydrophobic layers with planar boundary surfaces.     

The resolution of acyclic P‐stereogenic phosphine oxides via the formation of diastereomeric complexes: A case study on ethyl‐(2‐methylphenyl)‐phenylphosphine oxide

As an example of acyclic P‐chiral phosphine oxides, the resolution of ethyl‐(2‐methylphenyl)‐phenylphosphine oxide was elaborated with TADDOL derivatives, or with calcium salts of the tartaric acid derivatives. Besides the study on the resolving agents, several purification methods were developed in order to prepare enantiopure ethyl‐(2‐methylphenyl)‐phenylphosphine oxide. It was found that the title phosphine oxide is a racemic crystal‐forming compound, and the recrystallization of the enantiomeric mixtures could be used for the preparation of pure enantiomers. According to our best method, the (R)‐ethyl‐(2‐methylphenyl)‐phenylphosphine oxide could be obtained with an enantiomeric excess of 99% and in a yield of 47%. Complete racemization of the enantiomerically enriched phosphine oxide could be accomplished via the formation of a chlorophosphonium salt. Characterization of the crystal structures of the enantiopure phosphine oxide was complemented with that of the diastereomeric intermediate. X‐ray analysis revealed the main nonbonding interactions responsible for enantiomeric recognition.     

Characterization of the role of polar amino acid residues within predicted transmembrane helix 17 in determining the substrate specificity of multidrug resistance protein 3

Human multidrug resistance protein (MRP) 3 is the most closely related homologue of MRP1. Like MRP1, MRP3 confers resistance to etoposide (VP-16) and actively transports 17 beta-estradiol 17-(beta-D-glucuronide) (E(2)17 beta G), cysteinyl leukotriene 4 (LTC(4)), and methotrexate, although with generally lower affinity. Unlike MRP1, MRP3 also transports monovalent bile salts. We have previously demonstrated that hydrogen-bonding residues predicted to be in the inner-leaflet spanning segment of transmembrane (TM) 17 of MRP1 are important for drug resistance and E(2)17 beta G transport. We have now examined the importance of the hydrogen-bonding potential of residues in TM17 of MRP3 on both substrate specificity and overall activity. Mutation S1229A reduced only methotrexate transport. Mutations S1231A and N1241A decreased resistance to VP-16 and transport of E(2)17 beta G and methotrexate but not taurocholate. Mutation Q1235A also reduced resistance to VP-16 and transport of E(2)17beta G but increased taurocholate transport without affecting transport of methotrexate. Mutations Y1232F and S1233A reduced resistance to VP-16 and the transport of all three substrates tested. In contrast, mutation T1237A markedly increased VP-16 resistance and transport of all substrates. On the basis of the substrates analyzed, residues Ser(1229), Ser(1231), Gln(1235), and Asn(1241) play an important role in determining the specificity of MRP3, while mutation of Tyr(1232), Ser(1233), and Thr(1237) affects overall activity. Unlike MRP1, the involvement of polar residues in determining substrate specificity extends throughout the TM helix. Furthermore, elimination of the hydrogen-bonding potential of a single amino acid, Thr(1237), markedly enhanced the ability of the protein to confer drug resistance and to transport all substrates examined.     

A new hydrogen-bonding potential for the design of protein-RNA interactions predicts specific contacts and discriminates decoys

RNA-binding proteins play many essential roles in the regulation of gene expression in the cell. Despite the significant increase in the number of structures for RNA–protein complexes in the last few years, the molecular basis of specificity remains unclear even for the best-studied protein families. We have developed a distance and orientation-dependent hydrogen-bonding potential based on the statistical analysis of hydrogen-bonding geometries that are observed in high-resolution crystal structures of protein–DNA and protein–RNA complexes. We observe very strong geometrical preferences that reflect significant energetic constraints on the relative placement of hydrogen-bonding atom pairs at protein–nucleic acid interfaces. A scoring function based on the hydrogen-bonding potential discriminates native protein–RNA structures from incorrectly docked decoys with remarkable predictive power. By incorporating the new hydrogen-bonding potential into a physical model of protein–RNA interfaces with full atom representation, we were able to recover native amino acids at protein–RNA interfaces.     

An oxorhenium complex bearing a chiral cyclohexane‐1‐olato‐2‐thiolato ligand: Synthesis,stereochemistry, and theoretical study of parity violation vibrational frequency shifts

In our effort towards measuring the parity violation energy difference between two enantiomers, a simple chiral oxorhenium complex 5 bearing enantiopure 2‐mercaptocyclohexan‐1‐ol has been prepared as a potential candidate species. Vibrational circular dichroism revealed a chiral environment surrounding the rhenium atom, even though the rhenium is not a stereogenic center itself, and enabled to assign the (1S,2S)‐(?) and (1R,2R)‐(+) absolute configuration for 5 . For both compound 5 and complex 4 , previously studied by us and bearing a propane‐2‐olato‐3‐thiolato ligand, relativistic calculations predict parity violating vibrational frequency differences of a few hundreds of millihertz, above the expected sensitivity attainable by a molecular beam Ramsey interferometer that we are constructing.     

Enantioresolution by the chiral phthalic acid method: absolute configurations of substituted benzylic alcohols

Substituted benzylic alcohols were enantioresolved by the chiral phthalic acid method as follows; 1) esterification of racemic alcohols with chiral phthalic acid, 2) separation of a diastereomeric mixture of the esters formed by HPLC on silica gel, and 3) recovery of enantiopure alcohols from the separated esters. The absolute configurations of chiral phthalic acid esters of benzylic alcohols were unambiguously determined by the X-ray crystallography using the campharsultam moiety as the internal standard of absolute configuration.     

NMR and computational studies of interactions between remote residues in gangliosides

Conformational preferences of the gangliosides GM1, GM1b, and GD1a have been investigated by using a systematic combination of NMR distance constraints and molecular mechanics calculations. These gangliosides share a common four-sugar core but differ in the number or placement of sialic acid residues attached to the core. Placement of the sialic acid residues is shown to influence the preferred core conformation. The origin of these effects is postulated to be intramolecular interactions of the sialic acid residues with other remote residues. In the case of GM1, hydrogen bonds between the internal sialic acid and an N-acetyl group on GalNAc are suggested. In the case of GD1a, a hydrogen-bonding network between the terminal and internal sialic acids is suggested to play a role.     

Nmr and computer-aided modeling studies of the interactions between a cyclic hexapeptide and the two enantiomers of some Boc- and Fmoc-amino acids

The cyclic hexapeptide cyclo[-Pro¹-Gly²-Glu³(OBzl) -Pro⁴-Phes⁵-Leu⁶-] ( 1 ) was modeled and synthesized to be used for chiral discrimination studies. Total correlated spectroscopy and nuclear Overhauser effect spectroscopy spectra of the cyclic hexapeptide 1 in CDCl₃ showed the presence of three stereoisomers: two dominant stereoisomers 1a and 1b that exchanged chemically with each other, and a minor stereoisomer 1c (4%) that exchanged exclusively with the stereoisomer 1b . Of the two dominant stereoisomers, only 1a interacted specifically with t-butyloxycarbonyl (Boc-) and 9-flourenylmethyloxycarbonyl (Fmoc-) amino acids in CDCl₃. The interaction site of la when complexing with the derivatized amino acids was the chain segment Phe⁵-Leu⁶. The Phe⁵ NH and Leu⁶ NH protons are contiguous and solvent exposed. Their nmr signals shifted strongly downfield with the addition of Boc- or Fmoc- amino acids to the peptide solution. Thus, both NH protons hydrogen bond to the amino acids, forming a two-point hydrogen-bonding complex. The peptide stereoisomer 1b did not interact specifically with the Boc- and Fmoc-amino acids because of the lack of two contiguous and solvent-exposed peptidic NH protons that seem to be needed for specific interactions of the cyclic hexapeptide 1 with the Boc- and Fmoc-amino acids. A clear difference in the interaction of 1a with D - and L -enantiomers of BocTrp and Fmoc-Trp was observed with nmr spectroscopy. Docking models and molecular mechanics calculations together with nmr observations showed that the NH proton of the indole ring of the Boc-L -Trp and the Fmoc-L- Trp hydrogen bonded to the Pro¹ carbonyl group. In this three-point hydrogen-bonding complex, the indole ring becomes locked underneath the Leu residue. The nmr signals of all the Leu⁶ protons (except for Leu NH) shifted strongly upfield owing to the shielding effect of the indole aromatic ring currents. The indole NH of the D -enantiomer did not hydrogen bond to the Pro¹ carbonyl group because the formation of such a three-point hydrogen-bonding complex was thermodynamically unfavorable. © 1993 John Wiley & Sons, Inc.     

Structure and property of self-assemble valinyl bolaform amides having different chirality.

Bolaform amides were designed from N,N'-bis(carboethoxy-L-valinyl)-diaminoethane (1) by linking t-butyloxycarbonyl-valine through ethylenediamine (EDA) to enable spectroscopic and X-ray diffraction analyses. N,N'-Bis(Boc-L-valinyl)-diaminoethane (2) and N,N'-bis(Boc-D-valinyl)-diaminoethane (3) were composed of L-Val and D-Val, respectively. N-(Boc-L-valinyl)-N'-(Boc-D-valinyl)-diaminoethane (4) was composed of both L-Val and D-Val, and was achiral (meso-peptide). Peptide 5 was a 1:1 mixture of 2 and 3, and was also achiral (racemate). These peptides mediated gelation of corn oil at a concentration of approximately 1%. Within crystals, the peptides formed beta-sheet ribbons, but differences were observed in hydrogen-bonding patterns and side-chain arrangements. These differences were also deduced from temperature dependence of amide protons. Force-field calculations based on the crystal structures indicated that association of beta-sheet ribbons had energy benefits, and it was assumed that molecular aggregation progressed spontaneously. These structural studies indicated the chirality of amino acids affected for the properties of bolaform amides.     

Synthesis of enantiopure 2-aryl-2-methoxypropionic acids and determination of their absolute configurations by X-ray crystallography

Racemic 2-aryl-2-methoxypropionic acids were enantioresolved by the use of (S)-(-)-phenylalaninol 4. For instance, racemic 2-methoxy-2-phenylpropionic acid (+/-)-7 was condensed with phenylalaninol (S)-(-)-4 yielding a diastereomeric mixture of amides, which was easily separated by HPLC on silica gel affording the first-eluted amide (-)-13a and the second-eluted amide (+)-13b: alpha = 3.19, Rs = 3.49. The absolute configuration of amide (-)-13a was determined to be (R;S) by X-ray crystallography by reference to the S configuration of the phenylalaninol moiety. Amide (R;S)-(-)-13a was converted to oxazoline (R;S)-(-)-14a, from which enantiopure 2-methoxy-2-phenylpropionic acid (R)-(-)-7 was recovered. Other 2-aryl-2-methoxypropionic acids, (R)-(-)-8, (R)-(-)-9, (R)-(+)-10, (R)-(-)-11, and (R)-(-)-12, were similarly prepared in enantiopure forms with the use of phenylalaninol (S)-(-)-4, and their absolute configurations were clearly determined by X-ray crystallography or by chemical correlation.     

Partial resolution of racemic trans-4-[5-(4-alkoxyphenyl)-2,5-dimethylpyrrolidine-1-oxyl-2-yl]benzoic acids by the diastereomer method with (R)- or (S)-1-phenylethylamine

The partial resolution is described of a series of racemic trans-4-[5-(4-alkoxyphenyl)-2,5-dimethylpyrrolidine-1-oxyl-2-yl]benzoic acids (1), which are the key intermediates for the synthesis of chiral organic radical liquid crystalline compounds and are crystallized to give racemic compounds. Racemic acid 1 [(+/-)-1] with a long alkyl chain (C7 to C13) could be resolved by the conventional diastereomeric salt formation using (R)- or (S)-1-phenylethylamine (2) as the resolving agent, whereas resolution of (+/-)-1 with a short alkyl chain (C4 to C6) was unsuccessful. Use of six equiv of (R)- or (S)-2 for the initial diastereomeric salt formation of (+/-)-1 with a C7-C13 alkyl chain, followed by recrystallization of the resulting salts once or twice, gave 2S,5S- or 2R,5R-enriched 1, respectively, in an ee range of 75-92% and with an overall recovery of 11-27%, based on the original quantity of (+/-)-1.