Comparison of Separation Efficiency of Macrocyclic Glycopeptide-Based Chiral Stationary Phases for the LC Enantioseparation of β-Amino Acids

Direct reversed-phase high-performance liquid chromatographic methods were developed for the separation of enantiomers of eighteen unnatural β-amino acids, including several β-3-homo-amino acids. The direct separations of the underivatized analytes were performed on chiral stationary phases containing macrocyclic glycopeptide antibiotics such as teicoplanin (Chirobiotic T and T2), teicoplanin aglycone (Chirobiotic TAG), vancomycin (Chirobiotic V and V2), and ristocetin A (Chirobiotic R) as chiral selectors. The effects of the organic modifier, mobile phase composition and pH on the separations were investigated. A comparison of the separation performances of the macrocyclic glycopeptide stationary phases revealed that the Chirobiotic T2 column exhibited better selectivity than the Chirobiotic T column for the separation of β-3-homo-amino acid enantiomers; vancomycin or ristocetin A exhibited lower selectivity. The elution sequence was determined in some cases: the S enantiomers eluted before the R enantiomers, with the exception of the Chirobiotic R column, where the elution sequence R < S was observed.     

HPLC enantioseparation of phenylalanine analogs by application of (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester as a new chiral derivatizing agent

Summary The indirect stereochemical resolution of the enantiomers of phenylalanine analogs was studied by high-performance liquid chromatographic methods. The resolution was performed by applying pre-column derivatization with (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester, (S)-NIFE, as a new chiral derivatizing agent. Its applicability is demonstrated by the derivatization and separation of a series of ring-and α-methyl-substituted phenylalanines and phenylalanine amides, and especially by the derivatization of sterically hindered, less reactive α-methyl-substituted phenylalanine analogs. The diastereomeric, derivatives produced were separated by reversed-phase high-performance liquid, chromatography. The conditions of both derivatization and separation were optimized. The method described offers good enantioselectivity for various chiral amino compounds derived from chemo-enzymatic processes.     

High-performance liquid chromatographic separation of unusual amino acid enantiomers derivatized with (1S,2S)-1,3-diacetoxy-1-(4-nitrophenyl)-2-propyl-isothiocyanate

Summary A new chiral derivatizing agent (CDA), (1S,2S)-1,3-diacetoxy-1-(4-nitrophenyl)-2-propylisothiocyanate, (S,S)-DANI, was applied to the separation of the enantiomers of unusual amino acids containing two chiral centers. Different β-methyl-α-amino acids (β-MePhe, β-MeTyr and β-MeTrp) and β-amino acids with cycloalkane skeletons (2-aminocyclopentanecarboxylic acid and 2-aminocyclohexanecarboxylic acid) were derivatized and the thiourea derivatives produced were separated by reversed-phase high-performance liquid chromatography. The applicability of this new CDA in the separation of unusual amino acids is demonstrated. The four stereoisomers of the investigated amino acids (except β-MePhe) could be separated in one chromatographic run. Presented at Balaton Symposium on High Performance Separation Methods, Siófok, Hungary, September 1–3, 1999     

Asymmetric hydrogenation of acetophenone catalyzed by cinchonidine stabilized Ir/SiO2

A series of silica (SiO₂) supported iridium catalysts stabilized by cinchona alkaloids was prepared and applied in the heterogeneous asymmetric hydrogenation of acetophenone. Cinchona alkaloids exhibited a marked ability to stabilize and disperse the Ir particles. In the presence of (1S,2S)-diphenylethylenediamine ((1S,2S)-DPEN)) as chiral modifier, the cinchonidine (CD) stabilized catalyst 5%Ir/2CD-SiO₂ exhibited excellent catalytic performance in the asymmetric hydrogenation of acetophenone in MeOH. Under the optimum conditions, the ee value of (R)-phenylethanol achieved 79.8% and no other product was produced, a higher enantioselectivity than that reported up to now for acetophenone hydrogenation catalyzed by the supported metal catalysts modified by chiral reagents. In particular, a synergistic effect between (1S,2S)-DPEN and CD was observed, which significantly accelerated the reaction rate and enhanced the enantioselectivity. The catalyst can be reused several times without a significant loss of activity and enantioselectivity.     

Asymmetric Synthesis of （R）- and （S）-Moprolol

A simple and effective procedure for the enantioselective synthesis of （R）- and （S）-moprolol was described. The key step was the asymmetric synthesis of enantiopure （R）- and （S）-guaifenesin, which were synthesized from enantioenriched （R）-3-chloro-l,2-propanediol and （S）-epichlorohydrin via kinetics of hydrolysis resolution of racemic epichlorohydrin by chiral Salen-Co^Ⅲ complex. The e.e. values of both the optical compounds were above 98%, and the chemical structures of the target compounds were confirmed by ^1H NMR, ^13C NMR, IR, and MS.     

Synthesis of isomeric 2-oxazolidinones from (1<Emphasis Type="Italic">R</Emphasis>,2<Emphasis Type="Italic">R</Emphasis>)-and (1<Emphasis Type="Italic">S</Emphasis>,2<Emphasis Type="Italic">S</Emphasis>)-2-amino-1-(4-nitrophenyl)-1,3-propanediols

A synthesis is reported for (4R,5R)-and (4S,5S)-4-hydroxymethyl-5-(4-nitrophenyl)oxazolidin-2-ones and (1′R,4R)-and (1′S,4S)-4-[hydroxy(4-nitrophenyl)methyl]oxazolidin-2-ones from (1R,2R)-and (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediols. The effect of the experimental conditions on the formation of these compounds was studied. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1562–1570, October, 2007.     

Synthesis and chromatographic evaluation of new polymeric chiral stationary phases based on three (1<Emphasis Type="Italic">S</Emphasis>,2<Emphasis Type="Italic">S</Emphasis>)-(−)-1,2-diphenylethylenediamine derivatives in HPLC and SFC

Three new polymeric chiral stationary phases were synthesized based on (1S,2S)-1,2-bis(2,4,6-trimethylphenyl)ethylenediamine, (1S,2S)-1,2-bis(2-chlorophenyl)ethylenediamine, and (1S,2S)-1,2-di-1-naphthylethylenediamine via a simple free-radical-initiated polymerization in solution. These monomers are structurally related to (1S,2S)-1,2-diphenylethylenediamine which is the chiral monomer used for the commercial P-CAP-DP polymeric chiral stationary phase (CSP). The performance of these three new chiral stationary phases were evaluated in normal phase high-performance liquid chromatography (HPLC) and supercritical fluid chromatography and the results were compared with those of the P-CAP-DP column. All three new phases showed enantioselectivity for a large number of racemates with a variety of functional groups, including amines, amides, alcohols, amino acids, esters, imines, thiols, and sulfoxides. In normal phase, 68 compounds were separated with 28 baseline separations (Rs ≥ 1.5) and in SFC, 65 compounds were separated with 24 baseline separations. In total 72 out of 100 racemates were separated by these CSPs with 37 baseline separations. Complimentary separation capabilities were observed for many analytes. The new polymeric CSPs showed similar or better enantioselectivities compared with the commercial column in both HPLC and SFC. However, faster separations were achieved on the new stationary phases. Also, it was shown that these polymeric stationary phases have good sample loading capacities while maintaining enantioselectivity.     

Enantiomeric NMR signal separation mechanism and prediction of separation behavior for a praseodymium (III) complex with (S,S)-ethylenediamine-N,N-disuccinate

Because choice of chiral nuclear magnetic resonance (NMR) shift reagents and concentration conditions have been made empirically by trials and errors for chiral NMR analyses, the prediction of NMR signal separation behavior is an urgent issue. In this study, the separation of enantiomeric and enantiotopic ¹H and ¹³C NMR signals for α-amino acids and tartaric acid was performed by using the praseodymium(III) complex with (S,S)-ethylenediamine-N,N′-disuccinate ((S,S)-EDDS). All the present D-amino acids exhibited larger downfield shift of their α-protons and α-carbons compared with those for the corresponding L-amino acids in common. This regularity is applicable to absolute configurational assignment and determination of optical purity of amino acids. The chemical shifts of β-protons of d - and l -alanine fully bound with the Pr(III) ((S,S)-EDDS) complex (δ_bs) and the adduct formation constants of both enantiomers (Ks) were obtained by dependences of the observed downfield shifts of the β-protons on the total concentrations of the respective enantiomers in the presence of a constant concentration of the Pr(III) complex. The difference in the K values was found to be predominant determining factor for the enantiomeric signal separation. The chemical shifts of both enantiomers (δs) and the enantiomeric signal separations (Δδs) under given conditions could be calculated from the δ_b and K values. Furthermore, prediction of the signal separation behavior was enabled by using the calculated δ values and the signal broadening obtained by dependences of the half-height widths of the observed signals on the bound/free substrate concentration ratios for the respective enantiomers.     

The effect of anions in the coordination spherè of Mg complexes ofN-acetyldehydrophenylalanyl-(S)-valine on the diastereoselectivity of hydrogenation

Diastereoselective hydrogenation in ethanol over Pd/C ofN-acetyldehydrophenylalanyl-(S)-valine (1) as complexes with Mg salts of strong acids gives predominantlyN-acetyl-(S)-phenylalanyl-(S)-valine (de up to 60%). In the case of complexes of1 with Mg salts of weak acids, the sign of asymmetric induction changes. Data of¹⁹F NMR spectroscopy ofN-acetyldehydro(p-fluorophenylalanyl)-(S)-valine indicate that in the former case, the anion of a strong acid does not enter the coordination sphere of the complex, whereas in the larter case, the anion of the weak acid does. The nature of the solvent also influences the reaction stereoselectivity. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1704–1706, September, 1999.     

A comparison of the direct and indirect LC methods for separating enantiomers of unusual glycine and alanine amino acid analogues

Summary Reversed-phase high-performance liquid chromatographic methods were developed for the separation of the enantiomers of five glycine and twelve alanine analogues. The enantioselective separation involved two methods. The direct separations were performed on chiral stationary phases containing a macrocyclic glycopeptide antibiotic: teicoplanin (Chirobiotic T column), ristocetin A (Chirobiotic R column) or chiral crown ether (Crownpak CR(+) column). The indirect methods involved pre-column derivatization with the chiral derivatizing agents 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate andN-α-(2,4-dinitro-5-fluorophenyl)-L-alaninamide (Marfey's reagent). The different methods were compared in systematic chromatographic examinations. The effects of organic modifier content, mobile phase composition, pH and flow rate on the separation were investigated. Presented at Balaton Symposium '01 on High-Performance Separation Methods, Siófok, Hungary, September 2–4, 2001     

A novel polyfunctional chiral building block derived from (S)-ethyl lactate. Application to the synthesis of the sex pheromone of the southern corn rootworm (Diabrotica undecimpunctata howardi)

Highly enantiomerically pure (4S, 5E)-4-bromomethylhept-5-enenitrile was prepared from (S)-ethyl lactate by a six-step procedure involving a rearrangement of chiral cyclopropylcarbinol. This product was used for the synthesis of the sex pheromone of the southern corn rootworm (Diabrotica undecimpunctata howardi), (10R)-10-methyltridecan-2-one. For preliminary communication, see Ref. 1. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 151–155, January, 2000.     

A novel polyfunctional chiral building block derived from (S)-ethyl lactate. Application to the synthesis of the sex pheromone of the southern corn rootworm (Diabrotica undecimpunctata howardi)

Highly enantiomerically pure (4S, 5E)-4-bromomethylhept-5-enenitrile was prepared from (S)-ethyl lactate by a six-step procedure involving a rearrangement of chiral cyclopropylcarbinol. This product was used for the synthesis of the sex pheromone of the southern corn rootworm (Diabrotica undecimpunctata howardi), (10R)-10-methyltridecan-2-one. For preliminary communication, see Ref. 1. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 151–155, January, 2000.     

Synthesis and Stereochemistry of (1S,3S,4S,7R11R)-3-(4-Nitrophenyl)-11-aza-2,6-dioxatricyclo[5,3,1,04,11]undecane

The reaction of (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol with glutaraldehyde has been studied. It has been established on the basis of AM1 and PM3 calculations and ¹H NMR spectra recorded in the presence of the shift reagent Eu(fod)₃ that (1S,3S,4S,7R,11R)-3-(4-nitrophenyl)-11-aza-2,6-dioxatricyclo[5,3,1,0^4,11]undecane is formed as the result of the reaction.     

α-亚胺酮的不对称转移氢化合成(R)-沙丁胺醇

用手性(S,S)-Ru-TsDPEN催化剂不对称转移氢化α-亚胺酮化合物5-[(1,1-二甲基乙基)亚胺基]乙酰基-2-羟基苯甲酸甲酯(2)得光学纯β-氨基芳基乙醇类化合物(R)-5-[2-[(1,1-二甲基乙基)氨基]-1-羟乙基]-2-羟基苯甲酸甲酯(3), 再经一步还原反应即得(R)-(－)-沙丁胺醇. 对反应关键一步α-亚胺酮的不对称转移氢化反应条件进行了研究.     

High-Performance Liquid Chromatographic Separation of Stereoisomers of <Emphasis Type="Bold">β</Emphasis>-Amino Acids and a Comparison of Separation Efficiencies on Chirobiotic T and TAG Columns

Direct and indirect reversed-phase high-performance liquid chromatographic methods were developed for the separation of enantiomers of seventeen unnatural β-amino acids, including several β-3-homo amino acids. The direct separations of the underivatized analytes were performed on chiral stationary phases containing macrocyclic glycopeptide antibiotic teicoplanin (Chirobiotic T column) and teicoplanin aglycone (Chirobiotic TAG column). The indirect method involved pre-column derivatization with two new chiral derivatizing agents, (1S,2S)-1,3-diacetoxy-1-(4-nitrophenyl)-2-propylisothiocyanate, (S,S)-DANI and (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester, (S)-NIFE. The different methods were compared in systematic chromatographic examinations. The effects of organic modifier, mobile phase composition, pH and flow rate on the separation were investigated.     

Difference in the behavior of methyl (S)-α-bromopropionate in its addition to trimethylvinylsilane depending on the method of initiation

The addition of methyl (S)-2-bromopropionate to trimethylvinylsilane initiated by systems based on iron pentacarbonyl affords a racemic adduct and is accompanied by racemization of the unreacted chiral ester. In the presence of benzoyl peroxide, the reaction proceeds similarly, but no racemization of the starting chiral ester occurs.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 715–718, March, 1996.     

N,N'-二茂铁甲基-(1S,2S)-1,2-二苯基乙二胺的合成及其在烯烃的不对称双羟基化反应中的应用

(1S,2S)-1,2-二苯基乙二胺和甲酰基二茂铁经缩合和还原两步反应, 以90%的产率合成了N,N'-二茂铁甲基-(1S,2S)-1,2-二苯基乙二胺, 并以其为配体催化烯烃的不对称双羟基化反应, 获得了较高的对映选择性(71%～86% ee).     

Asymmetric alkylation catalyzed by chiral alkali metal alkoxides of TADDOL. Synthesis of α-methyl amino acids

It is shown that sodium alkoxides formed from (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-bis(diphenylmethanol) ((R,R)-TADDOL) and some of its derivatives can be used as chiral catalysts for enantioselective alkylation of Schiff's bases derived from alanine with reactive alkyl halides. Acid hydrolysis of the reaction products affords (R)-α-methylphenyl-alanine, (R)-α-allylalanine, and (R)-α-methylnaphthylalanine in 61–93% yields and withee 69–94%. When (S,S)-TADDOL is used, the (S)-amino acid is formed. A mechanism explaning the observed features of the reaction is proposed. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 926–932, May, 1999.     

Resolution of N-acyl-1-naphthylalkylamide on amide and sulfonamide-derived π-acidic chiral stationary phases

Two π-acidic chiral stationary phases (CSP 3, CSP 4) were prepared by connecting the N-3,5-dinitrobenzamide derivative or 2,4-dinitrobenzenesulfonamide derivative of (S)-leucinol to silica gel through the carbamate linkage. The CSPs were applied in resolving seven racemic N-acyl-1-naphthylaminoalkanes by chiral HPLC, and the chromatographic resolution results were compared. From the comparison of the resolution results of the two CSPs, the role of amide and sulfonamide group in each chiral selector of CSP 3 and CSP 4 and an iso-butyl and phenyl group on the chiral center of each CSP 2 and CSP 3 were explained.     

Synthesis of Cytotoxic 1,3,4-trisubstituted 2-azetidinones

A series of 1,3,4-trisubstituted and 3,4-disubstituted 2-azetidinones were synthesized in order to study the relation between their structure and biological characteristics. Study of the cytotoxic activity of these compounds revealed an anticancer effect in (3S,4S)-1-(4-methoxyphenyl)-3-methyl-2-azetidinones containing 2-acetoxybenzoyloxymethyl and 2,2-dicyanovinyl substituents at position 4 in vitro with respect to a wide range of monolayer cultures of cancer cells.