The Enantioresolution of Methylthiohydantoin-Amino Acids on R,S-2-hydroxypropyl Derivatized β-Cyclodextrin Bonded Stationary Phase Using the Water-Based Mobile Phase

The enantioresolution of thirteen methylthiohydantoin-amino acids (MTH-amino acids), which are substrates for producing D-amino acids through enzyme-catalyzed hydrolysis, is described on R, S-2-hydroxypropyl derivatized β-cyclodextrin bonded stationary phase (RSP-β-CD CSP) with a water-based mobile phase. The enantioresolution is relatively sensitive to the structural variation of group which is attached to the carbon at position five on methylthiohydantoin moiety and subsequently turns into side-chain group of corresponding D-amino acid produced after hydrolysis. The inclusion complexation is believed to be the mechanism responsible for the observed enantioresolution that cannot be reproduced either on native β-cyclodextrin CSP under the same chromatographic conditions or on both CSPs using the acetonitrile-based mobile phase. Approaches for enantioimprovement include varying the percentage of organic modifier in the mobile phase and using the buffer-typed mobile phase such as triethylammonium acetate (pH 4.1).     

Large-Scale Enantiomeric Enrichment via Solid State Extraction Using β-Cyclodextrin Crystalline and Anhydrous Acetonitrile as Solid and Liquid Phases

The process-scale enantiomeric enrichment of several adrenergic β-blockers, atropine, and ruelene was accomplished through solid state extraction using anhydrous acetonitrile and β-cyclodextrin crystalline as liquid and solid phases, respectively. This non-chromatographic method has the advantages of easy, low cost operation, simplicity, and a high percentage of enrichment for some of the β-blockers examined in a single batch. The percentage of enrichment in anhydrous acetonitrile was the best for all the racemates studied; however, it dropped dramatically when the extraction was carried out in a liquid phase of low polarity such as petroleum ether. No enantiomeric enrichment was observed in liquid phases that are polar and capable of participating in hydrogen bonding (e.g., methanol). Introducing additives (e.g., acetic acid, triethylamine) to the liquid phase also decreased the percentage of enrichment. Finally, lowering the operating temperature (0 °C) appeared to retard the enantiomeric extraction process, which could be restored to normal level by elevating liquid phase temperature to 28 °C.     

Use of Chemically Bonded β‐Cyclodextrin Silica Stationary Phase for Liquid Chromatographic Separation of Structural Isomers

The retention behavior of five disubstituted benzene derivatives and two naphthalene derivatives is examined by using a chemically bonded β‐cyclodextrin silica stationary phase with the moiety containing the s‐triazine. The chromatographic results of five disubstituted benzene derivatives and two naphthalene derivatives show that effective separation is achieved on this stationary phase by high‐performance liquid chromatography. The results of the present investigation indicate that the formation of inclusion complexes plays a dominant role in the separation mechanism. However, the selectivity can be significantly enhanced by the n‐n interactions between the s‐triazine ring of the chemically bonded β‐cyclodextrin silica stationary phase and the aromatic ring of solutes. For example, the effective separation of the o‐, m‐, and p‐toluidine isomers on this stationary phase with the moiety containing the s‐triazine ring was better than on that of some β‐cyclodextrin bonded stationary phases without the moiety containing s‐triazine ring.     

The HPLC Enantioresolution of Selected Native or Derivatized Amino Acids on Teicoplanin Bonded Chiral Stationary Phase Using a Methanol‐Based Mobile Phase

The facile HPLC enantiomeric resolution of a variety of selected native or derivatized amino acids is carried out on the glycopeptide antibiotic teicoplanin bonded chiral stationary phase using a methanol‐based mobile phase and found very sensitive to the structural variations. This mobile phase is mainly composed of methanol. Organic additives such as acetic acid and triethylamine are introduced to the mobile phase in small percentages to control the analyte's retention time. Additive of low viscosity such as ethyl ether or petroleum ether is incorporated in the mobile phase as well to improve the resolution. Further increasing its percentage in the mobile phase deteriorates the resolution slightly; however, it extends the retention scale of enantiomers. The change in enantioselectivity is found to be insignificant under these circumstances. The hydrogen bonding and π‐π complexation in the hydrophobic pocket of teicoplanin chiral selector is believed to be the mechanism mainly responsible for the enantioresolution observed in this report.     

Helical‐Ribbon Formation by a β‐Amino Acid Modified Amyloid β‐Peptide Fragment

An addition to the family : The introduction of β‐amino acid residues into a modified amyloid β peptide fragment resulted in well‐defined helical nanoribbons (see cryo‐TEM image) comprising β strands mainly oriented perpendicular to the ribbon axis. The nanoribbons order into a flow‐aligning nematic phase at higher concentration. The β‐strand nanoribbon structure is an addition to the known set of secondary structures adopted by β‐peptides.

     

Direct High‐Performance Liquid Chromatographic Enantioseparation of β‐Methyl‐Substituted Unusual Amino Acids on a Quinine‐Derived Chiral Anion‐Exchange Stationary Phase

A quinine‐derived chiral anion‐exchange stationary phase was used for the direct high‐performance liquid chromatographic separation of the enantiomers of the N‐protected unusual β‐substituted α‐amino acids, β‐methylphenylalanine, β‐methyltyrosine, β‐methyltryptophan, and β‐methyl‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid. The readily prepared 2,4‐dinitrophenyl and tert‐butyloxycarbonyl derivatives were well separated, and in most cases the separation of all four stereoisomers of these β‐methyl‐α‐amino acids could be obtained in one chromatographic run. The elution sequences of the enantiomers of the different derivatives were determined and revealed a dependence on the type of the N‐protecting group. In this context, the effects of different protecting groups (acetyl, tert‐butyloxycarbonyl, benzoyl, 3,5‐dinitrobenzoyl, benzyloxycarbonyl, 3,5‐dinitrobenzyloxycarbonyl, 2,4‐dinitrophenyl, and 9‐fluorenylmethoxycarbonyl) on the chromatographic behavior were investigated.     

The Enantioresolution of n-Benzoyl and Its Analogs Derivatized Amino Acids on Cyclodextrin Bonded Chiral Stationary Phases Using a Nonaqueous Acetonitrile-Based Mobile Phase

The separation of amino acids into enantiomers while derivatizing with benzoyl chlorides is demonstrated. It was found that enantioselectivity among these reagents tagging with the same amino acid is quite different and is very sensitive to its structural variations. A noninclusion complexation mechanism i.e. external association is thought to involve in the separation carried out with a nonaqueous polar organic mobile phase. Results also indicate that the chiral recognition seems to be controlled either by moieties from tagging reagents or functional groups on all amino acids examined in this study on the basis of competition. The polarity of side-chain group on peptide backbone can not be ignored in achieving a successful separation. Furthermore, chiral recognition appears to closely rely upon the location of stereogenic center that is simultaneously attached by amino and carboxyl groups. Finally, mechanism involved will be explored structurally with these tagging reagents derivatized amino acids which structures are highly ordered and amine-containing compounds with structures similar to that of amino acid.     

Synthesis of β‐Haloketones by β‐Addition Reactions of α,β‐Unsaturated Ketones with BX3 (X = Br,Cl) as Halide Source

A series of β‐bromoketones and β‐chloroketones were synthesized by the addition reactions of α,β‐unsaturated ketones under BX₃ (X = Br, Cl) and ethylene glycol reaction system. The α,β‐unsaturated ester also was successfully converted to its corresponding β‐bromoester under the reaction condition.     

Sulfamic Acid as a Cost‐Effective and Recyclable Catalyst for β‐Amino Carbonyl Compounds Synthesis

Sulfamic acid was used as a catalyst in the synthesis of β‐amino carbonyl compounds from amines, acetophenone and aldehyde. The reaction was carried out at room temperature. High selectivity, mild reaction temperature, cost‐effective catalyst, simple product separation and catalyst recycle were notable achievements in the reaction. Another feature was that the reaction could be performed on a relatively larger scale to the model reaction (50 times), which also gave good yields. In particular, the first preparation of β, β'‐diamino diketone derivatives via the direct coupling of amines, acetophenone and isophthalic aldehyde promoted by sulfamic acid has been developed.     

The HPLC Enantioresolution of Phenyl Isothiocyanated Amino Acids on Vancomycin Bonded Phase Using the Acetonitrile‐Based Mobile Phase: A Comparison to the Teicoplanin Phase

The phenyl isothiocyanate, an electrophilic reagent for peptide chain sequencing, is used to pre‐column derivatize a variety of α‐amino acids in alkaline medium before their enantioresolution on a vancomycin bonded chiral phase using the acetonitrile‐based mobile phase. The observed resolution is believed to be due to the re‐location of the hydrogen receptor site from sulfur to nitrogen on the isothiocyanyl fragment of derivatizing reagent, which in turn changes the enantioselectivity. Under the same chromatographic conditions, the resolution for N‐benzoylated, 3,5‐dinitrobenzoylated and N‐carbobenzyloxylated amino acids is either not found or unsatisfactory. Also, no resolution is obtained in the reversed‐ or normal phase mode for all phenyl isothiocyanated amino acids examined in this study.     

A Mild Isomerization Reaction for β,γ‐Unsaturated Ketone to α,β‐Unsaturated Ketone

A series of β,γ‐unsaturated ketones were isomerized to their corresponding α,β‐unsaturated ketones by the introduction of DABCO in iPrOH at room temperature. The endo‐cyclic double bond (β,γ‐position) on ketone was rearranged to exo‐cyclic double bond (α,β‐position) under the reaction conditions.     

Synthesis of new optically active α,α′,β‐trisubstituted‐β‐lactones as monomers for stereoregular biopolyesters

Various optically active (4R)‐alkyloxycarbonyl‐3,3‐dialkyl‐2‐oxetanones as monomers were synthesized from L‐(S)‐malic acid in six steps to prepare a new family of stereopolyesters for biomedical applications. The synthesis began with an esterification followed of a dialkylation in the aim to introduce hydrophobic groups as methyl or reactive group as allyl. Then, a saponification has permitted to obtain the corresponding diacids that reacted with appropriate alcohols to furnish different monoesters. The last and most important step was activation of hydroxyl group of monoesters with the asymmetric carbon configuration inversion according to the Mitsunobu reaction. Thus, this reaction has provided lactones from monoesters with 100% enantiomeric excess which was confirmed by ¹H NMR and by the synthesis of corresponding isotactic and semicrystalline homopolyesters. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2586–2597     

5-Amino-3-methyl-Isoxazole-4-carboxylic Acid as a Novel Unnatural Amino Acid in the Solid Phase Synthesis of α/β-Mixed Peptides

The hybrid peptides consisting of α and β-amino acids show great promise as peptidomimetics that can be used as therapeutic agents. Therefore, the development of new unnatural amino acids and the methods of their incorporation into the peptide chain is an important task. Here, we described our investigation of the possibility of 5-amino-3-methyl-isoxazole-4-carboxylic acid (AMIA) application in the solid phase peptide synthesis. This new unnatural β-amino acid, presenting various biological activities, was successfully coupled to a resin-bound peptide using different reaction conditions, including classical and ultrasonic agitated solid-phase synthesis. All the synthesized compounds were characterized by tandem mass spectrometry. The obtained results present the possibility of the application of this β-amino acid in the synthesis of a new class of bioactive peptides.     

Preparation,characterization and properties of β-chitin and N-acetylated β-chitin

Free amino groups in β-chitin from squid pen were acetylated to obtain N-acetylated β-chitin. After careful control of degree of acetylation, thermal and mechanical properties of β-chitin and N-acetylated β-chitin were compared. The structural differences of β-chitin and N-acetylated β-chitin were characterized by Fourier transform infrared (FTIR) and wide-angle x-ray diffraction (WAXD) analysis. The results indicated that the crystallinity of N-acetylated β-chitin was higher than that of β-chitin and N-acetylated β-chitin exhibited characteristics similar to α-chitin. Equilibrium water content (EWC) of β-chitin reached to about 50% and this hydrophilic nature was assumed to be caused by a relatively weak hydrogen bonding force of β-chitin with parallel main chains. On the other hand, EWC of N-acetylated β-chitin was 40% due to the introduction of ordered structure. β-chitin and N-acetylated β-chitin have the tensile strength of 0.4 and 0.7 Mpa in the swollen state, respectively. Viscoelastic properties and thermal relaxation behaviors were investigated by dynamic mechanical thermal analysis (DMTA). DMTA spectra of these samples showed that α-transition peaks of β-chitin and N-acetylated β-chitin were observed at 170 and 190°C, respectively. These relaxation peak maxima were assigned to be their glass transition temperature. In addition, a second relaxation peak of β-chitin resulting from acetamide groups was found at 112°C and a broad relaxation peak of N-acetylated β-chitin at around 81–100°C. As a result of thermogravimetric analysis, 10% weight loss temperatures of β-chitin and N-acetylated β-chitin were 270 and 285°C, respectively. © 1996 John Wiley & Sons, Inc.     

Photoinduced transformation of α,β-epoxyketones to β-hydroxyketones by Hantzsch 1,4-dihydropyridine

Irradiation (λ >300 nm) of Hantzsch 1,4-dihydropyridine with aromatic α,β-epoxyketones in acetonitrile selectively breaks the Cα---O bond of the epoxides giving the corresponding β-hydroxyketones in excellent yields.     

Chemoselective Synthesis of β‐Amino Ester or β‐Lactam via Sonochemical Reformatsky Reaction

A series of β‐amino esters were synthesized by the reaction of N‐tosyl aldimine or N‐hydroxy aldimine with bromoacetate by sonochemical Reformatsky reaction. The β‐N‐hydroxyamino ester was obtained and the formed sensitive hydroxylamino functionality was resistant under the reaction condition. The β‐lactam also was synthesized by the reaction of N‐p‐methoxy aldimine as reacting substrate under this sonochemical Reformatsky reaction condition.     

Studies on the Mass Spectra of N‐Aryl α,β‐Unsaturated γ‐Lactams

The mass spectra of a series of N‐aryl α,β‐unsaturated γ‐lactams were studied. Besides the molecular ion, the three characteristic fragments such as [M⁺‐29], [M⁺‐55], and [M⁺‐82] were commonly found in a series of N‐Aryl α,β‐unsaturated γ‐lactams in EI/MS. Further more the mechanism for the interpretation of these fragments is also de scribed.     

Enantiomeric Separation of β-Amino Alcohols by Capillary Electrophoresis Using DM-β-CD as Chiral Selector

Enantiomeric separations of several β-amino alcohol drugs, i.e., phenylephrine, epinephrine, norepinephrine, synephrine, and chlorprenaline were performed by capillary electrophoresis using DM-β-CD as a chiral selector. Five test solutes were baseline resolved in six minutes. The effects of DM-β-CD concentration, pH value, ionic strength of the buffer, and the type of β-CDs on resolution were investigated. The results indicated that DM-β-CD is suitable for enantiomeric separation of β-amino alcohols containing a phenyl group on the chiral atom. Enantiorecognition mechanisms for test solutes are also discussed.