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A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.

An alternative methodology for the synthesis of chiral 3-(p-tolyl) butanoic acids is presented. This was accomplished through the diastereoselective hydrogenation reaction of different chiral N-3-(p-tolyl) but-2-enamides, using Pd/C in EtOH, to produce the corresponding chiral N-3-(p-tolyl) butanamides with high chemical yields and moderate diastereomeric ratios. Removal of the chiral auxiliary from N-3-(p-tolyl) butanamides gave the respective enantiomerically pure acids.

We report the use of a chiral Cu(II) 3D metal-organic framework (MOF) based on the tripeptide Gly-l-His-Gly (GHG) for the enantioselective separation of metamphetamine and ephedrine. Monte Carlo simulations suggest that chiral recognition is linked to preferential binding of one of the enantiomers as a result of either stronger or additional H-bonds with the framework that lead to energetically more stable diastereomeric adducts. Solid-phase extraction of a racemic mixture by using Cu(GHG) as the extractive phase permits isolating >50% of the (+)-ephedrine enantiomer as target compound in only 4 min. To our knowledge, this represents the first example of a MOF capable of separating chiral polar drugs.

The illicit drug methylamphetamine is often prepared from the precursor ephedrine or pseudoephedrine, which in turn are obtained by three processes: extraction from the Ephedra plant ("natural"), via fermentation of sugars ("semi-synthetic"), and by a "fully synthetic" route from propiophenone. We report the first method to differentiate between the three industrial routes used to produce the precursors ephedrine and pseudoephedrine by measurement of stable isotope ratios of nitrogen (δ15N), hydrogen (δ2H), and carbon (δ13C). Analysis of 782 samples of seized methylamphetamine allowed classification into three groups using k-means clustering or the expectation-maximization algorithm applied to a Gaussian mixture model. By preparation of 30 samples of ephedrine by the "fully synthetic" industrial process and measuring their δ15N, δ2H, and δ13C values, we observed that 15N becomes significantly depleted compared to the methylamine starting material. Conversion of ten ephedrine samples to methylamphetamine showed that this depletion is maintained in the final drug product, of which the δ15N, δ13C, and δ2H values were distinct from those of ephedrine and methylamphetamine samples of a semi-synthetic (fermentation pathway) origin. Combining modeling analysis with the new experiments and published information on the values of δ2H gave a definitive assignment of the three model groups, and equations to obtain probabilities for the precursor origin of any new sample. A simple rule of thumb is also presented. Making an assignment using delta values is particularly useful when no other chemical profiling information is available.

The aim in this project was to synthesize and to study fluorine-18 labeled analogues of l-deprenyl which bind selectively to the enzyme monoamine oxidase B (MAO-B). Three fluorinated l-deprenyl analogues have been generated in multistep organic syntheses. The most promising fluorine-18 compound N-[(2S)-1-[18F]fluoro-3-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (4c) was synthesized by a one-step fluorine-18 nucleophilic substitution reaction. Autoradiography on human brain tissue sections demonstrated specific binding for compound 4c to brain regions known to have a high content of MAO-B. In addition, the corresponding nonradioactive fluorine-19 compound (13) inhibited recombinant human MAO-B with an IC50 of 170.5 ±29 nM but did not inhibit recombinant human MAO-A (IC50 > 2000 nM), demonstrating its specificity. Biodistribution of 4c in mice showed high initial brain uptake leveling at 5.2 ±0.04%ID/g after 2 min post injection. In conclusion, compound 4c is a specific inhibitor of MAO-B with high initial brain uptake in mice and is, therefore, a candidate for further investigation in PET.

2-Arylethylamine derivatives were synthesized using the Curtius reaction and with three different methods of preparing the acyl azide functional group. Carbamates derived from isocyanate were convenient protecting groups for alkylation of amines. Starting from benzaldehyde, amphetamine was prepared in three steps through an oxazolidin-2-one intermediate in 62% overall yield. Copyright Taylor & Francis Group, LLC.

Reduction of N-t-BOC-protected-N-alkyl α-aminoketones with LiEt 3BH or Li(S-Bu)3BH furnishes protected syn-β-aminoalcohols with high selectivities. In contrast, removal of the BOC group followed by reduction of the aminoketone gives anti-β- aminoalcohols with variable selectivities. With aromatic ketones, selectivities are typically high while aliphatic ketones show mediocre to high selectivities depending on steric considerations.

The present invention provides stereoscopically-pure diastereomers of Formula I: 1In a preferred embodiment, the stereoisomers of the present invention are of Formula II, depicted below: 2R2, R3 and le are independently H, OH, OCH3, CH2OH, NHCONH2, NH2, halogen or CF3, and R1 is pyridine, or an amine which may be substituted with hydrogen, lower alkyl, lower alkylenearyl, lower alkylenephenyl, lower alkylenehydroxyphenyl, lower alkyleneamine, lower alkyleneaminoaryl, lower alkylaminohydroxyphenyl, or a similar functional group. TV is hydrogen, hydroxyl or methyl; R6 is hydrogen, lower alkyl, lower alkylenaryl, lower alkylenephenyl, lower alkylenehydroxyphenyl, lower alkyleneamine, lower alkyleneaminoaryl, lower alkylaminohydroxyphenyl, and the like. For both Formula I and Formual II, the firs carbon on the side chain progressing from the ring is preferably in the R-configuration. The second carbon atom on the side chain of Formula II, which is attached to IV, may or may not be a chiral center. However, when the second carbon atom is a chiral center, it is preferably in the S-configuration. The present invention contemplates each stereoisomer of Formula I and II in substantially-pure form. The present invention also provides methods of relieving nasal, sinus and bronchial congestion and of treating attention deficit hyperactivity disorder and obesity. The present stereoisomers may also be used to induce pupil dilation. These methods include administering to a mammal a composition containing a therapeutically effective amount of a stereoscopically-pure stereoisomer of Formula I or II with a pharmaceutically acceptable excipient.

Protonated complexes involving cyclodextrin hosts and guest compounds that are pharmacologically important are produced in the gas phase and reacted with a gaseous amine. The guest is exchanged to produce a new protonated complex with the amine. The reaction is enantioselective and is used to develop a method for determining enantiomeric excess using only mass spectrometry. The pharmaceutical compounds include DOPA, amphetamine, ephedrine, and penicillamine. The presence of more than one reacting species is observed with DOPA and penicillamine. Molecular dynamics calculations are used to understand the nature of the interactions and the possible source of the variations in the reactivities.

The regio- and stereoselective synthesis of the protected cis-3- aminooxetanes cis-5 and cis-7 is reported. The oxetanes were obtained by the photocycloaddition of aliphatic (6c-e) and aromatic (4, 6a) aldehydes to the corresponding enamides (1a-d,h) or enecarbamates (1e-g). The enamine derivatives used in the Paterno-Buchi reaction were either commercially available or prepared from the corresponding acetaldehyde imines 2 by acylation. The oxetane formation proceeded with good-to-excellent simple diastereoselectivity for aromatic aldehydes (56-82% yield) and moderate selectivity for aliphatic aldehydes (46-55% yield). The cis-3-aminooxetanes are precursors for syn- and anti-1,2-amino alcohols. The relative configuration established in the photochemical step was retained upon nucleophilic ring opening between the oxygen atom and carbon atom C-4. By this means, syn-1,2-amino alcohols such as 8 and 10 were available in good yields. In contrast, the N-Boc-protected cis-3-aminooxetanes cis-5e and cis- 5f were transformed into anti-1,2-amino alcohols. Upon treatment with trifluoroacetic acid, they underwent an intramolecular nucleophilic substitution at the carbon atom C-2 of the oxetane and the oxazolidinones 11 and 12 were formed. Because the substitution occurs with inversion of configuration, anti-1,2-amino alcohols, e.g., ephedrine (15), are accessible.

N-t-Butyloxycarbonyl (Boc) substituted cis-2-phenyl-3-aminooxetanes 3 undergo a ring expansion to oxazolidinones 5 upon treatment with trifluoroacetic acid. The reaction occurs at the C(2) position under inversion of configuration. Alternatively, 3-aminooxetanes can be ring-opened at the less substituted C(4) position with retention of the relative configuration between C(2) and C(3) as exemplified by the synthesis of (+)-pseudoephedrine (2). The cis3-aminooxetanes serve as precursors for either syn- or anti-1,2-amino alcohols.

A capillary electrophoretic method for the enantiomeric separation of 11 drugs was developed using an uncoated fused-silica capillary and succinyl β-cyclodextrin as a chiral additive. The effect of the pH of the background electrolyte on selectivity and resolution was studied in the range pH 3.3-9.3. Best results were obtained in a neutral medium. Generally, the presence of a hydroxy group at the chiral C-atom of the analyte seems to be essential because similar compounds without a hydroxy group at the chiral centre did not show chiral resolution. In addition to the enantioselective inclusion into the chiral cavity, hydrogen bondings and formation of ion pairs between the negatively charged selector and cationic analytes can be assumed as mechanisms.

Reaction of the arylisocyanates 2a-c with ethyl (S)-(-)-lactate, followed by careful saponification, afforded the corresponding chiral acids (S)-(-)- 4a-c. The latter were successfully used for the resolution of various racemic bases belonging to both the ephedrine and α-aryl ethylamine series.

Process and intermediate useful in the preparation of optically active 3-formyltetrahydropyrans from racemic 3-formyltetrahydropyran.

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Ephedrine and related optically active β-aminoalcohols can be prepared by zinc borohydride reduction of aryl O-protected magnesium imines and aryl α-hydroxyimimes which in turn are readily available from optically active cyanohydrins.

A careafully coordinated study of the relations between structure and energetics of association in the crystalline state and solution is reported here.Hydrogen-bonded ion pairs formed from reaction between the enantiomers of mandelic acid, α-phenethylamine, ephedrine, and pseudoephedrine have been studied in dimethyl sulfoxide, dioxane, and water and as solid salts.Single-crystal X-ray analysis, performed on four unique diastereomeric pairs of (+/-)-ephedrinium and (+/-)-pseudoephedrinium (+/-)-mandelates yielded details of the solid-state hydrogen-bonding schemes for all eight diastereomeric salts. 1H NMR spectra (at 300 and 600 MHz) over a wide concentration range were determined and indicated a simple two-state equilibrium between ion pairs and free ions in dimethyl sulfoxide.The dissociation equilibria in dimethyl sulfoxide were examined more quantitatively by conductance and the results treated by the Fuoss-Justice, Fuoss-1977, and Onsager methods to yield calculated dissociation constants, equivalent conductances, and mean activity coefficients over a wide concentration range.Thermochemical properties determined by various techniques were (1) the heat of fusion by differential scanning calorimetry, (2) heats of solution of the crystalline salts to high dilution by isoperibolic batch calorimetry, and (3) heats of protonation and heats of dissociation from thermometric titration of solutions of mandelic acid with the bases.Extensive use was made of cross-chiral checks (e.g., R,R' vs S,S') to prove that observed chiral discrimination factors were real and accurate.Significant chiral discrimination factors were found for all properties of diastereomeric combinations.In several cases the largest differences in thermochemical properties and 1H NMR spectra of diastereomeric pairs could be related reasonably to differences in hydrogen-bonding schemes in their crystals.

Crown ethers I-VI were tested by partition experiments for their stereoselectivity towards α-amino alcohols 1-10.The stereoselectivity depends in a regular way on both the absolute and relative configuration of the crown ether and α-amino alcohol.Comments are made on some high stereoselectivities.

Several methods are described which allow determination on a small scale of the enantiomer distribution constant Q, and the affinity coefficient P, which characterize the enantioselectivity and the affinity of a lipophilic phase for ammonium salts of different constitution and configuration.The influence of concentration of the tartaric acid ester, temperature, concentration and type of the lipophilic anion on Q and P was investigated to find out favourable experimental conditions for resolutions of racemates by iterative processes, e.g. partition chromatography.The relation ship between Q and the configuration of aminoalcohols 1-12 was explored and the observed regularities are pointed out.In addition it was found that lipophilic tartaric acid esters are enantioselective to salts of threo-1,2-diphenyl-1,2-ethanediamine 13, and to phenylglycine and its derivatives 14-16.

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The anodic oxidation of several different types of β-alkanolamines, R1R2C(OH)CR3R4NR5R6, was studied by cyclic voltammetry and controlled potential electrolysis in an aqueous carbonat buffer of pH 10 at a glassy carbon electrode.Upon oxidation, both the (α)C-(β)C and the C-N bonds are cleaved.Substituents R1-R4 affect the first oxidation potential and product distribution.The relative rates of the bond cleavages were estimated from the oxidation products.It was found that most of the amine cleaves through the (α)C-(β)C bond when at least one of the R groups is phenyl, nearly half cleaves through this bond when R is alkyl, and only about a tenth does so when R1-R4 are all hydrogen.The stability of the transient intermediates at the e-c step of the e-c-e process seems to affect the oxidation potentials and to govern the relative rates of the (α)C-(β)C bond cleavage.A scheme for the reaction processes is proposed.Keywords---β-alkanolamines; anodic oxidation; (α)C-(βC) bond fission; C-N bond fission; carbonate buffer; aldehyde; acetone; glycolaldehyde

Organic compounds containing one or more alcoholic hydroxyl groups are transformed into fluorine compounds by reacting them with sulfur tetrafluoride in liquid hydrogen fluoride solution, at temperatures between around -80° C. and +20° C. The method can be descriptively termed "fluorodehydroxylation", because it represents the reaction: