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We present a one-pot cascade for the synthesis of phenylpropanolamines (PPAs) in high optical purities (er and dr up to >99.5 %) and analytical yields (up to 95 %) by using 1-phenylpropane-1,2-diols as key intermediates. This bioamination entails the combination of an alcohol dehydrogenase (ADH), an ω-transaminase (ωTA) and an alanine dehydrogenase to create a redox-neutral network, which harnesses the exquisite and complementary regio- and stereo-selectivities of the selected ADHs and ωTAs. The requisite 1-phenylpropane-1,2-diol intermediates were obtained from trans- or cis-β-methylstyrene by combining a styrene monooxygenase with epoxide hydrolases. Furthermore, in selected cases, the envisioned cascade enabled to obtain the structural isomer (1S,2R)-1-amino-1-phenylpropan-2-ol in high optical purity (er and dr >99.5 %). This is the first report on an enzymatic method that enables to obtain all of the four possible PPA stereoisomers in great enantio- and diastereo-selectivity.

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.

A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.

3D-printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D-printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best-performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee. The method was applied to the continuous-flow synthesis of biologically active chiral 1,2-amino alcohols (norephedrine, metaraminol, and methoxamine) through a two-step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches.

The invention relates to a method for preparing (1R, 2S)-norephedrine, (1R, 2R)-norpseudoephedrine and a midbody thereof. The method comprises the following steps: in the reaction process in the first step, by taking a carrot as a medium, carrying out bio-transforming on 2-oximido-1-phenylacetone and reducing into (R)-2-oximido-1-phenyl propyl alcohol; in the second step, reducing (R)-2-oximido-1-phenyl propyl alcohol into a mixture of (1R, 2S)-norephedrine and (1R, 2R)-norpseudoephedrine; adding a chiral reliquid reagent (R)-O-acetyl mandelic acid and decomposing, thereby acquiring an optical pure (1R, 2S)-norephedrine and (1R, 2R)-norpseudoephedrine monomeric compound.

An efficient route for the synthesis of 6 drugs belonging to phenethylamine and amphetamine classes in excellent overall yields and high optical purity has been described. The strategy involves introduction of stereogenic centers by means of two-stereocentered Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of racemic syn-benzyloxy epoxide followed by Pd-catalyzed regioselective cationic hydrogenation of amino alcohols as the key reactions.

Chiral 1,2-amino alcohols are important building blocks for chemistry and pharmacy. Here, we developed two different biocatalytic 2-step cascades for the synthesis of all four nor(pseudo)ephedrine (N(P)E) stereoisomers. In the first one, the combination of an (R)-selective thiamine diphosphate (ThDP)-dependent carboligase with an (S)- or (R)-selective ω-transaminase resulted in the formation of (1R,2S)-NE or (1R,2R)-NPE in excellent optical purities (ee >99% and de >98%). For the synthesis of (1R,2R)-NPE, space-time yields up to ～26 g L-1 d-1 have been achieved. Since a highly (S)-selective carboligase is currently not available for this reaction, another strategy was followed to complement the nor(pseudo)ephedrine platform. Here, the combination of an (S)-selective transaminase with an (S)-selective alcohol dehydrogenase yielded (1S,2S)-NPE with an ee >98% and a de >99%. Although lyophilized whole cells are cheap to prepare and were shown to be appropriate for use as biocatalysts, higher optical purities were observed with purified enzymes. These synthetic enzyme cascade reactions render the N(P)E-products accessible from inexpensive, achiral starting materials in only two reaction steps and without the isolation of the reaction intermediates. This journal is the Partner Organisations 2014.

Two steps in one pot: An enzyme cascade consisting of a lyase and an (R)- or (S)-selective ω-transaminase (TA) provides (1R,2R)-norpseudoephedrine and (1R,2S)-norephedrine in only two steps. The intermediate is not isolated in this one-pot reaction and the products are obtained in high enantio- and diastereomeric purity. Moreover, the by-product from the second reaction can be recycled to serve as the substrate for the first reaction. Copyright

Each of the enantiomers of both norephedrine and norpseudoephedrine were stereoselectively prepared from the common, prochiral cyclic sulfamidate imine of racemic 1-hydroxy-1-phenyl-propan-2-one by employing asymmetric transfer hydrogenation (ATH) catalyzed by the well-defined chiral Rh-complexes, (S,S)- or (R,R)-Cp*RhCl(TsDPEN), and HCO2H/Et3N as the hydrogen source. The ATH processes are carried out under mild conditions (rt, 15 min) and are accompanied by dynamic kinetic resolution.

An anthracenyl-modified chiral bis(oxazoline) copper complex has been demonstrated to efficiently promote nitroaldol reactions between structurally varying aldehydes and nitromethane or nitroethane. The catalyst was recovered through formation of a charge transfer complex between the chiral ligand and trinitrofluorenone and its subsequent precipitation with pentane. The efficiency of this procedure was proved through several consecutive catalytic cycles that allowed the sturdy formation of the expected product with a high enantioselectivity. The catalyst′s stability was also put to the test in an original multi-substrate procedure. Following the same recovery concept, a new heterogeneous procedure was tested for which trinitrofluorenone was covalently linked to a silica support. Asymmetric heterogeneous catalysis was performed under these conditions as one of the few examples demonstrating the potential catalyst recycling in nitroaldol reactions through reversible, non-covalent interactions. Copyright

Ephedra sinica Stapf (Ephedraceae) is a widely used Chinese medicinal plant (Chinese name: Ma Huang). The main active constituents of E. sinica are the unique and taxonomically restricted adrenergic agonists phenylpropylamino alkaloids, also known as ephedrine alkaloids: (1R,2S)-norephedrine (1S,2S)-norpseudoephedrine, (1R,2S)-ephedrine, (1S,2S)-pseudoephedrine, (1R,2S)-N-methylephedrine and (1S,2S)-N-methylpseudoephedrine. GC-MS analysis of freshly picked young E. sinica stems enabled the detection of 1-phenylpropane-1,2-dione and (S)-cathinone, the first two putative committed biosynthetic precursors to the ephedrine alkaloids. These metabolites are only present in young E. sinica stems and not in mature stems or roots. The related Ephedra foemina and Ephedra foliata also lack ephedrine alkaloids and their metabolic precursors in their aerial parts. A marked diversity in the ephedrine alkaloids content and stereochemical composition in 16 different E. sinica accessions growing under the same environmental conditions was revealed, indicating genetic control of these traits. The accessions can be classified into two groups according to the stereochemistry of the products accumulated: a group that displayed only 1R stereoisomers, and a group that displayed both 1S and 1R stereoisomers. (S)-cathinone reductase activities were detected in E. sinica stems capable of reducing (S)-cathinone to (1R,2S)-norephedrine and (1S,2S)-norpseudoephedrine in the presence of NADH. The proportion of the diastereoisomers formed varied according to the accession tested. A (1R,2S)-norephedrine N-methyltransferase capable of converting (1R,2S)-norephedrine to (1R,2S)-ephedrine in the presence of S-adenosylmethionine (SAM) was also detected in E. sinica stems. Our studies further support the notion that 1-phenylpropane-1,2-dione and (S)-cathinone are biosynthetic precursors of the ephedrine alkaloids in E. sinica stems and that the activity of (S)-cathinone reductases directs and determines the stereochemical branching of the pathway. Further methylations are likely due to N-methyltransferase activities.

The present invention provides a novel hydrogenation catalyst, process of preparing the catalyst and process for the preparation of optically active L-norephedrine, [(1R,2S)-2-amino-1-phenyl-1-propanol] by a catalytic hydrogenation process, said catalyst comprising of finely divided nickel metal containing a metal from group III A of the periodic table as an activator and a metal from group VI B or VIII as promoter,

(Figure Presented) Novel enzyme activity: Biocatalytic Henry reactions with nitromethane and nitroethane yielded the corresponding nitroalcohols with good enantio- and diastereo-control in the presence of the hydroxynitrile lyase from the tropical rubber tree Hevea brasiliensis. Molecular modeling and deuterated starting materials were used in mechanistic investigations.

An efficient cost-effective process for preparation of l-erythro-2-amino-1-phenyl-1-propanol from l-1-phenyl-1-hydroxy-2-propanone, which comprises converting l-1-phenyl-1-hydroxy-2-propanone to l-1-phenyl-1-hydroxy-2-propanone oxime and reducing the oxime with a catalyst consisting of finely divided nickel and aluminium metals giving good diastereomeric purity and yield.

A process for easily producing an optically active β-amino alcohol useful as a pharmaceutical intermediate from an inexpensive, readily available starting material is provided. A readily available α-substituted ketone is reacted with an optically active amine to yield a diastereomer mixture of an optically active α-substituted aminoketone. One of the diastereomers is isolated optionally after the diastereomers are converted to salts with an acid. The optically active α-substituted aminoketone or a salt thereof thus isolated was stereoselectively reduced to yield an optically active β-substituted amino alcohol. The optically active β-substituted amino alcohol is subjected to hydrogenolysis to produce an optically active β-amino alcohol or a salt thereof.

An efficient process for stereoselectively producing L-erythro-(1R,2S)-2-amino-1-phenylpropan-1-ol from L-(R)-phenylacetylcarbinol, which comprises reductively aminating L-(R)-phenylacetylcarbinol with a primary aralkylamine under catalytic reduction conditions and successively subjecting the resultant L-erythro-(1R,2S)-2-(N-aralkylamino)-1-phenylpropan-1-ol to catalytic reduction to remove the N-aralkyl group in a manner as in hydrogenolysis.

An efficient method for the quantitative preparation and isolation of a compound of formula I STR1 or its enantiomer, a chiral mediator used in enantioselective synthesis.

Asymmetric reduction of α-oxoketoxime ethers with the reagents prepared in situ from trimethyl borate and chiral amino alcohols derived from either L-proline or α-pinene was investigated. Both cyclic and acyclic α- oxoketoxime ethers were reduced to afford the corresponding chiral 1,2amino alcohols with high enantioselectivities.

The enantioselective Baker's yeast reduction of (E)-1-phenyl-1,2-propanedione 2-(O-methyloxime) 1 afforded (-)-(R)-1-hydroxy-1-phenyl-2-propanone 2-(O-methyloxime) 2 with 97% of enantiomeric excess (ee) which was diastereoselectively reduced by LiAlH4 to obtain the (-)-(R,S)-norephedrine with ee=82% and (-)-(R,R)-norpseudoephedrine with ee=93% in a ratio 4:1 respectively.

Hydrogenation of (R)-cyanohydrins (R)-1 with LiAlH4 occurs without racemization to give the (R)-2-amino alcohols (R)-3. (1R,2S)-2-Amino alcohols (1R,2S)-4 are obtained with high diastereoselectivity by addition of methyl Grignard to O-silyl protected cyanohydrins (R)-2 and subsequent hydrogenation with NaBH4. The N-alkylated 2-amino alcohols (R)-8 and (1R,2S)-9 can be prepared either by reductive alkylation of the corresponding 2-amino alcohols (R)-3 and (1R,2S)-4, respectively, or by a transimination reaction of the Grignard addition products with primary amines and subsequent hydrogenation with NaBH4. The lower diastereoselectivity of hydrogenation in case of the N-alkylmino compounds in comparison to the N-unsubstituted imines is explained by a weaker chelating effect.

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.

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erythro-2-Amino alcohols (1R,2S)- and (1S,2R)-4 may be synthesized stereoselectively by addition of Grignard compounds to cyanohydrins (R)-, (S)-1 and their O-trimethylsilyl derivatives 3, respectively, followed by hydrogenation.The threo-2-amino alcohols (1S,2S)- and (1R,2R)-4 are easily accessible by inversion at C-1 of the (1R,2S) and (1S,2R) compounds.

The "benzostabase" (BSB) protecting group has been applied to primary aliphatic amines. It can be introduced via a dehydrogenative silylation employing an air- and moisture-stable reagent, and is appreciably more acid-stable than the related "stabase" group. BSB protection has been used in a stereoselective synthesis of amino-alcohols involving the addition of organometallic reagents to protected amino-aldehydes under "non-chelation control".

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.

Sequential addition of iBu2AlH and RLi or RMgX to Schiff base esters derived from amino acids provides a simple route to β-amino alcohols. The reaction procedes without racemization, and with high threo selectivity. Several representative sphingosines are synthesized.

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2-(2,5-Dimethylpyrrol-1-yl)alkanals, 2-(pyrrol-1-yl)alkanals, and 2-(2,5-dimethylpyrrol-1-yl)alkan-1-ones were prepared.The reactions of these compounds with Grignard and hydride reagents proceeded stereoselectively to give the corresponding 2-(pyrrol-1-yl)alcohols, which were converted into 2-aminoalcohols, such as norephedrine and ephedrine, by cleavage of the pyrrole ring.

A mild ring cleavage of N-tert-butoxycarbonyl-2-oxazolidinones (N-BOC-2-oxazolidinones) 5a-5d and the recovery of β-amino alcohols 7a-7d from the corresponding N-BOC-derivatives are reported.

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Chiral 1,3-oxazolidines are readily prepared from methyl ketones and chiral norephedrine.Formation of stannous azaenolates from the oxazolidines and reaction with aldehydes followed by removal of the chiral auxiliary lead to the aldol products in high level of enantiomeric putity.

There is described the resolution of the racemate (1RS,2SR)-2-amino-1-phenyl-propan-1-ol. It is carried out by means of the optical isomers of S-(carboxymethyl)-cysteine.

There is described the resolution of the racemate S-(carboxymethyl)-(RS)-cysteine. It is carried out by means of the optical isomers of 2-amino-1-phenyl-propan-1-ol. This process makes it possible to obtain in a simple manner S-(carboxymethyl)-(R)-cysteine which is important for pharmaceutical purposes and is made from synthetically produced cysteine.

Separation of Enantiomers by Partition between Liquid Phases; Salts of enantiomeric α-aminoalcohols, such as norephedrin, with lipophilic anions, such as hexafluorophosphate ion, can be separated by partition between aqueous and lipophilic phase containing esters of tartaric acid.

α-N-Acylamino acids have been developed as useful reagents for the preparation of optically pure α-aminoalkylaryl ketones.Protection of the amino group as either the ethoxycarbonyl or benzenesulfonyl derivative allows alanine to serve as an effective educt for the chirally specific synthesis of a variety of structures containing the phenylethylamine backbone.Benzene undergoes Friedel-Crafts acylation with the N-acylalanine acid chloride.Catalyst complexation with oxagenated aromatics, however, prohibits acylation of aryl ethers.An arylmetallo reaction scheme overcomes this problem and also affords regiospecificity not attainable in conventional acylations.As examples, optically pure ephedrines and amphetamines were directly synthesized without recourse to resolution since the chirality of the amino acid educt was entirely conserved throughout the process.

Optically active bases are prepared by reacting the racemic base with an optically active half amide of an unsaturated aliphatic dicarboxylic acid of the formula STR1 where R1, R2 and R3 are the same of different and are hydrogen, halogen, a hydroxy group, a methyl group or a methoxy group or two of R1, R2 and R3 together are a methylenedioxy group, R4 is hydrogen or a methyl group, R5, R6 and R7 independently are hydrogen or a C1 -C4 alkyl group and n is 0 or 1 and optionally splitting an optically homogeneous salt fraction into the corresponding optically active base and the added half amide.