- Enantioselective Cascade Biocatalysis for Deracemization of Racemic β-Amino Alcohols to Enantiopure (S)-β-Amino Alcohols by Employing Cyclohexylamine Oxidase and ω-Transaminase
-
Optically active β-amino alcohols are very useful chiral intermediates frequently used in the preparation of pharmaceutically active substances. Here, a novel cyclohexylamine oxidase (ArCHAO) was identified from the genome sequence of Arthrobacter sp. TYUT010-15 with the R-stereoselective deamination activity of β-amino alcohol. ArCHAO was cloned and successfully expressed in E. coli BL21, purified and characterized. Substrate-specific analysis revealed that ArCHAO has high activity (4.15 to 6.34 U mg?1 protein) and excellent enantioselectivity toward the tested β-amino alcohols. By using purified ArCHAO, a wide range of racemic β-amino alcohols were resolved, (S)-β-amino alcohols were obtained in >99 % ee. Deracemization of racemic β-amino alcohols was conducted by ArCHAO-catalyzed enantioselective deamination and transaminase-catalyzed enantioselective amination to afford (S)-β-amino alcohols in excellent conversion (78–94 %) and enantiomeric excess (>99 %). Preparative-scale deracemization was carried out with 50 mM (6.859 g L?1) racemic 2-amino-2-phenylethanol, (S)-2-amino-2-phenylethanol was obtained in 75 % isolated yield and >99 % ee.
- Zhang, Jian-Dong,Chang, Ya-Wen,Dong, Rui,Yang, Xiao-Xiao,Gao, Li-Li,Li, Jing,Huang, Shuang-Ping,Guo, Xing-Mei,Zhang, Chao-Feng,Chang, Hong-Hong
-
p. 124 - 128
(2020/09/21)
-
- Asymmetric amination of meso-epoxide with vegetable powder as a low-toxicity catalyst
-
This paper describes the scope and limitation of substrates subjected to asymmetric amination with epoxides catalyzed by a soluble soybean polysaccharide (Soyafibe S-DN), which we recently discovered from the reaction of 1,2-epoxycyclohexane with cyclopropylamine. Various meso-epoxides reacted with various amines afforded the corresponding products with good enantiomeric selectivity. Since it was found that pectin was found to have a catalytic ability after screening commercially available polysaccharides, we studied 33 different vegetable powders having pectic substances, and we found that many vegetable powders showed catalytic ability. These results should guide in using vegetable components as low-toxic catalysts for the production of pharmaceuticals.
- Asano, Tatsuhiro,Kurata, Hiroyuki,Takeuchi, Yuki,Tsuzaki, Kazuya,Wada, Koichi
-
-
- Hybrid Organo- and Biocatalytic Process for the Asymmetric Transformation of Alcohols into Amines in Aqueous Medium
-
A hybrid organo- and biocatalytic system for the asymmetric conversion of racemic alcohols into amines was developed. Combining an organocatalyst, AZADO, an oxidant, NaOCl, and an enzyme, ω-transaminase, we implemented a one-pot oxidation-transamination sequential process in aqueous medium. The method showed broad substrate scope and was successfully applied to conventional secondary alcohols and sterically hindered β-substituted cycloalkanols, where a highly stereoselective dynamic asymmetric bioamination enabled us to set up both contiguous stereocenters with very high enantio- and diastereomeric ratio (>90% yield, >99% ee, and up to 49:1 dr).
- Liardo, Elisa,Ríos-Lombardía, Nicolás,Morís, Francisco,Rebolledo, Francisca,González-Sabín, Javier
-
p. 4768 - 4774
(2017/07/24)
-
- Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3or 2-CH3
-
A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3or 2-CH3was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED50MES = 42.56, ED50scPTZ = 58.38, ED506-Hz 44 mA = 42.27 mg/kg tested in mice after intraperitoneal (i.p.) administration); R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (6) (ED50MES = 53.76, ED50scPTZ = 90.31, ED506-Hz 44 mA = 92.86 mg/kg mice, i.p.); and R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (11) (ED50MES = 55.58, ED50scPTZ = 102.15, ED506-Hz 44 mA = 51.27 mg/kg mice, i.p.). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives.
- Gunia-Krzy?ak, Agnieszka,?elaszczyk, Dorota,Waszkielewicz, Anna M.,Pańczyk, Katarzyna,Marona, Henryk,Rapacz, Anna,Filipek, Barbara,?es?awska, Ewa,S?oczyńska, Karolina,P?kala, El?bieta,Nitek, Wojciech
-
p. 471 - 482
(2016/12/30)
-
- Method for synthesizing trans-cyclohexyldiamine
-
The invention discloses a method for synthesizing trans-cyclohexyldiamine. The method comprises the following steps: by using epoxy cyclohexane as the raw material, carrying out ring opening with ammonia water, adding sulfuric acid for dewatering and salification, adding free alkali, carrying out ring opening with ammonia water, and distilling to obtain the trans-cyclohexyldiamine. The method has the advantages of high repetitiveness of the synthesis route, and simple and accessible raw materials, and provides an alternative scheme for obtaining the trans-cyclohexyldiamine pure product.
- -
-
Paragraph 0013; 0014; 0015
(2017/08/29)
-
- Novel process for preparing beta-aminocyclohexanol by open loop of 1,2-cyclohexene oxide
-
The invention discloses a novel process for preparing beta-aminocyclohexanol by open loop of 1,2-cyclohexene oxide. The process comprises the following steps: preparing the beta-aminocyclohexanol by adopting open loop of 1,2-cyclohexene oxide and ammonia in a molar ratio of 1:1-10, reacting at 0-100 DEG C for 1-48 hours to obtain a crude product; recrystallizing and purifying the crude product obtained after the reaction to obtain the beta-aminocyclohexanol having a yield of 90% or above and an amine value of about 450. The beta-aminocyclohexanol preparation method has low cost, simple process flow, mild reaction, easy operation and high yield, and has a wide application and market prospect.
- -
-
Paragraph 0004
(2017/09/01)
-
- Chemo- and Site-Selective Alkyl and Aryl Azide Reductions with Heterogeneous Nanoparticle Catalysts
-
Site-selective modification of bioactive natural products is an effective approach to generating new leads for drug discovery. Herein, we show that heterogeneous nanoparticle catalysts enable site-selective monoreduction of polyazide substrates for the generation of aminoglycoside antibiotic derivatives. The nanoparticle catalysts are highly chemoselective for reduction of alkyl and aryl azides under mild conditions and in the presence of a variety of easily reduced functional groups. High regioselectivity for monoazide reduction is shown to favor reduction of the least sterically hindered azide. We hypothesize that the observed selectivity is derived from the greater ability of less-hindered azide groups to interact with the surface of the nanoparticle catalyst. These results are complementary to previous Staudinger reduction methods that report a preference for selective reduction of electronically activated azides.
- Udumula, Venkatareddy,Nazari, S. Hadi,Burt, Scott R.,Alfindee, Madher N.,Michaelis, David J.
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p. 4423 - 4427
(2016/07/12)
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- Anticonvulsant activity, crystal structures, and preliminary safety evaluation of N - trans -cinnamoyl derivatives of selected (un)modified aminoalkanols
-
Adequate control of seizures remains an unmet need in epilepsy. In order to identify new anticonvulsant agents, a series of N-trans-cinnamoyl derivatives of selected aminoalkanols was synthetized. The compounds were obtained in the reaction of N-acylation carried out in a two-phase system. The substances were tested in animal models of seizures induced either electrically (maximal electroshock - MES; 6-Hz test) or chemically, by subcutaneous injection of pentetrazol (scPTZ). Neurotoxicity was determined by the rotarod test. Lipophilicity of the active compounds, expressed as RM0, was determined by reversed-phase thin layer chromatography and it ranged from 1.390 to 2.219. From among the tested series of compounds, R,S-(E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide (1) and R,S-(E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide (3) exhibited the best anticonvulsant activity. Compound 1, when administered to mice by intraperitoneal (i.p.) injection, showed the ED50 values of 86.6, 60.9, and 109.6 mg/kg in the MES, 6-Hz, and scPTZ tests, respectively. For compound 3, the ED50 values were found to be 47.1 mg/kg in MES and 77.1 mg/kg in scPTZ (mice, i.p.). The distances measured in crystals of compound 1 were: 7.99 ? - from the phenyl ring to the hydroxyl group in the amide moiety, 5.729 ? - from the phenyl ring to the amide group, and 3.112 - from the amide group to the hydroxyl group in the amide moiety. The reported compounds did not exhibit mutagenic potential when assayed in the Ames test. Compounds 1 and 3 did not affect viability and morphology of human hepatocellular carcinoma cells (HepG2).
- Gunia-Krzyzak, Agnieszka,Zes?awska, Ewa,S?oczyńska, Karolina,Koczurkiewicz, Paulina,Nitek, Wojciech,Zelaszczyk, Dorota,Szkaradek, Natalia,Waszkielewicz, Anna M.,Pekala, Elzbieta,Marona, Henryk
-
-
- Preliminary evaluation of central nervous system activity of (E)-N-2-methyl-3-phenylprop-2-enyl ((E)-N- α-methylcinnamyl) derivatives of selected aminoalkanols
-
A series of (E)-α-methylcinnamyl derivatives of selected aminoalkanols was synthetized and evaluated for activity in central nervous system. All compounds were tested as anticonvulsants and one additionally in antidepressant- and anxiolytic-like assays. The compounds possessed pharmacophoric elements regarded as beneficial for anticonvulsant activity: hydrophobic unit and two hydrogen bonds donor/acceptor features. The compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scPTZ) induced seizures as well as neurotoxicity assessments. Eight of the tested substances showed protection in MES test at the dose of 100 mg/kg. The derivative of 2-aminopropan-1-ol was also tested in 6-Hz test in mice i.p. and showed anticonvulsant activity but at the same time the neurotoxicity was noted. The derivative of 2-amino-1-phenylethanol which possessed additional hydrophobic unit in aminoalkanol moiety was tested in other in vivo assays to evaluate antidepressant- and anxiolytic-like activity. The compound proved beneficial properties especially as anxiolytic agent remaining active in four-plate test in mice at the dose of 2.5 mg/kg (i.p.). In vitro biotransformation studies of 2-amino-1-phenylethanol derivative carried out in mouse liver microsomal assay indicated two main metabolites as a result of aliphatic and aromatic hydroxylation or aliphatic carbonylation. To identify possible mechanism of action, we evaluated serotonin receptors (5-HT1A, 5-HT6 and 5-HT7) binding affinities of the compounds but none of them proved to bind to any of tested receptors.
- Gunia-Krzyzak, Agnieszka,Pytka, Karolina,S?oczyńska, Karolina,Waszkielewicz, Anna M.,Sata?a, Grzegorz,Bojarski, Andrzej J.,Sapa, Jacek,Filipek, Barbara,Ceg?a, Marek,Pekala, Elzbieta,Marona, Henryk
-
p. 345 - 357
(2016/08/06)
-
- Experimental and theoretical investigations of the stereoselective synthesis of P-stereogenic phosphine oxides
-
An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides has been developed, incorporating the use of (1S,2S)-2-aminocyclohexanol as the chiral auxiliary. The method relies on three key steps: 1) Highly diastereoselective formation of PV oxazaphospholidine, rationalized by a theoretical study; 2) highly diastereoselective ring-opening of the oxazaphospholidine oxide with organometallic reagents that takes place with inversion of configuration at the P atom; 3) enantioselective synthesis of phosphine oxides by cleavage of the remaining P-O bond. Interestingly, the use of a PIII phosphine precursor afforded a P-epimer oxazaphospholidine. Hence, the two enantiomeric phosphine oxides can be synthesized starting from either a PV or a PIII phosphine precursor, which constitutes a clear advantage for the stereoselective synthesis of sterically hindered phosphine oxides. That's handy: An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides was developed, incorporating the use of (1S,2S)-2-aminocyclohexanol as a chiral auxiliary, whereby enantiomeric phosphine oxides can be synthesized starting from either a PV or a PIII phosphine precursor.
- Copey, Laurent,Jean-Gérard, Ludivine,Framery, Eric,Pilet, Guillaume,Robert, Vincent,Andrioletti, Bruno
-
supporting information
p. 9057 - 9061
(2015/06/16)
-
- Broadening the chemical scope of laccases: Selective deprotection of N-benzyl groups
-
Laccase from Trametes versicolor together with TEMPO has been found to be a very efficient system to deprotect N-benzylated primary amines, differing from previously described methods since it uses oxygen as a mild oxidant in aqueous medium. Chemoselective removal of the benzyl group was achieved with excellent yields when secondary amines and alcohol moieties were also present.
- Martínez-Montero, Lía,Díaz-Rodríguez, Alba,Gotor, Vicente,Gotor-Fernández, Vicente,Lavandera, Iván
-
supporting information
p. 2794 - 2798
(2015/05/27)
-
- Synthesis, anticonvulsant activity and metabolism of 4-chlor-3-methylphenoxyethylamine derivatives of trans-2-aminocyclohexan-1-ol
-
In this study, we report the synthesis, spectral characterization, antiepileptic activity and biotransformation of three new, chiral, N-aminoalkyl derivatives of trans - 2 aminocyclohexan-1-ol: 1 (R enantiomer), 2 (S enantiomer) and 3 (racemate). Antiepileptic activity of the titled compounds was studied using MES and scMet. Moreover, in this study, the biotransformation of 1, 2 and 3 in microbial model (Cunninghamella), liver microsomal assay as well as in silico studies (MetaSite) was evaluated. Studies have indicated that 1, 2 and 3 have good antiepileptic activity in vivo, comparable to valproate. Biotransformation assays showed that the most probable metabolite (indicated in every tested assays) was M1. The microbial model as well as in silico study showed no difference in biotransformation between tested enantiomers. However, in a rat liver microsomal study compound 1 and 2 (R and S enantiomer) had different main metabolite - M2 for 1 and M1 for 2. MS/MS fragmentation allowed us to predict the structures of obtained metabolites, which were in agreement with 1°alcohol (M1) and carboxylic acid (M2). Our research has shown that microbial model, microsomal assay, and computational methods can be included as useful and reliable tools in early ADME-Tox assays in the process of developing new drug candidates.
- Kubowicz, Paulina,Marona, Henryk,P?kala, Elzbieta
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p. 163 - 169
(2015/03/04)
-
- An improved and efficient process for the scalable preparation of optically pure trans-2-aminocyclohexanols
-
An improved and efficient process has been developed for a green and scalable preparation of optically pure (1R,2R) - and (1S,2S) -trans-2-aminocyclohexanols. The process utilised hot water to promote the aminolysis of cyclohexene oxide by benzylamine to afford racemic trans-2-(benzylamino)cyclohexanols, which were resolved by sequential and repeated use of (R)- and (S)-mandelic acid. Finally, after treatment of the two salts sequentially with HCl and NaOH and recovery of mandelic acid, liberation was achieved of the optically pure trans-2-benzylaminoaminocyclohexanols which were smoothly debenzylated using a low loading of a Pd/C catalyst to the trans-2-aminocyclohexanols. The synthetic route has been successfully applied to large-scale (1 mol) preparations in good yield.
- Xue, Feng,Li, Chang-Gong,Zhu, Yong,Lou, Tian-Jun
-
p. 322 - 324
(2014/06/09)
-
- CYCLOHEXANEDIAMINE COMPOUNDS AND METHODS FOR THEIR PREPARATION
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The present invention provides processes for the preparation of cyclohexanediamine compounds of formula Ia and intermediates thereof. The compounds are useful as Syk kinase inhibitors and in various pharmaceutical compositions, and particularly useful for treating conditions mediated at least in part by Syk kinase activity.
- -
-
-
- Helix-forming propensity of aliphatic urea oligomers incorporating noncanonical residue substitution patterns
-
Aliphatic N,N′-linked oligoureas are peptidomimetic foldamers that adopt a well-defined helical secondary structure stabilized by a collection of remote three-center H-bonds closing 12- and 14-membered pseudorings. Delineating the rules that govern helix formation depending on the nature of constituent units is of practical utility if one aims to utilize this helical fold to place side chains in a given arrangement and elaborate functional helices. In this work, we tested whether the helix geometry is compatible with alternative substitution patterns. The central -NH-CH(R)-CH2-NH-CO- residue in a model oligourea pentamer sequence was replaced by guest units bearing various substitution patterns [e.g., -NH-CH2-CH2-NH-CO-, -NH-CH2-CH(R)-NH-CO-, and -NH-CH(R1)-CH(R 2)-NH-CO-], levels of preorganization (cyclic vs acyclic residues), and stereochemistries, and the helix formation was systematically assessed. The extent of helix perturbation or stabilization was primarily monitored in solution by Fourier transform IR, NMR, and electronic circular dichroism spectroscopies. Our results indicate that although three new substitution patterns were accommodated in the 2.5-helix, the helical urea backbone in short oligomers is particularly sensitive to variations in the residue substitution pattern (position and stereochemistry). For example, the trans-1,2- diaminocyclohexane unit was experimentally found to break the helix nucleation, but the corresponding cis unit did not. Theoretical calculations helped to rationalize these results. The conformational preferences in this series of oligoureas were also studied at high resolution by X-ray structure analyses of a representative set of modified oligomers.
- Pendem, Nagendar,Douat, Celine,Claudon, Paul,Laguerre, Michel,Castano, Sabine,Desbat, Bernard,Cavagnat, Dominique,Ennifar, Eric,Kauffmann, Brice,Guichard, Gilles
-
supporting information
p. 4884 - 4892
(2013/05/09)
-
- Lipophilic oligopeptides for chemo- and enantioselective acyl transfer reactions onto alcohols
-
Inspired by the extraordinary selectivities of acylases, we envisioned the use of lipophilic oligopeptidic organocatalysts for the acylative kinetic resolution/desymmetrization of rac- and meso-cycloalkane-1,2-diols. Here we describe in a full account the discovery and development process from the theoretical concept to the final catalyst, including scope and limitations. Competition experiments with various alcohols and electrophiles show the full potential of the employed oligopeptides. Additionally, we utilized NMR and IR-spectroscopic methods as well as computations to shed light on the factors responsible for the selectivity. The catalyst system can be readily modified to a multicatalyst by adding other catalytically active amino acids to the peptide backbone, enabling the stereoselective one-pot synthesis of complex molecules from simple starting materials.
- Mueller, Christian E.,Zell, Daniela,Hrdina, Radim,Wende, Raffael C.,Wanka, Lukas,Schuler, Soeren M. M.,Schreiner, Peter R.
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p. 8465 - 8484
(2013/09/24)
-
- Efficient preparation of biologically important 1,2-amino alcohols
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An efficient three-step methodology developed for the preparation of 1,2-amino alcohols. In the first step a rapid coupling between bromoketones and potassium phthalimide in ionic liquid produced-phthalimido ketones in quantitative yields, which is followed by a facile reduction using NaCNBH 3 in acetic acid to give corresponding phthalimido alcohols and finally effecting hydrazinolysis in water at 60C to yield biologically important 1,2-amino alcohols.
- Gupta, Pankaj,Rouf, Abdul,Shah, Bhahwal A.,Mukherjee, Debaraj,Taneja, Subhash C.
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p. 505 - 519
(2013/01/15)
-
- A waste-minimized protocol for the preparation of 1,2-azido alcohols and 1,2-amino alcohols
-
Under solvent-free conditions the reaction of epoxides 1a-i with trimethylsilylazide (2) catalyzed by polystiryl-supported fluoride (PS-DABCOF2) has led to the efficient preparation of the corresponding O-TMS protected 1,2-azido alcohols 3a-i that, by treatment with Dowex-H, gave the related 1,2-azido alcohols 4a-i in excellent yields (83-99% and 82-96%, respectively). The use of a flow procedure has allowed us to significantly minimize waste in the preparation of representative 1,2-azido alcohols 4a, 4c and 4i that have been obtained with E-factors of 1.6, 2.1, and 1.9, respectively. The 1,2-amino alcohols 5a, 5c and 5f have been also prepared, in quantitative yields, by reduction of the corresponding O-TMS protected 1,2-azido alcohols 3a, 3c, and 3f by Pd on the Al2O3/HCOOH system.
- Ballerini, Eleonora,Crotti, Paolo,Frau, Ileana,Lanari, Daniela,Pizzo, Ferdinando,Vaccaro, Luigi
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supporting information
p. 2394 - 2400
(2013/09/12)
-
- Enzymatic transesterification of pharmacologically interesting β-aminocycloalkanol precursors
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Chemoenzymatic syntheses of both enantiomers of cis- and trans-2-aminocyclopentanol as well as cis- and trans-2-aminocyclohexanol, which are valuable building blocks for a plethora of ligands and pharmaceuticals have been efficiently carried out. The strategy involves the stereospecific syntheses of racemic aminocycloalkanol precursors via tagging of a phthalimide as a masking group and subsequent lipase-catalyzed kinetic resolution. Most of the lipases exhibited excellent enantioselectivity (E a‰ 200) in the transesterification reactions of trans-derivatives, with both N-protected (R,R)-amino acetates and (S,S)-amino alcohols being isolated in enantiopure form. With regard to cis-derivatives, lipases were also very selective, even though the biotransformations were significantly slower.
- Gonzalez-Sabin, Javier,Rios-Lombardia, Nicolas,Gotor, Vicente,Moris, Francisco
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p. 1421 - 1425
(2013/12/04)
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- A practical method for the synthesis of highly enantioenriched trans -1,2-amino alcohols
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A highly enantioselective addition of phenyl carbamate to meso-epoxides has been developed to efficiently generate protected trans-1,2-amino alcohols. This transformation is promoted by an oligomeric (salen)Co-OTf catalyst and has been used to prepare two useful 2-aminocycloalkanol hydrochlorides in enantiopure form on a multigram scale from commercially available starting materials.
- Birrell, James A.,Jacobsen, Eric N.
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p. 2895 - 2897
(2013/07/26)
-
- New procedure for the preparation of (1 R,2 R)-2-[(R)-3-(benzyloxy)pyr- rolidin-1-yl]cyclohexanol
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A novel route to an intermediate of vernakalant, (1R,2R)-2-[(R)-3- (benzyloxy)pyrrolidin-1-yl]cyclohexanol from ethyl (R)-4-chloro-3- hydroxybutanoate is described. It was found that the key intermediate (R)-4-(benzyloxy)-1-[(1R,2R)-2-(tert-butyldimethylsiloxy)cyclohexyl] pyrrolidin-2-one could be isolated with high dia-stereomeric excess (up to 99% de) from its isomer by column chromatography alone, without further chemical resolution. Georg Thieme Verlag Stuttgart. New York.
- Ye, Haiwei,Yu, Chuanming,Zhong, Weihui
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experimental part
p. 51 - 56
(2012/04/10)
-
- Cyclic trans-β-amino alcohols: Preparation and enzymatic kinetic resolution
-
Enantioenriched cyclic β-amino alcohols, trans-2-aminocyclohexanols (ee, >99%), trans-2-aminocyclopentanols (ee, >99%), trans-1-amino-2- indanols (ee, >99%) and trans-2-amino-1-indanols (ee, ~98%) were prepared in high yields via an Arthrobacter sp. Lipase/PLAP catalyzed kinetic resolution of racemic phthalimido acetates. The addition of toluene as a co-solvent dramatically improved the hydrolysis and enantioselectivity, whereas for indanols, substrate immobilization on Celite improved the efficacy of the kinetic resolution.
- Rouf, Abdul,Gupta, Pankaj,Aga, Mushtaq A.,Kumar, Brijesh,Parshad, Rajinder,Taneja, Subhash C.
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scheme or table
p. 2134 - 2143
(2012/05/04)
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- Polyolefin-supported recoverable/reusable Cr(III)-salen catalysts
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The design of functional soluble polyolefins for use as supports for salen ligands and metal complexes is described. Examples and applications that use both polyisobutylene (PIB)-and polyethylene (PEOlig)-bound recoverable/recyclable salen ligands/metal complexes are detailed. In the case of using PIB as a support, the polymer-bound complexes can be recovered through the use of latent biphasic or a thermomorphic mixed solvent systems. In the case of PEOlig-supported complexes, the thermomorphic PE Olig-bound salen species can be dissolved in "hot" solvents and quantitatively recovered as solids upon cooling to room temperature. Both the PIB-and PEOlig-bound salen catalysts were shown to catalyze the ring-opening of epoxides with various nucleophiles. Both sorts of polyolefin-bound catalysts can be recycled and reused with no observed loss in activity. However, limitations of catalyst concentration make chiral versions of these complexes uncompetitive in comparison to conventional chiral salen catalysts that can be used in neat substrate at higher concentration to produce high enantioselectivity in the ring-opening products. The preparation of a PIB-bound "half-salen" catalyst was also briefly examined.
- Bergbreiter, David E.,Hobbs, Christopher,Hongfa, Chayanant
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experimental part
p. 523 - 533
(2011/04/17)
-
- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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-
Page/Page column 45-49; 59
(2010/12/31)
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- METHOD FOR PRODUCING OPTICALLY ACTIVE TRANS-2-AMINOCYCLOHEXANOL AND INTERMEDIATE OF OPTICALLY ACTIVE TRANS-2-AMINOCYCLOHEXANOL
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A method of producing optically active trans-2-aminocyclohexanol includes allowing racemic trans-2-aminocyclohexanol to react with optically active 2-methoxyphenylacetic acid to produce an optically active 2-methoxyphenylacetic acid salt of optically active trans-2-aminocyclohexanol and separating the salt. An optically active 2-methoxyphenylacetic acid salt of optically active trans-2-aminocyclohexanol is also provided. The method makes it possible to produce optically active trans-2-aminocyclohexanol with ease and a high yield from an industrially-advantageous, inexpensive raw material.
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Page/Page column 6
(2010/04/25)
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- Asymmetric meso-epoxide ring-opening with trimethylsilyl cyanide promoted by chiral binuclear complexes of titanium. Dichotomy of C-C versus C-N bond formation
-
In the presence of chiral catalysts derived from the same chiral hexadentate ligand and aluminium, zinc or titanium ions, the reaction between cyclohexene oxide and trimethylsilyl cyanide can be controlled to give predominantly either the nitrile (up to 99% ee) or the isonitrile product (up to 94% ee). The metal ion, ligand stereochemistry and base concentration all play a role in determining the product ratio.
- Belokon, Yuri N.,Chusov, Denis,Peregudov, Alexander S.,Yashkina, Lidia V.,Timofeeva, Galina I.,Maleev, Victor I.,North, Michael,Kagan, Henri B.
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supporting information; experimental part
p. 3157 - 3167
(2010/07/03)
-
- Efficient ring opening of aziridines with carboxylic acids
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An efficient ring cleavage of aziridines with acids has been studied in the absence of any catalyst. The hydrolysis of the products, amino esters, leads to the corresponding amino alcohols. The reaction has been extended to chiral cycloalkyl aziridines, leading to the formation of diastereomers. After separation, these diastereomers have been converted to optically pure amino alcohols in two steps. Copyright Taylor & Francis Group, LLC.
- Kumar, Manoj,Gandhi, Shikha,Kalra, Swinderjeet Singh,Singh, Vinod K.
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p. 1527 - 1532
(2008/09/20)
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- Amine-directed hydroboration: Scope and limitations
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Iodine activation induces intramolecular hydroboration of homoallylic and bis-homoallylic amine boranes with good to excellent control of regiochemistry compared to control experiments using excess THF?BH3. Deuterium labeling and other evidence confirm that the iodine-induced hydroboration reaction of homoallylic amine boranes occurs via an intramolecular mechanism equivalent to the classical 4-center process and without competing retro-hydroboration. Longer carbon chain tethers result in lower regioselectivity, whereas the shorter tether in allylic amines results in a switch to dominant intermolecular hydroboration. Regioselectivity in THF?BH3 control experiments is higher for the allylic amine boranes compared to the iodine activation experiments, whereas the reverse is true for homoallylic amine borane activation.
- Scheideman, Matthew,Wang, Guoqiang,Vedejs, Edwin
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supporting information; experimental part
p. 8669 - 8676
(2009/02/03)
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- Use of enantiomerically pure 7-azabicyclo[2.2.1]heptan-2-ol as a chiral template for the synthesis of aminocyclitols
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(Chemical Equation Presented) Using enantiopure 7-azabicyclo[2.2.1]heptane- 2-ol, the synthesis of cis- as well as trans-2-aminocyclohexanols, dihydroconduramine E-1, and ent-conduramine F-1 has been described.
- Pandey, Ganesh,Tiwari, Keshri Nath,Puranik
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scheme or table
p. 3611 - 3614
(2009/05/07)
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- An efficient reduction protocol for the synthesis of β-hydroxycarbamates from β-nitro alcohols in one pot: a facile synthesis of (-)-β-conhydrine
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An efficient and practical one-pot protocol for the reduction of β-nitro alcohols to their corresponding N-(tert-butoxycarbonyl) amino alcohols using Zn-NH4Cl in aqueous methanol is described. Other reducible groups such as ketones and isolated double bonds remained intact. This methodology allows a short synthesis of (-)-β-conhydrine to be achieved.
- Saikia, Partha Pratim,Baishya, Gakul,Goswami, Abhishek,Barua, Nabin C.
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scheme or table
p. 6508 - 6511
(2009/04/06)
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- Cycloalkanediamine derivatives as novel blood coagulation factor Xa inhibitors
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This paper describes the synthesis of orally available potent fXa inhibitors 2 and 3 by modification of the piperazine part of lead compound 1. Carbonyl derivative 3 showed potent fXa activity but not sulfonyl derivative 2. Among the compounds synthesized, cyclohexane derivatives 3g and 3h and cycloheptane derivative 3j had potent anticoagulant activity as well as anti-fXa activity. Synthetic study of the optical isomers of 3g demonstrated that (-)-3g had more potent activity.
- Nagata, Tsutomu,Yoshino, Toshiharu,Haginoya, Noriyasu,Yoshikawa, Kenji,Isobe, Yumiko,Furugohri, Taketoshi,Kanno, Hideyuki
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p. 4683 - 4688
(2008/02/12)
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- Preparation of enantiopure trans-1,2-cyclohexanediol and trans-2-aminocyclohexanol
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Trans-1,2-cyclohexanediol and trans-2-aminocycloxexanol are useful chiral auxiliaries. Simple chemical resolution procedures for these molecules are presented. Copyright Taylor & Francis Group, LLC.
- Chatterjee,Sasikumar,Joshi
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p. 1727 - 1733
(2008/02/01)
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- Structure-activity studies of cyclic ketone inhibitors of the serine protease plasmin: Design, synthesis, and biological activity
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Three series of cyclic ketone inhibitors were synthesized and evaluated against the serine protease plasmin. Peptide inhibitors that incorporated 3-oxotetrahydrofuran and 3-oxotetrahydrothiophene 1,1-dioxide groups had the highest activities. Alkylamino substituents, which were designed to bind in the S1 subsite of plasmin, were attached to the inhibitors. Compounds 5c and 5g, which incorporated 6-aminohexyl substituents, were found to be optimal and demonstrated IC50 values in the low micromolar range. Incorporating conformationally constrained peptide segments into the inhibitors did not improve their activities.
- Xue, Fengtian,Seto, Christopher T.
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p. 8467 - 8487
(2008/02/05)
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- Resolution of racemic 2-aminocyclohexanol derivatives and their application as ligands in asymmetric catalysis
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A preparatively easy and efficient protocol for the resolution of racemic 2-aminocyclohexanol derivatives is described, delivering both enantiomers with >99% enantiomeric excess (ee) by sequential use of (R)- and (S)-mandelic acid. A simple aqueous workup procedure permits the isolation of the amino alcohols in analytically pure form and the almost quantitative recovery of mandelic acid. Debenzylation of enantiopure trans-2-(N-benzyl)amino-1- cyclohexanol by hydrogenation and subsequent derivatization give access to a broad variety of diversely substituted derivatives. Furthermore, the corresponding cis isomers are readily available. Applications of these optically active aminocyclohexanols in catalyzed asymmetric phenyl transfer reactions to benzaldehydes and transfer hydrogenations of aryl ketones lead to products with up to 96% ee.
- Schiffers, Ingo,Rantanen, Toni,Schmidt, Frank,Bergmans, Werner,Zani, Lorenzo,Bolm, Carsten
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p. 2320 - 2331
(2007/10/03)
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- A General Route to the Synthesis of N-Protected 1-Substituted and 1,2-Disubstituted Taurines
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N-Benzyloxycarbonyl protected α-substituted and αβ- disubstituted taurines were synthesized from olefins and epoxides via N-benzyloxycarbonylamino alcohol thioacetates as key intermediates. They are important sulfur analogues of naturally occurring amino acids and building blocks for the synthesis of α-substituted and α,β- disubstituted β-sulfonopeptides.
- Xu, Jiaxi,Xu, Shu
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p. 276 - 282
(2007/10/03)
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- Folding propensity of cyclohexylether-δ-peptides
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(Chemical Equation Presented) Linear (n = 2-18) and cyclic oligomers (n = 3-8) of a cyclohexylether-δ-amino acid (COA) were prepared in high yield and stereopurity. CD spectra of the linear oligomers were indicative of secondary structure formation. X-ray crystal structures of cyclic COA oligomers revealed hydrophobic packing and internal 5- and 10-membered-ring hydrogen bonds. Ether and amide oxygens reside preferably in an ap orientation. This conformational locking is apparently broken by a C-2 substituent in an asymmetric cyclotrimer, for which a zeolithe-like tubular structure was found.
- Arndt, Hans-Dieter,Ziemer, Burkhard,Koert, Ulrich
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p. 3269 - 3272
(2007/10/03)
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- (1S,2R/1R,2S)-aminocyclohexyl glycyl thymine PNA: Synthesis, monomer crystal structures, and DNA/RNA hybridization studies
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(Matrix Presented) The synthesis of ethyl cis-(1s,2R/1R,2S)-2.aminocyclohex-1-yI-N-(thymin-1-yl-acetyl) glycinate (10a and 10b) via enzymatic resolution of the key racemic intermediate trans-2-azido cyclohexanols 3 is reported. The crystal structures of 10 show equatorial disposition of the tertiary amide group, with the torsion angle β in the range 60-70°. The PNA oligomers incorporating these show differential effects in hybridizing with complementary DNA and RNA.
- Govindaraju,Gonnade, Rajesh G.,Bhadbhade, Mohan M.,Kumar, Vaijayanti A.,Ganesh, Krishna N.
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p. 3013 - 3016
(2007/10/03)
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- Resolution of β-aminoalcohols and 1,2-diamines using fractional crystallization of diastereomeric salts of dehydroabietic acid
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(S)-(+)-1-Amino-3-phenyloxy-2-propanol, (R)-(-)-2-amino-1-phenylethanol, (S)-(+)-1-amino-2-propanol, (1S,2S)-(+)-2-aminocyclohexanol and (1S,2S)-(+)-1,2-diaminocyclohexane were resolved using dehydroabietic acid. It was shown that good to high enantiomeric purity, between 81~>99% ee, was obtained and that dehydroabietic acid could be easily and efficiently recovered in a reusable form.
- Guangyou, Zhang,Yuquing, Liao,Zhaohui, Wang,Nohira, Hiroyuki,Hirose, Takuji
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p. 3297 - 3300
(2007/10/03)
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- Process for preparing 1,2-diamino compounds
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The invention provides a multistep process for preparing 1,2-diamino compounds and pharmaceutically acceptable addition salts thereof from 1,2-epoxides.
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- Application of new chiral auxiliaries, trans-2-(N-arylsulfonyl-N-benzyl)cyclohexanols, in an asymmetric radical cyclization
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New chiral auxiliaries, trans-2-(N-arylsulfonyl-N-benzyl)cyclohexanols, were prepared and applied to an asymmetric radical cyclization. Copyright (C) 2000 Elsevier Science Ltd.
- Nishida, Atsushi,Shirato, Fumie,Nakagawa, Masako
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p. 3789 - 3805
(2007/10/03)
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- Selective N-debenzylation of benzylamino derivatives of 1,6-anhydro-β-D-hexopyranoses
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(matrix presented) When the series of 2-, 3-, and 4-(benzylamino)-2-, 3-, and 4-deoxy derivatives of 1,6-anhydro-β-D-hexopyranoses in the D-gluco, D-lyxo, and D-arabino configurations were reacted with diisopropyl azodicarboxylate, N-benzyl groups were selectively cleaved in the presence of O-benzyl groups. The yields ranged from 51 to 97percent. The debenzylation of some aliphatic benzylamines is also discussed.
- Kroutil, Jiri,Trnka, Tomas,Cerny, Miloslav
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p. 1681 - 1683
(2007/10/03)
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- Cobalt(II) chloride-catalyzed chemoselective sodium borohydride reduction of azides in water
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Reduction of azides to amines and amides was carried out with NaBH4/CoCl2·6H2O in sole water at 25 °C under catalytic heterogeneous conditions. A broad spectrum of azides was reduced in a short time, chemoselectively in high yield and purity.
- Fringuelli, Francesco,Pizzo, Ferdinando,Vaccaro, Luigi
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p. 646 - 650
(2007/10/03)
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- Lipase-catalyzed Kinetic Resolution of (+/-)-trans- and cis-2-Azidocycloalkanols
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The lipase-catalyzed kinetic resolution of trans- and cis-2-azidocycloalkanols and the preparation of enantiomerically pure trans- and cis-2-aminocycloalkanols are described. Four kinds of lipases were screened for the acetylation of trans- and cis-2-azidocycloalkanols. Among them, Pseudomonas sp. lipases (lipase PS and lipase AK, Amamo Pharmaceutical Co.) showed the highest enantioselectivity. These products were converted to the corresponding 2-aminocycloalkanols to determine their enantiomeric excess (ee) and absolute configurations by HPLC and CD analyses, using (S)-TBMB carboxylic acid [(S)-2-tert-butyl-2-methyl-1,3-benzodioxole-4-carboxylic acid] as the chiral conversion reagent. The results of the CD analysis proved N,O-bis-(S)-TBMB carboxylated cis-2-aminocycloalkanols to adopt a predominantly N-equatorial conformation. The partially resolved trans- and cis-2-aminocycloalkanols, except for trans-2-aminocyclopentanol, were recrystallized from ethyl acetate to give enantiomerically pure forms.
- Ami, Ei'ichi,Ohrui, Hiroshi
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p. 2150 - 2156
(2007/10/03)
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- Enzymatic method of preparation of opticallly active trans-2-amino cyclohexanol derivatives
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Supported Lipase Amano PS-D catalyzes the resolution of (±)-trans-2- tert butoxycarbonyl amino cyclohexanol by a selective acylation reaction. Using the supported enzyme gave a much faster reaction compared to existing methodology on similar substrates. A variety of acylating agents were investigated, with vinyl acetate providing the most practical and convenient procedure.
- Ursini,Maragni,Bismara,Tamburini
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p. 1369 - 1377
(2007/10/03)
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- Second generation 'peptoid' CCK-B receptor antagonists: Identification and development of N-(adamantyloxycarbonyl)-α-methyl(R)-tryptophan derivative (CI-1015) with an improved pharmacokinetic profile
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We have previously described the design and development of CI-988, a peptoid analogue of CCK-4 with excellent binding affinity and selectivity for the CCK-B receptor. Due to its anxiolytic profile in animal models of anxiety, this compound was developed as a clinical candidate. However, during its development, it was determined that CI-988 had low bioavailability in both rodent and nonrodent species. In the clinic, it was further established that CI-988 had poor bioavailability. Thus, there was a need to identify an analogue with an improved pharmacokinetic (PK) profile. The poor bioavailability was attributed to poor absorption and efficient hepatic extraction. We envisaged that reducing the molecular weight of the parent compound (5, MW = 614) would lead to better absorption. Thus, we synthesized a series of analogues in which the key α-methyltryptophan and adamantyloxycarbonyl moieties, required for receptor binding, were kept intact and the C-terminus was extensively modified. This SAR study led to the identification of tricyclo[3.3.1.13,7]dec-2-yl [1S-[1α(S*)2β]-[2-[(2- hydroxycyclohexyl)amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2- oxoethyl]carbamate (CI-1015, 31) with binding affinities of 3.0 and 2900 nM for the CCK-B and CCK-A receptors, respectively. The compound showed CCK-B antagonist profile in the rat ventromedial hypothalamus assay with a K(e) of 34 nM. It also showed an anxiolytic like profile orally in a standard anxiety paradigm (X-maze) with a minimum effective dose (MED) of 0.1 μg/kg. Although the compound is less water soluble than CI-988, oral bioavailability in rat was improved nearly 10 times relative to CI-988 when dosed in HPβCD. The blood-brain permeability of CI-1015 (31) was also enhanced relative to CI- 988 (5). On the basis of the overall improved pharmacokinetic profile as well as enhanced brain penetration, CI-1015 (31) was chosen as a development candidate.
- Trivedi, Bharat K.,Padia, Janak K.,Holmes, Ann,Rose, Steven,Wright, D. Scott,Hinton, Joanna P.,Pritchard, Martyn C.,Eden, Jon M.,Kneen, Clare,Webdale, Louise,Suman-Chauhan, Nirmala,Boden, Phil,Singh, Lakhbir,Field, Mark J.,Hill, David
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- Synthesis of 6-amino-3,5-deoxyinositol 1-phosphates via (1R,2R,4R,6S)- 1,6-epoxy-2,4-bis-benzyloxycyclohexane aminolysis in aqueous ytterbium triflate solution
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(1R,2R,4R,6S)-1,6-Epoxy-2,4-bis-benzyloxycyclohexane was prepared from (-)-quinic acid and this, and cyclohexene oxide, were treated with various N- nucleophiles under a variety of conditions. In aqueous solution containing catalytic amounts of ytterbium (III) triflate, ammonia and alkylamines reacted smoothly to give the required trans-1,2-amino alcohols in quantitative recovery. Conversion of the 6-amino-2,4-bis-benzyloxycyclohexan- 1-ols to 6-amino-1,2,4-trihydroxycyclohexane 1-phosphates, probes for the mechanism of inositol monophosphatase, was achieved in good overall yield.
- Beaton, Martin,Gani, David
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p. 8549 - 8552
(2007/10/03)
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- Enzymatic resolution of (±)-trans-2-aminocyclohexanol and (±) trans-2-aminocyclopentanol
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Candida antarctica lipase (CAL) catalyzes the resolution of (±)-trans-2-aminocyclohexanol by alkoxycarbonylation or acylation reactions. Besides, N-benzyloxycarbonyl derivatives of (±)-trans-2-aminocyclohexanol and (±)-trans-2-aminocyclopentanol are efficiently resolved through O-acylation by Pseudomonas cepacia lipase (PSL).
- Maestro, Alicia,Astorga, Covadonga,Gotor, Vicente
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p. 3153 - 3159
(2007/10/03)
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- Synthesis and crystal structure of perhydro-1,4-benzoxazino[2,3-n]phenoxazine
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The oxidation of trans-2-aminocyclohexanol with nitrobenzene in the presence of catalytic amounts of iron inter alia yields perhydro-1,4-benzoxazino[2,3-n]phenoxazine (1). This compound has been characterized analytically, spectroscopically and by X-ray diffraction. It is postulated that the oxidation of the 2-aminoalcohol leads to the intermediate formation of a 1,2-dione. The direct synthesis of 1 from trans-2-aminocyclohexanol and 1,2-cyclohexandione supports this hypothesis.
- Kl?ui, Wolfgang,Schoger, Susanne,Nieger, Martin
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p. 801 - 804
(2007/10/03)
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- Enzymatic Preparation of Enantiomerically Pure (1R,2R)- and (1S,2S)-2-Aminocyclohexanols
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The Pseudomonas cepacia lipase-catalyzed enantioselective hydrolysis of trans-2-(t-butoxycarbonyl)aminocyclohexyl acetate was readily accomplished to provide a practical method for the industrial preparation of enantiomerically pure (1R,2R)- and (1S,2S)-2-aminocyclohexanols.
- Takada, Hironao,Takagi, Seiji,Kawakubo, Hiromu
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p. 1196 - 1197
(2007/10/02)
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