- Kinetic Resolution of Pipecolic Acid Using Partially-Purified Lipase from Aspergillus niger
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Synthesis of biologically active peptides, alkaloids, and immunosuppresants such as FK506 requires enantiomerically-pure pipecolic acid (2-piperidinecarboxylic acid).We report an efficient kinetic resolution of pipecolic acid esters by enzyme-catalyzed hydrolysis.We screened commercially available hydrolases and identified crude lipase from Aspergillus niger (ANL) as the most enantioselective catalyst for the hydrolysis of (+/-)-methyl pipecolate, E=20+/-4 in favor of the (S)-enantiomer at pH 7.Changing of the ester group to n-pentyl or n-octyl did not increase the enantioselectivity, while addition of an N-acetyl group decreased the enantioselectivity.Partial purification of ANL by fractional precipitation with ammonium sulfate (25-45percent saturation) increased the enantioselectivity to >100.A synthetic scale resolution of (+/-)-n-octyl pipecolate using this partially purified ANL gave (S)-(-)-pipecolic acid (93percent ee, 0.89 g) and (R)-(+)-pipecolic acid (97percent ee, 1.20 g).Further purification of ANL confirmed that the lipase (apparent molecular weight of 32 kDa), and not an impurity, was responsible for the enantioselective hydrolysis of octyl pipecolate.
- Ng-Youn-Chen, M. Christine,Serreqi, Alessio N.,Huang, Qingli,Kazlauskas, Romas J.
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- Preparation, characterization and photocatalytic performance of titania particles encapsulated in hollow silica shells as an efficient photocatalyst for redox-combined stereoselective synthesis of l-pipecolinic acid from l-lysine
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Hollow core-shell particles of a titania core and a silica shell, the latter of which was highly porous, water-swollen and not directly connected to the former, were synthesized by a multistep process including carbon and silica coatings followed by calcination of the carbon-layer combustion. The core-shell particles suspended in aqueous solutions of l-lysine showed improved stereoselectivity in photocatalytic redox-combined synthesis of l-pipecolinic acid (l-PCA), maintaining l-lysine conversion and PCA selectivity, compared with that by bare titania particles, presumably due to the acidic microenvironment of the titania core to control the position of oxidation by positive holes as the first step of the redox-combined process. Modification of the silica layers to acidify them was also beneficial for improvement of optical purity of the product, PCA.
- Chandren, Sheela,Ohtani, Bunsho
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- Photocatalytic redox-combined synthesis of L-pipecolinic acid from L-lysine by suspended titania particles: Effect of noble metal loading on the selectivity and optical purity of the product
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Photocatalytic (> 300 nm) conversion of L-(S)-lysine (L-Lys), in its neutralized aqueous solution, into L-pipecolinic acid (L-PCA) under deaerated conditions at 298 K was investigated in detail using suspended TiO2 powders (Degussa P-25, Ishihara ST-01, and HyCOM TiO2) loaded with platinum (Pt), rhodium (Rh), or palladium (Pd). A common feature of the results of experiments using a wide variety of metal-loaded TiO2 photocatalysts is that the rate of PCA formation (rPCA) was greatly reduced when higher optical purity of PCA (OPPCA), i.e., enantio excess of the L-isomer of PCA, was obtained; higher rPCA was achieved by the use of Pt-loaded TiO2 powders, while these powders gave relatively low OPPCA. Selectivity of PCA yield (S PCA), i.e., amount of PCA production based on L-Lys consumption, also tended to increase with decrease in OPPCA, giving a master curve in the plots of OPPCA versus SPCA. Among the TiO2 powders used in this study, HyCOM TiO2 showed relatively high OPPCA and SPCA but not optimum S PCA and OPPCA simultaneously. In order to interpret such relations, the mechanism of stereoselective synthesis of the L-isomer of PCA (L-PCA) was investigated using isotope-labeled α-15N-L-lysine with quantitative analysis of incorporation of 15N in PCA and ammonia (NH3), a by-product. It was observed for several photocatalysts that the 15N proportion (P15) in PCA was almost equal to OPPCA, suggesting that oxidative cleavage by photogenerated positive holes of the ε-amino moiety of L-Lys gave optically pure L-PCA through retention of chirality at the α-carbon in the presumed intermediate, a cyclic Schiff base (α-CSB), which undergoes reduction by photoexcited electrons into PCA. From P15 in NH 3 and PCA, the selectivity of oxidation between α and ε-amino groups in L-Lys by photoexcited positive holes (h+) and the efficiency of reduction of α-CSB (produced via ε-amino group oxidation to give optically pure PCA) and ε-CSB (produced via α-amino group oxidation to give racemic PCA) by photoexcited electrons (e-) were calculated. The former was found to be independent of the kind of photocatalyst, especially the loaded metal, while the latter was influenced markedly only by the loaded metal. It was clarified that OP PCA and SPCA obtained for various TiO2 powders used in the present study were strongly governed by the reduction stage, i.e., the efficiency of reduction of two types of CSB. When SPCA was relatively low, photocatalysts, favoring the reduction of α-CSB rather than ε-CSB, gave higher OPPCA but lower SPCA, since some ε-CSB remained unreduced to give racemic PCA. In contrast, at higher SPCA, both CSBs were reduced nonselectively and OPPCA was found to be determined mainly by the selectivity in the oxidation stage. The relatively low yield of molecular hydrogen (H2) when higher S PCA was achieved is consistent with the mechanism in which H 2 liberation occurs instead of the reduction of CSBs by e -. Thus, the general tendency of plots between OPPCA and SPCA could be explained by the above-described redox-combined mechanism of photocatalysis.
- Pal, Bonamali,Ikeda, Shigeru,Kominami, Hiroshi,Kera, Yoshiya,Ohtani, Bunsho
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- Titanium(IV) oxide photocatalyst of ultra-high activity for selective N-cyclization of an amino acid in aqueous suspensions
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Titanium(IV) oxide (TiO2) powder was prepared by the high-temperature hydrolysis of titanium(IV) tetrabutoxide in toluene as anatase crystallites of average diameter ca. 15nm.They were platinized by impregnation from aqueous chloroplatinic acid solution followed by hydrogen reduction.The catalyst was suspended in an aqueous L-lysine (Lys) solution and photoirradiated under argon at ambient temperature to obtain L-pipecolinic acid (PCA).Among several platinized commercial TiO2 powders, the present TiO2 showed the highest photocatalytic activity for both Lys consumption and PCA production.This result is attributed to both the higher activity owing to the larger surface area with lesser defects and the higher dispersion of platinum deposits acting as an efficient reduction site for a Schiff base intermediate into PCA.
- Ohtani, Bunsho,Iwai, Kunihiro,Kominami, Hiroshi,Matsuura, Takeshi,Kera, Yoshiya,Nishimoto, Sei-ichi
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- Chiral separation of the clinically important compounds fucose and pipecolic acid using ce: Determination of the most effective chiral selector
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In this study, simple electrophoretic methods were developed for the chiral separation of the clinically important compounds fucose and pipecolic acid. In recent years, these analytes, and particularly their individual enantiomers, have attracted considerable attention due to their role in biological functions and disorders. The detectability and sensitivity of pipecolic acid and fucose were improved by reacting them with fluorenylmethyloxycarbonyl chloride (FMOC-Cl) and 5-amino-2-naphthalene-sulfonic acid (ANSA), respectively. The enantioseparation conditions were optimized by initially investigating the type of the chiral selector. Different chiral selectors, such as polymeric surfactants and cyclodextrins, were used and the most effective ones were determined with regard to resolution and analysis time. A 10-mM β-cyclodextrin was able to separate the enantiomers of ANSA-DL-fucose and the polymeric surfactant poly(sodium N-undecanoyl-LL-leucine-valinate) was able to separate the enantiomers of FMOC-DL-pipecolic acid, with resolution values of 3.45 and 2.78, respectively. Additional parameters, such as the concentration and the pH of the background electrolyte (BGE), the concentration of the chiral selector, and the addition of modifiers were examined in order to optimize the separations. The addition of the chiral ionic liquid D-alanine tert-butyl ester lactate into the BGE was also investigated, for the first time, in order to improve resolution of the enantiomers. 2013 Wiley Periodicals, Inc.
- Hadjistasi, Christoforos A.,Stavrou, Ioannis J.,Stefan-Van Staden, Raluca-Ioana,Aboul-Enein, Hassan Y.,Kapnissi-Christodoulou, Constantina P.
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- Convenient Resolution of (+/-)-Piperidine-2-carboxylic Acid ((+/-)-Pipecolic Acid) by Separation of Palladium(II) Diastereomers Containing Orthometallated (S)-(-)-1-naphthalene
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(+/-)-Piperidine-2-carboxylic acid ((+/-)-pipecolic acid) has been resolved by the fractional crystallisation of diastereomeric palladium(II) complexes containing orthometallated (S)-(-)-1-naphthalene.The enantiomers of the acid were liberated from the individual configurationally homogeneous diastereomers of the complex in high yield with D +/- 26.0 (c 1.00, H2O).The crystal and molecular structures of both diastereomers of the complex have been determined.
- Hockless, David C. R.,Mayadunne, Renuka C.,Wild, S. Bruce
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- Cell-free biocatalytic syntheses of l-pipecolic acid: A dual strategy approach and process intensification in flow
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As an alternative to the traditional chemical synthesis or in vivo production of l-pipecolic acid, we have developed two ex vivo strategies using purified and immobilised enzymes for the production of this key building block. Firstly, a transaminase capable of lysine ?-deamination was coupled with a novel pyrroline-5-carboxylate reductase, yielding 60% conversion at the 50 mM scale with free enzymes and in situ recycling of the cofactor. A second, simpler, redox neutral system was then constructed by combining the pyrroline-5-carboxylate reductase with a lysine-6-dehydrogenase. This bienzymatic system, with catalytic amount of free cofactor yielded >99% of pipecolic acid in batch and, following co-immobilisation of both enzymes, it was applied as a packed-bed reactor in continuous flow achieving again a molar conversion of >99% with 30 min residence time, and a space-time yield up to 2.5 g L-1 h-1. The sustainability of the system was further improved by a catch-and-release strategy to purify the product, and recovery and recycling of the cofactor.
- Benítez-Mateos, Ana I.,Calvey, Liam,Paradisi, Francesca,Roura Padrosa, David
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supporting information
p. 5310 - 5316
(2020/09/17)
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- Polymer-supported (-)-8-phenylmenthyl auxiliary as an effective solidphase chiral inductor in the addition of nucleophiles to N-acyliminium Ions
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Aim and Objective: According to our interest in developing new methods for the construction of intricate molecules, a reliable polymer-supported (-)-8-phenylmenthyl chiral auxiliary for the addition of different nucleophiles to chiral-supported N-acyliminium precursors were developed. Material- and Method-: Merrifield resin was employed to anchor (-)-8-phenylmenthol, which was prepared by nitration of (-)-8-phenylmenthyl chloroacetate followed by reduction of nitro group and subsequent Merrifield resin coupling. Treatment of a suspension of polymer-supported chloroformate and piperidinone in the presence of Et3N resulted in attachment of the substrate onto the solid-support. Treatment of the resulting resin with LiEt3BH/MeOH afforded methoxypiperidine in 87% yield. Then, the addition of allyltrimethylsilane, TMSCN, 2-(trimethylsiloxy)propene and triisopropylsilyloxyfuran and others to the N-acyliminium ion derived from chiral 2-methoxypiperidine carbamate was studied. Results: The stereochemical outcome of the addition of nucleophiles to the supported N-acyliminium ion derived from 2-methoxypiperidine carbamate was proposed through the Si-face, affording after resin cleavage 2-substituted piperidines in 70%-84% yields and selectivities ranging from 4:1-11.1. Moreover, the key intermediates of chiral piperidines have been employed for the synthesis of simple chiral alkaloids such as (R)-pipecolic acid, (R)-pelletierine, (S)-coniine and (R,R)-myrtine. Conclusion: The proposed supported-chiral auxiliary for asymmetric approach may be expected to result not only in efficient solid-phase syntheses of a wide range of alkaloids but also in the development of useful new solid-phase methodologies, particularly for the asymmetric additions to iminium precursors. This work describes the first example of solid-phase synthesis by using supported (-)-8-phenylmenthyl as an effective chiral inductor and would be useful for the synthesis of chiral building block libraries.
- Forero-Doria, Oscar,Santos, Leonardo S.,Nachtigall, Fabiane M.,Shankaraiah, Nagula
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p. 696 - 702
(2018/02/27)
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- Enantioselective syntheses of (R)-pipecolic acid, (2R,3R)-3-hydroxypipecolic acid, β-(+)-conhydrine and (-)-swainsonine using an aziridine derived common chiral synthon
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Concise total syntheses of (R)-pipecolic acid, (R)-ethyl-6-oxopipecolate, (2R,3R)-3-hydroxypipecolic acid and formal syntheses of β-(+)-conhydrine, (-)-lentiginosine, (-)-swainsonine and 1,2-di-epi-swainsonine have been accomplished starting from a common chiral synthon. The present strategy employs regioselective aziridine ring opening, Wittig olefination and RCM as the key chemical transformations.
- Chavan, Subhash P.,Khairnar, Lalit B.,Pawar, Kailash P.,Chavan, Prakash N.,Kawale, Sanket A.
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p. 50580 - 50590
(2015/06/25)
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- Asymmetric synthesis of d -proline, d -pipecolic acid, (2 R,3 S,4 R)-3,4-dihydroxyproline, and 1,4-Dideoxy-1,4-imino- d -talitol from a Common Precursor
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Methodology involving stereoselective aza-Michael addition and ring-closing metathesis as key steps has been developed for the preparation of (2R)-pipecolic acid, (2R)-proline, (2R,3S,4R)-3,4-dihydroxyproline, and the known glycosidase inhibiting azasugar 1,4-dideoxy-1,4-imino-d-talitol from a common starting material namely (R)-cyclohexylideneglyceraldehyde in good overall yields. Georg Thieme Verlag Stuttgart New York.
- Chattopadhyay, Shital K.,Mukherjee, Jyoti Prasad
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p. 2481 - 2488
(2014/10/15)
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- Asymmetric Synthesis of d -Proline, d -Pipecolic Acid, (2 R,3 S,4 R)-3,4-Dihydroxyproline, and 1,4-Dideoxy-1,4-imino- d -talitol from a Common Precursor
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Methodology involving stereoselective aza-Michael addition and ring-closing metathesis as key steps has been developed for the preparation of (2R)-pipecolic acid, (2R)-proline, (2R,3S,4R)-3,4-dihydroxyproline, and the known glycosidase inhibiting azasugar 1,4-dideoxy-1,4-imino-d-talitol from a common starting material namely (R)-cyclohexylideneglyceraldehyde in good overall yields.
- Chattopadhyay, Shital K.,Mukherjee, Jyoti Prasad
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p. 2481 - 2488
(2015/12/26)
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- A short enantioselective total synthesis of (R)- and (S)-pipecolic acid
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A convenient and practical total synthesis of (R)- and (S)-pipecolic acid has been achieved by utilizing chiral cis-aziridine-2-carboxylate as the common synthetic precursor. The synthesis involves regioselective reductive cleavage of the aziridine ring and Wittig olefination as key reactions.
- Chavan, Subhash P.,Khairnar, Lalit B.,Chavan, Prakash N.,Kalbhor, Dinesh B.
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p. 1246 - 1251
(2015/02/19)
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- Total synthesis of sandramycin and its analogues via a multicomponent assemblage
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The total synthesis of sandramycin has been accomplished by using a Staudinger/aza-Wittig/diastereoselective Ugi three-component reaction sequence as a key step to obtain a linear pentadepsipeptide. Subsequent [5 + 5] coupling of the penptapeptide, macrolactamization, and introduction of the quinaldin chromophores afforded sandramycin. Dihydroxy and diacetoxy analogues were also prepared, and the cytotoxic activity of these analogues against a range of human cancer cell lines was evaluated.
- Katayama, Katsushi,Nakagawa, Koji,Takeda, Hiroshi,Matsuda, Akira,Ichikawa, Satoshi
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supporting information
p. 428 - 431
(2014/04/03)
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- Synthetic cascades are enabled by combining biocatalysts with artificial metalloenzymes
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Enzymatic catalysis and homogeneous catalysis offer complementary means to address synthetic challenges, both in chemistry and in biology. Despite its attractiveness, the implementation of concurrent cascade reactions that combine an organometallic catalyst with an enzyme has proven challenging because of the mutual inactivation of both catalysts. To address this, we show that incorporation of a d 6 -piano stool complex within a host protein affords an artificial transfer hydrogenase (ATHase) that is fully compatible with and complementary to natural enzymes, thus enabling efficient concurrent tandem catalysis. To illustrate the generality of the approach, the ATHase was combined with various NADH-, FAD- and haem-dependent enzymes, resulting in orthogonal redox cascades. Up to three enzymes were integrated in the cascade and combined with the ATHase with a view to achieving (i) a double stereoselective amine deracemization, (ii) a horseradish peroxidase-coupled readout of the transfer hydrogenase activity towards its genetic optimization, (iii) the formation of L-pipecolic acid from L-lysine and (iv) regeneration of NADH to promote a monooxygenase-catalysed oxyfunctionalization reaction.
- Koehler,Wilson,Duerrenberger,Ghislieri,Churakova,Quinto,Knoerr,Haeussinger,Hollmann,Turner,Ward
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- Structure elucidation and antimalarial activity of apicidin F: An apicidin-like compound produced by Fusarium fujikuroi
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Apicidins are cyclic tetrapeptides with histone deacetylase inhibitory activity. Since their discovery in 1996 a multitude of studies concerning the activity against protozoa and certain cancer cell lines of natural and synthetic apicidin analogues have been published. Until now, the only published natural sources of apicidin are the fungus Fusarium pallidoroseum, later known as F. semitectum and two unspecified Fusarium strains. The biosynthetic origin of apicidins could be associated with a gene cluster, and a biosynthetic pathway has been proposed. Recently, our group was able to identify for the first time an apicidin-like gene cluster in F. fujikuroi that apparently does not lead to the production of any known apicidin analogue. By overexpressing the pathway-specific transcription factor we were able to identify a new apicidin-like compound. The present study provides the complete structure elucidation of the new compound, named apicidin F. Activity evaluation against Plasmodium falciparum showed good in vitro activity with an IC50 value of 0.67 μM.
- Von Bargen, Katharina Walburga,Niehaus, Eva-Maria,Bergander, Klaus,Brun, Reto,Tudzynski, Bettina,Humpf, Hans-Ulrich
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p. 2136 - 2140
(2014/01/06)
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- Total synthesis of (+)-antofine and (-)-cryptopleurine
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The tylophorine alkaloid anticancer compounds antofine and cryptopleurine have been synthesized in optically active form. Both syntheses use optically pure α-amino acids as the starting materials, require only seven steps from known 2-ethynylpyrrolidine or 2-ethynylpiperidine derivatives, and are free of protecting groups. The key steps include an alkyne hydration and a chromium-carbene-complex-based net [5 + 5]-cycloaddition step. The alkyne hydration was accompanied by racemization of the β-amino ketone product under most of the conditions examined, and minimization of this side-reaction was achieved through careful pH control and choice of metal additive. The final ring closure involved a Bischler-Napieralski reaction using a carbamate (antofine) or urea (cryptopleurine) precursor. Single enantiomers of the tylophorine alkaloids antofine and cryptopleurine have been prepared by using a short synthesis that involves regioselective alkyne hydration of a chiral propargylic amide, Fischer carbene complex mediated net [5+5] cycloaddition, and urea-based Friedel-Crafts acylation as key steps. Copyright
- Ying, Weijiang,Herndon, James W.
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p. 3112 - 3122
(2013/06/26)
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- Enantioselective allylation of imines catalyzed by newly developed (-)-β-pinene-based π-allylpalladium catalyst: An efficient synthesis of (R)-α-propylpiperonylamine and (R)-pipecolic acid
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A newly developed π-allylpalladium with a (-)-β-pinene framework and an isobutyl side chain catalyzed the enantioselective allylation of imines in good yields and enantioselectivities (20 examples, up to 98% ee). An efficient enantioselective synthesis of the (R)-α-propyl piperonylamine part of DMP 777, a human leukocyte elastase inhibitor and (R)-pipecolic acid have been achieved as a useful application of this methodology. The Royal Society of Chemistry 2012.
- Fernandes, Rodney A.,Nallasivam, Jothi L.
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p. 7789 - 7800
(2013/04/23)
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- (R)-α-aminoadipic acid: An interesting chiral pool building block
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(R)-α-Aminoadipic acid is available on a large scale by enzymatic cleavage from cephalosporin C (CephC) in the production of 7- aminocephalosporanic acid (7-ACA). It can be converted into other interesting enantiomerically pure compounds, e.g. derivatives of (R)-pipecolic acid (Rpiperidine 2-carboxylic acid), (R)-6-oxopiperidine-2-carboxylic acid, (R)-1,2,3,4-tetrahydropyridine 2(2H)-carboxylates, and other compounds obtained by further conversions of these products. ARKAT-USA, Inc.
- Sadiq, Amina,Sewald, Norbert
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experimental part
p. 28 - 36
(2012/03/08)
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- Chiral imprinting with amino acids of ordered mesoporous silica exhibiting enantioselectivity after calcination
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Chiral ordered mesoporous silica (COMS) was synthesized in basic media by combining tetraethyl orthosilicate and quaternized aminosilane (with a templating role) silica sources together with four different standard amino acids (arginine, histidine, isoleucine, and proline). Besides the hexagonal MCM-41-type structure, narrow pore size distribution, and high specific surface area, it was found that these solids have potential for enantiomeric separation because of the transference of chirality from the amino acid to the silica. This is illustrated by the resolution of several racemic mixtures (those of proline, isoleucine, trans-4-hydroxyproline, pipecolic acid, valine, leucine, and phenylglycine) with the calcined COMS prepared with l-proline. The opposite behavior observed in induced circular dichroism experiments with calcined COMS, obtained using both enantiomers of proline, confirmed their chiral nature. The high number and variety of existing amino acids, and chiral organic compounds in general, makes these ordered silicas attractive for the production of enantiopure substances.(Figure Presented)
- Lacasta, Susana,Sebastian, Victor,Casado, Clara,Mayoral, Alvaro,Romero, Pilar,Larrea, Angel,Vispe, Eugenio,Lopez-Ram-De-Viu, Pilar,Uriel, Santiago,Coronas, Joaquin
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scheme or table
p. 1280 - 1287
(2012/02/15)
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- METHOD OF PRODUCING OPTICALLY ACTIVE AMINO ACID DERIVATIVE
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The present application relates to a method for producing an optically active α-amino acid derivative, comprising steps of reacting an α-haloester derivative represented by the general formula (1): of which alcohol part of the ester group is an optically active alcohol derivative, with an amine compound; then deprotecting the obtained compound; further carrying out an ester exchange reaction. According to the present invention method, it is possible to easily produce an optically active α-amino acid ester derivative which is useful as an intermediate for drugs with high selectivity.
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Page/Page column 12-13
(2011/04/18)
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- Synthesis of non-natural cyclic amino acids from available unsaturated tertiary amines
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New approach is developed to the synthesis of cyclic amino acids derivatives. Unsaturated tertiary amines react with ethyl diazoacetate under the catalysis by copper catalyst Cu(F3acac)2 leading to the formation of products of [2,3]-sigmatropic rearrangement which via the metathesis of double bonds undergo a ring closure. The subsequent hydrogenation of compounds obtained furnished esters of 6- and 7-membered cyclic α-amino acids. Besides the racemic also optically active compounds were obtained, in particular, esters of (R)- and (S)-pipecolic acid.
- Titanyuk,Beletskaya
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experimental part
p. 1277 - 1281
(2010/12/19)
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- Efficient syntheses of enantioenriched (R)-pipecolic acid and (R)-proline via electrophilic organocatalytic amination
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Five-step syntheses of (R)-pipecolic acid and (R)-proline are described, respectively, from cyclohexene and cyclopentene. The key step involves the organocatalytic α-amination of functionalized aldehydes.
- Kalch, Delphine,Rycke, Nicolas De,Moreau, Xavier,Greck, Christine
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body text
p. 492 - 494
(2009/05/07)
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- Enantioselective total syntheses of ropivacaine and its analogues
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An alternative asymmetric synthesis of ropivacaine and analogues employing the 'cation pool' strategy and host/guest supramolecular co-catalysis approach is presented. In this study, chiral auxiliaries, several soft nucleophiles as well as one-pot conditions for anodic oxidation, followed by nucleophilic addition, have been applied.
- Shankaraiah, Nagula,Pilli, Ronaldo Aloise,Santos, Leonardo S.
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p. 5098 - 5100
(2008/12/21)
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- An efficient synthesis of enantiomerically pure (R)-pipecolic acid, (S)-proline, and their N-alkylated derivatives
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Enantiomerically pure (R)-(+)-pipecolic acid was synthesized in four steps and 42% overall yield starting from dihydropyran and (R)-α- methylbenzylamine. A general short strategy is also described for preparing (S)-proline (47.5% overall yield) and derivatives.
- Fadel, Antoine,Lahrache, Nabil
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p. 1780 - 1784
(2007/10/03)
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- An efficient access to both enantiomers of pipecolic acid
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An efficient and convenient synthesis of both enantiomers of pipecolic acid has been developed using the intramolecular cyclization of 2-amino-6- bromohexanoic acid under mild conditions.
- Watanabe, Louis A.,Haranaka, Saori,Jose, Binoy,Yoshida, Minoru,Kato, Tamaki,Moriguchi, Mitsuaki,Soda, Kenji,Nishino, Norikazu
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p. 903 - 908
(2007/10/03)
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- EP4 receptor agonist, compositions and methods thereof
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This invention relates to potent selective agonists of the EP4 subtype of prostaglandin E2 receptors, their use or a formulation thereof in the treatment of glaucoma and other conditions, which are related to elevated intraocular pressure in the eye of a patient. This invention further relates to the use of the compounds of this invention for mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts.
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Page/Page column 10
(2010/02/14)
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- An efficient, asymmetric synthesis of pipecolic acid and 2-alkyl pipecolic acids
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Both (R)- and (S)-pipecolic acids and their 2-alkyl derivatives have been synthesized via diastereoselective alkylations of (R)-5-phenylmorpholin-2-one 5.
- Hou, Duen-Ren,Hung, Shin-Yi,Hu, Chung-Cheng
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p. 3858 - 3864
(2007/10/03)
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- EP4 receptor agonist, compositions and methods thereof
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This invention relates to potent selective agonists of the EP4 subtype of prostaglandin E2 receptors, their use or a formulation thereof in the treatment of glaucoma and other conditions, which are related to elevated intraocular pressure in the eye of a patient. This invention further relates to the use of the compounds of this invention for mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts.
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Page/Page column 10
(2010/02/08)
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- Enantioselective synthesis of (2R,4S)- and (2S,4R)-4-hydroxypipecolic acid from D-glucoheptono-1,4-lactone
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Enantiomerically pure (2R,4S)-4-hydroxypipecolic acid [(+)-1] was synthesized from D-glucoheptono-1,4-lactone (2) via the 3,5-dideoxy-D-xylo- heptono-1,4-lactone (7). The latter was readily prepared by benzoylation of 2, followed by β-elimination and diastereoselective hydrogenation of the resulting furanones (4). Compound 7 was converted into the 6,7-O- cyclohexylidene derivative 11, which on treatment with tosyl chloride for long periods afforded the 2-chloro derivative 14, the precursor of the azide 15. Hydrogenolysis of 15 and protection of the amine gave the N- benzyloxycarbonyl derivative 19, having the required configuration for the stereocenters at C-2 and C-4. Removal of the cyclohexylidene group by hydrolysis and subsequent oxidative degradation of the resulting glycol system afforded the hexurono-6,3-lactone 21 as a key intermediate. Chemoselective reduction of the aldehyde function of 21 led to the alcohol 23, which was derivatized as the mesylate 24. Releasing of the amino group by hydrogenation, and dissolution of resulting 25 in aqueous alkali, promoted the intramolecular nucleophilic displacement of the mesylate to give (+)-1. Its enantiomer [(-)-1] was prepared by a similar sequence starting from 2.
- Di Nardo, Christian,Varela, Oscar
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p. 6119 - 6125
(2007/10/03)
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- Synthesis of 2-piperidinecarboxylic acid derivatives as potential anticonvulsants
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A variety of 2-piperidinecarboxamides were synthesized and evaluated for anticonvulsant activity using the MES and sc PTZ tests in mice and rats. Neurotoxicity was determined by the rotorod test. Several N-(benzyl)-2- piperidinecarboxamides exhibited potent MES activity in mice [2-CF3 14, ED50 = 29 mg/kg; 3-F 16, ED50 = 31 mg/kg; and 3-CF3 17, ED50 = 24 mg/kg]. The most active compounds in the MES test in mice were the 2,6- dimethylanilides [(R,S)-34, ED50 = 5.8 mg/kg; (R)-35, ED50 = 5.7 mg/kg; and (S)-36, ED50 = 14.8 mg/kg]. The enantiomer (S)-36 was about two-fold less potent in the MES test than (R)-35 and also was less neurotoxic. Acylation of the piperidine ring nitrogen of 12 anal 34 led to a decrease in the MES activity. In the N-(α-methylbenzyl)-2-piperidine-carboxamides, the stereochemistry at either the 2-position of the piperidine ring or at the α- position of the N-(α-methylbenzyl) group does not significantly affect MES activity.
- Ho, Bin,Venkatarangan, Prabha M.,Cruse, Sharon F.,Hinko, Christine N.,Andersen, Peter H.,Crider, Albert M.,Adloo, Ahmad A.,Roane, David S.,Stables, James P.
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- Asymmetric Transformations of Proline and 2-Piperidinecarboxylic Acid via Formation of Salts with Optically Active Tartaric Acid
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The rates of racemization of optically active proline and 2-piperidinecarboxylic acid by using aldehydes as a catalyst tended to increase with a decrease in the acidity of the carboxylic acid used as solvent.Based on these results, the asymmetric transformations of DL-Pro and (RS)-Pia were carried out via formation of salts with (2R,3R)-tartaric acid to give optically pure L-Pro in over 80percent yield and (R)-Pia in 70percent yield.The asymmetric transformation of L-Pro was more successfully achieved by using (2S,3S)-tartaric acid to give optically pure D-Pro in 85percent yield based on the starting L-Pro.
- Shiraiwa, Tadashi,Shinjo, Kazuyuki,Kurokawa, Hidemoto
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p. 3251 - 3255
(2007/10/02)
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- ENANTIOSELECTIVE REDUCTIONS OF KETONES WITH OXAZABOROLIDINES DERIVED FROM (R) AND (S)-α,α-DIPHENYL-2-PIPERIDINE METHANOL
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Oxazaborolidnes obtained from (R) and (S)-α,α-diphenyl-2-piperidine methanol have been used as catalysts in the enantioselective reductions of ketones with borane.
- Rao, A. V. Rama,Gurjar, M. K.,Sharma, P. A.,Kaiwar, Vijay
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p. 2341 - 2344
(2007/10/02)
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- Photocatalytic One-Step Syntheses of Cyclic Imino Acids by Aqueous Semiconductor Suspensions
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Optically active cyclic imino acids, pipecolinic acid and proline, are readily obtained from α,ω-diamino carboxylic acids and their Nω-substituted derivatives by the photoirradiation of aqueous suspensions of TiO2 or CdS loaded with platinum oxides under Ar at room temperature.
- Ohtani, Bunsho,Tsuru, Shigeto,Nishimoto, Sei-ichi,Kagiya, Tsutomu
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p. 5551 - 5553
(2007/10/02)
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- Simultaneous Production of D-Pipecolic Acid and L-α-Aminoadipic Acid from DL-Pipecolic Acid Using a Microorganism
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The production of D-pipecolic acid from DL-pipecolic acid using a microbe was investigated.Some bacteria which assimilated L-pipecolic acid in preference to D-pipecolic acid and accumulated L-α-aminoadipic acid extracellularly when cultivated on DL-pipecolic acid were isolated.When one of these bacteria, which was designated as Alcaligenes sp. 309B1, was cultivated on a medium containing 5percent of DL-pipecolic acid, it assimilated all of the L-pipecolic acid, with most of the D-pipecolic acid not being assimilated.Ninety-five percent of the D-pipecolic acid remained after the complete disappearance of L-pipecolic acid from the culture broth.The amount of L-α-aminoadipic acid accumulated in the broth reached 56percent of the total quantity of L-pipecolic acid.
- Mochizuki, Kazuya,Yamazaki, Yoshimitsu,Maeda, Hidekatsu
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p. 1113 - 1116
(2007/10/02)
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- RESOLUTION AND USE IN α-AMINO ACID SYNTHESIS OF IMIDAZOLIDINONE GLYCINE DERIVATIVES
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The imidazolidinones (rac.-1 and rac.-2) obtained from pivalaldehyde and glycine amides are resolved efficiently by crystallization of diastereomeric ammonium salts with chiral acids (mandelates and a gulonate respectively).The free bases are acylated under Schotten-Baumann conditions to give enantiomerically pure 1-Bz-, 1-BOC-, 1-Z- or 1-formyl-2-t-butyl-3-methyl- or -3-benzyl-4-imidazolidinones.Diastereoselective alkylation of the 3-methyl derivatives (BMI) with a variety of electrophiles (LDA/THF -70 to +25 degC) gives trans-disubstituted imidazolidinones exclusively (3-22).Some of these are hydrolyzed by a procedure employing excess acidic ion exchange resin to give enantiomerically pure (R)- or (S)-amino acids.The procedure is compared with other methods of generating chiral glycine enolates.
- Fitzi, Robert,Seebach, Dieter
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p. 5277 - 5292
(2007/10/02)
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- An Asymmetric Synthesis of 2-Substituted Piperidines through Ozonolysis of Cyclopentenes and Reductive Aminocyclization
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By the action of ozone, sodium cyanoborohydride and the optically active benzylic amines 2, the 1-substituted cyclopentenes 1, 5 and 9 were converted to a diastereometric mixture of 1,2-disubstituted piperidines (3, 6 and 10), respectively.Hydrogenation of these compounds and the following work-up yielded optically active 2-alkylpiperidines (4, up to 68percente.e.), pipecolic acid (7, 84percent e.e.) and 2-(hydroxymethyl)piperidine (11, up to 85percente.e.).Chromatographic separation of the major isomers of 3b and 6 enabled optically pure coniine (4b) and pipecolic acid (7) to be prepared, respectively.
- Kawaguchi, Mamoru,Hayashi, Osamu,Sakai, Noriyuki,Hamada, Masayuki,Yamamoto, Yukio,Oda, Jun'ichi
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p. 3107 - 3112
(2007/10/02)
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- Hydrolysis of Active Esters of Aliphatic Carboxylic Acids with Cyclic Dipeptide Catalysts Consisting of L-Histidine and Different Aliphatic α-Amino Acids
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The hydrolyses of a series of p-nitrophenyl carboxylates with different acyl chains were investigated at 25 deg C, pH 7.8 using cyclic dipeptides as catalyst.Consequently, cyclo(-D-Leu-L-His) and cyclo(-D-Val-L-His-) were found to be specifically effective catalyst for the hydrolysis of p-nitrophenyl laurate.These trans (D-L-type) cyclic dipeptides were much more efficient catalysts than their diastereoisomers, and were more reactive than imidazole, despite the fact that the former are less basic than latter.The conformation of the cyclic peptides in solution was investigated using proton magnetic spectroscopy and the relationship between conformation and catalytic activity was investigated.Consequently, it was found that the hydrophobic interaction between a catalyst and a substrate and the stereochemical fit for the cooperation of functional groups in the intramolecular nucleophilic catalysis are very important in order to attain a highly efficient catalysis.It was also found that the functional groups should have a certain size and flexibility in order to realize an effective stereochemical fit between functional groups of catalysts and substrates.
- Masuda, Yoshihiko,Tanihara, Masao,Imanishi, Yukio,Higashimura, Toshinobu
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p. 497 - 504
(2007/10/02)
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