- Preparation and reaction of titania particles encapsulated in hollow silica shells as an efficient photocatalyst for stereoselective synthesis of pipecolinic acid
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Hollow coreshell particles of titania core and silica shell were synthesized by multistep process, and the coreshell particles showed improved stereoselectivity in the photocatalytic redox-combined synthesis of L-pipecolinic acid from L-lysine in an aqueous suspension without reducing the original activity of the bare titania core.
- Chandren, Sheela,Ohtani, Bunsho
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Read Online
- Enzymatic synthesis of L-pipecolic acid by Δ1-piperideine- 2-carboxylate reductase from Pseudomonas putida
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L-Pipecolic acid is a chiral pharmaceutical intermediate. An enzymatic system for the synthesis of L-pipecolic acid from L-lysine by commercial L-lysine α-oxidase from Trichoderma viride and an extract of recombinant Escherichia coli cells coexpressing Δ1-piperideine-2- carboxylate reductase from Pseudomonas putida and glucose dehydrogenase from Bacillus subtilis is described. A laboratory-scale process provided 27 g/l of L-pipecolic acid in 99.7% e.e.
- Muramatsu, Hisashi,Mihara, Hisaaki,Yasuda, Mari,Ueda, Makoto,Kurihara, Tatsuo,Esaki, Nobuyoshi
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- Biotransformation of L-lysine to L-pipecolic acid catalyzed by L-lysine 6-aminotransferase and pyrroline-5-carboxylate reductase
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The enzyme involved in the reduction of Δ1-piperideine-6- carboxylate (P6C) to L-pipecolic acid (L-PA) has never been identified. We found that Escherichia coli JM109 transformed with the lat gene encoding L-lysine 6-aminotransferase (LAT) converted L-lysine (L-Lys) to L-PA. This suggested that there is a gene encoding "P6C reductase" that catalyzes the reduction of P6C to L-PA in the genome of E. coli. The complementation experiment of proC32 in E. coli RK4904 for L-PA production clearly shows that the expression of both lat and proC is essential for the biotransformation of L-Lys to L-PA. Further, We showed that both LAT and pyrroline-5-carboxylate (P5C) reductase, the product of proC, were needed to convert L-Lys to L-PA in vitro. These results demonstrate that P5C reductase catalyzes the reduction of P6C to L-PA. Biotransformation of L-Lys to L-PA using lat-expressing E. coli BL21 was done and L-PA was accumulated in the medium to reach at an amount of 3.9 g/l after 159 h of cultivation. It is noteworthy that the ee-value of the produced pipecolic acid was 100%.
- Fujii, Tadashi,Mukaihara, Manabu,Agematu, Hitosi,Tsunekawa, Hiroshi
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Read Online
- Preparation method of caine drug intermediate (S)-2-piperidinecarboxylic acid
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The invention discloses a preparation method of a caine drug intermediate (S)-2-piperidinecarboxylic acid. The preparation method specifically comprises the following steps of a) carrying out a one-pot reaction on 5-chlorovaleraldehyde, L-phenylglycinol and trimethylsilyl cyanide under the action of a catalyst A to obtain a compound as shown in a formula (I), wherein the catalyst A is magnesium diiodide, magnesium dibromide and magnesium perchlorate, (b) carrying out catalytic hydrogenation reaction on the compound as shown in the formula (I) to obtain (S)-2-cyano piperidine as shown in a formula (II), and (c) hydrolyzing the compound as shown in the formula (II) to obtain (S)-2-piperidinecarboxylic acid as shown in a formula (III). The preparation method utilizes cheap and easily available organic raw materials, and has the advantages of simple operation, mild reaction conditions, good stereoselectivity, high yield and the like.
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- Preparation method of bupivacaine and intermediate (S)-2-piperidinecarboxylic acid thereof
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The invention discloses bupivacaine and a preparation method of an intermediate (S)-2-piperidinecarboxylic acid of the bupivacaine; wherein the intermediate (S)-2-piperidinecarboxylic acid is prepared by taking (R)-4-benzyl-2-oxazolidinone as a chiral auxiliary agent through amidation, asymmetric alkylation, hydrolysis, cyclization and auxiliary group removal; wherein the prepared (S)-2-piperidinecarboxylic acid is used as a raw material to prepare the local anesthetic (S)-bupivacaine. The method utilizes cheap and easily available organic raw materials, and has the advantages of simple operation, mild reaction conditions, good stereoselectivity, high yield and the like.
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Paragraph 0021; 0067-0071
(2021/06/13)
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- A convenient and highly enantioselective synthesis of (S)-2-pipecolic acid: an efficient access to caine anesthetics
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A novel and enantioselective synthesis of (S)-2-pipecolic acid (5) has been achieved from Oppolzer’s sultam (1) and ethyl N-(diphenylmethylene)glycinate (2) as readily available starting materials. The highly stereoselective alkylation of chiral glycine intermediate (3) with 1,4-dibromobutane afforded the key backbone of (S)-2-pipecolic acid (5) in one-step that was utilized into the preparation of the local anesthetics mepivacaine, ropivacaine and bupivacaine.
- Yang, Yuyan,Li, Hua,You, Zhonglin,Zhang, Xingxian
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p. 3084 - 3089
(2021/08/12)
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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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p. 5310 - 5316
(2020/09/17)
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- Preparation method of (S)-2-piperidinecarboxylic acid
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A preparation method of (S)-2-piperidinecarboxylic acid comprises the following steps: under the catalysis of Lewis acid, carrying out condensation reaction on L-camphor sulfonamide (I) and diphenyl imine ester (II) to generate a compound (III); enabling the compound (III) and the compound (IV) to be subjected to asymmetric alkylation under the action of strong base, imine hydrolysis under an acidic condition and intramolecular cyclization by a one-pot method to obtain a compound (V); and removing a chiral auxiliary group from the compound (V) under an alkaline condition to obtain a target compound (S)-2-piperidinecarboxylic acid (TM), wherein the formulas (I), (II), (III), (IV) and (V) are described in the specification. The target product can be obtained through three steps in total, themethod has the advantages of cheap and easily available raw materials, short route, high yield, good stereoselectivity and the like, and the (S)-2-piperidinecarboxylic acid is an important chiral intermediate of multiple medicines at present and has a good market prospect.
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Paragraph 0111-0120
(2020/12/09)
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- Furan-Derived Chiral Bicycloaziridino Lactone Synthon: Collective Syntheses of Oseltamivir Phosphate (Tamiflu), (S)-Pipecolic acid and its 3-Hydroxy Derivatives
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A unified synthetic strategy for oseltamivir phosphate (tamiflu), (S)-pipecolic acid, and its 3-hydroxy derivatives from furan derived common chiral bicycloaziridino lactone synthon is described here. Key features are the short (4-steps), enantiopure, and decagram-scale synthesis of common chiral synthon from furan and its first-ever application in the total synthesis of biologically active compounds by taking the advantages of high functionalization ability of chiral synthon.
- Chavan, Subhash P.,Gonnade, Rajesh G.,Kadam, Appasaheb L.,Shinde, Shrikrishna S.
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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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- New cytotoxic callipeltins from the Solomon Island marine sponge Asteropus sp.
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Four new callipeltin A derivatives (N–Q) have been isolated from the Solomon Island marine sponge Asteropus sp. Their structures were established by spectroscopic techniques followed by acid hydrolysis and derivatisation of the free amino acids, and subsequent LCMS analysis of the derivatives. The compounds were evaluated for their activity against cancer cell lines A2058 (melanoma), HT-29 (colorectal adenocarcinoma) and MCF-7 (breast adenocarcinoma) and non-malignant MRC-5 fibroblast cells. While the acyclic callipeltins P and Q were inactive the cyclic callipeltins N and O showed significant cytotoxicity against all exposed cell lines with IC50values as low as 0.16?μM confirming the role of cyclic configuration in biological activity.
- Stierhof, Marc,Hansen, Kine ?stnes,Sharma, Mukesh,Feussner, Klaus,Subko, Karolina,Díaz-Rullo, Fernando Fernández,Isaksson, Johan,Pérez-Victoria, Ignacio,Clarke, David,Hansen, Espen,Jaspars, Marcel,Tabudravu, Jioji N.
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p. 6929 - 6934
(2016/10/14)
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- Ulleungamides A and B, Modified α,β-Dehydropipecolic Acid Containing Cyclic Depsipeptides from Streptomyces sp. KCB13F003
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Two novel cyclic depsipeptides, ulleungamides A (1) and B (2), were isolated from cultures of terrestrial Streptomyces sp. Their structures were determined by analyses of spectroscopic data and various chemical transformations, including modified Mosher's method, advanced Marfey's method, PGME, GITC derivatizations, and Snatzke's method. Ulleungamides were determined to be a new class of peptides bearing unprecedented units, such as 5-hydroxy-6-methyl-2,3-dehydropipecolic acid, 4,5-dihydroxy-6-methyl-2,3-dehydropipecolic acid, and amino-linked 2-isopropylsuccinic acid. Ulleungamide A displayed growth inhibitory activity against Staphylococcus aureus and Salmonella typhimurium without cytotoxicity.
- Son, Sangkeun,Ko, Sung-Kyun,Jang, Mina,Lee, Jae Kyoung,Ryoo, In-Ja,Lee, Jung-Sook,Lee, Kyung Ho,Soung, Nak-Kyun,Oh, Hyuncheol,Hong, Young-Soo,Kim, Bo Yeon,Jang, Jae-Hyuk,Ahn, Jong Seog
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supporting information
p. 4046 - 4049
(2015/09/01)
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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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- Characterization of an enantioselective amidase from Cupriavidus sp. KNK-J915 (FERM BP-10739) useful for enzymatic resolution of racemic 3-piperidinecarboxamide
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A novel amidase (CsAM) acting on (R,S)-N-benzyl-3-piperidinecarboxamide was purified from Cupriavidus sp. KNK-J915 (FERM BP-10739) and characterized. The enzyme acts on (R,S)-N-benzyl-3-piperidinecarboxamide S-selectively to yield (R)-N-benzyl-3-piperidinecarboxamide. Analytical gel filtration column chromatography and SDS-PAGE revealed that the enzyme is a tetramer with a subunit of approximately 47 kDa. It has a broad substrate spectrum against nitrogen-containing heterocyclic amides. Its optimal pH and temperature are 8.0-9.0 and 50 °C, respectively. The CsAM gene was cloned and sequenced, and it was found to comprise 1341 bp and encode a polypeptide of 46,388 Da. The deduced amino acid sequence exhibited 78% identity to that of a putative amidase (CnAM) from Cupriavidus necator JMP134. The cultured cells of recombinant Escherichia coli producing CnAM could be used for the S-selective hydrolysis of (R,S)-N-benzyl-3-piperidinecarboxamide but could not be used for the S-selective hydrolysis of (R,S)-3-piperidinecarboxamide because of its very low level of selectivity. In contrast, the cultured cells of recombinant E. coli producing CsAM could hydrolyze both (R,S)-N-benzyl-3-piperidinecarboxamide and (R,S)-3-piperidinecarboxamide with high S-selectivity.
- Nojiri, Masutoshi,Taoka, Naoaki,Yasohara, Yoshihiko
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p. 136 - 142
(2014/12/10)
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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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- Total synthesis of quinaldopeptin and its analogues
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The first total synthesis of quinaldopeptin (1) was accomplished. Our approach to the synthesis of 1 includes the solid-phase peptide synthesis of the linear decapeptide 4 followed by macrocyclization and introduction of the quinoline chromophores 2 at a late stage of the synthesis. As for the preparation of 4, a fragment coupling approach was applied considering the C2 symmetrical structure of 1. Chromophore analogues 22 and 23 and desmethyl analogue 27 were also prepared in a manner similar to the synthesis of 1. Synthetic 1 exhibits a strong cytotoxicity with the IC50 value of 3.2 nM. On the other hand, the activity of 23 and 27 was largely reduced.
- Ichikawa, Satoshi,Okamura, Takuya,Matsuda, Akira
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p. 12662 - 12670
(2014/01/17)
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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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p. 556 - 560
(2013/09/12)
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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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p. 50 - 59,10
(2020/07/31)
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- Cytotoxic cyclic depsipeptides from the Australian marine sponge Neamphius huxleyi
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Three new cyclic depsipeptides, neamphamides B (2), C (3), and D (4), were isolated from the Australian sponge Neamphius huxleyi. The planar structural characterization of these molecules was elucidated using 2D NMR experiments and ESI-FTICR-MSn. Their configurations were determined by Marfey's method and J-based NMR analysis. These new metabolites inhibited the growth of human cell lines (A549, HeLa, LNCaP, PC3, and NFF) with IC50 values ranging from 88 to 370 nM. However, neamphamide D causes A549 cell proliferation at subcytotoxic doses and should be treated cautiously as a cytotoxic compound.
- Tran, Trong D.,Pham, Ngoc B.,Fechner, Gregory,Zencak, Dusan,Vu, Hoan T.,Hooper, John N.A.,Quinn, Ronald J.
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p. 2200 - 2208
(2013/02/25)
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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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- Stereoselective syntheses of L-pipecolic acid and (2S,3S)-3- hydroxypipecolic acid from a chiral n-imino-2-phenyl-1,2-dihydropyridine intermediate
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"Chemical Equation Presented" Stereoselective syntheses of L-pipecolic acid and (2S,3S)3-hydroxypipecolic acid were achieved from a chiral AMmino-2-phenyl-l,2-dihydropyridine intermediate. The 3-hydroxy substituent of the latter amino acid was introduced, by hetero-Diels-Alder reaction of singlet, oxygen with the 1,2-dihydropyridine.
- Lemire, Alexandre,Charette, Andre B.
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supporting information; experimental part
p. 2077 - 2080
(2010/06/16)
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- Insights into an unusual nonribosomal peptide synthetase biosynthesis: Identification and characterization of the GE81112 biosynthetic gene cluster
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The GE81112 tetrapeptides (1-3) represent a structurally unique class of antibiotics, acting as specific inhibitors of prokaryotic protein synthesis. Here we report the cloning and sequencing of the GE81112 biosynthetic gene cluster from Streptomyces sp. L-49973 and the development of a genetic manipulation system for Streptomyces sp. L-49973. The biosynthetic gene cluster for the tetrapeptide antibiotic GE81112 (getA-N) was identified within a 61.7-kb region comprising 29 open reading frames (open reading frames), 14 of which were assigned to the biosynthetic gene cluster. Sequence analysis revealed the GE81112 cluster to consist of six nonribosomal peptide synthetase (NRPS) genes encoding incomplete di-domain NRPS modules and a single free standing NRPS domain as well as genes encoding other biosynthetic and modifying proteins. The involvement of the cloned gene cluster in GE81112 biosynthesis was confirmed by inactivating the NRPS gene getE resulting in a GE81112 production abolished mutant. In addition, we characterized the NRPS A-domains from the pathway by expression in Escherichia coli and in vitro enzymatic assays. The previously unknown stereochemistry of most chiral centers in GE81112 was established from a combined chemical and biosynthetic approach. Taken together, these findings have allowed us to propose a rational model for GE81112 biosynthesis. The results further open the door to developing new derivatives of these promising antibiotic compounds by genetic engineering.
- Binz, Tina M.,Maffioli, Sonia I.,Sosio, Margherita,Donadio, Stefano,Mueller, Rolf
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scheme or table
p. 32710 - 32719
(2011/11/12)
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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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- 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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- Enzymatic synthesis of cyclic amino acids by N-methyl-l-amino acid dehydrogenase from Pseudomonas putida
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A new enzymatic system for the synthesis of enantiomerically pure cyclic amino acids (CAA) from the corresponding diamino acids or racemic CAA is described. α,ω-Diamino acids were oxidized to α-keto acids with amino acid oxidases (AAO). The α-keto acids were spontaneously transformed into cyclic imino acids in the reaction medium. The resulting imines were reduced to the l-form CAA with N-methyl-l-amino acid dehydrogenase (NMAADH) from Pseudomonas putida ATCC12633 using NADPH as a cofactor. l-Form CAA were also obtained from racemic CAA using d-amino-acid oxidase and NMAADH. Using this method, a new compound [1,4]-thiazepane-3-carboxylic acid (Fig. 1) was synthesized from aminopropylcystein.
- Yasuda, Mari,Ueda, Makoto,Muramatsu, Hisashi,Mihara, Hisaaki,Esaki, Nobuyoshi
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p. 1775 - 1779
(2007/10/03)
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- Biosynthesis of pipecolic acid by RapL, a lysine cyclodeaminase encoded in the rapamycin gene cluster
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Rapamycin, FK506, and FK520 are immunosuppressant macrolactone natural products comprised of predominantly polyketide-based core structures. A single nonproteinogenic pipecolic acid residue is installed into the scaffold by a nonribosomal peptide synthetase that also performs the subsequent macrocyclization step at the carbonyl group of this amino acid. It has been assumed that pipecolic acid is generated from lysine by the cyclodeaminases RapL/FkbL. Herein we report the heterologous overexpression and purification of RapL and validate its ability to convert L-lysine to L-pipecolic acid by a cyclodeamination reaction that involves redox catalysis. RapL also accepts L-ornithine as a substrate, albeit with a significantly reduced catalytic efficiency. Turnover is presumed to encompass a reversible oxidation at the α-amine, internal cyclization, and subsequent re-reduction of the cyclic Δ1-piperideine-2-carboxylate intermediate. As isolated, RapL has about 0.17 equiv of tightly bound NAD+, suggesting that the enzyme is incompletely loaded when overproduced in E. coli. In the presence of exogenous NAD+, the initial rate is elevated 8-fold with a K m of 2.3 μM for the cofactor, consistent with some release and rebinding of NAD+ during catalytic cycles. Through the use of isotopically labeled substrates, we have confirmed mechanistic details of the cyclodeaminase reaction, including loss of the α-amine and retention of the hydrogen atom at the α-carbon. In addition to the characterization of a critical enzyme in the biosynthesis of a medically important class of natural products, this work represents the first in vitro characterization of a lysine cyclodeaminase, a member of a unique group of enzymes which utilize the nicotinamide cofactor in a catalytic manner.
- Gatto Jr., Gregory J.,Boyne II, Michael T.,Kelleher, Neil L.,Walsh, Christopher T.
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p. 3838 - 3847
(2007/10/03)
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- Process of making optically pure L-pipecolic acid and process of making anesthetics and intermediates therefrom
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The present invention describes a novel process of preparation of optically pure L-Pipecolic acid and an improved process for the conversion of L-pipecolic acid to L-N-(2,6-dimethylphenyl)-1-propyl-2-piperidinocarboxamide, its hydrochloride salt and hydrochloride monohydrate.
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Page/Page column 3
(2008/06/13)
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- Synthesis of pipecolic acid and baikiain
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A straightforward synthesis of pipecolic acid and baikiain was achieved from trans-(2S,4R)-4-hydroxyproline via the key steps of regioselective Baeyer-Villiger reaction. and ring-closing metathesis.
- Chang, Meng-Yang,Kung, Yung-Hua,Wu, Tsun-Chang
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p. 2365 - 2373
(2007/10/03)
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- Stereoselective preparation of cyclic l-amino acids
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The invention concerns a method for producing a cyclic L-amino acid of formula (I), characterised in that it consists in reacting a L-diamino acid of formula (II) or an enantiomeric mixture comprising such a L-diamino acid and a corresponding D-diamino acid in variable proportions, in the presence of an ornithine cyclodeaminase or a polypeptide homologous to the ornithine cyclodeaminase. 1
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Page/Page column 13; 14
(2008/06/13)
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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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- 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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- 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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p. 152 - 159
(2007/10/03)
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- Highly diastereoselective alkylation of the Dellaria oxazinone template with bifunctional electrophiles
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This study investigates the efficiency of alkylation of the Dellaria oxazinone glycinate template with sensitive bifunctional electrophiles. In addition to improved access to the template, triflate/halide bifunctional combinations provided good yields (85-93%) of highly diastereoselective alkylation products.
- Roos, Gregory H. P.,Dastlik, Kim A.
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p. 2197 - 2208
(2007/10/03)
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- A Novel Cyclodepsipeptide, HA23, from a Fusarium sp
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(Matrix Presented) HA 23, a novel cyclodepsipeptide (1) of mixed peptide-polyketide origins, was isolated from a fungal isolate of a Fusarium sp. The structure was determined from 1D and 2D NMR and mass spectral data.
- Feng, Yunjiang,Blunt, John W.,Cole, Anthony L. J.,Munro, Murray H. G.
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p. 2095 - 2096
(2007/10/03)
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- Compounds possessing neuronal activity
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The present invention relates to compounds, methods and pharmaceutical compositions for stimulating the growth of neurites in nerve cells. The compounds and the compositions and methods that utilize them can be used, either alone or in conjunction with a neurotrophic factor, such as nerve growth factor, to promote repair of neuronal damage caused by disease or physical trauma.
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- Beauveria bassiana ATCC 7159 contains an L-specific α-amino acid benzamidase
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Biotransformation of a series of racemic N-benzoyl α-amino acids by the fungus Beauveria bassiana ATCC 7159 results in isolation of the corresponding D-amino acid benzamides in high enantiomeric purity and yield.
- Holland, Herbert L.,Andreana, Peter R.,Salehzadeh-Asl, Reza,Van Vliet, Aaron,Ihasz, Nancy J.,Brown, Frances M.
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p. 667 - 672
(2007/10/03)
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- A new enantioselective synthesis of (2S)-pipecolic acid
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A synthesis of enantiomerically pure (2S)-pipecolic acid, involving a highly diastereoselective reaction between iminium ion and vinylsilane moieties, is described.
- Agami, Claude,Kadouri-Puchot, Catherine,Kizirian, Jean-Claude
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p. 2565 - 2572
(2007/10/03)
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- Chemoenzymatic synthesis of (S)-2-cyanopiperidine, a key intermediate in the route to (S)-pipecolic acid and 2-substituted piperidine alkaloids
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The preparation of (S)-2-cyanopiperidine 4 provides a new access to 2- substituted piperidines. This synthesis is based on an enantioselective (R)- oxynitrilase-catalyzed reaction for the preparation of (R)-(+)-6-bromo-2- hydroxyhexanenitrile 1 and the subsequent cyclization of this compound to yield the piperidine ring. The utilization of 4 as the starting material for the synthesis of (S)-2-aminomethylpiperidine 6, (R)-(-)-coniine 10 and (S)- (-)pipecolic acid 13 is also described.
- Nazabadioko, Serge,Perez, Ramon J.,Brieva, Rosario,Gotor, Vicente
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p. 1597 - 1604
(2007/10/03)
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- Short syntheses of (S)-pipecolic acid, (R)-coniine, and (S)-δ-coniceine using biocatalytically-generated chiral building blocks
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The kinetic resolutions of both (±)-N-(benzyloxycarbonyl-2- (hydroxymethyl)piperidine [(±)-5] and (±)-N(tert-butoxycarbonyl)-2- (hydroxymethyl)piperidine [(±)-6] catalyzed by the enzyme acylase I from Aspergillus species (AA-I) afforded the chiral building blocks (S)-5 and (S)- 6, respectively; which were used for the syntheses of the title natural products and derivatives of (S)-pipecolic acid. The syntheses were short (2- 4 steps) and proceeded with satisfactory overall yield.
- Sanchez-Sancho, Francisco,Herradon, Bernardo
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p. 1951 - 1965
(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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- 2-oxoethyl derivatives as immunosuppressants
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A class of compounds that suppress human T-lymphocyte proliferation is disclosed. The active compounds essentially contain at least the following structure: STR1
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- Preparation of (S)-piperazine-2-carboxylic acid, (R)-piperazine-2-carboxylic acid, and (S)-piperidine-2-carboxylic acid by kinetic resolution of the corresponding racemic carboxamides with stereoselective amidases in whole bacterial cells
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Whole bacterial cells containing stereospecific amidases were used for the kinetic resolution of racemic piperazine-2-carboxamide and piperidine-2-carboxamide to (S)- and (R)-piperazine-2-carboxylic acid, and (S)-piperidine-2-carboxylic acid, respectively. (S)-Piperazinecarboxylic acid dihydrochloride produced with the biocatalysts Klebsiella terrigena DSM 9174 had an ee value of 99.4% (41% yield), and the ee value of (R)-piperazinecarboxylic acid dihydrochloride obtained with Burkholderia sp. DSM 9925 was 99.0% (22% yield). Using Pseudomonas fluorescens DSM 9924 (S)-piperidine-2-carboxylic acid with an ee value of 97.3% (20% yield) was isolated.
- Eichhorn, Eric,Roduit, Jean-Paul,Shaw, Nicholas,Heinzmann, Klaus,Kiener, Andreas
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p. 2533 - 2536
(2007/10/03)
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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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p. 315 - 319
(2007/10/02)
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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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p. 3031 - 3038
(2007/10/03)
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- 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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p. 2075 - 2081
(2007/10/02)
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- Asymmetric Synthesis. 32. A New Access to Enantiomerically Pure (S)-(-)-Pipecolic Acid and 2- or 6-Alkylated Derivatives
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Enantiomerically pure (S)-(-)-pipecolic acid (5) was synthesized in four steps and 47percent overall yield starting from 2-cyano-6-phenyloxazolopiperidine (1).A general strategy is described for preparing 2-alkylated and 6-alkylated pipecolic acid 7a-c and 11a-c using diastereoselective procedures.
- Berrien, J. -F.,Royer, J.,Husson, H. -P.
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p. 3769 - 3774
(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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