- Development of a Stereoselective Synthesis of (1 R,4 R)- and (1 S,4 S)-2-Oxa-5-azabicyclo[2.2.2]octane
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Despite the prevalence of morpholine derivatives and bridged heterocycles in medicinally relevant compounds, bridged bicyclic morpholines remain scarce because of the challenges associated with their synthesis. MRK A, an IDH1mut inhibitor for the treatment of glioma, derives its potency in part from substitution of a zigzag 2,5-bicyclic morpholine, 2-oxa-5-azabicyclo[2.2.2]octane, at C8. While existing entries suffered from low yields and lack of stereochemical control, we developed concise stereospecific routes toward both enantiomers of the zigzag morpholine antipode. The key common intermediate in the two routes was a chiral bicyclic lactone, which was readily synthesized following our previous synthesis of relebactam from optically pure (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (HPA). The desired (R,R) enantiomer for incorporation into MRK A required inversion of both stereocenters of the bicyclic lactone intermediate, which was accomplished by epimerization via a crystallization-induced diastereomer transformation process followed by a key Ti(OiPr)4-mediated intramolecular SN2 ring closure. By this method, the (R,R)-zigzag morpholine was synthesized in six steps from HPA in 25% overall yield.
- Alam, Mahbub,Cleator, Ed,Dieguez-Vazquez, Alejandro,Gibb, Andrew,Goodyear, Adrian,Keen, Stephen,Kirtley, Andy,Kong, Lingzhu,Lam, Yu-Hong,Maddess, Matthew L.,Morimoto, Mariko,Oliver, Steven F.,Qi, Ji,Wang, Jie,Wen, Xin
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supporting information
(2021/07/01)
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- Studies on the selectivity of proline hydroxylases reveal new substrates including bicycles
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Studies on the substrate selectivity of recombinant ferrous-iron- and 2-oxoglutarate-dependent proline hydroxylases (PHs) reveal that they can catalyse the production of dihydroxylated 5-, 6-, and 7-membered ring products, and can accept bicyclic substrates. Ring-substituted substrate analogues (such hydroxylated and fluorinated prolines) are accepted in some cases. The results highlight the considerable, as yet largely untapped, potential for amino acid hydroxylases and other 2OG oxygenases in biocatalysis.
- Smart, Tristan J.,Hamed, Refaat B.,Claridge, Timothy D.W.,Schofield, Christopher J.
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supporting information
(2019/11/26)
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- METHODS OF USING RAD51 INHIBITORS FOR TREATMENT OF PANCREATIC CANCER
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This application is directed to inhibitors of RAD51 represented by the following structural formula, and methods for their use, such as to treat pancreatic cancer.
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Paragraph 1238-1240
(2021/01/22)
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- RAD51 Inhibitors
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This application is directed to inhibitors of RAD51 represented by the following structural formula, and methods for their use, such as to treat cancer, autoimmune diseases, immune deficiencies, or neurodegenerative diseases.
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Paragraph 0539-0540
(2019/03/30)
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- METHOD FOR PRODUCING 5-HYDROXYPIPERIDINE-2-CARBOXYLIC ACID
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A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by formula (10) below: the method including removing the protecting group from the hydroxyl group in a compound represented by formula (7) below: (wherein P represents a protecting group, R3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms) to synthesize a compound represented by formula (8) below: (wherein R3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).
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- Synthetic methods for (1S,4S)-2,5-diazabicyclo[2.2.2] octane and derivatives thereof
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The invention discloses synthetic methods for (1S,4S)-2,5-diazabicyclo[2.2.2] octane and derivatives thereof, and belongs to the field of organic chemical synthesis. According to the method, 5-hydroxypyrazine-2-formate as a compound II is taken as a raw material, and high selectivity of a reaction is guaranteed through selective protection of hydroxyl and amino groups. A product obtained with the method has high yield, the by-product content is low, and the method is applicable to industrial production.
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Paragraph 0068; 0069; 0070
(2016/12/16)
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- MANUFACTURING METHOD OF (2S,5S)-5-HYDROXY-2-PIPERIDINECARBOXYLIC ACID AS WELL AS MANUFACTURING INTERMEDIATE OF THE SAME AND METHOD FOR MANUFACTURING THE SAME
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PROBLEM TO BE SOLVED: To provide synthesis methods of 5-hydroxy-6-methoxypiperidine-2-carboxylic acid derivatives and 5-oxopiperidine-2-carboxylic acid derivatives more safely than ever by using inexpensive raw ingredients. SOLUTION: In the provided method, a compound expressed by the following formula [X] is manufactured from a compound expressed by the following formula [I] through steps (1) through (9) [either steps (4) and (5) or steps (6) and (7) in the case of steps (4) through (7)]. COPYRIGHT: (C)2015,JPOandINPIT
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- METHOD FOR PRODUCING cis-5-HYDROXY-2-PIPERIDINECARBOXYLIC ACID DERIVATIVE, AND METHOD FOR PURIFYING cis-5-HYDROXY-2-PIPERIDINECARBOXYLIC ACID
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The present invention aims to provide a method for purifying cis-5-hydroxy-2-piperidinecarboxylic acid with high purity, and a method for producing its derivative. The present invention provides a method for producing a cis-5-hydroxy-2-piperidinecarboxylic acid derivative, which method comprises a step of converting cis-5-hydroxy-2-piperidinecarboxylic acid into a compound(s) of Formula (1) and/or Formula (2) (wherein R1 represents a protective group for an amino group, and R2 represents a C1-C6 alkyl group), and a method for purifying cis-5-hydroxy-2-piperidinecarboxylic acid.
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Paragraph 0119; 0120
(2015/07/15)
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- Regio- and stereoselective oxygenation of proline derivatives by using microbial 2-oxoglutarate-dependent dioxygenases
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We evaluated the substrate specificities of four proline cis-selective hydroxylases toward the efficient synthesis of proline derivatives. In an initial evaluation, 15 proline-related compounds were investigated as substrates. In addition to L-proline and L-pipecolinic acid, we found that 3,4-dehydro-L-proline, L-azetidine-2-carboxylic acid, cis-3-hydroxy-L-proline, and L-thioproline were also oxygenated. Subsequently, the product structures were determined, revealing cis-3,4-epoxy-L-proline, cis-3-hydroxy-L-azetidine-2-carboxylic acid, and 2,3-cis-3,4-cis-3,4-dihydroxy-L-proline.
- Hara, Ryotaro,Uchiumi, Naoko,Okamoto, Naoko,Kino, Kuniki
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p. 1384 - 1388
(2015/07/20)
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- Complementary and stereodivergent approaches to the synthesis of 5-hydroxy- and 4,5-dihydroxypipecolic acids from enantiopure hydroxylated lactams
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We describe two complementary and stereodivergent routes, from commercially available and inexpensive starting materials, for the synthesis of 4,5-dihydroxy- and 5-hydroxypipecolic acids based on the chemistry of lactam-derived enol phosphates. The synthesis of the 4,5-cis-4,5- dihydroxypipecolic acids required the preparation from 2-deoxy-D- and -L-ribose of the enantiopure cis-(4S,5R)- and -(4R,5S)-4,5-dihydroxy-δ-valerolactam, respectively. These new chiral synthons are potentially useful for the synthesis of other natural products. The key step is the Pd-catalyzed methoxycarbonylation reaction of the enol phosphates generated from these lactams. This reaction provided enecarbamate esters that were easily converted by stereoselective reduction to the target compounds. The synthesis of the 4,5-trans-4,5-dihydroxypipecolic acid, as well as of 5-hydroxypipecolic acids, was realized from a known (S)-5-hydroxy-δ-valerolactam derivative and, for the dihydroxylated compound, required a highly stereoselective allylic bromination reaction of the enecarbamate ester obtained by methoxycarbonylation of the enol phosphate. The preparation of the (4R,5S) enantiomer of the cis-4,5-dihydroxy-δ-valerolactam from 2-deoxy-L-ribose, alongside the fact that (R)-5-hydroxy-δ-valerolactam can be prepared from (R)-(-)-γ-hydroxymethyl-γ-butyrolactone, means our approach allows for the synthesis of all stereoisomers of these compounds, which can be employed as conformationally constrained scaffolds in drug discovery. The stereoselective synthesis of 5-hydroxy- and 4,5-dihydroxypipecolic acids was accomplished by sequential Pd-catalysed methoxycarbonylation and stereoselective reduction of enantiopure hydroxylated lactam-derived enol phosphates obtained from both enantiomers of commercially available γ-hydroxymethyl-γ- butyrolactone and 2-deoxyribose. Copyright
- Scarpi, Dina,Bartali, Laura,Casini, Andrea,Occhiato, Ernesto G.
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p. 1306 - 1317
(2013/04/10)
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- A simple procedure for selective hydroxylation of L -proline and l -pipecolic acid with recombinantly expressed proline hydroxylases
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Due to their diverse regio- and stereoselectivities, proline hydroxylases provide a straightforward access to hydroxprolines and other hydroxylated cylic amino acids, valuable chiral building blocks for chemical synthesis, which are often not available at reasonable expense by classical chemical synthesis. As yet, the application of proline hydroxylases is limited to a sophisticated industrial process for the production of two hydroxyproline isomers. This is mainly due to difficulties in their heterologues expression, their limited in vitro stability and complex product purification procedures. Here we describe a facile method for the production of cis-3-, cis-4- and trans-4-proline hydroxylase, and their application for the regio- and stereoselective hydroxylation of L-proline and its six-membered ring homologue l-pipecolic acid. Since in vitro catalysis with these enzymes is not very efficient and conversions are restricted to the milligram scale, an in vivo procedure was established, which allowed a quantitative conversion of 6 mM l-proline in shake flask cultures. After facile product purification via ion exchange chromatography, hydroxyprolines were isolated in yields of 35-61% (175-305 mg per flask). L-Pipecolic acid was converted with the isolated enzymes to prove the selectivities of the reactions. In transformations with optimized iron(II) concentration, conversions of 17-68% to hydroxylated products were achieved. The regio- and stereochemistry of the products was determined by NMR techniques. To demonstrate the applicability of the preparative in vivo approach for non-physiological substrates, L-pipecolic acid was converted with an E. coli strain producing trans-4-proline hydroxylase to trans-5-hydroxy-L-pipecolic acid in 61% yield. Thus, a synthetically valuable group of biocatalysts was made readily accessible for application in the laboratory without a need for special equipment or considerable development effort.
- Klein, Christian,Huettel, Wolfgang
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experimental part
p. 1375 - 1383
(2011/06/26)
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- Synthesis of functionalized 3-hydroxypiperidines
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The synthetic versatility of three chemoenzymatically prepared hydroxypiperidine building blocks has been explored, resulting in a library of enantiopure functionalized piperidines. Key steps involved N-acyliminium ion-mediated CC-bond formation and cross-metathesis reactions, after which full deprotection led to the set of free 3-hydroxypiperidines.
- Wijdeven, Marloes A.,Van Delft, Floris L.,Rutjes, Floris P.J.T.
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experimental part
p. 5623 - 5636
(2010/10/02)
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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 14
(2008/06/13)
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- Substrate selectivities of proline hydroxylases
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Substrate selectivities of microbial proline 4-hydroxylase and proline 3-hydroxylases, all of which were purified from recombinant Escherichia coli, were investigated. L-2-Azetidine carboxylate, 3,4-dehydro-L-proline and L- pipecolinic acid were hydroxylated by those enzymes in regio- and stereospecific manner.
- Shibasaki, Takeahi,Sakurai, Wataru,Hasegawa, Atsuhiro,Uosaki, Youichi,Mori, Hideo,Yoshida, Mayumi,Ozaki, Akio
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p. 5227 - 5230
(2007/10/03)
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- An efficient route to the α-methyl ester of L-glutamic acid, and its conversion into cis-5-hydroxy-L-pipecolic acid
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The treatment of the N-benzyloxycarbonyl α-methyl esters of L-glutamine or L-asparagine with tert-butyl nitrite in refluxing acetonitrile results in selective hydrolysis of the amide group, giving optically pure Z-Glu-OMe (74%) or Z-Asp-OMe (88%); these are versatile chiral building blocks, and an efficient synthesis of cis-5-hydroxy-L-pipecolic acid from Z-Glu-OMe is described.
- Adams, David R.,Bailey, Patrick D.,Collier, Ian D.,Heffernan, John D.,Stokes, Stephen
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p. 349 - 350
(2007/10/03)
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- Synthesis of unnatural 2R,5S-5-hydroxypipecolic acid via homochiral acyliminium ion-pipecolic acids - Part III
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Stereoselective functionalization of S-5-hydroxy-2-piperidone 1 via acyliminium ion was demonstrated to maintain the unnatural enantiomer of trans-5-hydroxypipecolic acid 6.
- Herdeis,Engel
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p. 945 - 948
(2007/12/18)
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- CHIRAL SYNTHESIS OF 5-HYDROXY-(L)-PIPECOLIC ACIDS FROM (L)-GLUTAMIC ACID
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A stereo- and enantio-specific synthesis of the naturally occuring cis-5-hydroxy-(L)-pipecolic acid (3) is described, starting from Z-(L)-glutamic acid; the key step involves cyclisation of a protected chlorohydrin, and also gives access to trans-5-hydroxy-(L)-pipecolic acid.
- Bailey, Patrick D.,Bryans, Justin S.
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p. 2231 - 2234
(2007/10/02)
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- PREPARATION OF TRANS-5-HYDROXY-L-PIPECOLIC ACID AND CIS-4-HYDROXY-L-PIPECOLIC ACID FROM L-BAIKIAIN (1,2,5,6-L-TETRAHYDROPYRIDINE-2-CARBOXYLIC ACID).
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Z-trans-5-OH-L-pipecolic acid together with Z-cis-4-OH-L-pipecolic acid is obtained in a 7:3 ratio by reduction of the oxymercuration product of Z-L-baikiain (Z-1,2,5,6-L-tetrahydropyridine-2-carboxylic acid).The opposite composition ratio is obtained using mercuric trifluoroacetate, thus giving access to the preparation of either of the two isomers.
- Callens, Roland E.A.,Anteunis, Marc J.O.,Reyniers, Francoise
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p. 713 - 724
(2007/10/02)
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