- Modular Chemoenzymatic Synthesis of GE81112 B1 and Related Analogues Enables Elucidation of Its Key Pharmacophores
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The GE81112 complex has garnered much interest due to its broad antimicrobial properties and unique ability to inhibit bacterial translation initiation. Herein we report the use of a chemoenzymatic strategy to complete the first total synthesis of GE81112 B1. By pairing iron and α-ketoglutarate dependent hydroxylases found in GE81112 biosynthesis with traditional synthetic methodology, we were able to access the natural product in 11 steps (longest linear sequence). Following this strategy, 10 GE81112 B1 analogues were synthesized, allowing for identification of its key pharmacophores. A key feature of our medicinal chemistry effort is the incorporation of additional biocatalytic hydroxylations in modular analogue synthesis to rapidly enable exploration of relevant chemical space.
- Zwick, Christian R.,Sosa, Max B.,Renata, Hans
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supporting information
p. 1673 - 1679
(2021/01/25)
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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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- 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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- 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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- Synthesis of (+)-L-733,060, (+)-CP-99,994 and (2S,3R)-3-hydroxypipecolic acid: Application of an organocatalytic direct vinylogous aldol reaction
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The γ-butenolide obtained from an organocatalyzed, direct vinylogous aldol reaction of γ-crotonolactone and benzaldehyde serves as the key starting material in the expedient synthesis of a 3-hydroxy-2-phenyl piperidine intermediate which is converted to the target 2,3-disubstituted piperidines.
- Pansare, Sunil V.,Paul, Eldho K.
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experimental part
p. 2119 - 2125
(2012/04/17)
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- A stereoselective route to cis-(2S,3R)-3-hydroxypipecolic acid and two enantiomeric cis-2-hydroxymethyl-3-hydroxypiperidine derivatives
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Stereoselective routes to cis-(2S,3R)-3-hydroxypipecolic acid and two enantiomeric cis-2-hydroxymethyl-3-hydroxypiperidine derivatives from a common precursor have been developed, which featured stereocontrolled vinylation of a -chiral aldehyde and ring-closing metathesis as key steps. Georg Thieme Verlag Stuttgart. New York.
- Chattopadhyay, Shital K.,Roy, Shankar P.,Saha, Tapan
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p. 2664 - 2670
(2011/10/04)
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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 cis-3-hydroxypipecolic acid via SmI2-mediated cyclization of aldehydo β-aminovinyl sulfoxides
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Stereoselective synthesis of cis-3-hydroxypipecolic acid was achieved via chirality transfer in the SmI2-mediated cyclization reactions of aldehydo β-aminovinyl sulfoxides.
- Chung, Hea Seung,Shin, Won Kyo,Choi, Soo Young,Chung, Young Keun,Lee, Eun
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supporting information; experimental part
p. 707 - 708
(2010/04/02)
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- Enantioselective ring expansion of prolinols: An efficient and short synthesis of 2-phenylpiperidin-3-ol derivatives and 3-hydroxypipecolic acids
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A very short route to 2-phenylpiperidin-3-ol derivatives and 3-hydroxypipecolic acids is described. The approach uses two key steps: a one-pot reduction/Grignard addition sequence applied to alkyl proline esters and a ring expansion applied to the corresp
- Cochi, Anne,Burger, Benjamin,Navarro, Cristina,Pardo, Domingo Gomez,Cossy, Janine,Zhao, Yang,Cohen, Theodore
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body text
p. 2157 - 2161
(2009/12/24)
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- Chiron approach to the synthesis of (2S,3R)-3-hydroxypipecolic acid and (2R,3R)-3-hydroxy-2-hydroxymethylpiperidine from D-glucose
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(Chemical Equation Presented) The first chiron approach from D-glucose for the total synthesis of (2S,3R)-3-hydroxypipecolic acid (-)-1a and (2R,3R)-3-hydroxy-2-hydroxymethylpiperidine (-)-2a is reported. The synthetic pathway involves conversion of D-glucose into 3-azidopentodialdose (5) followed by the Wittig olefination and reduction to give the piperidine ring skeleton (8) with a sugar appendage that on cleavage of an anomeric carbon followed by oxidation gives (-)-1a which on reduction affords (-)-2a.
- Kalamkar, Navnath B.,Kasture, Vijay M.,Dhavale, Dilip D.
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p. 3619 - 3622
(2008/09/20)
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- Synthesis of both enantiomers of hydroxypipecolic acid derivatives equivalent to 5-azapyranuronic acids and evaluation of their inhibitory activities against glycosidases
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We have synthesized 3-hydroxy- and 3,4,5-trihydroxypipecolic acid derivatives corresponding to 5-aza derivatives of uronic acids and evaluated their inhibitory activities against various glycosidases including β-glucuronidase. Compounds 4 and 5 were chosen as common intermediates for the synthesis of 3,4,5-trihydroxypipecolic acids and 3-hydroxypipecolic acids as well as for 3-hydroxybaikiain, a unique natural product isolated from a toxic mushroom. Cross aldol reaction of N-Boc-allylglycine derivative with acrolein followed by the ring-closing metathesis gave 4 and 5 as a mixture of diastereomers which could be separated by silica gel column chromatography. By employing lipase-catalyzed kinetic resolution, the synthesis of both l- and d-isomers of 3,4,5-trihydroxy- and 3-hydroxypipecolic acids was achieved. None of the compounds tested showed inhibitory activity against α- and β-glucosidases. On the other hand, l-23 and l-29 were found to have potent inhibitory activity against β-glucuronidase. In addition, it is interesting that some uronic-type azasugar derivatives showed moderate inhibitory activities against β-N-acetylglucosaminidase.
- Yoshimura, Yuichi,Ohara, Chiaki,Imahori, Tatsushi,Saito, Yukako,Kato, Atsushi,Miyauchi, Saori,Adachi, Isao,Takahata, Hiroki
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experimental part
p. 8273 - 8286
(2009/04/11)
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- Synthesis of all stereoisomers of 3-hydroxypipecolic acid and 3-hydroxy-4,5-dehydropipecolic acid and their evaluation as glycosidase inhibitors
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A highly practicable synthesis of both enantiomers of 3-hydroxypipecolic acid derivatives 1, 2, 3, 4 is described. Screening of these molecules for glycosidase inhibition has been examined. Compound 3 was shown to be a potent inhibitor of β-N-acetylglucosaminidase as well as Escherichia coli β-glucuronidase.
- Ohara, Chiaki,Takahashi, Ryouko,Miyagawa, Tatsunori,Yoshimura, Yuichi,Kato, Atsushi,Adachi, Isao,Takahata, Hiroki
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p. 1810 - 1813
(2008/12/20)
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- Bicyclic modulators of androgen receptor function
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The invention provides compounds of the formula I wherein the substitutents are as described herein. Further provided are methods of using such compounds for the treatment of nuclear hormone receptor-associated conditions, such as age related diseases, for example sarcopenia, and also provided are pharmaceutical compositions containing such compounds.
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- Synthetic studies on tetrazomine: Lipase PS resolution of racemic cis-β-hydroxypipecolic acid
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An efficient enzymatic resolution of racemic cis-β-hydroxypipecolic acid is described affording both the (2S,3R) and (2R,3S) protected amino acids in good yield and high enantiomeric ratios. (C) 2000 Elsevier Science Ltd.
- Scott,Williams
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p. 8413 - 8416
(2007/10/03)
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- Enantioselective synthesis of β-hydroxy-α-amino acid esters by aldol coupling using a chiral quaternary ammonium salt as catalyst
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A variety of chiral β-hydroxy-α-amino acids and derivatives thereof can be synthesized enantioselectively using the aldol reaction of an aldehyde, the gIycinate 1 and the cinchonidinederived catalyst 2, as indicated in Schemes 1 and 2 and Table 1.
- Horikawa, Manabu,Busch-Petersen, Jakob,Corey
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p. 3843 - 3846
(2007/10/03)
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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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- Synthetic studies on tetrazomine: Stereochemical assignment of the β- hydroxypipecolic acid
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The asymmetric syntheses of 2(R), 3(R)- and 2(S), 3(S)-β- hydroxypipecolic acids are described, including the determination of the absolute stereochemistry of the β-hydroxypipecolic acid moiety of tetrazomine.
- Scott, Jack D.,Tippie, Tracy N.,Williams, Robert M.
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p. 3659 - 3662
(2007/10/03)
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