- Binding and action of triphenylphosphonium analog of chloramphenicol upon the bacterial ribosome
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Chloramphenicol (CHL) is a ribosome-targeting antibiotic that binds to the peptidyl transferase center (PTC) of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving the properties of this inhib
- Chen, Chih-Wei,Pavlova, Julia A.,Lukianov, Dmitrii A.,Tereshchenkov, Andrey G.,Makarov, Gennady I.,Khairullina, Zimfira Z.,Tashlitsky, Vadim N.,Paleskava, Alena,Konevega, Andrey L.,Bogdanov, Alexey A.,Osterman, Ilya A.,Sumbatyan, Natalia V.,Polikanov, Yury S.
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- Triphenilphosphonium analogs of chloramphenicol as dual-acting antimicrobial and antiproliferating agents
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In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are lin
- Abad, Etna,Antonenko, Yuri N.,Bogdanov, Alexey A.,Kajiwara, Susumu,Khairullina, Zimfira Z.,Konevega, Andrey L.,Lukianov, Dmitrii A.,Lyakhovich, Alex,Makarov, Gennady I.,Murayama, Somay Y.,Nazarov, Pavel A.,Osterman, Ilya A.,Paleskava, Alena,Pavlova, Julia A.,Skvortsov, Dmitry A.,Sumbatyan, Natalia V.,Tereshchenkov, Andrey G.,Volynkina, Inna A.
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- One-Pot Asymmetric Synthesis of an Aminodiol Intermediate of Florfenicol Using Engineered Transketolase and Transaminase
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Florfenicol is the 3′-fluoro derivative of thiamphenicol and has been widely used in veterinary medicine for its high antibacterial activity and safety. However, the development of simplified and environmentally friendly catalytic methods for the stereoselective production of florfenicol is a key challenge. Herein, we established a highly stereoselective enzymatic one-pot reaction for the synthesis of an aminodiol intermediate of florfenicol bearing two stereocenters from industrial raw material 4-(methylsulfonyl) benzaldehyde by coupling transketolase (TK) and ω-transaminase (TA). The enantioselectivity of TK from E. coli was converted from (S) (93% ee) to (R) (95% ee), and we also inverted the enantiopreference (E(S) = 9 to E(R) = 12) and ketone/aldehyde substrate selectivity of TA ATA117 via structure-guided enzyme engineering. Docking calculations and molecular dynamics simulations of the wild-type and mutant enzymes unveiled the molecular basis for enzymatic stereocontrol. Using the engineered TK and TA, (1R,2R)-p-methylsulfonyl phenylserinol was biosynthesized with good yield (76%) and high stereoselectivity (96% de and >99% ee). Our work established an enzymatic synthetic route to (1R,2R)-p-methylsulfonyl phenylserinol, facilitating the development of a chemoenzymatic method for producing florfenicol.
- Deng, Zixin,Huang, Tingting,Lin, Shuangjun,Liu, Qi,Shi, Ting,Tang, Mancheng,Tao, Wentao,Xie, Xinyue,Zhang, Yuanzhen,Zhao, Yilei
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p. 7477 - 7488
(2021/06/30)
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- ENGINEERED POLYPEPTIDES AND THEIR APPLICATIONS IN SYNTHESIS OF BETA-HYDROXY-ALPHA-AMINO ACIDS
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Provided are engineered polypeptides that are useful for the asymmetric synthesis of β-hydroxy-α-amino acids under industrial-relevant conditions. The engineered polypeptides disclosed are developed through directed evolution based on the ability of catalytic synthesis of (2S, 3R) -2-amino-3-hydroxy-3- (4-nitrophenyl) propanoic acid. Also provided are polynucleotides encoding the engineered polypeptides, host cells capable of expressing engineered polypeptides, and methods of producing β-hydroxy-α-amino acids using engineered polypeptides. Compared to other processes of preparation, the use of the engineered polypeptides for the preparation of β-hydroxy-α-amino acids results in high purity of the desired stereoisomers, mild reaction conditions, low pollution and low energy consumption. It has good industrial application prospects.
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- Stereocontrolled synthesis of syn-β-hydroxy-α-amino acids by direct aldolization of pseudoephenamine glycinamide
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β-Hydroxy-α-amino acids figure prominently as chiral building blocks in chemical synthesis and serve as precursors to numerous important medicines. Reported herein is a method for the synthesis of β-hydroxy- α-amino acid derivatives by aldolization of pseudoephenamine glycinamide, which can be prepared from pseudoephenamine in a one-flask protocol. Enolization of (R,R)- or (S,S)-pseudoephenamine glycinamide with lithium hexamethyldisilazide in the presence of LiCl followed by addition of an aldehyde or ketone substrate affords aldol addition products that are stereochemically homologous with L- or D-threonine, respectively. These products, which are typically solids, can be obtained in stereoisomerically pure form in yields of 55-98 %, and are readily transformed into β-hydroxy-α-amino acids by mild hydrolysis or into 2-amino-1,3-diols by reduction with sodium borohydride. This new chemistry greatly facilitates the construction of novel antibiotics of several different classes. On aldol: Enolization of (R,R)- or (S,S)-pseudoephenamine glycinamide with lithium hexamethyldisilazide (LiHMDS) in the presence of LiCl followed by addition of either an aldehyde or ketone substrate affords aldol addition products which are stereochemically homologous with L- or D-threonine, respectively. These products can be obtained in stereoisomerically pure form in yields of 55-98 %, and are readily transformed into β-hydroxy-α-amino acids by mild hydrolysis or into 2-amino-1,3-diols by reduction.
- Seiple, Ian B.,Mercer, Jaron A. M.,Sussman, Robin J.,Zhang, Ziyang,Myers, Andrew G.
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supporting information
p. 4642 - 4647
(2014/05/20)
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- Stereoselective synthesis of (-)-chloramphenicol, (+)-thiamphenicol and (+)-sphinganine via chiral tricyclic iminolactone
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The stereoselective syntheses of (-)-chloramphenicol, (+)-thiamphenicol and (+)-sphinganine are described. The two continuous chiral centers within three target molecules were constructed through aldol reaction of chiral tricyclic iminolactone and aldehyde. Concise and efficient syntheses of (-)-chloramphenicol, (+)-thiamphenicol and (+)-sphinganine have been accomplished in practical four or three steps. The synthetic route featured in an aldol reaction between iminolactone 1a and 1b with aldehyde, which introduced the two continuous chiral centers within three target molecules. Copyright
- Li, Qiong,Zhang, Hongbo,Li, Chenguang,Xu, Pengfei
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p. 149 - 153
(2013/08/24)
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- Experimental and DEE study of the conversion of ephedrine derivatives into oxazolidinones. Double SN2 mechanism against SN1 mechanism
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Sulfonation of the N-Boc derivatives of 1,2-aminoalcohols, such as ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, thiomicamine, and chloramphenicol yields a mixture of the corresponding oxazolidinones with inversion (erythro derivatives) and!or retention of configuration (threo derivatives)at C5. We suggest a competition between two mechanisms: an intramolecular SN2 process initiated by attack of the carbonyl oxygen of the Boc group to the benzylic carbon and the other one through a double SN2 process. In the erythro derivatives the first mechanism is predominant, while in the threo derivatives both mechanisms have similar energy. This hypothesis is supported by theoretical calculations and additional experimental assays.
- El Moncef, Abdelkarim,El Hadrami, El Mestafa,González, Miguel A.,Zaballos, Elena,Zaragozá, Ramón J.
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body text
p. 5173 - 5184
(2010/08/22)
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- Method of Preparing Clopidogrel and Intermediates Used Therein
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Optically pure clopidogrel can be prepared in a high yield by optically resolving a racemic form of the compound of formula (II) using an optically active amine to form the optically active form of the compound of formula (III) or its acid-addition salt; and methylating the compound of formula (III) or its acid-addition salt.
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Page/Page column 5
(2008/12/08)
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- Straightforward access to protected syn α-amino-β-hydroxy acid derivatives
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(Chemical Equation Presented) Titanium stability: syn α-Amino-β- hydroxy acid derivatives were prepared in excellent diastereoselectivities by an aldol reaction with chiral N-(azidoacetyl)thiazolidin-2-thione derivatives (see scheme; NMP = N-methylpyrrolidinone). Titanium enolates of these derivatives are stable and provide a new and efficient method to access chiral amino acids.
- Patel, Jignesh,Clave, Guillaume,Renard, Pierre-Yves,Franck, Xavier
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supporting information; experimental part
p. 4224 - 4227
(2009/03/12)
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- A short asymmetric total synthesis of chloramphenicol using a selectively protected 1,2-diol
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A general route for the synthesis of chloramphenicol, thiamphenicol and fluoramphenicol is described. Chloramphenicol has been synthesized in 45% overall yield.
- Boruwa, Joshodeep,Borah, Jagat C.,Gogoi, Siddhartha,Barua, Nabin C.
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p. 1743 - 1746
(2007/10/03)
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- RESOLUTION OF α-(PHENOXY)PHENYLACETIC ACID DERIVATIVES
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The present invention provides a method for producing an enantiomerically enriched alpha-(phenoxy)phenylacetic acid compound of the formula (I): from its enantiomeric mixture, where R1 is alkyl or haloalkyl and X is halide.
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Page/Page column 48
(2010/02/10)
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- Hydrazinolysis of compounds containing oxazolidine ring
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We have studied hydrazinolysis of (4S, 5S)-3-benzyl-4-hydroxymethyl-5-(4-nitrophenyl)oxazolidine, (1R, 4S, 5S)-1-(4-nitrophenyl)-1-aza-3,7-dioxabicyclo[3,3,0]octane, and (1R, 4S,5S)-1-benzyl-4-(4-nitrophenyl)-1-azonia-3,7-dioxabicyclo[3,3,0]octane. We hav
- Madesclaire,Couquelet,Leal,Zaitsev,Sharipova
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- Synthetic applications of the cyclic iminocarbonate rearrangement Enantioselective syntheses of chloramphenicol and 4-epi-cytoxazone
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Chloramphenicol and 4-epi-cytoxazone have been enantioselectively synthesized using the asymmetric dihydroxylation and the cyclic iminocarbonate rearrangement as key steps. (C) 2000 Elsevier Science Ltd.
- Park, Jung Nam,Ko, Soo Y.,Koh, Hun Y.
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p. 5553 - 5556
(2007/10/03)
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- Stereoselective synthesis of chloramphenicol from D-serine
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An efficient synthesis of the widely used antibiotic chloramphenicol (1) is described. The key step in the synthesis involves chelation-controlled addition of phenylmagnesium bromide to a suitably protected D-serinal derivative, affording the pivotal D-threo 1,2-amino alcohol intermediate 3 in a highly stereoselective manner.
- Veeresa,Datta, Apurba
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p. 8503 - 8004
(2007/10/03)
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- Synthesis of chloramphenicol via a new intermediate 4-para-nitrophenyl- 5-formamido-1,3-dioxane
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4-Phenyl-5-amino-1,3-dioxane 4, obtained from β-bromo styrene 2 was protected as formamido derivative 5. Nitration of 5 followed by regioselective acylative cleavage of the nitro product 12 gave N-formyl-N- acetyl hemiacetal diacetate 16, which on sequential base and acid hydrolysis followed by dichloroacetylation gave chloramphenicol 1.
- Hazra, Braja G.,Pore, Vandana S.,Maybhate, Shailaja P.
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p. 1857 - 1864
(2007/10/03)
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- STEREOSELECTIVE SYNTHESIS OF (+/-)-threo-2-AMINO-1-(4-NITROPHENYL)-1,3-PROPANEDIOL
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Addition of hypobromic acid to styrene afforded styrene bromohydrin (I) which was dehydrated to ω-bromostyrene (II).Prince reaction of II with aqueous formaldehyde gave 5-bromo-4-phenyl-1,3-dioxane (III).The bromine atom in III was replaced with amino group by treatment with methanolic ammonia at 150 deg C and 6 - 8 MPa and the obtained threo-5-amino-4-phenyl-1,3-dioxane (IVa) was hydrolyzed to give (+/-)-threo-2-amino-1-phenyl-1,3-propanediol (V).Suitably chosen method of nitration converted the free base IVa or its N-acetyl derivative IVb into 5-amino-4-(4-nitrophe nyl)-1,3-dioxane (VIa) or its N-acetyl derivative VIb which without isolation were hydrolyzed to threo-2-amino-1-(4-nitrophenyl)-1,3-propanediol (VII), isolated as hydrochloride.The liberated base was resolved into enantiomers and dichloroacetylated in the known manner to give D-(-)-threo-2-dichloroacetylamino-1-(4-nitrophenyl)-1,3-propanediol (chloramphenicol).
- Cervinka, Otakar,Dudek, Vaclav,Fabryova, Anna,Kolar, Jiri,Lukac, Juraj,et al.
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p. 2748 - 2752
(2007/10/02)
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- Reversed-phase liquid chromatographic separation of enantiomeric and diastereomeric bases related to chloramphenicol and thiamphenicol.
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The important antimicrobial agents chloramphenicol and thiamphenicol are N-acylated amines whose chemical structures include two chiral centers. Each drug is the single enantiomer of R,R configuration. The N-deacylated bases of the drugs are important intermediates in their synthesis and optical resolution. In this report, reversed-phase HPLC methods are described for the separation of enantiomeric and diastereomeric bases of the two drugs and of two closely related bases used in some syntheses of the drugs. The stereoisomeric bases were derivatized with a homochiral isothiocyanate and the resulting diastereomeric thioureas were separated on C18 columns with methanol:water mixtures as mobile phases and detection at 254 nm. The four stereoisomeric bases of chloramphenicol and those of its unnitrated analogue were thus separable after derivatization with 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate. This reagent also allowed the separation of the D-threo isomer of the p-mercaptomethyl analogue of thiamphenicol base from its stereoisomers. The stereoisomers of thiamphenicol base were similarly separated with (R)-alpha-methylbenzyl isothiocyanate as the derivatizing agent. The diastereomers of chloramphenicol base and of thiamphenicol base were chromatographically separable after derivatization with the nonchiral reagent benzyl isothiocyanate. The procedures developed may be useful in the determination of the stereoisomeric composition of the drugs in research and in quality control, and may be applicable to other similar agents whose chemistry and pharmacology are receiving considerable attention.
- Gal,Meyer-Lehnert
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p. 1062 - 1065
(2007/10/02)
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- Resolution of Racemic Amines with 2-Methyl-2-phenylbutanedioic Acid
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Five racemic amines were resolved in high chemical and optical yields using (S)-(+)-2-methyl-2-phenylbutanedioic acid as resolving reagent.The reagent can be recovered quantitatively and without any change in its optical purity. (R)-(-)-2-Methyl-2-phenylbutanedioic acid was also obtained.
- Gharpure, Milind M.,Rao, A. S.
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p. 410 - 411
(2007/10/02)
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