- 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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- Oxidant controlled regio- and stereodivergent azidohydroxylation of alkenes via I2 catalysis
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A novel, I2 catalyzed regio- and stereodivergent vicinal azidohydroxylation of alkenes leading to 1,2-azidoalcohols in high yields (up to 92%) and excellent dr (up to 98%) has been developed. This unprecedented transformation employs NaN3 and DMF as N- and O-nucleophiles respectively. The role of DMF as the O-source in the reaction has been unequivocally proven by 18O labelling studies.
- Prasad,Reddi,Sudalai
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supporting information
p. 10276 - 10279
(2015/06/25)
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- Stereoselective syntheses of (-)-chloramphenicol and (+)-thiamphenicol
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Chloramphenicol and thiamphenicol have been enantioselectively synthesized using an asymmetric halohydrin reaction as a key step. In particular, halomethoxylation reaction was used, where O-methyl functions as a hydroxyl protecting group and eliminates an additional protection step.
- Hajra, Saumen,Karmakar, Ananta,Maji, Tapan,Medda, Amiya Kumar
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p. 8959 - 8965
(2007/10/03)
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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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- PPMP as a ceramide catabolism inhibitor for cancer treatment
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The present invention relates to a method of treating a hyperproliferative disorder comprising administering a ceramide generating retinoid comprising a retinoic acid derivative or a pharmaceutically acceptable salt thereof, and D-threo-PPMP as a ceramide degradation inhibitor or a pharmaceutically acceptable salt thereof, wherein the hyperproliferative disorder is a tumor; and wherein the ceramide generating retinoid is administered in an amount effective to produce necrosis, apoptosis or both in the tumor, and the ceramide degradation inhibitor is administered in an amount effective to increase the necrosis, apoptosis or both in the tumor over that expected to be produced by the sum of that produced by the ceramide generating retinoid and the ceramide degradation inhibitor when administered separately.
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Page/Page column 5; sheet 6
(2010/02/11)
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- Synthesis and biological evaluation of four stereoisomers of PDMP-analogue, N-(2-decylamino-3-hydroxy-3-phenylprop- 1-yl)-β-valienamine, and related compounds
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All stereoisomers with regard to C-1 and 2 of 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) analogue containing unsaturated (β-valienamine) and saturated 5a-carba-β-D-glucopyranosylamine (β-validamine) residues in place of morpholine moiety were synthesized. Although PDMP is a potent and specific glucosylceramide synthase inhibitor, the former valienamine analogues (4a-d) have been shown to be strong glucocerebrosidase inhibitors (IC50 3-7 x10-7 M). The latter validamine analogues (5a-d) were also moderate glucocerebrosidase inhibitors (IC50 5-20 x 10-6 M). A series of compounds synthesized lacked an inhibitory potency against the glucosyltransferase at all. Whereas the analogue 6a composed of epimeric α-valienamine residue did not possess any potency against both enzymes.
- Ogawa, Seiichiro,Mito, Tamami,Taiji, Eiichi,Jimbo, Masayuki,Yamagishi, Kiwamu,Inokuchi, Jin-Ichi
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p. 1915 - 1920
(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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- 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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- 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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- Note on a Simple Synthesis of (+/-)-threo-2-Amino-1-phenyl-1,3-propanediole
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A synthesis of the title compound starting from methyl trans-5-phenyl-2-oxazoline-4-carboxylate (3) is described.
- Schoellkopf, Ulrich,Scheunemann, Karl-Heinz
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p. 1348 - 1349
(2007/10/02)
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