- A smart library of epoxide hydrolase variants and the top hits for synthesis of (S)-β-blocker precursors
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Microtuning of the enzyme active pocket has led to a smart library of epoxide hydrolase variants with an expanded substrate spectrum covering a series of typical β-blocker precursors. Improved activities of 6- to 430-fold were achieved by redesigning the active site at two predicted hot spots. This study represents a breakthrough in protein engineering of epoxide hydrolases and resulted in enhanced activity toward bulky substrates. Hot pockets: Microtuning of the enzyme active pocket gives a smart library of epoxide hydrolase variants with an expanded substrate spectrum covering a series of typical β-blocker precursors. Improved activities of 6- to 430-fold were achieved by redesigning the active site at two predicted hot spots, and enhanced activity toward bulky substrates was found.
- Kong, Xu-Dong,Ma, Qian,Zhou, Jiahai,Zeng, Bu-Bing,Xu, Jian-He
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p. 6641 - 6644
(2014/07/08)
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- Enantioselective synthesis of (S)-timolol via kinetic resolution of terminal epoxides and dihydroxylation of allylamines
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An efficient enantioselective synthesis of (S)-timolol has been described using chiral Co-salen-catalyzed kinetic resolution of less expensive (±)-epichlorohydrin with 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole in good overall yield (55%) and excellent enantioselectivity (98%). Synthesis of (S)-timolol has also been achieved using hydrolytic kinetic resolution as well as asymmetric dihydroxylation routes in 90% ee and 56% ee, respectively.
- Narina, Srinivasarao V.,Sudalai, Arumugam
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p. 3026 - 3030
(2007/10/03)
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- Biocatalytic asymmetric synthesis of (S)- and (R)-Timolol
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A new biocatalytic route for the synthesis of both enantiomers of Timolol (1) is described. Starting from 3,4-dichloro-1,2,5-thiadiazole (2), (R)- and (S)-Timolol (87% ee) were obtained in 35% and 30% overall yield, respectively. Asymmetric reduction of the intermediate haloketone 5 with baker's yeast afforded the corresponding halohydrin 6 in the optically active form (87% ee), which gave the R enantiomer (distomer) of Timolol. The S enantiomer (eutomer) was obtained via inversion of configuration of the halohydrin following the Mitsunobu procedure.
- Tosi, Giovanni,Zironi, Federica,Caselli, Emilia,Forni, Arrigo,Prati, Fabio
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p. 1625 - 1628
(2007/10/03)
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- Arenesulfonate Derivatives of Homochiral Glycidol: Versatile Chiral Building Blocks for Organic Synthesis
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The preparation of a series of crystalline arenesulfonate derivatives of enantiomerically enriched glycidol is described.The enhancement of optical purity by recrystallization was particularly successful for two of these derivatives, glycidyl tosylate and glycidyl 3-nitrobenzenesulfonate, which were obtained in 97 percent ee and 99 percent ee, respectively.Very high regioselectivity was observed in the reactions of these compounds with a variety of nucleophiles, including aryl oxides, Et2AlCN, organometallic reagents, and BH3-NaBH4.The application of this methodology to the synthesis of homochiral β-adrenergic blocking agents and homochiral terminal epoxides is discussed.
- Klunder, Janice M.,Onami, Tetsuo,Sharpless, K. Barry
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p. 1295 - 1304
(2007/10/02)
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