- 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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- Integrated Chemical Process: Convenient Synthesis of Enantiopure 2-Hydroxymethyl-1,4-benzodioxane Derivatives under Iterative Catalysis of CsF
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One-pot processes to enantiopure 2-hydroxymethyl-1,4-benzodioxane derivatives have been established under catalysis of CsF. A sequence of O-alkylation of catechols with enantiopure 3-chloro-1,2-propanediol, tosylation of the alcohol, deprotection of the benzyl ether, and intramolecular etherification can be integrated. The O-alkylation is also feasible with enantiopure oxiranes. All reactions, except debenzylation, are catalyzed by a single catalyst, CsF. The hydrogenative deprotection of the benzyl ether with Pd-C is compatible with the CsF-catalyzed reactions. The integrated protocols give rise not only to compaction of the whole processes but also to increases in overall yields.
- Kitaori, Kazuhiro,Furukawa, Yoshiro,Yoshimoto, Hiroshi,Otera, Junzo
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- CsF in organic synthesis. Regioselective nucleophilic reactions of phenols with oxiranes leading to enantiopure β-blockers
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The two modes of the paths in the reaction of oxiranes with phenols are completely controlled by CsF. Glycidyl nosylate undergoes exclusive substitution at the C1 position whereas the ring-opening (C-3 attack) occurs with epichlorohydrin, glycidol, and 1,2-epoxyalkanes. These reactions provide convenient access to enantiopure β-blockers.
- Kitaori, Kazuhiro,Furukawa, Yoshiro,Yoshimoto, Hiroshi,Otera, Junzo
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p. 14381 - 14390
(2007/10/03)
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- N-Dealkylation of oxprenolol: Formation of 3-aryloxypropane-1,2-diol,3-aryloxylactic acid, and 2-aryloxyacetic acid metabolites in the rat
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Oxprenolol (1), like related β-adrenergic antagonists, undergoes oxidative N-dealkylation to form the corresponding 3-aryloxypropane-1,2-diol (2), 3-aryloxylactic acid (3), and 2-aryloxyacetic acid (4) metabolites. Compounds 3 and 4 were synthesized by conversion of 2-allyloxyphenol (5) to the aryloxyacetaldehyde 6 and subsequent elaboration to the desired acids. Both acids (3 and 4) and glycol 2 were confirmed as metabolites formed from 1 in vivo in the rat and in vitro in the rat liver 9000 x g supernatant fraction. Incubation of a pseudoracemate of 1, made up of equal molar amounts of (2S)-1-d0 and (2R)-1-d2, showed that 2 and 3 arise principally from (2S)-1 by S/R ratios of ~ 5:1 and 2:1, respectively. On the other hand, acetic acid derivative 4 arises about equally from both enantiomers of 1.
- Nelson,Bartels
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