- Synthesis of non-natural carbohydrates from glycerol and aldehydes in a one-pot four-enzyme cascade reaction
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A simple procedure has been developed for the synthesis of enantio- and diastereomerically pure carbohydrate analogues from glycerol and a variety of aldehydes in one pot using a four-enzyme cascade reaction. As a proof of concept of the usefulness of this enzymatic catalytic cascade the naturally occurring azasugar d-fagomine was synthesized. This work highlights the potential value of using enzymes in cascade reactions to selectively form complex products that by previous traditional organic chemistry could only be obtained via repeated isolation and purification of intermediates.
- Babich, Lara,Van Hemert, Lieke J. C.,Bury, Aleksandra,Hartog, Aloysius F.,Falcicchio, Pierpaolo,Van Der Oost, John,Van Herk, Teunie,Wever, Ron,Rutjes, Floris P. J. T.
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- A new concept for production of (3S,4R)-6-[(benzyloxycarbonyl)amino]-5,6-dideoxyhex-2-ulose, a precursor of d-fagomine
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A novel cascade reaction for the production of aldol adduct (3S,4R)-6-[(benzyloxycarbonyl)amino]-5,6-dideoxyhex-2-ulose was studied in this work. The strategy combines three enzymes in one pot: (i) horse liver alcohol dehydrogenase for the oxidation of N-Cbz-3-aminopropanol to the corresponding aldehyde, (ii) NADH oxidase for the regeneration of coenzyme NAD+ and (iii) d-fructose-6-phosphate aldolase from E. coli A129S variant for the aldol addition of dihydroxyacetone to N-Cbz-3-aminopropanal. On the basis of preliminary experiments, optimization of the initial reaction conditions was done using statistical methods, i.e. factorial design of experiments. 79% yield of aldol adduct was achieved in the batch reactor after optimization.
- Sudar, Martina,Findrik, Zvjezdana,Vasi-Raki, Durda,Soler, Anna,Claps, Pere
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- Structure-guided redesign of d-fructose-6-phosphate aldolase from E. coli: Remarkable activity and selectivity towards acceptor substrates by two-point mutation
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Structure-guided re-design of the acceptor binding site of d-fructose-6-phosphate aldolase from E. coli leads to the construction of FSA A129S/A165G double mutant with an activity between 5- to >900-fold higher than that of wild-type towards N-Cbz-aminoal
- Gutierrez, Mariana,Parella, Teodor,Joglar, Jesus,Bujons, Jordi,Clapes, Pere
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supporting information; experimental part
p. 5762 - 5764
(2011/07/08)
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- D-fructose-6-phosphate aldolase-catalyzed one-pot synthesis of iminocyclitols
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A one-pot chemoenzymatic method for the synthesis of a variety of new iminocyclitols from readily available, non-phosphorylated donor substrates has been developed. The method utilizes the recently discovered fructose-6-phosphate aldolase (FSA), which is functionally distinct from known aldolases in its tolerance of different donor substrates as well as acceptor substrates. Kinetic studies were performed with dihydroxyacetone (DHA), the presumed endogenous substrate for FSA, as well as hydroxy acetone (HA) and 1-hydroxy-2-butanone (HB) as donor substrates, in each case using glyceraldehyde-3-phosphate as acceptor substrate. Remarkably, FSA used the three donor substrates with equal efficiency, with kcat/KM-values of 33, 75, and 20 M -1 s-1, respectively. This level of donor substrate tolerance is unprecedented for an aldolase. Furthermore, DHA, HA, and HB were accepted as donors in FSA-catalyzed aldol reactions with a variety of azido- and Cbz-amino aldehyde acceptors. The broad substrate tolerance of FSA and the ability to circumvent the need for phosphorylated substrates allowed for one-pot synthesis of a number of known and novel iminocyclitols in good yields, and in a very concise fashion. New iminocyclitols were assayed as inhibitors against a panel of glycosidases. Compounds 15 and 16 were specific α-mannosidase inhibitors, and 24 and 26 were potent and selective inhibitors of β-N-acetylglucosaminidases in the submicromolar range. Facile access to these compounds makes them attractive core structures for further inhibitor optimization.
- Sugiyama, Masakazu,Hong, Zhangyong,Liang, Pi-Hui,Dean, Stephen M.,Whalen, Lisa J.,Greenberg, William A.,Wong, Chi-Huey
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p. 14811 - 14817
(2008/09/19)
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- Fructose-6-phosphate aldolase in organic synthesis: Preparation of D-fagomine, N-alkylated derivatives, and preliminary biological assays
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(Chemical Equation Presented) D-Fructose-6-phosphate aldolase (FSA) mediates a novel straightforward two-step chemo-enzymatic synthesis of D-fagomine and some of its N-alkylated derivatives in 51% isolated yield and 99% de. The key step is the FSA-catalyzed aldol addition of simple dihydroxyacetone (DHA) to N-Cbz-3-aminopropanal. The use of FSA greatly simplifies the enzymatic procedures that used dihydroxyacetonephosphate or DHA/esters. Some N-alkyl derivatives synthesized elicited antifungal and antibacterial activity as well as enhanced inhibitory activity, and selectivity against β-galactosidase and α-glucosidase.
- Castillo, Jose A.,Calveras, Jordi,Casas, Josefina,Mitjans, Montserrat,Vinardell, M. Pilar,Parella, Teodor,Inoue, Tomoyuki,Sprenger, Georg A.,Joglar, Jesus,Clapes, Pere
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p. 6067 - 6070
(2008/02/07)
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- ENZYMATIC ALDOL CONDENSATION AS A ROUTE TO HETEROCYCLES: SYNTHESIS OF 1,4-DIDEOXY-1,4-IMINO-D-ARABINITOL, FAGOMINE, 1-DEOXYNOJIRIMYCIN AND 1-DEOXYMANNOJIRIMYCIN
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1,4-Dideoxy-1,4-imino-D-arabinitol, fagomine (1,2,5-trideoxy-1,5-imino-D-arabinohexitol), 1-deoxynojirimycin (1,5-dideoxy-1,5-imino-D-glucitol) and 1-deoxymannojirimycin (1,5-dideoxy-1,5-imino-D-mannitol) have been prepared via fructose-1,6-diphosphate aldolase catalyzed condensation followed by catalytic intramolecular reductive amination.
- Pederson, Richard L.,Wong, Chi-Huey
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p. 477 - 480
(2007/10/02)
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