Enzyme in der organischen Synthese: das Problem der molekularen Erkennung von Kohlenhydraten (Teil 1)

Wong, Chi‐Huey; Halcomb, Randall L.; Ichikawa, Yoshitaka; Kajimoto, Tetsuya

doi:10.1002/ange.19951070405

Cited by 59 publications

(9 citation statements)

References 206 publications

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“…It is clear that there is a good correlation between the predicted and experimental values for products [5][6][7][8]18, and 19. Thus, the global minima determined for the 4S epimers of adducts 5, 6, 18, and 19 have lower energies than the corresponding minima determined for the 4R epimers and, accordingly, these are the major reaction products, while the opposite is true for the diastereoisomers of adducts 7 and 8.…”

Section: Resultsmentioning

confidence: 86%

“…The conformational spaces of compounds [5][6][7][8]18, and 19 were exhaustively searched by using the two different strategies available in the MOE program in order to find the global energy minima. First, starting from an initially optimized structure, a systematic conformational search was run in which every non-amide nonterminal single bond was rotated in 60-1208 steps.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, dihydroxyacetone phosphate (DHAP) dependent aldolases [3,4] catalyse the aldol addition of DHAP to a variety of non-natural aldehyde acceptors to generate two stereogenic centers and add three carbon atoms to the carbon backbone. [5] Aldolases react highly stereoselectively at the C-3 position of DHAP (i.e., the stereocenter arising from DHAP addition), whereas the stereoselectivity at the C-4 position (i.e., the one generated from the addition to Abstract: The potential of l-fuculose-1-phosphate aldolase (FucA) as a catalyst for the asymmetric aldol addition of dihydroxyacetone phosphate (DHAP) to N-protected amino aldehydes has been investigated. First, the reaction was studied in both emulsion systems and conventional dimethylformamide (DMF)/H 2 O (1:4 v/v) mixtures.…”

Section: Introductionmentioning

confidence: 99%

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Aldol Additions of Dihydroxyacetone Phosphate to N‐Cbz‐Amino Aldehydes Catalyzed by L‐Fuculose‐1‐Phosphate Aldolase in Emulsion Systems: Inversion of Stereoselectivity as a Function of the Acceptor Aldehyde

Espelt¹,

Bujons²,

Parella

et al. 2005

Chemistry A European J

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The potential of L-fuculose-1-phosphate aldolase (FucA) as a catalyst for the asymmetric aldol addition of dihydroxyacetone phosphate (DHAP) to N-protected amino aldehydes has been investigated. First, the reaction was studied in both emulsion systems and conventional dimethylformamide (DMF)/H2O (1:4 v/v) mixtures. At 100 mM DHAP, compared with the reactions in the DMF/H2O (1:4) mixture, the use of emulsion systems led to two- to three-fold improvements in the conversions of the FucA-catalyzed reactions. The N-protected aminopolyols thus obtained were converted to iminocyclitols by reductive amination with Pd/C. This reaction was highly diastereoselective with the exception of the reaction of the aldol adduct formed from (S)-N-Cbz-alaninal, which gave a 55:45 mixture of both epimers. From the stereochemical analysis of the resulting iminocyclitols, it was concluded that the stereoselectivity of the FucA-catalyzed reaction depended upon the structure of the N-Cbz-amino aldehyde acceptor. Whereas the enzymatic aldol reaction with both enantiomers of N-Cbz-alaninal exclusively gave the expected 3R,4R configuration, the stereochemistry at the C-4 position of the major aldol adducts produced in the reactions with N-Cbz-glycinal and N-Cbz-3-aminopropanal was inverted to the 3R,4S configuration. The study of the FucA-catalyzed addition of DHAP to phenylacetaldehyde and benzyloxyacetaldehyde revealed that the 4R product was kinetically favored, but rapidly disappeared in favor of the 4S diastereoisomer. Computational models were generated for the situations before and after C-C bond formation in the active site of FucA. Moreover, the lowest-energy conformations of each pair of the resulting epimeric adducts were determined. The data show that the products with a 3R,4S configuration were thermodynamically more stable and, therefore, the major products formed, in agreement with the experimental results.

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Section: Resultsmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aldol Additions of Dihydroxyacetone Phosphate to N‐Cbz‐Amino Aldehydes Catalyzed by L‐Fuculose‐1‐Phosphate Aldolase in Emulsion Systems: Inversion of Stereoselectivity as a Function of the Acceptor Aldehyde

Espelt¹,

Bujons²,

Parella

et al. 2005

Chemistry A European J

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“…The preparation of this keto sugar, however, is not without problems (REITZ and BAXTER 1990;BAXTER and REITZ 1994 (ZIEGLER et al 1988;STRAUß et al 1990;PEDERSON et al 1993;PEDERSON and WONG 1989;VON DER OSTEN et al 1989;LOOK et al 1993;EFFENßERGER et al 1993;WONG et al 1995). The chirality is introduced by stereoselective aldol addition of dihydroxyacetone phosphate (89) to 3-azido-2-hydroxypropanal (90) under catalysis by rabbit muscle aldolase.…”

Section: I-deoxynojirimycinmentioning

confidence: 96%

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

Junge¹,

Matzke²,

Stoltefuß³

1996

Oral Antidiabetics

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A. IntroductionWhen intestinal sucrase and pancreatic a-amylase were identified at Bayer as new targets for improved diabetes therapy (PULS et al. 1973), the problem remained of the best way to find a potent and selective inhibitor of these enzymes. The medicinal chemist today has two alternatives in the search for a first lead compound, firstly the screening of thousands of compounds with maximum structural diversity in a random screening approach, or secondly the rational design of a lead compound, when the biochemical mechanism and the structure of the enzyme are weIl known. In the late 1960s, when we started to look for such potent and selective inhibitors, we had to choose the random screening approach, relying mainly on testing of extracts of the culture broths of microorganisms.Today the mechanism of enzymatic splitting of sucrose by intestinal sucrase is fairly weIl understood. First the glucosidic oxygen atom of sucrose is protonated via a carboxyl group of the enzyme. The splitting of the glucosidic C-O bond is further facilitated by the glucosyl cation being stabilized by a second carboxylate group of the enzyme (COGOLI and SEMENZA 1975). FinaIly, the glucosyl cation reacts with water to give the products 0-glucose and o-fructose. The protonated sucrose molecule land the glucosyl cation 11 are two high-energy intermediates of the enzymatic reaction. Today we know that mimics of such high-energy intermediates are often potent inhibitors of the enzyme. Accordingly, compounds similar in structure to o-glucose but with an easily protonated basic N-atom either in the position of the anomeric oxygen atom (inhibitor type I) or in the position of the ring oxygen atom (inhibitor type 11) should be potent inhibitors of sucrase (Fig. 1). Interestingly, both types of inhibitors represented by either acarbose or I-deoxynojirimycin were found in our random screening. In the foIlowing sections these two types of inhibitors are not discussed in a historical order but under structural criteria. Not included in this discussion are the a-amylase inhibitors of protein nature because there is no evidence that they will find any therapeutic application.

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“…Die Anfangsgeschwindigkeit und die Transglycosylierungsausbeute steigen allerdings mit zunehrnender Konzentration an 3 (Nr. [4][5][6]. Das aus 2 entstehende aktive Intermediat ist demzufolge gegeniiber Wasser weuiger reaktiv als gegenuber 3.…”

Section: Zuschriftenunclassified

Eine praktikable Synthese von N‐Acetyl‐D‐lactosamin mit Galactose‐Oxidase und β‐Galactosidase

Kimura¹,

Takayama²,

Huang³

et al. 1996

Angewandte Chemie

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Gleich zwei Enzyme werden eingesetzt, um N‐Acetyl‐D‐lactosamine effizient zugänglich zu machen: Zunächst wird GalβOpNP mit dem p‐Nitrophenyl(pNP)‐Rest als guter Abgangsgruppe mit Galactose‐Oxidase zum 6‐Oxo‐Derivat oxidiert, das dann durch Transglycosylierung mit GlcNAcβOMe in Gegenwart von β‐Galactosidase aus Bacillus circulans in guten Ausbeuten zum Disaccharid umgesetzt wird [Gl. (a)].

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Enzyme in der organischen Synthese: das Problem der molekularen Erkennung von Kohlenhydraten (Teil 1)

Cited by 59 publications

References 206 publications

Aldol Additions of Dihydroxyacetone Phosphate to N‐Cbz‐Amino Aldehydes Catalyzed by L‐Fuculose‐1‐Phosphate Aldolase in Emulsion Systems: Inversion of Stereoselectivity as a Function of the Acceptor Aldehyde

Aldol Additions of Dihydroxyacetone Phosphate to N‐Cbz‐Amino Aldehydes Catalyzed by L‐Fuculose‐1‐Phosphate Aldolase in Emulsion Systems: Inversion of Stereoselectivity as a Function of the Acceptor Aldehyde

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

Eine praktikable Synthese von N‐Acetyl‐D‐lactosamin mit Galactose‐Oxidase und β‐Galactosidase

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