The Total Synthesis of a Glycosidase Inhibitor, Nagstatin

Tatsuta, Kuniaki; Miura, Shota; Gunji, Hiroki

doi:10.1246/bcsj.70.427

Cited by 38 publications

(22 citation statements)

References 17 publications

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“…Tetrahydroimidazopyridines, such as 24, are potent inhibitors of b-glycosidases [53] [54] [55]. To the best of our knowledge, only one imidazole has been shown to inhibit an a-glycosidase, viz.…”

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Synthesis of anL-Fucose-Derived Cyclic Nitrone and its Conversion toα-L-Fucosidase Inhibitors

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Vasella

1999

HCA

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The L‐fuco‐nitrone 1 has been synthesized from allyl 4,6‐O‐benzylidene‐α‐D‐glucopyranoside (4) in 11 steps and an overall yield of 18%. The key step is the intramolecular alkylation of an intermediary 1,1‐bis(hydroxylamine) derived from the tosyloxy oximes (E/Z)‐2. The nitrone 1 has been transformed into the diamine 30, the indolizidines 39 and 40, the indolizidinones 34 and 35, and the imidazole 44, all inhibiting bovine epididymis α‐L‐fucosidase with IC50 values between 105 nM and 240 μM.

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Synthesis of anL-Fucose-Derived Cyclic Nitrone and its Conversion toα-L-Fucosidase Inhibitors

Peer

Vasella

1999

HCA

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“…of 23 (51 mg, 94.0 mmol) in toluene (1 ml) was successively treated with DPPA (0.1 ml, 0.464 mmol) and DBU (70 ml, 0.469 mmol), stirred for 5 h at 238, diluted with CH 2 Cl 2 (50 ml), and washed with sat. NH 4 Cl soln. (3 Â 25 ml).…”

Section: Experimental Partmentioning

confidence: 99%

“…Under otherwise identical conditions, the gluco-imidazole 22 decomposed to a complex mixture from which the gluco-and manno-configured azides 25 and 26 were isolated in 6 and 3% yield, respectively. In contradistinction, the substitution of C(8)ÀOH of the galacto-analogue of 22 (HN 3 , Bu 3 P, DEAD) provided 77% of the galacto-azide [3] [4]. The inversion of configuration observed for the transformation of 23 to 25 marks only a formal contrast to the retention of configuration observed by Tatsuta et al for the substitution of the galacto-configured analogue of 23 [4] (cf.…”

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confidence: 96%

“…In contradistinction, the substitution of C(8)ÀOH of the galacto-analogue of 22 (HN 3 , Bu 3 P, DEAD) provided 77% of the galacto-azide [3] [4]. The inversion of configuration observed for the transformation of 23 to 25 marks only a formal contrast to the retention of configuration observed by Tatsuta et al for the substitution of the galacto-configured analogue of 23 [4] (cf. [15] [23]), considering the preferred pseudoaxial addition of azide to an intermediate azoniafulvenium cation of type B (Scheme 2) presumably formed in both cases.…”

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Synthesis of N‐Acetylglucosamine‐Derived Nagstatin Analogues and Their Evaluation as Glycosidase Inhibitors

Terinek¹,

Vasella²

2005

Helvetica Chimica Acta

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The gluco-configured analogue 15 of nagstatin (1) and the methyl ester 14 were synthesized via condensation of the thionolactams 17 or 18 with the b-amino ester 19. The silyl ethers 20 and 21 resulting from 17 were desilylated to 22 and 23; these alcohols were directly obtained by condensing 18 and 19. The attempted substitution of the C(8)ÀOH group of 22 by azide under Mitsunobu conditions led unexpectedly to the deoxygenated a-azido esters 24. The desired azide 25 was obtained by treating the manno-configured alcohol 23 with diphenyl phosphorazidate. The azide was transformed to the debenzylated acetamido ester 14 that was hydrolyzed to the nagstatin analogue 15. The imidazole-2-acetates 14 and 15 are nanomolar inhibitors of the Nacetyl-b-glucosaminidases from Jack beans and from bovine kidney, submicromolar to micromolar inhibitors of the b-glucosidase from Caldocellum saccharolyticum, and rather weak inhibitors of the snail b-mannosidase. In all cases, the ester was a stronger inhibitor than the corresponding acid. As expected from their glucoconfiguration, both imidazopyridines 14 and 15 are stronger inhibitors of the b-N-acetylglucosaminidase from bovine kidney than nagstatin.Introduction. ± Nagstatin (1), a strong inhibitor of several hexosaminidases [1 ± 4], is a N-acetylgalactosamine-derived tetrahydropyridoimidazole-2-acetic acid [5]. Its inhibitory activity is essentially associated with the imidazole ring and not with the carboxymethyl substituent [2], although substituents on the imidazole ring may strongly affect the inhibition of b (and a-)-glycosidases [6 ± 8]. In the preceding paper [9], we described the influence of the hydrophobic character of C(2)-methyl ester and carboxylic acid substituents on the inhibition of b-glycosidases. Imidazole-2-propionates 10 ± 13 are stronger inhibitors of the b-glucosidase from Caldocellum saccharolyticum and of the b-mannosidase from snail than imidazole-2-acetates 6 ± 9, and these are stronger than imidazole-2-carboxylates 2 ± 5. There is a parallel sequence of inhibitory activity for the methyl esters and the corresponding acids, with the esters being stronger inhibitors.

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“…The rational starting point is the aforesaid isomers 31 and 33 (ref. 10). The regioselective introduction of an allyl group on their C-2 positions was investigated under a variety of conditions.…”

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Recent Progress in Total Synthesis and Development of Natural Products Using Carbohydrates.

Tatsuta

1997

J. Syn. Org. Chem., Jpn.

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The Total Synthesis of a Glycosidase Inhibitor, Nagstatin

Abstract: A glycosidase inhibitor, nagstatin, has been synthesized from protected l-ribofuranose through the inter- and intra-molecular nucleophilic reactions of the imidazole moieties and the regioselective introduction of a carboxymethyl group.

Cited by 38 publications

References 17 publications

Synthesis of anL-Fucose-Derived Cyclic Nitrone and its Conversion toα-L-Fucosidase Inhibitors

Synthesis of anL-Fucose-Derived Cyclic Nitrone and its Conversion toα-L-Fucosidase Inhibitors

Synthesis of N‐Acetylglucosamine‐Derived Nagstatin Analogues and Their Evaluation as Glycosidase Inhibitors

Recent Progress in Total Synthesis and Development of Natural Products Using Carbohydrates.

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