Improved Access to Imidazole‐phosphonic Acids: Synthesis of <scp>D</scp>‐<i>manno</i>‐Tetrahydroimidazopyridine‐2‐phosphonates

Terinek, Miroslav; Vasella, Andrea

doi:10.1002/hlca.200490067

Cited by 17 publications

(9 citation statements)

References 66 publications

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“…± We planned to synthesize the gluco-and manno-configured methyl esters 16 and 20 by condensing the gluconothio-1,5-lactam 26 [7] with the b-amino ester 25. While the synthesis of imidazoles by condensation of thionolactams with 2-aminoacetaldehyde dimethyl acetal is well-precedented [7] [18 ± 20], there are only very few examples of the condensation with substituted amino acetals [21] [22]. To prepare the methyl ester 25 2 ) (Scheme), we started from benzyl[(2,2-dimethoxy)-ethylidene]amine (22), which we recently described as useful precursor of a-aminoScheme 1 a) AcOMe, BuLi, (i-Pr) 2 (27/28 56 : 44) by conducting the reaction on a larger scale (235 mg of 26) in the presence of HgCl 2 .…”

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confidence: 99%

Synthesis of Tetrahydropyridoimidazole‐2‐acetates: Effect of Carboxy and Methoxycarbonyl Groups at C(2) on the Inhibition of Some β‐ and α‐Glycosidases

Terinek

Vasella

2004

Helvetica Chimica Acta

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The gluco-and manno-tetrahydropyridoimidazole-2-acetates and -acetic acids 16 and 17, and 20 and 21, respectively, were synthesized by condensation, in the presence of HgCl 2 , of the known thionolactam 26 with the b-amino ester 25 that was obtained by addition of AcOMe to the imine 22, followed by debenzylation. The resulting methyl esters 16 and 20 were hydrolyzed to the acetic acids 17 and 21. The (methoxycarbonyl)-imidazole 14 and the acid 15 were obtained via the known aldehyde 29. The imidazoles 14 ± 17, 20, and 21 were tested as inhibitors of the b-glucosidase from Caldocellum saccharolyticum, the a-glucosidase from brewers yeast, the b-mannosidase from snail, and the a-mannosidase from Jack beans (Tables 1 ± 3). There is a similar dependence of the K i values on the nature of the C(2)-substituent in the gluco-and manno-series. With the exception of 19, manno-imidazoles are weaker inhibitors than the gluco-analogues. The methyl acetates 16 and 20 are 3 ± 4 times weaker than the methyl propionates 5 and 11, in agreement with the hydrophobic effect. The gluco-configured (methoxycarbonyl)-imidazole 14 is 20 times weaker than the methyl acetate 16, reflecting the reduced basicity of 14, while the manno-configured (methoxycarbonyl)-imidazole 18 is only 1.2 times weaker than the methyl acetate 20, suggesting a binding interaction of the MeOCO group and the b-mannosidase. The carboxylic acids 6, 12, 15, 17, 19, and 21 are weaker inhibitors than the esters, with the propionic acids 6 and 12 being the strongest and the carboxy-imidazoles 15 and 19 the weakest inhibitors. The manno-acetate 21 inhibits the b-mannosidase ca. 8 times less strongly than the propionate 12, but only 1.5 times more strongly than the carboxylate 19, suggesting a compensating binding interaction also of the COOH group and the b-mannosidase. The a/b selectivity for the gluco-imidazoles ranges between 110 for 15 and 13.4´10 3 for 6; the manno-imidazoles are less selective. The methyl propionates proved the strongest inhibitors of the a-glucosidase (IC 50 (5) 25 mm) and the a-mannosidase (K i (11) 0.60 mm). . The carboxymethyl group at C(2) does not appear to be important for the inhibitory activity, since debranched nagstatin analogues and related C(2)-unsubstituted glucose-and mannose-derived tetrahydroimidazopyridines are also potent inhibitors of b-glycosidases [5 ± 7]. These observations and the rationalisation of the inhibitory activity of these and analogous azoles ± their similarity with the putative reaction intermediate, and the cooperative interaction of the azole ring with the catalytic acid and nucleophile ± indicated a negligible role for the substituents at C(2) [8 ± 10]. Subsequently, however, it was shown that C(2)-substituents of tetrahydropyridoimidazoles (and corresponding substituents of related azoles and pyrroles) can strongly affect the inhibitory properties, either indirectly, by competing with the catalytic acid for H-bonding to the glycosidic heteroatom, and/or

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confidence: 99%

Synthesis of Tetrahydropyridoimidazole‐2‐acetates: Effect of Carboxy and Methoxycarbonyl Groups at C(2) on the Inhibition of Some β‐ and α‐Glycosidases

Terinek

Vasella

2004

Helvetica Chimica Acta

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“…s, CH 2 ÀC (2) 3304w, 3163w, 3089w, 3067w, 3031m, 3011m, 2954m, 2925m, 2869m, 1953w, 1877w, 1810w, 1736s, 1603w, 1564w, 1496w, 1454m, 1438m, 1407w, 1363m, 1306m, 1269m, 1099s, 1018m, 911w. 1 H-NMR (CDCl 3 , 300 MHz): see Table 5; additionally, 3.57 (d, J 16.5, CHÀC (2) 2926m, 2868m, 2109s, 1951w, 1879w, 1810w, 1747s, 1673w, 1603w, 1521w, 1496w, 1454m, 1437m, 1364m, 1334m, 1266m, 1163m, 1097s, 1076s, 1027m, 910w. 2) (25). a) A soln.…”

Section: Experimental Partmentioning

confidence: 98%

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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“…Normal workup (AcOEt/H 2 O/brine) and FC (AcOEt/hexane 1 : 4) gave 21 (123 mg, 37%) and 22 (125 mg, 37%). (22 (3) 3410w, 3067w, 2963m, 2892w, 2867s, 1604w, 1496w, 1483m, 1454m, 1362w, 1262m, 1090s, 1070s, 1028w. 1 H-NMR (300 MHz, CDCl 3 ): see Table 2; additionally, 7.42 -7.27 (m, 15 arom. H); 7.14 (d, J = 1.8), 7.05 (d, J = 1.5) (HÀC(2), HÀC (3) 3063w, 3032m, 3013w, 2966w, 2866w, 1738s, 1602m, 1496m, 1454w, 1265s, 1213s, 1087s, 1003m, 909w, 821w.…”

Section: A C H T U N G T R E N N U N G Si)mentioning

confidence: 99%

“…This expectation is also in agreement with the obser-of this galacturonate, possessing an axial leaving group at C(4), occurred particularly readily. It is known that aminoacetaldehyde dimethyl acetals substituted with an electron-withdrawing group are less reactive towards thionolactams than the unsubstituted analogue [22] [23]. The scope of this method for the formation of imidazopyridines from thionolactams and aminoacetaldehyde dimethyl acetals thus depends sensibly on the nucleophilicity of the acetal and of the intermediate amidine.…”

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confidence: 98%

Synthesis of Glucuronic, Mannuronic, and Galacturonic Acid-Derived Imidazoles as Inhibitors of Bovine Liverβ-Glucuronidase

Pabba¹,

Mohal²,

Vasella³

2006

HCA

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The gluco-, manno-, and galacto-configured imidazopyridine-5-carboxylates 5 -7, respectively, were synthesized and evaluated as inhibitors of bovine liver b-glucuronidase. The gluconolactam 15 was transformed into the gluco-and manno-imidazoles 5 and 6 in nine steps and in an overall yield of 9 and 12%, respectively. Oxidation and esterification of the selectively protected gluco-and manno-configured hydroxymethyl-imidazopyridines 23 and 25, respectively (both obtained from gluconolactam 15), provided the benzhydryl esters 24 and 26, respectively. Hydrogenolysis afforded the gluco-imidazopyridine-carboxylic acid 5 and the manno-isomer 6. Similarly, the hydroxymethyl-imidazopyridine 33, obtained from galactonolactam 27, was subjected to oxidation, esterification, and deprotection to afford the galacto-configured imidazopyridine-carboxylate 7 in ten steps from the galactonolactam 27 and in an overall yield of 13%. The gluco-configured imidazole 5 is the strongest known inhibitor of b-glucuronidases (K i = 12 nM), while the manno-and galacto-configured imidazoles 6 and 7 are micromolar inhibitors of bovine b-glucuronidase. The small difference between the inhibitory strength of the imidazopyridinecarboxylic acid 5 and the tetrazolopyridine-carboxylic acid 1, and the difference between the configurational selectivity of 5 -7 as compared to the unselectivity of the corresponding lactams 3 and 4 are discussed.Introduction. -Lactone-type inhibitors of retaining b-glycosidases possessing an annulated imidazole ring with a N-atom correctly located to mimic the glycosidic Oatom are stronger inhibitors 1 ) than the corresponding tetrazoles and triazoles 2 ); they are also stronger inhibitors than the corresponding glyconolactams and hydroximolactams . This correlation should also be valid for the inhibition of b-glucuronidases 3 ), and imidazopyridine-5-carboxylates are expected to be stronger glycuronidase inhibitors than the corresponding known glycarolactam and tetrazolopyridine-5-carboxylates [17] [18]. This expectation is also in agreement with the obser-

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Improved Access to Imidazole‐phosphonic Acids: Synthesis of D‐manno‐Tetrahydroimidazopyridine‐2‐phosphonates

Cited by 17 publications

References 66 publications

Synthesis of Tetrahydropyridoimidazole‐2‐acetates: Effect of Carboxy and Methoxycarbonyl Groups at C(2) on the Inhibition of Some β‐ and α‐Glycosidases

Synthesis of Tetrahydropyridoimidazole‐2‐acetates: Effect of Carboxy and Methoxycarbonyl Groups at C(2) on the Inhibition of Some β‐ and α‐Glycosidases

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

Synthesis of Glucuronic, Mannuronic, and Galacturonic Acid-Derived Imidazoles as Inhibitors of Bovine Liverβ-Glucuronidase

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