The phosphonic acids 3 and 4 were prepared to compare their inhibitory activity on Vibrio cholerae sialidase with the one of the corresponding N‐acetyl‐2‐deoxyneuraminic acids 5 and 6. Thus, hydrogenation and benzylation of methyl N‐acetyl‐2,3‐didehydro‐2‐deoxyneuraminate (1MeNeu2en5Ac; 7) gave a mixture of the fully O‐benzylated benzyl and methyl esters 9 and 10, the partially O‐benzylated benzyl and methyl esters 11 and 12, and the fully O‐and N‐benzylated benzyl and methyl esters 13 and 14 (Scheme 1). Transesterification of 9 to 10 and hydrolysis of 10 gave the acid 15. Oxidative decarboxylation of 15 with Pb(OAc)4 gave a 1:9 mixture of the α‐and β‐D‐glycero‐D‐galacto‐acetates 16 and 17. Phosphonoylation of 17 with P(OMe)3 and Me3SiOTf gave a 1.3:1 mixture of the phosphonates 18 and 19, which were deprotected to give the (4‐acetamido‐2,4‐dideoxy‐D‐glycero‐α‐and β‐D‐galacto‐octopyranosyl)phosphonic acids 3 and 4, respectively. The acid 6 was obtained by epimerization of the tert‐butyl ester 23 with lithium N‐cyclohexylisoproylamide and deprotection. The phosphonic acids 3 (Ki 5.5 10‐5 M) and 4 (Ki 2.3.10−4 M) are stronger inhibitors of Vibrio cholerae sialidase than the anomeric N‐acetyl‐2‐deoxyneuraminic acids 5(Ki 2.3 10−3 M) and 6. Both 3 and 4 inhibit the Vibrio cholerae sialidase, while only the carboxylic acid 5, possessing an equatorial COOH group is an inhibitor.

The 7-oxasphingosine (1), 7-oxaceramide (2), the thio-oxaceramide 3, and N-methyloxaceramide 4 were synthesised from D-galactose via the building block 9. The apoptosis-inducing properties of 1-4 were compared to those of sphingosine (Sph) and ceramide (Cer) using a human neuroblastoma (SK-N-BE) and a murine-promyelocyte-derived (32d) cell line. There were no differences between 2-4 and Cer in terms of their effects on the viability of cells and their ability to trigger cell proliferation. However, in the presence of N,N-dimethylsphingosine, an inhibitor of sphingosine kinase (SPHK), Cer was more potent than thio-ceramide 3 in 32d cells, while thio-ceramide 3 was more potent and efficacious in SK-N-BE cells, where it showed an IC50 value of 3 nM compared to 100 nM for Cer. In both SK-N-BE and 32d cells, 7-oxasphingosine (1) and Sph were equally toxic, even in the presence of N,N-dimethylsphingosine.

The synthesis of the C-glycosides 8,15, and 9 of N-acetylneuraminic acid is described. Hydroxymethylation of the Li-ester enolate, derived from 5, yielded the protected C-glycosides 7 and 10 (46%; 3:l), which were deprotected to yield 8 (54%) and 15 (51 %; Scheme 2). The mesylate 16 was obtained from 7 (73 %) and transformed uiu the azide 17 (75%) into the acid 18 (66%) and the amino acid 9 (Scheme 3). The configuration at C(2) of 17 was proved by transforming 17 into the bicyclic lactam 19. Both 8 and 15 are very weak inhibitors of Vibrio cholerue sialidase; 9 appears to stimulate this enzyme.Einleitung. -Trotz der Bedeutung der N-Acetylneuraminsaure (NeuSAc, 1) als Bestandteil von Glykokonjugaten [ 11 [2] und der Synthese einer bedeutenden Anzahl von NeuSAc-Analogen sind bisher nur wenige C-Glykoside von NeuSAc [3] [4] beschrieben worden. Solche Verbindungen, etwa vom Typ des Alkohols 8, ermoglichen im Prinzip eine hydrolysebestandige Verkniipfung von NeuSAc-Resten rnit Oligosacchariden, Peptiden oder Lipiden, wahrend C-Glykoside vom Typ der Verbindung 9, die wie die friiher hergestellten C-Glykoside 2 4 in der Nahe des anomeren Zentrums eine basische Aminogruppe tragen, als potentielle Sialidase-Hemmer Interesse beanspruchen [3] [5] [6].

The phosphonic acids 3 and 4 were prepared to compare their inhibitory activity on Vibrio cholerae sialidase with the one of the corresponding N-acetyl-2-deoxyneuraminic acids 5 and 6. Thus, hydrogenation and benzylation of methyl N-acetyl-2,3-didehydro-2-deoxyneuraminate (1 MeNeuZenSAc; 7) gave a mixture of the fully 0-benzylated henzyl and methyl esters 9 and 10, the partially 0-benzylated benzyl and methyl esters 11 and 12, and the fully 0-and N-henzylated henzyl and methyl esters 13 and 14 (Scheme I). Transesterification of 9 to 10 and hydrolysis of 10 gave the acid 15. Oxidative decarhoxylation of 15 with Pb(OAc), gave a 1 :9 mixture of the aand P-o-glycero-o-galacto-acetates 16 and 17. Phosphonoylation of 17 with P(OMe)3 and Me,SiOTf gave a 1.3:l mixture of the phosphonates 18 and 19, which were deprotected to give the (4-acetamido-2,4-dideoxy-~-glycero-aand P-o-galucto-octopyranosy1)phosphonic acids 3 and 4, respectively. The acid 6 was obtained by epimerization of the terf -butyl ester 23 with lithium N-cyclohexylisoproylamide and deprotection. The phosphonic acids 3 ( K , 5.5. M) and 4 (K, 2.3 lo-, M) are stronger inhibitors of Vibrio cholerae sialidase than the anomeric N-acetyl-2-deoxyneuraminic acids 5 (K, 2.6. lo-, M) and 6. Both 3 and 4 inhibit the Vibrio cholerae sialidase, while only the carhoxylic acid 5, possessing an equatorial COOH group is an inhibitor.

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