Carbocyclic analogs of glycoceramides, (2S,3R,4E)-1-(5a-glycosylceramides showed that both imino-linked E-3 and carba-~-~-glycopyranosyl)-2-(hexadecanoylamino)-4-octa-E-4 having gluco and galacto configurations are mild immudecen-3-01s E-3-E-6, linked by imino, ether and sulfide brid-nomodulators and possess a mild inhibitory activity against ges, were synthesized by coupling of aziridines, as the sphin-gluco-and galactocerebrosidases. These findings prompted gosine precursors, with protected 1-amino, 1-hydroxy and us to prepare the corresponding Z-isomers 2-3 and 2-4, 1-mercapto derivatives of 5a-carba sugars and subsequent which interestingly show a similar enzyme-inhibitory actideprotection and N-acylation. Biological assay of 5a-carba-vity.Glycosphingolipids for instance 1 or 2 play important roles in biological systems as essential constituents of membranes and cell walls. Biological functions of these compounds have therefore been extensively studied so far. In order to understand these functions, it would be necessary to provide structural analog^[^-^] as well as naturally occurring compounds.In this paper, we have elaborated a general method for the synthesis of carbocyclic analogs of glycoceramides E-3-E-6, the sugar residues of which being composed of 5a-carba sugars connected with each other by imino, ether and sulfide linkages. Their inhibitory activity against glycocerebrosidases has also been assayed. The methods involve coupling of the 1,Zaziridines E-10 or E-32, the sphingosine precursors, with the appropriately protected 1-amino 17 and 23, I-hydroxy 29, and 1-mercapto derivatives 37 of 5a-carbahexopyranoses. Furthermore, the finding that the imino-linked analogs E-3 and E-4 possess mild inhibitory activity against gluco-and galactocerebrosidases prompted us to prepare their corresponding Z-isomers 2-3 and 2-4.The 5a-carbaglycosyl acceptors E-and Z-10 were prepared from the known azidosphingosine[6-8] E-7. Selective benzoylation of E-I gave the 1-0-benzoyl derivative E-8 (65%), which was protected with the tert-butyldimethylsilyl group followed by ZemplCn 0-deacylation affording the I-OH unprotected derivativer91 E-9 (73%). Reduction of E-9 with triphenylphosphane and successive treatment with 2,4-dinitrofluorobenzene furnished the protected aziridine E-10 (350/,> and the amino alcohol E-11 (45%). The 'H-NMR spectrum of E-10 revealed three signals due to the protons of the aziridine moiety at 6 = 2.72 (d, J l a ,~ = 4.0 Hz, la-H), 2.61 (ddd, Jlb,2 = 6.2, J 2 ,~ = 3.6 Hz, 2-H), and 2.14 (d, 1 b-H), supporting the structure assigned. Compound E-11
Methyl 5a'-carbamaltoses linked by imino, ether, and sulfide bridges were synthesized by coupling of an amino carbasugar with a sugar epoxide and of the carbasugar epoxide with the oxide anion or thioacetate derived from sugar derivatives. Their unsaturated derivatives related to a potent a-glucosidase inhibitor, methyl acarviosin, were also synthesized. Moderate inhibitory activity against baker's yeast a-glucosidase was observed only for the imino-linked compounds 2 and 5.Methyl acar~iosin [~] (l), methyl 4-[Sa-carba-a-~-xylohex-S( Sa)-enopyranosylamino]-4,6-dideoxy-a-~-glucopyranoside, an essential core structure of a-amylase inhibitor acarbose, plays an important role in exhibiting a glycosidase-inhibitory activity. We have so far been engaged in elucidating the structure-inhibitory activity relationship of such imino-linked 5a'-carbadisaccharides by chemical modification of the sugar moiety14], thereby suggesting that the valienamine moiety is essential for inhibitory potency, while the sugar part was not exactly recognized by the active site of the enzyme.Therefore, in order to explain the biological importance of the carbasugar moieties, the development of practical synthetic routes to Sa-carbaoligosaccharides became important. As part of our efforts in using carbasugars in biological studies, we report in this paper on the synthesis of Sa'-carbamaltoses 2-4, linked by imino, ether and sulfide bridges. In addition, for the purpose of making clear the biological importance of the conduritol-type structure of the carbasugar component as seen in methyl acarviosin 1, the respective unsaturated carbadisaccharides 5-7 were synthesized, and their inhibitory activity against a-glucosidase was tested. Results and DiscussionSynthesis of Sa'-Curbumultoses: A conventional construction of the imino bridge between the carbasugar and carba-or true sugar was already carried out by our by simple coupling of the amine with the epoxide. Thus, the imino-linked Sa-carbamaltose 2 was synthesized by coupling of Sa-carbaglucopyranosylamine[61 9, derived from the penta-N,O-acetyl derivative 8, with methyl 3,4-anhydro-a-~-galactopyranoside[~I 10 in a sealed tube in 2-propanol for 6 days at 120°C. The products were isolated after acetylation by silica-gel column-chromatography to give the trans-diequatorially 11 and trans-diaxially opened product 12 in 37 and 36% yields, respectively. The assigned structures were confirmed on the basis of the 'H-NMR spectra.
5a-Carba-P-glucosyl-E-3 and galactosylceramide analogs E-4 were synthesized by coupling of the protected derivatives 5 of p-valienamine and 15 of 4-epi-0-valienamine with the aziridmes E-6 and Z-6, as the sphingosine precursors, respectively, and subsequent deprotection and N-acylation. Both the new analogs and their corresponding Z-isomers 2-3 and 2-4 were shown to be very potent and specific gluco-and galactocerebrosidase inhibitors, and, interestingly, the Z-isomers possess inhibitory activity comparable to that of the corresponding E-isomers.In the preceding paperr'), we described a general approach to the synthesis of several Sa-carba-sugar analogs of glycosylceramides, linked by imino, ether and sulfide bridges. Among them, the imino-linked analogs 1 and 2 have shown to be mild gluco-and galactocerebrosidase inhibitors, and, interestingly, the unnatural Z-isomers possess rather stronger inhibitory activity than the corresponding E-isomers. These findings have prompted us to synthesizeL41 the Sa-carba-unsaturated sugar analogs E-3 and E-4, together with the isomers 2-3 and 2-4, envisaging the more potent and specific glycocerebrosidase inhibitors.Methylacarvi~sin[~], the essential core structure of pseudo-oligosaccharidic a-amylase inhibitorsL6I, composed of the unsaturated Sa-carba sugar ~alienamine[~,*] and 4amino-4,6-dideoxy-~-glucopyranose, has been shown to decrease its inhibitory activity when the unsaturated cyclitol moiety is transformed into the saturated s t r~c t u r e [~~~] .By analogy with this knowledge, introduction of the unsaturation into carbaglycosylceramide analogs seemed conversely to enhance their inhibitory activity by mimicking the flattened half-chair conformation of the glycosyl cation formed during hydrolysis. Furthermore, the analogs E-3 and E-4 whose Sa-carba-sugar residues are structurally related to those of D-gluco-and D-galactopyranoses were expected to possess a specific inhibitory activity against respective p-gluco-and p-galactocerebrosidases.Coupling of a slight excess (1.2 molar equiv.) of Sa-carba-2,3 :4,6-di-O-isopropylidene-~-~-xylo-hex-5( 5 a)-enopyranosylamine (2,3:4,6-di-0-isopropylidene-~-~alienamine)~'~~ (5) with the aziridine (2,!7,3R,4E)-3-(tert-butyldimethylsilyloxy)-1,2-(2,4-dinitrophenyl)imino-4-octadecene~'~ (E-6)
Some oxo-linked 5a-carba-di- and tri-saccharides of biological interests including 5a-carbamaltose, were synthesized by coupling of 5a-carba-glycosyl donor, 1,2-anhydro-5a-carba-β-d-mannopyranose derivative with the alkoxides generated from the protected hexopyranose derivatives in N,N-dimethylformamide in the presence of a crown ether.
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