Pseudosugars, 32. – Synthesis of 1,4‐Imino‐linked Carbadisaccharides Composed of a 2‐Amino‐5a‐carba‐2‐deoxyglucopyranosylamine Residue and Its Congeners

Abstract

Carbadisaccharide 5, containing a 2-acetamido-5a-carba-2-deoxyhexopyranosylamine residue, was synthesized by coupling of methyl 4-amino-4-deoxy-a-D-glucopyranoside (41) with the N-(2,4-dinitrophenyl)epimino compound 16 followed by deprotection. The 6'-acetamido-6'-deoxy analog 3 of a potent a-glucosidase inhibitor methyl acarviosin (1) was synthesized from a condensate 50 obtained by coupling of 41 with the protected epimino compound 18, possessing an exomethylene function. This process involves a sequence of reactions: replacement by a benzoate ion and successive dehydrobromination of the dibromide 52 obtained from 50. Hydroxymercuration of 50 followed by demetalation and deprotecThe carbocyclic analog of hexopyranoses, Sa-carbahexopyranosesL21 were found in biologically active substances: antibiotic validamycin~[~] and a-glucosidase inhibitorsL4I, in which they are linked to the sugar or the cyclitol moiety via an imino function, namely a ,,pseudo-N-glycosidic linkage". In order to elucidate the structure-inhibitory activity relationship of the inhibitors of this kind, we have so far synthesized several of methyl acarviosinL61 (1) and its 1 '-epimerL71 2, and carried out their biological assay with some sugar hydrolases.In continuation of our research program, we were interested in preparing carbaoligosaccharides[81 related to the common core structures of the oligosaccharides occurring in cell-surface glycans [']. Since 2-acetamido-2-deoxy-Dhexopyranoses having mainly galacto and gluco configurations are important components of such oligosaccharide structures, we first attempted to prepare versatile precursors 16 and 18 of 2-acetamido-5a-carba-2-deoxyglucopyranosylamine, which may be introduced into the oligosaccharide chains as an imino-linked carbasugar residue instead of that of the true sugar congener. In this paper are described first the preparation of the 5a-carba-1,2-dideoxy-1,2-epiminohexopyranose derivatives 15, 16, 17, and 18 and their transformation into useful precursors of amino-5a-carbadeoxyhexopyranosylamines by substitution reaction with an azide ion. tion gave two carbadisaccharide analogs 3 and 9 containing the valiolamine-type branched aminocyclitol moieties. The free amines 4, 6, 8, and 10 were prepared by treatment of the corresponding N-protected derivatives with Amberlite IRA 400 (OH-) resin. Biological assays of all carbadisaccharides were carried out with three sugar hydrolases. Only compounds 6 and 8 were shown to be very weak a-mannosidase inhibitors. The introduction of the acetamido or amino function instead of the hydroxyl group into the C-6' position of the methyl acarviosin analog 2 resulted in an appreciable decrease of the inhibitory activity.

β-Mannosidase and β-hexosaminidase inhibitors: synthesis of 1,2-bis-epi-valienamine and 1-epi-2-acetamido-2-deoxy-valienamine from d-mannose

“…Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 718023 (15), CCDC 718024 (22) and CCDC 718025 (18). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).…”

“…1-Acetamido-2,3,4,6-tetra-O-acetyl-1-deoxy-5a-carba-b-D-lyxo-hex-5(5a)-enopyranose 22 Trichloroacetamide 20 (50 mg, 0.08 mmol) was dissolved in THF (freshly distilled, 3 mL) under Ar and cooled to À78°C. Ammonia (ca.…”

“…Starting from a partially protected mannose hemiacetal 3 with OH-2 free has several potential benefits: 19j firstly, we may expect a diastereoselective Grignard addition arising from a chelate effect; 20 secondly, the product of Grignard addition would contain a 1,2-diol that it should be possible to selectively protect leaving OH-5 free 21 and finally, it should be possible to access GlcNAc valienamine analogues 6,22 by S N 2 substitution of OH-2 of the carbocyclic product with a nitrogen nucleophile.…”

Synthesis of carbasugar-containing non-glycosidically linked pseudodisaccharides and higher pseudooligosaccharides

“…31 They used 2,4-dinitrophenyl carbasugar aziridines with a-gluco (86) or a-xylo (87) configuration. A fully protected aziridine derivative (the 3,4,6-triacetate of 86) failed to react to any great extent, while the reaction between the unprotected carbasugar aziridine (86) and amine 21 showed no regioselectivity, and the products of attack at both C-1 (89) and C-2 (88) were seen, along with the product of intramolecular attack by OH-6 (90) (Scheme 6).…”