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The radical C-glycosidation of (-)-(1S,4R,5R, 6R)-6-endo-chloro-3-methylidene-5-exo-(phenylseleno)-7-ox abi cyclo[2. 2.1]heptan-2-one ((-)-4) with 2,3,4, 6-tetra-O-acetyl-alpha-D-mannopyranosyl bromide gave (+)-(1S,3R,4R, 5R,6R)-6-endo-chloro-5-exo-(phenylseleno)-3-endo-(1',3',4', 5'-tetra-O-acetyl-2', 6'-anhydro-7'-deoxy-D-glycero-D-manno-heptitol-7'-C-yl)-7-oxabi cyc lo[ 2.2.1]hept-2-one ((+)-5) that was converted into (+)-(1R,2S,5R, 6R)-5-acetamido-3-chloro-2-hydroxy-6-(1',3',4',5'-tetra-O-acetyl)-2', 6'-anhydro-7'-deoxy-D-glycero-D-manno-heptitol-7'-C-yl)cyclohex -3-en- 1-yl acetate ((+)-10) and into (+)-(1R,2S,5R, 6S)-5-bromo-3-chloro-2-hydroxy-6-(1',3',4',5'-tetra-O-acetyl-2', 6'-anhydro-7'-deoxy-D-glycero-D-manno-heptitol-7'-C-yl)cyclohex -3-en- 1-yl acetate ((+)-19). Ozonolysis of (+)-10 and further transformations provided 2-acetamido-2,3-dideoxy-3-C-(2', 6'-anhydro-7'-deoxy-D-glycero-D-manno-heptitol-7'-C-yl)-D-galac tos e (alpha-C(1-->3)-D-mannopyranoside of N-acetylgalactosamine (alpha-D-Manp-(1-->3)CH(2)-D-GalNAc): 1). Displacement of the bromide (+)-19 with NaN(3) in DMF provided the corresponding azide ((-)-20) following a S(N)2 mechanism. Ozonolysis of (-)-20 and further transformations led to 2-acetamido-2,3-dideoxy-3-C-(2', 6'-anhydro-7'-deoxy-D-glycero-D-manno-heptitol-7'-C-yl)-D-talose (alpha-C(1-->3)-D-mannopyranoside of N-acetyl D-talosamine (alpha-D-Manp-(1-->3)CH(2)-D-TalNAc): 2). The neutral C-disaccharide 1 inhibits several glycosidases (e.g., beta-galactosidase from jack bean with K(i) = 7.5 microM, alpha-L-fucosidase from human placenta with K(i) = 28 microM, beta-glucosidase from Caldocellum saccharolyticum with K(i) = 18 microM) and human alpha-1, 3-fucosyltransferase VI (Fuc-TVI) with K(i) = 120 microM whereas it 2-epimer 2 does not. Double reciprocal analysis showed that the inhibition of Fuc-TVI by 1 displays a mixed pattern with respect to both the donor sugar GDP-fucose and the acceptor LacNAc with K(i) of 123 and 128 microM, respectively.

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A new route for the preparation of four new indolizidines, (1R,2S,6S,7S,8aS)- and (1R,2S,6R,7R,8aS)-1,2,6,7-tetrahydroxyindolizidine (30 and 32) and (1S,2R,7S,8S,8aR)- and (1S,2R,7R,8R,8aR)-1,2,7,8-tetrahydroxyindolizidine (44 and 46), is reported. The synthesis is based on Knoevenagel homologation of the readily available enantiomerically pure pyrrolidin-carbaldehydes 13 and 37followed by asymmetric dihydroxylation of the subsequent alkenyl pyrrolidines and cyclization of the corresponding imino-octitols. The new indolizidines and their precursors (imino-octitols 20, 25, 26) and indolizidinones 28a and 28b have been tested for inhibitory activities toward 26 glycosidases. The enzymatic inhibition of trans-7-hydroxy-d-(-)-swainsonine (44) toward alpha-mannosidases is similar to that described for trans-7-hydroxy-l-(+)-swainsonine (11b) toward naringinase (alpha-l-rhamnosidase from Penicillium decumbens).

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The GarcÌa-Gonza¬lez reaction of d-glucose and ethyl acetoacetate generated ethyl 5-[(1'S)-d-erythrosyl]-2-methyl-3-furoate (5), which was converted to ethyl 5-[(1'R)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-2-methyl-3-furoate (3c) and to ethyl 5-[(1'S)-1',4'-dideoxy-1',4'-imino-d-erythrosyl]-2-methyl-3-furoate (4c). Similar methods were developed to generate other carboxylic acid derivatives such as methyl (see 3e and 4e), isopropyl (see 3f), and butyl esters (see 3g), S-phenyl (see 3a) and S-ethyl thioesters (see 3m), N-benzylcarboxamides 3b and 4b, glycine-derived amide 3h, and N-phenyl (see 3i), N-isopropyl (see 3j and 4j), N,N-diethyl-(see 3k and 4k), and N-ethyl-carboxamides (see 3l). All the new 5-(1',4'-dideoxy-1',4'-imino-d-erythrosyl)-3-furoic acid ( 5-[(3S,4R)-3,4-dihydroxypyrrolidin-2-yl)furan-3-carboxylic acid) derivatives 3 and 4 were assayed for inhibitory activity towards 25 commercially available glycosidases. Derivative 3a with a S-phenyl thioester group is a good and selective a-l-fucosidase inhibitor (K i 2 ± 4 mm), whereas 4b (with a N-benzylcarboxamide group) is a good b-galactosidase inhibitor.Introduction. ± Derivatives of pyrrolidine-3,4-diols ( 1,4-dideoxy-1,4-iminoalditols) constitute an important class of glycosidase inhibitors [1] although, in some cases, there is a lack of selectivity due to the higher conformational flexibility compared to 1,5-dideoxy-1,5-iminoalditols and other imino-bicyclic structures. For instance, simple meso-pyrrolidine-3,4-diol (1) is a weak and nonselective inhibitor [2] that presents activity towards several glycosidases.

Condensation of 2,3,4,6-tetra-O-benzyl-beta-D-glucopyranosylcarbaldehyde with isolevoglucosenone induced by Et(2)AlI, followed by epoxidation, gave an aldol that was fluorinated into a monofluoromethylene C-glucopyranoside that was converted into the title C-disaccharide 1. Its conformational behavior in water has been studied by using a combination of NMR spectroscopy (J and NOE data) and molecular mechanics calculations.