Alexander Toepfer

Glycosylation with highly reactive glycosyl donors: efficiency of the inverse procedure

α-Fucosylation with the reactive trichloroacetimidate 1 as donor and disaccharides 2 and 4 as acceptors led to a remarkable increase in yield under “inverse conditions”, i.e. addition of the donor to an acceptor/catalyst solution. Thus, acceptor/catalyst complex formation enforcing, the generation of the glycosylating species in the vicinity of the acceptor is favored yielding building blocks for antigen determinant synthesis

Synthesis of a thio-linked analogue of sialyl Lewis X

Abstract Thiolinked sialyl Lewis X analogue 2 was obtained from neuraminic acid, D-galactose, and L-fucose. Galactose was transformed into 3-thiogalactose building block 6 and also into the required 3,4-dithioglucose moiety. Thioglycoside bond formation was performed via base-promoted S-glycosylation [Neu5Acα(2-3S)Gal and Galβ(1-4S)Glc linkages] and via acid catalyzed S-glycosylation [Fucα(1-3S)Glc and Glcβ-(1-1S)heptyl linkages].

An efficient synthesis of the Lewis X (Lex) antigen family

Abstract tert -Butyldimethylsilyl 2-azido-4,6-benzylidene-glucopyranoside 3 proved to be a versatile starting material for the synthesis of Le x trisaccharide building block 7 . Transformation into glycosyl donor 8a and acceptor 9 , respectively, led to all building blocks required for the extension to hexa-, nona-, and dodecasaccharides 8b–d ; with lactose acceptor 13 the corresponding octa-, undeca-, and tetradecasaccharides 15b−d were obtained. The “azidosphingosine glycosylation procedure” provided dimeric, trimeric, and tetrameric Le x antigens 1b−d .

Synthesis of novel mimetics of the sialyl Lewis X determinant

Abstract Mimctics of the sialyl Lewis-X determinant in which at least one sugar domain is simulated by a di-, tri- or tetraalcohol unit have been synthesized. The inhibitory potency of these compounds for E- and P-selectin mediated cell adhesion has been evaluated in cell culture assays. The receptor binding affinity of the best of these mimetics was slightly higher than that of the natural oligosaccharide ligand sialyl Lewis X.

An Efficient Synthesis of the Lewis A (Lea) Antigen Pentasaccharide Moiety

Abstract Starting material for the synthesis of Lewis A pentasaccharide (1) was azidoglucose derivative 2 which was readily transformed into the 3,4-O-unprotected derivative 3 or the 3-O-unprotected derivative 5, respectively. Reaction of 3 and O-galactosyltrichloroacetimidate 6 led preferentially to the desired β(1-3)-connected disaccharide 8 which could be selectively obtained from donor 6 and acceptor 5 via disaccharide 9. 4a-O-Fucosylation of 8 with fucosyl donor 10 furnished trisaccharide 11 which was transformed into triosyl donor 13; glycosylation of lactose derivative 14 as acceptor furnished the desired pentasaccharide in high yield. Azide reduction and N-acetylation and O-deprotection afforded the title compound 1 in high overall yield.

PITFALLS IN THE SYNTHESIS AND BIOLOGICAL EVALUATION OF SIALYL-LEWISX MIMETICS AS POTENTIAL SELECTIN ANTAGONISTS

Abstract The lower molecular weight analog 12 of sialyl LewisX was prepared and effected equal binding affinity to E- and P-selectin compared to the parent tetrasaccharide. If 12 was prepared using acidic ion exchange resins, false positive test were produced, especially binding to P-selectin seemed to be considerably enhanced. Traces of polyanions released from the resins which are difficult to detect by routine analysis were identified to be highly potent selectin inhibitors, probably by their action on a non-carbohydrate binding site.

Muramic acid derivatives as glycosyl donors for the synthesis of muramyl-containing glycosphingolipids and fatty acids.

2-Azido-2-deoxy-4,6-O-isopropylidene-3-O-[(1R)-(methoxycarbonyl)ethyl]- alpha-D-glucopyranosyl trichloroacetimidate (3 alpha) has been used as the glycosyl donor in the synthesis of glycosphingolipids 14 and 27. Reaction of 3 alpha with (2S, 3R, 4E)-2-azido-3-benzoyloxy-4-octadecen-1-ol (6) gave (2S, 3R, 4E)-2-azido-1-(2-azido-2-deoxy-4,6-O-isopropylidene-3-O-[(1R)-1-(m ethoxycarbonyl)ethyl]-beta-D-glucopyranosyloxyl)-3-benzoyloxy-4- octadecene (7), which was converted into (2S, 3R, 4E)-1-(2-deoxy-2-hexadecanoylamino-3-O-[(2R)-propanoyl-(L-alanyl-D -isoglutamine benzyl ester)-2-yl]-beta-D-glucopyranosyloxy)-2-hexadecanoylamino-4-oc tadecen-ol (14). Reaction of 3 alpha with tert-butyldimethylsilyl 2-azido-3,6-di-O-benzyl-2-deoxy-beta-D-glucopyranoside (15) gave tert-butyldimethylsilyl 2-azido-4-O-(2-azido-2-deoxy-4,6-O-isopropylidene-3-O-[(1R)-1-(methox ycarbonyl)ethyl]-beta-D-glucopyranosyl)-3,6-di-O-benzyl-2-deoxy-be ta- D-gluc opyranoside (16 beta), which was converted into 1,3,6-tri-O-acetyl-2-deoxy-4-O-(4,6-di-O-acetyl-2-deoxy-2-hexadecanoy lam ino-3-O-[2R)-propanoyl-(L-alanyl-D-isoglutamine methyl ester)-2-yl]-beta-D-glucopyranosyl)-2-hexadecanoylamino-D-glucopyranose (27).

Piperidine carboxylic acid derivatives as sialyl Lewis X mimetics

Abstract Four piperidine carboxylic acid derivatives designed as mimetics of the sialyl Lewis X determinant were synthesized. Their inhibitory potency for selectin mediated cell adhesion was evaluated in cell culture assays, in vivo and in a reperfusion model. Compound 7 showed strong inhibition of leukocyte adhesion in rats and a powerful decrease of the incidence of arrhythmias in a reperfusion model in isolated rabbit hearts.

Short synthesis of sulfatide- and SQDG-mimetics as small molecular weight selectin inhibitors

Abstract Small molecular weight sulfatide analogs were synthesised and tested in cell-based selectin mediated adhesion assays. The ceramide moiety of sulfatides could be replaced by simple glycerol ethers to obtain potent mimetics. The specific activity of these inhibitors towards P-selectin is illustrated by analogy with other polyanionic systems forming polyvalent arrays antagonising the polyanionic N-terminal binding sites of the dimeric PSGL-1 ligand.

A convenient synthesis of N-acetyllactosamine derivatives from lactal

In a thermal inverse-type hetero-Diels-Alder reaction of O-silyl-protected lactal 1 and bis(2,2,2-trichloroethyl) azodicarboxylate (2), the dihydrooxadiazine derivative 3 was obtained in a very high yield; transesterification with benzyl alcohol furnished the corresponding derivative 4. Treatment of 3 with methanol in the presence of BF3.OEt2 afforded the methyl lactoside derivative 5 which, after transesterification with benzyl alcohol, then hydrogenolytic debenzylation and concomitant NN-cleavage with Raney nickel, and N-acetylation, furnished methyl O-(2,4,6-tri-O-tert-butyldimethylsilyl-beta-D-galactopyranosyl)-(1-->4)- 2-acetamido-3,6-di-O-tert-butyldimethylsilyl-2-deoxy-beta-D-glucopyra nos ide (7) in high yield. Desilylation of 4, then O-acetylation, methyl glycoside formation with methanol-BF3.OEt2, hydrogenolytic debenzylation, and NN-cleavage with Raney nickel, and N-acylation afforded methyl O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-(1-->4)-2-acetamido-3 ,6-di-O-acetyl-2-deoxy-beta-D-glucopyranoside (10).