Synthesis of the 3-0, 4-0 and 6-0 Sulfates of Methyl 2-amino-2-deoxy-α-D-Glucopyranoside

Abstract

Starting with methyl 2-(benzyloxycarbonyl)amino-2-deoxy-α-D-glucopyranoside (1), the isomeric methyl 2-amino-2-deoxy-α-D-glucopyranoside 3-, 4-, and 6-sulfates have each been prepared by sulfation of suitably blocked intermediates. Tritylation and acetylation of 1 followed by detritylation gave methyl 3,4-di-0-acetyl-2-(benzyloxycarbonyl)amino-2-deoxy-α-D-glucopyranoside (3), having a free 6-hydroxyl group. Base catalyzed 0–4→0–6 acetyl migration provided the corresponding 3,6 di-O-acetyl derivative (4) posessing a free 4-hydroxyl group. Preparation of methyl 4,6-0-benzylidene-2-(benzyloxycarbonyl)amino-2-deoxy-α-D-glucopyranoside (9) provided the intermediate bearing a free 3-hydroxyl group. 0-sulfation of 3, 4, and 9 was effected with the pyridine sulfur trioxide complex in dry pyridine.     

Use of Unsaturated Sugars as Alkylating Agents. Addition of Enol Esters and Ethers to Glycals

Abstract

Addition of enol esters to acetylated 1,5-anhydro-D-hex-1-enitols (acetylated-D-glycals) in the presence of a Lewis acid catalyst yields acetylated 3-deoxy-α-D-hex-2-enopyranosyl compounds which can serve as starting materials for the synthesis of other C-(α-D-hexopyranosyl) compounds.     

Synthesis of O-α-L-Fucopyranosyl-(1→2)-O-β-D-galactopyranosyl-(1→4)-2-acetamido-2-deoxy-D-glucopyranose. The H-Blood Group Specific Trisaccharide

Abstract

Different reaction conditions were investigated for the preparation of benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-β-D-glucopyranoside (5). Compound 5 on reaction with 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide afforded the 4-O-substituted 2-acetamido-2-deoxy-β-D-glucopyranosyl derivative which, on O-deacetylation, gave benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-4-O-β-D-galactopyranosyl-β-D-glucopyranoside (8). The trimethylsilyl (Me₃Si) derivative of 8, on treatment with pyridineacetic anhydride-acetic acid for 2 days, gave the disaccharide derivative having an O-acetyl group selectively introduced at the primary position and Me₃Si groups at the secondary positions. The latter groups were readily cleaved by treatment with aqueous acetic acid in methanol to afford benzyl 2-acetamido-4-O-(6-O-acetyl-β-D-galactopyranosyl)-3,6-di-O-benzyl-2-deoxy-β-D-glucopyranoside, which on isopropylidenation gave the desired, key intermediate benzyl 2-acetamido-4-O-(6-O-acetyl-3,4-O-isopropylidene-β-D-galactopyranosyl)-3,6-di-O-benzyl-2-deoxy-β-D-glucopyranoside (12). Reaction of 12 with 2,3,4-tri-O-benzyl-α-L-fucopyranosyl bromide under catalysis by bromide ion afforded the trisaccharlde derivative from which the title trisaccharide was obtained by systematic removal of the protective groups. The structures of the final trisaccharide and of various intermediates were established by ¹H and ¹³C NMR spectroscopy.     

Accessibility of D-Mannopyranoside Glycosylating Synthons by Acetolysis for Preparations of Oligosaccharide Moieties of N-Linked Glycoproteins

Abstract

Selective acetolysis of methyl 2, 3, 4, 6-tetra-O-benzyl-α-D-manno-pyranoside (2) allows for easy preparation of 1-acetates of 2, 3,4, 6-tetra-O-benzyl (5), 6-O-acetyl-2, 3, 4, tri-O-benzyl-(6), 4, 6-di-O-acetyl-2,3-di-O-benzyl-(7), 3, 4, 6-tri-O-acetyl-2-O-benzyl-(8), and 2, 4, 6-tri-O-acetyl-3-O-benzyl-D-mannopyranoside (9). 8 and 9 formed are separated by preparative HPLC in 30-60g scale. The time course of previously described acetolyses of 3, 4, 6-tri-O-benzyl- 1, 2-O-(1-methoxyethyidene)-β-D-mannopyranose (3), and methyl 2, 3-dt-O-benzyl-4, 6-O-benzylldene-α-D-mannopyranoside (4) giving 9, 1, 2, 6-tri-O-acetyl-3, 4-di-O-benzyl-(10), and 1, 2-di-O-acetyl-3, 4, 6-tri-O-benzyl-(11) α-D-mannopyranose as well 7 have been studied.     

Synthesis of Potential Antimicrobial Agents from Maltose. III. Introduction of an Amino Group Into the 3′-Position of 1,6-Anhydro-Disaccharides

Abstract

Regioselective cleavage of 1,6-anhydro-maltose (1) with periodate and the subsequent recyclization with nitromethane gave 1,6-anhydro-3′-deoxy-3′-nitro-disaccharides (3). Three diastereomers, prepared by benzylidenation of 3, were separated by column chromatography. Each of 4′,6′-O-benzylidene derivatives successively underwent debenzylidenation, reduction of the nitro group, and peracetylation to give 3′-acetamido-3′-deoxy-disaccharide derivatives (7, 8, and 9). The configurations of the 3-amino sugar moietres in 7 (D-gluco), 8 (D-manno) and 9 (D-galacto) were determined on the basis of the ¹H NMR data. The main product (7) was further modified to the 6-deoxy-6-nitro derivative.     

Synthesis of N-[2-S -(2-Acetamido-2,3-dideoxy-D-glucopyranose-3-y1)-2-Thio-D-Lactoyl]-L-alanyl-D-isoglutamine

Abstract

N-[2-S-(2-Acetamido-2,3-dideoxy-D-glucopyranose-3-y1)-2-thio-D-lactoyl]-L-alanyl-D-isoglutamine, in which the oxygen atom at C-3 of N-acetylmuramoic acid moiety in N-acetylmuramoyl-L-alanyl-D-isoglutamine (MDP) has been replaced by sulfur, was synthesized from allyl 2-acetamido-2-deoxy-β-D-glucopyranoside (1).

Treatment with sodium acetate of the 3-O-mesylate, derived from 1 by 4,6-O-isopropylidenation and subsequent mesylation, gave allyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-β-D-allopyranoside (4). When treated with potassium thioacetate, the 3-O-mesylate, derived from 4, afforded allyl 2-acetamido-3-S-acetyl-2-deoxy-4,6-0-isopropylidence-β-D-glucopyranoside (6). S-Deacetylation of 6, condensation with 2-L-chloropropanoic acid, and subsequent esterification, gave the 3-s[D-1(methoxycarbonyl)ethyl]-3-thio-glucopyranoside derivative (7). Coupling of the acid, derived from 7, with the methyl ester of L-alanyl-D-isoglutamine, and subsequent hydrolysis, yielded the title compound.     

Reactions of Per-O-Acetylated Carbohydrate Triflates With Halide Ions

Abstract

The reactions of bromide, chloride, and iodide ions with 1,3,4, 6-tetra-O-acetyl-2-O-(trifluoromethylsulfonyl) -α-D-glucopyranose (2) and with 1, 3, 4, 6-tetra-O-acetyl-2-O-(trifluoromethylsulfonyl)-β-D-mannopyranose (3) gave good to excellent yields of the corresponding deoxyhalogeno sugars. In contrast, when the gluco triflate 2 and tetra-butylammonium fluoride were heated under reflux in benzene, only 5-(acetoxymethyl)-2-formylfuran (13) was formed. Reaction of the manno triflate 3 under similar conditions produced 1, 3,4, 6-tetra-O-acetyl-2-deoxy-2-fluoro-β-D-gluco-pyranose (17), 1. 3, 4. 6-tetra-O-acetyl-2-deoxy-β-D-erythro-hex-2-eno-pyranose (18), 4,6-di-O-acetyl-1, 5-anhydro-2-deoxy-D-erythro-hex-l-enitol-3-ulose (19), and 1, 2, 3, 4, 6-penta-O-acetyl-β-D-glucopyranose (20). The mechanisms of the reactions of The triflates 2 and 3 with fluoride ion are discussed.     

Synthesis of C-Glycosyl α-Glycines

Abstract

A scheme of asymmetric synthesis of C-glycosyl α-glycines is described. Reductive hydrolysis of 2-deoxy-3,5-di-O-p-toluoyl-β D-erythropentofuranose 1-cyanide (4) in the presence of N,N-diphenylethylenediamine gave the imidazolidine 5, which was converted to 2,5-anhydro-3-deoxy-4,6-di-O-p-toluoyl-β-D-allose (3)by acid hydrolysis. The aldehyde (3), chiralamine, benzoic acid and t-butyl isocyanide four component condensation afforded in good yield two diastereomeric adducts (6a and 6b), which were separated by column chromatography and deblocked to furnish 2-deoxy-β-D-erythropentofuranosyl R and S-glycines (1a) and (1b).     

A General Method for Stepwise Elongation of the (1→5)-α-D-Arabinofuranan Chain

Condensation reaction of 3,5-di-O-benzoyl-1,2-O-(1-cyanoben-zylidene)-β-D-arabinofuranose (2) with benzyl and allyl 2,3-di-O-benzoyl-5-O-triphenylmethyl-α-L-arabinofuranosides (5a and 5b) in methylene chloride in the presence of triphenylcarbenium tetrafluoroborate as catalyst under high vacuum gave α-(1→5)-linked dimeric D-arabinofuranoside derivatives (6a and 6b). One of the dimeric compounds (6a) was debenzoylated, triphenylmethylated, and rebenzoylated to give a dimeric homolog of 5a (8). Similarly for the preparation of 6a, 8 was condensed with 2 to provide an α-(1→5)-linked trimeric D-arabinofuranoside derivative (9). Further elongation of the glycoside chain might be possible in the same way.     

An Improved Method for the Synthesis of 3.6-Di-O-Methyl-D-Glucose: Preparation of the Neo-Glycoprotein Containing 3,6-Di-O-Methyl-β-D-Glucopyranosyl-Groups

Abstract

3,6-Di-O-methyl-D-glucose, the non-reducing terminal sugar of the phenolic glycolipid-I, elaborated by Mycobacterium leprae, has been synthesized by a simple procedure and in high yield. 3-O-Methyl-D-glucose was converted to the corresponding benzyl glycoside and then tosylated to give benzyl 3-O-methyl-6-O-tosyl-β-D-glucopyranoside. Displacement of tosyl group with sodium methoxide followed by debenzylation afforded 3,6-di-O-methyl-D-glucose in high yield. Condensation of the acetobromo derivative of 3,6-di-O-methyl-D-glucose with 8-ethoxycarbonyloctanol gave 8-ethoxycarbonyloctyl 2,4-di-O-acety 1–3, 6-di-O-methy 1-β-D-glucopyranoside. This was then deacetylated, converted to hydrazide, and finally coupled to bovine serum albumin via the acyl azide intermediate. The neo-glycoprotein containing the 3,6-di-O-methyl-β-D-glucopyranosyl group is useful for serodiagnosis of leprosy.     

The Application of the Trichloroacetimidate Method to the Synthesis of α-D-Gluco- and α-D-Galactopyranosides

Abstract

The trichloroacetimidate method has been applied to the construction of α-d-galacto- and α-d-glucopyranosides. The readily available β-trichloroacetimidates of 2,3,4,6-tetra-O-benzyl-d-galacto- and glucopyranose (1-β and 3-β, respectively) have been employed in glycosidations with several monosaccharides (either A, B, C or D) under varying experimental conditions. With the galactose derivative 1-β as a donor and each of the monosaccharides A-D as acceptors, the corresponding disaccharides 1A-1D, were obtained in high yield and with good α-stereoselectivity when employing diethyl ether as solvent and either trimethylsilyl- or tert-butyldimethylsilyl trifluoro-methane sulphonate as catalyst. Glycosidations with the glucose derivative 3-β, as donor, and with the monosaccharide acceptors A, B or D, gave the corresponding disaccharides 3A, 3B and 3D, in high yield but with somewhat lower α-diastereoselectivity than observed with the galactose derivative 1-β. The stereochemical outcome of the reactions is rationalised in terms of possible reaction mechanisms.     

Syntheses of Pseudo-α-D-Glucopyranose and Pseudo-β-L-Altropyranose From L-Arabinose

Abstract

Two optically active pseudo-hexopyranoses, pesudo-α-D-glucopyranose (1) and pseudo-β-L-altropyranose (2), were synthesized starting from L-arabinose. L-Arabinose was first converted to an acyclic aldehyde 9. The reaction of 9 with dimethyl malonate under basic conditions provided a tetra-hydroxylated cyclohexane-1,1-dicarboxylate 11 and a C-glycoside of β-L-arabinopyranose 12. From the compound 11, the desired two pseudo-sugars were synthesized by 1) thermal demethoxy-carbonylation, 2) LiAlH₄, reduction, 3) hydroboration of the resulting 1-hydroxymethyl-l-cyclohexene 14 followed by hydrogen peroxide treatment, and 4) removal of the protecting groups.     

Enzymatic Syntheses of N-Acetyllactosamine and N-Acetylallolactosamine by the Use of β-D-Galactosidases

Abstract

A β-D-galactosidase from Bacillus circulans induced β-D-galactopyranosyl transfer from lactose predominantly to a secondary (OH-4) rather than the primary hydroxyl group (OH-6) of 2-acetamido-2-deoxy-D-glucopyranose. 4-O-β-D-Galacto-pyranosyl-2-acetamido-2-deoxy-D-glucopyranose (N-acetyl-lactosamine) was thus readily synthesized on a gram scale and conveniently isolated by chromatography on a column of charcoal-Celite. On the other hand, the glycosyl transfer to the 6-position predominantly was efficiently induced to give 6-O-β-D-galactopyranosyl-2-acetamido-2-deoxy-D-glucopyranose (N-acetyl-allolactosamine) by consecutive use of β-D-galactosidases from Kluyveromyces lactis and B. circulans. These enzyme reactions were efficient enough to allow the one-pot preparation of the desired disaccharides.     

Synthesis of Glycosyl Cyanides and C-Allyl Glycosides by the use of Glycosyl Fluoride Derivatives

A treatment of 2,3,5-tri-O-benzyl-B-D-ribofuranosyl fluoride (1) with cyanotrimethylsilane in the presence of boron trifluoride diethyl etherate gave 2,3,5-tri-O-benzyl-α- (2α) and -β-D-ribofuranosyl (2β) cyanide in 46.2% and 46.6% yields, respectively. Confirmation of the corresponding isocyano isomer (3) formation and its conversion into 2 under boron trifluoride catalysis at -78°C made it possible to deduce that both 2α and 2β were produced by way of 3 which was formed preponderantly in the initial stage of the reaction. On the other hand, the reaction of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl fluoride (4) with cyanotrimethylsilane in diethyl ether by the use of boron trifluoride diethyl etherate (0.05 mol. equiv.) gave 2,3,4,6-tetra-O-benzyl-α -D-glucopyranosyl cyanide (5α), 2,3,4,6-tetra-O-benzyl-α- (6α), and -β-D-glucopyranosyl isocyanide (6β) as a 30:61:9 mixture (94% yield) but that in dichloromethane by the use of the catalyst (1.0 mol. equiv.) gave 5α (85% yield) as a sole product.

The reactions of 1 and of 4 with allyltrirnethylsilane under the same catalysis afforded C-allyl 2,3,5-tri-O-benzyl-α-D-ribofuranoside (7)(93.5% yield), and C-allyl 2,3,4,6-tetra-O-benzyl-α- (8α)(71.8% yield) and -β-D-glucopyranoside (8β) (22.4% yield), respectively.     

Synthesis of Methyl α-D-Kijanoside

Abstract

In 1981, Mallams and coworkers reported¹ the discovery of - D-kijanose 1, a branched-chain nitro sugar, isolated from the antitumor antibiotic kijanimicin by acid hydrolysis. The structure of this unusual carbohydrate was established ^1,2 as 2,3,4,6-tetadeo xy-4 - (methoxy carbony1 amino 1-3-c-methyl - 3 -nitro - D-xylo-hexopyranose by spectroscopic and crystallographic analysis, and comparison with D-rubranitrose 2, a carbohydrate found in the antibiotic rubradirin .³Two other nitro sugars, L-evernitrose 3 and - L-decilonitrose 4⁵, have been discoveredas components of antibiotics.     

Studies on the Thioglycosides of N-Acetylneuraminic Acid 1: Synthesis of Alkyl α-Glycosides of 2-Thio-N-Acetylneuraminic Acid

Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-S-acetyl-3,5-di-deoxy-2-thio-D-glycero-α-D-galacto-2-nonulopyranosonate (2) was prepared via methyl 5-acetamTdo-4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5-trideoxy-D-glycero-α-D-galacto-2-nonulopyranosonate (1) and was converted into the sodium salt (3). Condensation of 3 with n-alkyl bromides gave the corresponding methyl (alkyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-thio-D-glycero-α-D-galacto-2-nonulo-pyranosid)onates, which were converted, via O-deacetylation and hydrolysis of the methyl ester group, into the title compounds.     

Nonreducing-Sugar Subunit Analogs of Bacterial Lipid a Carrying the Ester-Bound (3R)-3-(Acyloxy)Tetradecanoyl Group

Abstract

In order to elucidate further the relationship between the composition of the fatty acyl groups in the nonreducing-sugar subunit of bacterial lipid A and its biological activity, 3-O-[(3R)-3-(acyloxy)tetradecanoyl]-2-deoxy-2-[(3R)-3-hydroxytetradecanamido]-4-O-phosphono-D-glucose [GLA-63(R, R) and GLA-64(R, R)], and 3-O-[(3R)-3-(acyloxy)tetradecanoyl]-2-deoxy-4-O-phosphono-2-tetradecanamido-D-glucose [GLA-67(R), GLA-68(R) and GLA-69(R)] have been synthesized. Benzyl 2-[(3R)-3-(benzyloxymethoxy)tetradecanamido]-2-deoxy-4,6-O-isopropylidene-β-D-glucopyranoside (5) and benzyl 2-deoxy-4,6-O-isopropylidene-2-tetradecanamido-β-D-glucopyranoside (6) were each esterified with (3R)-3-dodecanoyloxytetradecanoic acid (1), (3R)-3-tetradecanoyloxytetradecanoic acid (2) or (3R)-3-hexadecanoyloxy-tetradecanoic acid (3), to give 7-11, which were then transformed, by the sequence of deisopropylidenation, 6-O-tritylation and 4-O-phosphorylation, into a series of desired compounds.     

One-Pot Synthesis of Tri-Acetalated Aldohexoses with 1,1-Dialkoxycyclohexane–p-Toluenesulfonic Acid

Abstract

2-Deoxy-d-arabino-hexose (1), 2-acetamido-2-deoxy-d-glucose (2), and 2-deoxy-2-trifluoroacetamido-d-glucose (3) were each treated with 1,1-dimethoxycyclohexane or 1,1-dibenzyloxycyclohexane in 1,4-dioxane in the presence of p-toluenesulfonic acid. The major products were the 1,1-dimethyl or 1,1-dibenzyl acetals (4-9) of 3,4:5,6-di-O-cyclohexylidene-2-deoxy-aldehydo-d-arabino-hexose, and of 2- (acylamino)-3,4:5,6-di-O-cyclohexylidene-2-deoxy-aldehydo-D-glucose. The dibenzyl acetal derivatives were converted, by hydro-genolysis, into the corresponding, acyclic aldehydes (10-12) in good yields.     

Chemical Modification of Kanamycin A. II. Nucleophilic Displacement Reactions of Kanamycin-A-4″-sulfonates

Abstract

Reactions of 2′,3′,4′,2″,6″-penta-O-acetyl-tetra-N-tert-butyloxycarbonyl-kanamycin-A-4″-brosylate (4b) or-4″-triflate (4c) with acetate, thiolacetate, azide, and fluoride, respectively, result in the formation of the corresponding derivatives of 4″-epi-kanamycin A (5a-d). While 4b invariably forms an elimination byproduct (9), the only side—reaction of 4c consists in a neighboring group attack with formation of a 3″-epi-4″-cyclic urethane (7). Removal of the protecting groups yields 4″-epi-(6a), 4″-thio-4″-epi-(6b), 4″-deoxy-4″-fluoro-4″-epi-(6d), 4″-azido-4″-deoxy-4″-epi-(6c), and after hydrogenation of the latter, 4″-amino-4″-deoxy-4″-epi-kanamycin A (6f).

Methyl 2,6-di-O-acetyl-3-amino-3-N-tert-butyloxycarbonyl-3-deoxy-4-O-triflyl-β-D-glucopyranoside (1b) served as a model to anticipate preparation, handling, and reactivity of 4c.     

Synthetic Mucin Fragments: Methyl-3-O-(2-Acetamido-2-Deoxy-4-O- and 6-O-β-D-Galactopyranosyl-β-D-Glucopyranosyl)-β-D-Galactopyranoside and Methyl 3-O-(2-Acetamido-2-Deoxy-4-O- and 3-O-Methyl-β-D-Glucopyranosyl-3-D-Galactopyranoside

Abstract

Glycosylation of methyl 3-O-(2-acetamido-3, 6-di-O-benzyl-2-deoxy-β-D-glucopyranosyl)-2,4,6-tri-O-benzyl-β-D-galactopyranoside (2) with 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (1), catalyzed by mercuric cyanide, afforded a trisaccharide derivative, which was not separated, but directly O-deacetylated to give methyl 3-O-(2-acetamido-3,6-di-O-benzyl-2-deoxy-4-O-β-D-galactopyranosyl-β-D-giucopyranosyl)-2,4,6-tri-O-benzyl-β-D-galactopyranoside (8). Hydrogenolysls of the benzyl groups of 8 then furnished the title trisaccharide (9). A similar pflyccsylation of methyl 3-O-(2-acetamido-3-O-acetyl-2-deoxy-β-D-glucopyranosyl)-2,4,6-tri-O-benzyl- β-D-galactopyranoside (obtained by acetylation of 4, followed by hydrolysis of the benzylidene acetal group) with bromide 1 gave a tribenzyl trisaccharide, which, on catalytic hydrogenolysls, furnished the isomeric trisaccharide (12). Methylation of 4 and 2 with methyl iodide-silver oxide in 1:1 dichloro-methane-N, N-dimethylformamide gave the 3-O- and 4-O-monomethyl ethers (13) and (15), respectively. Hydrogenolysis of the benzyl groups of 13 and 15 then provided the title monomethylated disaechartdes (15) and (16), respectively. The structures of trisacchacides 9 and 12, and disaccharides 14 and 16 were all established by ¹³C MMR spectroscopy.