Convenient synthesis of epimeric indolizidines by the intramolecular 1,3-dipolar cycloaddition of a sugar derived N-(3-alkenyl)nitrone

The stereoselective synthesis of two epimeric penta-hydroxylated indolizidines was accomplished from 2,3:5,6-di-O-isopropylidene-α-d-mannofuranose and N-(2-methylpent-4-en-2-yl)hydroxylamine. The transformation of these substrates into the corresponding 7-oxa-1-azabicyclo[2.2.1]heptane by the intramolecular 1,3-dipolar cycloaddition was the key step of the synthesis. The adduct was transformed into the tricyclic ammonium salt by intramolecular N-alkylation. The tricyclic ammonium salt was converted to the target compounds by: (route 1) the catalytic hydrogenation; or (route 2) the reaction with sodium azide, followed by the enantioselective reduction of the resulting indolizidinone.     

Concise synthesis of 3-deoxy-d-manno-oct-2-ulosonic acid (KDO) as a protected form based on a new transformation of α,β-unsaturated ester to α-oxocarboxylic acid ester via diol cyclic sulfite

A concise synthesis of KDO (1) as the suitably protected form (2) from 2,3:5,6-di-O-isopropylidene-α-d-mannofuranose (3) was achieved in five steps (overall 65% yield). The key step is the efficient transformation of readily available α,β-unsaturated ester to α-oxocarboxylic acid ester. The newly β-elimination of the corresponding diol cyclic sulfite and the in situ trap (DBU/TMSCl) into enol silyl ether was developed to give the tautomeric equivalent of α-oxocarboxylic acid ester. The deprotection of acid labile TMS ether provided the desired product.     

Synthesis and oxidation of thioglicosides underlain by neomenthanethiol,D-glucose,and D-fructose

Synthesis of sulfides proceeding from neomenthanethiol, 1,2-O-isopropylidene-α-D-glucofuranose and 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose was performed to get 65 and 54% yield respectively. Oxidation of the sulfides afforded diastereomeric sulfoxides in the yields from 40 to 53%, and diastereomeric excess (de) up to 36%. After removing the isopropylidene protection from 1-deoxy-1-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexylsulfanyl]-2,3:4,5-di-O-isopropylidene-β-D-fructopyranose a water-soluble sulfide was obtained.     

Large scale synthesis of the acetonides of l-glucuronolactone and of l-glucose: easy access to l-sugar chirons

1,2-O-Isopropylidene-α-l-glucurono-3,6-lactone may be synthesized on a 100-200 g scale from cheaply available d-glucoheptonolactone in an overall yield of 94% in four steps via l-glucuronolactone. Subsequent elaboration to l-glucose, diacetone-l-glucose (1,2:5,6-di-O-isopropylidene-α-l-glucofuranose), and monoacetone-l-glucose (1,2-O-isopropylidene-α-l-glucofuranose) allows easy access to a range of l-sugar chirons.     

Direct vinylation of glucose derivatives with acetylene

Vinyl ethers, promising chiral carbohydrate synthons, have been synthesized by the addition of glucose acetals (1,2:5,6-di-O-isopropylidene-α-d-glucofuranose, methyl 4,6-O-benzylidene-α-d-glucopyranoside, 1,2-O-cyclohexylidene-α-d-glucofuranose, methyl α-d-glucopyranoside) to acetylene under atmospheric and elevated pressures in an autoclave in the presence of superbase catalytic systems (KOH-DMSO, t-BuOK-DMSO). The complete vinylation of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose and methyl α-d-glucopyranoside has been realized under elevated pressure of acetylene in the system KOH-THF as well.     

Introduction of a New Class of Ligands for the Metal-Catalyzed Enantioselective Synthesis

Protected thiosugars were prepared as ligands for the metal-catalyzed enantioselective synthesis. The protecting groups in these ligands were varied to test a proposed new concept for the metal-catalyzed enantioselective synthesis. This new concept centres on the use of a stair-like ligand with a large substituent on one side and a small substitutent on the other rather than the commonly employed ligands which have C₂ symmetry (see Fig.3). In such a ligand, both substituents should have a major influence on the coordination of a prochiral substrate. To test this proposal, 3-thio-α-D -glucofuranose derivatives with the following substituents were synthesized: 1,2-O-isopropylidene-5,6-O-methylidene (see 24 ), 1,2:5,6-di-O-isopropylidene (see 2 ), 5,6-O-cyclohexylidene-1,2-O-isopropylidene (see 23 ), 1,2-O-cyclohexylidene-5,6-O-isopropylidene (see 14 ), 1,2:5,6-di-O-cyclohexylidene (see 13 ), 5,6-O-(adamantan-2-ylidene)-1,2-O-isopropylidene (see 21 ), and 1,2:5,6-di-O-(adamantan-2-ylidene) (see 25 , Table 2). As a representative of the allofuranoses, 1,2:5,6-di-O-isopropylidene-3-thio-α-D -allofuranose ( 6 ) was chosen. The following derivatives of 1,2-O-isopropylidene-α-D -xylofuranose were also synthesized: 1,2-O-isopropylidene-5-deoxy-3-thio-α-D -xylofuranose ( 29 ), 1,2-O-isopropylidene-3-thio-α-D -xylofuranose ( 28 ) and 5-O-[(tert-butyl)-diphenylsilyl]-1,2-O-isopropylidene-3-thio-α-D -xylofuranose ( 15 , see Table 2). The proposed concept was tested using the copper-catalyzed 1,4-addition of BuMgCl to cyclohex-2-en-1-one. The enantioselectivity was very dependent on the ligand used and was up to 58%.     

First synthesis of 4,5-O-isopropylidene-6-thio-d-galactono-1,6-lactone as a precursor of d-galactothioseptanose

Displacement of the bromide group in methyl 6-bromo-6-deoxy-2,3:4,5-di-O-isopropylidene-d-galactonate 7, with potassium thioacetate gave methyl 6-(S)-acetyl-2,3:4,5-di-O-isopropylidene-6-thio-d-galactonate 8 in quantitative yield. Regioselective removal of the 2,3-ketal protecting group afforded methyl 6-(S)-acetyl-4,5-O-isopropylidene-6-thio-d-galactonate 11 in 70% yield. Saponification of compound 11 gave the 6-(S)-4,5-O-isopropylidene-6-thio-d-galactonic acid 12 in quantitative yield. Treatment of 12 with DIC/HOBt as coupling reagents gave, after cyclisation; the target compound: 4,5-O-isopropylidene 6-thio-d-galactono-1,6-lactone 13 in 49% yield.     

Determination of the configurations of tertiary alcoholic centers in branched-chain carbohydrate derivatives : PMR spectroscopy with a lanthanide shift-reagent

Examination of the PMR spectral changes (expressed as shift gradients of individual protons) wrought by graduated addition of the paramagnetic lanthanide complex tris [1,1,1,2,2,3,3-heptafluoro- 7,7-dimethyloctane-4,6-dionato]europium(III) [Eu(fod)₃] permitted assignment of the configuration at tertiary alcoholic centers of certain sugar derivatives. The configurations of the tertiary position of 3- C-(1,3-dithian-2-yl)-1,2:5,6-di-O-isopropylidene-α-d-allofuranose (1), lethyl of 4,6-O-benzylidene-2- deoxy-3-C-(dithian-2-yl)-α-d-ribo-hexopyranoside (2) and the corresponding 3-C-butyl compound (2a), and methyl 2-C-(1,3-dithian-2-yl)-3,4-O-isopropylidene-δ-d-ribopyranoside (3) were assigned by comparison with reference spectra. The proton shift-gradients for 5-C-benzoyloxymethyl-2,3-O- cyclohexylidene-1-O-p-tolylsulfonyl-1(R),2(S),3(S),5(R)-cyclohexanetetrol (4), taken in conjunction with the spin-spin coupling values, permit direct assignment of relative stereochemistry in the latter compound.     

One-pot carbanionic access to methylenebis(phosphonate) analogues of natural P,P-glycosyl-disubstituted pyrophosphates

Two novel lithiated carbanions derived from ethyl (1,2:3,4-diisopropylidene-α-d-galactopyranosyl) methyl phosphonate 3a and ethyl (1-O-methyl-2,3-O-isopropylidene-β-d-ribofuranosyl) methylphosphonate 3b were used in the one-pot alkylidene diphosphorylation of 2,3-O-isopropylidene uridine or 2,3:5,6-di-O-isopropylidene-d-mannofuranose to synthesise the methylenebis(phosphonate) analogues of natural P¹,P²-glycosyl-disubstituted pyrophosphates.     

Kiliani reactions on ketoses: branched carbohydrate building blocks from D-tagatose and D-psicose

D-Tagatose and D-psicose on treatment with sodium cyanide gave mixtures of branched sugar lactones; extraction of the crude products by acetone in the presence of acid permits direct access to branched carbohydrate diacetonides, likely to be of value as new chirons. In both cases, the major lactone products—diacetonides with a 2,3-cis-diol relationship—can be crystallised in around 40-50% yield from the ketohexose. A practical procedure for the conversion of 30 g of D-tagatose to give 24 g of 2,3:5,6-di-O-isopropylidene-2-C-hydroxymethyl-D-talono-1,4-lactone is reported.     

Thermal analysis of new glycopolymers derived from monosaccharides

A novel monomer carrying carbohydrate moiety was prepared by simple reaction of methacrylic acid with 3-O-(2′,3′-epoxy-propyl)-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose. Another d-glucose oligomer was synthesized by the polycondensation of a dicarboxylic acid including the carbohydrate residue into the main polymeric chain, 3-O-benzyl-5,6-(bis-O-(acryloyloxy))-1,2-di-O-isopropylidene-α-d-glucofuranose, with propane-1,3-diol using p-toluenesulfonic acid as catalyst. These products were copolymerized with styrene and 2-hydroxypropyl methacrylate, respectively, at different mass ratios, using benzoyl peroxide as initiator. Differential scanning calorimetry was performed in order to study the copolymerization process of the monomer and oligomer into the chosen co-monomers, respectively, and the activation energy of this process was evaluated using Kissinger–Akahira–Sunose (KAS) method. The storage and loss modulus of the obtained glycopolymers were evaluated using dynamic mechanical analysis. The thermal stability of the obtained products was studied via thermogravimetry.     

Chemical studies of carbohydrates. Part I. Conversion of derivatives of glucose and allose into pyrazoles and pyridazines

On reaction of 1,2:5,6-di-O-isopropylidenc-3-O-(p-tolylsulfonyl)-α-D-glueofuranose ( 1 ) with hydrazine hydrate at 140° besides formation of 3-deoxy-3-hydrazino-1,2:5,6-di-O-isopropylidene-α-D-allofuranose ( 2 ) and 3-dcoxy-1,2:5,6-di-O-isopropylidene-α-D-erythro-hex-3-enofuranose ( 3 ), ring transformation into 3-[4′-(2′,2′-dimethyl-1′,3′-dioxolanyl)]pyridazine ( 4 ) takes place. At 170°, however, only 2 and 4 are formed, indicating that 3 is the precursor of 4. Treatment of 3 with hydrazine hydrate at 170° indeed gives a nearly quantitative ring expansion into 4. Treatment of 3-dcoxy-3-hydrazino-1,2:5,6-di-O-isopropylidenc-α-D-glucofuranose ( 8 ) as well as the stereoisomeric allofuranose 2 with concentrated hydrochloric acid gives a nearly quantitative ring interconversion into 3-(D-erythro-trihydroxypropyl)pyrazole ( 9 ).     

Chemical studies of carbohydrates (II) On the mechanism of the conversion of a glucose derivative into a pyridazine compound

The formation of 3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)pyridazine ( 4 ) by reacting 1,2:5,6-di-O-isopropylidene-3-O-(p-tolylsulfonyl)-α-D-glucofuranose ( 1 ) with hydrazine hydrate via the intermediate 3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-erythro-hex-3-enofuranose ( 3 ) is explained by a mechanism, involving an initial attack of the hydrazine molecule at position 4 in compound 3 , a subsequent ring opening by fission of the C₄? O bond and a ring closure by formation of a N? C₁ bond.     

Synthesis of glucose phosphate derivatives by the phosphite triester method

Synthesis of sugar phosphate derivatives by means of phosphite triester method is described. Seven glucose phosphotriester derivatives have been prepared, i.e. dimethyl, methyl n-propyl, and methyl isopropyl (1, 2:5, 6-di-O-isopropylidene-α-D-glucofuranose-3-) phosphate (5, 7 and 8); methyl bis-(1, 2:5, 6-di-O-isopropylidene-α-D-glucofuranose-3-) phosphate (6); methyl bis-(1, 2, 3, 4-tetra-O-acetyl-β-D-glucopyranose-6-) phosphate (9); methyl bis-(1, 2-O-isopropylidene-3,5-O-benzylidene-α-D-glucofuranose-6-) phosphate (10); and methyl (1, 2, 5, 6-di-O-iso-propylidene-α-D-glucofuranose-3-) (1, 2, 3, 4-tetra-O-acetyl-β-D-glucopyranose-6-) [phosphate (11). The results of the displacement of second chlorine atom of the reagent by different alcohols showed that methanol, n-propanol, isopropanol and as well as the glucose derivatives reacted normally to give the expected phosphite esters which yield the expected phosphate products after oxidation, but not the t-butanol. Removal of methyl group from a phosphotriester linkage can be easily achieved by the action of t-butyl amine and thus, t-butyl ammonium bis-(1, 2:5, 6-di-O-isopropylidene-α-D-glucofuranose-3-) phosphate t-butyl amine salt (12) has been obtained from its parent phosphotriester in nearly quantitative yield. The mass spectra data of di-O-isopropylideneglucose phosphate reveals that the cleavage of these compounds follows a general pattern and can be used for their characterization.     

Synthesis and asymmetric oxidation of thioglycosides derived from neomenthanethiol and α-d-galactose

6-Deoxy-6-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexylsulfanyl]-1,2:3,4-di-O-isopropylidene-α-d-galactopyranose was synthesized in 94% yield from 1,2 : 3,4-di-O-isopropylidene-α-d-galactopyranose and neomenthanethiol, and its oxidation gave the corresponding diastereoisomeric sulfoxides in up to 84% yield and de values of up to 52%. The isopropylidene protective groups were removed from the sulfide and sulfoxides by treatment with trifluoroacetic acid in chloroform.     

Asymmetric Baylis–Hillman reaction using sugar acrylates—synthesis of optically active α-methylene-β-hydroxy alkanoates

A study on the asymmetric Baylis–Hillman reaction of three chiral acrylates; 1,2:5,6-di-O-iso-propylidine-α-d-glucofuranose-3-acrylate 1, 2,3:5,6-di-O-iso-propylidine-α-d-mannofuranose-1-acrylate 2 and 1,2-O-iso-propylidine-5-O-tert-butyldimethylsilyl-α-d-xylofuranose-3-acrylate 3, with various aldehydes was conducted, resulting in adducts with moderate diastereoselectivity (5–40% e.e.).     

Regioselective phthalation and succinylation of D-glucose and D-galactose using protecting groups: Conversion of the products to organotin derivatives

1,2: 5,6-Di-O-isopropylidene-α-D -glucofuranose was acylated at the free 0-3 position with phthalic and succinic anhydrides. Removal of the protecting groups gave the 3-O-acylglucopyranose compounds which were converted to their acetyl and organostannyl derivatives. A similar sequence of reactions was carried out with 1,2:3,4-di-O-isopropylidene-α-D -galactopyranose.     

Semicontinuous emulsion copolymerization of 3-O-methacryloyl-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose (3-MDG) and butyl acrylate (BA) by pre-emulsion addition technique

Semicontinuous emulsion copolymerization of sugar-carrying methacrylate, 3-O-methacryloyl-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose (3-MDG), and butyl acrylate (BA) was investigated at 70 °C with the pre-emulsion addition technique. The effect of the emulsifier concentration and its distribution on the particle size (D) as well as on the evolution of the number of particles (N_p) during the polymerization was studied. The influence of the initiator concentration and its addition manner on the colloidal features was also investigated. The chemical stability and the properties of the sugar latexes were studied in the presence of sodium bicarbonate as a buffer. The effect of the seed-stage on the particle size and its distribution was analyzed. The thermal, mechanical (such as film formation and stress-strain behavior), and rheological properties of the final sugar latexes were determined as well.     

Preparation of Primary and Secondary Azidosugars from Diols using the Dioxaphosphorane Methodology

ABSTRACT

Treatment of methyl 2,3-di-O-benzyl-α-D-glucopyranoside (1), methyl 2,3-di-O-acetyl-α-D-glucopyranoside (4), 3-O-benzyl-1,2-O-(1-methylethylidene)-α-D-glucofuranose (6), 3-O-acetyl-1,2-O-(1-methylethylidene)-α-D-glucofuranose (9), 1,2-O-(1-methylethylidene)-α-D-xylofuranose (11) and methyl 2,3-di-O-acetyl-α-D-galactopyranoside (15) with diisopropylazodicarboxylate-triphenylphosphine in tetrahydrofuran led to the corresponding dioxaphosphoranes, which were opened by trimethylsilyl azide affording the silylated primary azidodeoxysugars. When the same reaction was performed on methyl 2,3-di-O-benzyl-α-D-galactopyranoside (20), an inversion of the regioselectivity of the dioxaphosphorane opening was observed, leading mainly to the 4-azido-4-deoxy-α-D-glucopyranoside derivative 27.     

C-4 EPIMERIZATION OF α-D-GLUCOPYRANOSIDE: A FACILE SYNTHESIS OF 4-O-ACETYL-α-D-GALACTOPYRANOSYL DERIVATIVES

An unexpected epimerization resulting from the reaction of α-D-glucopyranosyl derivatives with DAST is described. The reaction of 3,4-di-O-acetyl-1,6-di-O-trityl-β-D-fructofuranosyl 2,3,6-tri-O-acetyl-α-D-glucopyranoside (1), methyl 2,3-di-O-acetyl-6-O-trityl-α-D-glucopyranoside (6), 2,3-di-O-acetyl-6-O-trityl-α-D-glucopyranosyl 2,3-di-O-acetyl-6-O-trityl-α-D-glucopyranoside (13), and 2,3-di-O-acetyl-6-O-tert-butyldiphenylsilyl-α-D-glucopyranosyl 2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside (14) with DAST at 0°C did not give the expected C-4 fluorodeoxy galacto derivatives, but instead, the corresponding 4-O-acetyl-3-hydroxy-α-D-galactopyranosides in yields of 52–78%. When the treatment of 6 was carried out at ?25°C for ～5 min the corresponding diastereomeric 4-O-diethylaminosulfinates (9a,b) were isolated as the major products (40%). Evidence suggests that the epimerization reaction most probably resulted from an intramolecular displacement of the intermediate diethylaminosulfur difluoride ester or diethylaminosulfinyl ester by the neighbouring acetoxy groups.