D-glucitol Derivatives Research Articles

Synthesis and Structure-Activity Relationship of C-Phenyl D-Glucitol (TP0454614) Derivatives as Selective Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitors.

Sodium-glucose cotransporter 1 (SGLT1) is the primary transporter for glucose absorption from the gastrointestinal tract. While C-phenyl D-glucitol derivative SGL5213 has been reported to be a potent intestinal SGLT1 inhibitor for use in the treatment of type 2 diabetes, no SGLT1 selectivity was found in vitro (IC50 29 nM for hSGLT1 and 20 nM for hSGLT2). In this study we found a new method of synthesizing key intermediates 12 by a one-pot three-component condensation reaction and discovered C-phenyl D-glucitol 41j (TP0454614), which has >40-fold SGLT1 selectivity in vitro (IC50 26 nM for hSGLT1 and 1101 nM for hSGLT2). The results of our study have provided new insights into the structure-activity relationships (SARs) of the SGLT1 selectivity of C-glucitol derivatives.

Discovery of potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor SGL5213 for type 2 diabetes treatment.

A new series of C-phenyl d-glucitol derivatives was designed and synthesized, and their SGLT1 inhibitory potency and absorbability were evaluated. We also investigated whether kidney drug retention could be avoided by creating molecules with different excretion pathways. To achieve a class of molecules with low absorption and that were excreted in bile, optimized synthesis was performed to bring the ClogP value and the topological polar surface area to within the appropriate ranges. Compounds 34d and 34j were poorly absorbed, but the absorbed compounds were mainly excreted in bile. Thus, smaller amounts of persistent residue in the kidneys were observed. Since 34d exerted a glucose-lowering effect at a dose of 0.3 mg/kg (p.o.) in SD rats, this compound (SGL5213) could be a clinical candidate for the treatment of type 2 diabetes.

ChemInform Abstract: A New Synthesis of L-Ascorbic Acid (Vitamin C) from Protected Derivatives of D-Glucitol.

Abstract Indirect, anodic oxidation of 1,3,2,4-diacetals of D-glucitol, leads to the 3,5,4,6-diacetals of 2-keto-L-gulonic acid. Hydrolysis of which provides L-xylo-2-hexulosonic acid and hence L-ascorbic acid by lactonization.

2-O-Benzylation in D-Gluconamide Derivative Under Basic Conditions with Complete Retention of Stereo-Integrity: Convenient Access to 2-O-benzyl-3,4:5,6- di-O-isopropylidene-D-glucitol and other Differently Protected D-glucitol Derivatives

A new and convenient synthesis of 2-O-benzyl-3, 4: 5, 6-di-O-isopropylidene-D-glucitol has been accomplished and has been generalized with the syntheses of differently protected D-glucitols at C-2 position. In the course of our new route to the differently protected D-glucitols at C-2 position, a new D-gluco configured building block, 1-morpholino-(3, 4: 5, 6-di-O-isopropylidene)-D-gluconamide has been achieved.

Peracetylated 1,6-dibromo- d-glucitol as efficient precursor of 1,6-diiodo and some mono-, disubstituted and heterocyclic d-glucitol derivatives

2,3,4,5-Tetra- O-acetyl-1,6-dibromo-1,6-dideoxy- d-glucitol ( 1a) obtained from d-glucitol was easily transformed into the 1,6-diiodo derivative in excellent yield (97%) by reaction with an excess of sodium iodide in refluxing butanone in 2 h. When the reaction time was prolonged to 24 h and the crude product was acetylated, 1,2,3,4,5-penta- O-acetyl-6-deoxy-6-iodo- d-glucitol and d-glucitol hexaacetate were isolated in 50 and 26% yields, respectively. The monodehalogenation then took place regioselectively at C-1. This regioselectivity allowed the synthesis of some mono- and disubstituted derivatives of d-glucitol. Thus, the peracetylated derivatives of d-glucitol, 6-bromo, 6-bromo-1- S-butyl, 6-bromo-1- S-octyl, 6- S-butyl, 6- S-butyl-1- S-octyl, 1- S-butyl, 1,6-di- S-octyl and 6- S-phenyl were synthesised in good to excellent yields. With S  as binucleophilic reagent, 1a gave mainly the thiepane derivative (75%) plus the 1- S-acetyl-2,6-anhydro- d-glucitol derivative as a by-product (10%).

Synthesis of 4-substituted phenyl 2,5-anhydro-1,6-dithio-α- d-gluco- and -α- l-guloseptanosides possessing antithrombotic activity

Two independent approaches were investigated for the synthesis of 3,4-di- O-acetyl-1,6:2,5-dianhydro-1-thio- d-glucitol ( 18), a key intermediate in the synthesis of 1,3,4-tri- O-acetyl-2,5-anhydro-6-thio-α- d-glucoseptanose ( 13), needed as glycosyl donor. In the first approach 1,6-dibromo-1,6-dideoxy- d-mannitol was used as starting material and was converted via 2,5-anhydro-1,6-dibromo-1,6-dideoxy-4- O-methanesulfonyl-3- O-tetrahydropyranyl- d-glucitol into 18. The second approach started from 1,2:5,6-di- O-isopropylidene- d-mannitol and the allyl, 4-methoxybenzyl as well as the methoxyethoxymethyl groups were used, respectively, for the protection of the 3,4-OH groups. The resulting intermediates were converted via their 1,2:5,6-dianhydro derivatives into the corresponding 3,4-O-protected 2,5-anhydro-6-bromo-6-deoxy- d-glucitol derivatives. The 1,6-thioanhydro bridge was introduced into these compounds by exchanging the bromine with thioacetate, activating OH-1 by mesylation and treating these esters with sodium methoxide. Among these approaches, the 4-methoxybenzyl protection proved to be the most suitable for a large scale preparation of 18. Pummerer rearrangement of the sulfoxide, obtained via oxidation of 18 gave a 1:9 mixture of 1,3,4-tri- O-acetyl-2,5-anhydro-6-thio-α- l-gulo- ( 12) and - d-glucoseptanose 13. When 12 or 13 were used as donors and trimethylsilyl triflate as promoter for the glycosylation of 4-cyanobenzenethiol, a mixture of 4-cyanophenyl 3,4-di- O-acetyl-2,5-anhydro-1,6-dithio-α- l-gulo- ( 58) and -α- d-glucoseptanoside ( 61) was formed suggesting an isomerisation of the heteroallylic system of the intermediate. A similar mixture of 58 and 61 resulted when 18 was treated with N-chloro succinimide and the mixture of chlorides was used in the presence of zinc oxide for the condensation with 4-cyanobenzenethiol. When 4-nitrobenzenethiol was applied as aglycon and boron trifluoride etherate as promoter, a mixture of 4-nitrophenyl 3,4-di- O-acetyl-2,5-anhydro-1,6-dithio-α- l-gulo- ( 60) and -α- d-glucoseptanoside ( 62) was obtained. Deacetylation of 58, 61 and 62 according to Zemplén afforded 4-cyanophenyl 2,5-anhydro-1,6-dithio-α- l-guloseptanoside ( 59), 4-cyanophenyl 2,5-anhydro-1,6-dithio-α- d-glucoseptanoside ( 63) and 4-nitrophenyl 2,5-anhydro-1,6-dithio-α- d-glucoseptanoside ( 66), respectively. The 4-cyano group of 63 was transformed into the 4-aminothiocarbonyl, and the 4-(methylthio)(imino)methyl derivative and the 4-nitro group of 66 into the acetamido derivative. All of these thioglycosides displayed a stronger oral antithrombotic effect in rats compared with beciparcil, used as reference.

Synthesis and biological evaluation of ureido and thioureido derivatives of 2-amino-2-deoxy- d-glucose and related aminoalcohols as N-acetyl-β- d-hexosaminidase inhibitors

Ureido and thioureido derivatives of 2-acetamido-2-deoxy-β- d-glucose, 1-amino-1-deoxy- d-glucitol and 2-(2-aminoethoxy)ethanol were prepared as N-acetyl-β- d-hexosaminidase (NAHase) inhibitors and were evaluated on Trichomonas vaginalis NAHase. Although none showed complete inhibition of the enzyme at 100 μM, 1-amino-1-deoxy- d-glucitol derivatives acted as competitive inhibitors of the NAHase of T. vaginalis.

Analysis of the positions of substitution of acetate and butyrate groups in cellulose acetate–butyrate by the reductive-cleavage method

The degree of substitution (ds) and the distribution pattern of the two ester substituents in commercial samples of cellulose acetate–butyrate (CAB) were determined by sequential neutral methylation, direct reductive cleavage and in situ acetylation. When the reductive-cleavage reaction was conducted with 35 equiv (per anhydroglucose unit) of Et 3SiH, 70 equiv of MeSO 3SiMe 3, and 14 equiv of BF 3·OEt 2 at room temperature for seven days, the O-acetyl groups were converted to O-ethyl groups and the O-butyryl groups were converted to O-butyl groups concurrent with reductive cleavage of the glycosidic linkages. Acetylation of the products gave 27 partially methylated, ethylated, and butylated 4- O-acetyl-1,5-anhydro- d-glucitol derivatives that were identified by GLC–CIMS (NH 3) and GLC–EIMS. Integration of the GLC profile and correction for molar response gave the mole percent of each product. From these data, the fractional degree of substitution for each ester at each position of the anhydroglucose unit was determined. The combined fractional degree of substitution of both esters at each position and the overall ds were also determined by sequential neutral methylation, acyl–ethyl exchange, and reductive cleavage, and the values so obtained were in good agreement with those derived by sequential neutral methylation and direct reductive cleavage.

Analysis of the positions of substitution of acetate and propionate groups in cellulose acetate–propionate by the reductive-cleavage method

The degree of substitution (ds) and the distribution pattern of the two ester substituents in commercial samples of cellulose acetate–propionate (CAP) were determined by sequential neutral methylation, direct reductive cleavage, and in situ acetylation. When the reductive-cleavage reaction was conducted with 35 equiv (per anhydroglucose unit) of Et 3SiH, 70 equiv of MeSO 3SiMe 3, and 14 equiv of BF 3·OEt 2 at room temperature for seven days, the O-acetyl groups were converted to O-ethyl groups, and the O-propionyl groups were converted to O-propyl groups concurrent with reductive cleavage of the glycosidic linkages. Acetylation of the products gave 27 partially methylated, ethylated, and propylated 4- O-acetyl-1,5-anhydro- d-glucitol derivatives that were identified by GLC–CIMS (NH 3) and GLC–EIMS. Integration of the GLC profile and correction for molar response gave the mole percent of each product. From these data, the fractional degree of substitution for each ester at each position of the anhydroglucose unit was determined. The combined fractional degree of substitution of both esters at each position and the overall ds were also determined by sequential neutral methylation, acyl–ethyl exchange, and reductive cleavage, and the values so obtained were in good agreement with those derived by sequential neutral methylation and direct reductive cleavage.

Synthesis of ester-and amide-linked pseudo-azadisaccharides via coupling of d-glucose with 6-amino-6-deoxy-2,5-imino- d-glucitol

Hydrolytically-resistant pseudodisaccharides incorporating an azafuranose have been prepared by coupling 6-amino-2,5-imino- d-glucitol derivatives with d-glucose, either through an ester or an amide bond. Synthesis of the azasugar templates was achieved by nucleophilic opening of a C 2 symmetric bis-aziridine deriving from d-mannitol.

Some 3,5-acetal derivatives of d-glucitol

Ethylidenation of 1,6-di- O-benzoyl-2,4- O-benzylidene- d-glucitol gave the 3,5- O-ethylidene derivative in poor yield, whereas reaction with 2,2-dimethoxypropane gave the 3,5- O-isopropylidene derivative in good yield. Removal of the benzoyl and benzylidene groups, with further derivatisation, gave a variety of compounds containing the relatively unstable 3,5-acetal ring. Attempted tosylation of 3,5- O-isopropylidene- d-glucitol gave a derivative of 1,4-anhydro- d-glucitol. Reduction of various ditosylates revealed selective reaction of axial tosyloxymethyl groups.

A New Synthesis of L-Ascorbic Acid (Vitamin C) from Protected Derivatives of D-Glucitol

Abstract Indirect, anodic oxidation of 1,3,2,4-diacetals of D-glucitol, leads to the 3,5,4,6-diacetals of 2-keto-L-gulonic acid. Hydrolysis of which provides L-xylo-2-hexulosonic acid and hence L-ascorbic acid by lactonization.

Potential glycosidase inhibitors: synthesis of 1,4-dideoxy-1,4-imino derivatives of D-glucitol, D- and L-xylitol, D- and L-allitol, D- and L-talitol, and D-gulitol

Conversion of 2,3,5,6-tetra-O-benzyl-D-galactofuranose (19) into its oxime and subsequent treatment with methanesulphonyl chloride gave 2,3,5,6-tetra-O-benzyl-4-O-methylsulphonyl-D-galactonitrile (21). Reductive cyclization by sodium borohydride/cobalt(II) chloride, followed by hydrogenolysis under acidic conditions yielded 1,4-dideoxy-1,4-imino-D-glucitol hydrochloride (11). A similar reaction sequence was used to convert 2,3,5-tri-O-benzyl L-arabinofuranose (23)via the nitrile (25) into 1,4-dideoxy-1,4-imino-D-xylitol hydrochloride (12), and the corresponding D-arabinose derivative (27) gave 1,4-dideoxy-1,4-imino-L-xylitol hydrochloride (13), using the same chemistry.Treatment of 2,3 : 5,6-di-O-isopropylidene-β-D-gulofuranose (31) with hydroxylamine and then methanesulphonyl chloride in pyridine gave 4-O-methylsulphonyl-2,3 : 5,6-di-O-isopropylidene-D-gulononitrile (32), which was converted by treatment with lithium aluminium hydride and subsequent acid hydrolysis into 1,4-dideoxy-1,4-imino-D-allitol hydrochloride (14); similar chemistry in the enantiomeric series gave the L-allitol derivative (15). An analogous reaction sequence was used to convert 2,3 : 5,6-di-O-isopropylidene-α-D-mannofuranose into 4-O-methylsulphonyl-2,3 : 5,6-di-O-isopropylidene D-mannononitrile (38) and thence into 1,4-dideoxy-1,4-imino-D-talitol hydrochloride (16); L-mannonolactone was converted via 2,3 : 5,6-di-O-isopropylidene-α-L-mannofuranose (41) into 1,4-dideoxy-1,4-imino-L-talitol hydrochloride (17).2,3 : 5,6-Di-O-isopropylidene-β-D-allofuranose (45) was converted via its oxime (46) into 4-O-methylsulphonyl-2,3 : 5,6-di-O-isopropylidene-D-allononitrile (47), which on reductive cyclization with lithium aluminium hydride, and subsequent acid hydrolysis, gave 1,4-dideoxy-1,4-imino-D-gulitol hydrochloride (18).

Distribution of substituents in O-(2-hydroxyethyl)cellulose: A 13C-N.M.R. approach

O-(2-Hydroxyethyl)cellulose was converted into a mixture of the corresponding d-glucitol derivatives by hydrolysis followed by reduction of the sugars with NaBH 4. On the basis of the spectra of individual O-(2-hydroxyethyl)- d-glucitols, the 13C-n.m.r. spectrum of this mixture was assigned to the extent that permitted quantitative analysis in terms of monomer composition of the polymer. The monomer mole-fractions conform to a statistical, kinetic model that assumes that the reactivity of the 3-hydroxyl group of the d-glucosyl residues of cellulose depends on the state of substitution at O-2. The relative rate-constants of the hydroxyl groups in the (hydroxyethyl)ation reaction are k 2: k 3: k 3′: k 6: k x = 6.0:1.0:4.0:11.1:34.6, indicating that the reactivity of OH-3 increases fourfold upon (hydroxyethyl)ation of OH-2.

Analysis of linkage positions in d-glucopyranosyl residues by the reductive-cleavage method

The positions of linkage in the d-glucans amylose, cellulose, laminaran, pullulan were established by permethylation and subsequent reductive cleavage with triethylsilane and either trimethylsilyl trifluoromethanesulfonate (Me 3SiO 3SCF 3) or boron trifluoride etherate (BF 3 • Et 2O) as the catalyst. Reductive cleavages with Me 3SiO 3SCF 3 as the catalyst were performed by adding a stock solution of Et 3SiH and catalyst in dichloromethane to the previously dried, fully methylated polysaccharides. Subsequent acetylation was accomplished in situ by adding acetic anhydride, and, after extraction of the reaction mixture with aqueous sodium hydrogencarbonate, the dichloromethane solution was analyzed directly by gas-liquid chromatography-mass spectrometry. With Me 3SiO 3SCF 3 as the catalyst, all of these d-glucans gave the methylated 1,5-anhydro- d-glucitol derivatives expected. Reductive cleavages with BF 3 • Et 2O as the catalyst were carried out in two steps, with an intermediate reaction workup prior to acetylation of the product. With BF 3 • Et 2O as the catalyst, permethylated amylose gave the methylated 1,5-anhydro- d-glucitol derivatives expected, but permethylated cellulose and laminaran were not cleaved. Interestingly, BF 3 • Et 2O effectively catalyzed reductive cleavage of the α-(1→4) linkages in permethylated pullulan but not the α-(1→6) linkages, yielding a methylated disaccharide-anhydroalditol derivative containing the intact α-(1→6) linkage as a major product. The independent synthesis, and n.m.r. and mass-spectral characterization, of the methylated 1,5-anhydro- d-glucitol derivatives formed from these d-glucans by reductive cleavage are repored.

Analysis of the linkage positions in d-fructofuranosyl residues by the reductive-cleavage method

The suitability of the reductive-cleavage method for analysis of the linkage positions in d-fructofuranosyl residues of d-fructans was examined by using sucrose, chicory-root inulin, and Aerobacter levanicum levan as models. Permethylation, and reductive cleavage with triethylsilane in the presence of either boron trifluoride etherate or trimethylsilyl trifluoromethanesulfonate, gave the expected methylated derivatives of 2,5-anhydro- d-mannitol and 2,5-anhydro- d-glucitol. With either catalyst, nonreducing (terminal) d-fructofuranosyl groups and d-fructofuranosyl residues linked at O-1 gave derivatives having the manno configuration as the major product, whereas d-fructofuranosyl residues linked at O-6, and at both O-1 and O-6, gave derivatives having the gluco configuration as the major product. The independent synthesis, and n.m.r.- and mass-spectral characterization, of the methylated 2,5-anhydro- d-mannitol and 2,5-anhydro- d-glucitol derivatives formed from these residues by reductive cleavage are reported.

Capillary gas chromatography of isopropylidene derivatives of d-glucitol: correlation between structure and retention

Reaction products of d-glucitol with acetone and zinc chloride were studied by gas chromatography and gas chromatography—mass spectrometry. Complete separation of the reaction mixtures was achieved on two capillary columns coated with Carbowax 20M and SE-30. The methylene unit values were determined for eleven derivatives of d-glucitol acetals. Correlations were found between the methylene units of the acetals on stationary phases of different polarities and their structures. An attempt is made to explain the relationship between the elution order and the preferred conformers of the d-glucitol acetals. The structures of all derivatives were confirmed by mass spectrometry.

Synthesis and biological activity of 1,4:3,6-dianhydro-2,5-diazido-2,5-dideoxyhexitols

Reaction of 1,4:3,6-dianhydro-2,5-di- O-mesyl- and -tosyl- d-mannitol with sodium azide afforded the 2,5-diazido- l-iditol derivative. The analogous d-glucitol isomer was obtained in a similar reaction starting from the corresponding d-glucitol derivatives, and showed significant, hypnotic activity. For establishing the structure-activity relationship, 1,4:3,6-dianhydro-2,5-diazido-2,5-dideoxy- l-mannitol ( 19), as well as its antipode 27, was synthesized, starting from dmannitol. Compound 19 was as effective as Doriden® (3-ethyl-3-phenylglutarimide), a well known, hypnotic drug. The antipode 27 and the bioisosteric 1(4),3(6)-dithio derivative were, however, inactive.

Synthesis and some reactions of 3,5-di- O-methyl- d-glucose and -fructose

Hydrolysis of 1,2- O-isopropylidene-3,5-di- O-methyl-α- d-glucofuranose by strong acid yielded 3,5-di- O-methyl- d-glucofuranose ( 6) and its 1,6-anhydride ( 10). The mechanism of the reaction giving 10 is discussed. On treatment with a catalytic amount of sodium methoxide, 1,2,6-tri- O-acetyl-3,5-di- O-methyl- d-glucofuranose ( 8) gives the 6- O-acetyl derivative, whereas complete deacetylation, and subsequent isomerization to the d-fructose derivative 16, takes place in the presence of 0.1 m sodium methoxide. The structure of 16 was proved both chemically and spectroscopically. Reduction of 6 or 8 with a borohydride afforded 3,5-di- O-methyl- d-glucitol. 2 2 According to carbohydrate nomenclature, this may also be named 2,4-di- O-methyl- l-gulitol. To avoid confusion, the alditols are named as d-glucitol derivatives.

Acid-catalysed formation of diacetals from butyraldehyde and certain D-glucitol derivatives

Acid-catalysed dibutyiidenation of 1-deoxy- D-glucitol and 3- O-methyl- D-glucitol yields the 2,4:5,6-diacetals as the main, thermodynamically controlled products, and 2-deoxy- D- arabino-hexitol ( i.e., 2-deoxy- D-glucitol) yields the 1,3:4,6-diacetal as the main, thermodynamically controlled product.