Application of Novel Glycosides Prepared with Odorless Benzenethiols in Glycosylation Reaction

p‐Dodecylbenzenethiol (1) and p‐octyloxybenzenethiol (2) were synthesized as new odorless benzenethiols. Moreover, preparation of novel 1‐thioglycosides using 1 and 2 as well as their application for glycosylation reactions was performed. As a result, it was found that these 1‐thio‐glycosides were excellent glycosyl donors, and especially 2‐thio‐sialoside prepared from 1 and 2 afforded the best result to date in terms of α‐ and β‐selectivity in the sialylation where only the single C‐3 hydroxyl group of acceptor D‐galactopyranoside was free. All procedures from the preparation of thioglycosides to glycosylation reaction were attainable under completely odorless conditions.     

A Practical One‐Pot Synthesis of New S‐Glycosyl Amino Acid Building Blocks for Combinatorial Neoglycopeptide Synthesis

S‐Glycosyl L‐aspartic acid building blocks were synthesized starting from 1‐thiosugars by reaction with 5‐aminopentanol and suitably protected L‐aspartic acid pentafluorophenyl ester in a one‐pot procedure under Mitsunobu conditions using 1,1′‐azodicarbonyl dipiperidine and trimethyl phosphine. The method allowed for the preparation of S‐glycosyl amino acid building blocks in one step without protection of the amino function for the Mitsunobu condensation. Alternatively, the title compounds were prepared by a stepwise approach via 5‐aminopentyl 1‐thioglycosides.     

First Synthesis of Thienopyrazole Thioglycosides

Reported is the first method to prepare a new class of thienopyrazole thioglycosides via a one‐pot reaction of the sodium thienopyrazolthiolate salts with 2,3,4,6‐tetra‐O‐acetyl‐α‐D‐gluco‐and galactopyranosyl bromides. The sodium thienopyrazolthiolate salts are prepared using pyrazoldithioic acids and their corresponding mono ‐ and dithiolate salts.     

Odorless Preparation of Thioglycosides and Thio‐Michael Adducts of Carbohydrate Derivatives

A general, odorless, one‐pot methodology has been developed for the preparation of 1,2‐trans‐thioglycosides and thio‐Michael addition products of carbohydrate derivatives through triphenyl phosphine‐mediated cleavage of disulfides and reaction of the thiolate formed in situ with glycosyl bromides and glycosyl conjugated alkenes.     

Lanthanum Trifluoromethane-sulfonate‐Catalyzed Facile Synthesis of Per‐O‐acetylated Sugars and Their One‐Pot Conversion to S‐Aryl and O‐Alkyl/Aryl Glycosides†

Lanthanum trifluoromethanesulfonate‐catalyzed solvent‐free per‐O‐acetylation with stoichiometric acetic anhydride proceeds in high yield (95%–99%) to afford exclusively pyranose products as anomeric mixtures. Subsequent anomeric substitution employing borontrifluoride etherate and thiols or alcohols furnished the corresponding 1,2‐trans‐linked thioglycosides and O‐glycosides, respectively, in good to excellent overall yield (75%–85%). Alternatively, reaction of free sugars in neat alcohol employing the same catalyst at elevated temperature gives the corresponding 1,2‐cis‐linked O‐glycosides (along with 1,2‐trans‐linked glycosides as minor product) in good yield (73%–80%). Anomeric mixtures of compounds thus produced were characterized as their per‐O‐acetylated derivatives.      

Modified One‐Pot Protocol for the Preparation of Thioglycosides from Unprotected Aldoses via S‐Glycosyl Isothiouronium Salts*

An efficient one‐pot protocol for the direct preparation of thioglycosides starting from unprotected reducing sugars via S‐glycosyl isothiouronium salts is reported. In this one‐pot methodology, BF₃ · OEt₂ has been used as a general catalyst for both per‐O‐acetylation of sugars and conversion of sugar per‐O‐acetates into S‐glycosyl isothiouronium salts, which was allowed to react with alkylating agents in the presence of a base to furnish thioglycosides in excellent yield.     

Application of a Model Building Approach to Molecular Mechanics (MM3) for Calculating Low‐Energy Conformations of Tetra‐O‐Acyl‐N,N′‐Dialkyl‐D‐Glucaramides

A model building approach was used in conjunction with the MM3 molecular mechanics program to find the low‐energy conformations of three tetra‐O‐acyl‐N,N′‐dimethyl‐d‐glucaramide molecules: tetra‐O‐propanoyl‐(2), 2‐methylpropanoyl‐(3) and 2,2‐dimethylpropanoyl‐N,N′‐dimethyl‐d‐glucaramide (4), and tetra‐O‐acetyl‐N,N′‐dihexyl‐d‐glucaramide (5). A set of models was chosen for calculation of the low‐energy conformations of parent tetra‐O‐acetyl‐N,N′‐dimethyl‐d‐glucaramide (1), with additional models required to simulate conformationally more complex diamides 2–5. The dominant low‐energy conformations of 2 and 3 were very similar to that from 1, whereas very sterically constrained 4, with four bulky pendant O‐2,2‐dimethylpropanoyl groups, and 5, with terminal n‐hexyl groups, adopted different conformations. Stereoregular alternating head tail–tail head and repeating head tail–poly(hexamethylene 2,3,4,5‐tetra‐O‐acetyl‐D‐glucaramide) oligomers were graphically generated to provide some insight into the possible conformations of the actual acylated polyamides in nonpolar solution.     

Synthesis and Properties of Surfactants derived from N‐Acetyl‐D‐Glucosamine

The synthesis of 2‐acetamido‐2‐deoxy‐6‐O‐octanoyl‐D‐glucono‐1,5‐lactone 9 and 2‐acetamido‐2‐deoxy‐6‐O‐octanoyl‐α‐D‐glucopyranose 7 from 2‐acetamido‐2‐deoxy‐α‐D‐glucopyranose is reported. For both targets, the key intermediate was allyl 2‐acetamido‐3,4‐di‐O‐benzyl‐2‐deoxy‐6‐O‐octanoyl‐α‐D‐glucopyranoside 5. Surface tension measurements (critical micellar concentration of 22.3 mM and 5 mM for 9 and 7, respectively) showed up the surface activity of both compounds, while enzyme inhibition assays indicated that 9 could inhibit bovine β‐N‐acetylglucosaminidase (K_i=6.5 µM) but not Serratia marcescens chitobiase nor hen egg‐white lysozyme. Moreover, 7 was shown to induce chitinase production of S. marcescens and to be readily metabolized by these bacteria.      

Syntheses of Acyclo‐C‐nucleoside Analogs from 2,3:4,5‐Di‐O‐isopropylidene‐D‐xylose

Treatment of 1,2‐dideoxy‐4,5:6,7‐di‐O‐isopropylidene‐D‐xylo‐hept‐1‐yn‐3‐uloses 4a,b with hydrazine hydrate and amidines yielded the 3‐(1,2:3,4‐di‐O‐isopropylidene‐D‐xylo‐1,2,3,4‐tetrahydroxy‐butyl)‐5‐phenyl‐1H(2H)‐pyrazole 5 and the substituted 4‐(1,2:3,4‐di‐O‐isopropylidene‐D‐xylo‐1,2,3,4‐tetrahydroxy‐butyl)pyrimidines 7a–f, respectively. Reaction of 4a,b with 2‐amino‐benzimidazol afforded the 2‐(1,2:3,4‐di‐O‐isopropylidene‐D‐xylo‐1,2,3,4‐tetrahydroxy‐butyl)benzo[4,5]imidazo[1,2‐a]pyrimidines 9a,b. Compound 4a and 5‐amino‐pyrazole‐4‐carbonic acid derivatives yielded the 5‐(1,2:3,4‐di‐O‐isopropylidene‐D‐xylo‐1,2,3,4‐tetrahydroxy‐butyl)pyrazolo[1,5‐a]pyrimidines 11a–d. Deprotection of pyrazole 5, pyrimidine 7a, and pyrazolo[1,5‐a]pyrimidine 11b yielded the acyclo‐C‐nucleosides 6, 8, and 12, respectively.     

Synthesis of 1,2,4‐Triazinediones, 1,2,4,3‐Triazaphospholines,and 1,2,4,3‐Triazaphospholine‐3‐oxide Derivatives

The reaction of N ¹‐tosylamidrazones 1 with oxalyl dichloride, phosphorus trichloride, and phosphoryl chloride leads to 1,2,4‐triazinediones 3 , 1,2,4,3‐triazaphospholines 4 , and 1,2,4,3‐triazaphospholine‐3‐oxides 5 , respectively. The structures of the new products have been established by IR; ¹H, ¹³C, and ³¹P NMR studies; and elemental analysis.     

Synthesis of (−)‐Isofagomine

Abstract

1,3‐Dipolar cycloaddition of N‐benzyl nitrone 2 to D‐threo δ‐lactone 15 proceeded with excellent stereoselectivity to provide only one adduct 16. Cycloadduct 16 was subsequently subjected to a sequence of reactions involving rearrangement to γ‐lactone, glycolic cleavage/reduction, protection of the terminal hydroxymethyl group, reduction of the lactone, desilylation/mesylation, and hydrogenolysis of the N‐O bond providing (?)‐isofagomine and its N‐substituted derivatives. The biologic activity of N‐substituted (?)‐isofagomines toward commercially available α‐ and β‐glucosidases, α‐D‐mannosidase, α‐L‐fucosidase, β‐D‐glucuronidase, and β‐D‐galactosidase was tested.     

Synthesis of “Reversed” Pyrazole‐C‐nucleoside Precursors from Push‐pull Activated Monosaccharide Derivatives

3‐O‐Benzyl‐6‐deoxy‐1,2‐O‐isopropylidene‐α‐d‐xylo‐hept‐5‐ulofuranurononitrile (1) was reacted with N,N‐dimethylformamide dimethylacetal in tetrahydrofuran to furnish the (E)‐3‐O‐benzyl‐6‐deoxy‐6‐dimethylaminomethylene‐1,2‐O‐isopropylidene‐α‐d‐xylo‐hept‐5‐ulofuranurononitrile (2) as a major product. Furthermore, treatment of compound 1 with carbon disulphide and methyl iodide under basic conditions afforded 3‐O‐benzyl‐6‐deoxy‐1,2‐O‐isopropylidene‐6‐[bis(methylsulfanyl)methylene]‐α‐d‐xylo‐hept‐5‐ulofuranurononitrile (6). Reaction of 2 and 6 with hydrazines yielded the “reversed” pyrazole‐C‐nucleoside analogs 4, 5a, 5b, 7, 8, and 9, respectively.     

Synthesis of Urine Drug Metabolites: Glucuronosyl Esters of Carboxymefloquine,Indoprofen, (S)‐Naproxen,and Desmethyl (S)‐Naproxen

Abstract

A general procedure for the synthesis of 1‐O‐acyl‐β‐D‐glucuronic acids using the benzyl 1-O-trichloroacetimidoyl-2,3,4-tri-O-benzyl-D-glucopyranuronate 6 as donor is exemplified by the synthesis of the urine metabolites of (S)‐naproxen, desmethyl (S)‐naproxen, indoprofen, and carboxymefloquine. The key intermediate benzyl 2,3,4‐tri‐O‐benzyl‐D‐glucopyranuronate 5 is easily accessible in four steps (29%) from the peracetylated β-D-glucuronic acid 1.     

Synthesis of C‐Nucleoside Analogues Starting from 1‐(Methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐yl)‐4‐phenyl‐but‐3‐yn‐2‐one

Abstract

1‐(Methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐yl)‐4‐phenyl‐but‐3‐yn‐2‐one (4) was synthesized by the reaction of (methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐yl)ethanal (2) with lithium phenylethynide and following oxidation. Compound 4 and hydrazine hydrate provided the 3(5)‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐yl‐methyl)‐5(3)‐phenyl‐1H‐pyrazole (5). The reactions of 4 with amidinium salts and a S‐methyl‐isothiouronium salt, respectively, furnished the pyrimidine C‐nucleoside analogues 6a–6c. Treatment of 4 with 2‐aminobenzimidazole afforded 2‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐ylmethyl)‐4‐phenyl‐benzo [4,5]imidazo[1,2‐a]pyrimidine (7a). Compound 4 and sodium azide yielded 2‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐D‐altropyranosid‐2‐yl)‐1‐[5(4)‐phenyl‐1H(2H)‐1,2,3‐triazole‐4(5)‐yl]ethanone (8).     

Synthesis of Differently Protected 1‐C‐Methyl‐Ribofuranoses Intermediates for the Preparation of Biologically Active 1′‐C‐Methyl‐Ribonucleosides

Starting from D‐ribose, differently protected 1‐C‐methyl‐D‐ribofuranoses have been prepared as intermediates for the synthesis of variously modified 1′‐C‐methyl‐ribonucleosides, a class of compounds potentially endowed with interesting biological activity.     

Synthesis of Interglycosidically S‐Linked 1‐Thio‐Oligosaccharides Under Microwave Irradiation*

Microwave irradiation (MWI) has accelerated the synthesis of S‐(2,3,4,6‐tetra‐O‐acetyl‐β‐D‐glucopyranosyl)thiouronium bromide (2a), whose reaction with 2,3,4,6‐tetra‐O‐acetyl‐α‐D‐glucopyranosyl bromide (1a) in the presence of Et₃N afforded stereoselectively the acetylated β,β‐1‐thiotrehalose 4a. Similarly, the respective D‐galactopyranosyl 4b and 2‐acetylamino‐2‐deoxy‐D‐glucopyranosyl 4c analog as well as 4,4′‐di‐O‐(2,3,4,6‐tetra‐O‐acetyl‐β‐D‐galactopyranosyl) 4d and 4,4′‐di‐O‐(2,3,4,6‐tetra‐O‐acetyl‐α‐D‐glucopyranosyl) 4e derivatives of 2,2′,3,3′,6,6′‐hexa‐O‐acetyl β,β‐1‐thiotrehalose were prepared.     

Synthesis of (Methyl 3‐O‐Benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐2‐yl)thiophene Derivatives as Precursors of New Iso‐C‐nucleoside Analogues

Treatment of 2‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐2‐yl)ethanal (3) with malononitrile in the presence of aluminium oxide provided 2‐cyano‐4‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐2‐yl)crotononitrile (4). Starting from 4, cyclization with sulphur and triethylamine yielded 2‐amino‐5‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐2‐yl)thiophene‐3‐carbonitrile (5). Further cyclization could be achieved with triethyl orthoformate/ammonia to furnish 4‐amino‐6‐(methyl 3‐O‐benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐2‐yl)thieno[2.3‐d]pyrimidine (8).     

Synthesis of the C‐Glycoside of Methyl α‐d‐Altropyranosyl‐(1→4)‐α‐d‐glucopyranoside

The C‐glycoside of methyl α‐d‐altropyranosyl‐(1→4)‐α‐d‐glucopyranoside 2 was prepared in a convergent fashion, from readily available precursors, 4‐O‐tert‐butyldiphenylsilyl‐1,2‐O‐isopropylidene‐d‐erythro‐S‐phenyl monothiohemiacetal 13 (five steps from D‐ribose) and the known acid, methyl 2,3,6‐tri‐O‐benzyl‐4‐C‐(carboxymethyl)‐4‐deoxy‐α‐d‐glucopyranoside 17 (seven steps from methyl α‐d‐glucopyranoside). The key reactions in the synthesis are the oxocarbenium ion cyclization of thioacetal‐enol ether 19 to a C1 substituted glycal 20, and the stereoselective hydroboration of 20 to the α‐C‐altroside 21.     

A General Method Based on the Use of N-Bromosuccinimide for Removal of the Thiophenyl Group at the Anomeric Position to Generate A Reducing Sugar with the Original Protecting Groups Still Present

Abstract

Efficient conversion of a range of different phenyl thioglycosides into their hemiacetals has been achieved by treatment with N-bromosuccinimide in aqueous acetone. The method is mild and general since it does not interfere with the presence of other protecting groups like acetate, benzyl, benzylidene acetal, tert-butyldiphenylsilyl groups, and the O-glycosidic bond (e.g. di-, tetra-, and pentasaccharide thioglycosides).     

MM3 Conformational Analysis and X‐ray Crystal Structure of 2,3,4,5‐Tetra‐O‐Acetyl‐N,N′‐Dimethyl‐D‐Glucaramide as a Conformational Model for the d‐Glucaryl Unit of Poly(Alkylene 2,3,4,5‐Tetra‐O‐Acetyl‐d‐Glucaramides)

This report describes the MM3 conformational analysis and X‐ray crystal structure of tetra‐O‐acetyl‐N,N′‐dimethyl‐d‐glucaramide as a conformational model for the D‐glucaryl monomer unit of poly(alkylene tetra‐O‐acyl‐d‐glucaramides). The driving force for this study was to determine the conformational preferences for the diacid unit as a function of the increasing steric bulk of pendant O‐acyl groups: acetyl, propanoyl, 2‐methylpropanoyl, and 2,2‐dimethylpropanoyl. The model dialkyl d‐glucaramides all displayed a large vicinal proton coupling between the central backbone glucaryl hydrogens, indicating an essentially fixed anti conformational arrangement of these protons. The MM3 molecular mechanics program was then applied to calculate the corresponding low‐energy conformations of the structurally simplest of these molecules, tetra‐O‐acetyl‐N,N′‐dimethyl‐d‐glucaramide (4). Given the large number of dihedral angles to be considered and the apparent rigidity of these molecules around the central carbons of the glucaryl backbone, a number of conformational approximations based upon model compounds were applied regarding the rotameric disposition of the pendant O‐acetyl and terminal N‐methyl groups. The calculated, and dominant, lowest energy conformer has a sickle structure very similar to the global minimum conformation previously calculated for unprotected d‐glucaramide. The x‐ray crystal structure data from 4 indicated an extended conformation in the solid state and gave solid‐state torsion angle information that was comparable to that obtained computationally.