Glycosyl Bunte Salts: A Class of Intermediates for Sugar Chemistry

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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Glycosyl Bunte Salts: A Class of Intermediates for Sugar Chemistry Yasuhiro Meguro, Masato Noguchi, Gefei Li, and Shin-ichiro Shoda* Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai 980-8579, Japan S Supporting Information *

ABSTRACT: S-Glycosyl thiosulfates have been discovered as a new class of synthetic intermediates in sugar chemistry, named “glycosyl Bunte salts” after 19th-century German chemist, Hans Bunte. The synthesis was achieved by direct condensation of unprotected sugars and sodium thiosulfate using a formamidine-type dehydrating agent in water−acetonitrile mixed solvent. The application of glycosyl Bunte salts is demonstrated with transformation reactions into other glycosyl compounds such as a 1thio sugar, a glycosyl disulfide, a 1,6-anhydro sugar, and an O-glycoside.

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Scheme 1. One-Step Synthesis of Unprotected Glycosyl Thiosulfates (Glycosyl Bunte Salts)

dvancement of glycoscience is heavily indebted to the discovery of key synthetic intermediates for production of useful sugar substances.1 One of the most typical examples is the introduction of glycosyl halides (X = F, Cl, Br, I) and their impact on chemical glycosylation reactions.2 On the contrary, modern carbohydrate chemistry provides various S-glycosyl derivatives as convenient building blocks for the architecture of sugar-based materials.3 Alkyl thioglycosides, for example, have extensively been employed in chemical and biological fields of glycoscience.4 Most S-glycosyl compounds so far report on a glycone part and an aglycone part, both of which are derived from organic compounds. Although plenty of glycosylated compounds having an inorganic aglycone such as glycosyl Ophosphates and glycosyl O-sulfates have been reported, there have been no reports on isolated S-glycosyl thiosulfates.5 One of the main reasons for the absence of S-glycosyl compounds with an inorganic aglycone is because there are no efficient methods for coupling an unprotected sugar and an inorganic salt to give the hybrid structure. To fabricate the required organic−inorganic hybrid substance, it is necessary to develop a new dehydration methodology that takes place in more hydrophilic media. Recently, we have reported the onestep synthesis of glycosyl compounds6a−j based on the concept of direct anomeric activation1c using formamidinium-type dehydrating agents,6k,l and a series of glycosidic compounds were prepared by the reaction of unprotected saccharides and nucleophilic agents. All of these dehydration reactions proceeded under extremely mild conditions in aqueous media without protection of the sugar hydroxy groups. In the course of our investigation for screening an appropriate sulfurcontaining nucleophile, we found that a thiosulfate ion showed excellent nucleophilicity. Herein, we report on the one-step synthesis of S-glycosyl thiosulfate salts 2 from unprotected sugars 1 as the first example of organic−inorganic hybrid-type S-glycosyl compounds (Scheme 1). Since the products possess a structure close to S-alkylthiosulfates, which are known as Bunte salts7 that were discovered by a 19th-century German chemist, Hans © XXXX American Chemical Society

Bunte, we propose to call these new class of S-glycosyl derivatives (glycosyl Bunte salts). The S-alkylthiosulfates (Bunte salts) attracted our interest because they are stable, easy-to-handle crystalline substances, and they have proven to be highly versatile synthetic intermediates in organic reactions used by pharmaceutical and surfactant manufacturers.8 For example, it is well-known that acid hydrolysis of Bunte salts affords the corresponding thiols and forms thioacetals in the presence of carbonyl compounds. In one case, Reeves et al. reported a novel route to sulfides by the reaction between Bunte salts and Grignard reagents to avoid the use of malodorous and air-sensitive thiol as starting materials.9 In another case, Bunte salts have been employed for C−S bond formation via thia-Michael addition.10 Moreover, Bunte salts have been used as sulfenylation agents for high-yielding synthesis of bioactive 3-thioindoles.11 In this way, the chemistry of Bunte salts has provided both chemists and practitioners with many useful synthetic reactions where the alkylthio moiety can be regarded as a thiol equivalent. The synthesis of glycosyl Bunte salts 2 was achieved by an extremely simple procedure. A mixture of an unprotected sugar 1 and inexpensive sodium thiosulfate was treated with a formamidinium-type dehydrating agent in an aqueous solution without protecting the hydroxy groups, giving rise to the condensation product in good yield. To a solution of D-glucose and Et3N in D2O/CH3CN were added 2-chloro-1,3-dimethylimidazolinium chloride (DMC) and sodium thiosulfate pentahydrate at 0 °C. The resulting mixture was stirred at Received: October 31, 2017

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DOI: 10.1021/acs.orglett.7b03400 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Partially substituted glucose derivatives, 3-O-methylglucose, 4O-methylglucose, 6-O-methylglucose, and 4,6-O-benzylideneglucose, were converted to the corresponding thiosulfates (2c− f) with excellent β-selectivity. To the contrary, 2-O-methylglucose gave the product 2b in lower yield and poorer selectivity due to the lack of the neighboring participation of OH group at the 2-position. These results are consistent with the proposed reaction mechanism including intermediates of 1,2-anhydro species. The present DMC-mediated thiosulfation reaction was applicable to other monosaccharides. For example, allose, xylose, mannose, and rhamnose were successfully condensed with sodium thiosulfate using DMC agent, giving rise to the corresponding 1,2-trans-thiosulfates (2g, 2h, 2l, 2m). The anomeric configuration of mannopyranosyl Bunte salt 2l was determined to be α-type by differential NOE measurements. The observed lower yield in case of galactose derivatives (2i−k) can be explained by the instablility of the reactive intermediate of 1,2-anhydrogalactose due to the stereoelectronic effect of the axial OH group on the 4-position of galactopyranose moiety.16 The oligosaccharide thiosulfates (2n−u) can be prepared without cleaving the acid-labile inner glycosidic bonds, indicating that the reaction proceeded under essentially neutral conditions. In the case of using N-acetylglucosamine (GlcNAc) and chitooligosaccharides as substrates, the reaction did not take place because oxazoline intermediates that are formed as the result of neighboring participation of the 2-acetamido group were not reactive enough against the thiosulfate ion nucleophile. When an excess amount of hydrochloric acid was added to activate the oxazoline ring, the desired thiosulfation occurred smoothly, giving rise to the corresponding thiosulfates of GlcNAc 2v and chitooligosacccharides (2w− z) in good yields. Interestingly, we found that the introduction of a thiosulfate moiety significantly increased the water solubility of the products. For example, when all of the hydroxy groups of the resulting glucosyl thiosulfate were acetylated, the per-acetylated product of 2,3,4,6-tetra-O-acetyl glucosyl thiosulfate was soluble in water despite the increased lipophilicity of the glycone part after the introduction of four acetyl groups. These phenomena are unusual in sugar chemistry considering that all peracetylated monosaccharide derivatives reported thus far are soluble in organic solvents and insoluble in water. These results clearly show that the existence of the thiosulfate moiety dramatically enhanced the water solubility of protected monosaccharides. It was, therefore, necessary for sugar chemists to protect the hydroxy groups of a monosaccharide thiosulfate with a more lipophilic protecting group like triethylsilyl group to achieve an extraction with organic solvents. The utility of the resulting S-glycosyl thiosulfates as a synthetic intermediate is shown by converting β-glucosyl Bunte salt into 1-thio-β-D-glucose, glucosyl disulfide, 1,6-anhydroglucose, and ethyl α-D-glucopyranoside. Since the resulting glycosyl Bunte salts prepared in this study possess a hybrid structure of an inorganic thiosulfate moiety and an organic saccharide unit, a duality has emerged concerning the mode of bond cleavage (S−S cleavage and C−S cleavage in Figure 3). First, we tried to convert glucosyl Bunte salt to 1-thio-β-Dglucose through the S−S bond cleavage. The 1-thio sugars have attracted increasing attention and interest as a building block in the synthesis of glyco-conjugates especially for the modification of proteins by an oligosaccharide.17 Reduction of the unprotected β-glucosyl Bunte salt with tris(2-carboxyethyl)

the same temperature for 90 min and directly subjected to MS, IR, and NMR analyses to characterize its chemical structure and to evaluate the yield. The yield of the resulting glycosyl Bunte salts was determined by using sodium mesitylene sulfonate as an internal standard. The resulting glycosyl Bunte salts could be purifed by using ion-exchange chromatography and an activated carbon column. The simple purification procedure with aqueous eluents is consistent with the principles of green glyco-process-chemistry. The high-resolution mass spectrum of the product showed an m/z value of 274.9900 in negative-ion mode (based on C6H11O8S2− = 274.9901), clearly indicating that the compound consists of a monosaccharide unit and inorganic thiosulfate moiety as the result of the condensation reaction between glucose and sodium thiosulfate. The existence of a thiosulfate group was confirmed by the characteristic absorptions at 1220 and 1027 cm−1 (S−O stretchings) in its IR spectra.12 There are two possible structures, an O-glucoside and an Sglucoside, concerning the glycosidic bond formed between glucose and thiosulfate ion, because the thiosulfate moiety contains three oxygen atoms and one sulfur atom as nucleophilic centers that could attack to the anomeric carbon atom. In the 13C NMR spectrum, the chemical shift of the signal derived from the anomeric carbon was 88.0 ppm, being observed at a higher magnetic field than those for O-glycosidic derivatives (around 100 ppm) (Figure 1B).13 The data confirmed that the anomeric carbon atoms of the products are connected to a sulfur atom.14

Figure 1. 1H and 13C NMR of β-glucosyl Bunte salt.

The 1H NMR spectrum showed a doublet peak at 4.96 ppm due to the anomeric proton (Figure 1A). The coupling constant of this peak was J1,2 = 10.0 Hz, indicating that the resulting glycosidic bond of the product was β-type. The nucleophilic attack of a thiosulfate ion occurred from the β-side of the pyranose ring, leading to the selective formation of βglucosyl thiosulfate. The observed β-selectivity may be explained by assuming the formation of 1,2-anhydroglucose intermediate as a result of neighboring participation of the 2OH group.15 The DMC-mediated condensation reactions between various monosaccharide derivatives and sodium thiosulfate proceeded efficiently under mild reaction conditions, affording the corresponding glycosyl thiosulfates in good yields (Figure 2). B

DOI: 10.1021/acs.orglett.7b03400 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Figure 2. Synthesis of various kinds of glycosyl thiosulfates (glycosyl Bunte salts) through direct anomeric activation. The yields were determined by 1 H NMR using sodium mesitylene sulfonate as an internal standard.

alkaline conditions, giving rise to the corresponding β-glucosyl disulfide derivative in 90% yield (Figure 3b). These results clearly show that glycosyl Bunte salts can behave as “masked sulfur” nucleophiles.21 We found that glycosyl Bunte salts were also able to be used for a protection-free intramolecular glycosylation and alcoholysis based on the direct anomeric activation.22 An intramolecular chemical O-glycosylation and a solvolytic reaction could be demonstrated by using glucosyl Bunte salt as a glycosyl donor based on the mode of the C−S bond cleavage. The β-D-glucosyl Bunte salt was converted into 1,6anhydroglucose in good yield in a basic aqueous solution by an intramolecular attack of the 6-OH of the glucosyl Bunte salt (Figure 3c). For the intermolecular reaction, N-bromosuccinimide (NBS)23 was found effective as a promoter for solvolysis reaction with ethanol, affording ethyl D-glucopyranoside (Figure 3d). In summary, new synthetic intermediates, glycosyl Bunte salts, have been synthesized for the first time starting from unprotected sugars and inexpensive sodium thiosulfate in water−acetonitrile mixed solvent with DMC as a dehydrative condensing agent. Notably, these unprotected glycosyl Bunte salts can be used in a direct and general manner for the preparation of a series of important carbohydrate derivatives under mild reaction conditions. The one-pot reaction and the use of aqueous media allow this approach to be fully compatible with unprotected oligosaccharides even for polysaccharides. The discovery of a method to prepare glycosyl Bunte salts will expand chemists’ repertoire of synthetic tools in organic chemistry and will give chemical manufacturers great flexibility in product design.

Figure 3. Glycosyl Bunte salts as a useful precursor for preparation of 1-thio sugar, glycosyl disulfide, 1,6-anhydro sugar, and O-glycoside.

phosphine hydrochloride (TCEP-HCl)18 afforded the corresponding 1-thioglucose in 70% yield (Figure 3a). It should be noted that we were able to prepare 1-thio sugars through a onepot process via glycosyl Bunte salt intermediates, starting from unprotected sugars. More importantly, the use of aqueous solution will make the present method efficient for synthesis of water-soluble oligosaccharide 1-thio sugars. Bunte salts were found to be a useful precursor for the direct construction of disulfide structures without isolating thiols.19 Disulfide bonds are an important linkage to connect a saccharide to biologically active macromolecules such as peptides and proteins20a as well as for cross-linking of polysaccharides.20b Since thiols are air-sensitive, alternative starting materials are required in place of 1-thio sugars for the construction of disulfide bridges between a sugar and an aglycone. We found that the disulfide bond can be easily formed between glucosyl Bunte salt with thiophenol under C

DOI: 10.1021/acs.orglett.7b03400 Org. Lett. XXXX, XXX, XXX−XXX

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03400. Experimental procedures and spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Shin-ichiro Shoda: 0000-0001-9224-4341 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan. We thank Mr. Ryohei Hayasaka for experimental support.

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DEDICATION This paper is dedicated to Professor Teruaki Mukaiyama in celebration of his 90th birthday (Sotsuju). REFERENCES

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DOI: 10.1021/acs.orglett.7b03400 Org. Lett. XXXX, XXX, XXX−XXX