Glycosylthiomethyl Chloride: A New Species for S-Neoglycoconjugate

Glycosylthiomethyl Chloride: A New Species for S-Neoglycoconjugate Synthesis. Synthesis of 1-N-Glycosylthiomethyl-1,2,3-triazoles Xiangming Zhu and Richard R. Schmidt* Fachbereich Chemie, Universita¨ t Konstanz, Fach M 725, D-78457 Konstanz, Germany [email protected] Received September 4, 2003

Reaction of O-acyl-protected glycosylthiols with dichloromethane afforded readily glycosylthiomethyl chlorides, which gave with sodium azide the corresponding glycosylthiomethyl azides 17-22. Reaction of these azides with dicyclopentadiene as dipolarophile led to tandem 1,3-dipolar cycloaddition/retro-Diels-Alder reaction furnishing the parent 1-glycosylthiomethyl-1,2,3-triazoles 23-25. Reaction of azides with acetylene derivatives gave directly 1-glycosylthiomethyl-1,2,3triazoles which are ring-substituted. The importance of carbohydrates and glycoconjugates in diverse biochemical processes has stimulated the development of glycomimetics and neoglycoconjugates as fundamental tools for biological research and as potential agents for therapeutic intervention.1 In this context, thioglycosides have received considerable attention because of their resistance to enzymatic hydrolysis and their similar solution conformation and biological activities compared to native counterparts.2 Therefore, many efforts have been devoted in the past two decades to synthesize S-glycoconjugates,3 in which the native Oglycosidic linkage has been replaced by the enzymatically and chemically more resistant S-glycosidic linkage. At the same time, chemists have also sought novel methods for attaching sugars to scaffolds to construct neoglycoconjugates4 that could be also employed in various glycobiological studies. For example, glycosyl iodoacetamides I,5 as shown in Figure 1, have been used to synthesize erythropoietin (EPO)-derived neoglycopeptides.4f Also, bromoethyl glycosides II6 have been utilized to synthesize neoglycopeptides derived from mucins and T-cell stimulating glycopeptides.4j Recently, Bertozzi et al. developed an approach for construction of neoglyco(1) (a) Carbohydrate Mimics: Concepts and Methods; Chapleur, Y., Ed.; Wiley-VCH: Weinheim, 1998. (b) Meldal, M. In Neoglycoconjugates: Preparation and Applications; Lee, Y. C., Lee, R. T., Eds.; Academic Press: San Diego, 1994; p 145. (c) Sears, P.; Wong, C. H. Angew. Chem., Int. Ed. 1999, 38, 2300-2324. (2) (a) Jahn, M.; Marles, J.; Warren, R. A. J.; Withers, S. G. Angew. Chem., Int. Ed. 2003, 42, 352-354. (b) Witczak, Z. J.; Chhabra, R.; Chen, H.; Xie, X. Carbohydr. Res. 1997, 301, 167-175. (c) Driguez, H. ChemBioChem 2001, 2, 311-318. (d) Kiefel, M. J.; Thomson, R. J.; Radovanovic, M.; Itzstein, M. V. J. Carbohydr. Chem. 1999, 18, 937959. (e) Falconer, R. A. Tetrahedron Lett. 2002, 43, 8503-8505. (3) For some examples of the synthesis of S-glycoconjugates, see: (a) Eisele, T.; Schmidt, R. R. Liebigs Ann./Recueil 1997, 865-872. (b) Zhu, X.; Pachamuthu, K.; Schmidt, R. R. J. Org. Chem. 2003, 68, 56415651. (c) Zhu, X.; Schmidt, R. R. Tetrahedron Lett. 2003, 44, 60636067. (d) Hasegawa, A.; Morita, M.; Kojima, Y.; Ishida, H.; Kiso, M. Carbohydr. Res. 1991, 214, 43-53. (e) Peerlings, H. W. I.; Nepogodiev, S. A.; Stoddart, J. F.; Meijer, E. W. Eur. J. Org. Chem. 1998, 18791886. (f) Knapp, S.; Myers, D. S. J. Org. Chem. 2001, 66, 3636-3638. (g) Knapp, S.; Myers, D. S. J. Org. Chem. 2002, 67, 2995-2999.

FIGURE 1. Four sugar species employed in the synthesis of neoglycoconjugates.

peptides employing aminooxy functionalized sugars III,4h which also has been applied very recently by Wong and Schultz et al. in the synthesis of neoglycoprotein derived from the Z domain of staphylococcal protein.4m (4) There are a large number of reports on the synthesis of neoglycoconjugates, particularly neoglycopeptides. For some recent examples, see: (a) Pe´rez-Balderas, F.; Ortega-Mun˜oz, M.; MoralesSanfrutos, J.; Herna´ndez-Mateo, F.; Calvo-Flores, F. G.; Calvo-Ası´n, J. A.; Isac-Garcı´a, J.; Santoyo-Gonza´lez, F. Org. Lett. 2003, 5, 19511954. (b) Peluso, S.; Imperiali, B. Tetrahedron Lett. 2001, 42, 20852087. (c) Bo¨ttcher, C.; Burger, K. Tetrahedron Lett. 2003, 44, 42234226. (d) Pratt, M. R.; Bertozzi, C. R. J. Am. Chem. Soc. 2003, 125, 6149-6159. (e) McGarvey, G. J.; Benedum, T. E.; Schmidtmann, F. W. Org. Lett. 2002, 4, 3591-3594. (f) Macmillan: D.; Daines, A. M.; Bayrhuber, M.; Flitsch, S. L. Org. Lett. 2002, 4, 1467-1470 and references therein. (g) Carrasco, M. R.; Nguyen, M. J.; Burneil, D. R.; MacLaren, M. D.; Hengel, S. M. Tetrahedron Lett. 2002, 43, 57275729. (h) Rodriguez, E. C.; Marcaurelle, L. A.; Bertozzi, C. R. J. Org. Chem. 1998, 63, 7134-7135. (i) Carrasco, M. R.; Brown, R. T.; Serafimova, I. M.; Silva, O. J. Org. Chem. 2003, 68, 195-197. (j) George, S. K.; Schwientek, T.; Holm, B.; Reis, C. A.; Clausen, H.; Kihlberg, J. J. Am. Chem. Soc. 2001, 123, 11117-11125. (k) Marcaurelle, L. A.; Pratt, M. R.; Bertozzi, C. R. ChemBioChem 2003, 2/3, 224228. (l) Renaudet, O.; Dump, P. Org. Lett. 2003, 5, 243-246. (m) Liu, H.; Wang, L.; Brock, A.; Wong, C.-H.; Schultz, P. G. J. Am. Chem. Soc. 2003, 125, 1702-1703. (5) Davis, N. I.; Flitsch, S. L. Tetrahedron Lett. 1991, 32, 67936796. (6) Bengtsson, M.; Broddefalk, J.; Dahme´n, J.; Henriksson, K.; Kihlberg, J.; Lo¨nn, H.; Srinivasa, B. R.; Stenvall, K. Glycoconjugate J. 1998, 15, 223-231.

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Published on Web 01/20/2004

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In view of the advantage conferred by neoglycoconjugate synthesis that allows rapid, convenient access to a wide array of glycoconjugates,4g together with the enzymatic stability of thioglycosides,3 we decided to pursue approaches to S-neoglycoconjugates for biological studies. We wish to report here a new chemically stable species, glycothiomethyl chloride, which could be used for the synthesis of a variety of S-neoglycoconjugates. As an application of this new species, an efficient synthesis of 1-N-glycosylthiomethyl-1,2,3-triazoles is also described based on Huisgen 1,3-dipolar cycloadditions7 of azides and alkynes. 1,2,3-Triazole derivatives gained extensive applications in industry and agriculture,8 e.g., use as fluorescent compounds, optical brighteners, corrosion inhibitors, and photostabilizers for fibers, plastics, or dyestuffs. More importantly, various 1,2,3-triazole derivatives have been implicated as bioactive agents9 and tested as cytostatic,10 TNF-R inhibitory,11 anti-imflammatory,12 anti-proliferative,13 and anti-microbial agents14 for quite some time. Accordingly, a large variety of syntheses of 1,2,3-triazole derivatives can be found in the literature, and among them, the Huisgen 1,3-dipolar cycloadditions between azides and alkynes is the most effective method.15-17 Notably, in a very recent paper, this reaction was exploited to construct well-defined multivalent neoglycoconjugates,4a and Wong et al. described the use of 1,2,3-triazole formation for the synthesis and in situ attachment of saccharides to the microtiter plate.18 Using Cowpea mosaic virus derived azide or alkyne, Finn and (7) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; WileyInterscience: New York, 1984. (8) Katritzky, A. R.; Rees, C. W. In Comprehensive Heterocyclic Chemistry; Potts, K. T., Ed.; Pergamon Press: Oxford, 1984; Vol. 5, Part 4A. (9) For a review, see: Bo¨hm, R.; Karow, C. Pharmazie 1981, 36, 243-247. (10) de las Heras, F. G.; Alonso, R.; Alonso, G. J. Med. Chem. 1979, 22, 496-501. (11) Tullis, J. S.; Van Rens, J. C.; Natchus, M. G.; Clark, M. P.; De, B.; Hsieh, L. C.; Janusz, M. J. Bioorg. Med. Chem. Lett. 2003, 13, 16651668. (12) Krentzberger, A.; Stratmann, J. J. Heterocycl. Chem. 1980, 17, 1505-1508. (13) Vicentini, C. B.; Manfredini, S.; Manfrini, M.; Bazzanini, R.; Musiu, C.; Putzolu, M.; Perra, G.; Marongiu, M. E. Arch. Pharm. Pharm. Med. Chem. 1998, 331, 269-272. (14) Hartzel, L. W.; Benson, F. R. J. Am. Chem. Soc. 1954, 76, 667670. (15) For some recent examples of the synthesis of 1,2,3-triazole derivatives without sugar substituents by 1,3-dipolar cycloadditions, see: (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596-2599. (b) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134-2136. (c) Melai, V.; Brillante, A.; Zanirato, P. J. Chem. Soc., Perkin Trans. 2 1998, 2447-2449. (d) Gardiner, M.; Grigg, R.; Sridharan, V.; Vicker, N. Tetrahedron Lett. 1998, 39, 435-438. (e) Gardiner, M.; Grigg, R.; Kordes, M.; Sridharan, V.; Vicker, N. Tetrahedron 2001, 57, 7729-7735. (f) Tuncel, D.; Steinke, J. H. G. Chem. Commun. 2002, 496-497. (g) Hlasta, D. J.; Ackerman, J. H. J. Org. Chem. 1994, 59, 6184-6189. (h) Howell, S. J.; Spencer, N.; Philp, D. Tetrahedron 2001, 57, 4945-4954. (16) For some recent examples of the synthesis of sugar-derived 1,2,3-triazole derivatives, see: (a) Hager, C.; Miethchen, R.; Reinke, H. J. Prakt. Chem. 2000, 342, 414-420. (b) Marco-Contelles, J.; Jime´nez, C. A. Tetrahedron 1999, 55, 10511-10526. (c) Somsa´k, L.; So´s, E.; Gyo¨rgydea´k, Z.; Praly, J. P.; Descotes, G. Tetrahedron 1996, 52, 9121-9136. (d) Sˇ timac, A.; Leban, I.; Kobe, J. Synlett 1999, 7, 1069-1073. (e) Al-Masoudi, N. A.; Al-Soud, Y. A. Tetrahedron Lett. 2002, 43, 4021-4022. (f) Al-Masoudi, N. A.; Al-Soud, Y. A. Nucleosides, Nucleotides Nucleic Acids 2002, 21, 361-375. (g) Chen, X. M.; Li, Z. J.; Ren, Z. X.; Huang, Z. T. Carbohydr. Res. 1999, 315, 262-267. (17) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004-2021. (18) Fazio, F.; Bryan, M. C.; Blixt, O.; Paulson, J. C.; Wong, C. H. J. Am. Chem. Soc. 2002, 124, 14397-14402.

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Sharpless et al. very recently reported a bioconjugation via azide-alkyne [3 + 2] cycloaddtion.19 As mentioned above, our initial goals were to construct S-neoglycoconjugates, which could be used in biological studies and as potential therapeutic agents. Although C-/ N-/O-neoglycoconjugate syntheses have been reported many times,4 only very few papers were devoted to the synthesis of S-neoglycoconjugates, and to the best of our knowledge, no generally applicable sugar building blocks, like I or II (Figure 1), are presently available for the construction of thioglycoside-linked neoglycoconjugates.20 Thus, it seems to be of interest to report a new sugar species, such as IV in Figure 1, which could be obtained under simple conditions and in satisfactory yields and, most importantly, could be used to provide a convenient access to libraries of S-neoglycoconjugates.21 The selection of IV as sugar building blocks for S-neoglycoconjugate synthesis was based on the following two points: (1) glycoconjugates generated from IV can be expected to mimic the natural structure better due to the shorter linker between sugar and nonsugar moieties; (2) Rchloromethyl thio groups should be good electrophiles, and the ensuing conjugation reactions of IV can be expected to take place smoothly. Obviously, the most convenient and direct route to glycosylthiomethyl chloride should be an SN2 reaction between the corresponding glycosyl thiol and dichloromethane.22 To test the feasibility of this approach, we performed exploratory experiments with glucosyl thiol 1.23a We feared the methylene-linked dimer of glucosylthiol would be the main byproduct when thiol 1 was exposed to dichloromethane in the presence of organic base;, however, fortunately, a high yield of glucopyranosylthiomethyl chloride 9 was isolated in this reaction.24 Encouraged by this result, a variety of glycosyl thiols 2-8 were then prepared23 and used to synthesize the corresponding glycosylthiomethyl chloride as outlined in Table 1. All the reactions proceeded smoothly and led to the desired chlorides 10-16 in good to high yields (5293%). It bears noting that under the same conditions perO-benzoylated glycosyl thiol may be more efficiently converted into the corresponding chloride as indicated by the excellent yield of per-O-benzoylated glucosylthiomethyl chloride 16 (entry 8).25 With these new sugar building blocks in hand, the task (19) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192-3193. (20) Imino-2-methoxyethyl 1-thioglycosides have been prepared and employed for attaching sugars to proteins, see: Lee, Y. C.; Stowell, C. P.; Krantz, M. J. Biochemistry 1976, 15, 3956-3963. (21) It is important to note that the new sugar species reported here has been also employed successfully in the synthesis of other Sneoglycoconjugates: Zhu, X. Unpublished results. (22) Very recently, dichloromethane has been observed to react with carbon nucleophiles, affording methylene-linked symmetric dimers, see: Armstrong, A.; Scutt, J. N. Org. Lett. 2003, 5, 2331-2334. (23) (a) Fulton, D. A.; Stoddart, J. F. J. Org. Chem. 2001, 66, 83098319. (b) Haque, M. B.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc., Perkin Trans. 1 1998, 2881-2889. (c) Paul, B.; Korytnyk, W. Carbohydr. Res. 1984, 126, 27-43. (d) Fujihira, T.; Chida, M.; Kamijo, H.; Takido, T.; Seno, M. J. Carbohydr. Chem. 2002, 21, 287-292. (e) Staneˇk, J.; Sˇ indlerova´, M.; C ˇ erny´, M. Collect. Czech. Chem. Commun. 1965, 30, 297-303. (f) Pastuch, G.; Szeja, W. Pol. J. Chem. 2000, 74, 227-230. (g) Cai, Y.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc., Perkin Trans. 1 2002, 1376-1386. (24) In the course of the studies to optimize the yield of the glycosylthiomethyl chlorides, it was noted that consistently high yields could be obtained with 0.05 M thiol in dichloromethane. See Experimental Section for details.

Synthesis of 1-N-Glycosylthiomethyl-1,2,3-triazoles TABLE 1. Synthesis of Glycosylthiomethyl Chloridesa

TABLE 2. Synthesis of Glycosylthiomethyl Azidesa,b

a All compounds have been fully characterized by standard spectral methods. b All reactions carried out at 72 °C. c Isolated yields based on starting chlorides after chromatographic separation.

now confronting us was to develop appropriate routes to achieve various desired S-neoglycoconjugates.21 As the first application of these chlorides, herein we describe the synthesis of 1-N-glycosylthiomethyl-1,2,3-triazoles, a new type of sugar-triazole derivatives, which could be tested as potential anticancer agents.16 1,2,3-Triazoles have received significant attention in the last years not only because of their biological activities in their own right but also because of their ready formation by Huisgen 1,3-dipolar cycloadditions, which was regarded as the “cream of the crop” of concerted reactions17 and recently secured wide applications in the fields of (bio)organic chemistry.26 To generate sugar-triazole conjugates from the aboveprepared chlorides, thioglycoside 9 was chosen as the model compound. It was first treated with sodium azide in aqueous acetone as previously described,27 and expectedly, the corresponding azide 17 was produced in satisfactory 90% yield. It is important to note that the Rf (TLC) values of 17 and 9 were nearly identical, but

the compounds gave different colors when sprayed with 10% sulfuric acid and heated. Encouraged by the ready formation of 17, some other chlorides, as shown in Table 2, were then investigated in this azidation reaction. Fortunately, all the chlorides used were transformed smoothly into the corresponding azides (Table 2), affording the azides in high yields (77-90%). Notably, more and more attention has recently been paid to the azido group, since it is exceptionally stable toward most chemicals and organic synthesis conditions and it is an ideal precursor for a variety of different nitrogen containing functionalities.17,18 Our attention turned then toward the formation of 1,2,3-triazoles from these azides. In the first set of experiments, norbornadiene was chosen as dipolarophile for the cycloaddition step. Hence, azide 17 was treated with norbornadiene under heating; not unexpectedly, triazole 23 was produced smoothly in 79% yield. This reaction was found to proceed well when the temperature of the reaction was maintained around 100 °C for more than 10 h with little solvent. Product 23 was characterized on the basis of its exact mass spectrometry and its NMR spectroscopic data,28 which exhibited two doublets (J ca. 1.0 Hz) at chemical shift δ 7.76 and 7.69 for H-5 and H-4 protons of the aromatic ring in 23. Similar spectra have been reported for 1-β-D-ribofuranosyl-1,2,3triazole.29 It is interesting to note that the new compound 23 was formed via cycloadduct 23-A, as shown in Figure

(25) Unlike entries 1-7, TLC indicated that almost no methylenelinked dimer was produced in entry 8. (26) For one more recent example, see: Lo¨ber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753-1755. (27) Deng, W. P.; Nam, G.; Fan, J.; Kirk, K. L. J. Org. Chem. 2003, 68, 2798-2802.

(28) The NMR spectra of various substituted 1,2,3-triazoles have been studied and the 5-H signals of 1-substituted-1,2,3-triazoles were found to occur at lower field than the 4-H resonance; see: Elguero, J.; Gonza´lez, E.; Jacquier, R. Bull. Soc. Chim. Fr. 1967, 2998-3003. (29) Lehmkuhl, F. A.; Witkowski, J. T.; Robins, R. K. J. Heterocycl. Chem. 1972, 9, 1195-1201.

a All reactions conducted at room temperature; see the Experimental Section for details. b Yield of pure, isolated product with correct analytical and spectral data. c NMR spectroscopic analysis indicated that compound 6 was contaminated with a small amount of R-isomer.

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Zhu and Schmidt TABLE 3. Synthesis of 1-N-Glycothiomethyl-1,2,3-triazolesa

FIGURE 2. Formation of triazole 23.

2, which was followed by retro-Diels-Alder reaction. Apparently, here norbornadiene reacted as an acetylene equivalent. Similar formation of 1,2,3-triazole derivatives by this tandem process has been reported previously.15e,30 The ready formation of 23 offered a preliminary suggestion that the present procedures may provide a general and convenient means to 1-N-glycosylthiomethyl1,2,3-triazoles, which otherwise would be troublesome to get by direct triazolylmethylation of glycosyl thiols due to the unavailability of the pure 1-N-chloromethyltriazole.31 By the same procedure, sugar derived triazoles 24 and 25 were also efficiently prepared from the corresponding azides 20 and 21 with norbornadiene in 78% and 74% yields, respectively (Table 3, entries 2 and 3). On the other hand, to synthesize 4- and/or 5-substituted 1,2,3triazoles, substituted acetylenes were then used as dipolarophiles instead of norbornadiene. Hence, various cycloaddition reactions between azides and alkynes were designed, as shown in Table 3. As expected, the coupling of azide 17 and dimethyl acetylenedicarboxylate (DMAD) took place smoothly and gave rise to the desired adduct 26 in almost quantitative yield (Table 3, entry 4). This is a really promising result in view of the ready availability of this type of S-neoglycoconjugates by using our synthetic schemes and the potential application of this type of compounds in medicinal chemistry due to the pronounced biological activities of 1,2,3-triazole heterocycles.32 Structural assignments of the new sugar-triazole derivative were made on the basis of NMR spectroscopy and exact mass spectral data. In the 13C NMR spectrum, the C-4 and C-5 carbons of the triazole ring in 26 appear at 140.6 and 128.8 ppm, respectively. Similarly, the azido group in glucosamine 19 can also be ring-closed by its transformation with DMAD to the S-neoglycoconjugate 27 in 91% yield (Table 3, entry 5). Again, ligation of disaccharides 20 and 21 with DMAD under the same conditions also led to the corresponding sugar-triazole derivatives 28 and 29 in quantitative and almost quantitative yields (Table 3, entries 6 and 7). It (30) Palacios, F.; de Retana, A. M. O.; Pagalday, J. Heterocycles 1995, 40, 543-550. (31) Machin, P. J.; Hurst, D. N.; Bradshaw, R. M.; Blaber, L. C.; Burden, D. T.; Melarange, R. A. J. Med. Chem. 1984, 27, 503-509. (32) Compounds bearing a methylene group linked to both a heteroatom and a heterocyclic nitrogen atom have been investigated as potential anticancer agents, see: Garcia-Mun˜oz, G.; Madron˜ero, R.; Rico, M.; Saldan˜a, M. C. J. Heterocycl. Chem. 1969, 6, 921-925. On the other hand, the presence of an aromatic heterocyclic group next to the glycosidic bond may enhance the interaction between neoglycoconjugates with lectins by increasing the hydrophobicity, see ref 7 cited in ref 4a.

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a

See the Experimental Section for details. b 33/34 ) 3:1.

is worth noting that these smooth reactions, together with the following reactions (as seen below), provided a convenient access to a large amount of new sugartriazole conjugates, which can be used for further chemical manipulation or biological screening. To widen the range and nature of the substituents, 1,4dichloro-2-butyne (DCB) was then used as dipolarophile. Thus, the coupling of azide 19 and DCB was conducted (Table 3, entry 8), and expectedly, the new S-neoglycoconjugate 30 was afforded smoothly in 71% yield. Notably, on the basis of previous studies,10,16f compound 30

Synthesis of 1-N-Glycosylthiomethyl-1,2,3-triazoles

could be a potential anticancer agent. Under the same conditions, disaccharides 20 and 21 were also converted into the corresponding triazoles by the 1,3-dipolar cycloaddition with DCB, and compounds 31 and 32 were isolated in 83% and 76% yields, respectively (Table 3, entries 9 and 10). These two new sugar-triazole derivatives could be also tested in connection with cancer chemotherapy. As the last example, ethyl propiolate was chosen as dipolarophile to react with galactothiomethyl azide 18 (Table 3, entry 11). Since ethyl propiolate is an asymmetric dipolarophile, two possible adducts were expected to form. Indeed, two isomeric triazoles 33 and 34 were produced during this reaction, in which the 1,4-substituted triazole 33 predominated (33/34 ) 3:1). Fortunately, these two isomers could be easily separated by column chromatography, and their structure elucidation was based mainly on NMR spectroscopy.33 Sugar-triazole conjugates 33 and 34 could be further modified (e.g., ligation with peptides at the carboxyl group of the heteroaromatic ring) to build up more complex S-neoglycoconjugates. In conclusion, from the readily available glycosyl thiols, a novel sugar species, glycosylthiomethyl chloride, was developed in this report and successfully applied in the synthesis of a new type of sugar-triazole derivatives. Given the difficulty in synthesizing native glycoconjugates containing acid-sensitive glycosidic bonds, the facile syntheses of the S-neoglycoconjugates described here highlight the utility of the new species.21 To date, no established building blocks for the synthesis of thioglycoside-linked neoglycoconjugates have been reported. In addition, the S-neoglycoconjugates derived from the present building blocks should be excellent mimics of natural glycoconjugates in view of the very short linker between sugar and nonsugar moieties. The ready availability, chemical stability, and good mimicry of glycosylthiomethyl chlorides render them excellent building blocks to potentially allowing for access to a greater variety of S-neoglycoconjugates. Further work is in progress to extend the application of this new species for novel S-neoglycoconjugates, and the results will be forthcoming.

Experimental Section Chloromethyl 2,3,4,6-Tetra-O-acetyl-1-thio-β-D-glucopyranoside (9). To a solution of the thiol 1 (847 mg, 2.32 mmol) in dry CH2Cl2 (46 mL) was added DBU (0.42 mL, 2.78 mmol). The resulting mixture was stirred overnight at room temperature, after which time TLC indicated the disappearance of (33) Biological studies are under way. (34) The chemical shift of 5-H proton in 33 is at a lower field than the 4-H proton in 34, which is consistent with a previous report, see: Alonso, G.; Garcı´a-Lo`pez, M. T.; Garcı´a-Mun˜oz, G.; Madron˜ero, R.; Rico, M. J. Heterocycl. Chem. 1970, 7, 1269-1272.

the starting material. Dichloromethane was then removed in vacuo, and the residue was purified by flash column chromatography (petroleum ether/EtOAc, 2:1) to give the desired product 9 (767 mg, 80%) as a white amorphous solid: TLC Rf ) 0.31 (petroleum ether/EtOAc, 1.3:1); [R]D ) -77.7 (c 0.9 CHCl3); 1H NMR (CDCl3) δ 5.29 (t, J ) 9.3 Hz, 1H), 5.13 (t, J ) 9.4 Hz, 1H), 5.09 (t, J ) 9.1 Hz, 1H), 4.94, 4.67 (AB peak, J ) 11.9 Hz, 2H), 4.85 (d, J ) 10.2 Hz, 1H), 4.28 (dd, J ) 12.5, 4.8 Hz, 1H), 4.17 (dd, J ) 12.4, 2.4 Hz, 1H), 3.79 (ddd, J ) 10.1, 4.8, 2.4 Hz, 1H), 2.10, 2.07, 2.04, 2.02 (4s, 12H); 13C NMR (CDCl3) δ 169.9, 169.5, 168.8, 80.6, 75.5, 73.2, 69.4, 67.7, 61.4, 45.1, 20.2, 20.0; MALDI-MS m/z 435.6 [M + Na+], 451.6 [M + K+]. Anal. Calcd for C15H21ClO9S (412.84): C, 43.64; H, 5.13. Found: C, 43.51; H, 4.97. Azidomethyl 2,3,4,6-Tetra-O-acetyl-1-thio-β-D-glucopyranoside (17). NaN3 (183 mg, 2.82 mmol) was added to a solution of chloride 9 (280 mg, 0.68 mmol) in acetone (9.6 mL) and water (4.8 mL), and the solution was heated under reflux for 20 h, diluted with 20 mL of water, and extracted with CH2Cl2. The organic layer was dried over MgSO4 and evaporated to a residue, which was purified by flash column chromatography (petroleum ether/EtOAc, 2:1) to afford the desired product 17 (256 mg, 90%) as a white amorphous solid: TLC Rf ) 0.30 (petroleum ether/EtOAc, 1.3:1); [R]D ) -118.2 (c 1.0 CHCl3); 1H NMR (CDCl3) δ 5.22 (t, J ) 9.3 Hz, 1H), 5.09 (t, J ) 9.7 Hz, 1H), 5.05 (t, J ) 9.2 Hz, 1H), 4.69 (d, J ) 10.0 Hz, 1H), 4.35 (AB peak, J ) 13.6 Hz, 2H), 4.23 (dd, J ) 12.4, 4.8 Hz, 1H), 4.12 (dd, J ) 12.4, 2.3 Hz, 1H), 3.73 (ddd, J ) 9.9, 4.8, 2.4 Hz, 1H), 2.054, 2.046, 2.00, 1.99 (4s, 12H); 13C NMR (CDCl3) δ 170.2, 169.7, 169.0, 81.4, 75.8, 73.3, 69.7, 67.8, 61.7, 50.7, 20.3, 20.2; MALDI-MS m/z 442.6 [M + Na+], 458.7 [M + K+]. Anal. Calcd for C15H21N3O9S (419.41): C, 42.96; H, 5.05; N, 10.02. Found: C, 42.82; H, 5.02; N, 9.95. 1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosylthiomethyl)1,2,3-triazole (23). To a stirred solution of the azide 17 (104 mg, 0.25 mmol) in dioxane (0.2 mL) was added norbornadiene (230 mg, 2.5 mmol). The mixture was heated at 100 °C for over 10 h, cooled, and concentrated to give a residue, which was purified by flash column chromatography (petroleum ether/EtOAc, 1:1.5) to afford the desired product 23 (87 mg, 79%) as a off-white amorphous solid: TLC Rf ) 0.10 (petroleum ether/EtOAc, 1:1.4); [R]D ) -51.2° (c 1.0 CHCl3); 1H NMR (CDCl3) δ 7.76 (d, J ) 0.97 Hz, 1H), 7.69 (d, J ) 0.97 Hz, 1H), 5.70, 5.35 (AB peak, J ) 14.6 Hz, 2H), 5.15 (t, J ) 9.2 Hz, 1H), 5.03 (t, J ) 9.8 Hz, 1H), 4.99 (t, J ) 9.1 Hz, 1H), 4.60 (d, J ) 9.9 Hz, 1H), 4.18 (dd, J ) 12.5, 4.7 Hz, 1H), 4.03 (dd, J ) 12.5, 2.2 Hz, 1H), 3.68 (ddd, J ) 9.8, 4.6, 2.2 Hz, 1H), 2.04, 1.97, 1.94 (3s, 12H); 13C NMR (CDCl3) δ 170.4, 169.9, 169.3, 134.6, 123.4, 82.0, 76.1, 73.5, 69.6, 67.9, 61.6, 48.1, 20.7, 20.5; MALDI-MS m/z 468.3 [M + Na+], 484.4 [M + K+]. Anal. Calcd for C17H23N3O9S (445.45): C, 45.84; H, 5.20; N, 9.43. Found: C, 46.58; H, 5.18; N, 9.14.

Acknowledgment. This work was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie. Supporting Information Available: General experimental procedures and analytical and spectral characterization data for all other new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. JO035300O

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