Dimethyl(methylthio)sulfonium trifluoromethanesulfonate

[85055-60-3]  · C3H9S2+ CF3O3S-  · (MW 258.30)

(methylsulfenylating agent; activates thioglycosides and other types of glycosyl donors for glycoside synthesis1-3)

Alternate Name: dimethyl(methylthio)sulfonium triflate, dimethylthiomethyl sulfonium trifluoromethanesulfonate, DMTST.

Physical Data: mp 28-36 °C;4 53-55 °C.5 Variation in reported melting points is probably due to the hygroscopic nature of the reagent.

Solubility: soluble in CH2Cl2, MeCN, MeNO2; sparingly soluble in diethyl ether, benzene, toluene; insoluble in petroleum ether.

Form Supplied in: white crystals; not commercially available.

Analysis of Reagent Purity: 1H NMR.

Purification: recrystallization from dichloromethane-diethyl ether.

Preparative Methods: readily prepared by alkylation of methyl disulfide with methyl trifluoromethanesulfonate in dichloromethane1,4,5 or neat6 (1). The reagent crystallizes from dichloromethane by the addition of diethyl ether. Alternatively, the dichloromethane solution can be used directly for most applications.

Handling, Storage, and Precautions: the reagent is hygroscopic, it liquifies in air. Store in a closed vessel or over a strong drying agent, preferably, in the refrigerator. A 1 M solution in dichloromethane, which partially crystallizes on storage in the refrigerator, can be stored for prolonged periods of time.1 In cases of doubts the use of freshly prepared DMTST is recommended.

Introduction

The sulfur-sulfur bond in alkylated disulfides [dialkyl(alkylthio)sulfonium salts] is susceptible to nucleophiles and thus alkylated disulfides are alkylsulfenylating agents, or potential sources of alkylsulfenyl (RS+) ions.7,8 This, in combination with the excellent leaving property of the triflate group, led to the introduction of dimethyl(methylthio)sulfonium triflate (DMTST) as a synthetic reagent for activation of thioglycosides in glycosylation reactions,1-3 which is still its primary use. Other applications of the reagent (acetalization, addition to unsaturated compounds) are also based on its alkylsulfenylating capability.

Glycosylation

Syntheses of O-glycosides from thioglycosides

Thioglycosides have the advantage over most glycosylating agents that they are stable, are easy to functionalize, can serve both as glycosyl acceptors and glycosyl donors, and are therefore widely used in oligosaccharide syntheses.9,10 DMTST, a highly thiophilic reagent, activates thioglycosides for glycosylations. It has been used in a large number of oligosaccharide syntheses for the construction of diverse glycosidic and interglycosidic linkages.

Activation of thioglycosides by DMTST takes place by sulfenylation of the thioglycoside sulfur. The resulting positively charged intermediate then can react directly or, more probably, through the common intermediates of glycosylation reactions (oxocarbonium ions, acyloxonium ions, glycosyl triflates) with alcohols (or other nucleophiles) to give glycosides (2).

In the presence of neighboring group participating substituents the glycosylations lead to 1,2-trans-glycosides, as shown in the synthesis of the cellobioside derivative (3).1

Reactions are usually performed at or below room temperature in solvents such as dichloromethane or acetonitrile with a 3-5-fold excess of the reagent. The reaction mixture may be buffered with 2,6-di-tert-butyl-4-methylpyridine or other sterically hindered bases if required. DMTST has been used to activate a variety of different monosaccharides including thioglycoside derivatives of D-glucose,1,2,11 D-galactose,1,12-14 D-mannose,15 D-fructofuranose,16 amino sugars,1,12,17 uronic acids15,18 and heptoses.19 Di-,13,14,17 tri-,20,21 tetra-,22 and even pentasaccharide23 thioglycosides have also been activated by this reagent. The most frequently used neighboring group participating protecting groups are O-acetyl, O-pivaloyl and O-benzoyl; for amino functions N-phthaloyl1,12,17 and N-trichloroethoxycarbonyl24,25 are the most frequently used ones. Reactions with O-benzoyl-protected thioglycosides tend to give higher yields and cleaner reactions than those of O-acetyl protected ones1,18. The thioglycosides commonly used in conjunction with DMTST have simple thioalkyl (SMe, SEt) and thioaryl (SPh, STol) groups; heterocyclic thioglycosides have been used occasionally.26 A wide range of alcohols, including mono- and oligosaccharides, as well as peptides,24,25,27 has been used as glycosyl acceptors. It should be noted that although neighboring group participation is generally used to govern the formation of trans-glycosides, several examples of stereoselective synthesis of trans-glycosides without neighboring group participation in DMTST-promoted glycosylations are also known.19,28,29

DMTST-promoted glycosylations with thioglycosides having non-participating substituents result in anomeric mixtures of O-glycosides,2 but very often useful, or even complete, stereoselectivity can be achieved. Methods increasing the stereoselectivity include the addition of bromide ion to the glycosylation mixture,2 changing the solvent,2 tuning the reactivity of the glycosyl donors and acceptors by the proper choice of the protecting groups, and intramolecular aglycon delivery. Addition of tetra-n-butylammonium bromide to the glycosylation mixture results in the in situ formation of a glycosyl bromide, which then reacts in a halide ion-catalyzed glycosylation reaction30 to yield 1,2-cis-glycosides. Performing the reaction in acetonitrile at low temperature changes the stereoselectivity due to the formation of nitrilium ion intermediates.2 Application of this principle to the biologically important sugar N-acetylneuraminic acid, resulted in a very useful synthesis of a-glycosides of N-acetylneuraminic acid31,32 (4), previously accessible only with great difficulty.

Ethereal solvents and solvents of low polarity such as benzene also shift the stereoselectivity towards cis-glycosides. Although DMTST is poorly soluble in diethyl ether or benzene, its solubility is sufficient for reactions to proceed.33 A large number of stereoselective a-L-fucosylations have been performed this way, as for example in the total synthesis of the biologically important sialyl Lewis x oligosaccharide.14 Internal aglycon delivery, i.e. performing the glycosylation on a tethered derivative of the glycosyl donor and acceptor, was found to be a valuable tool for the synthesis of b-D-fructofuranosides.34,35 Whereas common glycosylations with D-fructofuranosyl donors give a preponderance of a-D-fructoside,16 reactions of tethered derivatives gave exclusively the b-D-fructofuranosides. In an analogous manner DMTST-promoted reaction of the intramolecularly locked fructofuranosyl donor in 5 resulted in the first stereoselective, high-yielding synthesis of sucrose36 (5).

Compared with other promoters (methyl trifluoromethanesulfonate and the N-iodosuccinimide trifluoromethanesulfonic acid [NIS-TfOH] system) frequently used in glycosylation reactions with thioglycoside donors, DMTST is more efficient3,27 than methyl triflate, but it is less powerful than NIS-TfOH. DMTST has the advantage that side-reactions, such as alkylation of the acceptor (which can be encountered in methyl triflate-promoted reactions1,37), formation of glycosyl-succinimides,16,38,39 or iodination of certain protecting groups40 can be avoided. The related compound, dimethyl(methylthio)sulfonium tetrafluoroborate, which was introduced as a glycosylation promoter at the same time as DMTST,1 also found application in oligosaccharide synthesis.41 However, DMTSF-promoted glycosylations are likely to proceed through glycosyl fluoride intermediates, as glycosyl fluorides have been isolated in reactions of thioglycosides with the fluoroborate salt performed in the absence of glycosyl acceptors.42

The reactivity differences of thioglycosides depending on their substituents in the carbohydrate unit (‘armed-disarmed’ donors43,44) or in the thioaglycon (‘latent-active’ donors45-47) permit the use of thioglycosides both as glycosyl donors and glycosyl acceptors in the same reaction. Glycosylation of an unreactive thioglycoside with a more reactive one takes place without self-condensation of the acceptor. This was elegantly exploited in the programmable one-pot oligosaccharide synthesis developed by Wong.38,39 DMTST has found application in one-pot oligosaccharide synthesis, where its use is especially beneficial when the reactivities of glycosyl donors are relatively high.38,39 Chain termination by the accumulation of glycosylsuccinimide byproducts formed in NIS-promoted reactions is avoided in DMTST-promoted reactions. Among the applications of DMTST in oligosaccharide synthesis, its use in the solid-phase synthesis of large and structurally complex oligosaccharides11,21,48 and in the combinatorial synthesis of oligosaccharide libraries6,38,39 deserves particular attention.

Syntheses of O-Glycosides from Compounds other than Thioglycosides

Other types of compounds having a thio functionality at the anomeric center can be activated by DMTST. Anomeric S-xanthates49,50 (6) and dithiocarbamates51 have also been used as glycosyl donors in combination with the reagent. Isopropenyl glycosides,52 though not having sulfur at the anomeric leaving group, could also be activated for glycoside synthesis with DMTST.

Syntheses of other types of Compounds from Thioglycosides

DMTST promotes the reaction of thioglycosides with nucleophiles other than alcohols. Glycosylation of H-phosphonate monoesters followed by oxidation of the phosphonate diester was found to be a viable alternative to glycosyl phosphodiesters not accessible by other methods (7).53 Reaction of thioglycosides with pyrimidine bases gave nucleoside analogs,54-56 reaction with water constitutes a mild hydrolysis of thioglycosides to the hemiacetal57 and reaction with alcohols in the presence of excess base was used for the synthesis of orthoesters.58 The formation of glycosyl bromides from thioglycosides with the aid of DMTST and bromide ions2 was discussed earlier.

Acetalization

Cyclic acetals of pyruvic acid are not easily prepared by using commonly available acetalization methods. Cyclic pyruvic acid acetals of carbohydrates were prepared by DMTST-promoted transacetalization reaction between methyl pyruvate diphenyl dithioacetal and carbohydrate diols (8).59

Addition to Double Bonds

Compared with other alkylsulfenylating agents, addition of dimethyl(methylthio)sulfonium trifluoromethanesulfonate to double bonds is less frequently used. Treatment of olefins with the reagent followed by the addition of triphenylphosphine gave 2-methylthioalkylphosphonium salts in high yields, which could be converted into vinylphosphonium salts or vinyl phosphine oxides (9).5

Addition of the reagent to double bonds60,61 limits the use of unsaturated protecting groups (e.g. allyl, allyloxycarbonyl) in dimethyl(methylthio)sulfonium triflate-promoted glycosylation reactions.

Related Reagents.

Dimethyl(methylthio)sulfonium fluoroborate (DMTSF); dimethyl(methylthio)sulfonium tetrafluoroborate, methylsulfenyl trifluoromethanesulfonate, methyl trifluoromethanesulfonate, N-iodosuccinimide (with triflic acid).


1. Fügedi, P.; Garegg, P. J., Carbohydr. Res. 1986, 149, C9.
2. Andersson, F.; Fügedi, P.; Garegg, P. J.; Nashed, M., Tetrahedron Lett. 1986, 27, 3919.
3. Andersson, F.; Birberg, W.; Fügedi, P.; Garegg, P. J.; Nashed, M.; Pilotti, Å., ACS Symp. Ser. 1989, 386, 117.
4. Ravenscroft, M.; Roberts, R. M. G.; Tillett, J. G., J. Chem. Soc., Perkin Trans. 2 1982, 1569.
5. Okuma, K.; Koike, T.; Yamamoto, S.; Takeuchi, H.; Yonekura, K.; Ono, M.; Ohta, H., Bull. Chem. Soc. Japan 1992, 65, 2375.
6. Wong, C. H.; Ye, X. S.; Zhang, Z. Y., J. Am. Chem. Soc. 1998, 120, 7137.
7. Helmkamp, G. K.; Olsen, B. A.; Pettitt, D. J., J. Org. Chem. 1965, 30, 676.
8. Smallcombe, S. H.; Caserio, M. C., J. Am. Chem. Soc. 1971, 93, 5826.
9. Fügedi, P.; Garegg, P. J.; Lönn, H.; Norberg, T., Glycoconjugate J. 1987, 4, 97.
10. Garegg, P. J., Adv. Carbohydr. Chem. Biochem. 1997, 52,179.
11. Nicolaou, K. C.; Winssinger, N.; Pastor, J.; DeRoose, F., J. Am. Chem. Soc. 1997, 119, 449.
12. Kiso, M.; Katagiri, H.; Furui, H.; Hasegawa, A., J. Carbohydr. Chem. 1992, 11, 627.
13. Kameyama, A.; Ishida, H.; Kiso, M.; Hasegawa, A., Carbohydr. Res. 1990, 200, 269.
14. Kameyama, A.; Ishida, H.; Kiso, M.; Hasegawa, A., Carbohydr. Res. 1991, 209, C1.
15. Garegg, P. J.; Olsson, L.; Oscarson, S., Bioorg. Med. Chem. 1996, 4, 1867.
16. Krog-Jensen, C.; Oscarson, S., J. Org. Chem. 1996, 61, 1234.
17. Nilsson, M.; Norberg, T., Carbohydr. Res. 1988, 183, 71.
18. Garegg, P. J.; Olsson, L.; Oscarson, S., J. Org. Chem. 1995, 60, 2200.
19. Ekelöf, K.; Oscarson, S., J. Carbohydr. Chem. 1995, 14, 299.
20. Ishida, H. K.; Ishida, H.; Kiso, M.; Hasegawa, A., Tetrahedron: Asymmetry 1994, 5, 2493.
21. Nicolaou, K. C.; Watanabe, N.; Li, J.; Pastor, J.; Winssinger, N., Angew. Chem., Int. Ed. 1998, 37, 1559.
22. Chernyak, A.; Oscarson, S.; Turek, D., Carbohydr. Res. 2000, 329, 309.
23. Ruda, K.; Lindberg, J.; Garegg, P. J.; Oscarson, S.; Konradsson, P., J. Am. Chem. Soc. 2000, 122, 11067.
24. Schultz, M.; Kunz, H., Tetrahedron Lett. 1992, 33, 5319.
25. Schultz, M.; Kunz, H., Tetrahedron: Asymmetry 1993, 4, 1205.
26. Takeda, K.; Tsuboyama, K.; Torii, K.; Furuhata, K.; Sato, N.; Ogura, H., Carbohydr. Res. 1990, 203, 57.
27. Paulsen, H.; Rauwald, W.; Weichert, U., Liebigs Ann. Chem. 1988, 75.
28. Hällgren, C.; Hindsgaul, O., Carbohydr. Res. 1994, 260, 63.
29. Bernlind, C.; Oscarson, S., Carbohydr. Res. 1997, 297, 251.
30. Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K., J. Am. Chem. Soc. 1975, 97, 4056.
31. Murase, T.; Ishida, H.; Kiso, M.; Hasegawa, A., Carbohydr. Res. 1988, 184, C1.
32. Kanie, O.; Kiso, M.; Hasegawa, A., J. Carbohydr. Chem. 1988, 7, 501.
33. Garegg, P. J.; Oscarson, S.; Ritzén, H.; Szönyi, M., Carbohydr. Res. 1992, 228, 121.
34. Krog-Jensen, C.; Oscarson, S., J. Org. Chem. 1996, 61, 4512.
35. Krog-Jensen, C.; Oscarson, S., J. Org. Chem. 1998, 63, 1780.
36. Oscarson, S.; Sehgelmeble, F. W., J. Am. Chem. Soc. 2000, 122, 8869.
37. Bhattacharya, S. K.; Danishefsky, S. J., J. Org. Chem. 2000, 65, 144.
38. Zhang, Z. H.; Ollmann, I. R.; Ye, X. S.; Wischnat, R.; Baasov, T.; Wong, C. H., J. Am. Chem. Soc. 1999, 121, 734.
39. Ye, X. S.; Wong, C. H., J. Org. Chem. 2000, 65, 2410.
40. Mehta, S.; Whitfield, D. M., Tetrahedron 2000, 56, 6415.
41. Åberg, P. M.; Blomberg, L.; Lönn, H.; Norberg, T., J. Carbohydr. Chem. 1994, 13, 141.
42. Blomberg, L.; Norberg, T., J. Carbohydr. Chem. 1992, 11, 751.
43. Veeneman, G. H.; van Boom, J. H., Tetrahedron Lett. 1990, 31, 275.
44. Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H., Tetrahedron Lett. 1990, 31, 1331.
45. Roy, R.; Andersson, F. O.; Letellier, M., Tetrahedron Lett. 1992, 33, 6053.
46. Cao, S. D.; Hernández-Matéo, F.; Roy, R., J. Carbohydr. Chem. 1998, 17, 609.
47. Sliedregt, L. A. J. M.; Zegelaar-Jaarsveld, K.; van der Marel, G. A.; van Boom, J. H., Synlett 1993, 335.
48. Kanemitsu, T.; Kanie, O.; Wong, C. H., Angew. Chem., Int. Ed. 1998, 37, 3415.
49. Marra, A.; Gauffeny, F.; Sinaÿ, P., Tetrahedron 1991, 47, 5149.
50. Marra, A.; Sinaÿ, P., Carbohydr. Res. 1990, 195, 303.
51. Fügedi, P.; Garegg, P. J.; Oscarson, S.; Rosen, G.; Silwanis, B. A., Carbohydr. Res. 1991, 211, 157.
52. Chenault, H. K.; Castro, A.; Chafin, L. F.; Yang, J., J. Org. Chem. 1996, 61, 5024.
53. Garegg, P. J.; Hansson, J.; Helland, A. C.; Oscarson, S., Tetrahedron Lett. 1999, 40, 3049.
54. Sugimura, H.; Muramoto, I.; Nakamura, T.; Osumi, K., Chem. Lett. 1993, 169.
55. Sugimura, H.; Sujino, K., Jpn. Kokai Tokkyo Koho JP 10 182,691 (Chem. Abstr. 1998, 129, 149179e).
56. Sugimura, H., Jpn. Kokai Tokkyo Koho JP 10 237,090 (Chem. Abstr. 1998, 129, 245422z).
57. Hasegawa, A.; Murase, T.; Ogawa M.; Ishida, H.; Kiso, M., J. Carbohydr. Chem. 1990, 9, 415.
58. Hällgren, C., J. Carbohydr. Chem. 1992, 11, 527.
59. Lipták, A.; Szabó, L., Carbohydr. Res. 1988, 184, C5-C8.
60. Chernyak, A. Y.; Antonov, K. V.; Kochetkov, N. K., Bioorg. Khim. 1989, 15, 1113 (Chem. Abstr. 1990, 112, 158760p).
61. Kunz, H.; Wernig, P.; Schultz, M., Synlett 1990, 631.

Péter Fügedi

Chemical Research Center, Hungarian Academy of Sciences Budapest, Hungary



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.