Electrochemistry of Chalcogenoglycosides ... - ACS Publications

Electrochemistry of Chalcogenoglycosides. Rational Design of Iterative Glycosylation Based on Reactivity Control of Glycosyl Donors and Acceptors by Oxidation Potentials† Shigeru Yamago,* Koji Kokubo, Osamu Hara, Sadayoshi Masuda, and Jun-ichi Yoshida* Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan [email protected] Received July 3, 2002

Electrochemical properties of various para-substituted phenylthio-, phenylseleno-, and phenyltelluroglucopyranosides bearing acetyl, benzoyl, and benzyl protecting groups have been investigated to estimate the reactivity of chalcogenoglycosides toward electrochemical glycosylations. The oxidation potential of the chalcogenoglycosides shows good correlation with the ionization potential of chalcogen atoms, and decreases in the order thio-, seleno-, and telluroglycosides. It is also affected by the para-substituents, and the substitution effect correlates very well with the HOMO energy of para-substituted benzenechalcogenol and with the Hammett σp+ value. Electrochemical glycosylation of telluroglycosides has been examined, and it was found that the use of an undivided cell is more effective than the use of a divided cell. Selective activation of the chalcogenoglycosides in bulk electrolysis based on their oxidation potentials has been examined, and the relative reactivity of the telluroglycosides can be estimated from their oxidation potentials. However, the relative reactivity of selenoglycosides in the preparative glycosylation was rather insensitive to the oxidation potential values. Intensive efforts have been recently aimed at the synthesis of oligosaccharides because of their numerous important biological functions.1,2 Since oligosaccharides consist of several anomeric C-O bond linked monosaccharides, the synthesis would necessarily require iterative glycosylation. Therefore, the reactivity control of the anomeric substituents is one of the major challenges of a generalized oligosaccharide synthesis.3 To achieve efficient and high-throughput synthesis, several glycosylation strategies have recently been developed, including a two-stage activation method,4 the armed-disarmed glycosylation,5 a one-pot synthesis,6 an orthogonal method,7 enzymatic glycosylation,8 a programmable one-pot strategy,9 and solid-phase synthesis.10,11 Despite these recent * To whom correspondence should be addressed. Fax: +81-75-7535911. Email: (J.-i. Y.) [email protected]. † This paper is dedicated to Professor Hans J. Schafer on the occasion of his 65th birthday. (1) (a) Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 1. (b) Varki, A. Glycobiology 1993, 3, 97. (2) For recent review articles on oligosaccharide synthesis, see: (a) Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker, Inc.: New York, 1997. (b) Sears, P.; Wong, C.-H. Science 2001, 291, 2344. (c) Seeberger, P. H.; Haase, W.-C. Chem. Rev. 2000, 100, 4349. (d) Koeller, K. M.; Wong, C.-H. Chem. Rev. 2000, 100, 4465. (e) Herzner, H.; Reipen, T.; Schltz, M.; Kunz, H. Chem. Rev. 2000, 100, 4495. (3) (a) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239. (b) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T. Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734. (4) Nicolaou, K. C.; Ueno, H. In Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker, Inc.: New York, 1997; pp 313338. Nicolaou, K. C.; Bockovich, N. J.; Carcanague, D. R. J. Am. Chem. Soc. 1993, 115, 8843.

developments, the rational design of the oligosaccharide synthesis still remains unachieved, primarily due to the (5) (a) Green, L. G.; Ley, S. V. In Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 1, pp 427-448. (b) Mootoo, D. R.; Koradsson, P.; Udodong, U.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 5583. (c) Zuurmond, H. M.; van der Meer, P. H.; van der Klein, P. A. M.; van der Marel, G. A.; van Boom, J. H. J. Carbohydr. Chem. 1993, 12, 1091. (d) Hashimoto, S.; Sakamoto, H.; Honda, T.; Abe, H.; Nakamura, S.; Ikegami, S. Tetrahedron Lett. 1997, 38, 8969. (6) (a) Raghavan, S.; Kahne, D. J. Am. Chem. Soc. 1993, 115, 1580. (b) Yamada, H.; Harada, T.; Takahashi, T. J. Am. Chem. Soc. 1994, 116, 7917. Takahashi, T.; Adachi, M.; Matsuda, A.; Doi, T. Tetrahedron Lett. 2000, 41, 2599. (c) Douglas, N. L.; Ley, S. V.; Lu¨cking, U.; Warriner, S. J. Chem. Soc., Perkin Trans. 1 1998, 51. (d) Tsukida, T.; Yoshida, M.; Kurokawa, K.; Nakai, T.; Achiha, T.; Kiyoi, T.; Kondo, H. J. Org. Chem. 1997, 62, 6876. (7) Kanie, O. In Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 1, pp 407-426. Kanie, O.; Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 12073. (8) Vocadlo, D. J.; Withers, S. G. In Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 2, pp 723-844. Wong, C.-H.; Halcomb, R. L.; Ichikawa, Y.; Kajimoto, T. Angew. Chem., Int. Ed. Engl. 1995, 34, 521. Takayama, S.; McGarvey, G. J.; Wong, C.-H. Chem. Soc. Rev. 1997, 26, 407. (9) Ye, X. S.; Wong, C.-H. J. Org. Chem. 2000, 65, 2410. Fred, B.; Zhiyuan, Z.; Shirley, W.-S.; Wong, C.-H. Angew. Chem., Int. Ed. 2001, 40, 1274. (10) Danishefsky, S. J.; McClure, K. F.; Randolph, J. T.; Ruggeri, R. R. B. Science 1993, 260, 1307. Liang, R.; Yan, L.; Loebach, J.; Ge, M.; Uozumi, Y.; Sekanina, K.; Horan, N.; Gildersleeve, J.; Thompson, C.; Smith, A.; Biswas, K.; Still, W. C.; Kahne, D. Science 1996, 274, 1520. Seeberger, P.; Danishefsky, S. J. Acc. Chem. Res. 1998, 31, 685. Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523. (11) Mehta, S.; Pinto, B. M. Tetrahedron Lett. 1991, 32, 4435, Sliedregt, L. A. J. M.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 1994, 35, 4015, Chung, M.-K.; Douglas, N. L.; Hinzen, B.; Ley, S. V.; Pannecoucke, X. Synlett 1997, 257. 10.1021/jo0261350 CCC: $22.00 © 2002 American Chemical Society

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Published on Web 11/08/2002

Electrochemistry of Chalcogenoglycosides SCHEME 1

difficulty in predicting the reactivities of sugar derivatives, which are strongly affected by structures, protecting groups, and reaction conditions, e.g., activating reagents and solvents. Given these considerations, the programmable one-pot strategy seems to be the most effective, because one can design a combination glycosyl donor/acceptor strategy using an empirical database. However, prediction of the reactivity of new glycosides is, unfortunately, rather difficult. An alternative, and potentially more general, strategy to overcoming this problem is the use of a single anomeric substituent under single reaction conditions. However, this type of strategy has been limited to only the glycal assembly method,12 and two new methods have recently appeared from Gin et al.13 and from our own laboratory.14 We report here an alternative approach for the rational design and prediction of the reactivity of glycosyl acceptors and donors by an electrochemical reaction.15,16 Because oxidation potentials directly give us reactivity indices of sugar derivatives, we would be able to estimate their reactivity. Therefore, if we could synthesize several sugar derivatives possessing different oxidation potentials and reactivities, we would be able to repeat glycosylation iteratively, changing only the electronic voltage (Scheme 1). We focused on chalcogenoglycosides 1 (X ) S, Se, Te), because glycosides bearing oxygen, sulfur, and selenium atoms can be activated under electrochemical oxidation (Scheme 2).17,18 Since the ionization potential of the chalcogen atom is considerably different, the correspond(12) Williams, L. J.; Garbaccio, R. M.; Danishefsky, S. J. In Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 1, pp 61-92. (13) Nguyen, H. M.; Poole, J. L.; Gin, D. Y. Angew. Chem., Int. Ed. 2001, 40, 414. (14) Yamago, S.; Yamada, T.; Hara, O.; Ito, H.; Mino, Y.; Yoshida, J. Org. Lett. 2001, 3, 3867. (15) Organic Electrochemistry, 4th ed., revised and expanded; Lund, H., Hammerich, O., Eds.; Marcel Dekker: New York, 2001. (16) For other papers on our study of electrochemical synthesis, see: Yoshida, J.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto, A.; Fujiwara, K. J. Am. Chem. Soc. 1999, 121, 9546. Suga, S.; Suzuki, S.; Yamamoto, A.; Yoshida, J. J. Am. Chem. Soc. 2000, 122, 10244. Suga, S.; Suzuki, S.; Yoshida, J. J. Am. Chem. Soc. 2002, 124, 30.

SCHEME 2

ing sugar derivatives would also possess different oxidation potentials. We also expected that the para-substituent of the aryl group would finely tune the reactivity of the glycosides. In addition, since the C-2 protecting group is known to affect glycosidic reactivity,5 we also examined the effect of the protecting group on the oxidation potential. Since telluroglycosides possess the lowest oxidation potential of any chalcogenglycoside, they would be expected to be the most reactive. However, there had been no report on the O-glycosylation of telluroglycosides until our preliminary results appeared.19 We report here (1) the electrochemical study of various chalcogenoglycosides in terms of the electrochemical activation of chalcogenoglycosides, (2) the O-glycosylation of telluroglycosides, and (3) several attempts at the chemoselective activation of chalcogenoglycosides by the electrochemical method.20 Results and Discussion Oxidation Potentials of Chalcogenoglycosides. Various para-substituted phenylthio-, phenylseleno-, and phenyltelluroglucopyranosides bearing acetyl, benzoyl, and benzyl protecting groups (2-11) were prepared, and

(17) (a) Noyori, R.; Kurimoto, I. J. Org. Chem. 1986, 51, 4322. (b) Amatore, C.; Jutand, A.; Mallet, J.-M.; Meyer, G.; Sinay, P. J. Chem. Soc., Chem. Commun. 1990, 718. Mallet, J.-M.; Meyer, G.; Yvelin, F.; Jutand, A.; Amatore, C.; Sinay, P. Carbohydr. Res. 1993, 244, 237. (c) Balavoine, G.; Gref, A.; Fischer, J.-C.; Jubineau, A. Tetrahedron. Lett. 1990, 31, 5764. Balavoine, G.; Berteina, S.; Gref, A.; Fischer, J.-C.; Lubineau, A. J. Carbohydr. Chem. 1995, 14, 1217. Balavoine, G.; Berteina, S.; Gref, A.; Fischer, J.-C.; Lubineau, A. J. Carbohydr. Chem. 1995, 14, 1237. (d) Nokami, J.; Osafune, M.; Ito, Y.; Miyake, F.; Sumida, S.; Torii, S. Chem. Lett. 1999, 1053. (18) Yoshida, J.; Sugawara, M.; Kise, N. Tetrahedron Lett. 1996, 37, 3157. Yoshida, J.; Sugawara, M.; Tatsumi, M.; Kise, N. J. Org. Chem. 1998, 63, 5950. (19) Yamago, S.; Kokubo, K.; Yoshida, J. Chem. Lett. 1997, 111, Yamago, S.; Kokubo, K.; Murakami, H.; Mino, Y.; Hara, O.; Yoshida, J. Tetrahedron Lett. 1998, 39, 7905. (20) For other papers on our study of C-glycoside synthesis, see: Yamago, S.; Miyazoe, H.; Yoshida, J. Tetrahedron Lett. 1999, 40, 2339. Yamago, S.; Miyazoe, H.; Yoshida, J. Tetrahedron Lett. 1999, 40, 2343. Yamago, S.; Miyazoe, H.; Goto, R.; Yoshida, J. Tetrahedron Lett. 1999, 40, 2347. Yamago, S.; Miyazoe, H.; Goto, R.; Hashidume, M.; Sawazaki, T.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 3697. Yamago, S.; Hashidume, M.; Yoshida, J. Tetrahedron 2002, 58, 6805.

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Yamago et al. TABLE 1. Oxidation Potential of 1-Arylchalcogenoglycosides glycoside

Eoxa

glycoside

Eoxa

2a 2b 3a 3b 3c 4a 4b 5a 5b 5c 5d

1.65 1.46 (1.50) 1.52 1.47 (1.43) 1.22 1.24 1.25 (1.28) 1.31 1.25 (1.25) 1.15 0.69

6a 6b 6c 7a 7b 8a 8b 8c 8d 9b 10b 11b

1.31 (1.36) 1.18 (1.21) 1.18 (1.16) 0.95 0.98 (0.92) 0.90 (0.94) 0.97 (0.90) 0.91 (0.86) 0.59 (0.62) (1.43) (1.21) 0.76 (0.82)

a

FIGURE 2. Correlation between the calculated IP of parasubstituted benzenethiols and the Eox of 2 and 3.

Decomposition potentials (V vs Ag/AgCl) were measured in a 0.1 M CH3CN solution of LiClO4 at room temperature using linear sweep voltammetry equipped with a rotating disk electrode. Peak potentials (V vs Ag/AgCl) measured by Osteryoung square wave voltammetry are shown in parentheses.

FIGURE 3. Correlation between the calculated IP of parasubstituted benzeneselenols and the Eox of 4-6.

FIGURE 1. Correlation between the IP of the chalcogen atom and the Eox of 2-8 and 11.

their electrochemical properties were measured by cyclic voltammetry (CV), linear sweep voltammetry (LSV), or Osteryoung square wave voltammetry (OSW).21 An irreversible and single-electron oxidation was observed by CV analysis. The data on the oxidation potential of 2-11 by LSV (decomposition potential) or OSW (peak potential) are presented in Table 1. Due to the inherent baseline deviation near the decomposition potential in LSV, especially in the measurement of telluroglycosides, the oxidation potentials obtained by OSW may be more reliable than those obtained by LSV. The oxidation potential is strongly affected by the chalcogen atom, as we expected, and the potential decreases in the order thio- (X ) S), seleno- (X ) Se), and telluroglycosides (X ) Te) among the chalcogenoglycosides with the same protecting group P and the same para-substituent R. The oxidation potential of 1 and the ionization potential of the chalcogen atoms show good linear correlation with r > 0.99 (Figure 1). This result can be explained by the fact that the single-electron oxidation takes place from the n-orbital (lone pair) of the chalcogen atom, which is the HOMO of the chalcogenoglycosides (see below). It is also worth noting that the benzyl-protected glycosides (P ) Bn) possess lower oxidation potential than the acetyl-protected (P ) Ac) and benzoyl-protected (P ) Bz) ones, presumably because acyl groups are electron-withdrawing compared to the benzyl (21) Osteryoung, J.; O’Dea, J. J. In Electroanalytical Chemistry; Bard, A. J., Ed.; Dekker: New York, 1986; Vol. 14.

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group. The observed tendency is consistent with the armed-disarmed glycoside chemistry, in which glycosides bearing 2-alkyl protecting groups are more reactive than those bearing 2-acyl protecting groups.5 Ab initio molecular orbital calculations of various parasubstituted benzenechalcogenols (p-RC6H4XH; R ) H, Me, OMe, NMe2; X ) S, Se, Te) at the HF/LANL2DZ level were performed to delve more deeply into the differences in the oxidation potentials.22 The calculations indicate that the ionization potential (IP) thus obtained correlated nicely with the oxidation potential of the chalcogenoglycosides (Figures 2-4). Molecular orbital analyses of PhXH (X ) S, Se, Te) suggest that the magnitude of the orbital coefficient of the HOMO is largest at the n-orbital of the chalcogen atom, which is further conjugated with the aromatic p-orbitals. The interaction of the n-orbital and the p-orbitals is strongest when X ) S, slightly weaker when X ) Se, and even weaker when X ) Te. Electron-donating para-substituents further increase the HOMO energy level (R ) Me, OMe, NMe2), and the n-orbital of the nitrogen atom possesses the largest orbital coefficients for the HOMO orbital of the dimethylamino-substituted benzenethiol and benzeneselenol (X ) S and Se). The correlation between the oxidation potentials and the Hammett σp value of the para-substituents is shown in Figure 5. While several σp values have been reported, (22) Gaussian 94, Revision E.2: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.; Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T.; Petersson, G. A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J. V.; Foresman, J. B.; Cioslowski, J.; Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Binkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-Gordon, M.; Gonzalez, C.; Pople, J. A., Gaussian, Inc., Pittsburgh, PA, 1995.

Electrochemistry of Chalcogenoglycosides SCHEME 3

FIGURE 4. Correlation between the calculated IP of parasubstituted benzenetellurols and the Eox of 8.

theoretical calculations of the arylchalcogenols, and the formation of the ditelluride in the glycosylation reaction shown below, we proposed the following reaction mechanism (Scheme 3): A single-electron oxidation of the telluroglycoside takes place at the n-orbital of the tellurium moiety to generate the short-lived radical cation intermediate, which spontaneously dissociates to the aryltelluro radical and the oxycarbenium ion. The radical dimerizes to the ditelluride, and the oxycarbenium ion reacts with an alcohol to give the O-glycoside. Electrochemical Glycosylation of Telluroglycosides in a Divided Cell. The glycosylation of 8 and 3-phenylpropanol was carried out using constant-potential electrolysis at 1.1 V in a LiClO4 solution of MeCN in an H-type divided cell using a carbon fiber anode and a Pt foil cathode. The reaction mainly afforded a mixture of the O-glycoside 12, the ortho ester 13, and the diaryl ditelluride (eq 1). The ortho ester 13 was converted to

FIGURE 5. Correlation between the Hammett substituent constant (σp+) and the Eox of 3, 6, and 8.

the σp+ value shows a better linear correlation (r ) 0.950.96) than the σpo value (r ) 0.88-0.89).23 Because the σp+ value expresses enhanced resonance properties and fits well when the reaction involves a vacant orbital adjacent to the aryl ring, it is consistent with the hypothesis that the single electron oxidation takes place at the chalcogen n-orbital to generate the cation radical species. Figure 5 also indicates that the oxidation potentials of the telluroglycosides are less affected by the parasubstituents than those of the thio- and selenoglycosides. This is due to the weaker interaction of the n-orbital of the Te atom with the aryl group than that of the S and Se atoms, as suggested by the theoretical calculations. The effect of the C-6 substituents is negligible, and the C-6-modified chalcogenoglycosides 9 and 10 showed oxidation potentials virtually identical with those of the corresponding C-6-protected glycosides 3 and 6, respectively. Mechanism of the Activation of Chalcogenoglycosides. The CV and OSV analyses of the telluroglycosides 7, 8, and 11 were investigated in more detail in conjunction with the mechanism of the glycosylation of telluroglycosides as shown below. The CV of 7, 8, and 11 in a LiClO4 solution of MeCN only showed an irreversible single-electron oxidation wave. The corresponding reverse reduction wave could not be observed at the scan speed of 100-1000 mV/s. The OSV of 7b also showed an irreversible oxidation wave at a frequency of 500 Hz, indicating the lifetime of the intermediate is less than 2 ms. From the results of the electrochemical analyses, the (23) Isaacs, N. S. Physical Organic Chemistry, Longman Scientific & Technical: Essex, U.K., 1987; p 129.

12 in quantitative yield by treatment with Me3SiOTf. The yield of 12 is reported in Table 2 (entries 1-8) together with the anomeric stereoselectivity. The selective formation of β-12 is due to the well-known intramolecular participation of the 2-acyl protecting group. The efficiency of the glycosylation was slightly affected by the para-substituent R of the aryl group as well as the protecting group. The glycosylation of 8a-c (R ) H, Me, OMe) resulted in virtually identical results within experimental errors, though the reaction of 8d (R ) NMe2), which has the lowest oxidation potential among the telluroglycosides examined in this study, showed very low current efficiency (entries 1-8). The benzyl-protected telluroglycoside 11b also reacted smoothly with various glycosyl acceptors, including 3-phenylpropanol, cyclohexanol, and the 6-hydroxy glycoside 14 to give the corresponding O-glycosides 15 and 16C in good yields with moderate β-selectivities (entries 9-11). While the telluroglycosides are activated under electrochemical oxidation and serve as reactive glycosyl donors, the reaction in a divided cell usually requires a long reaction time due to the high ohmic resistance of the solution and the low electric current. Under these conditions, the effects of water that might come from J. Org. Chem, Vol. 67, No. 24, 2002 8587

Yamago et al. TABLE 2. Electrochemical O-Glycosylation of Telluroglycosides entry 1 2 3 4 5 6 7 8 9 10 11 12 13

donora

acceptorb

8b

HO(CH2)3Ph

8a 8c 8d 11b 11b 11b 8b 8b

HO(CH2)3Ph HO(CH2)3Ph HO(CH2)3Ph HO(CH2)3Ph c-C6H11OH 14 14 14

electricity (F/mol)

electrolyte/solvent LiClO4/MeCN n-Bu4NClO4/MeCN n-Bu4NBF4/MeCN n-Bu4NBF4/EtCN n-Bu4NBF4/EtNO2 n-Bu4NBF4/MeCN n-Bu4NBF4/MeCN LiClO4/MeCN n-Bu4NBF4/MeCN LiClO4/MeCN LiClO4/MeCN LiClO4/MeCN LiClO4/MeCN

3.2 2.5 3.5 2.6 3.5 3.7 3.9 3.0 3.6 1.8 2.9 4.0 7.0

major product 12

15A 15B 16C 16D 16D

yieldc (%)

R:βd

(90)e

76 54 (59) 53 (59)e 68 54 50 65 18 (56)e 70 68 63 36 90f

5:>95 5:>95 5:>95 5:>95 5:>95 5:>95 5:>95 5:>95 34:76 20:80 29:71 5:>95 5:>95

a The telluroglycosides were the single β-anomers (>95%), except for 11b, which consisted of a 70:30 mixture of R- and β-anomers. b A 1 equiv sample of alcohol was used. c Isolated yield. d Determined by 1H NMR and/or HPLC. e Yield based on reacted telluroglycoside. f The reaction was carried out in an undivided cell. See the text.

outside the cell cannot be negligible. For example, the desired disaccharide was obtained in only 36% yield due to the competitive reaction with water in the glycosylation of 8b with 14 (entry 12). To overcome this limitation, we next examined the glycosylation in an undivided cell, in which the electrodes are located in close proximity.

Electrochemical Glycosylation in an Undivided Cell. The glycosylation of 8b and 3-phenylpropanol in an undivided cell was carried out under the same conditions as in a divided cell except for the cell design. While the reaction afforded the desired O-glycoside 12 in 66% yield, the formation of 3-phenylpropyl benzoate (17) in 32% yield was also observed. Among several minor side products, we could also isolate the 3,4-dihydroxy-Oglucopyranoside 18 in 2% yield. Since the cathodic reduction of organic compounds sometimes generate bases,24 the formation of 17 and 18 could be attributed to the base-mediated reaction of the alcohol and 8b.

We found that addition of an organic acid was effective in decreasing the formation of the benzoate 17 (Table 3). For example, the addition of 1 equiv of benzoic acid (24) Kashimura, S. J. Synth. Org. Chem., Jpn. 1985, 43, 549. Niyazymbetov, M. E.; Evans, D. H. J. Org. Chem. 1993, 58, 779.

8588 J. Org. Chem., Vol. 67, No. 24, 2002

TABLE 3. Effect of Additives on Electrochemical Glycosylation of 8b in an Undivided Cell yield (%) entry

additive (equiv)

12

17

1 2 3 4 5

none PhCO2H (1.0) 2,6-Me2C6H3OH (1.0) 2,4,6-(t-Bu)3C6H2OH (1.0) 2,6-Me2C6H3OH (5.0)

66 80 75 77 89

32 10 17 16 7

decreased the formation of 17 from 32% to 10% and increased the formation of the O-glycoside 12 from 66% to 80%, but a small portion of benzoic acid reacted with 8b to form 1,2,3,4,6-penta-O-benzoylglucopyranoside (entry 1). Sterically bulky 2,6-dimethylphenol was found to be inert to the glycosylation reaction and also diminished the formation of 17, but the use of the bulkier 2,4,6-tritert-butylphenol showed only a small effect (entries 3 and 4). The use of 5 equiv of 2,6-dimethylphenol almost suppressed the formation of 17 and furnished 14 in 89% yield (entry 5). Using optimal conditions, we examined the disaccharide synthesis. The glycosylation of 8b and 14 was carried out in the presence of 5 equiv of 2,6-dimethylphenol in an undivided cell. While the previous synthesis in a divided cell afforded the disaccharide 16D in 36% yield, the reaction in an undivided cell afforded the same disaccharide in 90% yield (Table 2, entry 13). Selective Activation of Chalcogenoglycosides. We next examined the selective activation of the chalcogenoglycosides on the basis of their oxidation potentials (eq 2). First, we compared the reactivity of the telluro-

glycosides on the basis of the armed-disarmed glycosylation strategy. Intermolecular competition of the 2-benzoyl- and 2-benzyl-protected telluroglycosides 8b and 11b

Electrochemistry of Chalcogenoglycosides TABLE 4. Selective Activation of Chalcogenoglycosides b

entry

I

II

conditionsa

∆Eox (V)

(kJ/mol)

1 2 3 4 5 6 7

11b 11b 8b 8b 6b 6c 8b

8b 8b 8a 8a 5b 6a 5b

i ii i ii i i ii

0.08 0.08 0.04 0.04 0.02 0.20 0.35

7.7 7.7 3.9 3.9 2.1 21 33

∆Gq

recoveryc (%) I II 16 20 28 34 51 38 9

>95 >95 81 98 49 62 41

a (i) A mixture of I (1 equiv), II (1 equiv), and 3-phenylpropanol (1 equiv) was electrolyzed in a divided cell with 3.0 F/mol of electricity at a constant potential of 1.1 V. (ii) A mixture of I (1 equiv), II (1 equiv), and 3-phenylpropanol (2 equiv) in the presence of 2,6-dimethylphenol (10 equiv) was electrolyzed in an undivided cell at a constant potential of 1.1 V. In all cases, the corresponding O-glycosides were obtained. b ∆Eox ) Eox(II) - Eox(I). c Determined by 1H NMR and/or HPLC of the crude mixture.

in the presence of 3-phenylpropanol (1 equiv each) was carried out by a constant-potential electrolysis (1.1 V vs Ag/AgCl) in a divided cell at room temperature. After 3.0 F/mol of electricity was applied, the crude reaction mixture was analyzed by 1H NMR and HPLC, which revealed that all the O-glycoside came from 11b and that 8b was recovered quantitatively (Table 4, entry 1). The competition in an undivided cell also gave the same results (entry 2). The difference in the oxidation potential was 0.08 V, which corresponds to the difference of the Gibbs free energy of 7.7 kJ/mol. This energy difference nicely accounts for the observed experimental results. We next examined the competition between the telluroglycosides bearing different para-substituents R of the aryl group. A constant-potential electrolysis (1.1 V vs Ag/AgCl) of phenyl- and p-methylphenyl-substituted telluroglycosides 8a and 8b in the presence of 3-phenylpropanol (1 equiv each) in a divided cell resulted in the formation of the O-glycoside 12 in 72% yield, together with the recovery of 8a and 8b in 81% and 28% yield, respectively (entry 3). The competition in an undivided cell also gave virtually identical results (entry 4), indicating that 8b reacted at least 4 times faster than 8a. The difference in the oxidation potential of 8a and 8b was 0.04 V, a value corresponding to the difference in the Gibbs free energy of 3.9 kJ/mol. This energy difference is also consistent with the observed reactivity difference. Both experiments demonstrated that the telluroglycosides were selectively and predictably activated, depending on the difference of the oxidation potentials. We next examined the selective activation of the selenoglycosides on the basis of the C-2 protecting groups and the p-substituent. However, in sharp contrast to the telluroglycosides, we found that the selenoglycosides showed only modest selectivity. The difference in the oxidation potential of the 2-benzoyl- and 2-benzylprotected selenoglycosides 5b and 6b was small (∆Eox ) 0.02 V, ∆Gq ) 2.1 kJ/mol), but the latter is known to be selectively activated over the former by chemical reagents.10 However, the competition experiments revealed no preferential activation, and a 1:1 mixture of the corresponding O-glycosides was obtained together with an equal amount of recovered 6b and 7b (entry 5). Although the difference in the oxidation potential of the phenyl- and p-methoxyphenyl-substituted selenoglycosides 6a and 6c was 0.20 V, the competition revealed that

6c reacted only about 2 times faster than 6a (entry 6). Unfortunately, the activation of the telluroglycoside 8b and the selenoglycoside 5b was found to be nonselective despite the large differences in the oxidation potentials (entry 7). With the results of the intermolecular competition in hand, we next examined the disaccharide synthesis based on selective activation. Since chemical transformations of the telluroglycosides are problematic at the present time, we examined the competition between the telluroglycoside and the thio- and selenoglycosides. Electrolysis of the telluroglycoside 8b in the presence of the thioglycoside 9b was carried out in a divided cell, and the desired disaccharide 19 was obtained in 42% yield together with 46% of the unreacted 9b (eq 3). The same

reaction in an undivided cell in the presence of 5 equiv of 2,6-dimethylphenol resulted in the formation of 19 in 72% together with 25% of the unchanged 9b. In both cases, no oxidized products derived from 9b could be detected. The results indicated that complete selectivity was achieved between the telluroglycoside and the thioglycoside. The disaccharide 19 would be used for the following glycosylation reactions. The synthesis of the disaccharide with the telluroglycoside and the selenoglycoside revealed that the selenoglycosides were less selective than the thioglycosides (eq 4). When a mixture of 8b and 6-hydroxyselenoglyco-

side 10a was subjected to electrolysis, the desired disaccharide 20 formed in only 30% yield. Among the several side products, the anhydroglycoside 21 derived from 10a was isolated in 20% yield. Gel permeation chromatography analyses also indicated the formation of a small amount of trisaccharides, which arose from further activation of 20 under the reaction conditions. Summary We found that telluroglycosides serve as reactive glycosyl donors under electrochemical oxidation. We examined both divided and undivided cells, and observed that undivided cells were better for practical glycoside syntheses. Since electrochemical glycosylation proceeds under neutral conditions and does not require the use of expensive, explosive, or harmful heavy metal chemicals, it would be suitable for large-scale preparation. We also demonstrated that the precise tuning of the oxidation J. Org. Chem, Vol. 67, No. 24, 2002 8589

Yamago et al.

potential of chalcogenoglycosides is feasible by rational molecular design, and that the relative reactivity of telluroglycosides can be easily predicted, in many cases, from their oxidation potential. We believe that the current method provides a new idea for the rational design not only for the synthesis of oligosaccharides but also for various iterative synthetic transformations.

Experimental Section 1 H (300 and 400 MHz) and 13C (75 and 100 MHz) NMR spectra were recorded in CDCl3 as solvent. The chemical shifts are reported in parts per million (δ) with reference to TMS (for 1H) and to solvent (for 13C) as internal standards. Infrared (FTIR) spectra were recorded in KBr and are reported in cm-1. FAB mass spectra were obtained using nitorobenzyl alcohol as matrix. The oxidation potential was measured in a 0.1 M MeCN solution of LiClO4 at room temperature by CV, LSV, or OSW. Glassy carbon working electrodes (7.0 mm diameter for LSV and 3.0 mm diameter for CV and OSW) and a Pt wire auxiliary electrode (1.0 mm diameter) were used. IR compensation was employed throughout. Thioglycosides were prepared as reported.17c,25 The selenoglycosides 4a, 5a, 5c, and 6a were prepared as reported.17c,26 Other selenoglycosides were prepared by analogous procedures (see the Supporting Information). Preparations of telluroglycosides are provided in the Supporting Information.27 Preparation and characterization of glycosides 14,28 15B,29 and 2130 have already been reported. General Procedure for the Electrochemical Glycosylation in a Divided Cell. Synthesis of 1-(3-Phenylpropyl)2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside (12). An Htype cell separated by a sintered glass diaphragm (no. 4, pore size in the range 5-10 µm) was fitted with a platinum plate cathode (6 cm2), a carbon felt cathode (10 mm × 5 mm × 3 mm), and a platinum wire reference electrode which was connected to a saturated calomel electrode (SCE). To both the anodic and cathodic sides of the cell containing activated molecular sieves 3A (100 mg) was added a 0.1 M LiClO4 solution of MeCN (2 mL each) under an Ar atmosphere. To the cathodic side were added 1-p-methylphenyltelluro-2,3,4,6tetra-O-benzoyl-β-D-glucopyranoside (8b) (160.2 mg, 0.20 mmol) and 3-phenylpropanol (27.5 mg, 0.20 mmol), and the resulting mixture was electrolyzed at a constant potential of 1.1 V (vs SCE) with gentle stirring. After 3.2 F/mol of electricity was applied, 8b disappeared on TLC. The reaction mixture was filtered through a short cotton plug, and the resulting solution was partitioned between water and ethyl acetate. After the usual workup (extraction with ethyl acetate, washing with aqueous saturated sodium chloride solution, drying over magnesium sulfate, and evacuation under reduced pressure), purification of the crude mixture by flash column chromatography (elution with 17% ethyl acetate in hexane) afforded the title compound (108.6 mg, 76%) and 3,4,6-tri-O-benzoyl-1,2O-(1-exo-(3-phenylpropoxy)benzylidene)-R-D-glucopyranoside (13) (22.9 mg, 16%). The latter compound could be quantitatively converted to the former upon treatment by a catalytic amount of TMSOTf. Data for 12: IR (KBr) 1732, 1267, 1107, 1093, 1068, 1026, 710; 1H NMR (300 MHz, CDCl3) 1.74-1.96 (m, 2H), 2.46-2.63 (m, 2H), 3.48-3.56 (ddd, J ) 9.6, 7.2, 5.7 Hz, 1H), 3.90-3.98

(25) Nicolaou, K. C.; Randall, J. L.; Furst, G. T. J. Am. Chem. Soc. 1985, 107, 5556. (26) Benhaddou, R.; Czernecki, S.; Randriamandimby, D. Synlett 1992, 967. Mehta, S.; Pinto, B. M. J. Org. Chem. 1993, 58, 3269. (27) Yamago, S.; Kokubo, K.; Masuda, S.; Yoshida, J. Synlett 1996, 929. (28) Gan, L. X.; Whistler, R. L. Carbohydr. Res. 1990, 206, 65. (29) Koto, S.; Morishima, N.; Kihara, Y.; Suzuki, H.; Kosugi, S.; Zen, S. Bull. Chem. Soc. Jpn. 1983, 56, 188. (30) Bourke, D. G.; Collins, D. J.; Hibberd, A. I.; McLeod, M. D. Aust. J. Chem. 1996, 49, 425.

8590 J. Org. Chem., Vol. 67, No. 24, 2002

(dt, J ) 9.6, 6.3 Hz, 1H), 4.15 (ddd, J ) 9.6, 5.1, 3.3 Hz, 1H), 4.51 (dd, J ) 12.3, 5.1 Hz, 1H), 4.65 (dd, J ) 12.3, 3.3 Hz, 1H), 4.84 (d, J ) 7.8 Hz, 1H), 5.58 (dd, J ) 9.6, 7.8 Hz, 1H), 5.70 (dd, J ) 9.6 Hz, 1H), 5.93 (dd, J ) 9.6 Hz, 1H),6.97-8.03 (m, 25H); 13C NMR (75 MHz, CDCl3) 30.83 (CH2), 31.58 (CH2), 63.11 (CH2), 68.95 (CH2), 69.74 (CH), 71.90 (CH), 72.11 (CH), 72.87 (CH), 101.28 (CH), 125.75, 128.25, 128.34, 128.41, 128.45, 128.86, 129.36, 129.64, 129.77, 129.80, 129.83, 129.86, 133.17, 133.29, 133.48, 141.48, 165.21(CdO), 165.31(CdO), 165.97(CdO), 166.27 (CdO); HRMS (FAB) m/z calcd for C43H384O10 (M + H)+ 715.2543, found 715.2543. Data for 13: IR (KBr) 1725, 1266, 1104, 1091, 1071, 1026, 710; 1H NMR (300 MHz, CDCl3) 1.79-1.88 (m, 2H), 2.63 (t, J ) 7.8 Hz, 2H), 3.28-3.42 (m, 2H), 4.11-4.16 (m, 1H), 4.37 (dd, J ) 12.0, 4.8 Hz, 1H), 4.52 (dd, J ) 12.0, 3.0 Hz, 1H), 4.724.75 (ddd, J ) 5.4, 3.0, 1.2 Hz, 1H), 5.50 (dt, J ) 8.7, 1.2 Hz, 1H), 5.77 (dd, J ) 3.3, 1.2 Hz, 1H), 6.02 (d, J ) 5.4 Hz, 1H), 7.10-8.11 (m, 25H); 13C NMR (75 MHz, CDCl3) 30.88 (CH2), 32.18 (CH2), 63.31 (CH2), 63.94 (CH2), 67.43 (CH), 68.48 (CH), 69.18 (CH), 72.16 (CH), 97.53 (CH), 121.41(C), 125.86-141.68 (aromatic), 164.74 (CdO), 165.31 (CdO), 166.12 (CdO); HRMS (FAB) m/z calcd for C43H38O10 (M + H)+ 715.2543, found 715.2543. Data for 1-O-(3-phenylpropyl)-6-O-acetyl-2,3,4-tri-Obenzyl-r-D-glycopyranoside (r-15A): IR (neat) 1744, 1456, 1237, 1090, 1072, 1028, 739, 698; 1H NMR (400 MHz, CDCl3) 1.92-2.05 (m, 2 H), 1.98 (s, 3 H), 2.64-2.77 (m, 2 H), 3.393.51 (m, 2 H), 3.54 (dd, J ) 9.6, 3.6 Hz, 1 H), 3.64 (dt, J ) 9.9, 6.9 Hz, 1 H), 3.84 (ddd, J ) 9.9, 4.5, 2.4 Hz, 1 H), 4.04 (t, J ) 9.3 Hz, 1 H), 4.19 (dd, J ) 12.0, 2.4 Hz, 1 H), 4.26 (dd, J ) 12.0, 4.5 Hz, 1 H), 4.56 (d, J ) 10.8 Hz, 1 H), 4.66 (d, J ) 12.0 Hz, 1 H), 4.72 (d, J ) 3.3 Hz, 1 H), 4.79 (d, J ) 12.0 Hz, 1 H), 4.84 (d, J ) 10.5 Hz, 1 H), 4.89 (d, J ) 10.8 Hz, 1 H), 5.03 (d, J ) 10.8 Hz, 1 H), 7.19-7.36 (m, 20 H); 13C NMR (100 MHz, CDCl3) 20.80, 30.87, 32.33, 63.15, 67.59, 68.75, 73.22, 75.08, 75.74, 77.51, 80.24, 82.03, 96.97, 125.90, 127.66, 127.90, 127.93, 127.97, 127.98, 128.13, 128.38, 128.42, 128.44, 128.45, 128.50, 137.92, 138.27, 138.74, 141.58, 170.71; HRMS (FAB) m/z calcd for C38H42O7 (M + H)+ 611.3009, found 611.3007. Data for 1-O-(3-phenylpropyl)-6-O-acetyl-2,3,4-tri-Obenzyl-β-D-glycopyranoside (β-15A): IR (neat) 1744, 1455, 1366, 1237, 1154, 1092, 1070, 1030, 749, 698; 1H NMR (300 MHz, CDCl3) 1.92-2.05 (m, 2 H), 2.02 (s, 3 H), 2.73 (dt, J ) 7.5, 3.3 Hz, 2 H), 3.42-3.60 (m, 4 H), 3.68 (t, J ) 8.7 Hz, 1 H), 3.95 (dt, J ) 9.6, 6.3 Hz, 1 H), 4.23 (dd, J ) 11.7, 4.5 Hz, 1 H), 4.32 (dd, J ) 12.0, 2.1 Hz, 1 H), 4.40 (d, J ) 8.1 Hz, 1 H), 4.56 (d, J ) 10.8 Hz, 1 H), 4.76 (d, J ) 11.1 Hz, 1 H), 4.80 (d, J ) 11.1 Hz, 1 H), 4.86 (d, J ) 10.8 Hz, 1 H), 4.96 (d, J ) 7.5 Hz, 1 H), 4.99 (d, J ) 7.8 Hz, 1 H), 7.16-7.34 (m, 20 H); 13C NMR (75 MHz, CDCl3) 20.87, 31.34, 32.26, 63.15, 69.35, 72.75, 74.87, 75.01, 75.73, 77.38, 82.15, 84.64, 103.65, 125.84, 127.68, 127.71, 127.86, 127.97, 128.08, 128.11, 128.34, 128.40, 128.43, 128.49, 137.67, 138.28, 138.34, 141.64, 170.80; HRMS (FAB) m/z calcd for C38H42O7 (M + H)+ 611.3009, found 611.3003. Data for 1-O-(cyclohexyl)-6-O-acetyl-2,3,4-tri-O-benzylr-D-glycopyranoside (r-15B): IR (neat) 1744, 1454, 1237, 1072, 1028; 1H NMR (300 MHz, CDCl3) 1.17-1.94 (m, 10H), 2.02 (s, 3 H), 3.44-3.55 (m, 3 H), 3.95 (ddd, J ) 10.2, 3.9, 2.7 Hz, 1 H), 4.03 (t, J ) 9.3 Hz, 1 H), 4.23 (dd, J ) 12.0, 2.7 Hz, 1 H), 4.28 (dd, J ) 12.0, 3.9 Hz, 1 H), 4.56 (d, J ) 10.8 Hz, 1 H), 4.65 (d, J ) 11.7 Hz, 1 H), 4.74 (d, J ) 11.7 Hz, 1 H), 4.82 (d, J ) 10.8 Hz, 1 H), 4.88 (d, J ) 10.8 Hz, 1 H), 4.92 (d, J ) 3.6 Hz, 1 H), 5.02 (d, J ) 10.8 Hz, 1 H), 7.26-7.36 (m, 15 H); 13C NMR (75 MHz, CDCl ) 21.08, 24.40, 24.70, 25.78, 31.69, 3 33.51, 63.38, 68.78, 73.20, 75.34, 75.96 (2C), 77.69, 80.17, 82.25, 94.90, 127.89, 128.13, 128.22, 128.33, 128.45, 128.68, 128.74, 138.06, 138.38, 138.97, 171.02; HRMS (FAB) m/z calcd for C35H42O7 (M + H)+ 575.3009, found 575.3001. Data for 1-O-(cyclohexyl)-6-O-acetyl-2,3,4-tri-O-benzylβ-D-glycopyranoside (β-15B): IR (neat) 1742, 1231, 1117, 1084, 1067, 1030; 1H NMR (300 MHz, CDCl3) 1.23-1.94 (m, 10 H), 2.03 (s, 3 H), 3.44 (dd, J ) 9.0, 7.8 Hz, 1 H), 3.49-3.55

Electrochemistry of Chalcogenoglycosides (m, 2 H), 3.62-3.72 (m, 2 H), 4.22 (dd, J ) 12.0, 4.8 Hz, 1 H), 4.31 (dd, J ) 11.7, 2.1 Hz, 1 H), 4.50 (d, J ) 8.1 Hz, 1 H), 4.55 (d, J ) 11.1 Hz, 1 H), 4.71 (d, J ) 11.1 Hz, 1 H), 4.78 (d, J ) 11.1 Hz, 1 H), 4.85 (d, J ) 10.8 Hz, 1 H), 4.95 (d, J ) 11.1 Hz, 1 H), 4.99 (d, J ) 10.8 Hz, 1 H), 7.28-7.34 (m, 15 H); 13C NMR (75 MHz, CDCl3) 20.88, 23.98, 24.06, 25.54, 32.01, 33.65, 63.26, 72.63, 74.84, 75.00, 75.69, 77.50, 78.20, 82.13, 84.77, 101.99, 127.64, 127.68, 127.88, 127.95, 128.14, 128.20, 128.38, 128.47, 137.73, 138.37, 138.48, 170.82; HRMS (FAB) m/z calcd for C35H42O7 (M + H)+ 575.3009, found 575.3008. Data for methyl 6-O-(6-O-acetyl-2,3,4-tri-O-benzyl-rD-glucopyranosyl)-2,3,4-tri-O-benzoyl-r-D-glucopyranoside (r-16C): IR (KBr) 1734, 1280, 1262, 1108, 1095, 1070, 1028, 710; 1H NMR (300 MHz, CDCl3) 1.98 (s, 3 H), 3.43 (t, J ) 9.0 Hz, 1 H), 3.46 (s, 3 H), 3.51 (dd, J ) 9.6, 3.3 Hz, 1 H), 3.57 (dd, J ) 11.0, 2.0 Hz, 1 H), 3.83 (dd, J ) 10.8, 6.6 Hz, 1 H), 3.93 (dt, J ) 10.2, 3.5 Hz, 1 H), 4.01 (t, J ) 12.2 Hz, 1 H), 4.13 (br d, J ) 12.6 Hz, 1 H), 4.14 (br d, J ) 12.6 Hz, 1 H), 4.32 (ddd, J ) 10.2, 3.9, 1.8 Hz, 1 H, 4.55 (d, J ) 10.8 Hz, 1 H), 4.63 (d, J ) 12.0 Hz, 1 H), 4.70 (d, J ) 3.6 Hz, 1 H), 4.77 (d, J ) 12.0 Hz, 1 H), 4.79 (d, J ) 10.8 Hz, 1 H), 4.87 (d, J ) 10.8 Hz, 1 H), 4.96 (d, J ) 10.8 Hz, 1 H), 5.20-5.26 (m, 2 H), 5.49 (t, J ) 9.9 Hz, 1 H), 6.11-6.20 (m, 1 H), 7.16-7.56 (m, 24 H), 7.84-7.90 (m, 2 H), 7.92-8.02 (m, 4 H); 13C NMR (75 Hz, CDCl3) 20.79, 55.59, 62.97, 66.68, 68.53, 68.71, 69.48, 70.50, 72.16, 73.08, 74.75, 75.60, 77.18, 79.99, 81.62, 96.75, 97.00, 127.62, 127.74, 127.83, 127.91, 128.02, 128.24, 128.38, 128.91, 129.05, 129.20, 129.66, 129.88, 129.91, 133.06, 133.33, 133.41, 138.05, 138.22, 138.61, 165.22, 165.79, 170.67; HRMS (FAB) m/z calcd for C57H56O15 (M + H)+ 981.3697, found 981.3697. Data for methyl 6-O-(6-O-acetyl-2,3,4-tri-O-benzyl-β-Dglucopyranosyl)-2,3,4-tri-O-benzoyl-r-D-glucopyranoside (β-16C): IR (neat) 1732, 1280, 1263, 1108, 1094, 1069, 1028, 710; 1H NMR (400 MHz, CDCl3) 1.92 (s, 3 H), 3.39 (s, 3 H), 3.42-3.52 (m, 3 H), 3.62-3.70 (m, 1 H), 3.82 (dd, J ) 11.1, 7.5 Hz, 1 H), 4.07 (dd, J ) 11.2, 1.8 Hz, 1 H), 4.13-4.20 (m, 1 H), 4.24 (dd, J ) 11.0, 1.5 Hz, 1 H), 4.38 (ddd, J ) 9.9, 7.5, 2.2 Hz, 1 H), 4.47 (d, J ) 7.5 Hz, 1 H), 4.53 (d, J ) 11,1 Hz, 1H), 4.69 (d, J ) 10.8 Hz, 1 H), 4.77 (d, J ) 11.1 Hz, 1 H), 4.85 (d, J ) 11.1 Hz, 1 H), 4.95 (d, J ) 10.8 Hz, 1 H), 5.07 (d, J ) 11.1 Hz, 1 H), 5.21 (d, J ) 3.6 Hz, 1 H), 5.25 (dd, J ) 10.2, 3.6 Hz, 1 H), 5.46 (t, J ) 9.9 Hz, 1 H), 6.16 (t, J ) 9.8 Hz, 1 H), 7.207.56 (m, 24 H), 7.82-7.87 (m, 2 H), 7.92-8.00 (m, 4 H); 13C NMR (75 Hz, CDCl3) 20.68, 55.59, 63.28, 69.00, 69.14, 69.96, 70.48, 72.12, 72.87, 74.84, 75.00, 75.71, 77.54, 82.26, 84.56, 96.90, 104.08, 127.67, 127.74, 127.88, 127.97, 128.09, 128.22, 128.27, 128.40, 128.42, 128.43, 128.46, 128.50, 128.93, 129.12, 129.29, 129.67, 129.88, 129.94, 133.07, 133.35, 133.49, 137.75, 138.39, 138.48, 165.51, 165.77, 165.85, 170.71; HRMS (FAB) m/z calcd for C57H56O15 (M + H)+ 981.3697, found 981.3702. General Procedure for the Electrochemical Glycosylation in an Undivided Cell. Synthesis of Methyl 6-O(2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl)-2,3,4-tri-Obenzoyl-r-D-glucopyranoside (16D). A cylindrical reaction vessel was fitted with a cylindrical platinum cathode (6 cm2), a carbon felt anode (10 mm × 5 mm × 3 mm), and a platinum wire reference electrode, which was connected with a standard calomel electrode. The cathode and the anode were in close proximity but were separated by a Teflon fiber. To the undivided cell containing activated molecular sieves 3A (200 mg) were added 8b (570.9 mg, 0.72 mmol), 2,3,4-tri-O-benzoyl1-methyl-O-R-D-glucopyranoside (14; 242.8 mg, 0.48 mmol), 2,6-dimethylphenol (291.6 mg, 2.4 mmol), and a 0.2 M LiClO4 solution of MeCN (5 mL) under an argon atmosphere. The resulting mixture was electrolyzed at a constant potential of 1.1 V (vs SCE) with gentle stirring. After 7.0 F/mol of electricity was applied, 8b disappeared on TLC. TMSOTf (11.5 mg, 0.05 mmol) was added, and the resulting mixture was stirred for 30 min. The reaction mixture was filtered through a short cotton plug, and the resulting solution was partitioned between water and ethyl acetate. The usual workup, followed

by purification of the crude mixture by flash column chromatography (elution with 17% ethyl acetate in hexane), afforded the β-anomer of the desired disaccharide (467.4 mg, 90%): IR (KBr) 1728, 1266, 708; 1H NMR (300 MHz, CDCl3) 3.10 (s, 3H), 3.79 (dd, J ) 7.8, 11.4 Hz, 1H), 4.08-4.25 (m, 3H), 4.45 (dd, J ) 5.1, 12.0 Hz, 1H), 4.61 (dd, J ) 3.0,12.3 Hz, 1H), 4.94 (d, J ) 3.6 Hz, 1H), 4.98 (d, J ) 7.8 Hz, 1H), 5.09 (dd, J ) 3.6, 10.2 Hz, 1H), 5.32 (t, J ) 10.2 Hz, 1H), 5.57 (dd, J ) 8.1, 9.9 Hz, 1H), 5.66 (t, J ) 9.9 Hz, 1H), 5.92 (t, J ) 9.6 Hz, 1H), 6.07 (t, J ) 9.9 Hz, 1H), 7.26-7.49 (m, 20H), 7.77-8.01 (m, 15H); 13C NMR (75 MHz, CDCl3) 54.97 (CH3), 62.96 (CH2), 68.71 (CH), 68.89 (CH2), 69.64 (CH, 2C), 70.29 (CH), 71.82 (CH), 71.96 (CH), 72.25 (CH), 72.79 (CH), 96.45 (CH), 101.78 (CH), 128.28, 128.36, 128.39, 128.47, 128.86, 129.12, 129.29, 129.42, 129.64, 129.70, 129.82, 129.92, 133.10 (C), 133.19 (C), 133.29 (C, 2C), 133.39 (C), 133.51 (C, 2C), 165.30 (CdO, 2C), 165.57 (CdO), 165.78 (CdO), 165.84 (CdO), 165.94 (CdO), 166.24 (CdO); FABMS (matrix NBA) m/z 1085 (M + H)+. Anal. Calcd for C62H52O18: C, 68.63; H, 4.83. Found: C, 68.35; H, 4.67. 1-p-Methylphenylthio-6-O-(2,3,4,6-tetra-O-benzoyl-β-Dglucopyranosyl)-2,3,4-tri-O-benzyl-β- D -glucopyranoside (19). To an undivided cell containing activated molecular sieves 3A (200 mg) were added 8b (223.5 mg, 0.40 mmol), 1-pmethylphenylthio-2,3,4-tri-O-benzoyl-β-D-glucopyranoside (9b; 478.9 mg, 0.60 mmol), 2,6-dimethylphenol (246.6 mg, 2.0 mmol), and a 0.2 M LiClO4 solution of MeCN (4.0 mL) under an argon atmosphere. The resulting mixture was electrolyzed at a constant potential of 1.1 V (vs SCE) with gentle stirring until 8b dissappeared by TLC analysis. Electricity (7.0 F/mol) was applied, the reaction mixture was filtered through a short cotton plug, and the resulting solution was partitioned between water and ethyl acetate. The usual workup, followed by purification of the crude mixture by flash column chromatography (elution with 17% ethyl acetate in hexane), afforded the title compound in 72% yield (327.0 mg) The analytical sample was crystallized from hexane-ethyl acetate: mp 174-178 °C; IR (KBr) 3030, 1742, 1734, 1713, 1283 (br), 1121 (br), 1090, 1049, 708; 1H NMR (300 MHz, CDCl3) 2.34 (s, 3H), 3.33-3.47 (m, 3H), 3.58 (dd, J ) 8.7, 8.1 Hz, 1H), 3.85 (dd, J ) 11.4, 4.2 Hz, 1H), 4.02-4.08 (m, 1H), 4.13 (d, J ) 11.1 Hz, 1H), 4.404.87 (m, 9H), 4.94 (d, J ) 7.8 Hz, 1H), 5. 57 (dd, J ) 9.6, 7.8 Hz, 1H), 5.68 (t, J ) 9.6 Hz, 1H), 5.85 (t, J ) 9.6 Hz, 1H), 7.09-7.12 (m, 2H), 7.17-7.51 (m, 29H), 7.83-7.93 (m, 6H), 8.00-8.03 (m, 2H); 13C NMR (75 MHz, CDCl3) 21.03 (CH3), 63.08 (CH2), 67.92 (CH2), 69.74 (CH), 71.90 (CH), 72.16 (CH), 73.02 (CH), 74.81 (CH2), 75.28 (CH2), 75.56 (CH2), 77.46 (CH), 78.79 (CH), 80.54 (CH), 86.55 (CH), 87.61 (CH), 101.00 (CH), 127.68 (CH), 127.75 (CH), 127.83 (CH), 127.87 (CH), 128.27 (CH), 128.42 (CH), 128.45 (CH), 128.95 (C), 129.32 (C), 129.68 (C), 129.82 (CH), 129.86 (CH), 129.92 (CH), 132.88 (CH), 133.13 (CH), 133.26 (CH), 133.46 (CH), 137.96 (C), 138.06 (C), 138.18 (C), 138.47 (C), 165.12 (CdO), 165.33 (CdO), 165.92 (CdO), 166.24 (CdO); FABMS (matrix NBA) m/z 1136 (M + H)+, 1135 (M+). Anal. Calcd for C68H62O14S: C, 71.94; H, 5.50. Found: C, 71.64; H, 5.38. 1-p-Methylphenylseleno-6-O-(2,3,4,6-tetra-O-benzoylβ-D-glucopyranosyl)-2,3,4-tri-O-benzyl-β-D-glucopyranoside (20). To an undivided cell containing activated molecular sieves 3A (200 mg) were added 8b (479.9 mg, 0.60 mmol), 1-pmethylphenylseleno-2,3,4-tri-O-benzyl-β-D-glucopyranoside (10b; 241.3 mg, 0.40 mmol), 2,6-dimethylphenol (246.6 mg, 2.0 mmol), and a 0.2 M LiClO4 solution of MeCN (4.0 mL) under an argon atmosphere. The resulting mixture was electrolyzed at a constant potential of 1.1 V (vs SCE) with gentle stirring until 8b disappeared by TLC analysis. Electricity (7.0 F/mol) was applied, the reaction mixture was filtered through a short cotton plug, and the resulting solution was partitioned between water and ethyl acetate. The usual workup, followed by purification of the crude mixture by flash column chromatography (elution with 17% ethyl acetate in hexane), afforded the title compound in 14% yield (66.9 mg), together with 20% of the 1,6-anhydro-2,3,4-tri-O-benzyl-D-glucopyranoside (21) (34.5

J. Org. Chem, Vol. 67, No. 24, 2002 8591

Yamago et al. mg). An analytically pure sample of 20 was obtained by crystallization from hexane/ethyl acetate. Data for 20: IR (KBr) 1725, 1601, 1491, 1451, 1277 (br), 1069, 1026, 710; 1H NMR (400 MHz, CDCl3) 2.04 (s, 3H), 2.34 (s, 3H), 3.36-3.43 (m, 3H), 3.54 (dd, J ) 8.8 Hz, 1H), 3.84 (dd, J ) 11.2, 4.3 Hz, 1H), 4.06 (ddd, J ) 9.7, 5.0, 3.3 Hz, 1H), 4.11-4.15 (m, 1H), 4.40 (d, J ) 11.0 Hz), 4.49 (dd, J ) 12.1, 5.0 Hz, 1H), 4.57 (d, J ) 11.0 Hz, 1H), 4.61-4.66 (m, 2H), 4.70 (d, J ) 9.7 Hz, 1H), 4.71 (d, J ) 11.0 Hz, 1H), 4.79 (d, J ) 9.5 Hz, 1H), 4.82 (d, J ) 10.1 Hz, 1H), 4.94 (d, J ) 7.9 Hz, 1H), 5.57 (dd, J ) 9.7, 7.9 Hz, 1H), 5.68 (dd, J ) 9.7 Hz, 1H), 5.86 (dd, J ) 9.7 Hz, 1H), 7.07-8.03 (m, 34H); 13C NMR (100 MHz, CDCl3) 14.20 (CH3), 21.20 (CH3), 63.15 (CH2), 67.98 (CH2), 69.80 (CH2), 71.93 (CH), 72.20 (CH), 73.06 (CH), 74.85 (CH2), 75.12 (CH2), 75.58 (CH2), 77.50 (CH), 79.76 (CH), 81.10 (CH), 82.70 (CH), 86.64 (CH), 101.05 (CH), 124.44, 127.51, 127.57, 127.64, 127.70, 127.75, 127.82, 127.91, 127.94, 128.12, 128.14, 128.24, 128.30, 128.35, 128.38, 128.39, 128.48, 128.81, 128.88, 128.89, 129.25, 129.62, 129.73, 129.77, 129.80, 129.83, 129.99, 133.06, 133.11, 133.20, 133.40, 135.01, 137.89, 138.06, 138.10, 138.34, 164.99 (CdO), 165.21 (CdO), 165.81 (CdO), 166.13 (CdO); HRMS (FAB) m/z calcd for C68H59O16Se (M + H)+ 1211.2968, found 1211.2959. Anal. Calcd for C68H62O14Se: C, 69.29; H, 5.29. Found: C, 68.72; H, 5.33.

8592 J. Org. Chem., Vol. 67, No. 24, 2002

Data for 21: IR (KBr) 2895, 1497, 1454, 1102 (br), 1075 (br), 737, 698; 1H NMR (300 MHz, C6D6) 3.16 (d, J ) 3.9 Hz, 1H), 3.34 (dd, J ) 6.9, 6.0 Hz, 1H), 3.41 (d, J ) 3.3 Hz, 1H), 3.48 (d, J ) 6.6 Hz, 1H), 3.79 (m, 1H), 4.24-4.36 (m, 5H), 4.41 (d, J ) 11.7 Hz, 1H), 4.80 (d, J ) 12.0 Hz, 1H), 5.60 (s, 1H), 7.01-7.25 (m, 15H); 13C NMR (75 MHz, C6D6) 66.21 (CH2), 71.08 (CH2), 71.52 (CH2), 72.65 (CH2), 74.91 (CH), 78.89 (CH), 79.52 (CH), 79.89 (CH), 101.36 (CH), 127.76 (CH), 127.82 (CH), 127.89 (CH), 128.52 (CH), 128.58 (CH), 138.70 (C), 138.87 (C), 139.05 (C); FABMS (matrix NBA) m/z 433 (M + 1)+.

Acknowledgment. This work was partly supported by the Nissan Foundation and a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science. The experimental assistance of Tomokazu Maruyama is gratefully acknowledged. Supporting Information Available: Preparation and characterization of chalcogenoglycosides. This material is available free of charge via the Internet at http://pubs.acs.org. JO0261350