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Exploring the glycosylation properties of a sialyl thioimidate donor
Tetrahedron Letters 56 (2015) 5168–5171
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Exploring the glycosylation properties of a sialyl thioimidate donor Jun Rao a, Xiangming Zhu a,b,c,⇑ a
College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China c Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland b
a r t i c l e
i n f o
Article history: Received 28 April 2015 Revised 19 June 2015 Accepted 21 July 2015 Available online 26 July 2015
a b s t r a c t A new sialyl thioimidate donor 6 was prepared in high yields from the known sialyl hemiketal 1 over five steps. Under the action of catalytic TMSOTf, 6 exhibited excellent reactivity using a series of primary alcohols to give the desired sialylation products in high to excellent yields. Chemoselective activation of 6 in the presence of thioglycosides was also demonstrated. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Sialyl donor Thioimidate Catalytic activation Glycosylation
Sialic acids comprise a specific class of acidic monosaccharides, and include N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid and a-keto-deoxy-D-glycero-D-galactononulosonic acid.1 Among these, Neu5Ac is the most common, and is present in a variety of glycosidic linkages, most typically a-(2,6) and a(2,3), to galactose or in an a-(2,6) linkage to a galactosamine residue.2 These sialylated carbohydrates are intimately involved in a wide range of biological processes such as cell recognition and communication, bacterial and viral infection, and tumour metastasis.3 In view of their biological importance, tremendous efforts have been devoted to develop sialylation procedures,4 and substantial progress has been achieved in this field.5 However, a general sialylation procedure has not yet appeared, and more often than not, careful optimization of the glycosidation conditions is needed in order to achieve high yields and stereoselectivity for sialylation. Chemical sialylation remains a challenge in carbohydrate chemistry and is inherently problematic due to the unique structure of sialic acids. The electron-withdrawing carboxyl group at the anomeric centre and the lack of a participating functional group at the C-3 position of sialyl donors typically cause the sialylation reaction to proceed in low to moderate yields, with low a-selectivity and with the formation of unwanted 2,3-elimination products. Therefore, new sialylation methods and strategies are still welcome in carbohydrate chemistry. Recently, our laboratory introduced a new class of glycosyl thioimidates, glycosyl N-phenyl-trifluorothioacetimidates,6 as ⇑ Corresponding author. Tel.: +353 17162386; fax: +353 17162501. E-mail address: [email protected] (X. Zhu). http://dx.doi.org/10.1016/j.tetlet.2015.07.064 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
glycosylating agents. These thioimidates could be easily prepared from readily available glycosyl thiols in excellent yields and were effectively activated by catalytic amounts of a Lewis acid. We became curious whether similar sialyl thioimidates could also be used as new sialylating agents.7 Hence, investigations towards the synthesis and glycosylation properties of sialyl N-phenyl-trifluorothioacetimidate 6 (Scheme 1) was initiated. We now wish to report that 6 can serve as a sialylating agent for primary alcohols, proceeding in high to excellent yields with fairly good aselectivity. Our studies commenced with the preparation of sialyl chloride 3. It has been shown that in sialylation, protection of the C5 amino group is crucial to the success of the glycosidation reaction.4b We OAc
AcO Neu5Ac
Ref. 11
CO2Me
AcO TrocHN
O AcO
OAc CO2Me
AcO TrocHN
O AcO
6
AcCl, AcOH rt, 24 h
Cl
AcO TrocHN
O AcO
Ac2O, Py rt, 92%
1R=H 2 R = Ac
AcO
OR
OAc
AcO HCl (g)
S
CF3 NPh
CO2Me
3 KSAc, DMF rt, 12 h 79% (2 steps)
CF3C(=NPh)Cl K2CO3 acetone, H2O rt, 3 h 74%
OAc
AcO
CO2Me
AcO TrocHN
O
SR
AcO
4 R = Ac 5R=H
Scheme 1. Synthesis of sialyl thioimidate 6.
NaOMe, MeOH -40 oC, 30 min 83%
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J. Rao, X. Zhu / Tetrahedron Letters 56 (2015) 5168–5171
protected sialyl hemiketal 111 was prepared from N-acetylneuraminic acid following literature procedures then converted into sialyl acetate 2 in excellent yields by standard acetylation conditions. Subsequently, 2 was subjected to anomeric chlorination using anhydrous HCl in AcCl/AcOH to give sialyl chloride 3. Without purification, 3 was treated with potassium thioacetate in DMF to produce sialyl thioacetate 4 in 79% yield over two steps. The anomeric acetyl group of 4 was subsequently removed using
selected 2,2,2-trichloroethoxycarbonyl (Troc) group on the basis of its high stability under various reaction conditions, and more importantly, the reported high reactivity of N-Troc-protected sialyl donors8 which often exhibit higher reactivity than the corresponding N-Ac- and N-TFA-protected compounds, and have thus frequently been employed to synthesize different sialyl oligosaccharides, such as sialyl Lewis X9 and the pentasaccharide moiety of the neuritogenic ganglioside GAA-7.10 The known N-Troc-
Table 1 Sialylation of acceptors 7–14 with thioimidate 6a AcO
OAc
TrocHN
Entry
1
Acceptor
BnO BnO
AcO
CO2Me
AcO
O AcO
6
S
CF3
0.3 equiv TMSOTf
+
ROH
CH2Cl2/CH3CN 6:1 TrocHN AcO - 65 oC, 3 h
NPh
AcO
BnO OMe 7
TrocHN
AcO AcO
OH O
AcO
TrocHN
AcO
3
BzO BzO
AcO
TrocHN
AcO
O
10
OO
TrocHN
AcO
HO BnO
5
AcO OMP
OBn
AcO
6
OH O
AcO SPh
OBz 12
AcO
OH O STol
BzO
7
AcO
OBz
AcO
8
a b c
BnO BnO
OH O
AcO
BnO O OBn 14
S
TrocHN
O BzO BzO
O
3:1
94
5:1
92
5:1
90
2:1
87
a only
95
3:1
BzO OMe
O O O
O OO
O HO BnO
O
OMP
OBn
O BzO BzO
O SPh OBz
CO2Me O AcO
O BzO BzO
O
STol
OBz
OAc CO2Me
AcO BnO
96
AcO OMe
OAc
21
BnO BnO
3:1
CO2Me O
AcO TrocHN
13
O
OAc
20 BzO
O AcO AcO
CO2Me O
AcO TrocHN
91
BnO OMe
OAc
19
BzO BzO
5:1
CO2Me O
AcO TrocHN
11
86
OAc
18 OH O
O
CO2Me O
AcO
O
4
AcO
O BnO BnO
OAc
17 OH O
a/bc ratio
CO2Me O
AcO BzO OMe 9
Yieldb (%)
OAc
16 OH O
OR
CO2Me O
AcO AcO OMe 8
CO2Me O
OAc
AcO
15
2
AcO
Product OH O
OAc
O
O BnO BnO
AcO
22
BnO BnO
O BnO S BnO O OBn
Reaction conditions: 6 (1.2 equiv), acceptor 7–14 (1.0 equiv), TMSOTf (0.3 equiv), CH2Cl2/CH3CN 6:1, 65 °C under a N2 atmosphere. Isolated yield. Determined by integration of the proton signals in the 1H NMR spectrum after chromatographic purification.
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NaOMe in MeOH at low temperatures to give sialyl thiol 5 in 83% yield. Finally, 5 was treated with N-phenyl trifluoroacetimidoyl chloride12 and K2CO3 in the presence of water in acetone to give the desired sialyl N-phenyl-trifluorothioacetimidate 6 in 74% yield. With thioimidate 6 in hand, its glycosylation properties were investigated. 2,3,4-O-Benzylated glucoside 713 was initially examined as a glycosyl acceptor by treatment with 6 in the presence of catalytic amounts of TMSOTf (0.3 equiv) at 0 °C in CH2Cl2. Unfortunately, the desired disaccharide was produced in low yields (<10%) with significant amounts of the elimination by-product being isolated from the reaction. To avoid this elimination, the reaction was repeated at a lower temperature ( 40 °C). To our delight, the elimination reaction was dramatically reduced at this temperature and the sialylated disaccharide 1514 was generated in a much higher yield (52%) with only b selectivity. The reaction temperature was further lowered to 65 °C with the hope of further improving the glycosidation reaction. Unsurprisingly, the b-isomer of disaccharide 15 was isolated in a very high yield (91%), though trace amounts of the elimination product was also detected by TLC. Optimization of the solvent system was also carried out in order to obtain a-sialosides. In the literature, solvent effect, primarily the acetonitrile effect has frequently been applied to various sialylation reactions to boost a-selectivity.15 The above reaction was thus run in varying ratios of CH2Cl2 and CH3CN to give very good a-selectivity when the reaction was run in a 6:1 mixture of CH2Cl2 and CH3CN (Table 1, entry 1). The anomeric stereochemistry of 15 and all the following sialylation compounds were assigned on the basis of the empirical rules of chemical shifts.15c The a-sialosides had dH-3eq values varying from 2.6 to 2.8 ppm, whereas the analogous b-sialosides had dH-3eq values below 2.6 ppm. In some cases, the 3JC-1,H-3ax coupling constants were also used to confirm the a-configuration (a-anomer, 3JC-1,H-3ax = 5–6 Hz; b-anomer, 3JC-1,H-3ax < 1 Hz), which was consistent with the data reported in the literature.5b Next, the capability of thioimidate 6 as a sialyl donor was examined using a range of glycosyl acceptors under the optimized conditions (0.3 equiv TMSOTf, 65 °C, CH2Cl2/CH3CN 6:1). As shown in Table 1, the yields of all investigated acceptors were high. Additionally the catalytic properties of the examined reactions make this approach an attractive method to synthesize sialosides. Sialylation of glucosyl acceptor 816 or partially benzoylated acceptor 913 with thioimidate 6 gave rise to disaccharide 16 and 17 in excellent yield and modest a-selectivity (Table 1, entries 2 and 3). Considering that naturally occurring sialosides commonly incorporate an a-(2,6) linkage to galactose,2 commercially available galactosyl acceptor 10 was treated with donor 6 to give disaccharide 18 in excellent yield and very good a-selectivity (Table 1, entry 4). These results demonstrated that thioimidate 6 has a high reactivity towards primary alcohols and can be used as an effective sialylating agent. The high reactivity of thioimidate 6 was further confirmed by the reaction of galactosyl acceptor 1117 with 6 to give disaccharide 1917 in 92% yield and a/b 5:1 selectivity. It should be noted that the glycosylation reaction occurred only at the 6-OH position, and 4-Osialylation was not observed. The sialylation of a series of secondary OH groups with 6 was also attempted but no success was achieved even under more forcing conditions.18 The different behaviour observed for thioimidate 6 towards primary and secondary OH groups, and the underlying causes remain to be investigated. However, the current results clearly indicate that thioimidate 6 can serve as a sialylating agent for primary alcohols. To further explore the glycosylation properties of 6, we proceeded to examine thioglycosides 1219 and 1320 as acceptors. Reaction of 12 with donor 6 was conducted under the optimized conditions, and expectedly, the desired sialoside 20 was isolated in very high yield and moderate a/b 2:1 selectivity. Sialylation of
13 with donor 6 proceeded very cleanly as indicated by TLC to produce disaccharide 21 in 87% yield and perfect a-selectivity (Table 1, entry 7). This showed that thioglycosides would not be activated under the present conditions and chemoselective activation of thioimidate 6 in the presence of thioglycosides could thus be easily achieved. Finally, under the same conditions, thiotrehalose acceptor 14 was glycosylated with donor 6 to give the desired product 22 in excellent yield and modest a-selectivity (Table 1, entry 8). It should be mentioned that, like most glycosylation procedures, leaving group, catalyst, solvent and reaction temperature can all have significant effects on the reaction outcome.21 In other words, not only the new leaving group, but the N-Troc protecting group, acetonitrile and reaction temperature synergistically led to the above sialylation results, including the reaction yields and a-stereoselectivity, which are comparable to previously reported sialylation methods.8–10,14 In view of the limited number of catalytic glycosylation methods and sialyl donors in the literature,4 the present sialylation procedure may find valuable and versatile use in sialylation chemistry. In conclusion, as a continuation of our previous work,6 the glycosylation properties of sialyl thioimidate donor 6 have been investigated using a range of different glycosyl acceptors. The results indicate that 6 could serve as a sialylating agent for primary alcohols in a selective manner, proceeding in favour of the formation of a-sialosides with varying levels of selectivity. Moreover, all glycosylation products were isolated in very high to excellent yields. Extended studies on the scope of the glycosidation of 6 and applications of this sialylation procedure are currently underway. Acknowledgments This work was supported by the Science & Technology Department of Zhejiang Province (2013C24004) and the University College Dublin. Supplementary data Supplementary data (experimental procedures, characterization data, as well as copies of the 1H and 13C NMR of novel compounds) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.064. References and notes 1. Varki, A. Nature 2007, 446, 1023–1029. 2. Schauer, R. Sialic Acids: Chemistry, Metabolism and Function, Springer, New York 1982; p 10. 3. Amon, R.; Reuven, E. M.; Ben-Arye, S. L.; Padler-Karavani, V. Carbohydr. Res. 2014, 389, 115–122. 4. Reviewed in: (a) Hanashima, S. Trends Glycosci. Glycotechnol. 2011, 23, 111–121; (b) De Meo, C.; Priyadarshani, U. Carbohydr. Res. 2008, 343, 1540– 1552; (c) Ress, D. K.; Linhardt, R. J. Curr. Org. Synth. 2004, 1, 31–46. 5. For some recent examples (a) Harris, B. N.; Patel, P. P.; Gobble, C. P.; Stark, M. J.; De Meo, C. Eur. J. Org. Chem. 2011, 4023–4027; (b) Wang, Y.; Xu, F.-F.; Ye, X.-S. Tetrahedron Lett. 2012, 53, 3658–3662; (c) Premathilake, H. D.; Gobble, C. P.; Pornsuriyasak, P.; Hardimon, T.; Demchenko, A. V.; De Meo, C. Org. Lett. 2012, 14, 1126–1129; (d) Kancharla, P. K.; Navuluri, C.; Crich, D. Angew. Chem., Int. Ed. 2012, 51, 11105–11109; (e) Navuluri, C.; Crich, D. Angew. Chem., Int. Ed. 2013, 52, 11339–11342; (f) Zhang, X.-T.; Gu, Z.-Y.; Xing, G.-W. Carbohydr. Res. 2014, 388, 1–7; (g) Pokorny, B.; Kosma, P. Org. Lett. 2015, 17, 110–113. 6. Lucas-Lopez, C.; Murphy, N.; Zhu, X. Eur. J. Org. Chem. 2008, 4401–4404. 7. (a) De Meo, C.; Parker, O. Tetrahedron: Asymmetry 2005, 16, 303–307; (b) Ikeda, K.; Aizawa, M.; Sato, K.; Sato, M. Bioorg. Med. Chem. Lett. 2006, 16, 2618–2620. 8. Ando, H.; Koike, Y.; Ishida, H.; Kiso, M. Tetrahedron Lett. 2003, 44, 6883–6886. 9. Hanashima, S.; Castagner, B.; Esposito, D.; Nokami, T.; Seeberger, P. H. Org. Lett. 2007, 9, 1777–1779. 10. Tamai, H.; Ando, H.; Ishida, H.; Kiso, M. Org. Lett. 2012, 14, 6342–6345. 11. Akcay, G.; Ramphal, J. Y.; d’Alarcao, M.; Kumar, K. Tetrahedron Lett. 2015, 56, 109–114. 12. Kenji, T.; Hiromochi, M.; Kazuhiro, M.; Hisayuki, W.; Kenji, U. J. Org. Chem. 1993, 58, 32–35.
J. Rao, X. Zhu / Tetrahedron Letters 56 (2015) 5168–5171 13. Yan, M. C.; Chen, Y. N.; Wu, H. T.; Lin, C. C.; Chen, C. T.; Lin, C. C. J. Org. Chem. 2007, 72, 299–302. 14. Tanaka, H.; Adachi, M.; Takahashi, T. Chem. Eur. J. 2005, 11, 849–862. 15. (a) Hasegawa, A.; Nagahama, T.; Ohki, H.; Hotta, K.; Ishida, H.; Kiso, M. J. Carbohydr. Chem. 1991, 10, 493–498; (b) Castro-Palomino, J. C.; Tsvetkov, Y. E.; Schneider, R.; Schmidt, R. R. Tetrahedron Lett. 1997, 38, 6837–6840; (c) De Meo, C.; Demchenko, A. V.; Boons, G.-J. J. Org. Chem. 2001, 66, 5490–5497. 16. Kumar, G. D. K.; Baskaran, S. J. Org. Chem. 2005, 70, 4520–4523. 17. Nohara, T.; Imamura, A.; Yamaguchi, M.; Hidari, K. I. P. J.; Suzuki, T.; Komori, T.; Ando, H.; Ishida, H.; Kiso, M. Molecules 2012, 17, 9590–9620.
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18. Glycosylation of secondary alcohols did not proceed under the optimized conditions; while 2,3-elimination of donor 5 predominated under harsher conditions. 19. Balmond, E. I.; Coe, D. M.; Galan, M. C.; McGarrigle, E. M. Angew. Chem., Int. Ed. 2012, 51, 9152–9155. 20. Sun, B.; Jiang, H. Tetrahedron Lett. 2012, 53, 5711–6840. 21. Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900–1934.
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Exploring the glycosylation properties of a sialyl thioimidate donor Jun Rao a, Xiangming Zhu a,b,c,⇑ a
College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China c Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland b
a r t i c l e
i n f o
Article history: Received 28 April 2015 Revised 19 June 2015 Accepted 21 July 2015 Available online 26 July 2015
a b s t r a c t A new sialyl thioimidate donor 6 was prepared in high yields from the known sialyl hemiketal 1 over five steps. Under the action of catalytic TMSOTf, 6 exhibited excellent reactivity using a series of primary alcohols to give the desired sialylation products in high to excellent yields. Chemoselective activation of 6 in the presence of thioglycosides was also demonstrated. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Sialyl donor Thioimidate Catalytic activation Glycosylation
Sialic acids comprise a specific class of acidic monosaccharides, and include N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid and a-keto-deoxy-D-glycero-D-galactononulosonic acid.1 Among these, Neu5Ac is the most common, and is present in a variety of glycosidic linkages, most typically a-(2,6) and a(2,3), to galactose or in an a-(2,6) linkage to a galactosamine residue.2 These sialylated carbohydrates are intimately involved in a wide range of biological processes such as cell recognition and communication, bacterial and viral infection, and tumour metastasis.3 In view of their biological importance, tremendous efforts have been devoted to develop sialylation procedures,4 and substantial progress has been achieved in this field.5 However, a general sialylation procedure has not yet appeared, and more often than not, careful optimization of the glycosidation conditions is needed in order to achieve high yields and stereoselectivity for sialylation. Chemical sialylation remains a challenge in carbohydrate chemistry and is inherently problematic due to the unique structure of sialic acids. The electron-withdrawing carboxyl group at the anomeric centre and the lack of a participating functional group at the C-3 position of sialyl donors typically cause the sialylation reaction to proceed in low to moderate yields, with low a-selectivity and with the formation of unwanted 2,3-elimination products. Therefore, new sialylation methods and strategies are still welcome in carbohydrate chemistry. Recently, our laboratory introduced a new class of glycosyl thioimidates, glycosyl N-phenyl-trifluorothioacetimidates,6 as ⇑ Corresponding author. Tel.: +353 17162386; fax: +353 17162501. E-mail address: [email protected] (X. Zhu). http://dx.doi.org/10.1016/j.tetlet.2015.07.064 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
glycosylating agents. These thioimidates could be easily prepared from readily available glycosyl thiols in excellent yields and were effectively activated by catalytic amounts of a Lewis acid. We became curious whether similar sialyl thioimidates could also be used as new sialylating agents.7 Hence, investigations towards the synthesis and glycosylation properties of sialyl N-phenyl-trifluorothioacetimidate 6 (Scheme 1) was initiated. We now wish to report that 6 can serve as a sialylating agent for primary alcohols, proceeding in high to excellent yields with fairly good aselectivity. Our studies commenced with the preparation of sialyl chloride 3. It has been shown that in sialylation, protection of the C5 amino group is crucial to the success of the glycosidation reaction.4b We OAc
AcO Neu5Ac
Ref. 11
CO2Me
AcO TrocHN
O AcO
OAc CO2Me
AcO TrocHN
O AcO
6
AcCl, AcOH rt, 24 h
Cl
AcO TrocHN
O AcO
Ac2O, Py rt, 92%
1R=H 2 R = Ac
AcO
OR
OAc
AcO HCl (g)
S
CF3 NPh
CO2Me
3 KSAc, DMF rt, 12 h 79% (2 steps)
CF3C(=NPh)Cl K2CO3 acetone, H2O rt, 3 h 74%
OAc
AcO
CO2Me
AcO TrocHN
O
SR
AcO
4 R = Ac 5R=H
Scheme 1. Synthesis of sialyl thioimidate 6.
NaOMe, MeOH -40 oC, 30 min 83%
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J. Rao, X. Zhu / Tetrahedron Letters 56 (2015) 5168–5171
protected sialyl hemiketal 111 was prepared from N-acetylneuraminic acid following literature procedures then converted into sialyl acetate 2 in excellent yields by standard acetylation conditions. Subsequently, 2 was subjected to anomeric chlorination using anhydrous HCl in AcCl/AcOH to give sialyl chloride 3. Without purification, 3 was treated with potassium thioacetate in DMF to produce sialyl thioacetate 4 in 79% yield over two steps. The anomeric acetyl group of 4 was subsequently removed using
selected 2,2,2-trichloroethoxycarbonyl (Troc) group on the basis of its high stability under various reaction conditions, and more importantly, the reported high reactivity of N-Troc-protected sialyl donors8 which often exhibit higher reactivity than the corresponding N-Ac- and N-TFA-protected compounds, and have thus frequently been employed to synthesize different sialyl oligosaccharides, such as sialyl Lewis X9 and the pentasaccharide moiety of the neuritogenic ganglioside GAA-7.10 The known N-Troc-
Table 1 Sialylation of acceptors 7–14 with thioimidate 6a AcO
OAc
TrocHN
Entry
1
Acceptor
BnO BnO
AcO
CO2Me
AcO
O AcO
6
S
CF3
0.3 equiv TMSOTf
+
ROH
CH2Cl2/CH3CN 6:1 TrocHN AcO - 65 oC, 3 h
NPh
AcO
BnO OMe 7
TrocHN
AcO AcO
OH O
AcO
TrocHN
AcO
3
BzO BzO
AcO
TrocHN
AcO
O
10
OO
TrocHN
AcO
HO BnO
5
AcO OMP
OBn
AcO
6
OH O
AcO SPh
OBz 12
AcO
OH O STol
BzO
7
AcO
OBz
AcO
8
a b c
BnO BnO
OH O
AcO
BnO O OBn 14
S
TrocHN
O BzO BzO
O
3:1
94
5:1
92
5:1
90
2:1
87
a only
95
3:1
BzO OMe
O O O
O OO
O HO BnO
O
OMP
OBn
O BzO BzO
O SPh OBz
CO2Me O AcO
O BzO BzO
O
STol
OBz
OAc CO2Me
AcO BnO
96
AcO OMe
OAc
21
BnO BnO
3:1
CO2Me O
AcO TrocHN
13
O
OAc
20 BzO
O AcO AcO
CO2Me O
AcO TrocHN
91
BnO OMe
OAc
19
BzO BzO
5:1
CO2Me O
AcO TrocHN
11
86
OAc
18 OH O
O
CO2Me O
AcO
O
4
AcO
O BnO BnO
OAc
17 OH O
a/bc ratio
CO2Me O
AcO BzO OMe 9
Yieldb (%)
OAc
16 OH O
OR
CO2Me O
AcO AcO OMe 8
CO2Me O
OAc
AcO
15
2
AcO
Product OH O
OAc
O
O BnO BnO
AcO
22
BnO BnO
O BnO S BnO O OBn
Reaction conditions: 6 (1.2 equiv), acceptor 7–14 (1.0 equiv), TMSOTf (0.3 equiv), CH2Cl2/CH3CN 6:1, 65 °C under a N2 atmosphere. Isolated yield. Determined by integration of the proton signals in the 1H NMR spectrum after chromatographic purification.
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NaOMe in MeOH at low temperatures to give sialyl thiol 5 in 83% yield. Finally, 5 was treated with N-phenyl trifluoroacetimidoyl chloride12 and K2CO3 in the presence of water in acetone to give the desired sialyl N-phenyl-trifluorothioacetimidate 6 in 74% yield. With thioimidate 6 in hand, its glycosylation properties were investigated. 2,3,4-O-Benzylated glucoside 713 was initially examined as a glycosyl acceptor by treatment with 6 in the presence of catalytic amounts of TMSOTf (0.3 equiv) at 0 °C in CH2Cl2. Unfortunately, the desired disaccharide was produced in low yields (<10%) with significant amounts of the elimination by-product being isolated from the reaction. To avoid this elimination, the reaction was repeated at a lower temperature ( 40 °C). To our delight, the elimination reaction was dramatically reduced at this temperature and the sialylated disaccharide 1514 was generated in a much higher yield (52%) with only b selectivity. The reaction temperature was further lowered to 65 °C with the hope of further improving the glycosidation reaction. Unsurprisingly, the b-isomer of disaccharide 15 was isolated in a very high yield (91%), though trace amounts of the elimination product was also detected by TLC. Optimization of the solvent system was also carried out in order to obtain a-sialosides. In the literature, solvent effect, primarily the acetonitrile effect has frequently been applied to various sialylation reactions to boost a-selectivity.15 The above reaction was thus run in varying ratios of CH2Cl2 and CH3CN to give very good a-selectivity when the reaction was run in a 6:1 mixture of CH2Cl2 and CH3CN (Table 1, entry 1). The anomeric stereochemistry of 15 and all the following sialylation compounds were assigned on the basis of the empirical rules of chemical shifts.15c The a-sialosides had dH-3eq values varying from 2.6 to 2.8 ppm, whereas the analogous b-sialosides had dH-3eq values below 2.6 ppm. In some cases, the 3JC-1,H-3ax coupling constants were also used to confirm the a-configuration (a-anomer, 3JC-1,H-3ax = 5–6 Hz; b-anomer, 3JC-1,H-3ax < 1 Hz), which was consistent with the data reported in the literature.5b Next, the capability of thioimidate 6 as a sialyl donor was examined using a range of glycosyl acceptors under the optimized conditions (0.3 equiv TMSOTf, 65 °C, CH2Cl2/CH3CN 6:1). As shown in Table 1, the yields of all investigated acceptors were high. Additionally the catalytic properties of the examined reactions make this approach an attractive method to synthesize sialosides. Sialylation of glucosyl acceptor 816 or partially benzoylated acceptor 913 with thioimidate 6 gave rise to disaccharide 16 and 17 in excellent yield and modest a-selectivity (Table 1, entries 2 and 3). Considering that naturally occurring sialosides commonly incorporate an a-(2,6) linkage to galactose,2 commercially available galactosyl acceptor 10 was treated with donor 6 to give disaccharide 18 in excellent yield and very good a-selectivity (Table 1, entry 4). These results demonstrated that thioimidate 6 has a high reactivity towards primary alcohols and can be used as an effective sialylating agent. The high reactivity of thioimidate 6 was further confirmed by the reaction of galactosyl acceptor 1117 with 6 to give disaccharide 1917 in 92% yield and a/b 5:1 selectivity. It should be noted that the glycosylation reaction occurred only at the 6-OH position, and 4-Osialylation was not observed. The sialylation of a series of secondary OH groups with 6 was also attempted but no success was achieved even under more forcing conditions.18 The different behaviour observed for thioimidate 6 towards primary and secondary OH groups, and the underlying causes remain to be investigated. However, the current results clearly indicate that thioimidate 6 can serve as a sialylating agent for primary alcohols. To further explore the glycosylation properties of 6, we proceeded to examine thioglycosides 1219 and 1320 as acceptors. Reaction of 12 with donor 6 was conducted under the optimized conditions, and expectedly, the desired sialoside 20 was isolated in very high yield and moderate a/b 2:1 selectivity. Sialylation of
13 with donor 6 proceeded very cleanly as indicated by TLC to produce disaccharide 21 in 87% yield and perfect a-selectivity (Table 1, entry 7). This showed that thioglycosides would not be activated under the present conditions and chemoselective activation of thioimidate 6 in the presence of thioglycosides could thus be easily achieved. Finally, under the same conditions, thiotrehalose acceptor 14 was glycosylated with donor 6 to give the desired product 22 in excellent yield and modest a-selectivity (Table 1, entry 8). It should be mentioned that, like most glycosylation procedures, leaving group, catalyst, solvent and reaction temperature can all have significant effects on the reaction outcome.21 In other words, not only the new leaving group, but the N-Troc protecting group, acetonitrile and reaction temperature synergistically led to the above sialylation results, including the reaction yields and a-stereoselectivity, which are comparable to previously reported sialylation methods.8–10,14 In view of the limited number of catalytic glycosylation methods and sialyl donors in the literature,4 the present sialylation procedure may find valuable and versatile use in sialylation chemistry. In conclusion, as a continuation of our previous work,6 the glycosylation properties of sialyl thioimidate donor 6 have been investigated using a range of different glycosyl acceptors. The results indicate that 6 could serve as a sialylating agent for primary alcohols in a selective manner, proceeding in favour of the formation of a-sialosides with varying levels of selectivity. Moreover, all glycosylation products were isolated in very high to excellent yields. Extended studies on the scope of the glycosidation of 6 and applications of this sialylation procedure are currently underway. Acknowledgments This work was supported by the Science & Technology Department of Zhejiang Province (2013C24004) and the University College Dublin. Supplementary data Supplementary data (experimental procedures, characterization data, as well as copies of the 1H and 13C NMR of novel compounds) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.064. References and notes 1. Varki, A. Nature 2007, 446, 1023–1029. 2. Schauer, R. Sialic Acids: Chemistry, Metabolism and Function, Springer, New York 1982; p 10. 3. Amon, R.; Reuven, E. M.; Ben-Arye, S. L.; Padler-Karavani, V. Carbohydr. Res. 2014, 389, 115–122. 4. Reviewed in: (a) Hanashima, S. Trends Glycosci. Glycotechnol. 2011, 23, 111–121; (b) De Meo, C.; Priyadarshani, U. Carbohydr. Res. 2008, 343, 1540– 1552; (c) Ress, D. K.; Linhardt, R. J. Curr. Org. Synth. 2004, 1, 31–46. 5. For some recent examples (a) Harris, B. N.; Patel, P. P.; Gobble, C. P.; Stark, M. J.; De Meo, C. Eur. J. Org. Chem. 2011, 4023–4027; (b) Wang, Y.; Xu, F.-F.; Ye, X.-S. Tetrahedron Lett. 2012, 53, 3658–3662; (c) Premathilake, H. D.; Gobble, C. P.; Pornsuriyasak, P.; Hardimon, T.; Demchenko, A. V.; De Meo, C. Org. Lett. 2012, 14, 1126–1129; (d) Kancharla, P. K.; Navuluri, C.; Crich, D. Angew. Chem., Int. Ed. 2012, 51, 11105–11109; (e) Navuluri, C.; Crich, D. Angew. Chem., Int. Ed. 2013, 52, 11339–11342; (f) Zhang, X.-T.; Gu, Z.-Y.; Xing, G.-W. Carbohydr. Res. 2014, 388, 1–7; (g) Pokorny, B.; Kosma, P. Org. Lett. 2015, 17, 110–113. 6. Lucas-Lopez, C.; Murphy, N.; Zhu, X. Eur. J. Org. Chem. 2008, 4401–4404. 7. (a) De Meo, C.; Parker, O. Tetrahedron: Asymmetry 2005, 16, 303–307; (b) Ikeda, K.; Aizawa, M.; Sato, K.; Sato, M. Bioorg. Med. Chem. Lett. 2006, 16, 2618–2620. 8. Ando, H.; Koike, Y.; Ishida, H.; Kiso, M. Tetrahedron Lett. 2003, 44, 6883–6886. 9. Hanashima, S.; Castagner, B.; Esposito, D.; Nokami, T.; Seeberger, P. H. Org. Lett. 2007, 9, 1777–1779. 10. Tamai, H.; Ando, H.; Ishida, H.; Kiso, M. Org. Lett. 2012, 14, 6342–6345. 11. Akcay, G.; Ramphal, J. Y.; d’Alarcao, M.; Kumar, K. Tetrahedron Lett. 2015, 56, 109–114. 12. Kenji, T.; Hiromochi, M.; Kazuhiro, M.; Hisayuki, W.; Kenji, U. J. Org. Chem. 1993, 58, 32–35.
J. Rao, X. Zhu / Tetrahedron Letters 56 (2015) 5168–5171 13. Yan, M. C.; Chen, Y. N.; Wu, H. T.; Lin, C. C.; Chen, C. T.; Lin, C. C. J. Org. Chem. 2007, 72, 299–302. 14. Tanaka, H.; Adachi, M.; Takahashi, T. Chem. Eur. J. 2005, 11, 849–862. 15. (a) Hasegawa, A.; Nagahama, T.; Ohki, H.; Hotta, K.; Ishida, H.; Kiso, M. J. Carbohydr. Chem. 1991, 10, 493–498; (b) Castro-Palomino, J. C.; Tsvetkov, Y. E.; Schneider, R.; Schmidt, R. R. Tetrahedron Lett. 1997, 38, 6837–6840; (c) De Meo, C.; Demchenko, A. V.; Boons, G.-J. J. Org. Chem. 2001, 66, 5490–5497. 16. Kumar, G. D. K.; Baskaran, S. J. Org. Chem. 2005, 70, 4520–4523. 17. Nohara, T.; Imamura, A.; Yamaguchi, M.; Hidari, K. I. P. J.; Suzuki, T.; Komori, T.; Ando, H.; Ishida, H.; Kiso, M. Molecules 2012, 17, 9590–9620.
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18. Glycosylation of secondary alcohols did not proceed under the optimized conditions; while 2,3-elimination of donor 5 predominated under harsher conditions. 19. Balmond, E. I.; Coe, D. M.; Galan, M. C.; McGarrigle, E. M. Angew. Chem., Int. Ed. 2012, 51, 9152–9155. 20. Sun, B.; Jiang, H. Tetrahedron Lett. 2012, 53, 5711–6840. 21. Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900–1934.