Trichloroisocyanuric acid (TCCA)–TMSOTf: an efficient activator system for glycosylation reactions based on thioglycosides

Abstract

Trichloroisocyanuric acid (TCCA), a readily available, inexpensive and shelf-stable reagent, in combination with a catalytic amount of TMSOTf, has been used for the first time for efficient glycosylation reactions based on thioglycoside donors with SEt, SPh and S-pTol leaving groups at the anomeric centres.

---

Carbohydrates, including polysaccharides and glycoconjugates, play crucial roles in many life processes.¹ Isolation of these life chemicals in the homogeneous state ends up with very poor yields. Thus, biological studies with tailor-made glycoconjugates and their analogues can provide us with valuable information on the functions of these biomolecules. Glycosylations are the key reactions towards the synthesis of oligosaccharides and glycoconjugates.²

Because of several advantages, thioglycosides are probably the most used glycosyl donors for glycosylation reactions.^2c–e They can be prepared easily, and can withstand various conditions of protection and deprotection techniques. These features make these compounds easily convertible to the glycosyl donor and acceptor building blocks with different protecting groups of choice. The thioether functionality at the anomeric centre serves the combined role of an anomeric protection as well as a leaving group. So far, several promoters like NIS-TfOH,³ NIS-TESOTf,⁴ NIS-AgOTf,⁵ MeOTf,⁶ IDCP,⁷ DMTST,⁸N-(phenylthio)-ε-caprolactam-Tf₂O,⁹ BSP-Tf₂O,¹⁰ DPSO/Tf₂O,¹¹ BSM/Tf₂O,¹²etc. have been used for activation of thioglycosides for glycosylation reactions. Although some of these are promising towards the synthesis of oligosaccharides, some are not without problems. A few of these limitations are formation of a by-product, decreasing efficacy of the reaction, particularly using NIS-based promoter systems,¹³ instability of p-TolSCl and thus necessity of its predistillation under inert atmosphere,¹⁴ lower efficiency of BSP and BSM for the activation of some disarmed donors of low reactivity,¹⁵ fresh crystallisation of NBS prior to use, lower stability of DMTST and IDCP, etc. Moreover, in spite of a history of glycosylation procedures for more than a century, there is still no universal glycosylation technique for the synthesis of oligosaccharides.¹⁶ Thus, exploration of new and efficient promoters for glycosylation reactions still continues.

In continuation of our work on glycosylation reactions and on oligosaccharide synthesis,¹⁷ and also in connection with some research work related to a project on the synthesis of glycoconjugates, we choose thioglycosides as the glycosyl donor and acceptor building blocks. We were in need of preparing some disaccharides involving electron withdrawing groups on both the glycosyl donor and acceptor parts. Application of a few reported procedures¹⁸ towards such synthesis resulted in moderate yields with generation of undesired products in some of these cases. We were thus in search of an inexpensive and readily available thiophilic reagent that could give us our required products in good yields. Trichloroisocyanuric acid (TCCA), reported to be used in other organic reactions,¹⁹ can serve as an efficient chloronium ion supplier. To the best of our knowledge, TCCA has not yet been exploited for any glycosylation reaction. This prompted us to use it towards the activation of thioglycosides for glycosylation reactions. Herein, we report, for the first time, thioglycoside activation with a TCCA–TMSOTf combo-reagent system for efficient glycosylation reactions generating a variety of disaccharides having (1 → 3), (1 → 4) and (1 → 6) linkages in good to excellent yields. The results of our findings are summarized in Tables 1 and 3 and Schemes 1 and 2.

Table 1 Standardization of promoter system

Entry	Promoter system		Yield (%)
	TCCA (equiv)	Activator (mol%)
1	1	—	No reaction
2	1	TfOH (30)	86
3	1	TFA (30)	10 (decomposed)
4	0.35	TMSOTf (25)	Incomplete
5	0.5	TMSOTf (25)	Incomplete
6	0.5	TMSOTf (30)	65
7	1	TMSOTf (30)	95
8	1	TMSOTf (35)	86
9	—	TMSOTf (30)	No reaction

---

Fig. 1 Glycosyl donors.

Fig. 2 Glycosyl acceptors.

Fig. 3 Glycosylation products.

As an initial effort for the standardization of the glycosylation reaction, a comparatively disarmed glucose derived donor (1) and a glucose based acceptor (2) were employed and scanned under different reagent combinations. The results obtained from this screening are summarized in Table 1. Eventually, we found that 1.0 equiv TCCA in combination with 30 mol% TMSOTf gave the best result (Table 1, entry 7).

We presume that the choloronium ion, generated in situ from TCCA and TMSOTf, is immediately attacked by the ‘soft’ nucleophile 1 generating intermediate I₁, which in turn through formation of other intermediates (I₂ and I₃) and finally in reaction with the glycosyl acceptor (2) affords the corresponding disaccharide (3). TfOH formed in the final step then undergoes a reaction with the intermediate T₁, forming the by product T²⁰ and regenerating TMSOTf. The catalytic cycle of TMSOTf and the plausible reaction pathway are shown in Scheme 1. As TfOH itself can also activate TCCA (as evidenced from Table 1, entry 2) for generation of the choloronium ion, its role for the activation of thioglycosides cannot also be ruled out here.

Scheme 1 Plausible reaction pathway.

We then compared the efficiency of this procedure using the glycosyl donor 1 and acceptor 2 (Table 2, entry 1) with some reported ones based on DMTST (Table 2, entry 2); NIS in the presence of TMSOTf or TfOH and NBS–TMSOTf (entry 5). All these reactions furnished the desired disaccharide (3) in high yields (85–90%), but the best result (95%) was obtained based on the TCCA–TMSOTf combo catalyst system.

Table 2 Comparison of different catalyst combinations

Entry	Promoter system	Yield (%) of 3
	Activator (eq)/Co-activator (mol%)
1	TCCA (1.0)/TMSOTf (30)	95
2	DMTST (4.0)/–^8	90
3	NIS (1.5)/TMSOTf (20)^21	89
4	NIS (1.2)/TfOH (12)^3	86
5	NBS (2.2)/TMSOTf (20)^22	85

---

Exploiting the TCCA–TMSOTf reagent combination, a series of glycosylation reactions were carried out by varying both glycosyl donors and acceptors. Both “disarmed” and “armed” thioglycosides having different S-based anomeric leaving groups (viz. SEt, SPh and STol) were activated smoothly and reacted with different glycosyl acceptors having C-3, C-4 or C-6 free hydroxy groups to produce the corresponding disaccharides in good to excellent yields (Table 3). As shown, the low-reactive, “disarmed” glucose derived thioglycosides (1 and 9) reacted separately with a glucose based acceptor of low reactivity (2),¹⁴ furnishing the corresponding β-disaccharides in high yields (3 and 10, Table 3, entries 1 and 4, respectively). A better yield was obtained for 10 compared to that reported earlier.^18a Notably, the “disarmed” thiomannoside, 13, having a C-2 acetoxy, which sometimes suffers mainly from low yield owing to hemiacetal formation during the course of glycosylation reaction, also gives high yields of products 15 and 23 (Table 3, entries 6 and 11, respectively). The other “disarmed” thioglycoside donors prepared from galactose (entries 12 and 14), glucosamine (entries 3, 5 and 10), and rhamnose (Table 3, entries 8 and 9) were also investigated, which generated the corresponding products in high to excellent yields (80–93%). A number of 4-O-linked disaccharides (15 and 21) were prepared in high yields when the relatively low reactive acceptor 14 was used. In all cases, the “disarmed” thioglycoside expectedly afforded 1,2-trans-linked disaccharides by the virtue of neighbouring group participation; no orthoesters were detected.

As expected, the reactive “armed” glycosyl donors underwent the glycosylation reaction based on the present catalyst combination very smoothly and promptly. The glycosylation of perbenzylated thiogalactoside, 28, with glucose derived acceptor, 29, having a C-4 hydroxyl group exposed, resulted in the corresponding disaccharide 30 in excellent yield (Table 3, entry 15). The other “armed” thioglycoside donors, such as 31 and 33, also reacted very promptly with sterically demanding acceptor 14, prepared from glucose, affording the corresponding disaccharides in high yields (Table 3, entries 16 and 17). Although the perbenzylated thioglucoside 31 showed poor anomeric selectivity in 1→4 glycosylation reactions^17h,23 (as usual), the perbenzylated thiomannoside 33 demonstrated excellent α-selectivity (entry 17).

Table 3 Glycosylation of thioglycosides using TCCA–TMSOTf.^a See Fig. 1–3 for the structures of the donors, acceptors and products.

Entry	Donor/acceptor	Glycosylation product	Yield^b [%]	α : β
a All reactions were done in CH2Cl2. b Chromatographic yield. c Scale-up (∼13 fold) experiment.
1	1/2	3	95 (94)^c	β only
2	4/5	6	90	β only
3	7/5	8	86	β only
4	9/2	10	85	β only
5	7/11	12	90	β only
6	13/14	15	89	α only
7	16/17	18	73	α only
8	19/17	20	81	α only
9	19/14	21	90	α only
10	7/14	22	88	β only
11	13/2	23	83	α only
12	24/17	25	80	β only
13	4/2	26	93	β only
14	4/14	27	81	β only
15	28/29	30	89	α only
16	31/14	32	86	1.1 : 1
17	33/14	34	82	α only

---

To check the power of this combo catalyst system, we then turned our attention to the one-pot double glycosylation reaction. The coupling of glucose based diol 35 and fully acetylated rhamnose derived donor 19 afforded the trisaccharide 36²⁴ in high yield (81%) as the sole product (Scheme 2); no mono glycosylated disaccharide was detected. This protocol was also amenable to different protecting groups like –OBn, –OBz, –OAc, –NPhth, acetal, –OMe, –NHCBz, etc. present in the glycosyl donors and acceptors.

Scheme 2 Double glycosylation.

Finally, the efficacy of the present procedure was further proved through a scale-up (∼13 fold) experiment from the reaction of glycosyl donor 1 with glycosyl acceptor 2 (Table 3, entry 1, in parenthesis), which furnished the corresponding disaccharide 3 in excellent yield (94%).

In summary, TCCA, a very inexpensive, easy to handle, shelf-stable and readily accessible reagent, in combination with a catalytic amount of TMSOTf, serves as a convenient and efficient promoter for thioglycoside based glycosylation reactions. Both “disarmed” and “armed” thioglycosides were activated promptly at ice-bath temperature. One- and one-pot two-step glycosylation reactions furnished high yields of the requisite glycoside products. The present procedure is equally applicable under scale-up (1 g scale) conditions. Further scope and application of this promoter system in glycosylation reactions based on other glycosyl donors (other thioglycosides, glycals and pentenyl glycosides), and also in oligosaccharide synthesis are under way and will be published later.

Acknowledgements

Financial supports from CSIR, New Delhi, India (Scheme No. 01/2382/10/EMR-II) to RG and from CAS-UGC and FIST-DST, India to the Department of Chemistry, Jadavpur University are acknowledged. NB is grateful to CSIR for providing a fellowship (SRF).

References

1. (a) A. Varki, Glycobiology, 1993, 3, 97; (b) R. A. Dwek, Chem. Rev., 1996, 96, 683.
2. (a) B. Fraser-Reid, R. Madsen, A. S. Campbell, C. S. Roberts and J. R Merritt, in Bioorganic Chemistry: Carbohydrates, ed. S. M. Hecht, Oxford University Press, Oxford, 1999, p. 89; (b) P. Fugedi, in The Organic Chemistry of Sugars, ed. D. E. Levy and P. Fugedi, CRC Press, Boca Raton, FL, 2005, p. 89; (c) P. Fugedi, P. J. Garegg, H. Lonn and T. Norberg, Glycoconjugate J., 1987, 4, 97; (d) P. J. Garegg, Adv. Carbohydr. Chem. Biochem., 1997, 52, 179; (e) J. D. C. Codée, R. E. J. N. Litjens, L. J. van den Bos, H. S. Overkleeft and G. A. van der Marel, Chem. Soc. Rev., 2005, 34, 769.
3. G. H. Veeneman, S. H. van Leeuwen and J. H. van Boom, Tetrahedron Lett., 1990, 31, 1331.
4. T. Schmidt and R. Madsen, Eur. J. Org. Chem., 2007, 3935.
5. T. Nukada, A. Berces and D. M. Whitfield, J. Org. Chem., 1999, 64, 9030.
6. H. Lönn, Carbohydr. Res., 1985, 139, 105.
7. G. H. Veenenman and J. H. van Boom, Tetrahedron Lett., 1990, 31, 275.
8. P. Fugedi and P. J. Garegg, Carbohydr. Res., 1986, 149, C9.
9. S. G. Durón, T. Polat and C.-H. Wong, Org. Lett., 2004, 6, 839.
10. D. Crich and M. Smith, J. Am. Chem. Soc., 2001, 123, 9015.
11. J. D. C. Codée, R. E. J. N. Litjens, R. Den Heeten, H. S. Overkleeft, J. H. van Boom and G. A. van der Marel, Org. Lett., 2003, 5, 1519.
12. C. Wang, H. Wang, X. Huang, L.-H. Zhang and X.-S. Ye, Synlett, 2006, 2846.
13. Z. Zhang, I. R. Ollmann, X.-S. Ye, R. Wischnat, T. Baasov and C.-H. Wong, J. Am. Chem. Soc., 1999, 121, 734.
14. P. Peng and X.-S. Ye, Org. Biomol. Chem., 2011, 9, 616.
15. K.-K.T. Mong, H.-K. Lee, S.G. Duron and C.-H. Wong, Proc. Natl. Acad. Sci. U. S. A., 2003, 100, 797.
16. (a) H. Paulsen, Angew. Chem., Int. Ed. Engl., 1982, 21, 155; (b) Editorial by T. K. Lindhorst, Beilstein J. Org. Chem., 2010, 6(16).
17. (a) R. Ghosh, D. De, B. Shown and S. B. Maiti, Carbohydr. Res., 1999, 321, 1; (b) R. Ghosh, A. Chakraborty and S. Maiti, Arkivoc, 2004, 14, 1; (c) R. Ghosh, A. Chakraborty, D. K. Maiti and V. G. Puranik, Tetrahedron Lett., 2005, 46, 8047; (d) R. Ghosh, A. Chakraborty, D. K. Maiti and V. G. Puranik, Org. Lett., 2006, 8, 1061; (e) S. K. Maity, S. Maiti, A. Patra and R. Ghosh, Tetrahedron Lett., 2008, 49, 5847; (f) S. K. Maity, A. Patra and R. Ghosh, Tetrahedron, 2010, 66, 2809; (g) S. K. Maity and R. Ghosh, Synlett, 2012, 23, 1919; (h) S. K. Maity, N. Basu and R. Ghosh, Carbohydr. Res., 2012, 354, 40.
18. (a) C. Lucas-Lopez, N. Murphy and X. Zhu, Eur. J. Org. Chem., 2008, 26, 4401; (b) C. Uriel, J. Ventura, A. M. Gómez, J. C. López and B. Fraser-Reid, Eur. J. Org. Chem., 2012, 3122.
19. (a) L. De Luca, G. Giacomelli, S. Masala and A. Porcheddu, J. Org. Chem., 2003, 68, 4999; (b) G. A. Molander and L. N. Cavalcanti, J. Org. Chem., 2011, 76, 7195; (c) Z. D. Crane, P. J. Nichols, T. Sammakia and P. J. Stengel, J. Org. Chem., 2011, 76, 277; (d) A. Shiri and A. Khoramabadi-zad, Synthesis, 2009, 2797; (e) A. Sniady, M. S. Morreale, K. A. Wheeler and R. Dembinski, Eur. J. Org. Chem, 2009, 20, 3449; (f) J. C. Barros, Synlett, 2005, 2115.
20. That T is a by-product was proved by its isolation after completion of the reaction followed by its characterization by IR spectrum, which matched with that reported [CAS Registry No. 2782-57-2, Spectrum ID BR099518, (via SciFinder)]. ¹H NMR of a reaction mixture (from a reaction of 33 and 14 in CDCl₃) in CDCl₃-DMSO-d₆ mixed solvent showed a downfield singlet at δ 10.01 ppm, which corresponded to the NH of the by-product T.
21. G-J. Boons and T. Zhu, Synlett, 1997, 809.
22. Z-H. Qin, H. Li, M-S. Cai and Z-J. Li, Carbohydr. Res., 2002, 337, 31.
23. (a) J. Tatai and P. Fügedi, Org. Lett., 2007, 9, 4647; (b) B. A. Garcia and D. Y. Gin, J. Am. Chem. Soc., 2000, 122, 4269.
24. S. Deng, U. Gangadharmath and C-W Tom Chang, J. Org. Chem., 2006, 71, 5179.

---

Footnote

† Electronic Supplementary Information (ESI) available: Glycosylation procedures, copies of ¹H-, ¹³C-, COSY- and HSQC-NMR spectra of all unknown compounds. See DOI: 10.1039/c2ra21851h

---