C.-W. Chang et al. / Tetrahedron Letters 50 (2009) 4536–4540
4539
be mentioned that similar conversion explained in previous study
requires four reaction steps.21 Thus treatment of glycosyl orthoes-
ters 16a, 17a with the modified procedure of protocol B resulted in
the formation of glycosyl chlorides 16b, 17b in high yields (Table 2,
entries n and o).22
in turn enables the development of sequential chlorination–glyco-
sylation. Such a mild chlorination method should find useful for
oligosaccharide synthesis.
Acknowledgments
Particularly intriguing is the chlorination of glycosyl hemiace-
tals 18a and 19a; each of these substrates contains non-anomeric
and anomeric hydroxyl functions. Applying TCT–DMF chlorination
protocol B resulted in chemoselective anomeric hydroxyl chlorina-
tion and C-2 hydroxyl formylation. No traces of crossly functional-
ized products were detected. (Table 2, entries p and q).
We thank the National Science Council, Taiwan (96-2113-M-
009-016) and the Institute Francais de Taipei for financial support.
Supplementary data
Although TCT–DMF chlorination is useful for a wide range of
glycosyl substrates, its application to Neu5Ac hemiacetal 20a gave
rise to elimination product, Neu5Ac glycal 20b (Table 2, entry r).
This result may be explained by the high propensity of Neu5Ac gly-
cosyl chloride for elimination. Nevertheless, Neu5Ac glycal 20b is
the valuable precursor for preparing sialidase inhibitors;23 thus
by serendipity, our method provides an easy entry to Neu5Ac gly-
cal derivative.
It is worth mentioning that armed glycosyl chlorides (11b–13b
and 16b–19b) are prone to decomposition; nevertheless, brief
chromatography purification over short pad of silica gel is tolera-
ble. However, a prolonged contact would lead to substantial
decomposition of both armed and disarmed glycosyl chlorides;
while the extent of decomposition is much greater for the armed
chlorides than for the disarmed chlorides.24 Noted that TCT–DMF
chlorination method is amenable to larger scale preparation (5–
10 g of glycosyl hemiacetal), for which a slightly longer reaction
time is required.
Supplementary data associated with this article can be found, in
References and notes
1. Recent reviews for uses of TCT in synthetic chemistry: (a) Giacomelli, G.;
Porcheddu, A. Curr. Org. Chem. 2004, 8, 1487–1519; (b) Blotny, G. Tetrahedron
2006, 62, 9507–9522.
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231–234.
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Based on the literature review and experimental observations, a
plausible mechanism of TCT–DMF chlorination is outlined in
Scheme 1.8a,d At first, TCT was reacted with DMF giving Vilsme-
ier–Haack (VH) adduct and cyanurate; VH-adduct was then cou-
pled to glycosyl hemiacetal furnishing glycosyl iminium. The
presence of glycosyl iminium was supported by isolation of its
hydrolyzed product, glycosyl formate (data not shown). Subse-
quent cleavage of the ‘exo’ anomeric C–O bond in glycosyl iminium
was promoted by the ‘push and pull’ stereoelectronic feature of
substrate, which generated glycosyl oxocarbenium. Note that the
absence of such a stereoelectronic feature as is the case in aliphatic
alcohol results in hydroxyl formylation. Final coupling of oxocarbe-
10. Toshima, K. In Glycoscience; Fraser-Reid, B., Tatsuta, K., Thiem, J., Eds.; Springer:
Berlin, Heidelberg, 2008; pp 429–449.
11. (a) Demchenko, A. V. In Handbook of Chemical Glycosylation; Wiley-VCH, 2008;
pp 29–85; (b) Brito-Arias, M. In Synthesis and Characterization of Glycosides;
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12. Kim, C.; Hoang, R.; Theodorakis, E. A. Org. Lett. 1999, 1, 1295–1297.
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1997, 297, 175–180; (e) Pozsgay, V.; Dubois, E. P.; Pannell, L. J. Org. Chem. 1997,
62, 2832–2846; (f) Ghosh, R.; Chakraborty, A.; Maiti, S. Tetrahedron Lett. 2004,
45, 9631–9634; (g) Wang, Q. B.; Fu, J.; Zhang, J. B. Carbohydr. Res. 2008, 343,
2989–2991. and references cited therein.
14. Kocien´ ski, P. J. In Protecting Groups; Georg Thieme: Germany, 2005; pp 187–
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nium intermediate with chloride ion furnished a-glycosyl chloride.
15. (a) Ohrui, H.; Fox, J.-J. Tetrahedron Lett. 1973, 14, 1951–1954; (b) Copeland, C.;
McAdam, D. P.; Stick, R. V. Aust. J. Chem. 1983, 36, 1239–1247; (c) Ernst, B.;
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17. Preparation of glycosyl hemiacetals 3a–20a were detailed in the
Supplementary data.
18. TCT–DMF chlorination protocol A: DMF (1.55 mL, 20.0 mmol) was added to
2,4,6-trichloro-[1,3,5]-triazine (TCT) (1.0 g, 5.5 mmol) and the resulting
suspension was stirred at rt for 15 min under N2. Glycosyl hemiacetal
(5.0 mmol) (1, 3a, 4a, 5a, 6a, 7a, 8a, 9a, 10a, or 14a) in dichloroethane
solution (DCE) was added to the TCT–DMF suspension followed by addition of
DBU (0.8 mL, 5.5 mmol). The reaction mixture was stirred at 60 °C and progress
of reaction was monitored by TLC (ca. 1–4 h). Upon completion of chlorination,
the temperature was brought to rt and Et2O was added to the mixture for the
precipitation of cyanuric salt. After removal of cyanuric salt by filtration, the
combined filtrate was concentrated to yield the crude glycosyl chloride.
Further purification was performed by brief chromatography elution over a
As glycosyl chlorides are versatile donors for Koenigs–Knorr
glycosylation,25 it is reasonable to streamline TCT–DMF chlorina-
tion and Koenigs–Knorr glycosylation to a sequential process such
that apparently glycosyl hemiacetals act as donors for glycosyla-
tions. Kobayashi reported for direct activation of glycosyl hemiace-
tals with the Appel-Lee (PPh3–CBr4) reagent and DMF, though the
glycosylations were slow (required 1–3 days).26 In present context,
D
-galactopyranosyl hemiacetal 12a was first treated with TCT–DMF
protocol B giving galactopyranosyl chloride 12b (Scheme 2a).
Crude galactopyranosyl chloride 12b obtained after simple filtra-
tion and solvent removal was used directly as a donor for glycosyl-
ation of acceptor 21 without tedious chromatography isolation of
glycosyl chloride. Desired disaccharide 22 was obtained in 72%
overall yield as a 5:1 a:b-anomeric mixture. Such sequential chlo-
rination–glycosylation also works well for thioglycoside acceptor
rendering an orthogonal glycosylation possible (Scheme 2b). Thus
12a was chlorinated and thereof glycosylated with thiogalactopy-
ranoside 23 furnishing thioglycoside 24 in 76% overall yield and
short pad of silica gel to furnish the respective a-glycosyl chloride 2, 3b, 4b, 5b,
6b, 7b, 8b, 9b, 10b, or 14b. TCT–DMF chlorination protocol B (11a, 12a, 13a,
15a, 16a, 17a, 18a, 19a): Similar to protocol A except that CH2Cl2 and 5 mol
equiv of K2CO3, were used as solvent and proton scavenger, respectively, to
replace DCE and DBU in protocol A. The reaction was conducted at 45 °C and
for glycosyl orthoesters 16a and 17a, K2CO3 was omitted. Subsequent workup
excellent a-selectivity.
In summary, we report for the first time a mild and efficient
TCT–DMF chlorination method for different carbohydrate sub-
strates including glycosyl hemiacetals and glycosyl orthoesters.
Based on this new chlorination method, glycosyl chlorides in dif-
ferent protecting group settings become easily available, which
followed the same procedure as described in protocol
A
above and the
respective
obtained.
a-glycosyl chloride 11b, 12b, 13b, 15b, 16b, 17b, 18b, or 19b was
19. Juaristi, E.; Cuevas, G. Tetrahedron 1992, 52, 5019–5087.
20. Sugiyama, S.; Diakur, J. M. Org. Lett. 2000, 2, 2713–2715.
21. Wotovic, A.; Jacquinet, J.-C. Carbohydr. Res. 1990, 205, 235–245.