Direct glycosylation with anomeric hydroxy sugars by activation with 3-fluorophthalic anhydride and trifluoromethanesulfonic anhydride

Article abstract of DOI:10.1016/j.tetlet.2010.09.064

An efficient and direct one-pot glycosylation method using anomeric hydroxy sugars as glycosyl donors, employing 3-fluorophthalic anhydride and triflic anhydride as activating agents, has been developed. The present glycosylation utilizing 3-fluorophthali

Full text of DOI:10.1016/j.tetlet.2010.09.064

Tetrahedron Letters 51 (2010) 6250–6254
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Tetrahedron Letters
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Direct glycosylation with anomeric hydroxy sugars by activation
with 3-fluorophthalic anhydride and trifluoromethanesulfonic anhydride
⇑
Ju Yuel Baek, Bo-Young Lee, Rita Pal, Won-Yong Lee, Kwan Soo Kim
Center for Bioactive Molecular Hybrids and the Department of Chemistry, Yonsei University, Seoul 120-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and direct one-pot glycosylation method using anomeric hydroxy sugars as glycosyl donors,
employing 3-fluorophthalic anhydride and triflic anhydride as activating agents, has been developed. The
present glycosylation utilizing 3-fluorophthalic anhydride resulted in few to no undesired self-condensed
esters than the glycosylation using phthalic anhydride. Intermediates in the present glycosylation were
identified by an NMR study.
Received 11 August 2010
Revised 16 September 2010
Accepted 17 September 2010
Available online 29 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Glycosylation
3-Fluorophthalic anhydride
Glycosyl fluorophthalate
A great deal of effort has been devoted to the development of
efficient and stereoselective glycosylation methodologies1 over
the past decades due to important roles of complex oligosaccha-
rides in many fundamental life-sustaining processes.2 Devising
new glycosyl donors and developing new activating systems for
existing donors have led to major advances in this field. Glycosyl
trichloroacetimidates,3 thioglycosides,4 glycosyl sulfoxides,5
glycals,6 n-pentenyl glycosides,7 glycosyl fluorides,8 glycosyl phos-
phates,9 and glycosyl phosphites10 have been the most widely used
glycosyl donors for the synthesis of complex oligosaccharides. We
have also reported 20-carboxybenzyl (CB) glycosides,11 glycosyl
pentenoates,12 and glycosyl benzyl and aryl phthalates13 as new
glycosyl donors. Glycosylation methodologies employing these
aforementioned glycosyl donors consist of preparing the donor
by conversion of an anomeric substituent into a latent leaving
group in the first step. Activation of the isolated glycosyl donor
by a promoter followed by formation of a glycosyl bond by the
reaction between the activated donor and a nucleophilic glycosyl
acceptor occurs in the second step. On the other hand, a direct
glycosylation with anomeric hydroxy glycosyl donors, where the
anomeric derivatization, activation, and glycosyl bond formation
are combined in a one-pot procedure, would offer advantages over
current stepwise glycosylation methods. Although there have been
many reports on the direct glycosylation with C1-hydroxy glycosyl
donors,14 they have not attracted much attention partly because
most have not been utilized for the practical synthesis of oligosac-
charides. Recently, Gin and co-workers developed a new method
for the glycosylation with anomeric hydroxy sugars involving
oxosulfonium intermediates15 and reported its application to the
synthesis of complex oligosaccharides.16
We previously reported a new method for the one-pot direct
glycosylation with anomeric hydroxy sugars employing phthalic
anhydride and triflic anhydride (Tf2O) as activators,17 and success-
fully applied the new method to the synthesis of complex oligosac-
cahrides.17,18 Although the new glycosylation method employing
phthalic anhydride (1) proved to be efficient and stereoselective,
it did give undesired self-condensed ester E (R = H) in certain cases.
This probably resulted from the coupling of glycosyl phthalate an-
ion B (R = H) and oxocarbenium ion D as shown in Scheme 1.17
⇑
Corresponding author. Tel.: +82 2 2123 2640; fax: +82 2 365 7608.
E-mail address: kwan@yonsei.ac.kr (K.S. Kim).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.064

J. Y. Baek et al. / Tetrahedron Letters 51 (2010) 6250–6254
6251
the following sequence: (i) a solution of 10 or 11 (1.0 equiv), 3-flu-
orophthalic anhydride (2, 1.2 equiv), and 1,8-diazobicyclo[5,4,0]
undec-7-ene (DBU, 1.2 equiv) in the presence of 4 Å molecular
sieves was stirred for 15 min at room temperature in CH2Cl2
(2.0 mL/50 mg of the donor), (ii) the glycosyl acceptor (1.2 equiv)
in CH3CN (3.5 mL/50 mg of the donor) was added to the above
solution at 0 °C and stirred for 15 min, and (iii) Tf2O (1.5 equiv)
in CH2Cl2 (1.5 mL/50 mg of the donor) was slowly added to the
above solution at 0 °C, stirred for 15 min at 0 °C, and then subse-
quently warmed to room temperature for 30 min.
Indeed, glucosylations of primary alcohol acceptors 3 and 4
with the glucosyl donor 10 employing 3-fluorophthalic anhydride
(2) provided desired disaccharides 12 and 13, respectively, in high
yields without generation of the undesired self-condensed esters,
which were formed at approximately 10% in our original glucosy-
lations of 3 and 4 with 10 employing phthalic anhydride (entries 1
and 2 in Table 1). Glucosylations of secondary alcohol acceptors 5
and 6 with 10 gave not only desired disaccharides 14 and 15,
respectively, but also a small amount of undesired self-condensed
esters (entries 3 and 4). Nevertheless, the amounts (8% and 3%) of
the self-condensed esters generated in the present glucosylations
Figure 1. Glycosyl acceptors 3–9.
We envisioned that if 3-fluorophthalic anhydride (2) was used
as the activator instead of phthalic anhydride (1), the nucleophilic-
ity of glycosyl fluorophthalate anion B (R = F) would become weak-
er than that of glycosyl phthalate anion B (R = H) such that the
oxocarbenium ion D would preferentially react with the glycosyl
acceptor (sugar-OH) over the less nucleophilic glycosyl fluorophth-
alate anion B (R = F). Herein, a one-pot direct glycosylation method
with anomeric hydroxy sugars as glycosyl donors employing 3-flu-
orophthalic anhydride (2) and triflic anhydride as activating agents
is reported.
Glycosylations of acceptors 3–7 (Fig. 1) with benzyl-protected
glucosyl donor 10 and mannosyl donor 11 were carried out by
Table 1
Glycosylations with benzyl-protected donors 10 and 11
Entry
1
Donor
Acceptor (ROH)
Product
Yield%a (ratio,
a
/b)b
Self-condensed ester, %
12
84 (1:1.4)
73 (1.6:1)
0
10c
86 (1:1.5)
78 (1.2:1)
0
2
3
10
10
13
14
10c
82 (1:5)
70 (1:7.5)
8
10c
84 (1:1.8)
82 (1:7.5)
3
4
10
15
10c
5
6
7
3
5
16
17
18
85 (10:1) 0
0
0
0
11
11
85 (a only)
86 (1.8:1)
a
b
c
Determined after isolation.
The ratio was determined by 1H NMR.
The result from the original method employing phthalic anhydride, see Ref. 17.

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J. Y. Baek et al. / Tetrahedron Letters 51 (2010) 6250–6254
Table 2
Glycosylations with benzoyl-protected donors 19 and 20
b
Entry
1
Donor
Acceptor (ROH)
Product
Yield%a (ratio,
a/b)
3
21
85 (b only)
2
3
19
19
5
6
22
23
84 (b only)
82 (b only)
4
19
24
84 (b only)
5
3
25
86 (a
only)
6
7
20
20
6
7
26
27
84 (
85 (
a
a
only)
only)
a
Determined after isolation.
b
The ratio was determined by 1H NMR.
were less than those in our original glucosylations with 10 employ-
ing phthalic anhydride. On the other hand, mannosylations of
acceptors 3, 5, and 7 with donor 11 were more satisfactory than
the glucosylations, providing mannosyl disaccharides 16, 17, and
18, respectively, in high yields without the formation of self-
condensed esters (entries 5–7).19
Glycosylations of various acceptors with benzoyl-protected glu-
cosyl donor 19 and mannosyl donor 20 were also examined under
the same reaction conditions as described above, with the excep-
tion of using CH2Cl2 as the solvent (Table 2). Glucosylations of all
primary and secondary alcohol acceptors 3, 5, 6, and 8 with tetra-
benzoyl glucose 19 exclusively afforded corresponding b-disaccha-
rides 21–24, respectively, in high yields (entries 1–4 in Table 2)
while mannosylations of acceptors 3, 6, and 7 with tetrabenzoyl
mannose 20 were completely
a-selective, providing a-disaccha-
rides 25–27, respectively, in high yields (entries 5–7). The result
indicates that the neighboring group participation by the benzoate
at the C-2 position was fully operative in the present one-pot
glycosylation.
We then, applied the present method to the stereospecific for-
mation of 1,2-cis-b-mannopyranosyl linkages by employing 2,3-
di-O-benzyl-4,6-O-benzylidene-
D
-mannopyranose (28) as the
Table 3
Mannosylations with benzylidene-protected donor 28
b
Entry
Acceptor (ROH)
Product
Yield%a (ratio,
a/b)
1
2
3
4
5
6
3
4
5
6
7
8
29
30
31
32
33
34
88 (1:50)
88 (1:50)
84 (b only)
85 (b only)
84 (1:19)
87(1:40)
7
35
86 (1:18)
a
Determined after isolation.
The ratio was determined by LC–Mass.
b

J. Y. Baek et al. / Tetrahedron Letters 51 (2010) 6250–6254
6253
Table 4
Glucosylations with benzylidene-protected donor 36
b
Entry
1
Acceptor (ROH)
Product
Yield%a (ratio,
a/b)
Self-condensed ester, %
b
3
37
88 (1:1.4)
0
74 (
a
only)
20d
4
c
2
8
38
87 (30:1)
87 (18:1)
85 (1:17)b
85 (2:1)
87 (1:1.5)
5d
0
3
4
5
6
5
9
39
40
41
c
0
0
b
a
b
c
Determined after isolation.
The ratio was determined by 1H NMR.
The ratio was determined by LC–Mass.
d
The result from the original method employing phthalic anhydride, see Ref. 17.
mannosyl donor, since the directing effect of the 4,6-O-acetal of the
mannosyl donor on the mannopyranosylation is well estab-
lished.11a,12a,17,20 Mannosylations with the donor 28 were
conducted under a slightly modified condition: 2,6-di-t-butyl-4-
methylpyridine (DTBMP) was added to prevent cleavage of the
acid-labile benzylidene group by triflic acid, and triflic anhydride
was added before the acceptor in order to enhance the b-selectiv-
ity21 (see Supplementary data for General Procedure). Mannosyla-
tions of all primary and secondary alcohol acceptors 3–9 with the
4,6-O-benzylidene-protected mannose 28 using 3-fluorophthalic
anhydride and Tf2O as activators were highly b-selective, providing
b-mannopyranosides 29–35, exclusively or predominantly in high
yields without generation of the self-condensed esters (entries 1–7
in Table 3). Unlike glycosylations with donors 10 and 11, the 4,6-O-
benzylidene-protected mannosyl donor 28 did not generate the
self-condensed ester even when Tf2O was added prior to the
acceptor.
42
lates 42b and 43b. Almost the same amount of regioisomers 42
and 43 were formed while the anomeric ratio, (42 + 43 )/
(42b + 43b), was around 1.6:1. This ratio was unchanged at 25 °C;
however, during the temperature change from 25 to 35 °C, 1H
NMR indicated that b-anomers slowly converted to the corre-
a and 43a and at d 5.90 and 6.00 for b-mannosyl fluorophtha-
a
a
sponding stable
a-anomers (see Supplementary data). After
30 min at 35 °C, almost all b-anomers were converted into
a-ano-
mers, showing only two anomeric proton signals at d 6.31 and 6.34.
The reaction mixture in the NMR tube was then cooled down to
ꢀ40 °C, and DTBMP (3.0 equiv) and Tf2O (1.5 equiv) were added
sequentially. Immediately after addition of Tf2O, the 1H NMR spec-
trum showed an anomeric proton peak at
d
6.03 for
a
-mannopyranosyl triflate 44, the same species as that was pro-
duced in the original mannosylation.17 The 13C NMR spectrum at
ꢀ40 °C also indicated the formation of 44 with an anomeric carbon
peak at 105.4. The NMR study supported both the mechanism de-
We also applied the present modified one-pot glycosylation
method to the glucosylation with 2,3-di-O-benzyl-4,6-O-benzyli-
picted in Scheme 1 and the involvement of the a-mannopyranosyl
triflate 44 in the b-mannosylation with 4,6-O-benzylidene man-
dene-D-glucopyranose (36). To compare these results with those
nose 28 (see Supplementary data).
from the original glucosylation employing phthalic anhydride,
the glucosylation with 36 employing 3-fluorophthalic anhydride
was conducted under the same condition as that of the original,
under which triflic acid (TfOH) was added just before addition of
Tf2O.17 The glucosylation of the benzoyl-protected primary alcohol
glucose acceptor 3 with the benzylidene-protected glucosyl donor
36 employing 3-fluorophthalic anhydride provided desired disac-
charides 37 without generation of the self-condensed ester, while
the original glucosylation of 3 with 36 employing phthalic anhy-
dride gave 20% of the self-condensed ester (entry 1 in Table 4).
Although the glucosylation of 8 with 36 generated a small amount
(4%) of the self-condensed ester (entry 2), glucosylations of other
acceptors 6, 5 and 9 with 36 did not produce self-condensed esters
and provided desired disaccharides 39, 40, and 41, respectively, in
high yields (entries 3–5 in Table 4).
In conclusion, we described here an efficient direct glycosyla-
tion method with anomeric hydroxy sugars as glycosyl donors
employing 3-fluorophthalic anhydride and Tf2O as activating
agents. Few or no undesired self-condensed esters were formed
in the present glycosylation employing 3-fluorophthalic anhydride,
as compared with our original glycosylation employing phthalic
anhydride. Glycosyl 30-fluorophthalates and glycosyl 60-fluoroph-
thalates were identified as intermediates in the first step of the
present glycosylation reaction, while
a-mannosyl triflate was de-
tected in the second step of the mannosylation with 4,6-O-benzyl-
idene mannose, based on the NMR study.
We performed an NMR study to detect intermediates in the
glycosylation with 4,6-O-benzylidene mannose 28 as the model
donor. Intermediates in the reaction of 3-fluorophthalic anhydride
(2) and 28 in the first step of the mannosylation would be mannosyl
30-fluorophthalates 42
43a and 43b (Fig. 2). When a mixture of 28 (
a
and 42b and mannosyl 60-fluorophthalates
/b = 2.1:1) (1.0 equiv)
a
and 2 (1.2 equiv) in CD2Cl2 at 25 °C in the NMR tube was treated
with DBU (1.2 equiv), the 1H NMR spectrum showed anomeric pro-
ton resonances at d 6.31 and 6.34 for
a-mannosyl fluorophthalates
Figure 2. Intermediates identified in the mannosylation with

6254
J. Y. Baek et al. / Tetrahedron Letters 51 (2010) 6250–6254
11. (a) Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J. J. Am. Chem. Soc. 2001, 123,
Acknowledgments
8477–8481; (b) Kim, K. S.; Kang, S. S.; Seo, Y. S.; Kim, H. J.; Lee, Y. J.; Jeong, K.-S.
Synlett 2003, 1311–1314.
This work was supported by the National Research Foundation
(NRF) grant funded by the Korea government (MEST) through the
Center for Bioactive Molecular Hybrids (No. R11-2003-019-
00000-0).
12. (a) Baek, J. Y.; Choi, T. J.; Jeon, H. B.; Kim, K. S. Angew. Chem., Int. Ed. 2006, 45,
7436–7440; (b) Choi, T. J.; Baek, J. Y.; Jeon, H. B.; Kim, K. S. Tetrahedron Lett.
2006, 47, 9191–9194.
13. (a) Kim, K. S.; Lee, Y. J.; Kim, H. Y.; Kang, S. S.; Kwon, S. Y. Org. Biomol. Chem.
2004, 2, 2408–2410; (b) Kwon, S. Y.; Lee, B.-Y.; Jeon, H. B.; Kim, K. S. Bull. Korean
Chem. Soc. 2005, 26, 815–818.
14. For a review for glycosylations with C-1 hydroxy sugars, see: (a) Gin, D. Y. J.
Carbohydr. Chem. 2002, 21, 645–665; (b) Ryan, D. A.; Gin, D. Y. In Handbook of
Chemical Glycosylation: Advances in Stereoselectivity and Therapeutic Relevance;
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15. (a) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997, 119, 7597–7598;
(b) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269–4279; (c) Nguyen,
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.064.
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