A new efficient glycosylation method employing glycosyl pentenoates and PhSeOTf

Article abstract of DOI:10.1016/j.tetlet.2006.10.158

The PhSeOTf promoted glycosylations of various glycosyl acceptors with mannosyl pentenoates and glucosyl pentenoates as glycosyl donors afforded corresponding disaccharides in high yields. And the present glycosyl pentenoates/PhSeOTf method showed that th

Full text of DOI:10.1016/j.tetlet.2006.10.158

Tetrahedron Letters 47 (2006) 9191–9194
A new efficient glycosylation method employing glycosyl
pentenoates and PhSeOTf
Tae Jin Choi, Ju Yuel Baek, Heung Bae Jeon and Kwan Soo Kim*
Center for Bioactive Molecular Hybrids and Department of Chemistry, Yonsei University, Seodaemun-gu Sinchon-dong 134,
Seoul 120-749, Republic of Korea
Received 22 September 2006; revised 27 October 2006; accepted 31 October 2006
Abstract—The PhSeOTf promoted glycosylations of various glycosyl acceptors with mannosyl pentenoates and glucosyl penteno-
ates as glycosyl donors afforded corresponding disaccharides in high yields. And the present glycosyl pentenoates/PhSeOTf method
showed that the complete a-selective mannosylation of secondary alcohol acceptors was achieved with 2,3,4,6-tetra-O-benzyl-D-
mannopyranosyl pentenoate to give a-disaccharides in good yields.
Ó 2006 Elsevier Ltd. All rights reserved.
The development of efficient and stereoselective glycos-
ylation methodologies has attracted a great deal of
attention in the past a decade due to the explosive
growth of important biological functions of complex oli-
gosaccharides and glycoconjugates in glycobiology.1
Devising new glycosyl donors and developing new
activation systems for existing donors resulted in major
advances in this area. While glycosyl trichloroacet-
imidates2 and thioglycosides3 have been the most
commonly used methods for glycosylation, glycosyl
sulfoxides,4 glycals,5 n-pentenyl glycosides,6 glycosyl
fluorides,7 and glycosyl phosphates8 have been also
employed widely. Recently, there have been some reports
on glycosylation methods using new glycosyl donors
and employing new activation systems for existing gly-
cosyl donors.9 We have also reported a novel type of
glycosyl donor, the 20-carboxybenzyl (CB) glycosides
that is useful for the stereoselective glycosylation.10
Nevertheless, there is no generally applicable one single
glycosylation method available for the construction of
various glycosyl linkages and a combination of more
than one glycosyl donors is usually required for the syn-
thesis of complex oligosaccharides. In this regard, there
still remains a need for new glycosylation methodolo-
gies, which might be highly efficient and generally appli-
cable to the synthesis of oligosaccharides.
In the continuation of our effort to develop the efficient
glycosylation method, our attention was focused on the
use of glycosyl pentenoates, 1–3 (Fig. 1), as glycosyl
donors and phenylselenyl triflate (PhSeOTf), which
was readily generated in situ from PhSeBr and AgOTf,
as a highly potent promoter. The glycosyl pentenoates
themselves are not new but have been reported as the
glycosyl donors in the combination with iodonium
dicollidine perchlorate (IDCP), N-iodosuccinimide
(NIS)-trifluoromethanesulfonic acid (TfOH), or 1,3-
dithian-2-yl tetrafluoroborate as the promoter by
Kunz11 and Fraser-Reid12 independently. However,
the glycosylations using these promoters with the pente-
noates appeared to be not quite efficient: examples were
limited and yields of product disaccharides ranged from
53% to 65%. And no further studies on the glycosyl
pentenoates and no application to the oligosaccharide
synthesis have been reported until our recent paper, in
which we showed a highly reactive and stereoselective
procedure for the b-mannopyranosylation employing
4,6-O-benzylidene mannopyranosyl pentenoate 3 and
PhSeOTf.13 In order to explore the scope of glycosyl
pentenoates/PhSeOTf method, we further carried out
glycosylation reactions with mannopyranosyl penteno-
ates 1 and glucopyranosyl pentenoates 2. Herein we
report a highly reactive new glycosylation method using
1 and 2 as glycosyl donors and PhSeOTf as a highly
potent promoter.
Keywords: Glycosylation; Glycoside; Glycosyl pentenoate; Phenyl-
selenyl triflate.
We envisioned that treatment of glycosyl pentenoate A
with PhSeOTf in the absence or presence of 2,4,6-
tri-tert-butylpyrimidine (TTBP)14 would induce the
*
Corresponding author. Tel.: +82 2 2123 2640; fax: +82 2 365 7608;
e-mail: kwan@yonsei.ac.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.158

9192
T. J. Choi et al. / Tetrahedron Letters 47 (2006) 9191–9194
OR
O
OBn
O
RO
RO
RO
RO
RO
RO
Ph
O
O
O
BnO
O
O
O
RO
O
O
O
3
1a R = Bn
1b R = Bz
2a R = Bn
2b R = Bz
Figure 1. Various glycosyl pentenoates as glycosyl donors.
lactonization of A via selenonium ion B to generate c-
phenylselenylmethyl-c-butyrolactone and oxocarbenium
ion C (Fig. 2). Subsequent reaction of C with the glycos-
yl acceptor would provide desired glycoside D.
Although glycosylations of various acceptors with tet-
rabenzyl mannosyl pentenoate 1a were so efficient that
the glycosyl donor disappeared in 20 min at ꢀ78 °C
based on TLC, the reaction mixture was further warmed
to 0 °C to make sure the completion of the reaction. In
case of disarmed tetrabenzoyl mannosyl pentenoate 1b,
the donor 1b started to be activated at ꢀ40 °C and the
glycosylation was completed after the reaction tempera-
ture was reached to 0 °C. Glycosylations of primary
alcohol acceptors 4 and 5 with 1a gave a mixture of
a- and b-disaccharides 1015 (a/b = 1.1:1) and 11 (a/
b = 1.4:1), respectively, in high yields (entries 1 and 2),
while the glycosylation of secondary alcohol acceptor
6 with 1a afforded exclusively a-disaccharide 12 in 84%
yield, in spite of no participating group effect of benzyl-
protected glycosyl donor (entry 3). Interestingly, the
complete a-selective mannosylation of secondary alco-
hol acceptors 7–9 was also achieved with 1a to give a-
disaccharides 13–15 in good yields (entries 4–6).
Namely, in the case of the less-reactive secondary alco-
hol acceptors, complete a-selectivities were observed in
the mannopyranosylation with 1a. Glycosylations of
primary and secondary alcohol acceptors 4, 5, 6, and 7
with 1b afforded the corresponding a-disaccharides 16,
17, 18, and 19 exclusively in high yields (entries 7–10).
This result indicates that not only the 4,6-O-benzyl-
idene-protected mannosyl pentenoate13 but also manno-
syl pentenoates with other protective groups are efficient
mannosyl donors.
The glycosyl pentenoates 1 and 2 were prepared easily
from the corresponding 1-hydroxy sugars by simple
treatment with commercially available 4-pentenoic acid
in the presence of 1,3-diisopropylcarbodiimide (DIC)
and a catalytic amount of 4-dimethylaminopyridine
(DMAP) in good yields as shown in Scheme 1. Since
many glycosyl donors are prepared by anomeric oxygen
exchange reactions and preparation of the glycosyl tri-
chloroacetimidates from 1-hydroxy sugars requires a
base such as K2CO3 or DBU,2 the ready synthesis of
glycosyl pentenoates from 1-hydroxy sugars through
retention of anomeric oxygen atoms under the very mild
condition would be one of advantages of the present
glycosylation method.
Using the mannopyranosyl pentenoate 1 and PhSeOTf,
glycosylations of a number of glycosyl acceptors were
examined (Table 1). The glycosylation was carried out
with 5 equiv of PhSeBr and AgOTf in the presence of
˚
4 A molecular sieves and TTBP at ꢀ78 °C in CH2Cl2.
Although TTBP is not essential for all glycosylations,
it is necessary in the glycosylation of the acceptors hav-
ing the benzylidene or the isopropylidene protective
group in order to prevent their decomposition by triflic
acid generated during the glycosylation. The glycosyl-
ation proceeded smoothly with 1.5 or 2 equiv of PhSeBr
and AgOTf, but 5 equiv of the promoters guarantee the
high yield even in the case of slight deterioration of the
promoters or incomplete generation of PhSeOTf.
Glycosylations of various glycosyl acceptors with the
glucosyl pentenoate 2 using PhSeOTf as the promoter
were also carried out under the same reaction condition
as described above for the mannosyl pentenoate 1
(Table 2). Reactions of the benzyl-protected glucosyl
donor 2a with primary alcohol acceptors 4 and 5 affor-
ded a mixture of a- and b-disaccharides 20 in 90% yield
and 21 in 86% yield, respectively (entries 1 and 2), while
it has been reported that the reaction of 2a with 5 using
1,3-dithian-2-yl tetrafluoroborate as promoter gave 21
in 56% yield.11 Glycosylations of secondary alcohol
acceptors 6 and 7 with 2a also afforded the anomeric
mixture of disaccharides 22 and 23, respectively, in high
yields (entries 3 and 4). Reaction of 2a with diacetone
glucofuranose 9 under the present glycosylation condi-
tion also provided an anomeric mixture of disaccharide
24 in 85% yield (entry 5), while it has been reported that
the same reaction by Fraser-Reid group gave 24 in 65%
..
O
O
PhSeOTf
(TTBP)
SePh
RO
RO
O
O
O
O
A
B
O
O
SePh
O
O
R'OH
RO
RO
OTf
OR'
D
C
Figure 2. Plausible mechanism of glycosylation with glycosyl pente-
noate as the donor using PhSeOTf as a promoter.
4-pentenoic acid
O
O
O
cat. DMAP, DIC
CH2Cl2, RT, 1 h
90% - 95%
RO
HO
RO
O
O
OH
OH
1, 2
Scheme 1. Synthesis of glycosyl pentenoates 1 and 2.

T. J. Choi et al. / Tetrahedron Letters 47 (2006) 9191–9194
Table 1. Glycosylations of various acceptors with mannosyl pentenoate 1 in CH2Cl2
9193
OR
O
OR
O
RO
RO
RO
RO
RO
RO
PhSeOTf, TTBP
4A MS
-78 oC to 0 oC
+
R'OH
O
OR'
O
10-19
1a R = Bn
1b R = Bz
Entry
1
Glycosyl donor
Glycosyl acceptor (R0OH)
Product
Yielda (%)
92
Ratio (a/b)a
HO
O
BzO
BzO
1a
1a
1a
10
11
12
1.1:1
BzO
OMe
4
OH
O
O
O
2
3
89
84
1.4:1
O
O
5
BnO
O
HO
BnO
a Only
BnO
OMe
6
OBn
O
BnO
OH
4
5
1a
1a
13
14
82
80
a Only
a Only
BnO
OMe
7
OH
O
Ph
O
O
BnO
OMe
8
OH
O
O
O
6
1a
15
83
a Only
O
O
9
7
8
9
1b
1b
1b
1b
4
5
6
7
16
17
18
19
85
87
90
87
a Only
a Only
a Only
a Only
10
a Determined after isolation.
Table 2. Glycosylations of various acceptors with glucosyl pentenoate 2 in CH2Cl2
RO
RO
RO
RO
PhSeOTf, TTBP
O
O
+
R'OH
RO
4A MS
RO
-78 oC to 0 o
C
RO
2a R = Bn
2b R = Bz
O
RO OR'
20-28
O
Entry
Glycosyl donor
Glycosyl acceptor (R0OH)
Product
Yielda (%)
Ratio (a/b)a
1
2
2a
2a
4
5
20
21
90
86
1:1
1.3:1
(56)b
88
(1:1)b
1:1.1
3
4
5
2a
2a
2a
6
7
9
22
23
24
90
85
(65)c
(62)d
89
88
89
93
1:1.9
1:1.1
(3:1)c
(1:1)d
b Only
b Only
b Only
b Only
6
7
8
9
2b
2b
2b
2b
4
5
6
7
25
26
27
28
a Determined after isolation.
b The result with 1,3-dithian-2-yl tetrafluoroborate as promoter by Kunz, see Ref. 11.
c The result with IDCP as promoter by Fraser-Reid, see Ref. 12.
d The result with NIS–TfOH as promoter by Fraser-Reid, see Ref. 12.

9194
T. J. Choi et al. / Tetrahedron Letters 47 (2006) 9191–9194
6. Fraser-Reid, B.; Madsen, R. In Preparative Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York,
1997; pp 339–356.
7. Shimizu, M.; Togo, H.; Yokoyama, M. Synthesis 1998,
799.
yield using IDCP and 62% yield using NIS–TfOH,
respectively.12 Clearly, using PhSeOTf instead of IDCP,
NIS–TfOH, or 1,3-dithian-2-yl tetrafluoroborate as the
promoter for the glycosylation with 2a enhanced the effi-
ciency of the reaction. Reactions of the benzoyl-pro-
tected glucosyl donor 2b with acceptors 4, 5, 6, and 7
afforded the corresponding b-disaccharides 25, 26, 27,
and 28 exclusively in high yields without any problem
(entries 6–9).
8. Plante, O. J.; Andrade, R. B.; Seeberger, P. H. Org. Lett.
1999, 1, 211.
9. For recent examples of new glycosyl donors and activating
systems, see: (a) Plante, O. J.; Palmacci, E. R.; Andrade,
R. B.; Seeberger, P. H. J. Am. Chem. Soc. 2001, 123, 9545;
(b) Hinklin, R. J.; Kiessling, L. L. J. Am. Chem. Soc. 2001,
123, 3379; (c) Davis, B. J.; Ward, S. J.; Rendle, P. M.
Chem. Commun. 2001, 189; (d) Petersen, L.; Jensen, K. J.
J. Org. Chem. 2001, 66, 6268; (e) Nguyen, H. M.; Chen,
Y.; Duron, S. G.; Gin, D. Y. J. Am. Chem. Soc. 2001, 123,
8766; (f) Hadd, M. J.; Gervay, J. Carbohydr. Res. 1999,
320, 61; (g) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120,
435; (h) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123,
9015.
10. (a) Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J.
J. Am. Chem. Soc. 2001, 123, 8477; (b) Kim, K. S.; Park,
J.; Lee, Y. J.; Seo, Y. S. Angew. Chem., Int. Ed. 2003, 42,
459; (c) Lee, Y. J.; Lee, K.; Jung, E. H.; Jeon, H. B.; Kim,
K. S. Org. Lett. 2005, 7, 3263.
In conclusion, we have described a new efficient glycos-
ylation method employing the glycosyl pentenoate as
the glycosyl donor and PhSeOTf as the highly potent
promoter. We found that PhSeOTf is much more
efficient promoter than IDCP, NIS–TfOH, and 1,3-
dithian-2-yl tetrafluoroborate, which are used to date,
for glycosylations with glycosyl pentenoates as donor.
Moreover, the present methodology showed that the
complete a-selective mannosylation of secondary alco-
hol acceptors was achieved with 2,3,4,6-tetra-O-benzyl-
D-mannopyranosyl pentenoate (1a) to give a-disaccha-
rides in good yields.
11. Kunz, H.; Wernig, P.; Schultz, M. Synlett 1990, 631.
12. Lopez, J. C.; Frazer-Reid, B. J. Chem. Soc., Chem.
Commun. 1991, 159.
Acknowledgements
13. Baek, J. Y.; Choi, T. J.; Jeon, H. B.; Kim, K. S. Angew.
Chem., Int. Ed. 2006, 45, 7436.
14. Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001,
323.
This work was supported by a grant from the Korea
Science and Engineering Foundation through Center
for Bioactive Molecular Hybrids (CBMH).
15. General procedure (10, Table 1, entry 1): A solution of
PhSeBr (81 mg, 0.34 mmol) and AgOTf (88 mg,
˚
0.34 mmol) in CH2Cl2 (3 mL) in the presence of 4 A
molecular sieves (100 mg) was stirred for 15 min at room
temperature and cooled to ꢀ78 °C, then a solution of
2,3,4,6-tetra-O-benzyl-D-mannopyranosyl pentenoate (1a)
(42 mg, 0.067 mmol) and TTBP (2,4,6-tri-tert-butylpyrim-
idine) (85 mg, 0.34 mmol) in CH2Cl2 (1.5 mL) was added.
After the resulting solution was stirred at ꢀ78 °C for
15 min, methyl 2,3,4-tri-O-benzoyl-a-D-glucopyranoside
(4) (45 mg, 0.088 mmol) was added. The reaction mixture
was stirred at ꢀ78 °C for 20 min, allowed to warm over
1 h to 0 °C, stirred for further 20 min at 0 °C, quenched
with saturated aqueous NaHCO3 (10 mL), and then
extracted with CH2Cl2. The combined organic layer was
washed with saturated aqueous NaHCO3 and brine, dried
over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (hexanes/
EtOAc/CH2Cl2, 4:1:1) to afford the desired mannopyr-
anoside 10 (92%, a/b = 1.1:1).
References and notes
1. (a) Varki, A. Glycobiology 1993, 3, 97; (b) Dwek, R. A.
Chem. Rev. 1996, 96, 683; (c) Bertozzi, C. R.; Kiessling, L.
L. Science 2001, 291, 2357.
2. (a) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem.
Biochem. 1994, 50, 21; (b) Schmidt, R. R. In Modern
Methods in Carbohydrate Synthesis; Khan, S. H., O’Neil,
R. A., Eds.; Harwood Academic: Amsterdam, 1996; pp
20–54.
3. Garegg, P. J. Adv. Carbohydr. Chem. Biochem. 1997, 52,
179.
4. Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am.
Chem. Soc. 1989, 111, 6881.
5. Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed.
1996, 35, 1380.