Glycosylation with glycosyl benzyl phthalates as a new type of glycosyl donor

Article abstract of DOI:10.1039/b405793g

A glucopyranosyl benzyl phthalate, two mannopyranosyl benzyl phthalates, and a 2-deoxyglucopyranosyl benzyl phthalate, which were prepared from the corresponding 1-hydroxy sugars and benzyl hydrogen phthalate, were found to be efficient glycosyl donors in the glycosylations of various glycosyl acceptors using TMSOTf as a promoter.

Full text of DOI:10.1039/b405793g

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C O M M U N I C A T I O N
Glycosylation with glycosyl benzyl phthalates as a new type of
glycosyl donor†
Kwan Soo Kim,* Yong Joo Lee, Hye Young Kim, Sung Soo Kang and Soon Young Kwon
Centre for Bioactive Molecular Hybrids and Department of Chemistry, Yonsei University,
Seoul, 120-749, Korea. E-mail: kwan@yonsei.ac.kr; Fax: +82-2-364-7050; Tel: +82-2-2123-2640
Received 19th April 2004, Accepted 15th July 2004
First published as an Advance Article on the web 4th August 2004
A glucopyranosyl benzyl phthalate, two mannopyranosyl
benzyl phthalates, and
a 2-deoxyglucopyranosyl benzyl
phthalate, which were prepared from the corresponding
1-hydroxy sugars and benzyl hydrogen phthalate, were found
to be efficient glycosyl donors in the glycosylations of various
glycosyl acceptors using TMSOTf as a promoter.
Introduction
Development of efficient and stereoselective glycosylation metho-
dologies has been one of the major concerns in synthetic organic
chemistry in recent years due to important biological functions of
complex oligosaccharides and glycoconjugates.1–3 Devising new
glycosyl donors and developing new activation systems for exist-
ing donors have led to major advances in this field. In this respect,
there still remains a need for more efficient and generally applicable
new glycosyl donors although quite efficient glycosyl donors are
presently available.4,5 In fact, there have been recent reports on
new glycosyl donors and new activation systems.6–13 We have also
recently reported a novel type of glycosyl donor, the 2′-carboxy-
benzyl (CB) glycoside A, as shown in Fig. 1 for stereoselective
-mannopyranosylation14 and 2-deoxyglycosylation15 and applied
this methodology to the synthesis of a tetrasaccharide.16 Lactoni-
zation of the glycosyl triflate B, which was derived from the CB
glycoside A, was the driving force for the facile generation of the
oxocarbenium C for the glycosylation. In continuation of the search
for more efficient glycosyl donors, we envisaged that treatment of
the glycosyl benzyl phthalate D with Lewis acids would also gene-
rate the oxocarbenium ion C by cyclic anhydride formation as
shown in Fig. 1. An added impetus to design the phthalate D comes
from the fact that the method for the preparation of D could be useful
complement to that for the preparation of A. The CB glycoside A
was prepared from the glycosyl halide and thus the original anomeric
oxygen atom was replaced by 2-(hydroxymethyl)benzoic acid such
as in the case of preparation of thioglycosides17 while, alternatively,
the glycosyl benzyl phthalate D or the glycosyl hydrogen phthalate
E‡ would be prepared from the 1-hydroxy sugar through retention
of the anomeric oxygen atom such as in the case of the preparation
of glycosyl trichloroacetimidates.18 Herein we report the synthesis
and glycosylation with the glycosyl benzyl phthalate D as a novel
type of glycosyl donor.
Fig. 1
5 (/ = 1:1) were prepared from the corresponding 1-hydroxy
sugars in analogous fashions. These glycosyl benzyl phthalates
were stable enough to store at room temperature for a few months
without any change.
Scheme 1 Reagents and conditions: i, benzyl hydrogen phthalate (1),
DCC, DMAP (cat.), CH2Cl2, 0 °C to rt, 3 h, 86% (/ = 3:2); ii, 6, TMSOTf,
CH2Cl2, 0 °C, 1 h, 91% (/ = 2.4:1).
Glucopyranosyl donor 2 was readily activated by TMSOTf in di-
chloromethaneandcoupledwithvariousglycosylacceptorstoafford
disaccharides in high to moderate yields. For instance, a solution of
1.0 equiv. of compound 2, 2.0 equiv. of the primary alcohol acceptor
6, and 0.5 equiv. of TMSOTf in dichloromethane was stirred at 0 °C
for 1 h. After quenching with saturated aqueous sodium bicarbonate
solution, the reaction mixture was purified by column chromatogra-
phy to afford a mixture of - and -disaccharides 15 (/ = 2.4:1)
in 91% yield (Scheme 1 and entry 1 in Table 1). The glycosylation
also proceeded with less than 0.5 equiv. of TMSOTf although more
slowly. Reaction of compound 2 with other primary alcohol accep-
tors 7 and 8 similarly provided disaccharides 16 (/ = 1.4:1) in
90% yield and 17 (/ = 1.2:1) in 87% yield, respectively (entries
2 and 3 in Table 1). Coupling of donor 2 with secondary alcohol
acceptors required a larger quantity of TMSOTf (1.0 equiv.) and
a longer reaction time (1.5 h) and afforded -disaccharides as
Results and discussion
Crystalline benzyl hydrogen phthalate (1) was readily obtained in
large quantities by the reaction of inexpensive phthalic anhydride
and benzyl alcohol.19 Esterification reaction of 2,3,4,6-tetra-O-
benzyl-D-glucose and compound 1 using DCC in the presence
of a catalytic amount of DMAP provided glucopyranosyl benzyl
phthalate 2 (/ = 3:2) as shown in Scheme 1. Three more glycosyl
benzyl phthalates, namely, tetra-O-benzyl--mannopyranosyl
benzyl phthalate 3,20 2-O-acetyltri-O-benzyl--mannopyranosyl
benzyl phthalate 4, and 2-deoxyglucopyranosyl benzyl phthalate
† Electronic supplementary information (ESI) available: Spectroscopic
and analytical data for all new compounds. See http://www.rsc.org/
suppdata/ob/b4/b405793g/
2 4 0 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 0 8 – 2 4 1 0
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 1 Glycosylation with glycosyl benzyl phthalates 2, 3, and 4a
Product Yield (%)b Ratio (/)
Table 2 Glycosylation with the 2-deoxyglycosyl benzyl phthalate 5a
Entry Donor Acceptor
Entry Donor
Acceptor
Product Yield (%)b Ratio (/)
1
2
5
5
6
7
29
30
94
79
3:1
1.3:1
1
2
2
2
15
16
91
90
2.4:1
1.4:1
3
4
5
5
31
32
89
78
1:1.2
10
12
 only
5
6
5
5
33
34
88
88
 only
 only
3
4
5
2
2
2
17
18
19
87
63
66
1.2:1
1:5.5
a Glycosylation was carried out with 1.0 equiv.. of donor, 2.0 equiv..
of acceptor and 0.5 equiv.. of TMSOTf in dichloromethane at −78 °C
to −40 °C. b Isolated yield.
1:1.5
2-Deoxyglucosyl benzyl phthalate 5 was found to be more
reactive than glycosyl benzyl phthalates 2, 3, and 4 and could be
activated by TMSOTf even at −78 °C to give a little higher yield
of disaccharides. For example, to a solution of donor 5 (1.0 equiv.)
and acceptor 6 (2.0 equiv.) in dichloromethane was added
TMSOTf (0.5 equiv.) at −78 °C. The further reaction at −78 °C
for 30 min and warming the reaction mixture over 1 h to −40 °C
afforded disaccharide 29 (/ = 3:1) in 94% yield (entry 1 in
Table 2). Reaction of 5 with other primary alcohols 7 and 13 also
gave a mixture of - and -disaccharides 30 (/ = 1.3:1) in 79%
yield and 31 (/ = 1:1.2) in 89% yield, respectively (entries 2 and
3 in Table 2). Couplings of 5 with secondary alcohol acceptors 10,
12, and 14, on the other hand, were completely stereoselective and
afforded exclusively -disaccharides 32, 33, and 34, respectively in
high yields (entry 4–6 in Table 2).
In conclusion, we have found that glycosyl benzyl phthalates
behave as efficient glycosyl donors by extrusion of stable phthalic
anhydride upon treatment with TMSOTf to afford disaccharides
in the glycosylation of various glycosyl acceptors. Reactions of
mannopyranosyl benzyl phthalate 3 and 2-deoxyglucopyranosyl
benzyl phthalate 5, which both have no participating group at C-2,
with secondary alcohol acceptors were completely stereoselective
to afford exclusively -disaccharides.
6
7
8
3
3
3
6
7
8
20
21
22
89
82
85
4:1
25:1
2.6:1
9
3
23
75
3:2
10
11
3
3
9
10
24
25
73
68
 only
 only
12
3
26
62
 only
13
14
4
4
7
9
27
28
76
77
 only
 only
a Glycosylation was carried out with 1.0 equiv.. of donor, 1.7 equiv.. of
acceptor and TMSOTf (0.5 equiv.. for primary alcohol acceptors, 1.0 equiv..
for secondary alcohol acceptors) in dichloromethane at 0 °C for 1 h (for
primary alcohol acceptors) or 1.5 h (for secondary alcohol acceptors).
b Isolated yield.
major products but in a little lower yield than with primary alcohol
acceptors. Thus, the reaction of 1.0 equiv. of glycosyl donor 2 with
2.0 equiv. of secondary alcohol acceptors 9 and 10 in the presence
of 1.0 equiv. of TMSOTf in dichloromethane at 0 °C for 1.5 h gave
disaccharides 18 in 63% yield and 19 in 66% yield, respectively
(entries 4 and 5 in Table 1).
Acknowledgements
This work was supported by a grant form the Korea Science and
Engineering Foundation through Centre for Bioactive Molecular
Hybrids (CBMH).
Reactions of tetra-O-benzylmannopyranosyl benzyl phthalate
3 with various glycosyl acceptors were also carried out under
the same reaction condition as that with glucopyranosyl donor
2 and afforded disaccharides in reasonable yields. Unlike the
glucopyranosyl donor 2, the mannopyranosyl donor 3 exhibited -
selectivity regardless of primary or secondary alcohol acceptors and
the selectivity was also more pronounced than that with 2. Moderate
(/ = 2.6:1) to high (/ = 25:1) -selectivity was observed in the
reaction of 3 with primary alcohol acceptors (entries 6–9 in Table 1)
while -disaccharides 24, 25,21 and 26 were obtained exclusively
in the reactions of 3 with secondary alcohol acceptors 9, 10, and
12, respectively (entries 10–12 in Table 1). Coupling of 2-O-acetyl-
tri-O-benzylmannosyl donor 4 with the primary alcohol acceptor 7
and with the secondary alcohol acceptor 9 afforded exclusively -di-
saccharides 27 in 76% and 28 in 77% yields, respectively (entries 13
and 14 in Table 1). This result indicates that the neighboring group
participation by the acetate at the C-2 position is operative in the
present glycosylation using glycosyl benzyl phthalates.
Notes and references
‡ The glycosyl hydrogen phthalate E was readily prepared by the reaction
of 1-hydroxy sugar with phthalic anhydride in the presence of triethyl-
amine but was found not to be a practical donor because of its partial
decomposition during isolation and glycosylation.
1 A. Varki, Glycobiology, 1993, 3, 97.
2 R. A. Dwek, Chem. Rev., 1996, 96, 683.
3 C. R. Bertozzi and L. L. Kiessling, Science, 2001, 291, 2357.
4 K. Toshima and K. Tatsuta, Chem. Rev., 1993, 93, 1503.
5 B. G. Davis, J. Chem. Soc., Perkin Trans 1, 2000, 2137.
6 O. J. Plante, E. R. Palmacci, R. B. Andrade and P. H. Seeberger, J. Am.
Chem. Soc., 2001, 123, 9545.
7 R. J. Hinklin and L. L. Kiessling, J. Am. Chem. Soc., 2001, 123, 3379.
8 B. J. Davis, S. J. Ward and P. M. Rendle, Chem. Commun., 2001, 189.
9 L. Petersen and K. J. Jensen, J. Org. Chem., 2001, 66, 6268.
10 H. M. Nguyen, Y. Chen, S. G. Duron and D. Y. Gin, J. Am. Chem. Soc.,
2001, 123, 8766.
11 M. J. Hadd and J. Gervay, Carbohydr. Res., 1999, 320, 61.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 0 8 – 2 4 1 0
2 4 0 9

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12 D. Crich and S. Sun, J. Am. Chem. Soc., 1998, 120, 435.
13 D. Crich and M. Smith, J. Am. Chem. Soc., 2001, 123, 9015.
14 K. S. Kim, J. H. Kim, Y. Joo Lee, Y. Jun Lee and J. Park, J. Am. Chem.
Soc., 2001, 123, 8477.
15 K. S. Kim, J. Park, Y. J. Lee and Y. S. Seo, Angew. Chem., Int. Ed.,
2003, 42, 459.
PhCH2O), 6.46 (d, J1,2 1.8 Hz, 1 H, H-1), 7.13–7.79 (m, 29 H, ArH); 13
C
NMR (63 MHz, CDCl3)  67.6, 68.9, 71.9, 72.7, 73.3, 73.5, 74.2, 74.8,
75.4, 79.4, 93.7 (C-1), 127.6, 127.7, 127.7, 127.8, 127.9, 128.1, 128.3,
128.4, 128.4, 128.6, 128.9, 129.3, 131.2, 131.3, 131.6, 132.1, 135.4,
138.0, 138.3, 138.3, 138.4, 166.0 (CO), 166.8 (CO).; Anal. Calcd
for C49H46O9: C, 75.56; H, 5.95. Found: C, 75.59; H, 6.03.
16 K. S. Kim, S. S. Kang, Y. S. Seo, H. J. Kim, Y. J. Lee and K.-S. Jeong,
Synlett, 2003, 1311.
17 P. J. Garegg, Adv. Carbohydr. Chem. Biochem., 1997, 52, 179.
18 R. R. Schmidt and W. Kinzy, Adv. Carbohydr. Chem. Biochem., 1994,
50, 21.
21 Typical procedure for the synthesis of disaccharide 25 by glycosylation
with glycosyl benzyl phthalate 3. A solution of the mannopyranosyl
donor 3 (62 mg, 0.08 mmol, 1.0 equiv.), the acceptor 10 (74 mg,
0.16 mmol, 2.0 equiv.), and TMSOTf (14.5 L, 1.0 equiv..) in CH2Cl2
(5 mL) was stirred at 0 °C for 1.5 h. The reaction was quenched by
addition of saturated aqueous NaHCO3 solution (2 mL) and then
extracted with CH2Cl2 (3 × 5 mL). The combined organic layer was
washed with brine (10 mL), dried (MgSO4), and concentrated in vacuo.
The residue was purified by silica gel flash column chromatography
to afford the disaccharide 25 (54 mg, 68%): colorless oil, Rf = 0.35
19 A. Padwa, S. P. Carter, H. Nimmesgern and P. D. Stull, J. Am. Chem.
Soc., 1998, 110, 2894.
20 Typical procedure for the preparation of glycosyl benzyl phthalate 3.
To a solution of the 2,3,4,6-tetra-O-benzyl-D-mannopyranose (3.00 g,
5.4 mmol, 1.0 equiv.), benzyl hydrogen phthalate (1) (2.77 g, 10.8 mmol,
2.0 equiv.), and DMAP (200 mg, 1.64 mmol, 0.3 equiv.) in CH2Cl2
(20 mL) was added DCC (1.90 g, 9.2 mmol, 1.7 equiv.) at 0 °C. The
reaction mixture was stirred at room temperature for 3 h, diluted with
CH2Cl2 (50 mL), and filtered through Celite. The filtrate was washed
with water, the combined organic layer was dried (MgSO4), and con-
centrated in vacuo. The residue was purified by silica gel flash column
chromatography to afford mannosyl benzyl phthalate 3 (3.36 g, 80%):
Rf = 0.5 (n-hexane/EtOAc/CH2Cl2, 6:1:0.5, v/v); []D20 = +29.2 (c 0.2,
CHCl3); 1H NMR (250 MHz, CDCl3)  3.72 (dd, J5,6a 1.6, J6a,6b11.0 Hz,
1 H, H-6a), 3.81 (dd, J5,6b 4.2, J6a,6b 11.0 Hz, 1 H, H-6b), 3.88–3.95 (m,
2 H, H-2, H-3), 4.03–4.06 (m, 1 H, H-5), 4.14 (dd, J3,4 9.6, J4,5 9.6 Hz,
1 H, H-4), 4.53 and 4.67 (ABq, JAB 12.1 Hz, 2 H, PhCH2O), 4.54 and
4.90 (ABq, JAB 10.6 Hz, 2 H, PhCH2O), 4.57 (s, 2 H), 4.77 and 4.83
(ABq, JAB 12.3 Hz, 2 H, PhCH2O), 5.22 and 5.28 (ABq, JAB 12.4 Hz, 2 H,
1
(n-hexane/EtOAc, 3;1, v/v); []D20 = +14.2 (c = 2.3, CHCl3); H NMR
(500 MHz, CDCl3)  3.37 (s, 3 H, CH3O), 3.52 (d, J = 10.6 Hz, 1 H),
3.65 (dd, J = 4.22, 10.7 Hz, 1 H), 3.71–3.77 (m, 6 H), 3.81 (d, J = 8.5 Hz,
1 H), 3.83 (d, J = 9.3 Hz, 1 H), 3.98 (dd, J = 9.5, 9.5 Hz, 1 H), 4.06 (dd,
J = 9.0, 9.0 Hz, 1 H), 4.25 (br s, 2 H), 4.34 (d, J = 11.6 Hz, 1 H), 4.42
(d, J = 12.1 Hz, 1 H), 4.47 (d, J = 10.9 Hz, 1 H), 4.50 (d, J = 10.8 Hz,
1 H), 4.51–4.56 (m, 3 H), 4.57 (d, J = 11.3 Hz, 1 H), 4.61 (d, J = 12.2 Hz,
1 H), 4.62 (d, J = 12.6 Hz, 1 H), 4.66 (d, J = 12.5 Hz, 1 H), 4.79 (br s,
1H, H-1′), 4.83 (d, J = 10.8 Hz, 1 H), 5.32 (br s, 1H, H-1), 7.17–7.31
(m, 35 H, ArH); 13C NMR (125 MHz, CDCl3)  55.1, 69.3, 70.3, 71.2,
71.4, 72.0(2), 72.5, 73.0, 73.3, 73.5, 73.7, 74.8(2), 75.1, 75.9, 80.1, 80.3,
98.7 (C-1′), 100.1 (C-1), 127.2, 127.3, 127.6, 127.6, 127.8, 128.1, 128.4,
128.6, 138.3, 138.6, 138.7, 138.9.; Anal. Calcd for C62H66O11: C, 75.43;
H, 6.74. Found: C, 75.44; H, 6.78.
2 4 1 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 4 0 8 – 2 4 1 0