An efficient glycosidation method using 2,3-unsaturated glycosyl donors

Article abstract of DOI:10.1016/j.tetlet.2006.10.095

A novel class of 'armed' glycosyl donors containing a double bond at the C-2 position was designed by mimicking the mechanism of lysozyme-initiated hydrolysis. These donors were used to achieve chemoselective glycosidation of hex-2-enopyranosyl acetate an

Full text of DOI:10.1016/j.tetlet.2006.10.095

Tetrahedron Letters 47 (2006) 9039–9043
An efficient glycosidation method using 2,3-unsaturated
glycosyl donors
Kaname Sasaki, Shuichi Matsumura and Kazunobu Toshima*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
Received 17 August 2006; revised 17 October 2006; accepted 19 October 2006
Available online 7 November 2006
Dedicated to Professor K. C. Nicolaou on the occasion of his 60th birthday
Abstract—A novel class of ‘armed’ glycosyl donors containing a double bond at the C-2 position was designed by mimicking the
mechanism of lysozyme-initiated hydrolysis. These donors were used to achieve chemoselective glycosidation of hex-2-enopyranosyl
acetate and hexopyranosyl acetate, and synthesis of O-glycosidic linkages between highly deoxygenated sugars and tertiary alcohols.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Since the development by Koenigs and Knorr of a
glycosidation method using glycosyl halides and a silver
salt in 1901,1 much attention has been paid to improving
O-glycosidation reactions.2 The ‘armed–disarmed’ con-
cept introduced by Fraser-Reid and co-workers in
1988 has been one of the most influential ideas in this
field over the past few decades.3 Although glycosides
consisting of a 2,3,6-trideoxysugar and a tertiary alcohol
are found in several biologically important natural
products, such as lactonamycin4 and vineomycin B2,5
only a few attempts at constructing such a structure
have been reported, including that of Sulikowski and
co-workers.6 The purpose of this paper is to demon-
strate a novel glycosidation method inspired by an enzy-
matic reaction as a new concept in armed–disarmed
methodology and as a powerful protocol for construct-
ing glycosidic linkages between highly deoxygenated
sugars and alcohols with low nucleophilicity.
tion (4H5), which is very similar to the conformation
of the oxocarbenium intermediate;8 and (2) the carbox-
ylate anion of Asp 52 in the lysozyme stabilizes the
generated oxocarbenium cation via electrostatic interac-
tion.9 These factors, which increase the reaction rate of
hydrolytic cleavage of oligosaccharides, prompted us to
design a novel class of glycosyl donors possessing an
endo double bond at the C-2 position, as shown in Fig-
ure 1. The introduction of an unsaturated bond causes
distortion of the glycosyl donor into a half-chair confor-
mation in its ground state, similar to the change in
conformation of the mucopolysaccharide D-sugar
induced by lysozyme. In addition, when these glycosyl
donors are used, the oxocarbenium intermediate of the
glycosidation reaction may be stabilized in a similar
fashion to that described above, because the cation
center generated in the reaction is located at the allylic
position of the double bond. Therefore, we anticipated
that 2,3-unsaturated glycosyl donors would be very
useful and effective in mild chemical glycosidation
reactions.
The key idea in our study is lysozyme, which is known to
recognize six hexose residues of mucopolysaccharides
(A–F sugars) and to regioselectively cleave hexasaccha-
rides between the D- and E-sugars, as shown in Figure
1.7 The two most likely explanations for its regioselecti-
vity are as follows: (1) Conformational distortion forces
the D-sugar to adopt an unusual half-chair conforma-
To confirm our hypothesis, we examined glycosidation
reactions using 2,3-unsaturated glycosyl donors (hex-2-
enosyl donors) and 2,3-saturated glycosyl donors (hexos-
yl donors). Competitive glycosidation was investigated
using the hex-2-enosyl donor 1 or 6 (1.0 equiv), the
hexosyl donor 2 or 7 (1.0 equiv), and glycosyl acceptor
3 (0.9 equiv).10,11 The results are shown in Table 1. It
was found that the glycoside 4 was produced in prefer-
ence to 5 in all glycosidations of 1 and 2 with 3 using
Keywords: Carbohydrates; Chemoselectivity; Deoxy sugar; Glycosidation.
*
Corresponding author. Tel./fax: +81 45 566 1576; e-mail: toshima@
applc.keio.ac.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.095

9040
K. Sasaki et al. / Tetrahedron Letters 47 (2006) 9039–9043
Hydrolysis of mucopolysaccharide by lysozyme
OH
O
OH
O
C
C
D
OH
O
OH
O
D
OH
O
C
O
E
+
D
O
E
H2O
Lysozyme
O
O
O
HO
O
O
RO
O
RO
O
HO
RO
OH
HO
NHAc
Hydrolysis
NHAc
AcHN
NHAc
AcHN
O-
Half-chair conformation
induced by lysozyme
Intermediate stabilized
by Asp 52 of lysozyme
O
Asp
The present glycosidation
Activator
(PO)n
ROH
+
O
O
O
O
(PO)n
(PO)n
(PO)n
+
Glycosidation
OR
X
Half-chair conformation
induced by the double bond
Intermediate stabilized
by allylic cation
Figure 1. Regioselective hydrolysis of mucopolysaccharide by lysozyme (above), and the concept of the present glycosidation.
OAc
syl acceptor to obtain hex-2-enosyl-hexose disaccharide
12. Hex-2-enosyl-hexose disaccharides are found, for
example, in the angucycline group of antibiotics as acu-
rose–rhodinose disaccharides.13 As shown in Scheme 1,
glycosidation using TBSOTf at ꢀ78 ꢁC for 24 h pro-
ceeded chemoselectively to give the desired disaccharide
12 in good yield with a high a-stereoselectivity. In con-
trast, the oligosaccharide 13 was generated only to a
small extent, resulting from the undesired activation of
11, which leads to self-condensation. Based on these
results, we found that a pair consisting of a hex-2-enosyl
donor and the corresponding hexosyl donor forms a
new family of armed and disarmed donors.
BzO
BnO
AcO
O
O
BzO
21
22
Figure 2. Glycal 21 and 2,3,6-trideoxyglycosyl acetate 22.
BF3ÆOEt2, montmorillonite K-10 (MK-10), TfOH,
TMSOTf, and TBSOTf as activators (Table 1, entries
1–5).12 Similarly, glycoside 8 was selectively obtained
in preference to glycoside 9 in the glycosidation reac-
tions of 6 and 7 with 3 (Table 1, entries 6 and 7). These
results clearly show that the hex-2-enosyl donors, which
mimic the mechanism of the lysozyme hydrolysis reac-
tion, are much more reactive than the corresponding
hexosyl donors.
We then examined the possibility that this novel class of
glycosyl donors could be a powerful tool in the cons-
truction of glycosides of tertiary alcohols. The forma-
tion of O-glycosidic linkages between 3ꢁ-alcohols and
highly deoxygenated sugars is a challenging task, for
the following two reasons: (1) tertiary alcohols have a
tendency to generate carbocations along with elimina-
Based on these results, we then examined chemoselective
glycosidation using hex-2-enopyranosyl acetate 10 as a
glycosyl donor and hexopyranosyl acetate 11 as a glyco-
Table 1. Competitive glycosidation of 3 using 1 and 2 or 6 and 7
R3
R1
R2
OBz
O
OBz
O
HO
O
BnO
R4
BnO
BnO
OMe
OAc
OAc
1: R1 = H, R2 = OBz
6: R1 = OBz, R2 = H
2: R3 = H, R4 = OBz
7: R3 = OBz, R4 = H
3
R1
R3
OBz
O
OBz
O
activator
O
BnO
R4
R =
R2
BnO
CH2Cl2, MS 5A
BnO
OR
OR
OMe
5: R3 = H, R4 = OBz
9: R3 = OBz, R4 = H
4: R1 = H, R2 = OBz
8: R1 = OBz, R2 = H
Entrya
Donors
Activator (equiv)
Temperature, time
Yield/% (a:b ratio)b
1
2
3
4
5
6
7
1 and 2
1 and 2
1 and 2
1 and 2
1 and 2
6 and 7
6 and 7
BF3ÆOEt2 (1.0)
MK-10c
HOTf (0.5)
TMSOTf (0.3)
TBSOTf (0.3)
MK-10c
ꢀ60 ꢁC, 24 h
0 ꢁC, 4 d
4: 72 (80:20), 5: 3 (67:33)
4: 80 (56:44), 5: 4 (35:65)
4: 85 (80:20), 5: 10 (60:40)
4: 89 (69:31), 5: 5 (60:40)
4: 91 (68:32), 5: 4 (58:42)
8: 80 (80:20), 9: 5 (90:10)
8: 94 (94:6), 9: 6 (90:10)
ꢀ70 ꢁC, 24 h
ꢀ78 ꢁC, 3 h
ꢀ70 ꢁC, 3 h
ꢀ20 ꢁC, 4 d
ꢀ78 ꢁC, 24 h
TBSOTf (0.3)
a The ratio of unsaturated donor (1 or 6) to saturated donor (2 or 7) to acceptor 3 was 1:1:0.9.
b Yields and a:b ratios were determined by HPLC analysis.
c 100 wt % of MK-10 to 2,3-unsaturated donor 1 or 6 was used.

K. Sasaki et al. / Tetrahedron Letters 47 (2006) 9039–9043
9041
BzO
BzO
BnO
O
O
TBSOTf (0.3 eq.)
HO
CH2Cl2, MS
5A -78 oC, 24 h
OAc
10 (1.0 eq.)
OAc
11 (1.0 eq.)
OBz
O
BzO
BnO
O
H
O
OBz
O
BzO
O
O
nO
13
OAc
12 (81%, α:β = 8:1)
OAc
Scheme 1. Chemoselective glycosidation of 10 and 11.
tion of a hydroxyl group under acidic conditions; and
(2) because of the low nucleophilicity of tertiary alco-
hols, the active species—an oxocarbenium intermediate
generated from a glycosyl donor—is easily converted
to the corresponding glycal via deprotonation at the
C-2 position. Our novel glycosidation method succeeded
in overcoming these problems. Because hex-2-enopyr-
anosyl glycosyl donors can be activated under much
milder acidic conditions than the corresponding hexo-
pyranosyl donors, acid-sensitive tertiary alcohols could
be effectively glycosylated. In addition, the lack of a b-
proton at the cationic center of the oxocarbenium ion
prevents the side reaction mentioned above. As shown
in Table 2, glycosidation of adamantan-1-ol (14) and
tert-butanol (16) with an almost equal amount of the
erythro-type hex-2-enopyranosyl acetate 10 proceeded
effectively in the presence of a very mild Lewis acid,
Yb(OTf)3,14 at 0 ꢁC to give glycosides 15 and 17, respec-
tively, in high yields. For glycosidations using 18, whose
a-glycosides can easily be converted into naturally
occurring L-rhodinosides, L-acurosides, L-cinerulosides,
and L-rhamnosides by appropriate reduction and/or
oxidation,15 the corresponding glycosides 19 and 20
were also obtained in good to high yields with excellent
a-stereoselectivities.
When the glycal 21, which is the synthetic equivalent of
10 and can be converted into 15 and 17 by Ferrier
rearrangement,16 was used as a glycosyl donor for
glycosidation of 14 under the same conditions used for
10, the reaction did not proceed. In addition, when the
hexopyranosyl donor 22 was used instead of 18 for
glycosidation of 14, it could not be activated below
0 ꢁC in the presence of Yb(OTf)3, and when the reaction
was carried out between 0 and 25 ꢁC, the corresponding
a-glycoside was obtained in a yield of only 22%, accom-
panied by considerable amounts of by-products. These
results indicate that glycosidation using hex-2-enosyl
donors proceeds under conditions that are considerably
milder than usual, and that this method can be used for
effective construction of glycosidic linkages even for
tertiary alcohols with low nucleophilicity (Fig. 2).
In conclusion, we have designed a novel class of glycosyl
donors with a pyran ring containing an unsaturated
bond, and clearly demonstrated that they can act as
Table 2. Glycosidation of 3ꢁ-alcohols with 2,3-unsaturated donor 10 or 18 using Yb(OTf)3
Entrya
donor
ROH
Temperature, time
Yield/% (a:b ratiob)
BzO
O
1
10
10
0 ꢁC, 19 h
BnO
HO
O
14
15: 74% (89:11)
BzO
O
BnO
HO
2
3
0 ꢁC, 19 h
O
16
17: 71% (86:14)
OAc
O
O
O
14
ꢀ30 ꢁC, 3 d
BzO
18
BzO
19: 72% (α)
O
O
4
18
16
ꢀ30 ꢁC, 3 d
BzO
20: 80% (α)
a In all entries, the ratio of donor to ROH was 1.0:0.9.
b Isolated yield.

9042
K. Sasaki et al. / Tetrahedron Letters 47 (2006) 9039–9043
11. The 2,3-dideoxy glycosyl donor 2 was synthesized by
hydrogenation of 1 using Rh/Al2O3 in EtOAc–PhMe;
Sasaki, K.; Wakamatsu, T.; Matsumura, S.; Toshima, K.
Tetrahedron Lett. 2006, 47, 8271–8274.
armed glycosyl donors. Furthermore, they were found
to be very effective in the synthesis of O-glycosidic link-
ages between highly deoxygenated sugars and tertiary
alcohols.
12. The configurations at the anomeric positions of the 2,3-
1
unsaturated glycosides were determined by the H NMR
analyses of the corresponding 2,3-saturated glycosides
which were obtained by standard hydrogenations. Rep-
resentative 1H NMR (300 MHz, CDCl3): spectra [d
(TMS), J (Hz)] are the following. Compound 4a: 8.02–
7.95 (4H, m, ArH), 7.66–7.52 (2H, m, ArH), 7.52–7.22
Acknowledgements
This research was supported in part by Grant-in-Aid for
the 21st Century COE Program ‘KEIO Life Conjugated
Chemistry’, for Scientific Research on Priority Areas
0
0
(19H, m, ArH), 6.02 (1H, ddd, J2 ,3 = 10.2,
J1 ,3 = J3 ,4 = 0.9, H-30), 5.91 (1H, ddd, J2 ,3 = 10.2,
0
0
0
0
0
0
18032068 and for JSPS Fellows 18 6013 from the Min-
*
J1 ,2 = 2.4, J2 ,4 = 2.1, H-200), 5.68 (1H, ddd, J4 ,5 = 7.2,
0
0
0
0
0
0
istry of Education, Culture, Sports, Science, and Tech-
nology, Japan.
0
0
0
0
0
0
J2 ,4 = 2.1, J3 ,4 = 0.9, H-4 ), 5.16 (1H, dd, J1 ,2 = 2.4,
J1 ,3 = 0.9, H-10), 4.99 and 4.80 (2H, ABq, J = 10.8,
ArCH2), 4.91 and 4.64 (2H, ABq, J = 11.4, ArCH2), 4.78
and 4.67 (2H, ABq, J = 12.0, ArCH2), 4.61 (1H, d,
0
0
0
0
0
0
J1,2 = 3.6, H-1), 4.46 (1H, dd, J6 ,6 = 8.7, J5 ,6 = 4.5,
References and notes
H-60), 4.37 (1H, ddd, J4 ,5 = 7.2, J5 ,6 = 5.1, J5 ,6 = 4.5,
0
0
0
0
0
0
H-50), 4.34 (1H, dd, J6 ,6 = 8.7, J5 ,6 = 5.1, H-60), 4.01
(1H, dd, J6,6 = 11.4, J5,6 = 4.8, H-6), 4.00 (1H, dd,
J2,3 = J3,4 = 9.3, H-3), 3.82–3.72 (2H, m, H-5, 6), 3.53
(1H, dd, J3,4 = J4,5 = 9.3, H-4), 3.49 (1H, dd, J2,3 = 9.3,
J1,2 = 3.6, H-2), 3.38 (3H, s, OMe). Compound 4b: 8.04–
7.96 (4H, m, ArH), 7.61–7.46 (2H, m, ArH), 7.46–7.22
0
0
0
0
1. Koenigs, W.; Knorr, E. Chem. Ber. 1901, 34, 957–981.
2. (a) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25,
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¨
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1503–1531; (d) Boons, G.-J. Tetrahedron 1996, 52, 1095–
1121; (e) Davis, D. G. J. Chem. Soc., Perkin Trans. 1 2000,
0
0
0
0
(19H, m, ArH), 6.10 (1H, ddd, J2 ,3 = 10.2, J3 ,4 = 3.6,
2137–2160; (f) Fugedi, P. In The Organic Chemistry of
¨
J1 ,3 = 1.5, H-30), 5.92 (1H, ddd, J2 ,3 = 10.2,
0
0
0
0
Sugars; Levy, D. E., Fugedi, P., Eds.; CRC Press: Boca
¨
J1 ,2 = J2 ,4 = 1.5, H-20), 5.55 (1H, ddd, J4 ,5 = 11.4,
0
0
0
0
0
0
Raton, 2006; pp 89–179.
0
0
0
0
J3 ,4 = 3.6,
J1 ,3 = 1.5,
H-40),
5.16
(1H,
dd,
3. Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-
Reid, B. J. Am. Chem. Soc. 1988, 110, 5583–5584.
4. (a) Matsumoto, N.; Tsuchida, T.; Maruyama, M.; Sawa,
R.; Kinoshita, N.; Homma, Y.; Takahashi, Y.; Iinuma,
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(b) Matsumoto, N.; Tsuchida, T.; Maruyama, M.;
Kinoshita, N.; Homma, Y.; Iinuma, H.; Sawa, T.;
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Antibiot. 1999, 52, 269–275; (c) Matsumoto, N.; Tsuchida,
T.; Nakamura, H.; Sawa, R.; Takahashi, Y.; Naganawa,
H.; Iinuma, H.; Sawa, T.; Takeuchi, T.; Shiro, M. J.
Antibiot. 1999, 52, 276–280.
5. (a) Omura, S.; Tanaka, H.; Oiwa, R.; Awaya, J.; Masuma,
R.; Tanaka, K. J. Antibiot. 1977, 30, 908–916;
(b) Imamura, N.; Kakinuma, N.; Ikekawa, H.; Tanaka,
H.; Omura, S. J. Antibiot. 1981, 34, 1517–1518.
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61, 6–7.
7. (a) Jencks, W. P. In Catalysis in Chemistry and Enzymo-
logy; Dover: New York, 1987; pp 302–305; (b) Strynadka,
N. C. J.; James, M. N. G. J. Mol. Biol. 1991, 220, 401–424.
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D. C.; Tjian, R. J. Mol. Biol. 1974, 88, 349–371;
(b) Chipman, D. M.; Sharon, N. Science 1969, 167, 454–
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416–428; (e) Imoto, I.; Johnson, L. N.; North, A. C. T.;
Phillips, D. C.; Rupley, J. A. In The Enzymes; 3rd ed.;
Boyer, P., Ed.; Academic Press: New York, 1972; Vol. 7,
pp 665–868.
9. (a) Dahlquist, F. W.; Rand-Meir, T.; Raftery, M. A.
Biochemistry 1969, 8, 4214–4221; (b) Smith, L. E. H.;
Mohr, L. H.; Raftery, M. A. J. Am. Chem. Soc. 1973, 95,
7497–7501; (c) Rosenberg, S.; Kirsh, J. F. Biochemistry
1981, 20, 3196–3204.
J1 ,2 = J1 ,3 = 1.5, H-10), 4.98 and 4.80 (2H, ABq,
J = 11.1, ArCH2), 4.87 and 4.61 (2H, ABq, J = 11.1,
ArCH2), 4.78 and 4.66 (2H, ABq, J = 12.0, ArCH2), 4.59
0
0
0
0
0
0
(1H, d, J1,2 = 3.6, H-1), 4.54 (1H, dd, J6 ,6 = 11.7,
J5 ,6 = 6.0, H-60), 4.49 (1H, dd, J6 ,6 = 11.7, J5 ,6 = 5.4,
0
0
0
0
0
0
H-60), 4.31 (1H, ddd, J4 ,5 = 11.4, J5 ,6 = 6.0, J5 ,6 = 5.4,
H-60), 4.08–4.01 (1H, m, H-6), 3.97 (1H, dd,
J2,3 = J3,4 = 9.3, H-3), 3.79–3.71 (2H, m, H-5, 6), 3.57
(1H, dd, J3,4 = J4,5 = 9.3, H-4), 3.53 (1H, dd, J2,3 = 9.3,
J1,2 = 3.6, H-2), 3.30 (3H, s, OMe). Compound 5a: 8.02–
7.95 (2H, m, ArH), 7.93–7.88 (2H, m, ArH), 7.58–7.48
(2H, m, ArH), 7.42–7.22 (19H, m, ArH), 5.11–5.01 (1H,
m, H-40), 5.00 and 4.80 (2H, ABq, J = 10.8, ArCH2), 4.98
and 4.68 (2H, ABq, J = 10.8, ArCH2), 4.73 (1H, br dd, H-
10), 4.78 and 4.68 (2H, ABq, J = 12.0, ArCH2), 4.63 (1H,
0
0
0
0
0
0
0
0
0
0
d, J1,2 = 3.6, H-1), 4.46 (1H, dd, J6 ,6 = 9.9, J5 ,6 = 2.1,
H-60), 4.26 (1H, dd, J6 ,6 = 9.9, J5 ,6 = 6.0, H-60), 4.22
0
0
0
0
(1H, ddd, J4 ,5 = 9.3, J5 ,6 = 6.0, J5 ,6 = 2.1, H-50), 4.01
(1H, dd, J2,3 = J3,4 = 9.3, H-3), 3.96 (1H, dd, J6,6 = 11.1,
J5,6 = 4.8, H-6), 3.81 (1H, ddd, J4,5 = 10.2, J5,6 = 4.8,
J5,6 = 1.2, H-5), 3.68 (1H, dd, J6,6 = 11.1, J5,6 = 1.2, H-6),
3.53 (1H, dd, J4,5 = 10.2, J3,4 = 9.3, H-4), 3.48 (1H, dd,
J2,3 = 9.3, J1,2 = 3.6, H-2), 3.40 (3H, s, OMe), 2.21–2.11
(1H, m, H-30), 2.05–1.80 (3H, m, H-20 · 2, H-30). Com-
pound 5b: 8.02–7.95 (4H, m, ArH), 7.61–7.47 (2H, m,
ArH), 7.44–7.22 (19H, m, ArH), 5.02 (1H, ddd,
0
0
0
0
0
0
J3 ,4 = 9.3, J4 ,5 = 9.0, J3 ,4 = 5.1, H-40), 4.98 and 4.80
(2H, ABq, J = 10.5, ArCH2), 4.88 and 4.59 (2H, ABq,
J = 11.1, ArCH2), 4.78 and 4.65 (2H, ABq, J = 12.3,
ArCH2), 4.60 (1H, d, J1,2 = 3.6, H-1), 4.56 (1H, dd,
0
0
0
0
0
0
J6 ,6 = 12.0, J5 ,6 = 3.9, H-60), 4.43 (1H, br dd,
0
0
0
0
J1 ,2 = 9.0, H-10), 4.40 (1H, dd, J6 ,6 = 12.0, J5 ,6 = 6.0,
0
0
0
0
0
0
H-60), 4.09 (1H, br dd, J6,6 = 10.5, H-6), 3.98 (1H, dd,
0
0
J2,3 = J3,4 = 9.6, H-3), 3.93 (1H, ddd, J4 ,5 = 9.0,
J5 ,6 = 6.0, J5 ,6 = 3.9, H-50), 3.75 (1H, br ddd,
J4,5 = 9.6, J5,6 = 3.9, H-5), 3.64 (1H, dd, J6,6 = 10.5,
J5,6 = 3.9, H-6), 3.56 (1H, dd, J3,4 = J4,5 = 9.6, H-4),
3.54 (1H, dd, J2,3 = 9.6, J1,2 = 3.6, H-2), 3.33 (3H, s,
OMe), 2.40–2.30 (1H, m), 1.92–1.57 (3H, m).
0
0
0
0
10. The 2,3-unsaturated glycosyl donor 1 was prepared from
the known methyl a-D-erythro-hex-2-enopyranoside in
two steps including benzoylation followed by acetolysis
(Ac2O, H2SO4, ꢀ40 ꢁC): Fraser-Reid, B.; Boctor, B. Can.
J. Chem. 1969, 47, 393–401.

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