Glycosylation of alcohols using glycosyl boranophosphates as glycosyl donors

Article abstract of DOI:10.1016/j.tetlet.2013.04.032

A novel glycosylation that uses glycosyl boranophosphate triesters as glycosyl donors and trityl cation (Tr⁺) as an activator was developed. Two types of reactions were studied: (1) the boranophosphate triester was activated with TrNTf₂ to react with an alcohol and (2) O-trityl ethers worked as both glycosyl acceptors and Tr⁺ sources. The latter gave better results and the desired O-glycosylation products were rapidly generated and isolated in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2013.04.032

Tetrahedron Letters 54 (2013) 3731–3734
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Glycosylation of alcohols using glycosyl boranophosphates as
glycosyl donors
⇑
Shiro Tatsumi, Fumiko Matsumura, Natsuhisa Oka, Takeshi Wada
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 February 2013
Revised 4 April 2013
Accepted 9 April 2013
Available online 20 April 2013
A novel glycosylation that uses glycosyl boranophosphate triesters as glycosyl donors and trityl cation
(Tr+) as an activator was developed. Two types of reactions were studied: (1) the boranophosphate triest-
er was activated with TrNTf2 to react with an alcohol and (2) O-trityl ethers worked as both glycosyl
acceptors and Tr+ sources. The latter gave better results and the desired O-glycosylation products were
rapidly generated and isolated in moderate to good yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Glycosylation
Boranophosphate
Glycosyl donor
Trityl cation
Oligosaccharide
Glycosyl phosphate triesters and their analogs are known to
work as glycosyl donors and have been successfully applied to
the synthesis of oligosaccharides.1,2 One of their significant fea-
tures is that their reactivity can be tuned by modifying the ano-
meric phosphate group.3,4 Since glycosyl donors that can be
specifically activated in the presence of another kind of donor are
useful to simplify the synthesis of complex oligosaccharides and
glycoconjugates,5 various kinds of glycosyl phosphate analogs have
been developed. However, the development of glycosyl phosphate
analogs that are ‘orthogonal’ to each other is still a challenging
task, and only a few kinds of such glycosyl phosphate derivatives
have been reported to date.4
P+ moiety, which then acted as a glycosyl donor, though this reac-
tion mechanism is still hypothetical (Scheme 1, lower). We consid-
ered that the glycosyl boranophosphotriesters with such
properties might be useful as glycosyl donors orthogonal to other
kinds of glycosyl phosphates. We describe herein preliminary re-
sults of our study on the development of novel glycosylation reac-
tion using the glycosyl boranophosphotriesters as donors.
O
R1O
O
O
BH2
OR2
P
On the other hand, we have recently found that glycosyl bor-
anophosphate derivatives,1c,6,7 in which the P@O moiety of glyco-
syl phosphate triesters is replaced by a P?BH3 group,8 have
rather unusual properties for a glycosyl phosphate analog. Thus,
glycosyl boranophosphate triesters are fairly stable in the presence
of a Lewis acid, which can easily activate the corresponding glyco-
syl phosphite and phosphate triesters.7a Moreover, the glycosyl
boranophosphate derivatives were found to undergo unique reac-
tions. Since we had found that glycosyl boranophosphate diesters
were smoothly converted into the corresponding glycosyl H-phos-
phonate diesters by treatment with a trityl cation (Tr+) (Scheme 1,
upper),1c,7a,c we also treated a glycosyl boranophosphate triester
(1) with TrClO4 in the presence of 4-tert-butylcyclohexanol to find
that the mixture gave the glycosylation product. It is likely that Tr+
oxidatively activated 1 to generate an active intermediate having a
TrH
Tr+
O
O
H
R1O
R1O
H
BH2
OR2
O
O
O
H
P
P
−O
OR2
-phosphonate diester
boranophosphate diester
OBn
Tr+
OBn
O
H
BnO
BnO
O
BnO
BnO
BH2
OMe
O
MeO
BnO
OR3
P
BnO
R3OH
TrClO4
BnO
OBn
1
glycosylation
boranophosphate triester
O
BnO
O
MeO
+ BH2
BnO
P
OMe
Scheme 1. Reactions of Tr+ with glycosyl boranophosphate diester (upper) and
triester (lower). R3OH = trans-4-tert-butylcyclohexanol.
⇑
Corresponding author. Tel.: +81 4 7136 3611.
E-mail address: wada@k.u-tokyo.ac.jp (T. Wada).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.032

3732
S. Tatsumi et al. / Tetrahedron Letters 54 (2013) 3731–3734
Table 2
Since we found that the preparation of sufficiently active TrClO4
was not always reproducible, we compared several sources of Tr+
and chose trityl N,N-bis(trifluoromethanesulfonic)imidate (TrN
Tf2), which was superior in terms of preparation, handling, and
reactivity to the others (TrClO4, TrOCOCF3, TrOTf, and TrPF6). First
of all, glycosylation of cholesterol 29 was chosen as a model reac-
tion and the reactions were carried out with donor 1 (3.0 equiv)
and cholesterol 2 (1.0 equiv) in the presence of TrNTf2 (6.0 equiv)
in pure or mixed solvents at 0 °C for optimization of the reaction
conditions (Table 1). CH2Cl2 was used as a solvent in every case
to dissolve highly lipophilic cholesterol 2, and toluene, MeCN, diox-
ane, and THF were tested as cosolvents. We found that the yield of
the desired product 3 was low when the reaction was conducted in
CH2Cl2 (entry 1) and the addition of nonpolar toluene did not im-
prove the result (entry 2). In contrast, the use of polar MeCN and
1,4-dioxane as cosolvents improved the yield (entries 1 vs 3 and
4) and 1,4-dioxane with a little higher Gutmann donor number
(DN)10 (14.8) than MeCN (14.1) gave a better result. However,
the use of THF as a cosolvent resulted in a poor yield of 3 (entry
5), which can probably be attributed to the deactivation of TrNTf2
by highly coordinating THF (DN = 20.0); the color of the reaction
mixture gradually changed from clear yellow to black.11 The mod-
est Lewis basicity of dioxane may be appropriate to promote this
reaction without deactivating TrNTf2. Thus, the desired product 3
was obtained in a modest yield via the novel Tr+-promoted glyco-
sylation. But the yield was not improved further by changing reac-
tion conditions. For example, reactions conducted at rt yielded
substantial byproducts. The main byproduct was 1-deoxy-2,3,4,6-
tetra-O-Bn-glucose, which was probably formed by the reduction
of the oxocarbenium ion generated from 1 with the BH3 group of
another molecule of 1. Lowering the temperature significantly slo-
wed down the reaction and the desired product 3 was not obtained
in sufficient yield even with extended reaction time (entry 6).
In order to improve the reaction, we next focused on the use of
trityl ethers as glycosyl acceptors. Thus, O-tritylcholesterol 512 was
used in the place of cholesterol 2 and detritylated in situ by TfOH.
Glycosylation using O-tritylcholesterol 5 as acceptor
OR
O
RO
RO
+
BH3
O
MeO
RO
P
OMe
TrO
1: R = Bn (α:β = 74:26)
5
4: R = Bz (β only)
(2.0 equiv)
(1.0 equiv)
OR
TfOH (0.57 equiv)
solvent, rt
O
RO
RO
O
RO
3: R = Bn
6: R = Bz
Entry Donor Solvent
Time (min) Yield (%)a :b)b
(a
1
2
3
4
5
1
1
1
4
4
4
1
CH2Cl2
Dioxane–CH2Cl2 (2:1, v/v)
Dioxane
CH2Cl2
Dioxane–CH2Cl2 (2:1, v/v)
dioxane
240
10
10
120
10
10
40 (54:46)
76 (77:23)
83 (83:17)
61 (b Only)
74 (b Only)
67 (b Only)
55 (74:26)
6
7c
Dioxane–CH2Cl2 (2:1, v/v)
30
a
b
c
Isolated yield.
Determined by 1H NMR.
2.0 equiv of TrNTf2 and 2.0 equiv of cholesterol were used as activator and
acceptor, respectively.
The resultant Tr+ would activate the glycosyl boranophosphotriest-
ers to promote the glycosylation of cholesterol generated from 5 in
situ. As reported in the literature,13 the use of O-tritylalcohols as
glycosyl acceptors in the place of alcohols is advantageous when
complex acceptors are used because protecting group-manipula-
tion is simplified and this would also allow us to circumvent the
use of moisture-sensitive TrNTf2.
Table 1
As shown in Table 2, per-O-Bn- and Bz-glycosyl boranophos-
photriesters (1 and 4) were allowed to react with O-tritylcholester-
ol 5 in the presence of TfOH in CH2Cl2, dioxane, or a 1:2 mixture of
these two solvents. Tf2NH was found to be ineffective probably be-
cause of the low solubility in CH2Cl2. Compared with the method
using TrNTf2 and cholesterol 2, the desired product 3 was obtained
in better yield (entries 2 vs 7). Per-O-Bn-donor 1 gave the product 3
Tr+-promoted glycosylation of cholesterol
2
with glycosyl boranophosphotriester
derivative 1
OBn
O
BnO
BnO
+
BH3
O
MeO
BnO
as an a,b-mixture, while the per-O-Bz counterpart 4 gave b-6 ste-
reoselectively, indicating that the reaction proceeded via the
P
OMe
HO
1
2
(3.0 equiv)
(1.0 equiv)
Table 3
OBn
Optimization of molar equivalent of trityl ether 5a
TrNTf2 (6.0 equiv)
solvent, 0 °C, MS3A or 4A
O
BnO
OBn
BnO
TrOChol 5
TfOH (0.57 equiv)
OBn
O
BnO
O
BnO
BnO
O
BnO
BnO
3
BH3
O
MeO
dioxane, rt, 10 min
BnO
P
OChol
BnO
Entry
Solvent
CH2Cl2
Time (min)
Yield (%)a :b)b
(a
OMe
3
1
1
2
3
40
30
30
40
60
21 (34:66)
22 (52:48)
35 (17:83)
60 (38:62)
22 (46:54)
33 (32:68)
(1.0 equiv)
Toluene–CH2Cl2 (2:1, v/v)
MeCN–CH2Cl2 (4:1, v/v)
Dioxane–CH2Cl2 (2:1, v/v)
THF–CH2Cl2 (4:3, v/v)
Entry
equiv of 5
Yield (%)b
a
:bc
4
5c
6d
1
2
3
1.2
1.5
2.0
34
45
83
80:20
87:13
83:17
Dioxane–CH2Cl2 (1:1, v/v)
120
a
b
c
Isolated yield.
Determined by 1H NMR.
Additional 8.0 equiv of TrNTf2 was added after 40 min.
Reaction was conducted at À20 °C.
a
b
c
Chol = cholesteryl.
Isolated yield.
Determined by 1H NMR.
d

S. Tatsumi et al. / Tetrahedron Letters 54 (2013) 3731–3734
3733
Table 4
Glycosylations using glycosyl boranophosphotriesters as glycosyl donors and O-tritylalcohols as glycosyl acceptors
O
R1O
O
TfOH (0.57 equiv)
solvent, rt
TrOR2 (2.0 equiv)
R1O
BH3
+
O
MeO
OR2
P
OMe
(1.0 equiv)
Entry
Donor (
a
:b)b
Acceptor
Solvent
Time (min)
Product
Yield (%)a :b)b
(a
1
2
3
4
5
6
7
8
9
1 (74:26)
7 (67:33)
8 (90:10)
1 (74:26)
7 (67:33)
8 (90:10)
4 (4:96)
9 (7:93)
10 (96:4)
4 (4:96)
5
5
5
11
11
11
5
5
5
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane–CH2Cl2 (2:1, v/v)
Dioxane–CH2Cl2 (2:1, v/v)
Dioxane–CH2Cl2 (2:1, v/v)
Dioxane–CH2Cl2 (2:1, v/v)
Dioxane–CH2Cl2 (2:1, v/v)
Dioxane–CH2Cl2 (2:1, v/v)
10
10
10
10
10
15
10
10
10
15
15
15
3
83 (83:17)
74 (67:33)
71 (69:31)
68 (83:17)
56 (79:21)
64 (63:37)
74 (b Only)
83 (b Only)
77 (a Only)
12
13
14
15
16
6
17
18
19
20
21
10
11
12
11
11
11
72 (b Only)
77 (b Only)
73 (a Only)
9 (7:93)
10 (96:4)
a
Isolated yield.
b
Determined by 1H NMR.
BzO
BzO
OBn
OBz
OTr
BnO
BnO
BnO
OBz
BzO
OBn
O
O
O
BzO
O
BnO
BnO
O
BnO
BnO
BH3
BH3
O
MeO
O
MeO
BH3
BzO
BH3
OMe
O
O
MeO
BnO
P
P
BnO
P
P
BzO
OMe
OMe
OMe
MeO
OMe
7
8
9
10
11
OBn
OBn
BnO
BnO
BnO
BnO
OBn
O
O
O
BnO
BnO
BnO
OBn
BnO
BnO
BnO
BnO
BnO
O
OBn
O
O
O
BnO
BnO
O
O
BnO
O
O
BnO
BnO
BnO
OChol
OChol
OChol
BnO
BnO
BnO
BnO
BnO
BnO
OMe
OMe
OMe
12
13
14
15
16
BzO
BzO
OBz
OBz
O
OBz
O
O
BzO
BzO
BzO
OBz
O
BzO
BzO
BzO
BzO
OBz
BzO
BzO
O
O
O
O
BzO
BzO
BnO
BnO
BzO
O
BnO
BnO
O
O
BnO
BnO
BnO
BzO
OChol
BnO
BnO
OMe
OMe
OMe
17
18
19
20
21
oxocarbenium ions and the 1,2-trans-selectivity of 6 was due to the
neighboring group participation. Notably, the reaction rate was
dramatically increased when dioxane was used as a (co)solvent
(entries 1 vs 2, 3 and 4 vs 5, 6). It is also notable that the generation
of Ph3CH was confirmed by 1H NMR analysis of the crude mixtures,
indicating that the glycosyl donors 1 and 4 were oxidatively acti-
vated by Tr+ derived from 5.
Next, we conducted the reaction between 1 and 5 with different
molar ratios (Table 3). 1.2, 1.5, or 2.0 equiv of the trityl ether 5 was
used and found that the reaction was accomplished when 2.0 equiv
of 5 was used (analyzed by TLC). Thus we used 2.0 equiv of trityl
ethers as glycosyl acceptors in the following study.
counterparts (4, 9 and 10) afforded the products (6 and 17–21)
with complete 1,2-trans-selectivity (entries 7–12).
In conclusion, we developed a novel glycosylation that uses gly-
cosyl boranophosphotriesters as glycosyl donors. Two types of
reactions were studied, that is, (1) the donor was activated with
TrNTf2 to react with an alcohol and (2) O-trityl ethers worked as
both glycosyl acceptors and Tr+ sources. The latter was found to
give better results and the desired O-glycosylation products were
rapidly generated and isolated in moderate to good yields. Further
study on the reaction mechanism as well as the application of this
new glycosylation to the synthesis of more complex molecules is
now in progress.
By using the optimized conditions, glycosylation reactions
using six kinds of per-O-Bn and Bz-glycosyl boranophosphotriest-
ers (1, 4, and 7–10) were carried out (Table 4). The O6-tritylgluco-
side derivative 1114 was employed as a glycosyl acceptor in
addition to O-tritylcholesterol 5. All the reactions were completed
within 10–15 min and the desired products were obtained in mod-
erate to good yields. Per-O-Bn-donors 1, 7, and 8 gave the products
Acknowledgments
We thank Professor Kazuhiko Saigo (Kochi University of Tech-
nology) for helpful suggestions. This work was financially sup-
ported by the Ministry of Education, Culture, Sports, Science, and
Technology (MEXT) Japan.
3 and 12–16 as
a,b-mixtures (entries 1–6), while the per-O-Bz

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S. Tatsumi et al. / Tetrahedron Letters 54 (2013) 3731–3734
41, 7691–7695; (d) Plante, O. J.; Palmacci, E. R.; Andrade, R. B.; Seeberger, P.
Supplementary data
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