Silver(I) tetrafluoroborate as a potent promoter for chemical glycosylation

Article abstract of DOI:10.1016/j.tetlet.2007.12.105

We have identified silver tetrafluoroborate (AgBF₄) as an excellent promoter for the activation of various glycosyl donors including glycosyl halides, trichloroacetimidates, and thioimidates. Easy handling and no requirement for azeotropic dehydration prior to application makes AgBF₄ especially beneficial in comparison to the commonly used AgOTf. Selective activation of glycosyl halides or thioimidates over thioglycosides or n-pentenyl glycosides, including simple sequential one-pot syntheses, has also been demonstrated. Versatility of glycosyl thioimidates was further explored by converting these intermediates into a variety of other classes of glycosyl donors.

Full text of DOI:10.1016/j.tetlet.2007.12.105

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1542–1545
Silver(I) tetrafluoroborate as a potent promoter
for chemical glycosylation
Sophon Kaeothip, Papapida Pornsuriyasak, Alexei V. Demchenko *
Department of Chemistry and Biochemistry, University of Missouri—St. Louis, One University Boulevard, St. Louis, MO 63121, USA
Received 7 November 2007; revised 14 December 2007; accepted 18 December 2007
Available online 24 January 2008
Abstract
We have identified silver tetrafluoroborate (AgBF4) as an excellent promoter for the activation of various glycosyl donors including
glycosyl halides, trichloroacetimidates, and thioimidates. Easy handling and no requirement for azeotropic dehydration prior to appli-
cation makes AgBF4 especially beneficial in comparison to the commonly used AgOTf. Selective activation of glycosyl halides or thio-
imidates over thioglycosides or n-pentenyl glycosides, including simple sequential one-pot syntheses, has also been demonstrated. Versatility
of glycosyl thioimidates was further explored by converting these intermediates into a variety of other classes of glycosyl donors.
Ó 2008 Elsevier Ltd. All rights reserved.
With increasing demand for the synthesis of biologically
important and therapeutically active oligosaccharides and
glycoconjugates, efforts to expand the arsenal of glycosyl-
ation methods and techniques have emerged. In spite of
significant recent advances in the areas of stereoselective
glycosylation1,2 and expeditious oligosaccharide synthe-
sis,3,4 the construction of complex oligosaccharides with
high efficiency and complete stereoselectivity remains a
difficult task.
As a part of a program to develop new methods and
strategies for glycochemistry, we became interested in
glycosyl thioimidates, a class of glycosyl donors with the
generic leaving group SCR1 = NR2.5,6 We have already
reported the synthesis of S-benzoxazolyl (SBox)7,8 and
S-thiazolinyl (STaz)9,10 glycosides and evaluated their pro-
perties in stereoselective glycosylations and expeditious
oligosaccharide syntheses. Metal salt-based promoters were
shown to provide efficient activation of the thioimidoyl
moiety for glycosylation.8,11 Among a variety of metal salts
investigated, arguably, silver trifluoromethanesulfonate
(AgOTf) was one of the best choices for the activation of
the SBox and STaz moieties for a variety of synthetic
applications.
Beyond the scope of our own research program, AgOTf
has been commonly employed as an activator for many
other classes of glycosyl donors including glycosyl bro-
mides,12–14 chlorides,15 trichloroacetimidates,16 and seleno
glycosides.17 In spite of wide applicability and high versatil-
ity of AgOTf, there are some significant drawbacks that
limit the usage of this promoter in synthesis. In a majority
of applications, AgOTf requires fresh activation by repeti-
tive co-evaporation with toluene followed by extended
drying under vacuum directly prior to use. In addition,
we noticed that the quality of commercial reagent may sig-
nificantly vary depending on the supplier and the batch. It
should be noted that the use of AgOTf as an acidic additive
in NIS-promoted glycosidation of thioglycosides does not
require preactivation of AgOTf.
Bearing in mind these drawbacks, we wondered if any
other silver salts could be used to achieve an efficient
glycosidation of a variety of glycosyl donors and would pro-
duce reproducible results without the requirement of the
preactivation or azeotropic dehydration. Herein we present
a report that demonstrates the use of silver tetrafluoro-
borate (AgBF4) as a potent promoter for the activation of
various types of glycosyl donors. It should be noted that
*
Corresponding author. Tel.: +1 314 516 7995; fax: +1 314 516 5342.
E-mail address: demchenkoa@umsl.edu (A. V. Demchenko).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.105

S. Kaeothip et al. / Tetrahedron Letters 49 (2008) 1542–1545
1543
KSBox or
AgBF4 has already been used in glycosylations, yet
OP1
O
OP1
O
OP1
O
N
KS
Br2
P1O
P1O
P1O
P1O
P1O
N
X
these applications, including alcoholysis of glycosyl
bromides,18,19 synthesis of C-glycosides from chlorides,20
glycosidation of 2-deoxy thioglycosides,21 and a-stereose-
lective glycosidation of 1,2-anhydro sugars,22 were scarce
and far apart. In this context, the combination of
Cp2ZrCl2–AgBF4 in benzene has proven to be a powerful
promoter combination for the activation of tetra-O-
benzyl-D-mannosyl fluoride.23
S
DCM
N
S
S
P1O
acetone
P2O
P2O
P2O
S
Br
5b: P1= P2= Bz
2b
: P1= P2= Bz
2c: P1= Ac, P2= Bn
5c
3b
: P1= Ac, P2= Bn
: X=O, P1= P2= Bz (89%)
3c: X=O, P1= Ac, P2= Bn (91%)
4b
: X=S, P1= P2= Bz (89%)
Scheme 2. Conversion of the STaz glycosides 5b,c into thioimidates 3b,c
and 4.
To generate a broad array of glycosyl donors we inves-
tigated whether thiazolinyl 2,3,4,6-tetra-O-benzyl-1-thio-b-
D-glucopyranoside 5a10 could serve as a common precur-
sor. These studies were successful and we discovered that
the STaz glycoside 5a can be directly converted into the fol-
lowing glycosyl donors: acetate 1, bromide 2a, chloride 8,
fluoride 9, and hemiacetal 10 in excellent yields (84–95%,
Scheme 1). Moreover, glycosyl bromide 2a was then used
as a precursor for the next synthetic steps to obtain benz-
oxazolyl, benzothiozolyl, and ethyl thioglycosides (3a, 4a,
and 6), as well as n-pentenyl glycoside 7—all with exclusive
b stereoselectivity. The hemiacetal derivative 10 was con-
verted into the corresponding glycosyl trichloroacetimidate
11 as shown in Scheme 1. Synthesis of a range of differently
protected glycosyl thioimidates has been similarly accessed
and is depicted in Scheme 2. Yields given are over-all yields
for two synthetic steps.
Having synthesized a library of glycosyl donors, we per-
formed a number of test glycosylation reactions using
AgBF4 as a promoter (Table 1). Since we wanted to deter-
mine whether the glycosylations could be performed with-
out preactivation of AgBF4, all reactions were performed
with commercial reagent as received, without further con-
ditioning. Glycosidation of glycosyl acetate 1 with glycosyl
acceptor 13 in the presence of AgBF4 did not proceed
Table 1
AgBF4 promoted glycosylations of glycosyl acceptors 12–15
OH
O
OBn
O
BnO
BnO
HO
BnO
BnO
BnO
OMe
OMe
13
12
AgBF4
glycosyl acceptor (A)
glycosyl donor (D)
disaccharide
(Figure 1)
16-19
+
MS 3A
(Scheme 1,2)
OBn
O
O
1,2-DCE
1-11
Ph
O
O
BnO
BnO
HO
BnO
HO
OMe
OMe
15
14
Entry
D
A
Time
Product Yield (%) a/b Ratio
a
1
2b
3c
4
5
6
7
8
9
1
13 24 h
13 16 h
13 5 h
13 5 min
13 5 min
14 24 h
17a
17a
17a
17a
17b
18b
—
91
95
92
96
82
89
91
84
91
87
90
95
92
90
75
—
91
92
—
89
76
97
91
81
81
—
80
65
—
1
1.4/1
2.0/1
2.4/1
b Only
b Only
1.2/1
b Only
b Only
1.6/1
7.4/1
b Only
1.3/1
1.4/1
b Only
1.2/1
—
1.2/1
1.2/1
—
1.0/1
1.2/1
1.6/1
1/3.4
2.0/1
2.3/1
—
1
2a
2b
2b
3a
3b
3b
3c
4a
4b
5a
5a
5b
5c
6
13 10 min 17a
13 10 min 17b
14 15 min 18b
13 15 min 17c
10
11
12
13
14
15
16
17
18d
19e
20
21d
22e
23
24
25
26
27
28
29
a
15 5 min
19a
13 20 min 17b
13 5 min
14 5 min
17a
18a
13 10 min 17b
13 20 min 17c
a
a
13 24 h
13 24 h
17a
17a
6
6
13 10 min 17a
OBn
7
13 24 h
13 24 h
17a
17a
O
BnO
BnO
N
O
S
7
BnO
3a
KSBox
7
13 20 min 17a
13 5 min 17a
12 10 min 16a
acetone
82%
OBn
O
8
OBn
O
N
S
BnO
BnO
8
OBn
O
KS
BnO
acetone
81%
N
S
9
13 20 h
15 1.5 h
13 24 h
13 5 min
12 2 days
17a
19a
17a
17a
16a
BnO
BnO
OAc
BnO
S
BnO
9
1
BnO
BnO
Br
a
10
11
11
4a
2a
Pd(OAc)2
DCE
72%
4-penten-1-ol,
AgBF4, DCE
Br2
DCM
95%
1/1.5
1/5.4
α/β
=1.6/1
EtSH, NaH
DCM
92%
MS 3A
89%
OBn
O
No product formation was detected; all glycosylations were promoted
with AgBF4 except the following.
OBn
O
OBn
BnO
BnO
O
BnO
BnO
O
BnO
BnO
N
S
b
S
BnO
SEt
À3.0 equiv of BF3–Et2O were used.
BnO
5a
c
BnO
NBS
7
À3.0 equiv of BF3–Et2O and 0.5 equiv of AgBF4 were used.
6
d
À2.0 equiv of NIS was used.
SOCl2
DMF, DCM
84%
e
DAST, DMF
-20 ºC to rt
aq. acetone
À2.0 equiv of NIS and 0.5 equiv of AgBF4 were used.
88%
α/β
= 1/1
90%,
α/β
=1/2.8
OBn
O
OBn
OBn
O
OBn
CCl3CN
BnO
BnO
O
NaH, DCM
82%
O
BnO
BnO
BnO
BnO
BnO
BnO
(entry 1). A similar coupling in the presence of BF3–
Et2O, a conventional promoter for the activation of glyco-
syl acetates,24 gave disaccharide 17a (Fig. 1) in 91% yield,
although it required 16 h for the reaction to complete.
We determined that the reaction time of this reaction could
BnO
NH
O
BnO
BnO
BnO
F
OH
Cl
10
9
8
11
CCl3
Scheme 1. Conversion of a common STaz building block (5a) into a range
of glycosyl donors.

1544
S. Kaeothip et al. / Tetrahedron Letters 49 (2008) 1542–1545
Table 2
OP1
O
OP1
O
OBn
O
Selective activation of various glycosyl donors over n-pentenyl acceptor 20
and SEt acceptor 22
P1O
P1O
P1O
P1O
O
O
P2O
BnO
P2O
BnO
BnO
BnO
OMe
O
BnO
BnO
BnO
Ph
16
OP1
O
O
O
Ph
O
O
O
O
O
O
O
BnO
HO
O
17
OMe
P1O
P1O
TrocHN
TrocHN
BnO
20
glycosyl donor
(see below)
P1O
P1O
P1O
21
O
Ph
AgBF4
OMe
P2O
BnO
O
O
+
O
O
OBn
O
OH
O
O
BnO
BnO
BnO
O
OBn
BnO
BnO
BnO
OMe
O
P2O
SEt
18
19
O
BnO
BnO
BnO
SEt
BnO
22
23
a: P1= P2= Bn; b: P1= P2= Bz; c: P1= Ac, P2= Bn
BnO
Entry
D
A
Time
Product Yield (%) a/b Ratio
Fig. 1. Structures of disaccharides 16–19.
1
2
3
4
5
6
7
8
9
a
3a
4a
5a
9
20 10 min 21
20 20 min 21
20 10 min 21
86
85
83
65a
84
87
89
84
83a
1.1/1
3.3/1
1/1.2
1.6/1
1.6/1
2.0/1
2.4/1
2.2/1
2.4/1
be significantly reduced (16 h vs 5 h, entries 2 and 3) by
adding 20–50 mol % of AgBF4. In these couplings, even
higher yield of 17a (95%) and an improved stereoselectivity
were detected.
Glycosidation of glycosyl bromides 2a and 2b could be
efficiently accomplished with AgBF4, although the cou-
pling of per-benzoylated bromide 2b, prepared as shown
in Scheme 2, with the sterically hindered acceptor 14
required prolonged reaction time (entries 4–6). These
results were comparable with the glycosylations using
traditional bromide activators—silver carbonate25,26 or
mercury salts.27,28
20 16 h
21
2a
3a
5a
8
22 15 min 23
22 20 min 23
22 15 min 23
22 15 min 23
9
22 24 h
23
The yield is based on the recovered acceptor.
Based on the results summarized in Table 1, we antici-
pated that it might be possible to activate glycosyl halides,
S-benzothiazolyl, SBox, or STaz glycosides over the SEt or
n-pentenyl moieties in the presence of AgBF4. We have
already reported that selective activation of SBox and STaz
glycosides over SEt glycosyl acceptor can be achieved in
the presence of AgOTf.7,31 Also in this case, AgBF4 was
found to be capable of providing smooth couplings with
consistently high yields (Table 2). We observed that glycos-
idation of glycosyl fluoride 9 was sluggish and the moder-
ate to good yields presented in Table 2 were based on the
unreacted acceptor recovery (entries 4 and 9).
Based on the results of the selective activations, we
assumed that it could be possible to perform the activation
sequence in a highly efficient one-pot fashion. Presumably,
any building block that can be activated with AgBF4 can
be used as the glycosyl donor for the first activation step.
We chose to investigate SBox and STaz glycosides as well
as glycosyl bromides as glycosyl donors. Glycosyl acceptor
should withstand AgBF4 activation, but in turn could be
readily activated by addition of NIS. Either S-ethyl or
O-pentenyl leaving groups could be used for this purpose.
An example shown in Scheme 3 makes use of the STaz
leaving group in 5b for the first coupling step. At this stage
the S-ethyl moiety of the glycosyl acceptor 24 remains
inert. Upon the formation of the intermediate disaccharide,
its SEt moiety can then be activated for the reaction with
the newly added acceptor 13 by adding 2.0 equiv of NIS.
As demonstrated above, NIS along with AgBF4 (used in
excess and is remaining from the previous step) serves as
an efficient promoter for this type of glycosylation. As a
result of this two-step activation, trisaccharide 25 was iso-
lated in 72% yield. Other leaving group combinations men-
tioned above were also found to be capable of the one-pot
Glycosidation of glycosyl thioimidates 3–5 was
smoothly driven to completion in a matter of minutes
(entries 7–16). All glycosylations proceeded with very high
conversion yields, comparable or even exceeding those
achieved in glycosylations promoted with preactivated
AgOTf. For example, AgBF4-promoted couplings depicted
in entries 14 and 16 (Table 1) proceeded in 92% (90% with
AgOTf) and 75% (70% with AgOTf) yield, respectively.9
While the anchimerically assisted couplings with benzoyl-
ated glycosyl donors were b-stereoselective, only fair a-ste-
reoselectivity was achieved with 2-O-benzylated glycosyl
donors. All couplings were performed in the neutral solvent
since the stereoselectivity optimization was not a primary
intention of these studies.
Promoters for thioglycoside and n-pentenyl glycoside
activation include thiophilic reagents, among which NIS/
TfOH or NIS/TMSOTf are arguably the most com-
mon.29,30 Therefore, not surprisingly, the activation of
stable glycosyl donors, ethyl thioglycoside 6 or n-pentenyl
glycoside 7, did not take place in the presence of AgBF4.
It should be noted that NIS alone can also activate both
S-ethyl and pentenyl glycosides, however, these transfor-
mations require prolonged reaction time (entries 18 and
21). Having decided to investigate whether these glycosyl
donors can be activated by NIS/AgBF4 system, we discov-
ered that these coupling reactions proceeded very rapidly
and provided the corresponding disaccharide in minutes
(entries 19 and 22). We then demonstrated that AgBF4
could be employed as a suitable promoter for glycosidation
of chloride 8, fluoride 9, or trichloroacetimidate 11,
whereas the hemiacetal derivative 10 remained inert under
these reaction conditions (entries 23–29).

S. Kaeothip et al. / Tetrahedron Letters 49 (2008) 1542–1545
1545
OBz
O
References and notes
BzO
OH
O
BzO
BzO
N
S
SEt
BzO
24
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BzO
S
BzO
5b
AgBF4
disaccharide
(not isolated)
OH
O
BnO
NIS
OBz
O
BnO
BnO
BzO
BzO
13
OMe
O
BzO
BzO
O
O
BzO
BzO
O
BnO
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72%
25
BnO
OMe
Scheme 3. One-pot glycosylation: synthesis of trisaccharide 25.
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activations and provided the corresponding trisaccharides
in 55–70% overall yields.
In summary, we have identified silver tetrafluoroborate
as an excellent promoter for the activation of various
glycosyl donors, prepared from the common precursor
bearing temporary STaz anomeric moiety. Easy handling
and no requirement for azeotropic dehydration prior to the
application makes AgBF4 especially beneficial in compari-
son to the commonly used AgOTf. We also demonstrated
that selective activation of glycosyl halides or thioimidates
over thioglycosides or n-pentenyl glycosides could lead to
simple one-pot syntheses via sequential selective activation
of one leaving group over another. Therefore, we believe
that AgBF4 should be considered as a powerful and conve-
nient alternative for silver(I) activated glycosylations.
Acknowledgments
The authors thank the National Institutes of General
Medical Sciences (GM077170) and the American Heart
Association (AHA0660054Z) for financial support of this
research; NSF for grants to purchase the NMR spectrom-
eter (CHE-9974801) and the mass spectrometer (CHE-
9708640) used in this work.
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Supplementary data
Experimental procedures and characterization data for
new compounds. Supplementary data associated with this
article can be found, in the online version, at doi:
10.1016/j.tetlet.2007.12.105.
31. Pornsuriyasak, P.; Demchenko, A. V. Tetrahedron: Asymmetry 2005,
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