Hafnium(IV) tetratriflate as a glycosyl fluoride activation reagent

Article abstract of DOI:10.1021/jo400282x

Hafnium(IV) tetratriflate was found to be a good activator of glycosyl fluoride. The protocol was operationally simple and was widely applicable to a variety of substrates in both solid-phase and solution-phase glycosylation reactions.

Full text of DOI:10.1021/jo400282x

Note
pubs.acs.org/joc
Hafnium(IV) Tetratriflate as a Glycosyl Fluoride Activation Reagent
Shino Manabe*,† and Yukishige Ito*,†,‡
†RIKEN, Synthetic Cellular Chemistry Laboratory, Hirosawa Wako, Saitama 351-0198, Japan
‡ERATO, JST, Hirosawa Wako, Saitama 351-0198, Japan
S
* Supporting Information
ABSTRACT: Hafnium(IV) tetratriflate was found to be a good activator of glycosyl
fluoride. The protocol was operationally simple and was widely applicable to a variety of
substrates in both solid-phase and solution-phase glycosylation reactions.
lycosyl fluoride is one of the most frequently used
the β-selectivity being increased in CH3CN (entries 9 and 10)
Gglycosyl donors in glycosylation reactions. The relatively and the α-selectivity being increased in dioxane/toluene
(entries 11 and 12).24 Prolonged reaction periods completed
strong C−F bond imparts stability to such compounds;
the reaction, but did not increase the yields (entries 10 and 12),
because several unidentified byproducts were formed. Both the
pure α-anomer 1α and β-anomer 1β gave disaccharides 3α/3β
in a β-selective manner, with little variation in the α:β ratios
(entries 13 and 14). The excess of glycosyl fluoride 1a/1b was
changed to its corresponding hemiacetal and glycal as main
products under the conditions for entry 1.
however, glycosyl fluorides can be activated under the
appropriate reaction conditions. Several methodologies have
been developed for achieving glycosyl fluoride activation. For
example, Mukaiyama et al. reported for the first time that
SnCl2−AgClO4 could efficiently activate glycosyl fluoride,1 and
Noyori and Nicolaou reported that TMSOTf and BF3•OEt2
work as effective mediators for armed glycosyl fluorides,
respectively.2,3 Later, Suzuki reported that a combination of
Cp2HfCl2−AgClO4 had a high efficacy for glycosyl fluoride
activation,4 which is now a protocol widely applied to the
synthesis of complex oligosaccharides and glycoconjugates.5−7
However, most glycosyl fluoride activation methodologies are
not operationally simple. Multiple reagents and preactivated
molecular sieves are required, in addition to preactivation/
premixing of the activator prior to the addition of the glycosyl
donor and acceptor. In this paper, we report an operationally
simple glycosyl fluoride activation methodology.
The scope and limitations of the methodology were
subsequently investigated (Table 2). Reactive acceptor 4
reacted smoothly with donor 1α/1β to give disaccharides
5α/5β in a β-selective manner (entry 1). Using secondary
hydroxyl group acceptor 6, the disaccharides 7α/7β were
obtained, and a significant solvent effect was observed (entries
2−4). In CH3CN, the β-glycoside ratio was increased up to
80%, while dioxane−toluene gave an increase in the α-glycoside
ratio up to 85%. Mannose derivative 8 gave disaccharide 9 in
64% yield (entry 6), and disarmed donor 10 could also be
activated under these conditions at 4 °C (entry 7). After 2 h,
disaccharide 11 was obtained in 80% yield. Unfortunately, the
benzylidene group was cleaved because of the Lewis acidity of
Hf(OTf)4, and trisaccharide 14 was obtained in 37% yield
based on acceptor 12 (entry 8). However, disaccharide 15 was
obtained in the presence of 3 equiv of di-tert-butyl-4-
methylpyridine (DTBMP) (entry 9). Disaccharide 16 was
also activated at −30 °C, and trisaccharide 17 and
tetrasaccharide 19 were obtained in 85% and 58% yield,
respectively (entries 10 and 11).
The developed methodology was applied to rapid solid-phase
oligosaccharide synthesis on a polymer support. Methyl
poly(ethylene glycol) (MPEG, average Mw = 750) was used
to produce acid-stable linker25 21, which acted as a good
acceptor and enabled rapid purification by a silica gel short pad
because of the high polarity of MPEG, as previously reported
(Scheme 1).26,27 After removal of the chloroacetyl temporary
protecting group under basic conditions, the MPEG-glycoside
was submitted to the next glycosylation reaction, where 23 was
Hafnium(IV) tetratriflate (Hf(OTf)4) is a commercially
available solid that is easy to handle in air. It is known to be
a good Lewis acid for a variety of reactions.8−18 It was therefore
expected that it would be a good mediator for glycosyl fluoride
activation.
Glycosyl fluoride 1α/1β (1:4 mixture) was smoothly
activated, even at −78 °C, to give disaccharides 3α/3β
(16:84) in 58% yield in a β-selective manner after 2 h (Table
1, entry 1). After 14 h, the yield was increased up to 70% (entry
2). At −50 °C, the reaction was completed within 1 h, and the
disaccharides 3α/3β (20:80) were obtained in 99% yield (entry
3). Molecular sieves 3A and 4A did not help to increase the
yield (entries 6 and 7). Especially, the reaction in the presence
of molecular sieves 4A was messy and the disaccharide 3α/3β
was not isolated in a pure form. Although activation of glycosyl
fluoride using a catalytic amount of reagent has previously been
reported,19−21 the reaction did not complete, even after 10 h, if
the amount of Hf(OTf)4 was reduced (entry 8), with the
disaccharide 3α/3β being only obtained in 59% yield.
Interestingly, the α:β ratio was altered, with the α-isomer
obtained as the major product, although the reason was not
clear. The well-known solvent effect was observed,2,22,23 with
Received: February 6, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400282x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Glycosylation Reaction with 1 and 2 under Various Conditions
entry
donor
solvent
temp (°C)
time
2 h
yield (%)
3α:3β
a
1
2
3
4
5
6
7
1α/1β (1:4)
1α/1β (1:4)
1α/1β (1:4)
1α/1β (1:4)
1α/1β (1:4)
1α/1β (1:4)
1α/1β (1:4)
1α/1β (1:4)
1α/1β (1:4)
1α/1β (1:4)
1α/1β (1:4)
1α/1β (1:4)
1α
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
−78
−78
−50
−20
−20
−20
−20
−20
−20
−20
−20
−20
−50
58
16:84
12:88
20:80
31:69
30:70
39:61
_
14 h
70
99
1 h
b
10 min
0.5 h
10 min
10 min
10 h
88
91
c
CH2Cl2, MS 3A
CH2Cl2, MS 4A
CH2Cl2
45
mess
d
e
8
59
64:36
11:89
42:58
51:49
66:34
14:86
f
9
CH3CN
10 min
4 h
51
10
11
12
13
14
CH3CN
57
g
h
dioxane/toluene (1:1)
10 min
4 h
83
g
dioxane/toluene (1:1)
80
82
94
CH2Cl2
1 h
1β
CH2Cl2
−50
1 h
18:82
e
a
b
c
d
32% of 2 was recovered. 12% of 2 was recovered. 18% of 2 was recovered. 30% of 2 was recovered. 0.4 equiv of Hf(OTf)4 was used. 40% of 2
was recovered. 12% of 2 was recovered. Dioxane/toluene 3:1 solvent system reported in ref 23 was frozen at low temperature. The ratio of toluene
was increased. 17% of 2 was recovered.
f
g
h
Table 2. Scope and Limitations of the Glycosylation Reaction Mediated by Hf(OTf)4
entry
donor
acceptor
solvent
temp (°C)
time
product
yield (%)
α:β
1
1α/1β (1:4)
4
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
−50
−50
−20
−20
−20
−50
4
1 h
5α/5β
7α/7β
7α/7β
7α/7β
7α/7β
9
94
75
80
94
80
64
80
37
65
85
58
16:84
44:56
45:55
20:80
85:15
64:0
2
1α/1β (1:4)
6
1 h
3
1α/1β (1:4)
6
0.5 h
0.5 h
0.5 h
1 h
4
1α/1β (1:4)
6
5
1α/1β (1:4)
6
dioxane/toluene (1:1)
CH2Cl2
6
8
6
7
10
13
13
16
16
4
CH2Cl2
2 h
11
80:0
8
12
12
2
CH2Cl2
−50
−30
−30
−30
0.5 h
1 h
14
0:37
9
CH2Cl2, DTBMP (3 equiv)
CH2Cl2
15
0:65
10
11
0.5 h
0.5 h
17
0:85
18
CH2Cl2
19
0:58
B
dx.doi.org/10.1021/jo400282x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. Glycosylation Reaction on a Polymer Support Using Glycosyl Fluoride, Mediated by Hf(OTf)4
was purified by preparative TLC. The products 3a,22 3b,22 5a,29 5b,29
7a,30 7b,30 9,31 11,32 16,33 18,34 and 2026 were reported.
quantitatively yielded. The acceptor immobilized on TentaGel
2428 also served as a good substrate for the glycosylation
reaction with glycosyl fluoride 8 using the same methodology.
Disaccharide 25 was obtained after cleavage from the TentaGel
under basic conditions in 78% yield from 24 (Scheme 2), and
the corresponding acceptor was not obtained.
p-Methoxyphenyl 3,6-Di-O-(2-O-acetyl-3,4,6-O-tribenzyl-β-
D-glucopyranoside)-2-azido-2-deoxy-β-D-glucopyranoside. 1H
NMR δ 7.28−7.12 (m, 30H), 6.97 (d, J = 8.8 Hz, 2H), 6.81 (d, J =
8.8 Hz, 2H), 4.99 (t, J = 8.0 Hz, 1H), 4.98 (t, J = 8.0 Hz, 1H), 4.76−
4.60 (m, 6H), 4.53−4.38 (m, 8H), 4.20 (d, J = 11.2 Hz, 1H), 3.70−
3.40 (m, 17H), 3.34 (t, J = 8.8 Hz, 1H), 3.13 (t, J = 8.8 Hz, 1H), 1.99
(s, 3H), 1.77 (s, 3H); 13C NMR δ 169.5, 169.4, 155.5, 151.2, 138.2,
138.0, 137.9, 137.4, 128.5, 128.4, 128.3, 128.1, 128.1, 128.0, 127.9,
127.8, 127.7, 127.5, 118.0, 114.8, 102.0, 101.4, 101.1, 85.8, 83.1, 82.7,
78.0, 77.8, 75.7, 75.3, 75.1, 75.1, 75.0, 74.5, 73.5, 73.4, 73.0, 72.8, 69.1,
68.7, 68.7, 64.5, 55.6, 20.8, 20.6; [α] 13.3 (c 1.0, CHCl3); HRMS
(MALDI-Q-TOF) m/z: [M + Na]+ Calcd for C71H77N3O18Na
1282.5094; Found 1282.5103.
Scheme 2. Solid-Phase Glycosylation Reaction Using
Glycosyl Fluoride Mediated by Hf(OTf)4
p-Methoxyphenyl (2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-gluco-
pyranoside)-(1→3)-4,6-O-benzylidene-2-deoxy-2-azido-β-D-
1
glucopyranoside. H NMR δ 7.37−7.02 (m, 20H), 6.99 (d, J = 8.0
Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 5.45 (s, 1H), 5.04 (t, J = 8.8 Hz,
1H), 4.81−4.41 (m, 7H), 4.36 (d, J = 12.4 Hz, 1H), 4.31 (dd, J = 11.2,
5.2 Hz, 1H), 3.80−3.58 (m, 8H), 3.77 (s, 3H), 3.52−3.42 (m, 3H),
3.29 (m, 1H), 1.98 (s, 3H); 13C NMR δ 170.6, 155.9, 150.8, 138.2,
138.2, 137.9, 137.0, 129.1, 128.4, 128.4, 128.3, 128.2, 128.0, 127.9,
127.9, 127.8, 127.7, 127.6, 127.5, 126.1, 118.6, 114.7, 102.2, 101.6,
100.0, 82.9, 70.4, 78.7, 77.8, 75.2, 75.0, 74.9, 73.5, 73.4, 68.5, 68.4,
66.5, 66.1, 55.7, 30.2, 20.9; [α] 7.0 (c 0.64, CHCl3); HRMS (MALDI
Q-TOF) m/z: [M + Na]+ Calcd for C49H51N3O12Na 896.3365; Found
896.3377.
In conclusion, Hf(OTf)4 was shown to be a good activator
for glycosyl fluoride. The reagent was observed to be stable, and
the procedure was simple. This methodology is widely
applicable to solid-phase and polymer-supported oligosacchar-
ide synthesis, as well as solution-phase synthesis.
p-Methoxyphenyl (4-O-Acetyl-3,6-di-O-benzyl-2-deoxy-2-
phthalimido-β-glucopyranoside)-(1→4)-(3,6-O-dibenzyl-2-
deoxy-2-phthalimido-β-glucopyranoside)-(1→3)-2,3,4-tri-O-(4-
1
methylbenzoyl)-β-D-glucoside. H NMR δ 7.73 (d, J = 8.4 Hz,
2H), 7.50 (s, 4H), 7.32 (d, J = 8.4 Hz, 2H), 7.80−760 (br, 8H), 7.31−
6.89 (m, 21H), 6.85 (m, 3H), 6.69 (s, 4H), 5.69 (t, J = 9.2 Hz, 1H),
5.47 (t, J = 8.4 Hz, 1H), 5.27 (d, J = 8.4 Hz, 1H), 5.19 (t, J = 9.6 Hz,
1H), 5.12 (t, J = 9.2 Hz, 1H), 5.02 (d, J = 7.6 Hz, 1H), 4.94 (d, J = 7.6
Hz, 1H), 4.78 (d, J = 12.4 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.50−
4.03 (m, 11H), 3.94 (m, 1H), 3.79−3.76 (m, 1H), 3.76 (s 3H), 3.60−
3.30 (m, 5H), 3.18 (m, 1H), 2.31 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H),
1.88 (s, 3H); 13C NMR δ 169.6, 165.6, 155.4, 151.3, 144.1, 143.9,
138.4, 138.3, 138.2, 137.7, 133.3, 131.6, 129.8, 129.0, 129.0, 128.3,
128.1, 127.8, 127.6, 127.4, 127.3, 127.2, 126.9, 126.5, 126.1, 125.9,
123.1, 118.2, 114.6, 100.6, 98.2, 96.9, 75.8, 74.5, 74.4, 73.8, 73.5, 73.3,
72.7, 72.6, 71.5, 69.5, 69.4, 56.2, 55.7, 55.5, 21.6, 20.9; [α] 22.3 (c 1.45,
CHCl3); HRMS (MALDI Q-TOF) m/z: [M + Na]+ Calcd for
C95H88N2O23Na 1647.5670; Found 1647.5673.
EXPERIMENTAL SECTION
■
General Experimental Methods. All commercial reagents were
used without further purification. Analytical TLC was performed on
silica gel 60 F254 plates and visualized by UV fluorescence quenching
and 12 Molybdo(VI) phosphoric acid acid/phosphoric acid staining.
Flash column chromatography was performed on silica gel 60N
(spherical, neutral, 40−100 μm). Yields refer to chromatographically
and spectroscopically pure compounds. 1H and 13C NMR spectra were
recorded at ambient temperature (23−24 °C) in CDCl3 using a 400
MHz spectrometer. Chemical shifts are reported in ppm relative to
internal TMS (δ = 0.00 ppm) for 1H and CDCl3 (δ = 77.00 ppm) for
13C NMR spectra. HRMS was measured by Quadrupole-TOF mass
spectrometry. Novasyn TentaGel was purchased from Novabiochem.
General Procedure. Hf(OTf)4 was added to a solution of donor
(1.5 equiv) and acceptor (1.0 equiv) in CH2Cl2 (acceptor
concentration, 0.1 M) at the stated temperature. After the starting
material was consumed or after adequate periods, the reaction was
quenched with sat. NaHCO3, and the aqueous layer was extracted
several times with EtOAc. The combined layers were washed with
brine and dried over Na2SO4. After concentration, the crude product
p-Methoxyphenyl (3,4-Di-O-acetyl-6-O-benzyl-2-deoxy-2-
phthalimido-β-D-glucopyranoside)-(1→4)-(3-O-acetyl-6-O-ben-
zyl-2-deoxy-2-phthalimido-β-D-glucopyranoside) (1→4)-(3-O-
acetyl-6-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyrano-
side) (1→4)-3-O-acetyl-6-O-benzyl-2-deoxy-2-phthalimido-β-
1
D-glucopyranoside. H NMR δ 7.76−7.72 (m, 16H), 7.18−7.6.82
(m, 20H), 6.72 (d, J = 9.2 Hz, 2H), 6.60 (d, J = 9.2 Hz, 2H), 5.63 (d, J
= 8.0 Hz, 1H), 5.61 (t, J = 10.0 Hz, 1H), 5.41 (t, J = 9.2 Hz, 1H), 5.20
(t.d, J = 8.0 Hz, 1H), 5.07 (t, J = 9.2 Hz, 1H), 4.93 (d, J = 7.6 Hz, 1H),
C
dx.doi.org/10.1021/jo400282x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
4.79 (d, J = 12.4 Hz, 1H), 4.54 (t, J = 12.8 Hz, 1H), 4.48−3.92 (m,
30H), 3.62 (s, 3H), 3.49 (m, 3H), 3.38−3.36 (m, 5H), 3.13 (m, 2H),
2.94 (d, J = 9.6 Hz, 1H), 2.69 (d, J = 9.6 Hz, 1H), 1.72 (s, 3H), 1.54
(s, 3H), 1.52 (s, 3H); 13C NMR δ 170.3, 170.2, 169.6, 167.3, 155.4,
150.6, 138.5, 138.2, 137.7, 134.2, 131.5, 128.3, 128.2, 128.1, 128.0,
127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 127.1, 126.9, 126.8,
123.5, 123.3, 118.8, 114.3, 97.3, 96.5, 96.3, 76.7, 76.4, 75.2, 74.4, 73.9,
73.7, 73.3, 72.7, 72.5, 72.4, 72.1, 72.1, 70.9, 70.7, 69.3, 67.6, 67.5, 56.2,
56.0, 55.5, 55.2, 54.8, 20.9, 20.5, 20.3; [α] 10.4 (c 0.95, CHCl3);
HRMS (MALDI Q-TOF) m/z: [M + Na]+ Calcd for [C111H102N4O29
+ Na]+ 1977.6522, Found 1977.6520.
ASSOCIATED CONTENT
* Supporting Information
Spectroscopic and analytical data for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: smanabe@riken.jp; yukito@riken.jp.
Notes
■
Poly(ethylene glycol) Bound 4-Hydroxy-3-nitro-benzyloxy-
3,6-O-benzyl-4-O-chloroacetyl-2-azido-2-phthalimide-β-D-glu-
copyranoside. To a solution of glycosyl fluoride 20 (211 mg, 0.705
mmol) and MPEG bound linker 21 (211 mg, 0.235 mmol) in CH2Cl2
(5 mL), Hf(OTf)4 (546 mg, 0.705 mmol) was added at −30 °C. After
1 h, the reaction was quenched with sat. NaHCO3, and the aqueous
layer was extracted with CHCl3. The combined layers were extracted
with CHCl3 and then washed with brine. After drying the extract over
Na2SO4, the solvent was removed in vacuo. The residue was passed
through a short silica gel pad (AcOEt only−MeOH/AcOEt 1:1) to
give compound 22 (340 mg, quant.). Representative peaks of 1H
NMR δ 5.18 (d, J = 8.0 Hz, 1H), 4.76−4.50 (m, 8H), 4.45 (d, J = 12.4
Hz, 1H), 4.27−4.12 (m, 5H).
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
■
This research was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology (Grant No. 24590041), Yamada
Science Foundation, Takeda Foundation, and a Shiseido
Female Research Grant. We thank Ms. A. Takahashi for
technical assistance and Dr. Kaori Otsuki, Dr. Masaya Usui, and
Dr. Aya Abe at the Research Resource Center of RIKEN’s Brain
Science Center for the HRMS measurement.
Poly(ethylene glycol) Bound 4-Hydroxy-3-nitro-benzyloxy-
(3,4,6-tri-O-benzyl-2-O-acetyl-β-D-glucopuranosy)3,6-O-ben-
zyl-2-azido-2-phthalimide-β-D-glucopyranoside. To a solution
of compound 22 (150 mg, 0.10 mmol) in MeOH (1 mL), 1 drop of
NaOMe (28% MeOH solution) was added by Pasteur pipet, in the
presence of phenolphthalein. The progress of the reaction was
monitored using a p-nitrobenzyl pyridine color test.26 The mixture was
then neutralized by Amberlyst 15E and filtered, and the resin was
washed with MeOH. After concentration, the crude product was
passed though a short silica gel pad (AcOEt only−MeOH/AcOEt 1:1)
to give the acceptor (141 mg, quant.). The PEG-bound acceptor was
dried in vacuo overnight and then dissolved in CH2Cl2 (2 mL).
Glycosyl fluoride 13 (141 mg, 0.285 mmol) and Hf(OTf)4 (221 mg,
0.285 mmol) were added at −30 °C. After 1 h, the reaction was
quenched with sat. NaHCO3, and the aqueous layer was extracted with
CHCl3. The combined layers were extracted with CHCl3 and then
washed with brine. After drying the extract over Na2SO4, the solvent
was removed in vacuo. The residue was passed through a short silica
gel pad (AcOEt only−MeOH/AcOEt 1:1) to give compound 23 (177
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11.2 Hz, 1H), 4.28 (d, J = 8.0 Hz, 1H), 4.01 (s, 1H), 3.83−4.49 (m,
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