Synthesis of d-fructopyranosides with 2-O-acyl-β-d-fructopyranosides

Article abstract of DOI:10.1016/j.tetlet.2013.10.128

Glycosylation of 2-O-acyl fructopyranosides was investigated, which were shown to be effective glycosyl donors for d-fructopyranoside synthesis with good β-selectivity and yields. For bulky acceptor 4e, α-anomer 5e was obtained with α/β = 65:23. Unexpected ring-opening was observed during acetylation of 9, indicating the sensitivity of the fructopyranosyl ring.

Full text of DOI:10.1016/j.tetlet.2013.10.128

Tetrahedron Letters 55 (2014) 98–100
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of D-fructopyranosides with 2-O-acyl-b-D-fructopyranosides
⇑
Feng Lin , Qiulong Xu, Rui Lu, Liqun Yue
State Key Laboratory of New Drugs & Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 1111 Zhongshanbeiyi Road, Shanghai 200437, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2013
Revised 18 October 2013
Accepted 27 October 2013
Available online 5 November 2013
Glycosylation of 2-O-acyl fructopyranosides was investigated, which were shown to be effective glycosyl
donors for
mer 5e was obtained with
indicating the sensitivity of the fructopyranosyl ring.
D
-fructopyranoside synthesis with good b-selectivity and yields. For bulky acceptor 4e,
a-ano-
a
/b = 65:23. Unexpected ring-opening was observed during acetylation of 9,
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Glycosylation
Fructopyranoside
Ketose
Acetyl donor
The glycosylation methods for frutopyranoside synthesis are
limited,1,2 though
-fructose is the second most abundant simple
sugar in nature. We expected that the easily accessible fructose
could provide some valuable molecular frameworks for drug dis-
covery,3–5 as demonstrated by TopamaxÒ (Fig. 1).
Surprisingly, acetylation with pyridine/Ac2O at 25 °C resulted in
no reaction at all (Table 1, entry 2), reminiscent of an abnormal re-
sult reported previously by Lichtenthaler.10 When NEt3 was used
as base, acetate 2 was obtained, and Ac2O was a milder and better
reagent than AcCl in this sensitive acetylation (entry 3, 4). The ben-
zoylation of compound 1 gave similar results—benzoylate 3 was
obtained in high yield when NEt3 was used as base, while no reac-
tion occurred with pyridine (entry 5, 6). Why the pyridine hindered
this acylation was not clear. It was reported that 3 tends to
eliminate to form exocyclic enol-ethers,2 which was not observed
under our conditions. Moreover, by recrystallization from ethanol,
3 was stable at 4 °C for 30 days. According to 1H, 13C NMR, and
D
Recently we reported the efficient synthesis of fructosides6,7
with N-phenyltrifluoroacetimidate donor, introducing a new and
practical glycosylation method for fructoside synthesis. As a re-
lated work, we also evaluated from the literature the feasibility
of glycosylation with 2-O-acyl frutopyranosides as donors.
Reported studies showed that 2-O-acyl frutopyranosides had been
used as intermediates for 2-halo frutopyranosides,2,8 but were-
seldom considered as donors.9 An accidentally failed experiment,
described below, led us to study 2-O-acyl frutopyranoside as a
glycosyl donor.
O
S
NH2
O
O
O
O
When 20 mg tetra-O-benzoyl-b-D-fructopyranose 1 was acety-
O
O
lated under normal conditions (1.2 equiv of AcCl at 25 °C, air bath),
a strong exotherm turned the reaction mixture black and evapo-
rated the majority of the solvent (CH2Cl2). By TLC, acetate 2 had
disappeared and was replaced by highly polar, black spots (Table 1,
entry 1). This abnormal result implied that, in this ketose’s acety-
lation, the anomeric center of the resulting acetate 2 could be acti-
vated at 25 °C by NEt3HCl, and then without proper cooling, some
strongly exothermic side reactions occurred, even at 20 mg scale.
This accidental finding provided a clue for us that acetate 2 might
be a promising fructopyranosyl donor candidate. Our study is
reported herein.
O
Figure 1. TopamaxÒ, blockbuster fructopyranoside drug.
Table 1
Preparation of 2-O-acyl-b-D-fructopyranoses 2 and 3a
Entry Reagent Base Solvent Temp (°C) Reaction time Yield (%)
1
2
3
4
5
6
AcCl
Ac2O
AcCl
Ac2O
BzCl
BzCl
NEt3 CH2Cl2
Py
NEt3 CH2Cl2
NEt3 CH2Cl2
NEt3 CH2Cl2
25b
25
0
0
0
30 min
36 h
2 h
2 h
2 h
36 h
0
0
62
80
85
0
—
—
Py
25
a
The reaction was carried out under water bath unless otherwise indicated.
Air bath.
⇑
Corresponding author. Tel.: +86 21 65310547; fax: +86 21 65169893.
E-mail address: linfeng@sioc.ac.cn (F. Lin).
b
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.128

F. Lin et al. / Tetrahedron Letters 55 (2014) 98–100
99
OH
optical rotation, compounds 2 and 3 were assigned as b-anomers
(Scheme 1).
BzO
BzO
OBz
O
O
OR
Glycosylation of acetate 2 or 3 under mild conditions with sev-
eral types of acceptors provided fructopyranosides with good
yields (Scheme 2). The reaction proceeded smoothly in CH2Cl2 at
À20 °C with TMSOTf (0.1 equiv), and for simple alcohols (Table 2,
entry 1 and 2), the reaction temperature had to be raised to 0 °C,
otherwise the reaction would be very slow. For most of the alco-
hols, b-fructopyranosides were obtained in high yields and high
b-selectivity. Although the b-selectivity for 4a was better than
the case of N-phenyl trifluoroacetimidate donor (entry 1, 89:5 vs
BzO
OBz
OBz
OBz
2 R=Ac
3 R=Bz
OBz
1
Scheme 1. Preparation of 2-O-acyl-b-
D-fructopyranoside.
BzO
O
BzO
BzO
O
TMSOTf
OR
OBz
OR1
OBz
+
ROH
BzO
3.2:1), the
alcohol 4e (entry 5), which was opposite to the case of N-phenyl
trifluoroacetimidate donor.6 This practical synthesis of
-fructo-
a-selectivity predominated for the bulky secondary
OBz
OBz
2 R1=Ac
3 R1=Bz
4a-4i
5a-5i
a
OH
O
pyranoside is interesting. For allylic alcohol (entry 3), there was
no reaction at À20, 0, or 25 °C for 4 h, due to the poorly nucleo-
philic allylic OH. For tert-butyl alcohol (entry 9), there was no reac-
tion at 0 °C for 4 h, and at 25 °C acetate 2 changed to 1 in 2 h with
78% yield. These findings indicate that glycosylation of fructopyr-
anosyl acetate is more sensitive to the steric hindrance of the
acceptor. Although 3 was reported to be labile, it provided two
b-fructopyranosides with high yields (entry 10, 11) by this glyco-
sylation method.
Acetate 10 was designed in order to investigate the effect of the
1-O protecting group on glycosylation selectivity. Compound 51
was benzoylated, underwent 1,2-O-isopropylidene deprotection,
then selectively protected with TBSCl on 1-OH to obtain compound
9. Compound 9 was acetylated under various conditions, but no
pure form of desired fructopyranoside 10 could be isolated.
Instead, only keto-fructoside 10a was obtained (Scheme 3).
1H NMR and 13C NMR clearly proved that compound 9 was in
pyranosyl form, while compound 10a was in keto-fructose form.
The steric hindrance and the sensitive 2-OAc leaving group may
affect this transformation, which was interpreted in Scheme 4.
Similar ring-opening side reactions have been reported in fructo-
pyranoside chemistry, indicating that protecting groups have a
strong effect on the distribution of tautomers during acylation.2
In conclusion, 2-O-acyl fructopyranosides 2 and 3 were prepared
under mild conditions, and b-fructopyranosides could subsequently
be obtained with good yields and stereo-selectivity under mild gly-
O
O
O
O
O
OH
O
OH
OH
O
O
O
HO
4a
4b
4c
4e
4d
OMe
OBz
O
O
HO
OH
HO
BnO
O
N
3OMe
OH
4g
4f
4h
4i
Scheme 2. Fructopyranosyl glycosylation with donor 2 or 3.
Table 2
Glycosylation with fructopyranosyl donor acetate 2 and benzoylate 3a
Entry
Donor
Acceptor
Product
Yieldb (%)
b:ac
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
2
2
2
3
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
5g
5h
1
94
70
0
89:5
b only
—
b only
23:65
b only
b only
b only
—
95
88
85
97
53
78
91
94
cosylation conditions. For the bulky acceptor 4e, the
a-selectivity
10
11
4d
4g
5d
5g
b only
b only
showed that the stereoselectivity of this glycosylation could be
affected by the acceptor. For 1-O-TBS fructoside 9, the unexpected
production of keto-fructose 10a underscored the sensitivity of the
fructopyranosyl ring. Though acetate donor seems simple, acyl
a
b
c
Reagents and condition: À20 °C, 0.1 equiv TMSOTf, CH2Cl2, 30 min then 0 °C 3 h.
Isolated yield.
Determined by isolated yield.
BzO
BzO
BzO
BzO
BzO
BzO
HO
HO
O
O
O
O
a
b
c
O
OH
OH
OH
OTBS
O
O
O
OBz
OBz
OBz
OH
6
7
8
9
BzO
BzO
OBz O
O
pure 10 could
OAc
OTBS
d
not be isolated
OTBS
AcO
OBz OBz
10a
OBz
10
Scheme 3. Reagents and conditions: (a) BzCl, py 83%; (b) 80% aq HOAc, 53%; (c) TBSCl, imidazol, DMF, 82%; (d) Ac2O, NEt3, DMAP, 51% (for 10a).
Ph
Ph
O
OAc
O
BzO
BzO
OAc
O
+
OAc OBz O
O
O
OAc
OTBS
O
O
BzO
OTBS
BzO
OBz
OBz OBz OTBS
10a
OTBS
OBz
OBz
10
Scheme 4. The tautomer equilibrium during acetylation of fructoside 9.

100
F. Lin et al. / Tetrahedron Letters 55 (2014) 98–100
fructopyranosides provide valuable methods for fructose chemistry,
which is interesting and requires further study.
References and notes
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Heterocycles 2005, 66, 453.
2. Kraska, B.; Lichtel, R. Tetrahedron Lett. 1983, 24, 361.
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1982, 25, 1495.
4. Huo, C.-X.; Wang, C.; Zhao, M.; Peng, S.-Q. Chem. Res. Toxicol. 2004, 17, 1112.
5. Tatibouet, A.; Yang, J.; Morin, C.; Holman, G. D. Bioorg. Med. Chem. 2000, 8,
1825.
6. Lin, F.; Lian, G.; Xu, Q.; Lu, R. Tetrahedron 2013, 69, 1128.
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Acknowledgments
This work was supported by the Committee of Science and
Technology of Shanghai (10QB1403900), the National Natural Sci-
ence Foundation of China (20902059) and MOST (2011ZX09202-
101-01). F.L. thanks Dr. Jason C. Wong for helpful discussions.
Supplementary data
9. Lichtenthaler, F. W.; Hoyer, F. Carbohydr. Res. 1994, 253, 141.
10. Lichtenthaler, F. W.; Klotz, J.; Flath, F.-J. Liebigs Ann. 1995, 2069.
Supplementary data (experiments and spectra data) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.10.128.