An efficient procedure for synthesis of fructose derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.03.045

We developed a very simple procedure to prepare fructose derivatives or fructosides. This procedure waived the requirement of isomer separation, which is usually a very common and difficult problem in fructose derivative syntheses. In this procedure, the hydroxyl groups were differentiated to expedite the preparation of many kinds of other fructose derivatives and the alkoxy group in the fructosides could exchange easily with alcohols under the mild acidic condition, which offered a new method to synthesize other fructosides through alcohol exchanging. By using this procedure, we successfully synthesized fluorogenic fructose derivatives for high throughput enzyme screening. This methodology could expand the usage of the abundant fructose in organic synthesis.

Full text of DOI:10.1016/j.tetlet.2013.03.045

Tetrahedron Letters 54 (2013) 2788–2790
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient procedure for synthesis of fructose derivatives
Kui Yu a,b, Xu Zhao b, Wenjie Wu a, , Zhangyong Hong b,
⇑
⇑
a College of Material Science and Chemical Engineering, Tianjin University of Science and Technology, Tianjin 300457, PR China
b State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
We developed a very simple procedure to prepare fructose derivatives or fructosides. This procedure
waived the requirement of isomer separation, which is usually a very common and difficult problem
in fructose derivative syntheses. In this procedure, the hydroxyl groups were differentiated to expedite
the preparation of many kinds of other fructose derivatives and the alkoxy group in the fructosides could
exchange easily with alcohols under the mild acidic condition, which offered a new method to synthesize
other fructosides through alcohol exchanging. By using this procedure, we successfully synthesized
fluorogenic fructose derivatives for high throughput enzyme screening. This methodology could expand
the usage of the abundant fructose in organic synthesis.
Received 8 January 2013
Revised 2 March 2013
Accepted 8 March 2013
Available online 27 March 2013
Keywords:
Fructose derivative
Fructoside
Fluorogenic marker
One pot
Ó 2013 Elsevier Ltd. All rights reserved.
Directed evolution
Fructose is one of the most abundant natural products. Its deriv-
atives have many important applications in biological or medical
sciences. For examples, its analogs were tested as inhibitors for
fructose transporter GLUT5;1 2,3:4,5-bis-O-(1-methylethylidene)-
We first test methods to efficiently differentiate the three
hydroxyl groups in fructose, especially the two primary ones. Reac-
tion of fructose with TsCl, TPSCl (2,4,6-triisopropylbenzene-sulfo-
nyl chloride) or trityl chloride was very complex and showed low
selectivity to these hydroxyl groups. Treatment of fructose with
formic acid8 afforded 6-formic fructose derivative but only in
25% yield. The reaction of fructose with 2,3-butadione, acetone,
or benzaldehyde was also very complex.
beta-D-fructopyranosesulfamate (Topiramate, brand name Topa-
max) is an anticonvulsant (antiepilepsy) drug approved by FDA;2
fructose-1,6-diphosphate (FDP) is used as clinical drug in the pre-
vention and treatment of acute hypophosphatemia and phosphate
depletion, and also has substantial cytoprotective effects in a vari-
ety of ischemia-reperfusion injury scenarios;3 fluorescent fructose
derivatives were used as diagnostic reagents for breast cancer.4 In
addition, its unlimited source and three chiral hydroxyl groups
make fructose very useful in organic synthesis.5,6 For example, its
diacetonide derivatives were used as catalyst for asymmetric epox-
idation.7 Among them, derivatives with 1- or 6-position modifica-
tion are very common and useful.
Then we treated fructose with acidic MeOH and got methyl
D-fructofuranoside 1 and 2 in 80% total yield with an isomer ratio
of 1:1 (Scheme 1). But fructoside 1 and 2 were quite polar and
showed little difference on TLC, and could only be separated by sil-
ica gel column with very careful operation. Then we treated
a-methyl fructofuranoside 1 with acidic MeOH and 2,2-dime-
thoxypropane to afford -methyl 1,3-O-isopropylidene- -fructo-
a
D
furanoside 3 in 75% yield, in which 1,3-dihydorxyl group were
Fructose exists as a mixture of two pyranoid, two furanoid, and
one acyclic keto-form tautomers. Simple derivatizations of fructose,
such as glycosidations, acylations, and alkylations, usually yield
product mixtures of, at worst, all five tautomeric forms. Therefore,
literature methods always required quite complex purification and
low yield procedures to prepare derivatives.5 Separation of the ma-
jor component is cumbersome and highly detrimental to the yields
obtainable. Considering the important applications of many deriv-
atives of fructose, herein we report a new procedure for fructose
derivative syntheses, in which the operation offered a single isomer
product and waived complex isomer separation procedures.
selectively protected. However, to our surprise, when b-methyl
D-fructofuranoside 2 was treated under the same acidic condition,
the same product 3 was obtained in almost the same yield. In the-
ory, because 1,3-dihydroxyl group in b-methyl fructofuranoside 2
exists as trans-form, they could not form cyclic acetonide. It means
that the configuration of the methoxy group in 2 reversed under
mild acidic conditions, and both glycoside 1 and 2 will offer the
same product 3 under the same acidic conditions. Thus we tried
to simplify the procedure and run in large scale in an one pot pro-
cedure, by skipping the separation procedure of the two polar iso-
mers. Therefore, when the reaction mixture of the two
fructofuranoside 1 and 2 obtained by the reaction of fructose with
acidic MeOH was treated with 2,2-dimethoxypropane in the one
pot procedure, product 3 was obtained directly in 70% yield.9
⇑
Corresponding authors. Tel./fax: +86 22 23498707.
E-mail addresses: wwjie@tust.edu.cn (W. Wu), hongzy@nankai.edu.cn (Z. Hong).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.045

K. Yu et al. / Tetrahedron Letters 54 (2013) 2788–2790
2789
OH
O
O
BnO
O
HO
OH
HO
O
D-fructose
O
O
a
O
OH
OH
a
OMe
OMe
BnO
O
HO
6
3
HO
HO
BnO
OMe
OH
OH
OMe
O
O
b
HO
O
HO
+
O
O
HO
HO
( 1 : 2 =1:1 )
1
2
BnO
7
Configuration
Inversion
O
Scheme 3. Synthesis of a-butyl 4,6-di-O-benzyl-1,3-O-isopropylidene-D-fructofur-
anoside 7. Reagents and conditions: (a) DMF, NaH, BnBr, 90%; (b) 2,2-dimethoxy
b
b
HO
propane/n-butyl alcohol = 1:1, cat. TsOH, rt, 30 min, 80%.
O
O
OMe
HO
3
O
O
a
HO
O
Scheme 1. ‘One pot’ synthesis of
a-methyl 1,3-O-isopropylidene-fructofuranoside
3. Reagents and conditions: (a) MeOH, cat. TsOH, rt, overnight; (b) Then added 2,2-
O
O
O
O
O
O
OMe
OMe
dimethoxypropane, rt, 40 min, 70%.
8
HO
HO
HO
3
b
O
HO
HO
O
O
O
HO
O
O
O
OMe
OH
HO
9
3
b
a
Scheme 4. Synthesis of
tose). Reagents and conditions: (a) coumarin, PPh3, DEAD, THF, 90%; (b) TFA/H2O
(19:1), rt, 70%.
D-fructose fluorogenic derivative 9 (6-coumarin-D-fruc-
O
O
HO
HO
O
O
O
O
markers12 for high throughput screening of FDP and RhaD, which
are two broadly used aldolases in organic synthesis.13 The require-
ment of phosphoralated substrate seriously restricted the applica-
tions of aldolases,14 and directed evolution is one possible way to
solve this problem.15,16 The published procedure only offered com-
O
OBn
HO
HO
4
5
Scheme 2. Synthesis of 1,3-O-isopropylidene-a-D-fructofuranoside 4 and 5.
Reagents and conditions: (a) vinyl acetate/acetone/1-octanol = 1:1:1, 1% TsOH, rt,
30 min, 60%; (b) vinyl acetate/acetone/BnOH = 1:1:1, 1% TsOH, rt, 30 min, 70%.
pound 9 in very low yield (7.8% overall yield) starting for
tose.12 It was even more difficult to synthesize enough amount of
12 which required expensive unnatural
-fructose17 as the starting
material. Herein we used this procedure to efficiently synthesize
these two fluorogenic fructose derivatives for directed enzyme
evolution.
D-fruc-
L
Usually the product from one pot will contaminate with a little bit
of unknown byproduct from the NMR (about 5%) when silica gel
chromatography separation was used for the purification, but it
is easy to be removed in the follow up transformation. The 1-OH
and 6-OH in compound 3 were differentiated and could be easily
derivatized separately. This procedure will produce a single isomer
product directly and waived any isomer separation, which is usu-
ally a very common and difficult problem in fructose derivative
synthesis.
Coumarin was coupled with
fructofuranoside 3 at the 6-position through Mitsunobu reaction
(PPh3, DEAD) to afford -methyl 6-coumarin-1,3-O-isopropyli-
dene- -fructofuranoside 8 in 90% yield (Scheme 4). The free
4-OH has no any influence to this process. Then 8 was deprotected
with TFA at room temperature to afford the desired 6-coumarin-
a-methyl 1,3-O-isopropylidene-D-
a
D
D
-
The configuration of the methoxy group in the b-methyl
fructose 9 in 70% yield which has the same NMR spectrum with the
published data.12 The total yield for 9 was improved to 44% when
calculated from fructose.
D
-fructofuranoside 2 easily reversed under mild acidic condition.
We proposed that the process may occur through a carbonion pro-
cess, which resulted in the reversion of the configuration. Therefore,
we thought that we may use this procedure to synthesize other
fructosides by adding different alcohols under mild acidic condition.
Under the reaction condition of vinyl acetate, acetone, PTSA, when
We then tried to use the above route to synthesize the
L
-form
-fructose was expensive, we started the
-glucose. -glucose was isomerized with
product. As unnatural
synthesis from cheap
L
L
L
NaAlO2 as base to give a mixture of glucose, mannose, and fructose,
in which fructose was the major component (70% from NMR)
(Scheme 5). Without separation, the mixture was used directly
for the following methyl glycosidation and acetonide protection.
1-octanol or BnOH was added, 1,3-O-isopropylidene-a-D-fructofur-
anoside 4 and 5 were obtained in 60% and 70% yields, respectively
(Scheme 2).10 The 4,6-di-O-benzyl protected fructofuranoside 6
can also take the similar reaction by treatment with 2,2-dimethoxy
Product
a-methyl 1,3-O-isopropylidene-L-fructofuranoside 10
propane/n-butyl alcohol and PTSA to afford
a-butyl 4,6-di-O-ben-
was obtained in 40% yield in three steps. Then according to the
zyl-1,3-O-isopropylidene-
D
-fructofuranoside
7
in 80% yield
(Scheme 3).11 This procedure was quite simple to prepare
similar procedure for compound 9, Mitsunobu reaction and TFA
deprotection, the desired 6-coumarin-L
-fructose 1212 was obtained
fructosides.
in five steps with a total yield of 27% in a multigram scale.
In conclusion, we developed a very simple procedure to prepare
fructose derivatives or fructosides. This procedure waived the
The developed procedure is very simple and could be used to
prepare many other kinds of fructose derivatives efficiently.
6-Coumarin D- and L-fructose (9 and 12) were used as fluorogenic

2790
K. Yu et al. / Tetrahedron Letters 54 (2013) 2788–2790
TsOH (9 mg). The solution was stirred at rt for 5 min. Then fructose (1.8 g) was
OMe
O
O
added, and the mixture was stirred overnight. To the reaction mixture was
added 2,2-dimethoxy propane (10 ml). The mixture was stirred at rt for 40 min
before terminated with anhydrous NaHCO3 to neutralize the solution. The
mixture was filtered and evaporated, then purified through silica gel column to
afford product 3 (1.6 g, 70% yield). 1H NMR (400 MHz, CDCl3) d 4.19–3.87 (m,
5H), 3.82 (qd, J = 11.8, 4.3 Hz, 2H), 3.32 (s, 3H), 1.48 (s, 3H), 1.39 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 101.28, 98.79, 87.68, 79.62, 77.66, 62.79, 61.80, 48.75,
27.86, 19.27.
OH
OH
a
HO
O
OH
OH
HO
O
HO
L-Glucose
10
OMe
O
OH
10. Typical procedure for alcohol exchange experiment: To compound 3 (500 mg) in
flask was added (0.5 ml) vinyl acetate, (0.5 ml) acetone, and (0.5 ml) 1-octanol
with a ratio of 1:1:1, then added 5 mg (1%) TsOH. The mixture was sittred at rt
for 30 min and terminated with anhydrous NaHCO3 by stirring until
neutralization. The mixtrue was filtered, concentrated, and purified with
b
O
O
O
O
O
O
O
11
silica gel column to afford a-octyl 1,3-O-isopropylidene- -fructofuranoside 4
a-
D
OH
O
(380 mg, 70% yield). -Benzyl 1,3-O-isopropylidene-a-D-fructofuranoside 5
a
OH
c
was synthesized by the same procedure but exchanging 1-octanol to BnOH. For
compound 4: 1H NMR (400 MHz, CDCl3) d 4.24–3.90 (m, 5H), 3.90–3.75 (m,
2H), 3.69 (dt, J = 8.9, 6.9 Hz, 1H), 3.40 (dt, J = 9.0, 6.5 Hz, 1H), 1.65–1.16 (m,
18H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 101.70, 99.36, 89.01,
79.71, 78.41, 63.58, 62.86, 62.07, 32.47, 30.72, 29.98, 29.87, 28.81, 26.84,
23.32,19.67, 14.78. For compound 5: 1H NMR (400 MHz, CDCl3) d 7.45–7.23 (m,
5H), 4.75 (d, J = 11.2 Hz, 1H), 4.49 (d, J = 11.2 Hz, 1H), 4.19 (dd, J = 2.5, 1.3 Hz,
1H), 4.14 (s, 1H), 4.03 (q, J = 12.1 Hz, 3H), 3.84 (dd, J = 7.2, 4.3 Hz, 2H), 1.50
(s,3H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3) d 137.55, 129.15 (2C), 128.47,
128.37 (2C), 101.75, 98.80, 88.12, 79.51, 77.69, 63.74, 62.85, 62.39, 27.99,
19.22.
O
OH
OH
12
Scheme 5. Synthesis of L-fructose fluorogenic derivative 12 (6-coumarin-L-fruc-
tose). Reagents and conditions: (a) (I) aquous NaAlO2, rt, 2 days, (II) MeOH, cat.
TsOH, rt, overnight, (III) 2,2-dimethoxy propane, rt, 40 min, 40% overall yield for
three steps; (b) coumarin, PPh3, DEAD, THF, 85%; (c) TFA/H2O (19:1), rt, 80%.
11. Compound 3 (1.8 g) was dissolved in DMF (about 18 ml). Then sodium hydride
(0.9 g) and BnBr (3.95 g) were added to the solution, respectively. The mixture
was stirred at rt until compound 3 disappeared while checking by TLC (PE/
EA = 5/1). The mixture was diluted with EA, washed with deionized water and
brine, dried with Na2SO4, and concentrated. Silica gel purification afforded oil
4,6-di-O-benzyl protected fructofuranoside 6 (2.0 g, 90% yield). To a solution of
2,2-dimethoxy propane (1.0 ml) and n-butyl alcohol (1.0 ml) with a ratio of 1:1
was added TsOH (10 mg). The mixture was stirred at rt for 30 min and
concentrated with evaporator to remove methanol and excess 2,2-dimethoxy
propane. Then to the residue were added n-butyl alcohol (1.0 ml) and
compound 6 (100 mg) and the mixture was stirred at rt for 30 min before
terminated with andydrous NaHCO3. The mixture was filtered and evaporated,
requirement of isomer separation, which is usually a very common
and difficult problem in fructose derivative syntheses. In this
procedure, the hydroxyl groups were differentiated to expedite
the preparation of many kinds of other fructose derivatives and
the alkoxy group in the fructosides could exchange easily with
alcohols under the mild acidic condition, which offered a new
method to synthesize other fructosides through alcohol exchang-
ing. By using this procedure, we successfully synthesized fluoro-
genic fructose derivatives for high throughput enzyme screening.
This methodology could expand the usage of the abundant fructose
in organic synthesis.
then purified through silica gel column to afford
a-butyl 4,6-di-O-benzyl-1,3-
O-isopropylidene-
D
-fructofuranoside 7 (90 mg, 80% yield). For compound 6: 1
H
NMR (400 MHz, CDCl3) d 7.29 (m, 10H), 4.72–4.40 (m, 4H), 4.24–4.15 (m, 1H),
4.08 (d, J = 1.1 Hz, 1H), 3.91 (d, J = 12.1 Hz, 1H), 3.80–3.72 (m, 2H), 3.62 (qd,
J = 10.6, 5.4 Hz, 2H), 3.30 (s, 3H), 1.40 (s, 3H), 1.32 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 138.13, 138.03, 128.39 (4C), 127.99 (4C), 127.64 (2C), 103.40, 99.37,
85.43, 81.77, 79.88, 73.38, 72.28, 70.38, 62.11, 48.52, 26.61, 21.30. For
compound 7: 1H NMR (400 MHz, CDCl3) d 7.49–7.14 (m, 10H), 4.65–4.41 (m,
4H), 4.21 (dd, J = 11.0, 5.0 Hz, 1H), 4.11 (d, J = 1.0 Hz, 1H), 3.90 (d, J = 12.1 Hz,
1H), 3.84–3.72 (m, 2H), 3.71–3.52 (m, 3H), 3.43 (dt, J = 9.2, 6.2 Hz, 1H), 1.62–
1.24 (m, 4H), 1.42 (s, 3H), 1.33 (s, 3H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 138.22, 137.93, 128.31 (4C), 127.62 (4C), 127.54 (2C),
102.83, 99.13, 85.60, 81.57, 79.59, 73.31, 72.00, 70.46, 62.71, 60.65, 32.14,
26.81, 21.10, 19.35, 13.90.
Acknowledgments
We thank the National Natural Science Foundation of China
(No. 21072107) and Tianjin Technology Support Project (No.
07ZCKFSH03600) for the financial support of this work.
Supplementary data
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Fessner, W.-D.; Reymond, J.-L. Chem. Eur. J. 2003, 9, 893–899; (b) Hanaya, T.;
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Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
03.045.
References and notes
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steps synthesis from dihydroxy acetone, see: Jung, S. H.; Jeong, J.-H.; Miller, P.;
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In many cases, the phosphate moiety of the products usually needs to be
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Bloom, J. D.; Meyer, M. M.; Meinhold, P.; Otey, C. R.; MacMillan, D.; Arnold, F. H.
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specificity, stereoselectivity or stability. See: (a) Jennewein, B.; Schurmann,
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17.
L
-Fructose can also be synthesized through published procedures in 5–8 steps.
(a) Bach, T.; Hofer, F. J. Org. Chem. 2001, 66, 3427–3434 (6 steps, 9.4% total yield
from -sorbose); (b) Matsumoto, T.; Enomoto, T.; Kurosaki, T. J. Chem. Soc.,
Chem. Commun. 1992, 610–611 (5 steps, 35% total yield from -arabinose); (c)
Wolfrom, M. L.; Thompson, A. J. Am. Chem. Soc. 1946, 68, 791–792 (8 steps, 16%
total yield from -arabinose).
9.
a-Methyl 1,3-O-isopropylidene-D-fructofuranoside 3 has been reported in: (a)
Wang, G.-N.; Yang, L.; Zhang, L.-H.; Ye, X.-S. J. Org. Chem. 2011, 76, 2001–2009;
(b) Cortes-Garcia, R.; Hough, L.; Richardson, A. C. J. Chem. Soc., Perkin Trans. 1
1981, 3176–3181
L
L
Typical ‘one pot’ procedure for 3: To anhydrous MeOH (10 ml) in flask was added
L