Sulfuric acid immobilized on silica: an efficient reusable catalyst for the synthesis of O-isopropylidene sugar derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.06.050

Sulfuric acid immobilized on silica proved to be an efficient catalyst for the synthesis of O-isopropylidene sugar derivatives from reducing sugars. The method is very simple and economic for large-scale synthesis in which the catalyst is recovered and reused several times. Reactions with d-glucose, d-galactose, d-mannose, l-rhamnose, l-arabinose, d-xylose and l-sorbose led to the formation of the corresponding thermodynamically stable di-O- and/or mono-O-isopropylidene derivatives in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2006.06.050

Tetrahedron Letters 47 (2006) 5939–5941
Sulfuric acid immobilized on silica: an efficient reusable catalyst
for the synthesis of O-isopropylidene sugar derivativesI
Vishal Kumar Rajput and Balaram Mukhopadhyay*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226 001, UP, India
Received 4 May 2006; revised 26 May 2006; accepted 8 June 2006
Available online 30 June 2006
Dedicated to Dr. Alan H. Haines, University of East Anglia, Norwich, UK
Abstract—Sulfuric acid immobilized on silica proved to be an efficient catalyst for the synthesis of O-isopropylidene sugar deriva-
tives from reducing sugars. The method is very simple and economic for large-scale synthesis in which the catalyst is recovered and
reused several times. Reactions with D-glucose, D-galactose, D-mannose, L-rhamnose, L-arabinose, D-xylose and L-sorbose led to the
formation of the corresponding thermodynamically stable di-O- and/or mono-O-isopropylidene derivatives in good to excellent
yields.
Ó 2006 Elsevier Ltd. All rights reserved.
Formation of O-isopropylidene derivatives of aldoses
and ketoses by condensation with acetone has been
widely used in synthetic, structural and conformational
studies.1 Acetonides of sugars are important due to their
pharmacological properties and utility as reaction inter-
mediates for the synthesis of bioactive molecules. For
example, 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose
is well known for its anti-inflammatory and antipyretic
activities with very low toxicity,2 and therefore has
become commercially demanding as a starting material
for a diverse range of bioactive molecules such as anti-
biotics, cytotoxic, anti-inflammatory and antipyretic
agents. The corresponding di-O-isopropylidene deriva-
tive of L-sorbose has been used for the synthesis of
vitamin C3 and for the large-scale preparation of 1-
deoxynojirimycin.4 Other di- and/or mono-O-isopropyl-
idene derivatives have also found wide applications in
total syntheses of large macromolecules.
chloride along with phosphoric acid,6 ion exchange res-
ins,7 anhydrous copper(II) sulfate,8 iodine,9 anhydrous
ferric chloride,10 boron trifluoride etherate,11 anhydrous
aluminium chloride12 and Zeolite HY.13 However, many
of these methods suffer from the use of toxic chemicals,
low yields, very long reaction times and harsh reaction
conditions. Moreover, in each case, extensive work-up
and chromatographic purification become almost inevi-
table to achieve pure products. Hence, there is a clear
need for a simple and practical methodology for the syn-
thesis of this useful class of molecules on large scale.
Silica-supported reagents have gained much attention as
alternative catalysts to develop stoichiometric and/or
work-up free reaction methods in sugar chemistry.14
Noting recent reports on the use of sulfuric acid immo-
bilized on silica in various organic reactions,15 including
a one-pot acetalation–acetylation of glycosides16 from
our laboratory, we have extended its application. In this
communication, we report a simple, work-up free meth-
od for the synthesis of O-isopropylidene derivatives
from free sugars using sulfuric acid immobilized on
silica as a catalyst.
Several methods are available in the literature for the
synthesis of O-isopropylidene derivatives of sugars.
The conventional method consists of the condensation
of a sugar diol with acetone in the presence of a suitable
catalyst under anhydrous conditions. Catalysts used in
these reactions include mineral acids,5 anhydrous zinc
When a mixture of commercially available D-glucose (1,
1 mmol) in dry acetone (5 mL) was stirred in the pres-
ence of H2SO4–silica17 at room temperature, no change
in the starting material was evident by TLC even after
several hours. Next, the mixture was stirred under reflux
q CDRI Communication No. 6976.
*
Corresponding author. E-mail: sugarnet73@hotmail.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.050

5940
V. K. Rajput, B. Mukhopadhyay / Tetrahedron Letters 47 (2006) 5939–5941
ature, the kinetically controlled product was favoured.
O
To increase the amount of furanoside derivative the
reaction was conducted at 40 °C, but the ratio remained
the same after 5 h and the yield dropped to ꢀ30%.
O
O
dry acetone
O
D-glucose
H2SO4-silica
89%
O
1
HO
D-Mannose, L-rhamnose and L-arabinose led to the for-
mation of the corresponding pyranoside derivatives,
exclusively, in 82%, 87% and 91% yields, respectively.
D-Xylose and L-sorbose were converted to their di-O-iso-
propylidene furanoside derivatives under similar condi-
tions. The results are summarized in Table 1. A 25 mmol
scale acetonation reaction with D-glucose (1) gave the de-
siredcompound 8withoutaffectingtheoverallyieldwhich
suggests that this reagent system is equally viable on large
scale. After filtration of the product, the H2SO4–silica was
recovered and used again after drying. Reuse up to five
times showed almost no change in the reactivity of the
catalyst or the yield of the desired product.
8
Scheme 1. Acetonation of D-glucose.
and the starting material was completely converted to a
faster running component,18 presumably 1,2:5,6-di-O-
isopropylidene-a-D-glucofuranoside (8), within 3 h in
89% yield (Scheme 1). The compound collected after
filtration through a pad of CeliteÒ was proved to be
>95% pure 813 by NMR and mass spectrometry. Under
the same conditions, D-galactose afforded 1,2:3,4-di-O-
isopropylidene-a-D-galactopyranose (9) in 78% yield. It
is worth mentioning that in this case, when the reaction
was started on a pre-heated oil-bath, only a pyranoside
product was obtained but slow elevation of the temper-
ature resulted in a mixture of furanoside and pyranoside
in a 1:5 ratio. It was presumed that at the lower temper-
In conclusion, a simple work-up and purification free
method has been developed for the synthesis of di-
and/or mono-O-isopropylidene derivatives from free
sugars using reusable H2SO4–silica as the catalyst.
Table 1. Synthesis of O-isopropylidene derivatives from free sugars using H2SO4–silicaa
Entry
Starting material
Productb
Time (h)
3
Yield (%)
89
Ref.
13
O
O
O
O
1
D-glucose (1)
O
HO
8
O
OH
O
O
2
3
4
5
D-galactose (2)
D-mannose (3)
L-rhamnose (4)
L-arabinose (5)
3
3
2
2
78
82
87
91
13
19
20
13
O
O
9
O
O
O
O
O
OH
10
OH
O
HO
O
O
11
O
O
O
O
O
12
O
O
6
7
D-xylose (6)
L-sorbose (7)
1.5
2
83
86
13
13
O
O
O
O
O
13
O
O
O
OH
14
a All reactions were started on a pre-heated oil bath so that reflux commenced immediately after addition of the catalyst.
b Analytical data for all products were consistent with known products from the literature.

V. K. Rajput, B. Mukhopadhyay / Tetrahedron Letters 47 (2006) 5939–5941
5941
10. Singh, P. P.; Gharia, M. M.; Dasgupta, F.; Srivastava, H.
C. Tetrahedron Lett. 1977, 439–440.
11. Pfaff, P. K.; Paust, J.; Hartmann, H. (BASF, A: -G.) Ger.
Offen. DE 3, 505, 150 (cl. C07H9/04), 21 August 1986,
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The strategy is equally compatible to large-scale
synthesis.
Acknowledgements
12. Lal, B.; Gidwani, R. M.; Rupp, R. H. Synthesis 1989, 711–
713.
V.K.R is thankful to CSIR, New Delhi, for providing a
fellowship. Instrumentation facilities from SAIF, CDRI
are gratefully acknowledged.
13. Rauter, A. P.; Ramoˆa-Ribeiro, F.; Fernandes, A. C.;
Figueiredo, J. A. Tetrahedron 1995, 51, 6529–6540.
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Supplementary data
Copies of 1H and 13C NMR spectra of compounds 8, 9,
10, 11, 12, 13, and 14 are available. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2006.06.050.
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