Simple and efficient synthesis of 2,5-anhydro-d-glucitol

Article abstract of DOI:10.1016/j.tetlet.2012.12.062

The synthesis of 2,5-anhydro-d-glucitol is described via intramolecular cyclization of diepoxide using ammonium formate in MeOH by a microwave-assisted reaction. The overall yield was 32% from d-mannitol derivative involving seven steps.

Full text of DOI:10.1016/j.tetlet.2012.12.062

Tetrahedron Letters 54 (2013) 1087–1089
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Simple and efficient synthesis of 2,5-anhydro-D-glucitol
⇑
Valquiria Aragão-Leoneti, Ivone Carvalho
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café s/n, Monte Alegre, Ribeirão Preto 14040-930, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2012
Revised 11 December 2012
Accepted 12 December 2012
Available online 27 December 2012
The synthesis of 2,5-anhydro-D-glucitol is described via intramolecular cyclization of diepoxide using
ammonium formate in MeOH by a microwave-assisted reaction. The overall yield was 32% from
nitol derivative involving seven steps.
D-man-
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrate synthesis
Glucitol
Microwave-assisted reaction
Furanose sugars are essential components of nucleic acids and
were considered a central core for the development of antiviral
and antitumor drugs, which also encompass uncommon natural
nucleosides. These nucleosides contain the furanose-linked pyra-
zole or imidazole, isolated from Streptomyces,1 being pyrazomycin
(1), a potential anti-HIV agent, and showdomycin (2) which has
antitumor and antibacterial properties (Fig. 1).2
Similar low yields were also achieved by treatment of the di-O-
methyl diepoxide 5 (Fig. 2), prepared from 1,2:5,6-di-O-isopropyl-
idene-
chiral (salen)CoIII complex to provide 2,5-anhydro-6-bromo-6-
deoxy- -gluci-
-glucitol (16%)15 or 2,5-anhydro-3,4-di-O-methyl-
tol (12%),16 respectively. Alternatively, 5-endo-tet cyclization of
2,3-epoxy alcohols, 6 or 7 (Fig. 2), starting from (+)-diethyl tarta-
D
-mannitol in four steps,14 with either hydrogen bromide or
D
D
L
The fructose analogue 2,5-anhydro-
D
-mannitol (3), is a valuable
rate and allyl bromide or cis-but-2-ene-1,4-diol, respectively, were
also effective in producing 4 with approximately 21% overall yield,
when performed from 7 (eight steps).17
furanose sugar involved in the inhibition of gluconeogenesis3 and
glucogenolysis,4 and the increase of food intake in rats (Fig. 1),5
whereas 2,5-anhydro-
D
-glucitol (4) and its derivatives have been
In addition, silylation of methyl fructo-furanoside or pyrano-
side, followed by treatment with triethylsilane and trimethylsilyl
described as an antitumor agent, able to inhibit tumor cell growth,6
as well as being a phytotoxic agent7,8 (Fig. 1). Furthermore, com-
pound 4 has been used as a key intermediate in the synthesis of
natural products, such as (+)-muscarine9 and -chitaric acid.10
D
The classical method established for the synthesis of 2,5-
anhydro- -glucitol (4) and its corresponding derivatives is based
on the acid dehydration of -mannitol, which results in a non-
D
D
separable mixture of three anhydride derivatives resulting in com-
pound 4 (45% of the mixture), as revealed by gas chromatography
analysis.11,12 An attempt to isolate compound 4 through isopro-
pylidenation and tritylation of these mixed anhydrides gave
2,5-anhydro-1,3-O-isopropylidene-6-O-trityl-D-glucitol, which was
deprotected by acid hydrolysis to yield 4 in approximately 15%
overall yield.11 A slight improvement in the yield involving an
alternative derivative of 4, 2,5-anhydro-1,3-O-isopropylidene-D-
glucitol, was accomplished by treating these mixed anhydrides
with acetone under acid catalysis followed by either high vacuum
fraction distillation13 or dry column vacuum chromatography.8
⇑
Corresponding author. Tel.: +55 16 36024709; fax: +55 16 36024879.
E-mail address: carronal@usp.br (I. Carvalho).
Figure 1. Structures of furanose sugars with relevant biological activity.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.062

1088
V. Aragão-Leoneti, I. Carvalho / Tetrahedron Letters 54 (2013) 1087–1089
Figure 2. Important intermediates applied to the synthesis of 2,5-anhydro-D-glucitol (4).
trifluoromethanesulfonate for reductive cleavage gave 4 in 19%
yield,18 while regio- and stereoselective cyclization of manno open
olefin 8 (Fig. 2) allowed the preparation of deuterium labeling in
performed in 1,4-dioxane, THF, DMF, and H2O using the same reac-
tion conditions applied to MeOH (90 °C for 1 h under microwave
irradiation). Despite the moderate yield (41%) of 11 achieved in
the reaction using a mixture of MeOH/H2O (8:2), diepoxide 10
was not converted into the product 11 in the majority of the exper-
iments, being quantitatively recovered from the reaction mixture,
with exception of the use of DMF, which also led to the degradation
of 10. Additionally, the effect of the protective group on the cycli-
zation reaction was pursued using two derivatives of 10, contain-
ing either free hydroxyl groups at 3- and 4-positions, as
exemplified for compound 12, or 3,4-isopropylidene group in the
place of the original 3,4-dibenzyl protective group of 10, such as
compound 13. Thus, a time controlled hydrogenolysis of 10
(10 min) gave the diol 12 in 78% yield after purification by chroma-
tography column, which was treated with acetone and zinc chlo-
ride to give isopropylidene 13 (20% yield).26 While the
cyclization of diol 12 in the presence of ammonium formate re-
different positions of 4 from protected
with approximately 12% overall yield.19 Finally, oxidative cycliza-
tion of 1,5-diene 9 using OsO4, prepared from -mannitol (three
steps), gave the intermediate 2,5-anhydro-3,4-di-O-benzyl- -gluc-
-chitaric acid
D-mannose in four steps,
D
D
itol, which was converted into either compound 4 or
D
with approximately 42% and 13% overall yields, respectively.10
However, to the best of our knowledge the synthesis of com-
pound 4 from diepoxide derivatives with ammonium formate un-
der microwave conditions has not been described. In this Letter, an
alternative route to obtain 2,5-anhydro-
D-glucitol (4) is reported
from commercially available 1,2:5,6-di-O-isopropylidene-
D-man-
nitol via intramolecular cyclization of diepoxide 10 using ammo-
nium formate in a microwave-assisted reaction (Scheme 1).
The protection of hydroxyl groups of 1,2:5,6-di-O-isopropyli-
dene-
D
-mannitol was achieved by treatment with benzyl bromide
quired 2 h to give 2,5-anhydro-D-glucitol (4) in 22% yield, instead
and NaH in the presence of Bu4NI, after purification in silica gel
chromatography (96% yield).20 The cleavage of the isopropylidene
group was undertaken by treatment with MeOH/HCl, instead of
AcOH 70%,20 yielding the corresponding product with 98%
yield.21,22 The 1- and 6-positions were selectively protected with
TBDMS group followed by functionalization of secondary hydroxyl
groups (2- and 5-positions) using mesyl chloride. The crude prod-
uct was used in the next step without any purification.23 Treat-
ment of this compound with MeOH/HCl, followed by KOH gave
diepoxide 10 by intramolecular SN2 reaction (52% yield), involving
inversion of configuration at C-2 and C-5 (Scheme 1).23 Compound
10, which is an important intermediate in the synthesis of glycosi-
dase azasugar inhibitors (1-deoxynojirimycin and polyhydroxylat-
ed pyrrolidines),23 was converted into the furanose derivative 11
by treatment with ammonium formate in MeOH at 90 °C for 1 h
under microwave irradiation with 65% yield after purification in
silica gel chromatography (Scheme 1).24 The first step of this reac-
tion involves the regioselective opening of 1,2-epoxide of 10 fol-
lowed by the O-cyclization leading to glucitol 11. Alternatively,
ammonium formate has been described to reduce alkyl linear
1,2-epoxides to produce saturated alcohols in the presence of a
palladium catalyst.25
1 h for the corresponding 3,4-dibenzyl 10 to produce 11 (65%), at-
tempts to convert compound 13 into glucitol derivative under sim-
ilar reaction conditions provided just a complex mixture.
Finally, the hydrogenation reaction of glucitol 11 in the pres-
ence of Pd/C afforded 2,5-anhydro-
D-glucitol (4) in quantitative
yield (Scheme 1).27
In conclusion, 2,5-anhydro-D-glucitol (4) was successfully pre-
pared via intramolecular cyclization reaction of dibenzyl diepox-
ide 10, in the presence of ammonium formate, with overall
yield of 32% in seven steps from 1,2:5,6-di-O-isopropyllidene-D-
mannitol.
Acknowledgments
We acknowledge financial support from Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq), and Coorde-
nação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
References and notes
1. (a) Gutowski, G. E.; Chaney, M. O.; Jones, N. D.; Hamill, R. L.; Davis, F. A.; Miller,
R. D. Biochem. Biophys. Res. Commun. 1973, 51, 312; (b) Bottcher, T.; Sieber, S. A.
J. Am. Chem. Soc. 2010, 132, 6964.
2. Soares, M. C.; de Souza, M. C. B. V.; Ferreira, V. F. Quim. Nova 2001, 24, 206.
3. Wu, W.; Vesonder, R. F. Nat. Toxins 1997, 5, 80.
In order to check the influence of the solvents on solubility, sta-
bility of the reactants, and cyclization rates, the reaction was also
4. Otero, D. A.; Simpson, R. Carbohydr. Res. 1984, 128, 79.
5. (a) Tordoff, M. G.; Rawson, N.; Friedman, M. I. Am. J. Physiol. 1991, 261, R283;
(b) Horn, C. C.; Ji, H.; Friedman, M. I. Physiol. Behav. 2004, 81, 157.
6. Sun, H.; Niu, B.; Liu, J.; Wu, X. CN 101401803 (A), 2009.
7. Tanaka, T.; Hatano, K.; Watanabe, M.; Abbas, H. K. J. Nat. Toxins 1996, 5, 317.
8. Doboszewski, B.; Siqueira, E. C. Synth. Commun. 2010, 40, 744.
9. Mubarak, A. M.; Brown, D. M. Tetrahedron Lett. 1980, 21, 2453.
10. Donohoe, T. J.; Butterworth, S. Angew. Chem., Int. Ed. 2003, 42, 948.
11. Koerner, T. A. W., Jr.; Voll, R. J.; Younathan, E. S. Carbohydr. Res. 1977, 59, 403.
12. Barker, R. J. Org. Chem. 1970, 35, 461.
13. (a) Hartmann, L. A. U.S. Patent 3,480,651, 1969.; (b) Hartmann, L. A. U.S. Patent
3,484,459, 1969.
14. Kuszmann, J. Carbohydr. Res. 1979, 71, 123.
15. Kuszmann, J. Carbohydr. Res. 1979, 73, 93.
16. Satoh, T.; Imai, T.; Umeda, S.; Tsuda, K.; Hashimoto, H.; Kakuchi, T. Carbohydr.
Res. 2005, 340, 2677.
O
OR2
O
HO
R1O
OH
ii
i
4
R1O
OR2
O
1
2
1
2
11
R = R = Bn
10
12
R = R = Bn
1
2
R = R = H
13 R1,R2= C(CH3)2
Scheme 1. Synthesis of 2,5-anhydro-
HCO2NH4, MeOH, MW, 90 °C, 65%; (ii) H2, Pd/C, AcOH, MeOH, 100%.
D-glucitol (4). Reagents and conditions: (i)
17. Das, B.; Kumar, D. N. Tetrahedron Lett. 2010, 51, 6011.

V. Aragão-Leoneti, I. Carvalho / Tetrahedron Letters 54 (2013) 1087–1089
1089
18. Bennek, J. A.; Gray, G. R. J. Org. Chem. 1987, 52, 892.
19. Persky, R.; Albeck, A. J. Org. Chem. 2000, 65, 5632.
(d, 1H, J 11.8, CH2Ph); 4.15–4.11 (m, 3H, H-5, H-3, H-4); 4.04–4.02 (m, 1H, H-
2); 3.91 (dd, 1H, J 11.9, 4.5, H-6b); 3.85–3.82 (m, 2H, H-6a, H-1b); 3.68 (dd, 1H,
J 11.9, 4.0, H-1a); 2.65 (sl, OH). 13C NMR (125 MHz, CDCl3) d 137.8 (C-Ph);
137.3 (C-Ph); 128.8 (C-Ph); 128.7 (C-Ph); 128.3 (C-Ph); 128.2 (C-Ph); 128.0 (C-
Ph); 127.8 (C-Ph); 84.3, 84.0, 83.1, 80.6 (C-2, C-3, C-4, C-5); 72.3 (CH2Ph); 72.2
(CH2Ph); 62.9 (C-1); 61.7 (C-6). The data are in good agreement with literature
values.10
20. Jurczak, J.; Bauer, T.; Chmielewski, M. Carbohydr. Res. 1987, 164, 493.
21. Ghosh, S.; Rao, R. V.; Shashidhar, J. Tetrahedron Lett. 2005, 46, 5479.
22. Aragão, V.; Constantino, M. G.; Beatriz, A.; Silva, G. V. J. Molecules 2005, 10,
1413.
23. Merrer, Y. L.; Poitout, L.; Depezay, J. C.; Dosbaa, I.; Geoffroy, S.; Foglietti, M. J.
Bioorg. Med. Chem. Lett. 1997, 5, 519.
25. Dragovich, P. S.; Prins, T. J.; Zhou, R. J. Org. Chem. 1995, 60, 4922.
26. Baer, E.; Fischer, H. O. L. J. Biol. Chem. 1939, 128, 463.
24. Procedure for the synthesis of 3,4-dibenzyloxy-2,5-dihydroxymethyl-
tetrahydrofuran (11): ammonium formate (0.019 g, 0.3062 mmol) was added
27. 2,5-Anhydro-D
-glucitol (4): 1H NMR (500 MHz, D2O) d 4.09 (dd, 1H, J 4.3, 2.5, H-
to
a
solution of 1,2:5,6-dianhydro-3,4-di-O-benzyl-l-iditol (10) (0.050 g,
4); 4.03 (dd, 1H, J 7.0, 4.3, H-5); 3.92 (dd, 1H, J 4.3, 2.5, H-3); 3.75 (1H, m, H-2);
3.73 (dd, 1H, J 12.0, 4.3, H-6b); 3.68 (dd, 1H, J 12.0, 3.8, H-1b); 3.65 (dd, 1H, J
12.0, 7.0, H-6a); 3.60 (dd, 1H, J 12.1, 6.0, H-1a). 13C NMR (125 MHz, D2O) d 85.0,
81.3, 78.4, 77.3 (C-2, C-3, C-4, C-5); 62.1, 60.5 (C-1, C-6). ESI-MS m/z, calcd for
C6H12O5 [M+Na]+ 187.0582, found 187.0577. The data are in good agreement
with literature values.10,19
0.1531 mmol) in MeOH (0.5 mL). The mixture was stirred at 90 °C for 1 h
under microwave irradiation then concentrated in vacuum. Purification of the
crude product by silica gel chromatography, eluting with CH2Cl2 and methanol
(9:1), provided 3,4-dibenzyloxy-2,5-dihydroxymethyl-tetrahydrofuran (11)
(0.034 g, 65%) as a yellow oil: Rf 0.3 (toluene/ethyl acetate 1:1); 1H NMR
(500 MHz, CDCl3) d 7.36–7.30 (m, 10H, Ar H); 4.64–4.57 (m, 3H, CH2Ph); 4.45