SCHEME 1
FIGURE 2. Structure of SB-219383, a selective inhibitor of bacterial
tyrosyl tRNA synthetase.
We considered the use of D-fructose as a cheap and readily
available starting ketose to access the six-membered-ring
ketonitrone 8 and derivatives exhibiting the manno configuration
(Scheme 1).26
In the course of our work on the synthesis and uses of
carbohydrate-derived nitrones,15 it appeared that these interme-
diates could give access not only to a variety of iminosugars
but also to their N-hydroxy derivatives, as soon as a method
was available for deprotecting alkoxy groups without affecting
NsO bonds.16 Strikingly, while a few polyhydroxylated pip-
eridine N-oxides have been previously studied,17 the potential
of polyhydroxylated nitrones or N-hydroxy piperidines as
glycosidase or glycosyltranferase inhibitors remains largely
unknown. To the best of our knowledge, the only N-hydrox-
ypiperidine for which biological activity has been reported is
SB-219383 (7, Figure 2), a natural product extracted from
Micromonospora sp. The latter was developped by GlaxoSmith-
Kline as a potent and selective inhibitor of bacterial tyrosyl
tRNA synthetase.18
In this note, we describe the synthesis of a carbohydrate-
derived six-membered-ring ketonitrone (from D-fructose) and
its stereoselective transformation to DMJ and N-hydroxy DMJ.
A number of polyfunctionalized five-membered-ring cyclic
nitrones have been prepared from carbohydrates and tartaric acid
derivatives, mostly in the groups of Goti and Brandi.19 Such
intermediates have been used in a variety of reactions including
addition of organometallics,20 1,3-cycloaddition,21 or SmI2-
induced reductive coupling.22 In contrast, six-membered-ring
endocyclic nitrones are scarce in the literature,23 and most of
them were reported to be unstable.24 Probably for this reason,
such nitrones have been used in synthesis without isolation.25
1,3,4,5-Tetra-O-benzyl ꢀ-D-fructopyranose 9 was first pre-
pared using the method of Chittenden27 with slight modificia-
tions.28 An O-protected oxime functionality was next introduced
at the anomeric position by treating compound 9 with O-tert-
butyldiphenylsilylhydroxylamine,29 in the presence of a catalytic
amount of pyridinium p-toluenesulfonate and with azeotropic
elimination of water.30 Then, adapting the method proposed by
Tamura for the synthesis of carbohydrate-derived cyclic aldoni-
trones, the primary alcohol was mesylated to produce the oximes
10a and 10b in 86% yield (for the two steps) as a mixture of
diastereomers, E(10a):Z(10b) ) 60:40.31 Nitrone cyclization was
then induced by fluoride attack at the silyl protecting group of
the oxime. In this case, the use of silica-supported tetrabuty-
lammonium fluoride32 was found advantageous when compared
to tetrabutylammonium triphenyl-difluorosilicate (TBAT)33 or
other fluoride sources, conciliating good yields and easy isolation
of the polar nitrone 8. However, only the E isomer 10a cyclized
to the corresponding nitrone, while the Z isomer 10b was
transformed quantitatively to the corresponding deprotected
oxime 11. Attempts to isomerize 11 and transform it into the
nitrone 8 were not met with success.34
Nitrone 8 was next reduced stereoselectively as shown in
Scheme 3. First, its hydrogenation over 10% Pd/C afforded
(23) (a) Peer, A.; Vasella, A. HelV. Chim. Acta 1999, 82, 1044. (b) Berge,
J. M.; Copley, R. B. C.; Eggleston, D. S.; Hamprecht, D. W.; Jarvest, R. L.;
Mensah, L. M.; O’Hanlon, P. J.; Pope, A. J. Bioorg. Med. Chem. Lett. 2000, 10,
1811. (c) Duff, F. J.; Vivien, V.; Wightman, R. H. J. Chem. Soc., Chem. Commun.
2000, 2127. (d) Tamura, O.; Toyao, A.; Ishibashi, H. Synlett 2002, 1344.
(24) (a) Thesing, J.; Mayer, H. Chem. Ber. 1956, 89, 2159. (b) Ali, S. A.;
Wazeer, M. I. M. J. Chem. Soc., Perkin Trans. 2 1986, 1789. (c) van den Broek,
L. A. G. M. Tetrahedron 1996, 52, 4467. (d) Chackalamannil, S.; Wang, Y.
Tetrahedron 1997, 53, 11203. (e) Brandi, A.; Cicchi, S.; Paschetta, V.; Gomez
Pardo, D.; Cossy, J. Tetrahedron Lett. 2002, 43, 9357. See also ref 23a.
(25) See for example: (a) Herczegh, P.; Kova´cs, I.; Szila´gyi, L.; Varga, T.;
Dinya, Z.; Sztaricskai, F. Tetrahedron Lett. 1993, 34, 1211. (b) Markandu, J.;
Dondas, H. A.; Frederickson, M.; Grigg, R. Tetrahedron 1997, 53, 13165. (c)
Ooi, H.; Urushibara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett.
2001, 3, 953.
(15) (a) Carmona, A. T.; Wightman, R. H.; Robina, I.; Vogel, P. HelV. Chim.
Acta 2003, 86, 3066. (b) Desvergnes, S.; Py, S.; Valle´e, Y. J. Org. Chem. 2005,
70, 1459. (c) Desvergnes, S.; Desvergnes, V.; Martin, O. R.; Itoh, K.; Liu, H.-
W.; Py, S. Bioorg. Med. Chem. 2007, 15, 6443. (d) Pillard, C.; Desvergnes, V.;
Py, S. Tetrahedron Lett. 2007, 48, 6209.
(16) (a) Desvergnes, S.; Valle´e, Y.; Py, S. Org. Lett. 2008, 10, 2967. (b)
Liautard, V.; Desvergnes, V.; Martin, O. R. Tetrahedron: Asymmetry 2008, 19,
1999.
(17) (a) Kajimoto, T.; Liu, K. K.-C.; Pederson, R. L.; Zhong, Z.; Ichikawa,
Y.; Porco Jr, J. A.; Wong, C.-H. J. Am. Chem. Soc. 1991, 113, 6187. (b) Dong,
W.; Jespersen, T.; Bols, M.; Skrydstrup, T.; Sierks, M. R. Biochemistry 1996,
35, 2788. (c) Sun, L.; Li, P.; Landry, D. W.; Zhao, K. Tetrahedron Lett. 1996,
37, 1547. (d) O’Neil, I. A.; Southern, J. M. Tetrahedron Lett. 1998, 39, 9089.
(18) (a) Stefanska, A. L.; Coates, N. J.; Mensah, L. M.; Pope, A. J.; Ready,
S. J.; Warr, S. R. J. Antibiot. 2000, 53, 345. (b) Berge, J. M.; Houge-Frydrych,
C. S. V.; Jarvest, R. L. J. Chem. Soc., Perkin Trans. 1 2001, 2521.
(19) For a recent review on enantiopure cyclic nitrones, see: Revuelta, J.;
Cicchi, S.; Goti, A.; Brandi, A. Synthesis 2007, 485.
(26) D-Fructose as been previously used as a starting material for iminosugar
syntheses: (a) Furneaux, R. H.; Tyler, P. C.; Whitehouse, L. A. Tetrahedron
Lett. 1993, 34, 3613. (b) Spreitz, J.; Stu¨tz, A. E.; Wrodnigg, T. M. Carbohydr.
Res. 2002, 337, 183. (c) Izquierdo, I.; Plaza, M. T.; Rodriguez, M.; Franco, F.;
Martos, A. Tetrahedron 2005, 61, 11697.
(20) For representative examples, see:(a) Goti, A.; Cicchi, S.; Mannucci, V.;
Cardona, F.; Guarna, F.; Merino, P.; Tejero, T. Org. Lett. 2003, 5, 4235. (b)
Evans, G. B.; Furneaux, R. H.; Hausler, H.; Larsen, J. S.; Tyler, P. C. J. Org.
Chem. 2004, 69, 2217. (c) Yu, C.-Y.; Huang, M.-H. Org. Lett. 2006, 8, 3021.
(d) Gurjar, M. K.; Borhade, R. G.; Puranik, V. G.; Ramana, C. V. Tetrahedron
Lett. 2006, 47, 6979. (e) Kaliappan, K. P.; Das, P. Synlett 2008, 841. See also
ref 15d.
(27) (a) Raaijmakers, H. W. C.; Arnouts, E. G.; Zwanenburg, B.; Chittenden,
G. J. F. Carbohydr. Res. 1994, 257, 293. (b) Sung’hwa, F.; Strik, A.; Regeling,
H.; Zwanenburg, B.; Chittenden, G. J. F. Carbohydr. Res. 2006, 341, 846.
(28) See Supporting Information.
(29) (a) Battaro, J. C.; Bedford, C. D.; Dodge, A. Synth. Commun. 1985, 15,
1333. (b) Denmark, S. E.; Dappen, M. S.; Sear, N. L.; Jacobs, R. T. J. Am.
Chem. Soc. 1990, 112, 3466.
(30) Azeotropic elimination of water proved necessary for complete conver-
sion of the starting material.
(31) The configuration of each isomer was assigned from nOe experiments
(see Supporting Information) and their ratio was determined from 1H NMR
spectra.
(32) Clark, J. H. J. Chem. Soc., Chem. Commun. 1978, 789.
(33) Pilcher, A. S.; DeShong, P. J. Org. Chem. 1996, 61, 6901.
(34) Treatment of 11 with catalytic amounts of various acids (CSA, APTS,
HClO4), with catalytic amounts of KCN, or excesses of hydroxylamine
hydrochloride only led to recovery of the starting material, together with products
of decomposition.
(21) For representative examples, see: (a) Cardona, F.; Faggi, E.; Liguori,
F.; Cacciarini, M.; Goti, A. Tetrahedron Lett. 2003, 44, 2315. (b) Toyao, A.;
Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003, 35. (c) Alibes, R.; Blanco,
P.; de March, P.; Figueredo, M.; Font, J.; Alvarez-Larena, A.; Piniella, J. F.
Tetrahedron Lett. 2003, 44, 523. (d) Chevrier, C.; LeNouen, D.; Neuburger,
M.; Defoin, A.; Tarnus, C. Tetrahedron Lett. 2004, 45, 5363. (e) Cicchi, S.;
Marradi, M.; Vogel, P.; Goti, A. J. Org. Chem. 2006, 71, 1617. (f) Liautard, V.;
Christina, A. E.; Desvergnes, V.; Martin, O. R. J. Org. Chem. 2006, 71, 7337.
(g) Coutouli-Argyropoulou, E.; Xatzis, C.; Argyropoulos, N. G. Nucleosides,
Nucleotides Nucleic Acids 2008, 27, 84.
(22) See ref 15b and 15c.
J. Org. Chem. Vol. 74, No. 4, 2009 1767