were oxidized 11 with N-chlorosuccinimide in the presence of
Et3N to give directly the furoxans 7 and 15, in very good overall
yields.†
Because of the C2-symmetry of the starting -mannitol the
two N-oxide isomeric forms of furoxan 7 are identical and
retain the chirality of -mannitol. On the other hand, the
dimerization of the bis(nitrile) oxide derived from the meso-
xylitol produces a racemate.
The furoxan ring can be easily opened or transformed in a
variety of ways.1 To demonstrate this possibility, the furoxan
ring in compounds 7 and 15 was reductively opened by selective
hydrogenolysis over Pd–C in EtOH. As shown by NMR spec-
troscopy, the resulting dioxime exists exclusively in the amphi-
configuration in both products 8 and 16, thus reflecting their
formation pathway.
In conclusion, the method reported here offers a simple and
efficient way for preparing five- and six-membered cyclitol
derivatives from cheap, commercially available alditols, demon-
strating the potential of the carbon–carbon bond formation
reaction in the dimerization of nitrile oxides. A cyclitol of a
desired stereochemistry can be prepared by selecting the
appropriate alditol and transferring its stereochemistry to the
products.
and a mixture of the resulting residue along with NH2OHؒHCl
(2.0 g, 28.8 mmol) and NaHCO3 (2.45 g, 28.8 mmol) in MeOH
(45 ml) was vigorously stirred overnight at 20 ЊC. The reaction
mixture was then transferred to a separatory funnel, H2O (100
ml) and CH2Cl2 (100 ml) were added and the organic layer was
separated, while the aqueous layer was extracted with CH2Cl2
(2 × 100 ml). The combined organic layers were dried over
Na2SO4, the solvent was then evaporated and the mixture
chromatographed on silica gel with hexane–ethyl acetate as the
eluent to give dioxime 6 as an oil (2.55 g) in 93% overall yield.
A solution of the dioxime 6 (1.137 g, 2 mmol) in CHCl3 (100
ml) was added dropwise through a dropping funnel to a reflux-
ing solution of N-chlorosuccinimide (NCS) (0.614 g, 4.6 mmol)
and pyridine (0.363 g, 4.6 mmol) in CHCl3 (100 ml) in a two-
necked flask equipped with a reflux condenser, during a period
of 1 h. The mixture was allowed to cool at room temperature,
the solvent was evaporated and the product purified by chrom-
atography (silica gel, ethyl acetate–hexane 1:4) to give the oily
furoxan 7 (1.04 g, 92%).
Acknowledgements
A. E. K. thanks the Leonidas Zervas Foundation for a
fellowship.
Experimental
References
(4S,5S,6S,7S)-4,5,6,7-Tetrahydro-4,5,6,7-tetra(benzyloxy)-
benzofurazan 1-oxide
1 (a) R. M. Paton, in Comprehensive Heterocyclic Chemistry, ed. K. T.
Potts, Pergamon, Oxford, 1984, vol. 6, pp. 393–426; (b) W. Sliwa
and A. Thomas, Heterocycles, 1985, 23, 399; (c) A. Gasco and
A. J. Boulton, Adv. Heterocycl. Chem., 1981, 29, 251; (d) K. Ley and
F. Seng, Synthesis, 1975, 415; (e) M. J. Hadadin and C. H.
Issidoridis, Heterocycles, 1976, 4, 767; 1993, 35, 1503; ( f ) W. Sliwa
and B. Mianowska, Chem. Pap., 1988, 42, 697; (g) J. K. Gallos,
P. S. Lianis and N. A. Rodios, J. Heterocycl. Chem., 1994, 31, 481
and references therein.
2 For a survey of the biological activities of furoxans see ref. 3(a).
3 (a) M. Feelisch, K. Schonafinger and E. Noack, Biochem.
Pharmacol., 1992, 44, 1149; (b) C. Medana, G. Ermondi,
R. Fruttero, A. Di Stilo, C. Ferretti and A. Gasco, J. Med. Chem.,
1994, 37, 4412.
4 For general reading: (a) P. L. Feldman, O. W. Griffith and D. J.
Stuehr, Chem. Eng. News, 1993, December 20, 26; (b) A. R. Butler
and D. L. H. Williams, Chem. Soc. Rev., 1993, 22, 233; (c) A. R.
Butler, Chem. Ind., 1995, 828; (d) R. J. P. Williams, Chem. Soc. Rev.,
1996, 25, 77; (e) A. Gasco, R. Fruttero and G. Sorba, Il Farmaco,
1996, 51, 617; (f) D. L. H. Williams, Chem. Commun., 1996, 1085;
(g) A. P. Dicks and D. L. H. Williams, Chem. Biol., 1996, 3, 655.
5 (a) K.-J. Huang, I. Jo, Y. A. Shin, S. Yoo and J. H. Lee, Tetrahedron
Lett., 1995, 36, 3337; (b) R. Calvino, R. Fruttero, D. Ghico,
A. Bosia, G. P. Pescarmora and A. Gasco, J. Med. Chem., 1992, 35,
3296; (c) G. Sorba, C. Medana, R. Fruttero, C. Cena, A. Di Stilo,
U. Galli and A. Gasco, J. Med. Chem., 1997, 40, 463 and references
therein; (d) A. M. Gasco, C. Cena, A. Di Stilo, G. Ermondi,
C. Medana and A. Gasco, Helv. Chim. Acta, 1996, 79, 1803;
(e) R. Fruttero, D. Boschi, A. Di Stilo and A. Gasco, J. Med. Chem.,
1995, 38, 4944.
A solution of dry DMSO (1.8 ml, 25 mmol) in dry CH2Cl2 (10
ml) was added to a solution of (COCl)2 (1.15 ml, 13 mmol) in
dry CH2Cl2 (20 ml) which had been cooled to Ϫ60 ЊC under an
argon atmosphere. The resulting mixture was further stirred at
the same temperature for another 2 min and a solution of 4 (2.6
g, 4.8 mmol) in dry CH2Cl2 (15 ml) was subsequently added
carefully during a period of 5 min, while the temperature was
kept at Ϫ60 ЊC. The stirring was continued for 15 min and then
Et3N (7.7 ml, 55 mmol) was added at the same temperature.
After another 10 min stirring at low temperature the mixture
was allowed to warm to room temperature. CH2Cl2 (200 ml)
was subsequently added and the solution was washed with sat-
urated aqueous NaCl (2 × 100 ml). The organic layer was dried
over Na2SO4, the solvent was removed on a rotary evaporator
† All new compounds gave satisfactory CHN microanalyses and spectral
data consistent with their assigned structures. Selected analytical data
for compounds prepared (J values are given in Hz): Compound 7: oil
[α]D Ϫ155.9 (c 1 in CHCl3); δH (300 MHz, CDCl3) 3.95 (1H, dd, J 3.7
and 7.2), 4.02 (1H, dd, J 3.0 and 7.2), 4.56 (1H, d, J 12.0), 4.59 (1H, d, J
11.8), 4.67 (1H, d, J 12.0), 4.69 (1H, d, J 11.8), 4.75 (1H, d, J 12.1), 4.7
(1H, d, J 11.4), 4.83 (1H, d, J 3.7), 4.84 (1H, d, J 3.0), 4.90 (1H, d, J
11.5), 4.98 (1H, d, J 12.1) and 7.3 (20H, m); δC(75 MHz, CDCl3) 68.81,
69.33, 72.68, 73.77, 74.04, 74.64, 75.56, 75.96, 111.13, 127.81, 127.86,
127.92, 127.95, 128.10, 128.15, 128.20, 128.37, 128.45, 128.50, 137.08,
137.31, 137.58, 137.66 and 154.56. Compound 8: oil, [α]D Ϫ0.8 (c 2.4 in
CHCl3); δH (300 MHz, CDCl3) 4.10 (1H, dd, J 10.1 and 2.3), 4.17 (1H,
dd, J 10.1 and 3.0), 4.28 (1H, d, J 3.0), 4.6 (8H, m), 5.26 (1H, d, J 2.3),
7.3 (20H, m) and 9.81 (2H, s); δC(75 MHz, CDCl3) 66.90, 69.64, 71.69,
72.87, 73.14, 74.80, 77.04, 77.61, 127.49, 127.63, 127.66, 127.69, 128.08,
128.13, 128.21, 128.25, 128.34, 137.18, 137.65, 138.24, 138.28, 147.08
and 148.09. Compound 15: oil, δH (300 MHz, CDCl3) 4.55 (1H, dd as t,
J 3.6), 4.58 (2H, s), 4.68 (4H, m), 4.88 (1H, d, J 11.9), 4.96 (1H, d, J
11.5) and 7.3 (15H, m); δC(75 MHz, CDCl3) 72.27, 72.60, 73.01, 75.11,
75.67, 93.87, 112.72, 127.76, 128.01, 128.10, 128.15, 128.36, 128.42,
128.44, 136.24, 136.27, 136.64 and 160.74. Compound 16: oil, δH (300
MHz, CDCl3) 4.01 (1H, s), 4.35 (1H, s), 4.39 (2H, s), 4.62 (1H, d, J
12.3), 4.70 (1H, d, J 11.7), 4.74 (1H, s), 4.80 (1H, d, J 11.7), 4.82 (1H, d,
J 12.3), 7.3 (15H, m), 9.75 (1H, br s) and 12.13 (1H, br s); δC(75 MHz,
CDCl3) 70.61, 71.55, 72.90, 76.96, 79.10, 82.74, 127.65, 127.71, 127.83,
127.91, 127.94, 128.13, 128.31, 128.37, 128.42, 137.08, 137.42, 137.71,
149.85 and 153.54.
6 K. B. G. Torssel, Nitrile Oxides, Nitrones, and Nitronates in Organic
Synthesis, VCH, Weinheim, 1989.
7 M. Marx, F. Marti, J. Reisdorff, R. Sandmeier and S. Clark, J. Am.
Chem. Soc., 1977, 99, 6754.
8 (a) J. K. Gallos, E. G. Goga and A. E. Koumbis, J. Chem. Soc.,
Perkin Trans. 1, 1994, 613; (b) J. K. Gallos, T. V. Koftis and A. E.
Koumbis, J. Chem. Soc., Perkin Trans. 1, 1994, 611; (c) J. K. Gallos
and A. E. Koumbis, Carbohydr. Lett., 1995, 353.
9 T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, Wiley, New York, 2nd edn., 1991.
10 K. Omura and D. Swern, Tetrahedron, 1978, 34, 1651.
11 A. N. Boa, D. A. Dawkins, A. R. Hergueta and P. R. Jenkins,
J. Chem. Soc., Perkin Trans. 1, 1994, 953.
Paper 7/04208F
Received 16th June 1997
Accepted 7th July 1997
2462
J. Chem. Soc., Perkin Trans. 1, 1997