of carbon-carbon bonds.13 After the carbon framework has
been set up, the nitro group can be converted into a range
of other functionalities.14
As a continuation of our present interest on new synthetic
applications of nitrosugars,15 herein we describe the first
enantiospecific synthesis of azafuranose 4a, which includes
the early introduction of its two hydroxymethyl substituents
at C-4 of a nitrosugar by a double Henry condensation with
formaldehyde. In the course of our studies, the N-hydroxy-
pyrrolidine 5a was also obtained.
Nitro compound 6, easily prepared from D-mannitol,16 was
treated with aqueous acetic acid to afford the corresponding
trihydroxynitro compound 7a. Selective protection of its
primary hydroxyl group as t-butyldiphenylsilyl ether, fol-
lowed by protection of the resulting diol 7b by reaction with
2,2-dimethoxypropane and p-toluenesulfonic acid in acetone,
provided the key isopropylidene nitro derivative 8 (Scheme
1). The double condensation of nitro compound 8 with
Figure 1. 1,4-Dideoxy-1,4-imino-pentanol derivatives.
iminosugar 1 (Figure 1),5 such as natural imino-D-ribitols.6
Moreover, derivatives of compounds 1 provide an op-
portunity for altering and hopefully increasing the specificity
of inhibition of individual glycosidases. Thus, derivatives
such as 2, bearing an aromatic group at position C-1, are
purine nucleoside phosphorylase (PNPase) inhibitors,7 and
derivatives such as 3, analogues of 1 substituted at the C-1
position, have also been reported as powerful and specific
glycosidase inhibitors.8 Accordingly, it is of interest to
prepare families of branched pyrrolidine iminosugars 4 and
5, analogues of 1, to test their activity against a range of
glycosidases and hence to know how the introduction of a
branch in different ring positions can alter the inhibitory
activity.9 The carbon branched pyrrolidine 4a may be
considered as a 4-C-hydroxymethyl analogue of the imino-
D-lyxitol 1a, a powerful R-galactosidase inhibitor.2a Removal
of the diastereotopic hydroxymethyl group in 4a would allow
it to be considered as an imino-L-ribitol 1b.10 Derivative
2a with an aromatic substituent is a potent inhibitor of
PNPases.11
Scheme 1. Synthesis of Linear Branched Nitroderivative
Precursor 11
Nitrosugars are powerful synthetic materials because they
combine the synthetic potential of sugars and the chemical
versatility of the nitro group;12 the nitroaldol condensation
(the Henry reaction) is a classical method for the construction
(5) (a) Fleet, G. W. J.; Witty, D. R. Tetrahedron: Asymmetry 1990, 1,
119. (b) Behling, J. R.; Campbell, A. L.; Babiak, K. A.; Neg, J. S.; Medich,
J.; Farid, P.; Fleet, G. W. J. Tetrahedron 1993, 49, 3359. (c) Fleet, G. W.
J.; Nicholas, S. J.; Smith, P. W.; Evans, S. V.; Fellows, L. E.; Nash, R. J.
Tetrahedron Lett. 1985, 26, 3127.
(6) Mizushina, Y.; Xu, X.; Asano, N.; Kasai, N.; Kato, A.; Takemura,
M.; Asahara, H.; Linn, S.; Sugawara, F.; Yoshida, H.; Sakaguchi, K.
Biochem. Biophys. Res. Commun. 2003, 304, 78.
(7) (a) Yu, C.-Y.; Mu-Hua, H. Org. Lett. 2006, 8, 3021. (b) Schramm,
V. L.; Tyler, P. C. Curr. Top. Med. Chem. 2003, 3, 525. (c) Ringia, E. A.
T.; Tyler, P. C.; Evans, G. B.; Furneaux, R. H.; Murkin, A. S.; Schramm,
V. L. J. Am. Chem. Soc. 2006, 128, 7126.
(8) Yu, C.-Y.; Asano, N.; Ikeda, K.; Wang, M.-X.; Butters, T. D.;
Wormald, M. R.; Dwek, R. A.; Winters, A. L.; Nash, R. J.; Fleet, G. W. J.
Chem. Commun. 2004, 17, 1936.
formaldehyde was achieved by using paraformaldehyde as
the source of the two hydroxymethyl groups. After protection
of the dihydroxymethyl system of 9 by reaction with 2,2-
dimethoxypropane and p-toluenesulfonic acid in acetone,
treatment of diacetonide derivative 10a with tetrabutylam-
monium fluoride gave the expected nitroalcohol 10b, which
was transformed into mesylate 11 by reaction with mesyl
chloride in pyridine.
(9) For preliminary work in this field, see: (a) Blanco, M. J.; Sardina,
F. J. J. Org. Chem. 1998, 63, 3411. (b) Burley, I.; Hewson, A. T.
Tetrahedron Lett. 1994, 35, 7099. (c) Bols, M. Tetrahedron Lett. 1996, 37,
2097.
(10) Fleet, G. W. J.; Son, J. C.; Green, D. S. C.; di Bello, I. C.;
Winchester, B. Tetrahedron 1988, 44, 2649.
(12) (a) Barret, A. G. M.; Graboski, G. G. Chem. ReV. 1986, 86, 751.
(b) Nitroalkanes and Nitroalkenes in Synthesis; Tetrahedron Symposia;
Barret, A. G. M., Ed.; 1990; Vol. 46, p 7313. (c) Noboru, O. In The Nitro
Group in Organic Synthesis; Feuer, H., Ed.; Organic Nitro Chemistry Series;
Wiley-VCH: New York, 2001.
(13) Luzzio, F. A. Tetrahedron 2001, 57, 915.
(11) Clinch, K.; Evans, G. B.; Fleet, G. W. J.; Furneaux, R. H.; Johnson,
S. W.; Lenz, D.; Mee, S.; Rands, P. R.; Schramm, V. L.; Ringia, E. A. T.;
Tyler, P. C. Org. Biomol. Chem. 2006, 4, 1131.
(14) (a) Pinnick, H. W. Org. React. 1990, 38, 655. (b) McMurry, J. E.;
Melton, J.; Padgett, H. J. Org. Chem. 1974, 39, 259. (c) McMurry, J. E.;
Melton, J. J. Org. Chem. 1973, 38, 4367.
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