azasugars, iminosugars, or iminocyclitols) have emerged as
potential glycosidase inhibitors worthy of further investigation.6,7
Our interest in this field stems from our previous synthetic
efforts to prepare chiral azetidines. En route to these compounds,
diastereomeric mixtures of hydroxylated chiral 9-oxa-1-azabicyclo-
[4.2.1]nonanes were produced through an intramolecular 1,3-
dipolar cycloaddition involving ω-unsaturated nitrones derived
from D-glucose and 2-furaldehyde.8 This nitrone-alkene cy-
cloaddition is a well-known powerful tool that has successfully
been employed in the literature to construct a variety of
isoxazolidines, 1,3-aminoalcohols, and derivatives9,10 usually
starting from carbohydrate precursors.11,12 Recently, a ring-
contracted dihydroxylated 8-oxa-1-azabicyclo[3.2.1]octane and
its ring-opened azepane derivative have been found to be
effective glycosidase inhibitors.13
Single Diastereomers of Polyhydroxylated
9-Oxa-1-azabicyclo[4.2.1]nonanes from
Intramolecular 1,3-Dipolar Cycloaddition of
ω-Unsaturated Nitrones
Petra Pa´da´r,† Attila Bokros,† Ga´bor Paragi,‡ Pe´ter Forgo´,§
Zolta´n Kele,† Nicola M. Howarth,| and Lajos Kova´cs*,†
Department of Medicinal Chemistry, UniVersity of Szeged,
H-6720, Hungary, Protein Chemistry Research Group,
Hungarian Academy of Sciences, Szeged, H-6720, Hungary,
Department of Organic Chemistry, UniVersity of Szeged,
H-6720, Hungary, and Chemistry, School of Engineering and
Physical Sciences, William H. Perkin Building, Heriot-Watt
UniVersity, Riccarton, Edinburgh, EH14 4AS, U.K.
As highlighted above, because of the increasing biological
interest in this class of compounds, we have decided to explore
the scope of this intramolecular 1,3-dipolar cycloaddition.
Therefore, we have investigated the utility of other aldehydes
and sugars, namely, D-glucose and D-galactose, and our findings
are presented herein.
koVacs@oVrisc.mdche.u-szeged.hu
ReceiVed July 19, 2006
We first embarked on investigation of the iodination of methyl
R-D-glucopyranoside 1 using the conditions described by
Vasella14-16 and Garegg17 (Scheme 1). After extensive experi-
mentation, we have found that iodo compound 2 can only be
obtained reproducibly in good yields (60%) on a large scale
when using a modified procedure that requires careful consid-
eration of reaction conditions (e.g., reagent addition times,
temperature, strirring) and a combination of different purification
procedures. Subsequent benzoylation of compound 218-20 suc-
cessfully afforded benzoate 3.21-23 The latter halo derivative 3
was then subjected to the Boord-Vasella reaction14-16,24-28
8-Benzyloxymethyl-3,4,5-tribenzoyloxy-9-oxa-1-azabicyclo-
[4.2.1]nonane has been prepared as the single diastereoisomer
8 from an intramolecular 1,3-dipolar cycloaddition involving
2-(benzyloxy)acetaldehyde and ω-unsaturated hydroxylamine
7 derived from methyl R-D-glucopyranoside. The analogous
8-methoxycarbonyl 9-oxa-1-azabicyclo[4.2.1]nonane was af-
forded in a similar manner, from methyl D-galactopyranoside
and methyl glyoxylate, as a 3:1 mixture of diastereoisomers
15 and 16. When conducted in achiral ionic liquid 17 this
ratio increased to 8:1, and in chiral ionic liquid 18, compound
15 was formed exclusively.
(6) Stu¨tz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond; Wiley-VCH: Weinheim, 1999.
(7) Pearson, M. S. M.; Mathe-Allainmat, M.; Fargeas, V.; Lebreton, J.
Eur. J. Org. Chem. 2005, 2159.
(8) Pa´da´r, P.; Hornya´k, M.; Forgo´, P.; Kele, Z.; Paragi, G.; Howarth, N.
M.; Kova´cs, L. Tetrahedron 2005, 61, 6816.
(9) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410.
(10) Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1.
(11) Osborn, H. M. I.; Gemmell, N.; Harwood, L. M. J. Chem. Soc.,
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Glycosidases are intimately involved in a plethora of meta-
bolic pathways, and the development of glycosidase inhibitors
presents an enormous challenge for the treatment of associated
disorders, e.g., diabetes, Gaucher’s disease, cancer, and viral
infections including AIDS.1-5 Recently, highly oxygenated
chiral heterocycles containing nitrogen (also referred to as
(18) Raymond, A. L.; Schroeder, E. F. J. Am. Chem. Soc. 1948, 70, 2785.
(19) Leon-Ruaud, P.; Plusquellec, D. Tetrahedron 1991, 47, 5185.
(20) Skaanderup, P. R.; Poulsen, C. S.; Hyldtoft, L.; Jorgensen, M. R.;
Madsen, R. Synthesis 2002, 1721.
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† Dept of Medicinal Chemistry, University of Szeged.
‡ Hungarian Academy of Sciences.
§ Dept of Organic Chemistry, University of Szeged.
| Heriot-Watt University.
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10.1021/jo061503b CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/07/2006
J. Org. Chem. 2006, 71, 8669-8672
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