the increased yields (89-100%) obtained when DBU/
Me3SiNMe2 was used as the silylating reagent.
Whereas crude N-(trimethylsilyloxy)isoxazolidines 9a-d
were stable enough8 to provide satisfactory spectroscopic
data, N-(tert-butyldimethylsilyloxy)isoxazolidines 10a-c
could be easily purified by flash chromatography.
they are likely to be intermediates in our transformation.
Indeed, we have been able to isolate and fully characterize
nitroso intermediate 11a, which gave a spontaneous uncata-
lyzed aerobic oxidation to furnish the expected hydroxy-
methyl nitro tetrahydrofuran 5a in quantitative yield (fol-
lowed by NMR) (Table 1).
With these isoxazolidines in hand, we looked at the TBAF-
promoted desilylation to find a general and unprecedented
oxidative cleavage affording 3-nitro-4-hydroxymethyl tetra-
hydrofurans 5; only one diastereomer having three consecu-
tive stereogenic centers was obtained in fair to good yields.
As previously shown, the cis relationship between R1 and
R2 is the result of 1,3-allylic strain in the nitronate2 coupled
with the stereoselective cycloaddition fixing the NO2 function
in a cis orientation to the hydroxymethyl group after
fragmentation. It is worth noting that bicyclic compound 5e,9
obtained with 66% yield from 1a and crotonic alcohol, can
be totally epimerized at the carbon bearing the hydroxy group
to give 5f, probably via an intramolecular transesterification
during chromatography on silica gel (Scheme 3).
Silylation of nitronate 12a, obtained by aza Michael
addition of tosylallylamine to 1a afforded N-(silyloxy)-
isoxazolidine 13a in 31% yield, diastereoselectively trans-
formed into 3-nitro 4-hydroxymethyl pyrrolidine 14a after
desilylation (52% yield, Scheme 4).
Scheme 4. Transformation of Nitronate 12 into Pyrrolidine 14
Scheme 3. Epimerization of Compound 5e into 5f
In conclusion, the work reported herein provides an
efficient route to silyloxyisoxazolidines 9a-e, 10a-c,e, and
13a, which are subsequently desilylated and oxidized into
3-nitro 4-hydroxymethyl heterocycles 5a-f and 14a. Im-
provements for increasing the yield of the direct transforma-
tion of nitronates 2 or 12 into nitro alcohols 5 or 14 are
currently under investigation. Moreover, the improved
methods for the conversion of the nitro functionality11 stress
the potential interest in this diastereoselective formation of
highly functionalized furans and pyrrolidines.
Acknowledgment. P.Y.R. thanks the Ministere de
l’Education Nationale de la Recherche et de la Technologie
for financial support. NMR, MS, and IR analyses were
provided by “Spectropole” facilities, Centre de St Je´roˆme.
The crucial point in this new transformation is the in situ
oxidative ring cleavage of the isoxazolidine intermediate,
which does not need addition of any specific metallic or
organometallic oxidant. From a mechanistic point of view,
although oxidation of nitroso compounds to the correspond-
ing nitro derivatives usually requires powerful oxidants,10
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
OL049394F
(8) To our knowledge, N-trimethylsilyloxyisoxazolidines have only
scarcely been characterized by 1H NMR when the ISOC reaction was
conducted in CDCl3 in an NMR tube (see ref 5b), whereas N-trimethyl-
silyloxysilabicyclic isoxazolidine derivatives gave satisfactory NMR data:
Kudoh, T.; Ishikawa, T.; Shimizu, Y.; Saito, S. Org. Lett. 2003, 5, 3875-
3878.
(10) Hassner, A.; Heathcock, C. J. Org. Chem. 1964, 29, 1350-1355.
Jorgensen, K. A. J. Chem. Soc., Chem. Commun. 1987, 1405-1406. Boyer,
J. H. Chem. ReV. 1980, 80, 495-561. Ashok, K.; Scaria, P. M.; Kamat, P.
V.; George, M. V. Can. J. Chem. 1987, 65, 2039-2049. McKillop, A.;
Tarbin, J. A. Tetrahedron 1987, 43, 1753-1758.
(11) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979, 33,
1-18. Pereekalin, V. V.; Lipina, E. S.; Berestovitskaya, V. M.; Efremov,
D. A. Nitroalkenes; Wiley: New York, 1994.
(9) The relative stereochemistry of the stereocenter bearing the hydroxy
group in 5e was deduced from NOESY experiments performed on 10e.
Org. Lett., Vol. 6, No. 12, 2004
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