Practical synthesis of N-alkyl-N-glycosylhydroxylamines, multitalented precursors of enantiomerically pure nitrones

Article abstract of DOI:10.1016/S0040-4039(02)00372-6

A practical synthesis of N-benzyl-N-glycosylhydroxylamines 3 (R=CH₂Ph) is reported. The ability of these compounds to act as versatile synthetic intermediates is demonstrated by their oxidation followed by cycloaddition to N-glycosyl isoxazolidines and by the novel direct cycloaddition as masked acyclic, highly functionalized chiral nitrones.

Full text of DOI:10.1016/S0040-4039(02)00372-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2741–2743
Practical synthesis of N-alkyl-N-glycosylhydroxylamines,
multitalented precursors of enantiomerically pure nitrones
Stefano Cicchi, Massimo Corsi, Marco Marradi and Andrea Goti*
Dipartimento di Chimica Organica ‘Ugo Schiff’, Centro di Studio sulla Chimica e la Struttura dei Composti Eterociclici e loro
Applicazioni (CSCEA), C. N. R., Polo Scientifico, Universita` di Firenze, via della Lastruccia 13, I-50019 Sesto Fiorentino,
Firenze, Italy
Received 22 January 2002; accepted 21 February 2002
Abstract—A practical synthesis of N-benzyl-N-glycosylhydroxylamines 3 (R=CH2Ph) is reported. The ability of these compounds
to act as versatile synthetic intermediates is demonstrated by their oxidation followed by cycloaddition to N-glycosyl isoxazolidi-
nes and by the novel direct cycloaddition as masked acyclic, highly functionalized chiral nitrones. © 2002 Elsevier Science Ltd.
All rights reserved.
N-Glycosylhydroxylamines 3 (R=H) have received
considerable attention as chiral equivalents of the sim-
ple hydroxylamine, the glycosyl moiety acting as an
auxiliary which can be easily removed by acid treat-
ment at an advanced stage of a synthetic sequence after
reacting the hydroxylamine function. This concept has
been extensively applied, demonstrating the synthetic
utility of intermediates 3 (R=H), particularly by
Vasella and co-workers.1
amine by a modification of the above procedure and
have used the compound as a hidden nitrone in an
alkylation reaction.3
In this communication we report an alternative, practi-
cal synthesis of N-benzyl-N-glycosylhydroxylamines 3
(R=CH2Ph) which can be extended to other N-alkyl
congeners. Also, their usefulness as versatile intermedi-
ates in organic synthesis is addressed, since we demon-
strate that they are either precursors of chiral nitrones
with the glycosyl moiety working as a chiral auxiliary
or highly functionalized hidden chiral nitrones by them-
selves, which are able to undergo highly stereoselective
1,3-dipolar cycloadditions.
Conversely, N-substituted N-glycosylhydroxylamines 3
(R"H) have been the object of only two reports, to the
best of our knowledge, specifically dealing with N-ben-
zyl derivatives. The first, by Merino and co-workers,
details the synthesis of several compounds of structure
3 (R=CH2Ph) by reaction of the corresponding
monosaccharides 1 with 1.5 equiv. of N-benzylhydroxyl-
amine in the presence of MgSO4 (3 equiv.) and ZnCl2
(1.5 equiv.) (Scheme 1).2 In the second, published while
this work was in progress, Dondoni and co-workers
have synthesized an N-benzyl-N-arabinosylhydroxyl-
The N-benzyl-N-glycosylhydroxylamines 3a–g were
obtained by reacting the corresponding sugar derivative
1a–g with N-benzylhydroxylamine (2a) (1.2 equiv.) in
dry pyridine at room temperature.4 The hydroxyl-
amines were purified and isolated in good yield after
column chromatography (see Table 1).5 The same
method can be extended to the synthesis of other
N-alkyl-N-glycosylhydroxylamines, as demonstrated by
the synthesis of 3h (entry 8). The products are obtained
at the end of the reaction simply by a filtration and
removal of the solvent and purified by a flash column
chromatography over silica. The yields compare with
those obtained with the previous method.2 The final
N-glycosylhydroxylamines are obtained as an anomeric
mixture, where the thermodynamically most stable iso-
mer prevails. In several cases the major isomer is the
only detectable one by 1H NMR spectroscopy. This
observation suggests the occurrence of a rapid equi-
OH
O
O
OH
N
RNHOH
+
(R'O)m
R
(R'O)m
n
n
1
2
3
Scheme 1.
Keywords: monosaccharides; nitrones; isoxazolidines; chiral auxiliary;
enantiospecific synthesis.
* Corresponding author. E-mail: andrea.goti@unifi.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00372-6

2742
S. Cicchi et al. / Tetrahedron Letters 43 (2002) 2741–2743
Table 1. Synthesis of N-alkyl-N-glycosylhydroxylamines from the corresponding lactols
librium between the two isomers through an open-chain
nitrone functionality, i.e. via an uncommon 1,4 H-shift.
This same explanation has been advanced by Dondoni
and indirectly proved by alkylation of the acyclic nitrone
in equilibrium with the stable N-benzyl-N-arabinosylhy-
droxylamine.3 In the single case of compound 3f confir-
1
mation of this hypothesis was collected by a careful H
NMR analysis (500 MHz), which showed the signals of
the open-chain nitrone tautomer 4 (Scheme 2), present
in 6% amount at the equilibrium in CDCl3.6
Scheme 2.

S. Cicchi et al. / Tetrahedron Letters 43 (2002) 2741–2743
2743
Compound 3f was then chosen to demonstrate the
References
versatility of this class of compounds in 1,3-dipolar
cycloaddition chemistry (Scheme 2). We tested the reac-
tivity of this compound with dimethyl maleate by itself,
through the tautomeric nitrone form, and after oxida-
tion to the N-glycosyl nitrone. The latter is a useful
class of nitrones, affordable as well by condensation of
hydroxylamines 3 (R=H) with aldehydes,1 albeit C-
phenyl nitrones have never been synthesized by this
way. The nitrone 5, obtained in high yield by oxidation
1. (a) Vasella, A. Helv. Chim. Acta 1977, 60, 426; (b)
Vasella, A. Helv. Chim. Acta 1977, 60, 1273; (c) Vasella,
A.; Voeffray, R. Helv. Chim. Acta 1982, 65, 1134; (d)
Vasella, A.; Voeffray, R. Helv. Chim. Acta 1982, 65,
1953; (e) Vasella, A.; Voeffray, R.; Pless, J.; Huguenin,
R. Helv. Chim. Acta 1983, 66, 1241; (f) Huber, R.;
Knierzinger, A.; Obrecht, J.-P.; Vasella, A. Helv. Chim.
Acta 1985, 68, 1730; (g) Bernet, B.; Krawczyk, E.;
Vasella, A. Helv. Chim. Acta 1985, 68, 2299; (h) Huber,
R.; Vasella, A. Helv. Chim. Acta 1987, 70, 1461; (i)
Huber, R.; Vasella, A. Tetrahedron 1990, 46, 33.
2. Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T.
Synth. Commun. 1997, 27, 3529.
of 3f with MnO2 (or HgO)8 reacted with dimethyl-
7
maleate (6) affording the adduct 7 in good yield with a
high diastereoselectivity. Since the N-glycosyl bond can
be cleaved by acid treatment,1 this class of nitrones is a
tool for the enantioselective synthesis of simple isoxazo-
lidines, the glycosyl moiety acting as a chiral auxiliary.
3. Dondoni, A.; Perrone, D. Tetrahedron Lett. 1999, 40,
9375.
On the other hand, compounds 3 are also able to
undergo cycloaddition reactions through species such as
4, when heated in the presence of dipolarophiles. With
dimethyl maleate (6), 3f afforded, also with a high
degree of stereoselectivity, the highly functionalized
isoxazolidine 8 possessing the appendage deriving from
the sugar skeleton in the 3-position.
4. General procedure: A solution (0.3 M) of lactol 1 (1–6
,
mmol) in dry pyridine was added with 3 A molecular
sieves (1–5 g) and N-benzyl- (or methyl-) hydroxylamine
hydrochloride (1.2 equiv.). The resulting suspension was
stirred overnight at room temperature, then filtered,
concentrated and purified by flash column chromatogra-
phy.
5. All new compounds gave satisfactory spectroscopic and
analytical data.
This novel reactivity opens the way to a variety of
isoxazolidines which can be envisaged as useful precur-
sors of natural products, such as pyrrolizidine alka-
loids, and biologically active compounds, and expands
the range of useful chiral nitrones available for syn-
thetic purposes.9,10
6. Detectable signals of 4: 1H NMR: l=6.89 (d, J=6.0
Hz, 1H), 5.32 (t, J=5.5 Hz, 1H), 5.06 (s, 1H), 1.43 (s,
3H), 1.39 (s, 3H) ppm.
7. Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetra-
hedron Lett. 2001, 42, 6503.
8. Do¨pp, D.; Do¨pp, H. In Houben-Weyl-Methoden der
organischen Chemie, Part 2; Klamann, D.; Hagemann,
H., Eds.; Georg Thieme: Stuttgart, 1990; Vol. E14b.
9. For leading references on acyclic chiral nitrones, see: (a)
Merino, P.; Franco, S.; Merchan, F. L., Tejero, T. Syn-
lett 2000, 442; (b) Frederickson, M. Tetrahedron 1997,
53, 403–425.
Further studies are currently underway in our laborato-
ries to fully explore the synthetic potential of this new
class of chiral nitrones.
Acknowledgements
10. For recent works on cyclic chiral nitrones, see: Goti, A.;
Cacciarini, M.; Cardona, F.; Cordero, F. M.; Brandi, A.
Org. Lett. 2001, 3, 1367 and references cited therein.
The authors thank the Ministry of University and
Scientific and Technological Research (M.U.R.S.T.
Cofin 2000), Italy.