Preparation of N-Glycosylhydroxylamines and Their Oxidation to Nitrones for the Enantioselective Synthesis of Isoxazolidines

Article abstract of DOI:10.1002/ejoc.200300353

N-benzyl- and N-methyl-N-glycosylhydroxylamines 3a-i were conveniently obtained by reaction of sugars with N-substituted hydroxylamines according to a novel procedure. Subsequent oxidation occurred at the alkyl group, selectively affording the correspondi

Full text of DOI:10.1002/ejoc.200300353

FULL PAPER
Preparation of N-Glycosylhydroxylamines and Their Oxidation to Nitrones for
the Enantioselective Synthesis of Isoxazolidines[‡]
Stefano Cicchi,[a] Marco Marradi,[a] Massimo Corsi,[a] Cristina Faggi,[a] and Andrea Goti*[a]
Keywords: Hydroxylamines / Sugars / Nitrones / Chiral auxiliaries / Enantioselectivity
N-benzyl- and N-methyl-N-glycosylhydroxylamines 3a−i
were conveniently obtained by reaction of sugars with N-
substituted hydroxylamines according to a novel procedure.
Subsequent oxidation occurred at the alkyl group, selectively
affording the corresponding C-phenyl- and C-unsubstituted
with dimethyl maleate, with the sugar moiety acting as a
chiral auxiliary. Final removal of the glycosyl moiety afforded
enantiopure enantiomeric isoxazolidines 17 and ent-17
which are oxa-analogues of proline diester derivatives.
N-glycosylnitrones. C-phenyl-N-glycosylnitrones 10 and 13 ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
underwent highly stereoselective 1,3-dipolar cycloaddition
Germany, 2003)
Introduction
anomeric carbon atom (more generally a lactol) and hy-
droxylamine hydrochloride (2, R ϭ H) affords N-glycos-
ylhydroxylamines 4 (Scheme 1). Ribosyl and mannofurano-
syl derivatives were isolated as E/Z-oxime mixtures;[3][4a]
however, they can be more conveniently employed directly
in the synthesis of C-unsubstituted-, C-alkoxycarbonyl-, C-
alkyl-, C-phosphonoyl- and C-aryl-N-glycosylnitrones 5 by
condensation with a carbonyl compound.[3Ϫ5] These nitro-
nes have usually been prepared in situ, and reacted with
olefins in 1,3-dipolar cycloadditions, to afford, ultimately,
enantioenriched isoxazolidines.[3,4aϪ4e,5aϪ5f] Alternatively,
they have undergone nucleophilic addition reactions
Suitably protected carbohydrate derivatives, and lactols
in general, are valuable tools for the synthesis of chiral ni-
trogen heterocycles. In particular, they can be readily con-
verted into chiral cyclic nitrones,[1] or into N-glycosylhyd-
roxylamines, which, in turn, are precursors of chiral acyclic
nitrones.[2] With this in mind, N-glycosylhydroxylamines 4
(R ϭ H) (Scheme 1) have received considerable attention
as chiral equivalents of simple hydroxylamine. The glycosyl
moiety acts as an auxiliary which can be easily removed by
acid treatment at an advanced stage of a synthetic sequence,
i.e. after the hydroxylamine moiety has reacted. This con-
cept was introduced by Vasella,[3] and then extensively ap-
plied by the same group[4] and others,[5] thus demonstrating
the synthetic utility of intermediates 4. The reaction be-
tween a suitably protected sugar 1 with a free OH at the
with dialkyl
phosphites, affording
N-hydroxy-N-
glycosylaminophosphonates.[4fϪ4i]
Conversely, to the best of our knowledge, N-substituted
N-glycosylhydroxylamines 3 (R ϭ Alkyl) have been the sub-
ject of only a few reports, and these deal specifically with
N-benzyl derivatives. Merino and co-workers have per-
formed the synthesis of several compounds of structure 3
(R ϭ CH2Ph) by reaction of the corresponding monosac-
charides 1 with 1.5 equiv. of N-benzylhydroxylamine in the
presence of MgSO4 (3 equiv.) and ZnCl2 (1.5 equiv.)
(Scheme 1).[6] Dondoni and co-workers have synthesized N-
arabinosyl-N-benzylhydroxylamine by a modification of the
above procedure,[7] and have also, while this work was in
progress, reported a convenient solventless transformation
of four pentofuranosyl derivatives into the corresponding
hydroxylamines in short times by heating the reagents at
high temperature.[8]
Scheme 1
[‡]
Chiral Nitrones from Lactols, 1.
In this paper, we report full details of our own results on
the synthesis of several N-benzyl-N-glycosylhydroxylamines
3 (R ϭ CH2Ph), using a methodology which can be ex-
tended to other N-alkyl congeners (Scheme 1 and
Table 1).[9] These compounds are versatile intermediates in
[a]
`
Dipartimento di Chimica Organica ‘‘Ugo Schiff’’, Universita
di Firenze
Polo Scientifico, via della Lastruccia 13, 50019 Sesto Fiorentino
(Firenze), Italy
Fax: (internat.) ϩ39-055/457-3531
E-mail: andrea.goti@unifi.it
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DOI: 10.1002/ejoc.200300353
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N-Glycosylhydroxylamines and Their Oxidation to Nitrones
FULL PAPER
organic synthesis: they can be oxidized to N-glycosylni- products were isolated simply by filtration and removal of
trones 5 where the glycosyl moiety behaves as a chiral the solvent, and were found to be spectroscopically pure,
auxiliary, or they themselves can act as masked acyclic chi- except for some residual pyridinium salts, which were read-
ral nitrones.[8,9] Exemplification of the former behaviour is ily eliminated by elution through a short pad of silica gel.
also reported in this article.
The N-glycosylhydroxylamines were obtained as mixtures
of the two equilibrating anomers. In several cases, the equi-
librium lies far over to one side, with the thermo-
dynamically most stable anomer being the one only detect-
Table 1. Synthesis of N-alkyl-N-glycosylhydroxylamines from the
corresponding lactols
1
able by H NMR spectroscopy (Table 1, Entries 1, 3 and
6Ϫ9). The differences in experimental conditions with re-
spect to the above reported alternative procedures may ac-
count for the observed discrepancies between our results
and the previously reported anomeric composition of com-
pounds 3a, 3d and 3e.[10]
The anomeric equilibration must occur through an open-
chain nitrone, according to previous hypotheses[6] and find-
ings,[7] in analogy to the well-known behaviour of N-(2-
hydroxyalkyl)nitrones, which undergo a ring-chain taut-
omerism to the corresponding N-hydroxyoxazolidines via a
formal intramolecular 1,3-OH addition to the nitrone
group.[11] The open-chain tautomer (i.e. the nitrone form)
of N-glycosylhydroxylamines is usually hardly detectable in
the equilibrium mixture by NMR spectroscopy, meaning
that the ring-chain equilibrium is heavily shifted towards
the cyclic forms (Scheme 2). However, in a few cases, a sig-
nal (doublet) of low intensity in the range
δ ϭ
7.0Ϫ6.5 ppm, which may be assigned to the Csp2-H reson-
ance, demonstrates the presence of the open-chain nitrone.
Among compounds 3 in Table 1, these signals are most evi-
1
dent for compounds 3d, 3f and 3h. For example, the H
NMR spectrum of compound 3f in CDCl3 solution at equi-
librium showed 6% of the open-chain nitrone 6f (Scheme 2,
see Exp. Sect.).[9] An analogous observation has recently
been reported for tribenzyl xylosyl-, ribosyl- and lyxosylhy-
droxylamine derivatives, which showed doublets resonating
at δ ϭ 6.75, 6.93, and 6.81 ppm, respectively.[8]
Scheme 2
Oxidation of N-glycosylhydroxylamines
3 gives an
Results and Discussion
alternative access to N-glycosylnitrones,[3Ϫ5] particularly to
C-phenyl and C-unsubstituted ones. Indeed, it has been ob-
The N-benzyl-N-glycosylhydroxylamines 3aϪg (Table 1, served that oxidation of 3g occurs with complete regioselec-
Entries 1Ϫ7) were generally obtained by reacting the corre- tivity affording the corresponding C-phenyl-N-mannofur-
sponding sugar derivative 1aϪg with 1.2 equiv. of N-benzyl- anosylnitrone.[6] The utility of N-glycosylnitrones in enanti-
hydroxylamine hydrochloride (2a) in dry pyridine at room oselective synthesis has been investigated in reactions with
temperature for 12Ϫ15 h. The same method can be ex- dipolarophiles[3,4a] and nucleophiles,[4fϪ4i] and both cyclo-
tended to the synthesis of other N-alkyl-N-glycosylhydroxy- addition
reactions[4c,4e,5aϪ5f]
and
nucleophilic
lamines, as demonstrated by the synthesis of N-methyl-N- additions[4h,5gϪ5i] have found applications to the synthesis
glycosylhydroxylamines 3hϪi (Table 1, Entries 8Ϫ9) when of relevant chiral compounds. Concerning cycloaddition re-
N-methylhydroxylamine hydrochloride (2b) was used. The actions, it has mainly been N-glycosylnitrones derived from
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S. Cicchi, M. Marradi, M. Corsi, C. Faggi, A. Goti
FULL PAPER
formaldehyde (C-unsubstituted)[3,5a,5f] or from glyoxylates
As anticipated, oxidation of N-benzyl-N-glycosylhydroxyl-
[13]
(C-alkoxycarbonyl)[4c,4e,5bϪ5e] which have been used, and amines 3f and 3g with MnO2
occurred with complete
these compounds usually showed very interesting stereo- regioselectivity, affording the corresponding nitrones 10 and
selectivities. Conversely, C-aryl-N-glycosylnitrones have 13 in nearly quantitative yields as stable, crystalline com-
been synthesized,[4h,4i,6] but their behaviour in cycloaddition pounds (Scheme 4). These N-glycosylnitrones reacted
reactions has not been studied, the only exception being the smoothly with dimethyl maleate (11) by heating at 80 °C in
cycloadditions of unprotected C-phenyl-N-glucosylnitrone toluene (Scheme 4).
to monosubstituted alkenes and maleimides, which gener-
ally afforded low yields of adducts.[12] Moreover, among
aldonitrones with simple C-substituents, only C-methyl-N-
ribosyl- and N-mannosyl- nitrones, derived from acetalde-
hyde, have been used in cycloaddition to methyl methacry-
late, and these reactions gave a complex mixture of all four
possible adducts.[3,4a] The cycloadditions showed good dia-
stereocontrol over the formation of the isoxazolidine C5
stereogenic center, since the two main components derived
from attack at the same diastereoface of methacrylate, but
very poor, if any, control of chirality at the C3 carbon.
E/Z Configurational isomerization of nitrones under the re-
action conditions was invoked in order to account for this
lack of selectivity.[3,4a] Thus, we decided to study the degree
of asymmetric induction that could be achieved in the
cycloaddition of C-phenyl-N-glycosylnitrones to dimethyl
maleate, leading to simple trisubstituted isoxazolidines with
simultaneous formation of three new stereogenic centers.
In addition, we wanted to clarify the structural features
of the glycosyl moiety required for optimal stereoselectivity.
From the literature data, it is apparent that 2,3-cis-dioxyfur-
anosides protected as ketals all perform well in terms of
diastereocontrol (Scheme 3).[3Ϫ5] The opposite diastereofa-
cial preference, with similar selectivities, shown by N--rib-
osyl- 7 and N--mannosyl- 8 nitrones,[4a] suggests that the
configuration at C2 and C3 of the sugar moiety is crucial
in determining the face of attack of the dipolarophile, while
the branch and stereochemistry at C4 play a negligible role.
Confirmation of this assumption rests in the finding that
N--gulosylnitrone 9 showed analogous stereofacial prefer-
ence as N--ribosylnitrone 7 (and N--gulosylnitrone,
which can be synthesized from -glucurono-6,3-lactone, the
same preference as the -mannose derivative 8).[5b] The sim-
plest way to prove this assumption was to test the behaviour
of the nitrone obtained by oxidation of N--erythrosylhyd-
roxylamine 3f, and to prove its complementarity, in terms
Scheme 4
of diastereoselectivity, to that derived from N--mannosyl-
hydroxylamine 3g (i.e. 8, R ϭ Ph).
The reaction of nitrone 10 with 11 afforded, in high yield
and selectivity, the isoxazolidine 12, which was by far the
major isomer (Ͼ 94% diastereoselectivity). Traces of two
minor isomers were identified in the reaction mixture, and
they were collected as an inseparable mixture. The structure
of compound 12 was unambiguously assigned on the basis
1
of X-ray analysis (Figure 1). The H NMR spectrum of 12
shows that the proton at C4 of the isoxazolidine ring res-
onates at δ 3.83 ppm as a triplet with the same coupling
constant J ϭ 9.0 Hz as the vicinal protons at C5 and C3,
even though it has opposite relative relationships with them
(cis and trans, respectively). This finding is in agreement
with the large dihedral angle HϪC3ϪC4ϪH measured in
the crystal structure (164.4°), suggesting that the H,H-anti-
Scheme 3
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N-Glycosylhydroxylamines and Their Oxidation to Nitrones
FULL PAPER
periplanar conformation around the C3ϪC4 bond should was by no means certain, having never been carried out
also be the most stable in solution.
before. Oxidation of hydroxylamine 3h with MnO2 in
CH2Cl2 led to a complex mixture of products. However,
when treated with DDQ in CHCl3, 3h rapidly gave the cor-
responding aldonitrone 15 with complete regioselectivity.
Nitrone 15 was identified by the signal at δ ϭ 6.60 ppm in
the 1H NMR spectrum of the reaction mixture, but its com-
plete characterization was prevented by its instability. In-
deed, it decomposed on attempted purification on silica or
alumina, and it was unstable even on standing in solution
or on concentration of the product mixture. However, when
dimethyl maleate (11) was added to the reaction mixture,
nitrone 15 reacted directly, and very quickly, to afford the
adducts 16 in excellent yield (Scheme 4). In contrast with
the above results, the reaction of nitrone 15 with 11 is
characterized by a virtually complete absence of diastereo-
selectivity, adducts 16a and 16b being formed in ca. 1:1 ra-
tio. The two diastereomeric adducts were not separable by
column chromatography, and were characterized by their
spectroscopic data in the mixture, which were very similar.
Their diastereomeric nature was ascertained by recording
1H and 13C NMR spectra at high temperatures, thus exclud-
Figure 1. Crystal structure of cycloadduct 12
The cycloaddition of nitrone 13 afforded, in good yield, ing the possibility of their being rotamers or invertomers.
a mixture of the two diastereoisomeric isoxazolidines A few, but nevertheless striking, differences, which de-
14aϪb in a 11.6:1 ratio. A third isomer, present in traces serve to be noted here, arise from a comparison of the
in the reaction mixture, was recovered in 0.5% yield after above findings with the results of cycloadditions of related
separation by flash column chromatography.[14] The major N-glycosylnitrones to methyl methacrylate reported by Va-
isomer 14a was assigned the structure depicted in Scheme 4, sella:[3,4a,4i] (i) the high diastereoselectivity of additions of
1
after comparison of its H NMR spectrum with that of 12. nitrones 10 and 13 to 11 vs. the poor selectivity reported
The two spectra show striking similarities: H3, H4 and H5 for a C-methyl-substituted nitrone;[4a] (ii) the lack of stereo-
protons of the isoxazolidine ring resonate at almost the selectivity in the reaction of nitrone 15 with 11 vs. the good
same frequencies (δ ϭ 4.62 vs. 4.50 ppm, 3.83 vs. 3.76 ppm selectivity reported for a related C-unsubstituted nitro-
and 4.93 vs. 4.91 ppm in 12 and 14a, respectively) and with ne.[3,4a] Thus, the outcome of the cycloadditions to N-gly-
almost identical coupling constants (J3Ϫ4 ϭ J4Ϫ5 ϭ 9.0 Hz cosylnitrones appears to be dramatically influenced either
vs. 8.9 Hz in 12 and 14a, respectively). This suggests that by the nature of the dipolarophile or the substituents at the
both adducts possess the same relative stereochemistry at nitrone carbon atom. However, the sense of chiral induction
the isoxazolidine ring, which was ultimately proved by de- at C5 of the isoxazolidine ring is the same when selective
tachment of the N-glycosyl chiral auxiliary (see below). The additions occur, i.e. both compound 14a and the major ad-
minor isomer 14b was assigned the all-cis relative configura- duct obtained from the C-unsubstituted nitrone with the
tion at the isoxazolidine stereocenters on the basis of the same N-mannosyl chiral auxiliary residue with methyl
high difference in the chemical shifts of the two methyl sig- methacrylate[4a] possess the (5S) absolute configuration.
nals of the methoxycarbonyl groups (δ ϭ 3.78 ppm and This feature makes N-glycosylnitrones useful tools for en-
3.21 ppm for 14b vs. δ ϭ 3.78 ppm and 3.65 ppm for 12 and antioselective synthesis of isoxazolidines with predictable
3.76 ppm and 3.62 ppm for 14a). The strong upfield shift selectivity.
of one methyl signal suggests that it falls in the shielding
In order to get a decisive proof of the opposite chiral
cone of the phenyl group, thus disclosing the cis phenyl- induction achieved by use of N--erythrosyl and N--man-
methoxycarbonyl relationship. The absolute stereochem- nosyl auxiliaries, and, at the same time, to demonstrate
istry at the isoxazolidine stereocenters of 14b as reported their utility in enantioselective synthesis, the adducts 12 and
in Scheme 4 has been tentatively assigned on the basis of 14a were separately subjected to acidic treatment according
considerations on the preferred approach of reagents (see to Vasella’s method (Scheme 5).[3,4] Removal of the glycosyl
below).
residue with HCl afforded, respectively, 2-unsubstituted
These results clearly show that both cycloadditions of isoxazolidines 17 and ent-17 which, as anticipated, were en-
nitrones 10 and 13 with dimethyl maleate occur with excep- antiomers. Compounds 17, which possess three stereogenic
tionally high diastereoselectivity, unprecedented for cyclo- centers, newly-created with high stereocontrol, can be con-
additions of related N-glycosyl aldonitrones.
sidered as oxa-analogues of proline diesters, besides being
We also wanted to test the possibility of accessing C-un- valuable chiral intermediates suitable for further synthetic
substituted N-glycosylnitrones from N-methyl-N-glycosyl- transformations. This result, besides confirming the struc-
hydroxylamines. The regioselectivity of such an oxidation ture of compound 14a, demonstrates that maleate 11 ap-
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S. Cicchi, M. Marradi, M. Corsi, C. Faggi, A. Goti
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Figure 3. Minimum energy transition-states for the cycloaddition
of 10 with 11 (endo approaches)
Scheme 5
Transition-state modeling (HF STO-3G level)[15] for the
two possible endo approaches of maleate to nitrone 10 gave
the minimized structures depicted in Figure 3 for the ap-
proaches to the Re face (anti-TS) and to the Si face (syn-
TS) of nitrone, respectively. Calculations resulted in a lower
activation energy (∆∆E϶ ϭ 0.8 kcal·molϪ1) for the former
TS, in qualitatively good agreement with the observed selec-
tivity. The two transition-structures were found to have only
one negative eigenvalue, with the corresponding eigenvector
involving the formation of the newly created CϪC and
CϪO bonds (imaginary frequencies ν ϭ Ϫ339 for both anti-
TS and syn-TS). The structures of the two transition-states
are consistent with a rather asynchronous process: in both
proaches the opposite diastereofaces of the two nitrones 10
and 13, due to the complementary behaviour of the two
glycosidic fragments.
The stereoselectivity of the cycloadditions to N-glycosyl-
nitrones has been rationalized by Vasella in terms of a pre-
ferred attack of the dipolarophile to the less sterically-hin-
dered face of the nitrone, in a conformation which puts the
ring oxygen anti and the nitrone oxygen atom in the ‘‘endo’’
position. This conformation of the nitrone allows a co-
planar arrangement of the C1ϪO bond σ*-orbital with the
doubly-occupied nonbonding orbital developing at the ni-
trogen atom during the reaction, and should be the more
reactive based on a stabilizing ‘‘kinetic anomeric ef-
fect’’.[4a,4i] Semi-empirical AM1 calculations on a model
nitrone suggested that the proposed reacting conformation
is also very close to the most stable conformer in terms of
both geometry and energy.[4i] However, rationalization of
selectivities based on different models has also been propo-
sed.[5b]
˚
cases the CϪO bond length (anti-TS: 2.044 A; syn-TS:
˚
1.962 A) is much shorter than that of the forming CϪC
˚
˚
bond (anti-TS: 2.766 A; syn-TS: 2.782 A), in agreement
with the results of a previous study on 1,3 dipolar cycload-
dition reaction of nitrones with electron poor olefins.[16]
That we found the anti-TS structure to be preferred, sub-
stantiates the TS model proposed by Vasella.[4i] However,
these results suggest that the diastereofacial selectivity is de-
termined mainly by steric factors, since the early nature of
the TS, with negligible nitrogen pyramidalization, appears
to make stereoelectronic factors less important.
In order to get an insight into the mechanism of the reac-
tions performed in the present study, an ab initio compu-
tational study was performed on the nitrones 10 and 13
(Figure 2) and on the transition-state of the cycloaddition
of 10 to dimethyl maleate (11) (Figure 3).[15]
Conclusion
A highly diastereo- and enantioselective synthesis of
3,4,5-trisubstituted isoxazolidines has been accomplished
by means of a carbohydrate-derived chiral auxiliary ap-
proach, which demonstrates the great potential of cycload-
dition reactions applied to C-phenyl-N-glycosylnitrones.
The high degree of diastereoselectivity induced by the sugar
moiety allows the synthesis of adducts which are readily
converted into the enantiopure targets by removal of the
Figure 2. Minimum energy conformers of nitrones 10 and 13
The two structures depicted in Figure 2, the lowest en- chiral auxiliary. The sense of chiral induction in the final
ergy conformers of 10 and 13 respectively (dihedral drive isoxazolidine is easily predictable on the basis of the con-
along the NϪC1 bond, HF STO-3G), show that the less figuration at C2 and C3 of the sugar, locked in its furanos-
hindered face of the nitrone double bond is the Re face for idic form, as proved by the complementary behaviour of N-
10 and the Si face for 13, according to the experimental erythrosyl and N-mannosyl nitrones.
results. The obtained lowest energy conformers are in per-
This study demonstrates that isopropylidene erythrose is
fect agreement with that reported by Vasella for a similar a convenient, versatile and low molecular-weight chiral
model nitrone[4i] [dihedral angle ϕ(O-NϪCϪO) ϭ 219° for auxiliary for nitrone reactions. The N-erythrosyl nitrone has
nitrone 10 vs. 221°].
the obvious advantage of being easily accessible in both en-
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N-Glycosylhydroxylamines and Their Oxidation to Nitrones
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cmϪ1
.
1H NMR: δ ϭ 7.38Ϫ7.29 (m, 5 H), 4.49Ϫ3.69 (m, 8 H),
antiomeric forms, which therefore must lead exactly to the
same results and opposite configuration in reactions with
achiral substrates, starting from -arabinose and -arabi-
nose, both equally inexpensive, using the same synthetic
procedure.
1.38 (s, 3 H), 1.35 (s, 3 H) ppm. 13C NMR: δ ϭ (major anomer)
136.7 (s), 129.8 (d, 2 C), 128.4 (d, 2 C), 127.6 (d), 109.9 (s), 91.9
(d), 78.9 (t), 73.4 (d), 69.7 (d), 65.3 (d), 59.7 (t), 28.0 (q), 26.0 (q);
(minor anomer) 136.3 (s), 129.6 (d, 2 C), 129.1 (d, 2 C), 128.6 (d),
111.9 (s), 85.1 (d), 80.4 (t), 71.4 (d), 69.0 (d), 64.8 (d), 60.5 (t), 27.0
(q), 24.6 (q) ppm. MS: m/z (%) ϭ 295 (1) [Mϩ], 280 (4), 115 (20),
91 (100), 59 (55). C15H21NO5 (295.38): calcd. C 61.00, H 7.17, N
4.74; found C 60.51, H 7.34, N 4.57.
Experimental Section
N-Benzyl-N-hydroxy-2,3-O-(1-methylethylidene)-β-D-ribo-
General Remarks: All reactions requiring anhydrous conditions
were carried out under nitrogen, and solvents were appropriately
dried before use. Rf values refer to TLC on 0.25-mm silica gel plates
(Merck F254) obtained using the same eluent as in the separation
of the compound by flash column chromatography (FCC), except
where indicated. Melting points (m.p.) were determined with an
RCH Kofler apparatus. Optical rotation measurements were per-
formed (at the equilibrium for tautomeric compounds) with a Jasco
DIP-370 polarimeter. 1H and 13C NMR spectra (in CDCl3 solu-
tion, unless otherwise stated) were recorded at 200 MHz and
50.3 MHz, respectively, with a Varian Gemini spectrometer; the
chemical shifts for 1H and 13C NMR spectra are given in ppm
from TMS. IR spectra were recorded with a PerkinϪElmer 881
spectrophotometer. Mass spectra (EI, 70 eV) were recorded with a
QMD 1000 Carlo Erba instrument by direct inlet. Elemental analy-
ses were performed with a PerkinϪElmer 240 C instrument.
furanosylamine (3c): From N-benzylhydroxylamine (2.2 equiv.).
White solid, 195 mg, 66% yield. Rf (ethyl acetate) ϭ 0.45. M.p.
102Ϫ103 °C. [α]2D4 ϭ Ϫ43.2 (c ϭ 1.00, CH2Cl2). IR (CDCl3): ν˜ ϭ
3244, 3050, 2991, 2905, 1455, 1371, 1100, 1076 cmϪ1 1H NMR:
.
δ ϭ 7.46Ϫ7.28 (m, 5 H), 4.84 (m, 2 H), 4.61 (s, 1 H), 4.39Ϫ4.34
(m, 1 H), 3.97 (m, 2 H), 3.69 (m, 2 H), 1.51 (s, 3 H), 1.32 (s, 3 H)
ppm. 13C NMR: δ ϭ 136.1 (s), 129.7 (d, 2 C), 128.3 (d, 2 C), 127.5
(d), 112.4 (s), 101.0 (d), 87.2 (d), 83.5 (d), 81.7 (d), 63.8 (t), 59.9
(t), 26.8 (q), 25.1 (q) ppm. MS: m/z (%) ϭ 295 (0.6) [Mϩ], 280 (0.7),
265 (2), 173 (38), 91 (100), 59 (40). C15H21NO5 (295.38): calcd. C
61.00, H 7.17, N, 4.74; found C 61.32, H 7.32, N 4.58.
N-Benzyl-2,3,5-tri-O-benzyl-N-hydroxy-L-xylofuranosylamine
(3d):[8] From N-benzylhydroxylamine hydrochloride (1.8 equiv.).
Dark green oil, 315 mg, 60% yield (as a 4:1 α/β anomeric mixture
in CDCl3 solution containing ca. 10% of the open-chain nitrone
tautomer). Rf (ethyl acetate/petroleum ether, 1:2) ϭ 0.65. [α]2D6
ϭ
2,3,4,6-Tetra-O-benzyl--glucopyranose (1a) was purchased from
Aldrich, 3,4-O-isopropylidene--arabinopyranose (1b),[17] 2,3-O-
isopropylidene--ribofuranose (1c),[18] 2,3,5-tri-O-benzyl--xylofu-
ranose (1d),[19] 2,3,5-tri-O-benzyl--arabinofuranose (1e),[20] 2,3-O-
isopropylidene--erythrose (1f)[21]and (2,3:5,6)-di-O-isopropylid-
ene--mannofuranose (1g)[22] were prepared according to pub-
lished procedures.
ϩ24.8 (c ϭ 0.11, CH2Cl2). IR (CDCl3): ν˜ ϭ 3574, 3432, 3034, 2925,
2865, 1448, 1353, 1100 cmϪ1 1H NMR: δ ϭ (selected signals of
.
the open-chain nitrone isomer) 6.78 (d, J ϭ 6.7 Hz, 1 H), 5.16 (t,
J ϭ 6.8 Hz, 1 H) ppm. 13C NMR: δ ϭ (major anomer) 137.9 (s),
137.6 (s), 137.5 (s), 137.1 (s), 129.2Ϫ126.8 (d, 20 C), 98.7 (d), 82.5
(d), 81.5 (d), 78.6 (d), 73.3 (t), 71.9 (t), 71.5 (t), 68.4 (t), 60.3 (t);
(minor anomer, selected signals) 91.4 (d) ppm. MS: m/z (%) ϭ 525
(4) [Mϩ], 510 (2), 181 (17), 91 (100). C33H35NO5 (525.71): calcd. C
75.41, H 6.71, N 2.66; found C 75.10, H 6.39, N 2.43.
General Procedure for the Synthesis of N-Alkyl-N-glycosylhydroxyl-
˚
amines: N-Benzylhydroxylamine hydrochloride (1.2 equiv.) and 3 A
molecular sieves (800 mg) were added to a 0.3  solution of lactol
1 (1 mmol) in dry pyridine. The mixture was stirred at room tem-
perature overnight , then diluted with CH2Cl2 (3 mL), filtered
through Celite, and concentrated. The resulting product was puri-
fied by chromatography over a short pad of silica using the eluent
reported for Rf values. Variations from the general procedure,
which were applied in the syntheses of 3a, 3c and 3d, are given in
the relevant Exp. Sect.
N-Benzyl-2,3,5-tri-O-benzyl-N-hydroxy-D-arabinofuranosylamine
(3e):[8] Colourless oil, 347 mg, 66% yield (as a 6:1 α/β anomeric
mixture in CDCl3 solution). Rf (ethyl acetate/petroleum ether,
1:3) ϭ 0.60. [α]2D6 ϭ ϩ23.7 (c ϭ 2.15, CH2Cl2). IR (CH2Cl2): ν˜ ϭ
3566, 3032, 2914, 2870, 1452, 1362, 1078 cmϪ1 1H NMR: δ ϭ
.
7.42Ϫ7.20 (m, 20 Hαϩ20 Hβ), 4.76Ϫ4.51 (m, 4 Hαϩ4 Hβ),
4.50Ϫ4.40 (m, 2 Hβ), 4.34Ϫ4.23 (m, 4 Hα), 4.22Ϫ4.39 (m, 2 Hα ϩ
4 Hβ), 3.96Ϫ3.85 (m, 2 Hβ), 3.75Ϫ3.66 (m, 2 Hα), 3.64Ϫ3.55 (m, 2
Hβ), 3.54Ϫ3.49 (m, 2 Hα) ppm. 13C NMR: δ ϭ (major anomer)
138.3 (s), 138.2 (s), 138.1 (s), 137.5 (s), 129.5Ϫ127.4 (d, 20 C), 98.0
(d), 85.2 (d), 83.5 (d), 81.9 (d), 73.5 (t), 72.3 (t), 72.1 (t), 70.1 (t),
60.1 (t); (minor anomer) 138.4 (s), 138.1 (s), 138.0 (s), 137.8 (s),
129.3Ϫ127.3 (d, 20 C), 91.1 (d), 83.7 (d), 82.7 (d), 79.2 (d), 73.5
(t), 72.7 (t), 72.5 (t), 71.0 (t), 58.9 (t) ppm. MS: m/z (%) ϭ 418 (3),
388 (2), 310 (7), 280 (8), 253 (21), 181 (61), 107 (31), 105 (30), 91
(100), 77 (67), 65 (99). C33H35NO5 (525.71): calcd. C 75.41, H 6.71,
N 2.66; found C 75.04, H 6.58, N 2.63.
N-Benzyl-2,3,4,6-tetra-O-benzyl-N-hydroxy-β-D-glucopyranosyl-
amine (3a): From N-benzylhydroxylamine hydrochloride (2.2
equiv.), 48 h. White solid, 510 mg, 79% yield. Rf (ethyl acetate/
petroleum ether, 1:3) ϭ 0.49. M.p. 113Ϫ114 °C. [α]2D6 ϭ ϩ20.5 (c ϭ
1.10, CH2Cl2). IR (CHCl3): ν˜ ϭ 3545, 3511, 3034, 2911, 1450, 1362,
1
1054, 1028 cmϪ1. H NMR: δ ϭ 7.48Ϫ7.17 (m, 25 H), 5.11Ϫ4.74
(m, 5 H), 4.67Ϫ4.53 (m, 3 H), 4.33Ϫ4.04 (m, 3 H), 3.90Ϫ3.84 (m,
1 H), 3.82Ϫ3.42 (m, 5 H) ppm. 13C NMR: δ ϭ 139.0 (s), 138.4 (s),
138.3 (s), 137.5 (s, 2 C), 129.4Ϫ127.6 (d, 25 C), 93.0 (d), 86.1 (d),
78.5 (d), 78.0 (d), 76.6 (d), 75.9 (t), 75.2 (t), 74.7 (t), 73.7 (t), 69.3
(t), 60.4 (t) ppm. MS: m/z (%) ϭ 645 (0.6) [Mϩ], 181 (29), 91 (100).
C41H43NO6 (645.82): calcd. C 76.25, H 6.71, N 2.17; found C
75.86, H 6.90, N 2.11.
(3aR,4R,6aR)-N-Benzyl-tetrahydro-N-hydroxy-2,2-dimethylfuro-
[3,4-d]-1,3-dioxol-4-amine (3f): White solid, 233 mg, 88% yield (as
a 16:1 mixture with the open-chain nitrone tautomer in CDCl3
solution). Rf (ethyl acetate/petroleum ether, 1:3) ϭ 0.35. M.p.
86Ϫ87 °C. [α]2D0 ϭ Ϫ70.0 (c ϭ 1.00, CHCl3). IR (CHCl3): ν˜ ϭ
N-Benzyl-N-hydroxy-3,4-O-(1-methylethylidene)-
D-arabino-
pyranosylamine (3b): White solid, 180 mg, 61% yield (as a 3:1 α/β
3580, 3040, 2981, 2943, 1380, 1371, 1098, 1057 cmϪ1 1H NMR
.
anomeric mixture in CDCl3 solution). Rf (ethyl acetate) ϭ 0.26. (500 MHz): δ ϭ (N-glycosylhydroxylamine) 7.43Ϫ7.27 (m, 5 H),
M.p. 144Ϫ157 °C. [α]2D7 ϭ Ϫ68.0 (c ϭ 1.00, CH2Cl2). IR (CDCl3):
ν˜ ϭ 3550, 3400, 3040, 2990, 2910, 1455, 1380, 1218, 1125, 1080
4.92 (d, J ϭ 6.0 Hz, 1 H), 4.88 (dd, J ϭ 6.0, 4.2 Hz, 1 H), 4. 73 (s,
1 H), 4.68 (br. s, 1 H), 4.27 (dd, J ϭ 9.5, 4.2 Hz, 1 H), 4.09 (d, J ϭ
Eur. J. Org. Chem. 2003, 4152Ϫ4160
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S. Cicchi, M. Marradi, M. Corsi, C. Faggi, A. Goti
FULL PAPER
13.5 Hz, 1 H), 4.07 (d, J ϭ 9.5 Hz, 1 H), 3.88 (d, J ϭ 13.5 Hz, 1 H), 1.51 (s, 3 H), 1.43 (s, 3 H), 1.38 (s, 3 H), 1.36 (s, 3 H) ppm.
H), 1.51 (s, 3 H), 1.35 (s, 3 H); (open-chain nitrone) 6.89 (d, J ϭ 13C NMR: δ ϭ 132.8 (d), 131.0 (d, 2 C), 129.6 (s), 128.9 (d, 2 C),
6.0 Hz, 1 H), 5.32 (t, J ϭ 5.5 Hz, 1 H), 5.06 (s, 1 H), 1.43 (s, 3 H),
1.39 (s, 3 H) ppm. 13C NMR: δ ϭ 137.0 (s), 129.5 (d, 2 C), 128.5
128.5 (d), 112.9 (s), 104.0 (d), 84.4 (d), 80.5 (d), 77.2 (t), 26.3 (q),
24.7 (q) ppm. MS: m/z (%) ϭ 263 (4) [Mϩ], 248 (2), 143 (67), 85
(d, 2 C), 127.5 (d), 112.1 (s), 99.7 (d), 83.9 (d), 81.1 (d), 76.4 (t), (39), 59 (41), 57 (100). C14H17NO4 (263.35): calcd. C 63.87, H 6.51,
59.4 (t), 26.5 (q), 24.8 (q) ppm. MS: m/z (%) ϭ 265 (4) [Mϩ], 159
(4), 143 (22), 91 (100), 57 (52) ppm. C14H19NO4 (265.37): calcd. C
63.38, H 7.22, N 5.28; found C 63.33, H 7.24, N 5.20.
N 5.32; found C 63.64, H 6.49, N 5.21.
2,3:5,6-Di[O-(1-methylethylidene)]-N-(phenylmethylene)-α-D-
mannofuranosylamine N-Oxide (13):[6] White solid, 350 mg, 97%
yield. M.p. 179Ϫ181 °C. [α]2D5 ϭ ϩ62.7 (c ϭ 1.00, CHCl3). [ref. m.p.
182Ϫ183 °C, [α]D ϭ ϩ66.4 (c ϭ 1.50, CHCl3);[4h] m.p. 184 °C,
N-Benzyl-N-hydroxy-2,3:5,6-di[O-(1-methylethylidene)]-α-D-
mannofuranosylamine (3g):[6] White solid, 266 mg, 73% yield. Rf
(CH2Cl2/CH3OH, 30:1) ϭ 0.68. 1H NMR: δ ϭ 7.36Ϫ7.28 (m, 5 [α]D ϭ ϩ62.1 (c ϭ 1.50, CHCl3).[6] 1H NMR: δ ϭ 8.26Ϫ8.23 (m,
H), 5.52 (br. s, 1 H), 4.96 (d, J ϭ 6.1 Hz, 1 H), 4.84 (dd, J ϭ 6.1, 2 H), 7.59 (s, 1 H), 7.46Ϫ7.42 (m, 3 H), 5.49 (s, 1 H), 5.32 (d, J ϭ
3.2 Hz, 1 H), 4.66 (s, 1 H), 4.42Ϫ4.28 (m, 2 H), 4.20Ϫ4.08 (m, 2
6.2 Hz, 1 H), 5.01 (dd, J ϭ 6.2, 4.1 Hz, 1 H), 4.52 (dd, J ϭ 9.8,
H), 4.00 (d, J ϭ 13.2 Hz, 1 H), 3.86 (d, J ϭ 13.2 Hz, 1 H), 1.48 (s, 4.1 Hz, 1 H), 4.31 (d, J ϭ 9.8 Hz, 1 H), 4.10 (m, 2 H), 1.51 (s, 3
6 H), 1.40 (s, 3 H), 1.37 (s, 3 H) ppm.
H), 1.43 (s, 3 H), 1.38 (s, 3 H), 1.36 (s, 3 H) ppm.
(3aR,4R,6aR)-Tetrahydro-N-hydroxy-N,2,2-trimethylfuro[3,4-d]-
1,3-dioxol-4-amine (3h): White solid, 134 mg, 71% yield (as a 6:1
General Procedure for the Cycloadditions of C-Phenyl-N-glycosylni-
trones with Dimethyl Maleate (11): Dimethyl maleate (11) (2 equiv.)
mixture with the open-chain nitrone tautomer in CDCl3 solution). was added to a 0.5  suspension of C-phenyl-N-glycosylnitrone 10
Rf (ethyl acetate/petroleum ether, 1:2) ϭ 0.23. M.p. 101Ϫ102 °C. or 13 (0.5 mmol) in toluene in a Sovirel vial. The mixture was
[α]2D0 ϭ Ϫ65.1 (c ϭ 1.04, CH2Cl2). IR (CHCl3): ν˜ ϭ 3166, 2999, heated at 80 °C in the sealed vial in an oven for 4 days, then concen-
2974, 2946, 1456, 1383, 1203, 1108, 1057 cmϪ1. 1H NMR: δ ϭ (N-
glycosylhydroxylamine) 4.88 (m, 2 H), 4. 52 (s, 1 H), 4.16 (dd, J ϭ
9.8, 3.4 Hz, 1 H), 4.02 (d, J ϭ 9.8 Hz, 1 H), 2.68 (s, 3 H), 1.51 (s,
3 H), 1.35 (s, 3 H); (open-chain nitrone) 6.94 (d, J ϭ 5.1 Hz, 1 H),
5.33 (dd, J ϭ 7.3, 5.1 Hz, 1 H), 4.60 (td, J ϭ 7.3, 3.7 Hz, 1 H),
3.74 (s, 3 H), 3.72 (dd, J ϭ 11.7, 3.7 Hz, 1 H), 3.55 (dd, J ϭ 11.7,
7.3 Hz, 1 H), 1.51 (s, 3 H), 1.41 (s, 3 H) ppm. 13C NMR: δ ϭ (N-
glycosylhydroxylamine) 112.0 (s), 101.0 (d), 82.8 (d), 80.9 (d), 75.7
(t), 42.9 (q) 26.4 (q), 24.7 (q); (open-chain nitrone) detected signals
79.5 (d), 73.8 (d), 61.5 (t), 52.0 (q), 27.0 (q), 24.3 (q) ppm. MS:
m/z (%) ϭ 189 (1) [Mϩ], 171 (2), 143 (30), 114 (19), 84 (75), 56
(100). C8H15NO4 (189.21): calcd. C 50.78, H 7.99, N 7.40; found
C 51.13, H 7.96, N 7.54.
trated and purified by FCC.
Dimethyl (3R,4S,5R)-2-[(3aR,4R,6aR)-Tetrahydro-2,2-dimethyl-3-
phenylfuro[3,4-d][1,3]dioxol-4-yl]isoxazolidine-4,5-dicarboxylate
(12):[23] White solid, 157 mg, 77% yield. Rf (ethyl acetate/petroleum
ether, 1:2) ϭ 0.35. M.p. 70Ϫ71 °C. [α]2D0 ϭ Ϫ62.1 (c ϭ 0.59,
1
CHCl3). H NMR: δ ϭ 7.43Ϫ7.29 (m, 5 H), 5.13 (d, J ϭ 6.2 Hz,
1 H), 4.93 (d, J ϭ 9.0 Hz, 1 H), 4.86 (s, 1 H), 4.81 (dd, J ϭ 6.2,
4.5 Hz, 1 H), 4.62 (d, J ϭ 9.0 Hz, 1 H), 3.83 (t, J ϭ 9.0 Hz, 1 H),
3.80 (d, J ϭ 10.0 Hz, 1 H), 3.78 (s, 3 H), 3.73 (dd, J ϭ 10.0, 4.5 Hz,
1 H), 3.65 (s, 3 H), 1.43 (s, 3 H), 1.34 (s, 3 H) ppm. 13C NMR: δ ϭ
169.5 (s), 169.2 (s), 136.7 (s), 128.8 (d, 2 C), 128.3 (d), 127.7 (d, 2
C), 112.1 (s), 98.8 (d), 82.4 (d), 80.7 (d), 77.7 (d), 74.3 (d), 68.7 (t),
58.9 (d), 52.6 (q), 52.5 (q), 26.3 (q), 24.8 (q) ppm. IR (KBr): ν˜ ϭ
3003, 2957, 2895, 1740, 1436, 1373, 1265, 1157, 1092 cmϪ1. MS:
m/z (%) ϭ 407 (9) [Mϩ], 146 (60), 143 (47), 91 (100), 85 (43), 59
(54), 57 (72). C20H25NO8 (407.48): calcd. C 58.96, H 6.18, N 3.44;
found C 59.03, H 6.22, N 3.33.
N-Hydroxy-N-methyl-2,3:5,6-di[O-(1-methylethylidene)]-α-D-
mannofuranosylamine (3i): White solid, 202 mg, 70% yield. Rf (elu-
ent ethyl acetate/petroleum ether, 1:2) ϭ 0.26. M.p. 61Ϫ62 °C.
[α]2D2 ϭ ϩ20.3 (c ϭ 1.00, CH2Cl2). IR (CHCl3): ν˜ ϭ 3582, 2992,
2937, 1454, 1372, 1205, 1060 cmϪ1 1H NMR: δ ϭ 5.70 (br. s, 1
.
Dimethyl (3S,4R,5S)-2-[2,3:5,6-Di-O-(1-methylethylidene)-α-D-man-
H), 4.92 (d, J ϭ 6.1 Hz, 1 H), 4.82 (dd, J ϭ 6.1, 3.2 Hz, 1 H), 4.48
(s, 1 H), 4.40Ϫ4.20 (m, 2 H), 4.12Ϫ4.05 (m, 2 H), 2.68 (s, 3 H),
1.44 (s, 3 H), 1.42 (s, 3 H), 1.38 (s, 3 H), 1.37 (s, 3 H) ppm. 13C
NMR: δ ϭ 112.6 (s), 109.2 (s), 100.8 (d), 83.9 (d), 83.7 (d), 80.8
(d), 73.8 (d), 66.9 (t), 43.1 (q), 27.0 (q), 26.2 (q), 25.3 (q), 24.6 (q)
ppm. MS: m/z (%) ϭ 274 (15) [M Ϫ CH3ϩ], 258 (5), 231 (6), 101
(44), 99 (36), 84 (100). C13H23NO6 (289.34): calcd. C 53.97, H 8.01,
N 4.84; found C 53.99, H 8.28, N 4.83.
nofuranosyl]-3-phenylisoxazolidine-4,5-dicarboxylate (14a): White
solid, 178 mg, 70% yield. Rf (ethyl acetate/petroleum ether, 1:3) ϭ
0.35. M.p. 115Ϫ116 °C. [α]2D5 ϭ ϩ46.1 (c ϭ 1.00, CH2Cl2). 1H
NMR: δ ϭ 7.48Ϫ7.28 (m, 5 H), 5.08 (d, J ϭ 6.0 Hz, 1 H), 4.92 (s,
1 H), 4.91 (d, J ϭ 8.9 Hz, 1 H), 4.77 (dd, J ϭ 6.0, 3.7 Hz, 1 H),
4.50 (d, J ϭ 8.9 Hz, 1 H), 4.11 (ddd, J ϭ 8.4, 4.8, 2.6 Hz, 1 H),
3.76 (t, J ϭ 8.9 Hz, 1 H), 3.76 (s, 3 H), 3.66 (dd, J ϭ 8.8, 2.6 Hz,
1 H), 3.62 (s, 3 H), 3.56 (dd, J ϭ 8.4, 3.7 Hz, 1 H), 2.78 (dd, J ϭ
8.8, 4.8 Hz, 1 H), 1.43 (s, 3 H), 1.33 (s, 3 H), 1.26 (s, 3 H), 1.25 (s,
3 H) ppm. 13C NMR: δ ϭ 169.4 (s), 168.5 (s), 137.2 (s), 128.7 (d,
2 C), 128.1 (d), 127.3 (d, 2 C), 112.4 (s), 108.9 (s), 100.0 (d), 83.5
(d), 82.5 (d), 80.2 (d), 77.6 (d), 72.5 (d), 69.6 (d), 66.4 (t), 59.7 (d),
General Procedure for the Synthesis of C-Phenyl-N-glycosylnitrones:
Commercially available ‘‘activated’ MnO2 (90% purity, 1.5 equiv.)
was added to a stirred 0.5  solution of N-benzyl-N-glycosylhyd-
roxylamine 3fϪg (1 mmol) in CH2Cl2 which was cooled to 0 °C.[13]
The mixture was stirred at room temperature for 12 h, then filtered 52.5 (q), 52.4 (q), 26.7 (q), 26.0 (q), 25.3 (q), 24.6 (q) ppm. IR
through a short pad of Celite and Na2SO4. The resulting solution
was concentrated to afford the corresponding pure C-phenyl-
nitrone.
(KBr): ν˜ ϭ 3050, 2989, 2957, 1740, 1465, 1380, 1202, 1062 cmϪ1
.
MS: m/z (%) ϭ 507 (0.5) [Mϩ], 294 (22), 185 (29), 115 (29), 101
(100), 85 (53), 69 (42), 59 (68). C25H33NO10 (507.60): calcd. C
59.16, H 6.55, N 2.76; found C 59.27, H 6.99, N 2.83.
(3aR,4R,6aR)-Tetrahydro-2,2-dimethyl-N-(phenylmethylene)furo-
[3,4-d][1,3]dioxol-4-amine N-Oxide (10): White solid, 255 mg, 97%
yield. M.p. 110Ϫ112 °C. [α]2D0 ϭ Ϫ148.2 (c ϭ 1.09, CHCl3). IR
Dimethyl (3S,4S,5R)-2-[2,3:5,6-Di-O-(1-methylethylidene)-α-D-man-
nofuranosyl]-3-phenyl-4,5-isoxazolidinedicarboxylate (14b): White
1
(CHCl3): ν˜ ϭ 2991, 1582, 1448, 1375, 1100 cmϪ1. H NMR: δ ϭ
solid, 15 mg, 6% yield. Rf (ethyl acetate/petroleum ether, 1:3) ϭ
1
8.26Ϫ8.23 (m, 2 H), 7.59 (s, 1 H), 7.46Ϫ7.42 (m, 3 H), 5.49 (s, 1 0.20. M.p. 94Ϫ97 °C. [α]2D1 ϭ ϩ7.6 (c ϭ 0.50, CH2Cl2). H NMR:
H), 5.32 (d, J ϭ 6.2 Hz, 1 H), 5.01 (dd, J ϭ 6.2, 4.1 Hz, 1 H), 4.52
(dd, J ϭ 9.8, 4.1 Hz, 1 H), 4.31 (d, J ϭ 9.8 Hz, 1 H), 4.10 (m, 2
δ ϭ 7.40Ϫ7.28 (m, 5 H), 5.13 (d, J ϭ 6.2 Hz, 1 H), 4.96 (d, J ϭ
6.6 Hz, 1 H), 4.77 (dd, J ϭ 6.2, 3.7 Hz, 1 H), 4.63 (d, J ϭ 8.4 Hz,
4158
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 4152Ϫ4160

N-Glycosylhydroxylamines and Their Oxidation to Nitrones
FULL PAPER
1 H), 4.60 (s, 1 H), 4.12 (ddd, J ϭ 8.4, 6.6, 4.8 Hz, 1 H), 4.03 (dd,
CH2Cl2). C13H15NO5(265.27): calcd. C 58.86, H 5.70, N 5.28;
J ϭ 8.4, 6.6 Hz, 1 H), 3.78 (s, 3 H), 3.67 (dd, J ϭ 8.4, 6.6 Hz, 1 found C 58.71, H 5.81, N 4.95.
H), 3.59 (dd, J ϭ 8.4, 3.7 Hz, 1 H), 3.21 (s, 3 H), 2.78 (dd, J ϭ
X-ray Crystallographic Study of Compound 12: C20H25NO8, M ϭ
8.4, 4.8 Hz, 1 H), 1.43 (s, 3 H), 1.33 (s, 3 H), 1.26 (s, 3 H), 1.21 (s,
3 H) ppm. 13C NMR: δ ϭ 168.5 (s), 168.4 (s), 136.2 (s), 128.2 (d,
2 C), 128.0 (d), 127.2 (d, 2 C), 112.4 (s), 109.0 (s), 100.0 (d), 84.2
(d), 82.4 (d), 80.1 (d), 77.6 (d), 72.4 (d), 70.8 (d), 66.4 (t), 57.8 (d),
52.4 (q), 51.7 (q), 26.6 (q), 26.0 (q), 25.3 (q), 24.5 (q) ppm. IR
407.41, Triclinic, space group P1, a ϭ 6.247(1), b ϭ 9.807(1), c ϭ
˚
9.346(1) A, α ϭ 106.48(1)°, β ϭ 105.14(2)°, γ ϭ 95.08(1)°, V ϭ
3
521.75(11) A , Z ϭ 1 Dcalcd. ϭ 1.297, µ ϭ 0.847 mmϪ1, F(000) ϭ
˚
216.
(KBr): ν˜ ϭ 3055, 2988, 2956, 1737, 1453, 1381, 1199, 1065 cmϪ1
.
Analysis of a single crystal was carried out with a Siemens P4 X-
ray diffractometer at room temperature. Graphite-monochromated
Cu-Kα radiation was used for cell parameter determination and
data collection. The intensities of three standard reflections were
monitored during data collection to check the stability of the crys-
tal: no loss of intensity was recognized. The integrated intensities,
measured using the θ/2θ scan mode, were corrected for Lorentz and
polarization effects.[25] The reflection collected were 1421 with a
4.78 Ͻ θ Ͻ 49.92 range; 1421 were indipendent and the parameters
were 288. The final R index was 0.0350 for reflections having I Ͼ
2σI, and 0.0355 for all data. The non-hydrogen atoms were refined
anisotropically; aromatic, methylene and methyl hydrogen atoms
were assigned in calculated positions while the others (H1, H2, H3,
H8, H11 and H14) were found in the Fourier difference synthesis;
all of them were refined as isotropic. This structure was solved by
direct methods of SIR97[26] and refined using the full-matrix least-
squares on F2 provided by SHELXL-97.[27]
MS: m/z (%) ϭ 507 (4) [Mϩ], 294 (49), 185 (50), 115 (70), 101 (97),
85 (100). C25H33NO10 (507.60): calcd. C 59.16, H 6.55, N 2.76;
found C 58.91, H 6.55, N 2.78.
One-Pot Oxidation of Hydroxylamine 3h. ؊ Cycloaddition with Di-
methyl Maleate (11): A solution of hydroxylamine 3h (55 mg,
0.29 mmol) in CHCl3 (5 mL) was cooled to 0 °C in an ice-bath and
DDQ (73 mg, 0.32 mmol) was added. The cold-bath was removed
and then, after 5 min, dimethyl maleate (11, 75 µL, 0.50 mmol) was
added. The mixture was then refluxed for 1 h. The solution was
concentrated and purified by flash column chromatography, to af-
ford a 1:1 mixture of diastereoisomers 16aϪb as a colourless oil
(82 mg, 85% yield, Rf (ethyl acetate/pentane, 1:3) ϭ 0.17).
Dimethyl
(4S,5R)-2-{(3aR,4R,6aR)-Tetrahydro-2,2-dimethylfuro-
[3,4-d][1,3]dioxol-4-yl}isoxazolidine-4,5-dicarboxylate (16a) and Di-
methyl (4R,5S)-2-{(3aR,4R,6aR)-Tetrahydro-2,2-dimethylfuro[3,4-
d][1,3]dioxol-4-yl}isoxazolidine-4,5-dicarboxylate
(16b):
IR
1
CCDC-209316 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, UK; fax: (internat.) ϩ44Ϫ1223/336Ϫ033; E-mail:
deposit@ccdc.cam.ac.uk].
(CH2Cl2): ν˜ ϭ 2987, 2954, 1744, 1437, 1374, 1210, 1096 cmϪ1. H
NMR ([D6]DMSO, 70 °C, 400 MHz): δ ϭ (the signals of the two
diastereoisomers are not discernible and are reported together)
4.85Ϫ4.75 (m, 3 H), 4.67 (s, 1 H), 4.58 (s, 1 H), 4.02 (dd, J ϭ 6.1,
3.9 Hz, 1 H), 3.99 (dd, J ϭ 6.1, 3.9 Hz, 1 H), 3.94Ϫ3.86 (m, 4 H),
3.65 (s, 3 H), 3.64 (s, 3 H), 3.63 (s, 3 H), 3.62 (s, 3 H), 3.49 (dd,
J ϭ 13.4, 8.1 Hz, 1 H), 3.47 (dd, J ϭ 13.4, 7.8 Hz, 1 H), 3.31 (dd,
J ϭ 11.5, 8.1 Hz, 1 H), 3.27 (dd, J ϭ 11.5, 8.1 Hz, 1 H), 1.41 (s, 3
H), 1.40 (s, 3 H), 1.29 (s, 3 H), 1.28 (s, 3 H) ppm. 13C NMR: δ ϭ
(the signals of the two diastereoisomers are not discernible and are
reported together) 112.3 (s), 112.2 (s), 100.5 (d), 97.3 (d), 83.9 (d),
83.8 (d), 80.6 (d), 80.4 (d), 77.9 (d), 77.1 (d), 75.8 (t), 75.0 (t), 52.4
(q, 2 C), 52.4 (q, 2 C), 52.4 (t), 51.3 (t), 50.6 (d), 49.3 (d), 26.5 (q),
26.3 (q), 24.8 (q), 24.7 (q) ppm. MS: m/z (%) ϭ 331 (1) [Mϩ], 256
(5), 218 (17), 143 (36), 85 (80), 57 (100).C14H21NO8 (331.32): calcd.
C 50.75, H 6.39, N 4.23; found C 51.13, H 6.46, N 4.26.
Acknowledgments
Authors thank the Ministry of Instruction, University and Scien-
tific and Technological Research (M.I.U.R. Cofin 2002), Italy for
financial support.
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S. Cicchi, M. Corsi, A. Brandi, A. Goti, J. Org.
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1  Na2CO3, the mixture was extracted with Et2O. The collected
organic phases were washed with 0.5  Na2CO3, dried with
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Dimethyl
(3R,4S,5R)-3-Phenylisoxazolidine-4,5-dicarboxylate
A. Vasella, Helv. Chim. Acta 1977, 60, 426Ϫ446.
[4] [4a]
[4b]
(17):[24] Colourless oil, 38 mg, 71% yield. Rf (ethyl acetate/diethyl
ether/petroleum ether, 1:2:3) ϭ 0.31. [α]2D2 ϭ Ϫ169.4 (c ϭ 0.28,
CH2Cl2). IR (CH2Cl2): ν˜ ϭ 3688, 3052, 2971, 1741, 1446, 1365,
A. Vasella, Helv. Chim. Acta 1977, 60, 1273Ϫ1295.
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1134Ϫ1144. [4d] A. Vasella, R. Voeffray, Helv. Chim. Acta 1982,
1198, 1080 cmϪ1. H NMR: δ ϭ 7.46Ϫ7.25 (m, 5 H), 4.92 (d, J ϭ
1
[4e]
65, 1953Ϫ1964.
A. Vasella, R. Voeffray, J. Pless, R. Hug-
4.0 Hz, 1 H), 4.90 (d, J ϭ 8.4 Hz, 1 H), 3.82 (dd, J ϭ 8.4, 4.0 Hz,
1 H), 3.76 (s, 3 H), 3.74 (s, 3 H) ppm. 13C NMR: δ ϭ 171.0 (s),
170.3 (s), 140.0 (s), 128.9 (d, 2 C), 127.8 (d), 126.3 (d, 2 C), 80.6
(d), 66.2 (d), 60.8 (d), 52.8 (t), 52.5 (t) ppm. MS: m/z (%) ϭ 265
(1) [Mϩ], 146 (100), 120 (31), 104 (51), 84 (62), 77 (43), 51 (61).
C13H15NO5 (265.27): calcd. C 58.86, H 5.70, N 5.28; found C
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4159

S. Cicchi, M. Marradi, M. Corsi, C. Faggi, A. Goti
FULL PAPER
[5d]
4205Ϫ4208.
O. Tamura, N. Mita, N. Kusaka, H. Suzuki,
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Received June 12, 2003
1
[27]
1 H), 4.96 (d, J ϭ 6.6 Hz, 1 H), 4.80 (dd, J ϭ 6.2, 3.7 Hz, 1
4160
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4152Ϫ4160