Microwave-induced 1,3-dipolar intramolecular cycloadditions of N-substituted oximes, nitrones, and azomethine ylides for the chiral synthesis of functionalized nitrogen heterocycles

Article abstract of DOI:10.1039/b006000n

A report on the research efforts on the intramolecular cycloaddition reactions of oximes, nitrones, and azomethine ylides was presented. The oximes, nitrones, and azomethine ylides were derived from L-serine methyl ester on the surface of silica gel without a solvent under microwave irradiation. It resulted in the chiral preparation of functionalized tricyclic isoxazolidines fused with a pyrrolidine or piperidine ring.

Full text of DOI:10.1039/b006000n

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Microwave-induced 1,3-dipolar intramolecular cycloadditions of
N-substituted oximes, nitrones, and azomethine ylides for the
chiral synthesis of functionalized nitrogen heterocycles
1
a
b
a
a
Qian Cheng,* Wen Zhang, Yoshimichi Tagami and Takayuki Oritani
a
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science,
Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
Institute of Pesticides & Pharmaceuticals, East China University of Science and Technology,
b
1
30 Meilong St., Shanghai 200237, P. R. China. E-mail: chengq@biochem.tohoku.ac.jp
Received (in Cambridge, UK) 25th July 2000, Accepted 22nd December 2000
First published as an Advance Article on the web 29th January 2001
Highly stereoselective intramolecular cycloadditions of unsaturated N-substituted oximes, nitrones, and azomethine
ylides on the surface of silica gel without a solvent, which have been conducted under microwave irradiation, to
produce functionalized tricyclic isoxazolidines fused with a pyrroline or piperidine ring in good yields, are presented.
Introduction
wave irradiation, which result in the chiral preparation of
functionalized tricyclic isoxazolidines fused with a pyrrolidine
or piperidine ring.
The nitrone cycloaddition reaction with olefins, particularly
an intramolecular nitrone cycloaddition reaction (INC), has
experienced impressive growth, and finds broad applications
in organic synthesis due to the production of their product
isoxazolidines, which have a labile N–O bond which is easily
converted into various functionalized groups. These sequences
have been utilized as a key step for the synthesis of highly func-
tionalized pyrrolidines and piperidines which have been applied
to the synthesis of biologically active natural products. How-
ever, it is known that a disadvantageous factor of the reaction
is that the cycloaddition only takes place at high temperature
and after long reaction times. In the past decade, microwave
irradiation has been widely used in organic synthesis. However,
Results and discussion
The five- and six-membered nitrogen heterocycles belong to
the largest class of heterocyclic compounds with diverse
5
biological activities. Naturally an intensive effort has been
1
directed towards the development of efficient strategies for their
6
synthesis. The synthesis of substituted chiral pyrrolidines as
potential glycosidase inhibitors via an intramolecular NH–
nitrone cycloaddition reaction (also named an intramolecular
oxime–olefin cycloaddition, IOOC) starting from -serine
2
3
7
so far, only a limited number of microwave-assisted 1,3-dipolar
intermolecular cycloaddition reactions of nitrilimines and
nitrile oxides giving cycloadducts in moderate yields have been
has recently been reported by Hassner and his colleagues. It
has been found that an oxime 2a undergoes the IOOC reaction,
via an intermediate 3a, which requires heating at 170 ЊC in
toluene in a sealed tube for 16 h to form an isoxazolidine 4a.
Very recently, it has been observed that the oxime 2a, mixed
with silica gel and irradiated by microwaves for 15 min, affords
the desired isoxazolidine 4a in 82% yield through the IOOC
reaction (Scheme 1). The product 4a was determined to be
4
reported. Recently, we have investigated the possibility of intra-
molecular nitrone cycloaddition reaction under microwave
irradiation. In this paper, we report our research efforts on
the intramolecular cycloaddition reactions of oximes, nitrones,
and azomethine ylides derived from -serine methyl ester
on the surface of silica gel without a solvent under micro-
7
consistent with the previously reported compound. Similarly,
Scheme 1
4
52
J. Chem. Soc., Perkin Trans. 1, 2001, 452–456
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b006000n

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compounds 2b and 2c, prepared from -serine methyl ester
according to the previously reported method, were sub-
methylene carbon resonance, at δ 26.28 (t), together with two
proton resonances, at δH 2.32 (ddd, J 12.6, 6 and 4.8 Hz) and
C
7
sequently mixed with silica gel and irradiated by microwaves to
produce the intermediates 3b and 3c, which in situ underwent
the IOOC reaction to give the isoxazolidines 4b (80% yield)
and 4c (77% yield) respectively. The structure and stereo-
chemistry of 4b and 4c were unambiguously established by
extensive NMR studies involving 2D-NMR experiments. The
δH 1.88 (d, J 12.6 Hz), these indicated the presence of a piper-
idine ring. The stereochemistry of 8a was established by
characteristic H NMR signals for a six-membered ring,
1
enabling a credible stereochemical assignment for a piperidine
ring to be made. The same coupling JHH 4.8 Hz observed for
both H-1 to H -2 and H-1 to H -11, and the coupling J
HH
ax
ax
1
H NMR spectrum of 4b showed that a coupling JHH 8.5 Hz
6.0 Hz of H-8 to H -11 plus the coupling J 4.8 Hz of H-8 to
ax HH
between H-3a and H-8b accompanied by the smaller coupling
JHH 5.1 Hz between H-8a and H-8b suggested the trans stereo-
chemistry of H-8a and H-8b, and cis stereochemistry of H-8b
and H-3a. This tentative assignment was further confirmed by a
H -7, indicated that both H-1 and H-8 possess an equatorial
ax
orientation in the piperidine ring, therefore they have a cis
relationship, which was confirmed by 2D-NOESY of 8a
(Fig. 2). The nitrone 6b, which was prepared from 5a by
reaction with N-benzylhydroxylamine, underwent an in situ
INC reaction to afford an isoxazolidine 7b in 64% yield and a
bridged isoxazolidine 8b in 13% yield, which were determined
by NMR experiments and 2D-NOESY studies. Formation of
the bridged isoxazolidines 8a,b may be rationalized to arise
from INC reactions via the bridged-ring transition state (Z-
nitrone) whereas the isoxazolidines 7a,b from the INC reactions
arose via the fused-ring transition state (E-nitrone), respectively.
Since Z- and E-nitrone transition states are known to inter-
4
% NOE enhancement between H-3a and H-8b and a 3% NOE
enhancement between H-8 and H-8b (Fig. 2). On the other
1
hand, the H NMR spectrum of 4c displayed a coupling J 8.8
HH
Hz of H -9a to H -9b along with a small coupling J 4.8 Hz
ax
ax
HH
of H -3a to H -9b, and their NOE data exhibited by arrows in
eq
ax
Fig. 2, all indicated that H-3a and H-9b possess a cis stereo-
chemistry, and H-9a and H-9b possess a trans stereochemistry.
The interesting findings for the IOOC reaction induced by
microwave irradiation have prompted us to widely investigate
the intramolecular cycloaddition reaction of chiral N-substi-
tuted nitrones which is induced by microwave irradiation.
Usually, the intramolecular nitrone cycloaddition reaction, like
the IOOC reaction, can be carried out in a solvent under reflux
9
convert under our reaction conditions, we may assume tenta-
tively that the diastereoisomeric ratio depends only on the
respective transition-state energies (Fig. 1). The observation
of the pyrrolidine derivatives 7, which were formed highly
selectively (≈7:1), led to a conclusion that the E-nitrone
transition state was energetically more favourable.
8
to give rise to the cycloadducts. For comparison of the intra-
molecular cycloaddition reaction of N-substituted nitrones
derived from -serine methyl ester, which is induced and
occurred under different reaction conditions, the process which
involves both oxidation and INC reaction of an intermediate
However, when the intermediate 5a and N-methylhydroxyl-
amine were mixed with silica gel and irradiated by microwaves
for 15 min, it provided only the pyrrolidine derivative 7a,
in 82% yield, as the cycloadduct. Similarly, a mixture of 5a, N-
benzylhydroxylamine and silica gel was irradiated by micro-
waves to give only the pyrrolidine derivative 7b, in 79% yield.
These results indicated that the bridged-ring transition states
(Z-nitrone) for the formation of bridged isoxazolidines were
not likely to form under these reaction conditions, probably due
to the higher temperature. In order to confirm this hypothesis,
a mixture of the intermediate 5a and N-methylhydroxylamine
in alcohol was placed in a sealed tube and heated at 120 ЊC
for 6 h. Unfortunately, both products 7a and 8a, in an 8:1 ratio,
were obtained in this reaction. Therefore, it may be proposed
5
a under reflux in alcohol was studied first (Scheme 2).
Reduction of 1a with an excess of DIBAL-H gave the inter-
mediate 5a, which on treatment with N-methylhydroxylamine
generated the corresponding nitrone 6a, which in situ under-
went the INC reaction to furnish an isoxazolidine 7a in 72%
yield along with a bridged isoxazolidine 8a in 10% yield. The
NMR data of 7a displayed high structural correlations to
the previously described compound 1a except that a methyl
group was located at the N-atom of the isoxazolidine ring.
On the other hand, the NMR data of 8a showed only one
methylene carbon resonance, at δC 66.37 (t), and a high-field
Scheme 2
Fig. 1 The transition states for the INC leading to 7 and 8.
J. Chem. Soc., Perkin Trans. 1, 2001, 452–456
453

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that the selectivity in the microwave-induced reactions results
from a faster transformation that leads to the kinetically con-
trolled product.
It is known that azomethine ylides, which can be regarded
as nitrones in the INC reaction, are used as the dipoles in the
silica gel 60 (230–400 mesh). Mps were measured on a micro-
melting point apparatus (Yanagimoto) and are uncorrected. All
microwave-irradiated reactions were performed in a domestic
microwave oven (Koizumi, power source 100 V, 50 Hz; micro-
wave frequency: 2450 MHz) at 750 W in the temperature range
110–120 ЊC for a certain period of time (specified for each
reaction).
1
,3-dipolar azomethine ylide cycloaddition reactions leading
10
to cycloadducts in high stereoselectivity. For further investi-
gation into the possibility of 1,3-dipolar azomethine ylide
cycloaddition reactions irradiated by microwaves, the cyclo-
additions of two N-substituted azomethine ylides 9a,b derived
from 1a were studied (Scheme 3). Non-stabilized azomethine
ylides can be generated by direct treatment of aldehydes with
N-substituted α-amino esters and subsequently trapped
smoothly by olefin dipolarophiles. A mixture of the aldehyde
General procedure for reduction and oximation of esters 1a–c to
aldoximes 2a–c
To a solution of 1a (1.85 g, 10 mmol) in CH Cl (30 ml) cooled
2
2
to Ϫ78 ЊC under nitrogen was added dropwise DIBAL-H
1.0 M in hexane; 16 ml). After stirring of the mixture at
(
Ϫ78 ЊC for 2 h, methanol (4 ml) was added and then the
reaction mixture was partitioned between EtOAc (70 ml) and
saturated aq. potassium sodium tartrate (30 ml), followed by
5
a and N-methylglycine ethyl ester on the surface of silica
gel therefore was irradiated under microwaves for 15 min,
generating an azomethine ylide 9a, which then in situ smoothly
underwent intramolecular cycloaddition to afford the corre-
sponding cycloadduct 10a in 79% yield. Similarly, 5a and
N-benzylglycine ethyl ester were mixed on the surface of silica
gel, followed by irradiation under microwaves for 15 min,
leading to ylide 9b, which underwent intramolecular cyclo-
addition to furnish the cycloadduct 10b in 81% yield. The
structure and stereochemistry of 10a,b were established by
extensive NMR and NOE studies. The most important proof
of stereochemistry by NOE is indicated with arrows in Fig. 2.
In conclusion, microwave irradiation effected highly stereo-
selective 1,3-dipolar intramolecular cycloaddition reactions
of N-substituted oximes, nitrones, and azomethine ylides on the
surface of silica gel without a solvent in a short time leading
to the cycloadducts in good yields. Accordingly, we believe that
this method will be potentially useful for the chiral synthesis
of functionalized nitrogen heterocycles using suitable starting
materials.
addition of NH OHؒHCl (2.09 g, 30 mmol) and NaOH (1.4 g,
2
3
5 mmol). The resulting mixture was vigorously stirred at room
temperature until all the solids dissolved. The organic layer
was separated and the aqueous phase was extracted with
EtOAc. The combined organic layer was dried over MgSO and
4
evaporated under reduced pressure to give a residue, which was
chromatographed (EtOAc–hexane 4:1 v/v) to give 2a (1.04 g,
2
2
6
1%) as a white solid, mp 110–112 ЊC; [α]D ϩ 29.3 (c 0.05,
1
CHCl ); the major (E-form) isomer in mixture: H NMR δ 7.86
3
(
5
br s, 1H), 7.35 (d, J 7.2 Hz, 1H), 5.76 (m, 1H), 5.26 (m, 1H),
.24 (m, 1H), 4.52 (dd, 1H, J 9, 8.5 Hz), 4.45 (ddd, J 9, 7.2, 5
Hz, 1H), 4.20 (dd, 1H, J 8.5, 5 Hz), 4.10 (m, 1H), 3.64 (m, 1H).
1
The minor (Z-form) isomer in mixture: H NMR δ 8.10 (br s,
1
(
6
H), 6.91 (d, 1H, J 5.5 Hz), 5.79 (m, 1H), 5.27 (m, 2H), 5.01
ddd, J 9, 6, 5.5 Hz, 1H), 4.57 (t, 1H, J 9 Hz), 4.14 (dd, 1H, J 9,
Hz), 4.12 (m, 1H), 3.68 (m, 1H).
2
b. Obtained from 1b in 57% yield as a white solid when
chromatographed (EtOAc–hexane 4:1 v/v), mp 76–78 ЊC;
22
[
α] ϩ26.1 (c 0.02, CHCl ); the major (E-form) isomer in
D 3
1
Experimental
H NMR, C NMR, NOE, COSY, NOESY and HMQC
spectra were recorded on a Varian Unity INOVA 500 (500
MHz) spectrometer for samples in CDCl using SiMe (TMS)
as internal standard. Optical rotations were recorded on a
mixture: H NMR δ 7.84 (br s, 1H), 7.32 (d, 1H, J 7.0 Hz),
5.14 (m, 1H), 4.53 (dd, 1H, J 9.0, 8.8 Hz), 4.45 (ddd, 1H, J 9.0,
7.0, 5.0 Hz), 4.21 (dd, 1H, J 8.8, 5.0 Hz), 4.12 (dd, 1H, J 15.0,
6.0 Hz), 3.82 (dd, 1H, J 15.0, 8.0 Hz), 1.73 (s, 3H), 1.64 (s, 3H);
1
13
3
4
13
C NMR δ 157.48 (s, C᎐O), 147.60 (d), 139.01 (s), 117.30
᎐
Horiba SEPA-300 polarimeter. [α] -values are given in units of
(d), 65.40 (t), 54.71 (d), 40.84 (t), 25.70 (q), 17.63 (q). The minor
(Z-form) isomer in mixture: H NMR δ 8.09 (br s, 1H), 6.94 (d,
D
Ϫ1
2
Ϫ1
1
1
0
deg cm g . MS and HRMS were measured on a JEOL
JMS-700 spectrometer using EI and FAB modes. Diethyl ether
was refluxed and distilled from sodium. Dichloromethane
was refluxed and distilled from CaH2 under nitrogen. All
commercially available reagents were used without further
purification. Chromatography was carried out on Merck
J 5.5 Hz, 1H), 5.16 (m, 1H), 4.57 (t, 1H, J 9.0 Hz), 4.98 (ddd,
1H, J 9.0, 6.0, 5.5 Hz), 4.17 (dd, J 9.0, 6.0 Hz, 1H), 4.12 (dd,
1H, J 15.0, 6.0 Hz), 3.83 (dd, 1H, J 15.0, 8.0 Hz), 1.75 (s, 3H),
13
1.68 (s, 3H); C NMR δ 157.69 (s, C᎐O), 148.50 (d), 139.14 (s),
᎐
117.36 (d), 64.81 (t), 51.00 (d), 42.36 (t), 25.63 (q), 18.25 (q);
Scheme 3
Fig. 2 The key NOE (%) enhancements of 4b, 4c and 10a and NOESY interaction of 8a (m: medium; w: weak).
J. Chem. Soc., Perkin Trans. 1, 2001, 452–456
4
54

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HRMS-EI Calc. for C H N O (M), 198.1003. Found: M,
The reaction mixture was warmed to room temperature
9
14
2
3
1
98.1006.
and then partitioned between EtOAc (10 ml) and saturated aq.
potassium sodium tartrate (5 ml). Vigorous stirring was con-
tinued until all the solids dissolved. The organic layer was
2
c. Obtained from 1c in 56% yield as a white solid when
chromatographed (EtOAc–hexane 4:1 v/v), mp 89–92 ЊC;
separated, and dried over MgSO . Evaporation of EtOAc
under reduced pressure gave a residue; this, and N-methyl-
hydroxylamine hydrochloride (323 mg, 3 mmol), were dissolved
4
22
[
α] ϩ23.4 (c 0.1, CHCl ); the major (E-form) isomer in
D
3
1
mixture: H NMR δ 7.83 (br s, 1H), 7.36 (d, 1H, J 7.0 Hz),
5
8
6
.67 (m, 1H), 4.99 (m, 1H), 4.97 (m, 1H), 4.54 (dd, 1H, J 9.0,
.5 Hz), 4.47 (ddd, 1H, J 8.5, 7.0, 6.0 Hz), 4.23 (dd, 1H, J 9.0,
.0 Hz), 3.39 (t, 2H, J 7.4 Hz), 2.21 (m, 1H), 2.19 (m, 1H);
in 90% aq. EtOH (8 ml). NaHCO (378 mg, 4.5 mmol) was
added and the resulting mixture was heated under reflux for
6 h. Removal of EtOH gave a residue, which was extracted with
3
1
3
C NMR δ 158.20 (s, C᎐O), 147.20 (d), 134.39 (d), 117.00 (t),
EtOAc. The combined organic layer was dried over MgSO and
᎐
4
6
5.32 (t), 54.90 (d), 46.75 (t), 34.29 (t). The minor (Z-form)
evaporated under reduced pressure. The residue was purified by
chromatography (EtOAc–EtOH 8:1 v/v) to give products 7a
(129 mg, 70%) and 8a (18 mg, 10%) as white solids. 7a: mp 113–
1
isomer in mixture: H NMR δ 8.15 (br s, 1H), 6.90 (d, 1H, J 5.6
Hz), 5.64 (m, 1H), 5.07 (ddd, 1H, J 9.0, 6.0, 5.6 Hz), 4.97 (m,
2
3
22
1
H), 4.61 (dd, 1H, J 9.0, 8.8 Hz), 4.15 (dd, 1H, J 9.0, 6.0 Hz),
114 ЊC; [α]D Ϫ72.5 (c 0.07, CHCl ); H NMR δ 4.56 (dd, J 9.5,
3
13
.37 (m, 2H), 2.24 (m, 1H), 2.18 (m, 1H); C NMR δ 158.62
8 Hz, 1H), 4.33 (dd, 1H, J 9.5, 2.5 Hz), 4.18 (dd, J 12.0, 9.0 Hz,
1H), 4.16 (dd, 1H, J 9.5, 6.5 Hz), 3.78 (ddd, 1H, J 8.0, 6.5,
2.5 Hz), 3.74 (dd, 1H, J 9.5, 2.0 Hz), 3.51 (dd, 1H, J 9.0,
6.5 Hz), 3.43 (ddddd, 1H, J 9.0, 9.0, 6.5, 6.0, 2.0 Hz), 3.03 (dd,
(
s, C᎐O), 147.83 (d), 134.52 (d), 117.65 (t), 65.80 (t), 51.00
᎐
(
d), 46.23 (t), 33.51 (t); HRMS-EI Calc. for C H N O (M),
8
12
2
3
ϩ
1
84.0847. Found: M 184.0852.
13
J 12.0, 6.0 Hz, 1H), 2.65 (s, 3H); C NMR δ 160.69 (C᎐O),
General procedure for IOOC leading to isoxazolidines 4a–c
78.45 (d), 71.11 (t), 67.27 (t), 60.87 (d), 51.96 (t), 47.93 (d),
ϩ
4
4.82 (q); MS-EI (m/z, %) 184 (M , 20), 140 (68), 98 (13), 85
A mixture of 2a (0.85 g, 50 mmol) and silica gel (60 PF254; 3 g)
was placed on a Pyrex plate with a cover. The Pyrex plate con-
taining the reaction mixture was put in a microwave oven
and irradiated for 12 min as required to complete the reaction.
The mixture was eluted with EtOAc. After removal of EtOAc,
the residue was chromatographed (EtOAc–EtOH 4:1 v/v) to
give 4a (0.7 g, 82%) as a white solid which was identified as
(
100), 84 (87); HRMS-EI Calc. for C H N O (M), 184.0847.
8 12 2 3
ϩ
Found: M , 184.0849. Calc. for C H N O : C, 52.15; H, 6.57;
8
12
2
3
N, 15.21. Found: C, 52.34; H, 6.72; N, 15.17%). 8a: mp 81–
22
1
8
3 ЊC; [α]D ϩ37.6 (c 0.05, CHCl ); H NMR δ 4.65 (ddd, 1H,
3
J 6.0, 4.8, 4.2 Hz), 4.58 (t, 1H, J 9.0 Hz), 4.16 (dd, 1H, J 9.0,
7
4
2
.8 Hz), 3.99 (ddd, 1H, J 9.0, 7.8, 4.8 Hz), 3.73 (dd, 1H, J 13.8,
.8 Hz), 3.22 (dd, 1H, J 13.8, 4.2 Hz), 3.18 (t, J 4.8 Hz, 1H),
7
being consistent with the previously reported compound. Mp
.65 (s, 3H), 2.32 (ddd, 1H, J 12.6, 6.0, 4.8 Hz), 1.88 (d, 1H,
2
3
1
1
11–113 ЊC; [α] Ϫ69.7 (c 0.5, CHCl ); H NMR δ 5.22 (s, 1H),
D
3
13
J 12.6 Hz); C NMR δ 158.88 (C᎐O), 73.46 (d), 66.54 (d), 66.37
4
.58 (dd, 1H, J 9.5, 8.0 Hz), 4.34 (dd, J 9.5, 3.0 Hz, 1H), 4.17
(
(
t), 57.83 (d), 49.96 (t), 47.38 (q), 26.28 (t); MS-EI (m/z, %) 184
(
dd, 1H, J 12.0, 9.0 Hz), 4.00 (dd, 1H, J 9.5, 1.2 Hz), 3.96 (dd,
ϩ
M , 34), 169 (10), 149 (32), 140 (31), 128 (52), 94 (95), 84 (100);
J 9.0, 6.0 Hz, 1H), 3.76 (ddd, 1H, J 8.0, 6.0, 3.0 Hz), 3.51 (dd,
ϩ
HRMS-EI Calc. for C H N O (M); 184.0847. Found: M ,
8
12
2
3
1
2
H, J 9.5, 6.5 Hz), 3.32 (ddddd, J 9.0, 9.0, 7.0, 6.5, 1.2 Hz, 1H),
13
1
84.0852.
.94 (dd, 1H, J 12.0, 7.0 Hz); C NMR δ 160.74 (s, C᎐O), 76.76
(
t), 71.64 (d), 67.46 (t), 63.61 (d), 51.65 (t), 49.43 (d).
7
b. 7b (166 mg, 64%) and 8b (34 mg, 13%) were obtained as
white solids from 3a and N-benzylhydroxylamine hydrochloride
following method A. Chromatography (EtOAc–hexane 2:1 v/v)
4
b. Obtained from 2b in 80% yield as a white solid following
the general procedure when chromatographed (EtOAc–EtOH
:1 v/v), mp 97–99 ЊC; [α]D Ϫ63.2 (c 1.3, CHCl ); H NMR
3
δ 5.19 (s, 1H), 4.53 (t, 1H, J 8.8 Hz), 4.27 (dd, 1H, J 8.8, 3.7
Hz), 3.94 (ddd, 1H, J 8.8, 5.1, 3.7 Hz), 3.79 (dd, 1H, J 12.1, 8.5
Hz), 3.36 (dd, 1H, J 8.8, 5.1 Hz), 3.26 (dd, 1H, J 12.1, 7.0 Hz),
.05 (td, 1H, J 7.0, 8.5 Hz), 1.34 (s, 3H), 1.28 (s, 3H); C NMR
δ 161.14 (s, C᎐O), 81.08 (s), 73.50 (d), 67.25 (t), 65.27 (d),
4.59 (t), 50.11 (d), 29.07 (q), 24.17 (q); HRMS-EI Calc. for
22
1
gave 7b: mp 145–146 ЊC; [α]D Ϫ69.1 (c 0.1, CHCl ); H NMR
23
1
3
4
δ 7.29–7.34 (m, 5H), 4.59 (dd, J 9.2, 8.0 Hz, 1H), 4.35 (d, 1H,
J 11.5 Hz), 4.36 (dd, 1H, J 9.2, 2.5 Hz), 4.21 (dd, 1H, J 12.0,
9
3
3
2
1
6
.0 Hz), 4.15 (dd, 1H, J 9.5, 7.0 Hz), 3.73 (d, 1H, J 11.5 Hz),
.79 (ddd, 1H, J 8.0, 6.5, 2.5 Hz), 3.75 (dd, J 9.5, 2.0 Hz, 1H),
.54 (dd, 1H, J 9.0, 6.5 Hz), 3.44 (ddddd, 1H, J 9.0, 9.0, 7.0, 6.0,
.0 Hz), 3.07 (dd, 1H, J 12.0, 6.0 Hz); C NMR δ 160.42 (C᎐O),
35.48 (s), 129.25 (d), 128.75 (d), 128.17 (d), 77.54 (d), 71.01 (t),
13
3
᎐
13
5
ϩ
C H N O (M), 198.1003. Found: M , 198.0998. Calc. for
9
14
2
3
6.35 (t), 62.54 (t), 61.87 (d), 49.96 (t), 47.91 (d); MS-EI
C H N O : C, 54.52; H, 7.12; N, 14.14. Found: C, 54.762;
9
14
2
3
ϩ
(
m/z, %) 260 (M , 24), 140 (56), 91 (21), 85 (100), 84 (83);
H, 7.34; N, 14.17%.
ϩ
HRMS-EI Calc. for C H N O (M), 260.1160. Found: M ,
14
16
2
3
2
60.1164. Calc. for C H N O : C, 64.59; H, 6.20; N, 10.77.
14 16 2 3
4
c. Obtained from 2c in 77% yield as a white solid following
Found: C, 64.47; H, 6.09; N, 10.72%. 8b: mp 105–107 ЊC;
the general procedure when chromatographed (EtOAc–EtOH
:1 v/v), mp 75–76 ЊC; [α]D Ϫ31.3 (c 0.7, CHCl ); H NMR
3
δ 5.20 (s, 1H), 4.57 (dd, 1H, J 9.0, 8.0 Hz), 4.29 (dd, 1H, J 9.0,
.1 Hz), 4.05 (dd, 1H, J 9.5, 1.5 Hz), 3.89 (ddd, 1H, J 8.8, 8.0,
.1 Hz), 3.82 (dd, 1H, J 8.8, 4.8 Hz), 3.75 (ddd, 1H, J 13.6, 11.5,
.8 Hz), 3.57 (dd, 1H, J 9.5, 7.0 Hz), 3.20 (ddd, 1H, J 13.6, 4.8,
.2 Hz), 3.11 (ddddd, J 7.0, 4.8, 4.8, 4.2, 1.5 Hz, 1H), 2.08
m, 1H), 1.74 (m, 1H); C NMR δ 161.31 (s, C᎐O), 74.56 (t),
2.97 (d), 66.52 (t), 62.74 (d), 48.46 (d), 40.18 (t), 31.02 (t);
2
2
1
[
α] ϩ34.5 (c 0.04, CHCl ); H NMR δ 7.30–7.33 (m, 5H), 4.51
23
1
D
3
4
(
ddd, J 6.0, 5.0, 4.2 Hz, 1H), 4.38 (t, 1H, J 9.0 Hz), 4.32 (d, 1H,
J 12.0 Hz), 4.02 (dd, 1H, J 9.0, 7.5 Hz), 3.84 (ddd, 1H, J 9.0,
.5, 4.8 Hz), 3.75 (d, 1H, J 12.0 Hz), 3.64 (dd, 1H, J 13.6, 5.0
Hz), 3.16 (dd, J 13.6, 4.2 Hz, 1H), 3.11 (dd, 1H, J 5.0, 4.8 Hz),
7
7
4
4
(
7
7
13
2
,25 (ddd, 1H, J 12.6, 6.0, 5.0 Hz), 1.86 (d, J 12.6 Hz, 1H);
C
NMR δ 159.12 (C᎐O), 135.23 (s), 129.21 (d), 128.87 (d), 128.31
13
᎐
(
d), 72.98 (d), 66.46 (d), 66.18 (t), 62.47 (t), 58.03 (d), 50.06 (t),
ϩ
2
1
7.12 (t); MS-EI (m/z, %) 260 (M , 30), 204 (52), 169 (11),
ϩ
HRMS-EI Calc. for C H N O (M), 184.0847. Found: M ,
84.0848.
8
12
2
3
49 (28), 140 (34), 94 (89), 84 (100); HRMS-EI Calc. for
1
ϩ
C H N O (M), 260.1160. Found: M , 260.1157.
14
16
2
3
General procedure for reduction of 1a and INC leading to
isoxazolidines 7a,b and 8a,b
Method B. To a solution of 1a (185 mg, 1 mmol) in dry
CH Cl2 (7 ml) at Ϫ78 ЊC under nitrogen was added drop-
2
Method A. To a solution of 1a (185 mg, 1 mmol) in dry
CH Cl (7 ml) at Ϫ78 ЊC under nitrogen was added dropwise
DIBAL-H (1.0 M in hexane; 1.6 ml). After stirring of the
wise DIBAL-H (1.0 M in hexane; 1.6 ml). After stirring of the
mixture for 2 h at Ϫ78 ЊC, MeOH (0.5 ml) was added.
The reaction mixture was warmed to room temperature and
then partitioned between EtOAc (10 ml) and saturated aq.
2
2
mixture for 2 h at Ϫ78 ЊC, MeOH (0.5 ml) was added.
J. Chem. Soc., Perkin Trans. 1, 2001, 452–456
455

View Article Online
potassium sodium tartrate (5 ml). Vigorous stirring was con-
tinued until all the solids dissolved. The organic layer was
10b. Obtained in 81% yield as a white solid from 1a and N-
benzylglycine ethyl ester following the general procedure.
separated, and dried over MgSO . Evaporation of EtOAc
under reduced pressure gave a residue; this, and N-methyl-
Chromatography (EtOAc–hexane 2:1 v/v) gave 10b, mp 162–
4
22
1
164 ЊC; [α]D Ϫ24.9 (c 0.3, CHCl ); H NMR δ 7.30–7.35 (m,
3
hydroxylamine hydrochloride (323 mg, 3 mmol), were dissolved
5H), 4.62 (dd, 1H, J 8.5, 2.5 Hz), 4.40 (dd, 1H, J 9.0, 8.5 Hz),
4.34 (d, 1H, J 11.5 Hz), 4.19 (dd, 1H, J 9.0, 2.5 Hz), 4.16 (q, 2H,
J 7.0 Hz), 3.98 (dd, J 12.0, 8.8 Hz, 1H), 3.75 (d, 1H, J 11.5 Hz),
3.72 (ddd, 1H, J 8.5, 6.0, 2.5 Hz), 3.41 (dd, 1H, J 9.0, 6.0 Hz),
3.07 (dd, 1H, J 12.0, 6.5 Hz), 2.97 (ddddd, 1H, J 9.0, 8.8, 7.0,
6.5, 2.0 Hz), 2.72 (ddd, J 9.5, 8.5, 2.5 Hz, 1H), 2.38 (ddd, 1H,
in CH Cl2 (10 ml) followed by the addition of NaHCO3
2
(
504 mg, 6 mmol) and silica gel (60 PF254; 5 g). The resulting
mixture was carefully mixed, and evaporated by a rotary
vacuum evaporator. The reaction mixture was placed in a Pyrex
plate with a cover and then irradiated in a microwave oven for
13
1
5 min to complete the reaction. The mixture was eluted with
J 9.5, 2.5, 2.0 Hz), 1.30 (t, 3H, J 7.0 Hz); C NMR δ 170.34 (s,
C᎐O), 160.37 (s, C᎐O), 135.40 (s), 129.17 (d), 128.69 (d), 128.21
(d), 77.92 (d), 66.54 (t), 62.46 (t), 61.94 (d), 59.02 (t), 55.48 (d),
50.17 (t), 48.02 (d), 28.57 (t), 14.95 (q); MS-FAB (m/z, %) 331
EtOAc. After removal of EtOAc, the residue was chromato-
graphed (EtOAc–EtOH 8:1 v/v) to give only the isoxazolidine
7
a (151 mg, 82%), which was consistent with the previously
ϩ
ϩ
ϩ
described compound.
(MH , 67), 330 (M , 36), 329 (M Ϫ 1, 42); HRMS-FAB Calc.
ϩ
for C H N O ϩ H (MH ), 331.165. Found: m/z, 331.1658.
18
22
2
4
7
b. Obtained in 79% yield from 3a and N-benzylhydroxyl-
amine hydrochloride following method B. Chromatography
EtOAc–hexane 2:1 v/v) gave 7b consistent with the previously
Acknowledgements
We are thankful to Mrs Teiko Yamada for measuring NMR
and MS spectra.
(
described compound.
Reduction of 1a and INC in sealed tube leading to isoxazolidines
7
a and 8a
References
The crude aldehyde (116 mg, 0.75 mmol), prepared following
the above reduction procedure, and N-methylhydroxylamine
hydrochloride (242 mg, 2.25 mmol) were dissolved in 90% aq.
EtOH (6 ml). NaHCO (283 mg, 3.37 mmol) was added and the
mixture was heated in a sealed tube under nitrogen at 120–
1
For recent reviews: (a) J. J. Tufariello, in 1,3-Dipolar Cycloaddition
Chemistry, ed. A. Padwa, Wiley, New York, 1984, pp. 83–168;
(
b) A. Padwa and A. M. Schoffstall, Advances in Cycloaddition,
3
ed. D. Curran, JAI Press, Greenwich, CT, 1990, pp. 2–28; (c) S. E.
Denmark and A. Thorarsensen, Chem. Rev., 1996, 96, 137 and
references cited therein; (d) W. Carruthers, Cycloaddition Reactions
in Organic Synthesis, ed. J. E. Baldwin and P. D. Magnus, Tetrahedron
Organic Chemistry Series, Pergamon Press, Oxford, 1990, vol. 8,
pp. 296–313.
1
25 ЊC for 6 h. Opening the sealed tube and removal of EtOH
gave a residue, which was extracted with EtOAc. The combined
organic layer was dried over MgSO and evaporated under
reduced pressure. The residue was purified by chromatography
4
2
(a) A. Hassner and R. Maurya, Tetrahedron Lett., 1989, 30, 2289;
(
EtOAc–EtOH 8:1 v/v) to give products 7a (99 mg, 72%) and
(
b) A. Hassner, R. Maurya, A. Padwa and W. H. Bullock, J. Org.
8
a (15 mg, 11%).
Chem., 1991, 56, 2775; (c) A. Hassner, R. Maurya, O. Friedman,
H. E. Gottlieb, A. Padwa and D. Austin, J. Org. Chem., 1993, 58,
4539; (d) M. Noguchi, H. Okada, S. Nishimura, Y. Yamagata,
S. Takamura, M. Tanaka, A. Kakeihi and H. Yamamoto, J. Chem.
Soc., Perkin Trans. 1, 1999, 185.
3 (a) A. Loupy, A. Petit, J. Hamelin, F. Texier-Boullet, P. Jacquault
and D. Math, Synthesis, 1998, 1213; (b) S. Kasmi, J. Hamelin and
H. Benhaoua, Tetrahedron Lett., 1998, 39, 8093; (c) P. M. Bendale
and B. M. Khadilkar, Synth. Commun., 2000, 30, 1713;
General procedure for reduction of 1a and [2 ؉ 3]cycloaddition
leading to cycloadducts 10a,b
To a solution of 1a (185 mg, 1 mmol) in dry CH Cl (7 ml) at
2
2
Ϫ78 ЊC under nitrogen was added dropwise DIBAL-H (1.0 M
in hexane; 1.6 ml). After stirring of the mixture for 2 h at
Ϫ78 ЊC, MeOH (0.5 ml) was added. The reaction mixture was
warmed at room temperature and then partitioned between
EtOAc (10 ml) and saturated aq. potassium sodium tartrate
(
d) M. Gianotti, G. Martelli, G. Spunta, E. Campana, M. Panunzio
and M. Mendozza, Synth. Commun., 2000, 30, 1725.
H. Kaddar, J. Hamelin and H. Benhaoua, J. Chem. Res. (S), 1999,
4
(
5 ml). Vigorous stirring was continued until all the solids
718.
dissolved. The organic layer was separated, and dried over
MgSO . Evaporation of EtOAc under reduced pressure gave a
residue, and this and sarcosine ethyl ester (176 mg, 1.5 mmol)
were dissolved in CH Cl (5 ml) followed by addition of silica
gel (60 PF254; 3 g). The resulting mixture was carefully mixed,
and evaporated by rotary vacuum evaporator. The reaction
mixture was placed on a Pyrex plate with a cover and then
irradiated in a microwave oven for 15 min to complete the
reaction. The mixture was eluted with EtOAc. After removal of
EtOAc, the residue was chromatographed (EtOAc–hexane 2:1
v/v) to give product 10a (200 mg, 79%) as a white solid, mp
5 (a) R. J. Bernacki and W. Korytnyk, Cancer Metastatis Rev., 1985,
4
, 81; (b) G. Casiraghi and F. Zanardi, Chem. Rev., 1995,
5, 1677; (c) Y. Chen and P. Vogel, J. Org. Chem., 1994, 59, 2487;
4
9
(
d) K. Koide, M. E. Bunnage, L. G. Paloma, J. R. Kanter, S. S.
2
2
Taylor, L. L. Brunton and K. C. Nicolaou, Chem. Biol., 1995, 2,
601.
6 (a) G. W. J. Feelt and P. W. Smith, Tetrahedron Lett., 1985, 26,
1469; (b) H. Setoi, J, H. Kayakiri, H. Tekeno and M. Hashimoto,
Chem. Pharm. Bull., 1987, 35, 3995; (c) D. K. Thompson,
C. N. Hubert and R. H. Wightman, Tetrahedron, 1993, 49, 3827;
(
3
d) S. E. Denmark and L. R. Marcin, J. Org. Chem., 1993, 58,
857; (e) M. S. Vissor, N. M. Heron, M. T. Didiuk, J. F. Sagal and
A. H. Hoveyda, J. Am. Chem. Soc., 1996, 118, 4291; ( f ) K. Asano,
T. Hakogi, S. Iwama and S. Katsumura, Chem. Commun., 1999, 41.
7 (a) E. Falb, Y. Bechor, A. Nudelman, A. Hassner, A. Albeck and
H. E. Gottlieb, J. Org. Chem., 1999, 64, 498; (b) A. Hassner,
E. Falb, A. Nudelman, A. Albeck and H. E. Gottlieb, Tetrahedron
Lett., 1994, 35, 2397.
2
2
1
1
23–125 ЊC; [α] Ϫ21.4 (c 0.8, CHCl ); H NMR δ 4.57 (dd, 1H,
D
3
J 8.0, 3.0 Hz), 4.53 (t, 1H, J 8.8 Hz), 4.17 (dd, J 8.8, 3.7 Hz,
1
3
H), 4.14 (q, 2H, J 7.0 Hz), 3.94 (ddd, 1H, J 8.8, 5.5, 3.7 Hz),
.79 (dd, J 12.1, 7.0 Hz, 1H), 3.36 (dd, 1H, J 9.0, 5.5 Hz), 3.26
(
dd, 1H, J 12.1, 8.5 Hz), 3.01 (ddddd, J 9.0, 8.5, 7.0, 6.5, 2.0 Hz,
8
(a) T. K. M. Shing, D. A. Elsey and J. G. Gillhouley, J. Chem. Soc.,
Chem. Commun,, 1989, 1281; (b) T. K. M. Shing, C. H. Wong and
T. Yip, Tetrahedron: Asymmetry, 1996, 7, 1323; (c) B. Alcaide,
J. M. Alonso, M. F. Aly, E. Saez, M. P. Martinez-Alcazar and
F. Hernandez-Cano, Tetrahedron Lett., 1999, 40, 5391.
1
1
H), 2.76 (ddd, 1H, J 9.5, 8.0, 6.5 Hz), 2.67 (s, 3H), 2.44 (ddd,
H, J 9.5, 3.0, 2.0 Hz), 1.29 (t, J 7.0 Hz, 3H); C NMR δ 170.54
13
(
(
s, C᎐O), 160.75 (s, C᎐O), 76.72 (d), 67.43 (t), 61.20 (d), 59.45
t), 56.24 (d), 50.97 (t), 46.84 (d), 43.79 (q), 28.45 (t), 15.14 (q);
᎐ ᎐
ϩ
ϩ
9 (a) T. K. M. Shing, W. C. Fung and C. H. Wong, J. Chem. Soc.,
Chem. Commun., 1994, 449; (b) Y. Inoue, J. Hara and H. Kakisawa,
Chem. Lett., 1980, 1407.
10 M. Nyerges, L. Gajdics, A. Szollosy and L. Toke, Synlett, 1999,
111.
MS-FAB (m/z, %) 255 (MH , 56), 254 (M , 43); HRMS-FAB
Calc. for C H N O ϩ H (MH ), 255.1344. Found: m/z,
ϩ
12
18
2
4
2
55.1350. Calc. for C H N O : C, 56.66; H, 7.14; N, 11.02.
12 18 2 4
Found: C, 56.42; H, 6.91; N, 10.89%.
4
56
J. Chem. Soc., Perkin Trans. 1, 2001, 452–456