Stereoselective synthesis of 1-nitrobicyclo[3.1.0]hexanes and fused isoxazoline-N-oxides from primary nitro compounds

Article abstract of DOI:10.1021/jo202489v

The one-step preparation of 1-nitrobicyclo[3.1.0]hexane and bicycloisoxazoline-N-oxide was readily achieved from conjugate adducts of nitro alkenes and allylmalonates by treatment with Ag₂O and iodine under basic conditions. We observed that when a primary alkyl group was present at the β-position of the nitro group, bicyclo[3.1.0]hexane was preferentially formed, whereas if a secondary alkyl group occupied that position, isoxazoline-N-oxide was predominantly produced. High cis-selectivity was observed for the formation of cyclopentane units for both reactions. An iodomethyl adduct, considered an intermediate of the cyclization, was isolated, and its conversion to isoxazoline-N-oxide was successfully achieved. The isoxazoline-N-oxide underwent 1,3-dipolar cycloaddition with alkenes to yield tricycloheterocyclic compounds, which were readily converted to spirolactam in good yield by reductive cleavage of N-O bonds using Raney-Ni. On the other hand, 1,3-dipolar cycloaddition of the isoxazoline-N-oxide to terminal alkynes yielded tricyclic aziridines stereoselectively.

Full text of DOI:10.1021/jo202489v

Article
pubs.acs.org/joc
Stereoselective Synthesis of 1-Nitrobicyclo[3.1.0]hexanes and Fused
Isoxazoline-N-oxides from Primary Nitro Compounds
Akio Kamimura,*,† Ryota Takeuchi,† Kosuke Ikeda,† Takaaki Moriyama,† and Michinori Sumimoto‡
†Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Ube 755-8611, Japan
‡Department of Material Chemistry, Graduate School of Science and Engineering, Yamaguchi University, Ube 755-8611, Japan
S
* Supporting Information
ABSTRACT: The one-step preparation of 1-nitro-
bicyclo[3.1.0]hexane and bicycloisoxazoline-N-oxide was read-
ily achieved from conjugate adducts of nitro alkenes and
allylmalonates by treatment with Ag2O and iodine under basic
conditions. We observed that when a primary alkyl group was
present at the β-position of the nitro group, bicyclo[3.1.0]hexane was preferentially formed, whereas if a secondary alkyl group
occupied that position, isoxazoline-N-oxide was predominantly produced. High cis-selectivity was observed for the formation of
cyclopentane units for both reactions. An iodomethyl adduct, considered an intermediate of the cyclization, was isolated, and its
conversion to isoxazoline-N-oxide was successfully achieved. The isoxazoline-N-oxide underwent 1,3-dipolar cycloaddition with
alkenes to yield tricycloheterocyclic compounds, which were readily converted to spirolactam in good yield by reductive cleavage
of N−O bonds using Raney-Ni. On the other hand, 1,3-dipolar cycloaddition of the isoxazoline-N-oxide to terminal alkynes
yielded tricyclic aziridines stereoselectively.
describe the details of the cyclopropanation of malonate-
derived precursors and the preparation of 1-nitrobicyclo[3.1.0]-
hexanes stereoselectively. The chemoselectivity of the isoxazo-
line-N-oxide/cyclopropane depended on the substituent at the
adjacent position of the nitro group. During the investigation,
we observed that the formation of bicyclic isoxazoline-N-oxide
occurred through O-alkylation of the nitronate anion of an
iodomethyl intermediate rather than through C-alkylation.9 A
convenient method to prepare tricycloheterocyclic compounds
via 1,3-dipolar cycloaddition of the isoxazoline-N-oxides to
alkenes or alkynes is also demonstrated.10
INTRODUCTION
■
Recently, domino reactions have been attracting attention in
the field of organic synthesis because they provide a convenient
and economical method to prepare desired organic molecules.1
Domino reactions afford two or more bonds continuously
under single reaction conditions, and the latter bond formation
occurs as a result of the former bond formation reaction.
Therefore, it reduces the experimental manipulation and
enhances synthetic efficiency. Cyclopropanes are recognized
as an important class of organic compounds because of their
unique biological activities. Preparation of fused cyclopropanes
has been of interest because they exhibit interesting biological
activity. The total synthesis of fused cyclopropanes such as
indolizomycin,2 trovafloxacin,3 duocarmycin, and CC-10654 has
been achieved. To prepare these structures, the Kulinkovich
reaction, in which low valence titanium plays an important role,
provides a useful method.5,6 Recently, we discovered a new
synthetic method to prepare fused cyclopropanes by a one-pot
reaction from primary nitro compounds, which underwent a
domino process involving single electron oxidation of the α-
nitro anion, radical cyclization, and an intramolecular SN2
reaction.7 Using this strategy, aza- and oxa-bicyclo[3.1.0]-
hexanes were prepared in a highly stereoselective manner. The
precursors of the reaction were readily prepared by the
conjugate addition reaction of amides or alkoxides to nitro
alkenes. Thus, this method provided a convenient way to
synthesize these compounds. In order to enhance the synthetic
utilities of this methodology, we examined the reaction for the
conjugate adducts of nitroalkenes with carbon nucleophiles
such as malonate derivatives. It was previously reported that a
similar process of primary nitro compounds driven by CAN
gave isoxazoline-N-oxides exclusively.8 In this paper, we
RESULTS AND DISCUSSION
■
Cyclization precursors 1 were prepared by the conjugate
addition of allylmalonate derivatives to nitro alkenes (Scheme 1).
The results are summarized in Table 1.
a
Scheme 1
a
Reagents and conditions: (i) t-BuOK, THF, −30 °C.
The conjugate addition occurred smoothly in the presence of
t-BuOK as a base to give the desired precursors 1a−1l in good
yields. For example, the conjugate addition of dimethyl
Received: December 4, 2011
Published: January 27, 2012
© 2012 American Chemical Society
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Article
exhibited a characteristic peak at approximately 120 ppm in 13
C
Table 1. Preparation of Cyclization Precursors
NMR and 1660 cm−1 in IR spectra, both of which suggested
that the side product 3a contained a CN double bond in an
isoxazoline ring. Compound 3a was somewhat less stable
because it decomposed during recrystallization in an alcoholic
solvent. The structure was confirmed by the result that
compound 3 underwent the 1,3-dipolar cycloaddition to give
tricyclic compounds (vide infra). The side product 3a also
contained only single diastereomer and was formed stereo-
selectively.
Nitro compounds such as 1b, 1d, 1e, 1f, 1i, and 1k, in which
a nonbulky primary alkyl substituent occupies the R2 position,
afforded similar results; cyclopropanes 2 were isolated as the
main products, and side products 3 were obtained in approxi-
mately 20% yields (Table 2, entries 2, 4, 5, 6, 9, and 11). These
products consisted of single diastereomers, indicating that the
transformation occurred in a highly stereoselective manner.
Compound 1h, which possesses an aromatic substituent at the
R2 position, also gave the corresponding cyclopropane 2h in
moderate yield but with a lower stereoselectivity than that of
the other compounds that contain nonbulky groups at the R2
position (Table 2, entry 8). On the other hand, isoxazoline-
N-oxide 3 was formed as the major product when the nitro
compounds 1c, 1g, and 1j, all of which attached a bulky
secondary alkyl group at the R2 position, were treated under
the same reaction conditions, although the formation of
bicyclo[3.1.0]hexane 2c, 2g, and 2j in small amounts was
observed (Table 2, entries 3, 7, and 10). Using a malononitrile
precursor 1l gave the corresponding 2l and 3l; however, the
yields remained in a low level (Table 2, entry 12).
a
entry
R1
R2
1
yield (%)
1
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CN
Et
1a
1b
1c
1d
1e
1f
88
92
98
100
94
94
98
51
91
89
93
89
2
nPr
3
iPr
4
n-C4H9
n-C5H11
n-C6H13
c-C6H11
Ph
5
6
7
1g
1h
1i
8
9
Et
10
11
12
iPr
1j
n-C5H11
n-C5H11
1k
1l
a
Isolated yields.
allylmalonate to 1-nitrobutene proceeded smoothly in the
presence of t-BuOK, providing compound 1a in 88% yield
(Table 1, entry 1). The procedure was easily performed, and
most of compounds 1 were isolated in almost quantitative
yields.
We then examined the cyclopropanation of 1. Treatment of
1 with Ag2O and iodine in the presence of DBU resulted in a
smooth consumption of 1, and the desired bicyclo[3.1.0]hexane
2 was isolated in good yields (Scheme 2). The results are
summarized in Table 2.
a
Scheme 2
The stereochemistry of bicyclo[3.1.0]hexane 2 was deter-
mined by X-ray crystallographic analyses. Compound 2d, which
was isolated as a single isomer, gave a good crystal, which
verified the configuration unambiguously. Other compounds 2
exhibited NMR patterns similar to those of compound 2d. X-
ray crystallographic analysis for 2h clearly indicated a fused
cyclopropane structure with an identical configuration.
a
Reagents and conditions: (i) DBU (1.2 equiv), Ag2O (2.0 equiv), I2,
(2.0 equiv), THF, rt, 4h.
Isoxazoline-N-oxide 3 was readily converted to correspond-
ing hydroxylketone without epimerization at chiral centers. For
example, treatment of 3b with an aqueous HCl in MeOH gave
4b in 50% yield as a single diastereomeric isomer (Scheme 3).
Table 2. Cyclopropanation or Nitrone Formation of Nitro
Compounds 1
a
a
entry
R1
R2
1
2; yield (%)
3; yield (%)
b
c
1
CO2Me Et
1a
1b
1c
1d
1e
1f
2a; 72 (1/99)
2b; 60 (1/99)
3a; 23 (1/99)
3b; 19 (1/99)
a
Scheme 3
b
c
2
CO2Me nPr
b
b
c
3
CO2Me iPr
2c; 16 (1/99)
3c; 80 (1/99)
3d; 25 (1/99)
c
4
CO2Me n-C4H9
CO2Me n-C5H11
CO2Me n-C6H13
CO2Me c-C6H11
CO2Me Ph
2d; 61 (1/99)
b
c
5
2e; 51 (1/99)
3e; 17 (1/99)
b
c
6
2f; 60 (1/99)
2g; 16 (1/99)
3f; 12 (1/99)
b
c
7
1g
1h
1i
3g; 66 (1/99)
3h; 0
b
8
2h; 58 (16/84)
a
Reagents and conditions: (i) 1 M HCl, MeOH, rt, 48 h, 50%.
c
c
9
CO2Et
CO2Et
CO2Et
CN
Et
2i; 66 (1/99)
3i; 22 (1/99)
3j; 54 (1/99)
c
c
10
11
12
iPr
1j
2j; 31 (1/99)
c
c
n-C5H11
n-C5H11
1k
1l
2k; 64 (1/99)
3k; 19 (1/99)
The present transformation was modified to a one-pot
reaction procedure (Scheme 4). For example, dimethyl
allylmalonate and 1-nitroheptene were mixed together in the
presence of t-BuOK in THF, and the mixture was stirred
overnight at −30 °C. Then, Ag2O, I2, and DBU were added to
the mixture at room temperature, promoting the cyclization
reaction to give 2e and 3e in 42 and 22% yields, respectively. The
product ratio of 2 and 3 varied slightly compared to that of the
products obtained from the two-step preparation of 2 and 3.
There was nearly no loss in the yield by combining the two steps;
therefore, the compounds were obtained rapidly and effectively.
b
c
2l; 21 (5/95)
b
3l; 7 (1/99)
a
Isolated yields, cis/trans ratios. Determined by GC analyses.
c
Determined by NMR.
For example, primary nitro compound 1a underwent the
reaction smoothly to give 1-nitrobicyclo[3.1.0]hexane 2a in
72% yield, accompanied by a side product of isoxazoline-N-
oxide 3a in 23% yield (Table 2, entry 1). Isolated 2a contained
only one diastereomer, indicating that the stereoselectivity of
the cyclopropanation was very high. The side product 3a
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a
Scheme 4
Scheme 6
a
Reagents and conditions: (i) t-BuOK, THF, −30°C, 2 h; (ii) DBU
(1.2 equiv), Ag2O (2.0 equiv), I2 (1.7 equiv), THF, rt, 3 h.
Surprisingly, when compound 1c was treated with wet THF
under similar conditions, iodomethylcyclopentane 5 was
isolated in 65% yield (Scheme 5); compound 3c was not
a
Scheme 5
conformer B to give radical D stereoselectively. The primary
radical in D must be trapped by iodine to give iodomethyl
intermediate E. When R2 is a nonbulky primary alkyl group or
an aryl group, an intramolecular SN2 reaction by C-alkylation
occurred to give cyclopropane 2. On the other hand, with a
bulky secondary alkyl substituent at the R2 position, O-
alkylation occurs dominantly to give isoxazoline-N-oxide 3 or
its hydrolyzed product 4.
The differences between the C-alkylation and O-alkylation
reactions from E were not clear; therefore, we performed
calculations for compounds 2a, 2c, 3a, and 3c. Geometry
optimization was performed using the MP2 method. Relative
energies were estimated from an MP4(SDQ) calculation on the
optimized structures. These calculations were performed with
the Gaussian 03 program.12 For C, N, and O atoms, the 6-
311+G(2d) basis sets were employed in these calculations,
whereas for H atoms, the 6-31G basis set was used. Figure 1
a
Reagents and conditions: (i) DBU (1.2 equiv), Ag2O (2.0 equiv), I2
(2.0 equiv), THF−H2O (10−0.2 mL); (ii) DBU, THF, rt, 3 h.
detected in the reaction mixture. The reaction progressed in a
highly stereoselective manner to yield a single diastereomer of 5
in 99/1 ratio. Compound 5 was stable and provided a good
crystal suitable for X-ray crystallographic analysis, which
unambiguously revealed the configuration of 5 (Scheme 5).
This compound was considered as an intermediate of the
present cyclization that would yield a cyclopropane or
isoxazoline-N-oxide. Compound 5 was converted to isoxazo-
line-N-oxide 3c by treatment with DBU, obtained in 83% yield.
This result clearly indicated that the intramolecular SN2
reaction by the O-anion of the nitronate dominantly occurred
to yield 3c. Although we attempted to isolate a corresponding
iodomethyl intermediate from precursors 1 containing a
primary alkyl group at the R2 position, the desired iodomethyl
compounds were not isolated or observed in the reaction
mixture.
Figure 1. MP2 optimized structures of 2a, 3a, 2c, and 3c. The relative
energies (kcal/mol) calculated with the MP4(SDQ) method are in
parentheses. (a) Relative energy to 2a. (b) Relative energy to 2c.
Combining all the results obtained so far, we propose the
reaction pathway shown in Scheme 6. Initially, precursor 1 is
deprotonated in the presence of DBU to give nitronate anion
A, which is immediately oxidized by silver oxide to yield α-nitro
radical B.11 Radical B attacks the terminal carbon−carbon
double bond to give a primary alkyl radical D. During the
cyclization process, the two conformations B and C are
possible. Because the R2 group at the C2 position occupies a
pseudoequatorial position in conformer B and a pseudo-
axial position in conformer C, conformer B is favored over
conformer C, and radical cyclization dominantly occurs through
shows the optimized structures and their relative energies.
A comparison of the energies reveals that 2a is more stable
than 3a by 0.5 kcal/mol, while 3c is more stable than 2c by
1.3 kcal/mol. Therefore, when a bulky secondary alkyl group
was substituted at the R2 position, the O-alkylated product was
more thermodynamically stable than cyclopropane. On the
contrary, the cyclopropane adduct is more favorable than
isoxazoline-N-oxide when a nonbulky primary alkyl group
occupies the R2 position. This can be one of the reasons for the
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reaction undergoing O-alkylation or C-alkylation depending on
the substituent pattern in the substrate.
Alternatively, the following reaction pathway may be possible
(Scheme 7): intermediate E easily epimerizes under basic
6aB, which were readily separated by chromatographic
treatment. The configurations of 6aA, 6eA, and 6eB were
determined by X-ray crystallographic analyses. The cyclo-
addition also occurred with acrylonitrile to give 6c and 6f in
98 and 89% yield, respectively. Although the stereoselectivity ratio
of the reaction was approximately 6:4, the treatment provided an
easy three-step preparation of multicyclic heterocyclic compounds
6 from nitro alkenes and active methylene compounds.
Scheme 7
When alkynes were used as dipolarophiles, polycyclic
aziridines 7 were prepared (Scheme 9). For instance, when
a
Scheme 9
conditions to give its epimer E′. The thermodynamic stability of
the intermediates depends on the bulkiness of R2. For example,
a bulky substituent at the R2 position causes steric repulsion of
the nitro group and prefers intermediate E that has trans
configuration between the nitro group and the R2 group. As a
result, the configuration between the nitro group and the
iodomethyl group becomes cis, and O-alkylation should be
preferred, giving isoxazoline-N-oxide 3. On the other hand,
intermediate E′ contains trans configuration between the nitro
and the iodomethyl group, which enables the intramolecular
SN2 reaction by the C-nucleophile to give cyclopropane 2. An
investigation of the reason to explain the difference in
selectivity between C-alkylation and O-alkylation is in progress
in our laboratory.
Isoxazoline-N-oxides 3 are considered to be cyclic nitrones.
These compounds serve as good dipoles for 1,3-dipolar
cycloaddition,10 which has been frequently used in organic
synthesis.13,14 To enhance the synthetic utility of the present
methodology, we examined the 1,3-dipolar cycloaddition of 3
with various alkenes (Scheme 8).
a
Reagents and conditions: (i) CHCR1, toluene, 80 °C, 9 h.
3c was treated with tert-butyl acetylenecarboxylate, an
azirinoisoxazole 7a was obtained in 90% yield. Compound 7d
was formed as a single isomer, and its structure was confirmed
by X-ray crystallographic analysis. The results clearly showed
that good regio- and stereoselectivity were achieved during
cycloaddition. This formation of aziridine can be due to the
rearrangement of the cycloadduct intermediate, which was
reported by Seebach.15 Other alkynes also underwent the
cycloaddition and rearrangement reaction to give aziridinoiso-
xazole 7 in good yield in a highly regio- and stereoselective
manner.
The two isoxazolidine parts of compound 6 were reductively
cleaved using Raney-Ni. Starting with 6aA, the amino group
formed through the reduction attacked the ester group to form
spirolactam 8 in 79% yield in a single diastereomer (Scheme 10).
a
a
Scheme 8
Scheme 10
a
Reagents and conditions: (i) Raney-Ni, H2, MeOH, rt, 24 h; (ii)
reflux, MeOH, 24 h.
In conclusion, treatment of nitro compounds with a
combination use of base, Ag2O, and iodine constitutes a new
simple method for the transformation to give multicyclic
compounds in a stereoselective manner. The present method
employed a simple manipulation, and complicated heterocyclic
units were readily prepared from nitro alkenes and active
methylene compounds in three steps. Because cyclic adducts
such as fused cyclopropane and isoxazoline-N-oxide prepared
by this method are regarded as potentially useful for the
a
Reagents and conditions: (i) CH2CHR1, toluene, 80 °C, 12 h.
Heating the mixture of 3c and methyl acrylate at 80 °C
afforded the corresponding tricyclic dipolar adduct 6a in 98%
yield. Compound 6a contained two diastereomers 6aA and
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8.4, 7.4, 1.6 Hz, 1 H), 5.13 (d, J = 10.0 Hz, 1 H), 5.12 (d, J = 17.5 Hz,
1 H), 4.74 (ddd, J = 14.4, 3.4, 1.3 Hz, 1 H), 4.32 (ddd, J = 14.4, 6.6,
1.6 Hz, 1 H), 3.74 (s, 3 H), 3.70 (s, 3 H), 3.02−2.95 (m, 1 H), 2.77
(ddd, J = 14.4, 6.5, 1.0 Hz, 1 H), 2.64 (dd, J = 14.5, 8.1 Hz, 1 H),
1.68−1.15 (m, 10 H), 0.86 (t, J = 6.3 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 170.5, 170.3, 132.2, 119.7, 78.1, 61.1, 52.7, 52.6, 40.2, 38.3,
31.6, 30.0, 29.4, 27.0, 22.6, 14.1; HRMS (ESI M + H) m/z 330.1904.
Calcd for C16H28NO6 330.1917.
synthesis of heterocyclic compounds, this method provides an
effective method for the construction of multiheterocyclic com-
pounds.
EXPERIMENTAL SECTION
■
Preparation of Dimethyl 2-Allyl-2-(1-nitrobutan-2-yl)-
malonate (1a). General Procedure. Under nitrogen atmosphere,
t-BuOK (476.2 mg, 4.24 mmol) was added to a solution of dimethyl 2-
allylmalonate (884.5 mg, 5.14 mmol) in dry THF (35 mL) at room
temperature. The reaction mixture was cooled to −35 °C, and a
solution of (E)-1-nitrobut-1-ene (784.9 mg, 7.76 mmol) in dry THF
(3 mL) was added to the solution. The reaction mixture was stirred for
1 h at −35 °C. Saturated aqueous NH4Cl (50 mL) was added, and
THF was removed under reduced pressure. The aqueous residue was
extracted with EtOAc (60 mL × 3). The organic phase was dried over
Na2SO4. After filtration and concentration, the crude product was
purified by flash chromatography (silica gel/ethyl acetate−hexane 3:1)
Dimethyl 2-Allyl-2-(1-cyclohexyl-2-nitroethyl)malonate (1g).
1
Pale yellow oil: H NMR (500 MHz, CDCl3) δ 5.74 (dddd, J = 12.2,
9.8, 7.2, 1.3 Hz, 1 H), 5.14 (d, J = 9.9 Hz, 1H), 5.13 (d, J = 17.8 Hz, 1
H), 4.65 (dd, J = 14.8, 2.7 Hz, 1 H), 4.55 (ddd, J = 14.9, 7.5, 1.3 Hz, 1
H), 3.74 (s, 3 H), 3.70 (s, 3 H), 3.10 (d, J = 7.4 Hz, 1 H), 2.83 (ddd,
J = 14.4, 6.3, 1.2 Hz, 1 H), 2.66 (dd, J = 14.5, 8.5 Hz, 1 H), 1.80−1.51
(m, 5 H), 1.34−0.92 (m, 6 H); 13C NMR (126 MHz, CDCl3) δ 170.9,
170.7, 132.2, 119.7, 75.0, 60.1, 52.7, 52.7, 44.8, 38.6, 37.4, 33.0, 27.4,
27.1, 26.6, 26.0. Anal. Calcd. for C16H25NO6: C, 58.70; H, 7.70; N,
4.28. Found: C, 58.71; H, 7.55; N, 4.33.
Dimethyl 2-Allyl-2-(2-nitro-1-phenylethyl)malonate (1h).
Pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.34−7.27 (m,
3 H), 7.14−7.07 (m, 2 H), 5.72 (dddd, J = 16.8, 10.2, 8.0, 6.6 Hz, 1 H),
5.14 (dd, J = 10.0, 0.7 Hz, 1 H), 5.05 (ddd, J = 8.0, 3.1, 1.5 Hz, 1 H),
4.98 (dd, J = 13.5, 10.9 Hz, 1 H), 4.19 (dd, J = 10.9, 3.3 Hz, 1 H),
3.81 (d, J = 2.0 Hz, 3 H), 3.75 (s, 3 H), 2.56 (ddt, J = 14.5, 6.5, 1.4 Hz,
1 H), 2.28 (dd, J = 14.5, 8.0 Hz, 1 H); 13C NMR (126 MHz, CDCl3)
δ 170.2, 170.1, 134.8, 131.9, 129.0, 128.9, 128.7, 120.1, 78.4, 60.9, 53.0,
52.9, 46.8, 38.6; HRMS (ESI M + H) m/z 322.1292. Calcd for
C16H20NO6 322.1291.
1
to give 1a in 88% yield (1242.0 mg). Pale yellow oil: H NMR (500
MHz, CDCl3) δ 5.75 (dddd, J = 18.8, 9.1, 6.6, 1.2 Hz, 1 H), 5.14 (d,
J = 10.5 Hz, 1 H), 5.13 (d, J = 17.6 Hz, 1 H), 4.74 (ddd, J = 14.4, 3.2,
0.6 Hz, 1 H), 4.35 (ddd, J = 14.4, 7.0, 1.1 Hz, 1 H), 3.74 (s, 3 H), 3.71
(s, 3 H), 2.95 (dtd, J = 6.7, 3.2, 2.3 Hz, 1 H), 2.78 (ddd, J = 14.5, 6.6,
1.2 Hz, 1 H), 2.65 (ddd, J = 14.6, 8.1, 0.8 Hz, 1 H), 1.69−1.60 (m, 1
H), 1.33−1.22 (m, 1 H), 0.93 (td, J = 7.5, 1.1 Hz, 3 H); 13C NMR
(126 MHz, CDCl3) δ 170.2, 170.1, 170.0, 169.9, 132.0, 119.3, 119.3,
77.3, 60.5, 52.4, 52.4, 52.4, 52.3, 41.0, 37.8, 37.8, 22.3, 22.3, 11.0, 11.0.
Anal. Calcd. for C12H19NO6: C, 52.74; H, 7.01; N, 5.13. Found: C,
52.54; H, 6.92; N, 5.23.
Diethyl 2-Allyl-2-(1-nitrobutan-2-yl)malonate (1i). Pale yellow
1
oil: H NMR (500 MHz, CDCl3) δ 5.85−5.68 (m, 1 H), 5.20−5.07
Dimethyl 2-Allyl-2-(1-nitropentan-2-yl)malonate (1b). Pale
1
(m, 2 H), 4.77 (dd, J = 14.5, 3.1 Hz, 1 H), 4.35 (dd, J = 14.4, 7.1 Hz,
1 H), 4.25−4.14 (m, 4 H), 2.95 (ddd, J = 12.9, 6.8, 3.2 Hz, 1 H), 2.77
(ddt, J = 14.6, 6.6, 1.3 Hz, 1 H), 2.65 (dd, J = 14.6, 8.1 Hz, 1 H), 1.66
(dqd, J = 15.2, 7.6, 3.2 Hz, 1 H), 1.32−1.25 (m, 1 H), 1.28 (t, J =
7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 0.93 (t, J = 7.5 Hz, 3 H); 13C
NMR (126 MHz, CDCl3) δ 170.1, 169.9, 132.3, 119.6, 77.9, 61.9, 61.8,
60.7, 41.2, 38.1, 22.8, 14.1, 14.0, 11.5; HRMS (FAB M + H) m/z
302.1603. Calcd for C14H24NO6 302.1604.
yellow oil: H NMR (500 MHz, CDCl3) δ 5.80−5.70 (m, 1 H), 5.13
(d, J = 10.7 Hz, 2 H), 5.13 (d, J = 17.5 Hz, 2 H), 4.75 (dd, J = 14.5, 3.4
Hz, 1 H), 4.32 (dd, J = 14.4, 6.6 Hz, 1 H), 3.75 (s, 3 H), 3.71 (s, 3 H),
3.01 (dd, J = 9.3, 5.9 Hz, 1 H), 2.78 (dd, J = 14.5, 6.5 Hz, 1 H), 2.64
(dd, J = 14.5, 8.1 Hz, 1 H), 1.54−1.45 (m, 1 H), 1.40−1.17 (m, 3 H),
0.90 (t, J = 7.1 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 170.5, 170.3,
132.2, 119.6, 78.1, 61.0, 52.7, 52.6, 39.8, 38.2, 32.1, 20.2, 14.1; HRMS
(FAB M + H) m/z 288.1448. Calcd for C13H22NO6 288.1447.
Dimethyl 2-Allyl-2-(3-methyl-1-nitrobutan-2-yl)malonate
Diethyl 2-Allyl-2-(3-methyl-1-nitrobutan-2-yl)malonate (1j).
Pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 5.73 (tdd, J = 14.9, 8.6,
6.2 Hz, 1 H), 5.19−5.08 (m, 2 H), 4.73 (dd, J = 15.0, 2.8 Hz, 1 H),
4.48 (dd, J = 15.0, 7.1 Hz, 1 H), 4.27−4.11 (m, 4 H), 3.16 (dt, J =
7.0, 2.7 Hz, 1 H), 2.82 (dd, J = 14.6, 6.3 Hz, 1 H), 2.67 (dd, J = 14.6,
8.5 Hz, 1 H), 2.11 (dtd, J = 14.0, 6.9, 2.4 Hz, 1 H), 1.29 (t, J = 7.2 Hz,
3 H), 1.23 (t, J = 7.1 Hz, 3 H), 0.94 (d, J = 7.1 Hz, 3H), 0.77 (d, J =
6.9 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 170.5, 170.3, 132.1,
119.7, 74.3, 62.0, 61.8, 60.4, 44.1, 38.3, 26.5, 22.7, 16.6, 14.1, 14;
HRMS (ESI M + H) m/z 316.1762. Calcd for C15H26NO6 316.1760.
Diethyl 2-Allyl-2-(1-nitroheptan-2-yl)malonate (1k). Pale
yellow oil: 1H NMR (500 MHz, CDCl3) δ 5.83−5.70 (m, 1 H),
5.19−5.06 (m, 2 H), 4.77 (dd, J = 14.4, 3.3 Hz, 1 H), 4.32 (dd, J =
14.4, 6.8 Hz, 1 H), 4.26−4.14 (m, 4 H), 3.04−2.95 (m, 1 H), 2.77 (dd,
J = 14.6, 6.6 Hz, 1 H), 2.64 (dd, J = 14.6, 8.1 Hz, 1 H), 1.55−1.50 (m,
1 H), 1.29−1.20 (m, 7 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz,
3 H), 0.86 (t, J = 6.9 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 170.1,
169.9, 132.3, 119.6, 78.4, 61.9, 61.8, 60.8, 39.9, 38.2, 31.9, 30.0, 26.7,
22.5, 14.2, 14.1, 14.0; HRMS (ESI M + H) m/z 344.2062. Calcd for
C17H30NO6 344.2073.
1
(1c). Pale yellow oil: H NMR (500 MHz, CDCl3) δ 5.72 (dddd,
J = 16.6, 10.4, 8.5, 6.2 Hz, 1 H), 5.13 (d, J = 18.5 Hz, 1 H), 5.12 (d, J =
9.3 Hz, 1 H), 4.71 (dd, J = 14.9, 3.1 Hz, 1 H), 4.47 (dd, J = 14.9, 6.9
Hz, 1 H), 3.74 (s, 3 H), 3.70 (s, 3 H), 3.16 (dt, J = 6.7, 2.8 Hz, 1 H),
2.83 (dd, J = 14.5, 6.2 Hz, 1 H), 2.66 (dd, J = 14.5, 8.5 Hz, 1 H), 2.19−
1.97 (m, 1 H), 0.95 (d, J = 7.1 Hz, 3 H), 0.75 (d, J = 6.9 Hz, 3 H); 13C
NMR (126 MHz, CDCl3) δ 170.8, 170.7, 132.1, 119.8, 74.2, 60.6, 52.7,
52.7, 44.4, 38.4, 26.5, 22.7, 16.5. Anal. Calcd. for C13H21NO6: C, 54.35;
H, 7.37; N, 4.88. Found: C, 54.02; H, 7.15; N, 4.93.
Dimethyl 2-Allyl-2-(1-nitrohexan-2-yl)malonate (1d). Pale
1
yellow oil: H NMR (500 MHz, CDCl3) δ 5.74 (dddd, J = 11.0,
9.1, 8.2, 7.4 Hz, 1 H), 5.13 (d, J = 10.5 Hz, 1 H), 5.12 (d, J = 16.7 Hz,
1 H), 4.74 (dd, J = 14.4, 3.5 Hz, 1 H), 4.32 (dd, J = 14.4, 6.6 Hz, 1 H),
3.74 (s, 3 H), 3.71 (s, 3 H), 2.99 (ddt, J = 9.7, 6.6, 3.3 Hz, 1 H), 2.77
(dd, J = 14.5, 6.7 Hz, 1 H), 2.64 (dd, J = 14.5, 8.2 Hz, 1 H), 1.62−1.16
(m, 6 H), 0.86 (t, J = 6.6 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ
170.5, 170.3, 132.2, 119.7, 78.1, 61.1, 52.7, 52.6, 40.1, 38.3, 29.7, 29.2,
22.8, 13.9; HRMS (ESI M + H) m/z 302.1604. Calcd for C14H24NO6
302.1604.
Dimethyl 2-Allyl-2-(1-nitroheptan-2-yl)malonate (1e). Pale
yellow oil: 1H NMR (500 MHz, CDCl3) δ 5.75 (dddd, J = 17.0, 10.7,
8.1, 6.6 Hz, 1 H), 5.13 (d, J = 10.3 Hz, 1 H), 5.13 (d, J = 17.0 Hz, 1
H), 4.75 (dd, J = 14.4, 3.5 Hz, 1 H), 4.33 (dd, J = 14.4, 6.6 Hz, 1 H),
3.74 (s, 3 H), 3.71 (s, 3 H), 3.00 (ddd, J = 9.7, 6.6, 3.4 Hz, 1 H), 2.77
(dd, J = 14.5, 6.5 Hz, 1 H), 2.64 (dd, J = 14.5, 8.1 Hz, 1 H), 1.61−1.13
(m, 8 H), 0.86 (t, J = 6.9 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ
170.6, 170.4, 132.2, 119.7, 78.1, 61.0, 52.6, 52.6, 40.1, 38.2, 31.8, 29.8,
26.6, 22.3, 13.9; HRMS (FAB M + H) m/z 316.1755. Calcd for
C15H26NO6 316.1760.
2-Allyl-2-(1-nitroheptan-2-yl)malononitrile (1l). Pale yellow
oil: H NMR (500 MHz, CDCl3) δ 5.90 (dddd, J = 10.1, 9.7, 7.4, 6.9
1
Hz, 1 H), 5.49 (d, J = 10.1 Hz, 1 H), 5.45 (d, J = 16.9 Hz, 1 H), 4.65
(dd, J = 14.3, 5.3 Hz, 1 H), 4.53 (dd, J = 14.3, 5.5 Hz, 1 H), 2.87 (td,
J = 9.1, 5.3 Hz, 1 H), 2.76−2.67 (m, 1 H), 1.90−1.82 (m, 1 H), 1.68−
1.60 (m, 1 H), 1.56−1.21 (m, 9 H), 0.89 (t, J = 6.6 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 127.8, 124.28, 113.7, 113.6, 75.3, 42.3,
41.7, 39.6, 31.4, 30.1, 29.0, 26.5, 22.5, 14.0; HRMS (ESI M + H) m/z
250.1558. Calcd for C13H20N3O2 250.1556.
Preparation of (1R*,2S*,5R*)-Dimethyl 2-Ethyl-1-
nitrobicyclo[3.1.0]hexane-3,3- dicarboxylate (2a). General
Procedure. Under a nitrogen atmosphere, DBU (0.16 mL, 1.1 mmol)
Dimethyl 2-Allyl-2-(1-nitrooctan-2-yl)malonate (1f). Pale
1
yellow oil: H NMR (500 MHz, CDCl3) δ 5.75 (dddd, J = 12.7,
2240
dx.doi.org/10.1021/jo202489v | J. Org. Chem. 2012, 77, 2236−2245

The Journal of Organic Chemistry
Article
was added to a solution of 1a (234.6 mg, 0.86 mmol) in dry
THF (10 mL) at room temperature. Then, Ag2O (419.4 mg, 1.81
mmol) and iodine (319.5 mg, 1.26 mmol) were added to the solution,
and the resulting mixture was stirred for 5 h at room temperature.
Solid residue was removed by filtration, and the filtrate was
concentrated. The obtained crude product was purified by flash
chromatography (silica gel/ethyl acetate−hexane 3:1) to give 2a in
72% yield (167.1 mg) along with 3a in 23% (54.0 mg). Colorless oil:
1H NMR (500 MHz, CDCl3) δ 3.74 (s, 3 H), 3.73 (s, 3 H), 3.58 (dd,
J = 5.6, 3.4 Hz, 1 H), 2.93 (ddd, J = 14.1, 5.3, 0.9 Hz, 1 H), 2.64 (ddd,
J = 10.1, 5.4, 5.0 Hz, 1 H), 2.23 (d, J = 14.2 Hz, 1 H), 1.95 (dqd, J =
15.2, 7.6, 5.7 Hz, 1 H), 1.67 (ddd, J = 9.8, 6.7, 1.1 Hz, 1 H), 1.48 (dqd,
J = 15.1, 7.5, 3.4 Hz, 1 H), 1.13 (dd, J = 6.6, 5.7 Hz, 1 H), 0.86 (t, J =
7.6 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 172.3, 168.8, 71.9, 63.6,
53.4, 53.1, 45.3, 33.5, 27.5, 24.6, 21.1, 10.7; IR (neat) ν 1732, 1527,
1244 cm−1; HRMS (ESI M + H) m/z 272.1135. Calcd for C12H18NO6
272.1134.
Dimethyl 6-Ethyl-3a,4-dihydro-3H-cyclopenta[c]isoxazole-
5,5(6H)-dicarboxylate-N-oxide (3a). Pale yellow oil: 1H NMR
(500 MHz, CDCl3) δ 4.64 (dd, J = 9.2, 7.6 Hz, 1 H), 4.37−4.28 (m, 1 H),
4.10 (dd, J = 9.9, 7.6 Hz, 1 H), 3.74 (s, 3 H), 3.71 (s, 3 H), 3.53 (ddd,
J = 10.5, 5.1, 2.2 Hz, 1 H), 2.67 (dd, J = 13.4, 7.9 Hz, 1 H), 1.86 (dd,
J = 13.5, 8.8 Hz, 1 H), 1.62 (dqd, J = 14.9, 7.5, 5.2 Hz, 1 H), 1.39
(ddq, J = 14.5, 10.5, 7.3 Hz, 1 H), 1.03 (t, J = 7.4 Hz, 3 H); 13C NMR
(126 MHz, CDCl3) δ 170.8, 170.1, 122.0, 72.4, 67.3, 53.2, 52.8, 47.6,
44.1, 37.0, 23.0, 12.8; IR (neat) ν 1732, 1712, 1664 cm−1; HRMS (ESI
M − H) m/z 270.0977. Calcd for C12H16NO6 270.0978.
(1R*,2S*,5R*)-Dimethyl 2-Propyl-1-nitrobicyclo[3.1.0]-
hexane-3,3-dicarboxylate (2b). Pale yellow oil: 1H NMR (500
MHz, CDCl3) δ 3.74 (s, 3 H), 3.73 (s, 3 H), 3.54 (dd, J = 5.8, 3.6 Hz,
1 H), 2.90 (ddd, J = 14.1, 5.3, 0.7 Hz, 1 H), 2.60 (dt, J = 10.1, 5.2 Hz,
1 H), 2.20 (d, J = 14.1 Hz, 1 H), 1.81−1.72 (m, 1 H), 1.70 (ddd, J =
9.8, 6.7, 1.0 Hz, 1 H), 1.46−1.22 (m, 2 H), 1.18 (dd, J = 13.6, 6.6 Hz,
1 H), 1.13 (dd, J = 6.6, 5.7 Hz, 1 H), 0.84 (t, J = 7.2 Hz, 3 H); 13C
NMR (126 MHz, CDCl3) δ 172.2, 169.0, 72.3, 63.9, 53.3, 53.0, 44.9,
33.5, 30.3, 27.7, 25.0, 20.0, 14.5; IR (neat) ν 1732, 1529, 1260, 1240
cm−1; HRMS (ESI M + H) m/z 286.1315. Calcd for C13H20NO6
286.1291.
Dimethyl 6-Propyl-3a,4-dihydro-3H-cyclopenta[c]isoxazole-
5,5(6H)-dicarboxylate-N-oxide (3b). Pale yellow oil: 1H NMR
(500 MHz, CDCl3) δ 4.66 (dd, J = 9.1, 7.7 Hz, 1 H), 4.44−4.26 (m, 1
H), 4.12 (dd, J = 9.8, 7.5 Hz, 1 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.64
(d, J = 10.7 Hz, 1 H), 2.70 (dd, J = 13.2, 7.8 Hz, 1 H), 1.89 (dd, J =
13.5, 8.7 Hz, 1 H), 1.56−1.43 (m, 2 H), 1.31−1.20 (m, 2 H), 0.93 (t,
J = 7.1 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 170.9, 170.1, 122.1,
72.3, 67.3, 53.3, 52.8, 47.6, 42.3, 37.0, 31.8, 21.4, 14.0; IR (neat) ν
2958, 1730, 1712, 1663 cm−1; HRMS (ESI M − H) m/z 284.1154.
Calcd for C13H18NO6 284.1134.
(1R*,2S*,5R*)-Dimethyl 2-Isopropyl-1-nitrobicyclo[3.1.0]-
hexane-3,3-dicarboxylate (2c). Pale yellow oil: 1H NMR (500
MHz, CDCl3) δ 3.78 (s, 3 H), 3.70 (s, 3 H), 2.97 (ddd, J = 13.5, 6.6,
1.5 Hz, 1 H), 2.85 (d, J = 8.3 Hz, 1 H), 2.49−2.36 (m, 2 H), 2.22 (dd,
J = 8.1, 7.3 Hz, 1 H), 1.77 (ddd, J = 13.6, 2.7, 2.0 Hz, 1 H), 1.29 (td,
J = 6.3, 1.6 Hz, 1 H), 0.98 (dd, J = 6.8, 2.0 Hz, 3 H), 0.89 (dd, J = 6.7,
2.2 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 171.3, 169.4, 73.3, 68.3,
58.6, 53.0, 52.9, 37.9, 31.5, 30.8, 27.9, 21.4, 21.2; IR (neat) ν 1730,
1527, 1250 cm−1; HRMS (ESI M + H) m/z 286.1315. Calcd for
C13H20NO6 286.1291.
(1R*,2S*,5R*)-Dimethyl 2-Butyl-1-nitrobicyclo[3.1.0]hexane-
1
3,3-dicarboxylate (2d). White solid: mp 64.9−66.3 °C; H NMR
(500 MHz, CDCl3) δ 3.74 (s, 3 H), 3.73 (s, 3 H), 3.58−3.54 (m, 1 H),
2.92 (dd, J = 14.1, 5.4 Hz, 1 H), 2.62 (dt, J = 10.8, 5.5 Hz, 1 H), 2.21
(d, J = 14.2 Hz, 1 H), 1.80 (dtd, J = 16.4, 10.4, 4.5 Hz, 1 H), 1.69 (dd,
J = 9.7, 6.8 Hz, 1 H), 1.42 (dddd, J = 9.9, 8.4, 4.5, 1.0 Hz, 1 H), 1.32
(qd, J = 12.4, 5.8 Hz, 1 H), 1.22 (dq, J = 14.9, 7.3 Hz, 2 H), 1.12 (t, J =
5.5 Hz, 1 H), 1.16−1.04 (m, 1 H), 0.83 (t, J = 7.3 Hz, 3 H); 13C NMR
(126 MHz, CDCl3) δ 172.1, 168.7, 72.1, 63.6, 53.2, 52.9, 44.5, 33.2,
28.4, 27.6, 27.5, 24.7, 22.9, 13.6; IR (neat) ν 1735, 1529, 1363 cm−1;
HRMS (ESI M + H) m/z 300.1454. Calcd for C14H22NO6 300.1447.
Dimethyl 6-Butyl-3a,4-dihydro-3H-cyclopenta[c]isoxazole-
5,5(6H)-dicarboxylate-N-oxide (3d). Pale yellow oil: 1H NMR
(500 MHz, CDCl3) δ 4.66 (dd, J = 9.2, 7.6 Hz, 1 H), 4.34 (tdd, J =
10.2, 8.9, 2.2 Hz, 1 H), 4.18−4.06 (m, 1 H), 3.77 (s, 3 H), 3.74 (s, 3
H), 3.63 (ddd, J = 10.2, 4.9, 2.0 Hz, 1 H), 2.70 (dd, J = 13.5, 8.0 Hz, 1
H), 1.89 (dd, J = 13.5, 8.6 Hz, 1 H), 1.69−1.20 (m, 6 H), 0.88 (t, J =
7.3 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 170.9, 170.0, 122.1,
72.3, 67.3, 53.3, 52.8, 47.5, 42.5, 36.9, 30.1, 29.3 22.6, 13.9; IR (neat) ν
1732, 1710, 1667 cm−1; HRMS (ESI M + H) m/z 300.1449. Calcd for
C14H22NO6 300.1447.
(1R*,2S*,5R*)-Dimethyl 2-Pentyl-1-nitrobicyclo[3.1.0]-
hexane-3,3-dicarboxylate (2e). Pale yellow oil: 1H NMR (500
MHz, CDCl3) δ 3.74 (s, 3 H), 3.72 (s, 3 H), 3.54 (dd, J = 5.8, 3.7 Hz,
1 H), 2.95−2.87 (m, 1 H), 2.61 (dt, J = 6.2, 5.5 Hz, 1 H), 2.20 (d, J =
14.1 Hz, 1 H), 1.77 (dddd, J = 14.7, 11.6, 5.8, 4.4 Hz, 1 H), 1.69 (ddd,
J = 9.8, 6.7, 1.0 Hz, 1 H), 1.43 (dddd, J = 14.9, 11.3, 5.1, 3.8 Hz, 1 H),
1.39−1.30 (m, 1 H), 1.28−1.09 (m, 5 H), 1.12 (dd, J = 6.7, 5.6 Hz, 1
H), 0.84 (t, J = 7.1 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 172.2,
168.9, 72.2, 63.7, 53.4, 53.0, 44.7, 33.4, 32.1, 28.0, 27.6, 26.1, 24.9,
22.3, 14.0; IR (neat) ν 1732, 1529, 1248 cm−1; HRMS (ESI M + H)
m/z 314.1588. Calcd for C15H24NO6 314.1604.
Dimethyl 6-Pentyl-3a,4-dihydro-3H-cyclopenta[c]isoxazole-
5,5(6H)-dicarboxylate-N-oxide (3e). Pale yellow oil: 1H NMR (500
MHz, CDCl3) δ 4.66 (dd, J = 9.2, 7.6 Hz, 1 H), 4.34 (tdd, J = 10.2, 8.9,
2.2 Hz, 1 H), 4.12 (dd, J = 9.9, 7.7 Hz, 1 H), 3.77 (s, 3 H), 3.75 (s, 3
H), 3.63 (ddd, J = 10.4, 5.0, 2.0 Hz, 1 H), 2.71 (ddd, J = 13.4, 8.0, 0.4
Hz, 1 H), 1.89 (dd, J = 13.5, 8.6 Hz, 1 H), 1.59−1.22 (m, 8H), 0.87 (t,
J = 6.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.9, 170.0, 122.0,
72.3, 67.3, 53.3, 52.8, 47.5, 42.5, 36.9, 31.7, 29.6, 27.7, 22.5, 14.1; IR
(neat) ν 2950, 1732, 1710, 1667 cm−1; HRMS (ESI M − H) m/z
312.1454. Calcd for C15H22NO6 312.1447.
(1R*,2S*,5R*)-Dimethyl 2-Hexyl-1-nitrobicyclo[3.1.0]-
hexane-3,3-dicarboxylate (2f). Pale yellow oil: 1H NMR (500
MHz, CDCl3) δ 3.74 (s, 3 H), 3.73 (s, 3 H), 3.55 (dd, J = 5.8, 3.6 Hz,
1 H), 2.91 (ddd, J = 14.1, 5.3, 0.8 Hz, 1 H), 2.61 (ddd, J = 6.1, 5.4, 2.7
Hz, 1 H), 2.21 (d, J = 14.2, 1 H), 1.78 (dddd, J = 14.7, 11.8, 5.8, 4.4
Hz, 1 H), 1.69 (dd, J = 9.8, 6.7 Hz, 1 H), 1.42 (dddd, J = 14.8, 11.4,
4.9, 3.7 Hz, 1 H), 1.37−1.16 (m, 8 H), 1.12 (dd, J = 6.7, 5.6 Hz, 1 H),
0.85 (t, J = 7.1 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 172.2, 168.9,
72.3, 63.9, 53.3, 53.0, 45.0, 33.5, 31.5, 29.7, 28.1, 27.6, 26.6, 25.0, 22.6,
14.1; IR (neat) ν 1732, 1529, 1246 cm−1; HRMS (ESI M + H) m/z
328.1758. Calcd for C16H26NO6 328.1760.
Dimethyl 6-Hexyl-3a,4-dihydro-3H-cyclopenta[c]isoxazole-
5,5(6H)-dicarboxylate-N-oxide (3f). Pale yellow oil: 1H NMR
(500 MHz, CDCl3) δ 4.66 (dd, J = 9.2, 7.6 Hz, 1 H), 4.39−4.29 (m, 1 H),
4.11 (dd, J = 10.0, 7.6 Hz, 1 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.63 (ddd,
J = 10.2, 4.9, 2.2 Hz, 1 H), 2.70 (dd, J = 13.4, 8.0 Hz, 1 H), 1.88 (dd,
J = 13.5, 8.6 Hz, 1 H), 1.59−1.11 (m, 10 H), 0.86 (dd, J = 9.9, 4.0 Hz,
3 H); 13C NMR (126 MHz, CDCl3) δ 170.9, 170.0, 122.0, 72.3, 67.3,
53.3, 52.8, 47.5, 42.5, 36.9, 31.7, 29.6, 29.2, 28.0, 22.6, 14.1; IR (neat)
ν 2955, 1732, 1670 cm−1; HRMS (ESI M − H) m/z 326.1599. Calcd
for C16H24NO6 326.1604.
(1R*,2S*,5R*)-Dimethyl 2-Cyclohexyl-1-nitrobicyclo[3.1.0]-
hexane-3,3-dicarboxylate (2g). White solid: mp 107.4−108.0 °C;
1H NMR (500 MHz, CDCl3) δ 3.82 (s, 3 H), 3.70 (s, 3 H), 2.98 (dd,
J = 13.3, 7.5 Hz, 1 H), 2.74 (d, J = 9.2 Hz, 1 H), 2.41−2.32 (m, 2 H),
2.14 (qt, J = 11.9, 3.0 Hz, 1 H), 1.78 (d, J = 12.5 Hz, 1 H), 1.74−1.60
(m, 4 H), 1.51 (d, J = 12.6 Hz, 1 H), 1.34 (t, J = 4.9 Hz, 1 H), 1.27−
0.93 (m, 5 H); 13C NMR (126 MHz, CDCl3) δ 171.2, 169.6, 73.2,
Dimethyl 6-Isopropyl-3a,4-dihydro-3H-cyclopenta[c]-
isoxazole-5,5(6H)-dicarboxylate-N-oxide (3c). Pale yellow solid:
mp 103.9−105.3 °C; 1H NMR (500 MHz, CDCl3) δ 4.65 (dd, J = 9.2,
7.6 Hz, 1 H), 4.29 (dtd, J = 17.3, 8.2, 2.2 Hz, 1 H), 4.09 (dd, J = 9.9,
7.6 Hz, 1 H), 3.74 (s, 6 H), 3.52 (dd, J = 5.3, 2.2 Hz, 1 H), 2.72 (dd,
J = 13.5, 8.2 Hz, 1 H), 1.94 (tt, J = 13.4, 6.7 Hz, 1 H), 1.86 (dd, J =
13.5, 8.4 Hz, 1 H), 1.08 (d, J = 6.7 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H);
13C NMR (126 MHz, CDCl3) δ 171.2, 170.1, 121.4, 72.3, 67.0, 53.3,
53.0, 49.6, 48.5, 37.5, 29.7, 23.1, 20.1; IR (CH2Cl2) ν 2953, 1726, 1654
cm−1; HRMS (ESI M − H) m/z 284.1136. Calcd for C13H18NO6
284.1134.
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Article
69.2, 59.2, 53.0, 52.9, 38.6, 37.9, 32.5, 32.3, 32.3, 31.9, 26.7, 26.4, 26.2;
IR (CHCl3) ν 1732, 1527 cm−1. Anal. Calcd. for C16H23NO6: C,
59.06; H, 7.13; N, 4.31. Found: C, 59.17; H, 7.21; N, 4.31.
δ 4.27−4.10 (m, 4 H), 3.55 (dd, J = 5.5, 3.7 Hz, 1 H), 2.90 (dd, J =
14.1, 5.3 Hz, 1 H), 2.61 (dd, J = 10.0, 5.3 Hz, 1 H), 2.19 (d, J = 14.0
Hz, 1 H), 1.87−1.71 (m, 1 H), 1.66 (dd, J = 9.7, 6.8 Hz, 1 H), 1.51−
1.30 (m, 2 H), 1.28−1.10 (m, 6 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.24 (t,
J = 7.0 Hz, 3 H), 1.16 (t, J = 6.3 Hz, 1 H), 0.84 (t, J = 7.1 Hz, 3 H);
13C NMR (126 MHz, CDCl3) δ 171.8, 168.5, 72.4, 63.9, 62.2, 62.1,
Dimethyl 6-Cyclohexyl-3a,4-dihydro-3H-cyclopenta[c]-
isoxazole-5,5(6H)-dicarboxylate-N-oxide (3g). Pale yellow solid:
1
mp 115.0−116.0 °C; H NMR (500 MHz, CDCl3) δ 4.64 (ddd, J =
7.9, 7.0, 1.8 Hz, 1 H), 4.29 (p, J = 8.5 Hz, 1 H), 4.14−4.04 (m, 1 H),
3.78 (s, 6 H), 3.55−3.45 (m, 1 H), 2.70 (ddd, J = 13.4, 8.1, 1.7 Hz,
1 H), 1.84 (ddd, J = 13.4, 8.6, 1.1 Hz, 1 H), 1.78 (d, J = 13.4 Hz, 1 H),
1.71 (d, J = 10.4 Hz, 2 H), 1.62−1.49 (m, 3 H), 1.38−1.00 (m, 5 H);
13C NMR (126 MHz, CDCl3) δ 171.2, 170.3, 121.6, 72.2, 67.0, 53.3,
52.9, 48.9, 48.7, 39.6, 37.7, 33.5, 30.7, 26.6, 26.4, 25.9; IR (CH2Cl2) ν
2928, 1732, 1661 cm−1; HRMS (ESI M − H) m/z 324.1429. Calcd for
C16H22NO6 324.1447.
(1R*,2S*,5R*)-Dimethyl 2-Phenyl-1-nitrobicyclo[3.1.0]-
hexane-3,3-dicarboxylate (2h). White solid: mp 162.2−163.0 °C;
1H NMR (500 MHz, CDCl3) δ 7.31−7.14 (m, 5 H), 4.83 (s, 1 H),
3.78 (s, 3 H), 3.25 (ddd, J = 14.5, 5.1, 1.1 Hz, 1 H), 3.18 (s, 3 H), 2.95
(dt, J = 9.8, 5.3 Hz, 1 H), 2.39 (d, J = 14.6 Hz, 1 H), 1.76 (ddd, J = 9.8,
6.8, 1.3 Hz, 1 H), 1.35 (dd, J = 6.6, 5.7 Hz, 1 H); 13C NMR (126
MHz, CDCl3) δ 172.2, 167.4, 136.4, 128.6, 128.1, 73.0, 64.4, 53.6,
52.7, 50.6, 32.0, 27.7, 22.8; IR (CHCl3) ν 1732, 1701, 1532, 1248
cm−1. Anal. Calcd. for C16H17NO6: C, 60.18; H, 5.37; N, 4.39. Found:
C, 59.96; H, 5.32; N, 4.29.
(1R*,2S*,5R*)-Diethyl 2-Ethyl-1-nitrobicyclo[3.1.0]hexane-
3,3-dicarboxylate (2i). Pale yellow oil: 1H NMR (500 MHz,
CDCl3) δ 4.33−4.09 (m, 4 H), 3.58 (dd, J = 5.5, 3.4 Hz, 1 H), 2.91
(ddd, J = 14.1, 5.3, 1.0 Hz, 1 H), 2.63 (dt, J = 10.1, 5.2 Hz, 1 H), 2.21
(d, J = 14.2 Hz, 1 H), 1.97 (dqd, J = 15.2, 7.6, 5.5 Hz, 1 H), 1.64 (ddd,
J = 9.8, 6.6, 1.1 Hz, 1 H), 1.51 (dqd, J = 15.1, 7.6, 3.4 Hz, 1 H), 1.25 (t,
J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.17 (dd, J = 6.6, 5.6 Hz, 1
H), 0.86 (t, J = 7.6 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 171.9,
168.4, 72.0, 63.7, 62.3, 62.2, 44.9, 33.4, 27.5, 24.5, 21.0, 14.1, 14.0,
10.7; IR (neat) ν 1730, 1529, 1363 cm−1; HRMS (FAB M + H) m/z
300.1450. Calcd for C14H22NO6 300.1447.
Diethyl 6-Ethyl-3a,4-dihydro-3H-cyclopenta[c]isoxazole-
5,5(6H)-dicarboxylate-N-oxide (3i). Pale yellow oil: 1H NMR
(500 MHz, CDCl3) δ 4.66 (dd, J = 9.2, 7.6 Hz, 1 H), 4.38−4.29 (m, 1
H), 4.29−4.14 (m, 4 H), 4.12 (dd, J = 10.1, 7.6 Hz, 1 H), 3.56 (ddd,
J = 10.4, 5.2, 2.2 Hz, 1 H), 2.69 (dd, J = 13.4, 8.0 Hz, 1 H), 1.86 (dd,
J = 13.5, 8.6 Hz, 1 H), 1.73−1.61 (m, 1 H), 1.50−1.36 (m, 1 H), 1.26
(t, J = 7.2 Hz, 6 H), 1.06 (t, J = 7.4 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 170.4, 169.6, 122.2, 72.4, 67.4, 62.2, 62.0, 47.6, 44.0, 36.9,
22.9, 14.1, 14.0, 12.8; IR (neat) ν 2980, 1726, 1713, 1667 cm−1;
HRMS (ESI M − H) m/z 298.1284. Calcd for C14H20NO6 298.1291.
(1R*,2S*,5R*)-Diethyl 2-Isopropyl-1-nitrobicyclo[3.1.0]-
hexane-3,3-dicarboxylate (2j). Pale yellow oil: 1H NMR (500
MHz, CDCl3) δ 4.35−4.07 (m, 4 H), 2.99 (dd, J = 13.5, 6.6 Hz, 1H),
2.90 (d, J = 8.0 Hz, 1H), 2.48 (td, J = 13.7, 6.8 Hz, 1 H), 2.45−2.37
(m, 1 H), 2.20 (dd, J = 9.9, 6.4 Hz, 1 H), 1.78 (dd, J = 13.5, 1.9 Hz,
1 H), 1.31−1.28 (m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1 Hz,
3 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H); 13C NMR
(126 MHz, CDCl3) δ 171.0, 169.1, 73.3, 68.3, 62.0, 61.9, 58.0, 37.7,
31.3, 30.5, 28.0, 21.4, 21.3, 14.0; IR (CHCl3) ν 1728, 1529, 1361, 1246
cm−1; HRMS (ESI M − H) m/z 312.1457. Calcd for C15H22NO6
312.1447.
44.5, 33.4, 32.2, 28.1, 27.6, 26.2, 24.9, 22.4, 14.1, 14.0, 13.9; IR (neat)
ν 1730, 1531, 1244 cm−1; HRMS (ESI M − H) m/z 340.1768. Calcd
for C17H26NO6 340.1760.
Diethyl 6-Pentyl-3a,4-dihydro-3H-cyclopenta[c]isoxazole-
5,5(6H)-dicarboxylate-N-oxide (3k). Pale yellow oil: 1H NMR
(500 MHz, CDCl3) δ 4.65 (dd, J = 9.2, 7.6 Hz, 1 H), 4.31 (tdd, J =
10.1, 8.2, 2.0 Hz, 1 H), 4.26−4.14 (m, 4 H), 4.09 (dd, J = 10.1, 7.6 Hz,
1 H), 3.60 (ddd, J = 10.1, 4.9, 2.1 Hz, 1 H), 2.69 (dd, J = 13.5, 8.1 Hz,
1 H), 1.86 (dd, J = 13.6, 8.4 Hz, 1 H), 1.64−1.17 (m, 10 H), 1.25 (t,
J = 7.1 Hz, 6 H), 0.85 (t, J = 7.0 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 170.5, 169.5, 122.3, 72.4, 67.3, 62.2, 62.0, 47.4, 42.4, 36.7,
31.7, 29.5, 27.7, 22.5, 14.1, 14.0; IR (neat) ν 1931, 1726, 1667 cm−1;
HRMS (ESI M − H) m/z 340.1765. Calcd for C17H26NO6 340.1760.
(1R*,2S*,5R*)-1-Nitro-2-pentylbicyclo[3.1.0]hexane-3,3-di-
carbonitrile (2l). Pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 3.22
(dd, J = 5.8, 3.7 Hz, 1 H), 2.88−2.82 (m, 1 H), 2.82 (dd, J = 16.7, 4.9
Hz, 1 H), 2.53 (d, J = 13.1 Hz, 1 H), 2.13−1.95 (m, 2 H), 1.92 (dd, J =
7.3, 5.5 Hz, 1 H), 1.48−1.19 (m, 7 H), 0.87 (dd, J = 9.8, 4.2 Hz, 3 H);
13C NMR (126 MHz, CDCl3) δ 116.6, 113.2, 71.6, 49.5, 49.5, 38.2,
31.6, 29.2, 27.7, 25.8, 24.9, 22.2, 14.0; IR (CHCl3) ν 2251, 1533, 1359
cm−1; HRMS (FAB M + H) m/z 248.1400. Calcd for C13H18N3O2
248.1399.
(3aS*,6S*)-6-Pentyl-3a,4-dihydro-3H-cyclopenta[c]-
isoxazole-5,5(6H)-dicarbonitril-N-oxide (3l). White solid: mp
1
98.4−99.7 °C; H NMR (500 MHz, CDCl3) δ 4.78 (dd, J = 8.9,
8.0 Hz, 1 H), 4.36 (dd, J = 9.5, 7.9 Hz, 1 H), 4.33−4.20 (m, 1 H), 3.43
(td, J = 7.8, 2.8 Hz, 1 H), 2.85 (dd, J = 12.7, 6.5 Hz, 1 H), 2.36 (ddd,
J = 12.4, 10.5, 1.8 Hz, 1 H), 2.06−1.93 (m, 1H), 1.87 (dddd, J = 13.9,
10.1, 8.4, 5.7 Hz, 1 H), 1.65−1.52 (m, 2 H), 1.46−1.26 (m, 4 H), 0.91
(t, J = 7.1 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 117.7, 114.3,
112.8, 71.1, 46.8, 46.6, 42.3, 41.4, 31.3, 30.2, 27.0, 22.3, 14.0; IR
(CHCl3) ν 2931, 2251, 1706, 1668 cm−1; HRMS (ESI M − H) m/z
246.1254. Calcd for C13H16N3O2 246.1243.
One-Pot Preparation of (1R*,2S*,5R*)-Dimethyl 2-Pentyl-1-
nitrobicyclo[3.1.0]-hexane-3,3-dicarboxylate (2e). A solution of
dimethyl 2-allylmalonate (353.5 mg, 2.05 mmol) in dry THF (1 mL)
was added to t-BuOK (237.6 mg, 2.12 mmol) in dry THF (20 mL). 1-
Nitro-1-heptene (441.3 mg, 3.08 mmol) was added to the solution at
−30 °C, and the reaction mixture was stirred at room temperature for
4 h. DBU (0.35 mL, 2.34 mmol), Ag2O (958.6 mg, 4.14 mmol), and
iodine (843.9 mg, 3.32 mmol) were added to the solution in this order.
The resulting reaction mixture was stirred at room temperature for 3 h.
The precipitate was removed via filtration, and the filtrate was
concentrated under reduced pressure. The residue was purified by
flash chromatography (silica gel/ethyl acetate−hexane 3:1) to give 2e
in 42% yield (272.2 mg) along with 3e in 22% yield (141.4 mg).
Conversion of 3b into 4b. A solution of 3b (91.7 mg, 0.32
mmol) was solved in MeOH (20 mL), and 1 M HCl (0.6 mL) was
added. The solution was allowed to stand at room temperature for two
days. MeOH was removed in vacuo, and the residue was purified by
flash chromatography (silica gel/ethyl acetate−hexane 3:1) to give 4b
in 50% yield (42.4 mg). Pale yellow oil: 1H NMR (500 MHz, CDCl3)
δ 3.89 (dd, J = 10.9, 4.4 Hz, 1 H), 3.76 (s, 3 H), 3.70 (s, 3 H), 3.63
(dd, J = 10.9, 5.0 Hz, 1 H), 2.76 (dddd, J = 10.5, 9.2, 4.7, 1.1 Hz, 1 H),
2.71−2.62 (m, 2 H), 2.46−2.17 (br, 1 H), 2.11 (dd, J = 13.4, 10.7 Hz,
1 H), 1.69−1.49 (m, 2 H), 1.48−1.30 (m, 2 H), 0.88 (t, J = 7.1 Hz, 3
H); 13C NMR (126 MHz, CDCl3) δ 217.3, 171.5, 171.1, 61.6, 59.3,
55.6, 52.9, 52.6, 48.8, 31.9, 29.2, 21.3, 14.1; IR (CHCl3) ν 3587−3259,
2958, 2875, 1728 cm−1; HRMS (FAB M + H) m/z 273.1334. Calcd
for C13H21O6 273.1338.
Diethyl 6-Isopropyl-3a,4-dihydro-3H-cyclopenta[c]-
isoxazole-5,5(6H)-dicarboxylate-N-oxide (3j). White solid: mp
1
53.3−54.2 °C; H NMR (500 MHz, CDCl3) δ 4.66 (dd, J = 9.1, 7.6
Hz, 1 H), 4.33−4.25 (m, 1 H), 4.23 (q, J = 7.1 Hz, 2 H), 4.19 (q, J =
7.1 Hz, 2 H), 4.10 (dd, J = 10.0, 7.6 Hz, 1 H), 3.53 (dd, J = 5.2, 2.0 Hz,
1 H), 2.73 (dd, J = 13.5, 8.2 Hz, 1 H), 2.00 (dqd, J = 13.3, 6.7, 1.2 Hz,
1 H), 1.86 (dd, J = 13.6, 8.2 Hz, 1 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.26 (t,
J = 7.1 Hz, 3 H), 1.11 (d, J = 6.7 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H);
13C NMR (126 MHz, CDCl3) δ 170.8, 169.8, 121.5, 72.4, 67.1, 62.2,
62.1, 49.5, 48.5, 37.4, 29.6, 23.2, 20.2, 14.1, 14.0; IR (CH2Cl2) ν 2980,
1726, 1712, 1658 cm−1; HRMS (ESI M − H) m/z 312.1444. Calcd for
C15H22NO6 312.1447.
Preparation of Dimethyl 4-(iodomethyl)-2-isopropyl-3-ni-
trocyclopentane-1,1-dicarboxylate (5). Under nitrogen atmos-
phere, DBU (182.7 mg, 1.20 mmol) in dry THF (1 mL) was added to
a solution of 1c (284.2 mg, 0.99 mmol) in dry THF (15 mL) and
(1R*,2S*,5R*)-Diethyl 2-Pentyl-1-nitrobicyclo[3.1.0]hexane-
1
3,3-dicarboxylate (2k). Colorless oil: H NMR (500 MHz, CDCl3)
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water (0.2 mL) at room temperature. Then, Ag2O (469.7 mg, 2.03
mmol) and iodine (512.1 mg, 2.02 mmol) were added to the solution,
and the resulting mixture was stirred for 1 h at room temperature.
Solid residue was removed via filtration, and the filtrate was
concentrated. The obtained crude product was purified by flash
chromatography (silica gel/ethyl acetate−hexane 3:1) to give 5 in 65%
11.0 Hz, 1 H), 2.22 (dd, J = 13.5, 3.9 Hz, 1 H), 2.11 (ddd, J = 17.7,
12.9, 6.3 Hz, 1 H), 1.69 (dd, J = 12.3, 9.6 Hz, 1 H), 1.47 (s, 9 H), 1.02
(d, J = 6.5 Hz, 3 H), 0.97 (d, J = 6.5 Hz, 3 H); 13C NMR (126 MHz,
CDCl3) δ 171.8, 170.7, 169.7, 88.8, 82.5, 75.6, 75.3, 63.3, 58.0, 52.7,
52.5, 51.2, 41.5, 36.4, 28.0, 27.9, 22.3, 21.8. Anal. Calcd. for
C20H31NO8: C, 58.10; H, 7.56; N, 3.39. Found: C, 58.04; H, 7.60;
N, 3.32.
1
yield (264.9 mg). Pale yellow solid: mp 67−68 °C; H NMR (500
MHz, CDCl3) δ 4.92 (dd, J = 8.2, 5.7 Hz, 1 H), 3.72 (s, 3 H), 3.69 (s,
3 H), 3.40 (dd, J = 6.6, 5.8 Hz, 1 H), 3.16−3.06 (m, 1 H), 3.03 (dd,
J = 10.0, 6.6 Hz, 1 H), 2.89 (dd, J = 9.9, 9.1 Hz, 1 H), 2.71 (dd, J =
13.1, 6.3 Hz, 1 H), 2.05 (t, J = 12.9 Hz, 1 H), 2.00 (dd, J = 13.5, 6.8
Hz, 1 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.79 (d, J = 6.7 Hz, 3 H); 13C
NMR (126 MHz, CDCl3) δ 171.0, 170.9, 91.7, 61.3, 57.8, 53.1, 52.9,
45.5, 41.6, 28.8, 22.7, 19.1; IR (CHCl3) ν 1735, 1550, 1365 cm−1;
HRMS (FAB M + H) m/z 414.0419. Calcd for C13H21INO6 414.0414.
Conversion of 5 to 3c. Under nitrogen atmosphere, DBU (34.4
mg, 0.23 mmol) in dry THF (1 mL) was added to a solution of 5 (68.2
mg, 0.17 mmol) in dry THF (7 mL) at room temperature, and the
reaction mixture was stirred for 3 h. Then, 1 M aqueous HCl (20 mL)
was added, and the resulting solution was extracted with EtOAc (50
mL × 3). The organic phase was washed with brine (20 mL × 1) and
dried over Na2SO4. After filtration, concentration in vacuo afforded
crude product, which was purified by flash chromatography (silica gel/
ethyl acetate−hexane 3:1) to give 3c in 83% yield (39.2 mg).
(6aS*,9S*,9aR*) Dimethyl 2-Cyano-9-isopropyltetrahydro-
1H-cyclopenta[c]-isoxazolo[2,3-b]isoxazole-8,8(2H)-dicarboxy-
1
late (6c). 6cA. Colorless solid: mp 186.6−187.5 °C; H NMR (500
MHz, CDCl3) δ 4.86 (dd, J = 9.9, 6.2 Hz, 1 H), 4.18 (dd, J = 9.3, 6.7
Hz, 1 H), 3.87 (d, J = 9.2 Hz, 1 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 2.81
(dd, J = 11.3, 7.2 Hz, 1 H), 2.77 (dd, J = 11.7, 8.6 Hz, 1 H), 2.68 (dd,
J = 15.4, 8.6 Hz, 1 H), 2.52 (d, J = 11.1 Hz, 1 H), 2.44 (dd, J = 13.0,
6.2 Hz, 1 H), 2.08−1.98 (m, 1 H), 1.70 (dd, J = 12.6, 9.9 Hz, 1 H),
1.06 (d, J = 6.5 Hz, 3 H), 0.98 (d, J = 6.5 Hz, 3 H); 13C NMR (126
MHz, CDCl3) δ 171.2, 170.8, 116.6, 89.6, 76.0, 65.6, 63.3, 57.2, 52.9,
52.8, 50.9, 41.4, 39.3, 27.9, 22.1, 21.6. Anal. Calcd. for C16H22N2O6: C,
56.80; H, 6.55; N, 8.28. Found: C, 56.70; H, 6.58; N, 8.27. 6cB.
1
Colorless solid: mp 105.8−106.3 °C; H NMR (500 MHz, CDCl3) δ
4.91 (d, J = 9.0 Hz, 1 H), 4.48 (dd, J = 9.5, 6.6 Hz, 1 H), 4.00 (d, J =
9.5 Hz, 1 H), 3.81 (s, 3 H), 3.72 (s, 3 H), 2.98 (td, J = 8.9, 7.4 Hz,
1 H), 2.91 (dd, J = 13.7, 9.3 Hz, 1 H), 2.85 (dd, J = 12.6, 8.6 Hz, 1 H),
2.50 (d, J = 11.1 Hz, 1 H), 2.35 (d, J = 13.7 Hz, 1 H), 2.08 (ddd, J =
17.3, 12.9, 6.4 Hz, 1 H), 1.77 (dd, J = 12.6, 10.1 Hz, 1 H), 0.99 (d, J =
6.9 Hz, 3 H), 0.97 (d, J = 6.9 Hz, 3 H); 13C NMR (126 MHz, CDCl3)
δ 171.4, 170.6, 117.6, 89.2, 76.7, 65.3, 63.1, 57.5, 52.9, 52.8, 50.4, 41.7,
38.3, 27.6, 22.0, 21.5. Anal. Calcd. for C16H22N2O6: C, 56.80; H, 6.55;
N, 8.28. Found: C, 56.79; H, 6.60; N, 8.25.
1,3-Dipolar Cycloaddition of 4c to Methyl Acrylate.
(6aS*,9S*,9aR*)-Trimethyl 9-Isopropyldihydro-1H-cyclopenta-
[c]isoxazolo[2,3-b]isoxazole-2,8,8(2H,6H,9H)-tricarboxylate
(6a). General Procedure. Under a nitrogen atmosphere, a mixture of
4c (102.4 mg, 0.36 mmol) and methyl acrylate (2 mL) in dry toluene
(2 mL) was heated at refluxing temperature for 3 h. After cooling and
concentration in vacuo, the crude product was purified by flash
chromatography (silica gel/ethyl acetate−hexane 3:1) to give 6a in
98% yield (130.0 mg). 2S*-6aA (major) and 2R*-6aB (minor) were
carefully separated by chromatography. 6aA. Colorless solid: mp
(6aS*,9S*,9aR*)-Trimethyl 9-Cyclohexyldihydro-1H-
cyclopenta[c]isoxazolo[2,3-b]-isoxazole-2,8,8(2H,6H,9H)-tricar-
1
boxylate (6d): 6dA. Colorless solid: mp 133.8−134.5 °C; H NMR
(500 MHz, CDCl3) δ 4.72 (ddd, J = 10.5, 5.7, 1.9 Hz, 1 H), 4.17 (t, J =
8.8 Hz, 1 H), 3.84 (d, J = 9.4 Hz, 1 H), 3.79 (s, 3 H), 3.76 (s, 3 H),
3.70 (s, 3 H), 2.80 (dd, J = 11.4, 9.3 Hz, 1 H), 2.70 (dd, J = 16.3, 7.9
Hz, 1 H), 2.63 (d, J = 11.0 Hz, 1 H), 2.53 (t, J = 11.4 Hz, 1 H), 2.25
(dd, J = 12.0, 4.9 Hz, 1 H), 1.94 (d, J = 13.6 Hz, 1 H), 1.80−1.53 (m,
6H), 1.26−0.91 (m, 5H); 13C NMR (126 MHz, CDCl3) δ 171.6,
170.7, 170.2, 89.5, 77.6, 75.4, 62.9, 56.0, 52.9, 52.8, 52.7, 51.4, 41.3,
38.2, 37.7, 32.1, 31.5, 26.9, 26.3, 26.2. Anal. Calcd. for C20H29NO8: C,
58.38; H, 7.10; N, 3.40. Found: C, 58.21; H, 7.17; N, 3.41. 6dB.
1
138.8−139.6 °C; H NMR (500 MHz, CDCl3) δ 4.74 (dd, J = 10.8,
5.6 Hz, 1 H), 4.19 (dd, J = 9.1, 6.5 Hz, 1 H), 3.86 (d, J = 9.2 Hz, 1 H),
3.80 (s, 3 H), 3.77 (s, 3 H), 3.71 (s, 3 H), 2.81 (dd, J = 12.3, 8.5 Hz,
1 H), 2.72 (dd, J = 15.7, 9.1 Hz, 1 H), 2.58 (t, J = 11.3 Hz, 2 H), 2.26
(dd, J = 12.8, 5.7 Hz, 1 H), 2.07−1.98 (m, 1 H), 1.71 (dd, J = 12.2,
10.1 Hz, 1 H), 1.05 (d, J = 6.5 Hz, 3 H), 0.98 (d, J = 6.5 Hz, 3 H); 13C
NMR (126 MHz, CDCl3) δ 171.5, 170.8, 170.2, 89.5, 77.6, 75.5, 63.4,
57.2, 52.8, 52.7, 52.6, 51.3, 41.3, 38.1, 27.9, 22.0, 21.6. Anal. Calcd. for
C17H25NO8: C, 54.98; H, 6.79; N, 3.77. Found: C, 54.93; H, 6.90; N,
1
Colorless solid: mp 115.6−116.4 °C; H NMR (500 MHz, CDCl3) δ
4.60 (dd, J = 9.9, 3.8 Hz, 1 H), 4.51 (dd, J = 8.7, 6.7 Hz, 1 H), 3.80 (d,
J = 7.0 Hz, 1 H), 3.80 (s, 3 H), 3.77 (s, 3 H), 3.71 (s, 3 H), 2.83−2.73
(m, 2 H), 2.69 (dd, J = 15.2, 8.6 Hz, 1 H), 2.53 (d, J = 10.9 Hz, 1 H),
2.30 (dd, J = 13.5, 3.8 Hz, 1 H), 1.89 (d, J = 13.7 Hz, 1 H), 1.79−1.59
(m, 5H), 1.30−0.92 (m, 6H); 13C NMR (126 MHz, CDCl3) δ 171.8,
171.2, 170.7, 88.8, 75.6, 74.9, 62.8, 56.8, 52.8, 52.7, 52.6, 51.3, 41.6,
37.8, 36.5, 32.3, 31.6, 26.9, 26.3, 26.2. Anal. Calcd. for C20H29NO8: C,
58.38; H, 7.10; N, 3.40. Found: C, 58.35; H, 7.18; N, 3.39.
1
3.74. 6aB. Colorless solid: mp 125.4−126.6 °C; H NMR (500 MHz,
CDCl3) δ 4.60 (dd, J = 9.8, 4.0 Hz, 1 H), 4.53 (dd, J = 8.7, 6.6 Hz,
1 H), 3.82 (dd, J = 8.7, 1.1 Hz, 1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.71
(s, 3 H), 2.86−2.75 (m, 2 H), 2.71 (dt, J = 15.3, 4.9 Hz, 1 H), 2.44 (d,
J = 11.0 Hz, 1 H), 2.30 (dd, J = 13.6, 4.0 Hz, 1 H), 2.10 (qd, J = 13.0,
6.5 Hz, 1 H), 1.70 (dd, J = 12.4, 9.6 Hz, 1 H), 1.03 (d, J = 6.5 Hz,
3 H), 0.97 (d, J = 6.5 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 171.7,
171.1, 170.8, 88.9, 75.7, 74.8, 63.3, 58.0, 52.8, 52.6, 52.5, 51.4, 41.6,
36.5, 28.0, 27.9, 22.3, 21.8. Anal. Calcd. for C17H25NO8: C, 54.98; H,
6.79; N, 3.77. Found: C, 55.06; H, 6.87; N, 3.82.
(6aS*,9S*,9aR*) 2-tert-Butyl 8,8-Dimethyl 9-Cyclohexyldihy-
dro-1H-cyclopenta-[c]isoxazolo[2,3-b]isoxazole-2,8,8-
(2H,6H,9H)-tricarboxylate (6e). 6eA. Colorless solid: mp 197.8−
1
198.4 °C; H NMR (500 MHz, CDCl3) δ 4.58 (dd, J = 10.8, 5.6 Hz,
(6aS*,9S*,9aR*)-2-tert-Butyl 8,8-Dimethyl 9-Isopropyldihy-
dro-1H-cyclopenta-[c]isoxazolo[2,3-b]isoxazole-2,8,8-
(2H,6H,9H)-tricarboxylate (6b): 6bA. Colorless solid: mp 113.6−
1 H), 4.16 (dd, J = 9.2, 6.4 Hz, 1 H), 3.82 (d, J = 9.2 Hz, 1 H), 3.80 (s,
3 H), 3.71 (s, 3 H), 2.78 (dd, J = 12.3, 8.4 Hz, 1 H), 2.68 (dd, J = 15.8,
9.1 Hz, 1 H), 2.64 (d, J = 11.1 Hz, 1 H), 2.49 (dd, J = 12.6, 11.0 Hz,
1 H), 2.18 (dd, J = 12.7, 5.6 Hz, 1 H), 2.00 (d, J = 14.2 Hz, 1 H),
1.82−1.61 (m, 6 H), 1.46 (s, 9 H), 1.28−1.09 (m, 3 H), 1.07−0.94
(m, 2 H).; 13C NMR (126 MHz, CDCl3) δ 171.7, 170.8, 168.8, 89.3,
82.6, 78.9, 75.2, 62.9, 56.0, 52.8, 52.7, 51.7, 41.3, 38.3, 37.8, 32.0, 31.5,
28.0, 26.9, 26.3, 26.3. Anal. Calcd. for C23H35NO8: C, 60.91; H, 7.78;
N, 3.09. Found: C, 60.92; H, 7.84; N, 3.12. 6eB. Colorless solid: mp
1
114.6 °C; H NMR (500 MHz, CDCl3) δ 4.58 (dd, J = 10.4, 6.0 Hz,
1 H), 4.16 (dd, J = 8.8, 6.8 Hz, 1 H), 3.83 (d, J = 9.2 Hz, 1 H), 3.79 (d,
J = 1.1 Hz, 3 H), 3.71 (d, J = 1.1 Hz, 3 H), 2.78 (dd, J = 12.3, 8.4 Hz,
1 H), 2.70 (dd, J = 15.7, 9.1 Hz, 1 H), 2.60−2.48 (m, 2 H), 2.17 (dd,
J = 12.6, 5.4 Hz, 1 H), 2.04 (tt, J = 12.7, 6.4 Hz, 1 H), 1.70 (dd, J =
12.2, 10.2 Hz, 1 H), 1.46 (d, J = 1.0 Hz, 9 H), 1.06 (d, J = 6.5 Hz,
3 H), 0.97 (d, J = 6.5 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ 171.6,
170.9, 168.8, 89.4, 82.6, 78.8, 75.3, 63.4, 57.2, 52.8, 52.6, 51.6, 41.3,
38.1, 28.0, 27.9, 22.0, 21.64. Anal. Calcd. for C20H31NO8: C, 58.10; H,
7.56; N, 3.39. Found: C, 58.03; H, 7.60; N, 3.45. 6bB. Colorless solid:
mp 121.2−122.0 °C; 1H NMR (500 MHz, CDCl3) δ 4.60 (dd, J = 8.5,
6.6 Hz, 1 H), 4.45 (dd, J = 9.8, 3.9 Hz, 1 H), 3.80 (d, J = 9.6 Hz, 1 H),
3.79 (s, 3 H), 3.70 (s, 3 H), 2.78 (dd, J = 12.0, 8.9 Hz, 1 H), 2.76 (dd,
J = 12.9, 9.5 Hz, 1 H), 2.70 (dd, J = 15.8, 8.9 Hz, 1 H), 2.42 (d, J =
1
150.9−151.7 °C; H NMR (500 MHz, CDCl3) δ 4.60 (dd, J = 8.6,
6.7 Hz, 1 H), 4.45 (dd, J = 10.0, 3.7 Hz, 1 H), 3.80 (s, 3H), 3.79 (d, J =
8.8 Hz, 1 H), 3.71 (s, 3 H), 2.82−2.70 (m, 2 H), 2.69 (dd, J = 15.2,
8.6 Hz, 1 H), 2.51 (d, J = 10.9 Hz, 1 H), 2.23 (dd, J = 13.5, 3.6 Hz,
1 H), 1.90 (d, J = 13.9 Hz, 1 H), 1.79−1.61 (m, 6 H), 1.49−1.45 (m, 9
H), 1.26−0.92 (m, 5 H). 13C NMR (126 MHz, CDCl3) δ 171.9, 170.7,
169.8, 88.8, 82.5, 75.5, 75.4, 62.8, 56.8, 52.8, 52.6, 51.1, 41.6, 37.8,
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36.4, 32.3, 31.6, 28.0, 26.9, 26.3, 26.2. Anal. Calcd. for C23H35NO8: C,
60.91; H, 7.78; N, 3.09. Found: C, 60.88; H, 7.89; N, 3.15.
171.6, 169.8, 136.6, 134.0, 129.1, 128.8, 82.2, 67.9, 64.2, 55.2, 53.3,
53.2, 52.9, 43.2, 36.8, 29.1, 23.2, 19.4. Anal. Calcd. for C21H25NO6: C,
65.10; H, 6.50; N, 3.62. Found: C, 65.16; H, 6.60; N, 3.66.
(6aS*,9S*,9aR*) Dimethyl 2-Cyano-9-cyclohexyltetrahydro-
1H-cyclopenta[c]-isoxazolo[2,3-b]isoxazole-8,8(2H)-dicarboxy-
(7S*,7aR*)-Dimethyl 1-(2-(tert-Butoxy)-2-oxoacetyl)-7-cyclo-
hexyltetrahydro-azirino[1,2-b]cyclopenta[c]isoxazole-6,6(1H)-
dicarboxylate (7c). Colorless solid: mp 95.3−97.2 °C; 1H NMR
(500 MHz, CDCl3) δ 4.35 (t, J = 8.3 Hz, 1 H), 3.80 (s, 1 H), 3.67 (t,
J = 7.7 Hz, 1 H), 3.66 (s, 3 H), 3.61 (s, 3 H), 3.25 (q, J = 8.8 Hz, 1 H),
2.70 (d, J = 9.5 Hz, 1 H), 2.67 (dd, J = 6.5, 2.8 Hz, 1 H), 2.23 (dd, J =
14.4, 2.3 Hz, 1 H), 1.65−1.38 (m, 5 H), 1.43 (s, 9 H), 1.28−0.87 (m,
6 H); 13C NMR (126 MHz, CDCl3) δ 186.7, 171.3, 169.5, 159.4, 84.7,
83.4, 72.1, 64.7, 53.3, 52.9, 52.8, 52.6, 43.4, 39.4, 37.2, 33.1, 30.3, 27.8,
27.3, 26.8, 26.1; HRMS (ESI M + H) m/z 452.2267. Calcd for
C23H34NO8 452.2284.
(7S*,7aR*) Dimethyl 1-Benzoyl-7-cyclohexyltetrahydro-
azirino[1,2-b]cyclopenta[c]-isoxazole-6,6(1H)-dicarboxylate
(7d). White solid: mp 142.2−143.0 °C; 1H NMR (500 MHz, CDCl3)
δ 8.19 (dd, J = 8.2, 1.5 Hz, 2 H), 7.59 (td, J = 7.2, 1.3 Hz, 1 H), 7.48 (t,
J = 7.0 Hz, 2 H), 4.13 (t, J = 8.3 Hz, 1 H), 3.80 (s, 3H), 3.93−3.64 (m,
3 H), 3.76 (s, 3 H), 2.93 (ddd, J = 14.4, 9.5, 1.8 Hz, 1 H), 2.87 (s,
1 H), 2.38 (d, J = 14.4 Hz, 1 H), 1.89−1.43 (m, 6H), 1.45−0.97 (m,
5 H); 13C NMR (126 MHz, CDCl3) δ 192.3, 171.5, 169.8, 136.6,
134.0, 129.1, 128.8, 82.2, 68.0, 64.3, 55.3, 53.3, 53.2, 52.9, 43.2, 39.8,
37.2, 33.6, 30.1, 27.3, 26.9, 26.1. Anal. Calcd. for C24H29NO6: C, 67.43;
H, 6.84; N, 3.28. Found: C, 67.55; H, 7.02; N, 3.29.
1
late (6f). 6fA. Colorless solid: mp 182.2−183.0 °C; H NMR (500
MHz, CDCl3) δ 4.85 (dd, J = 10.0, 6.0 Hz, 1 H), 4.17 (dd, J = 9.3, 6.7
Hz, 1 H), 3.88 (d, J = 9.0 Hz, 1 H), 3.83−3.79 (m, 3 H), 3.72 (s, 3 H),
2.81 (dd, J = 12.5, 8.6 Hz, 1 H), 2.74 (dd, J = 13.0, 10.0 Hz, 1 H), 2.68
(dd, J = 15.5, 8.8 Hz, 1 H), 2.62 (d, J = 11.0 Hz, 1 H), 2.43 (dd, J =
13.0, 6.1 Hz, 1 H), 1.97 (d, J = 13.9 Hz, 1 H), 1.85−1.61 (m, 6 H),
1.29−0.93 (m, 5 H). 13C NMR (126 MHz, CDCl3) δ 171.3, 170.8,
116.5, 89.6, 75.9, 65.7, 62.8, 56.0, 53.0, 52.9, 50.9, 41.4, 39.4, 37.8,
32.2, 31.5, 26.8, 26.3, 26.2. Anal. Calcd. for C19H26N2O6: C, 60.30; H,
6.93; N, 7.40. Found: C, 60.37; H, 7.03; N, 7.48. 6fB. Colorless solid:
1
mp 118.6−119.6 °C; H NMR (500 MHz, CDCl3) δ 4.91 (d, J = 9.2
Hz, 1 H), 4.47 (dd, J = 8.7, 7.4 Hz, 1 H), 3.99 (d, J = 9.5 Hz, 1 H),
3.81 (s, 3 H), 3.72 (s, 3 H), 2.97 (dd, J = 16.7, 8.5 Hz, 1 H), 2.91−2.81
(m, 2 H), 2.58 (d, J = 10.9 Hz, 1 H), 2.34 (d, J = 13.7 Hz, 1 H), 1.86−
1.59 (m, 7 H), 1.33−0.91 (m, 5 H). 13C NMR (126 MHz, CDCl3) δ
171.5, 170.6, 117.6, 89.1, 76.6, 65.4, 62.6, 56.3, 53.0, 52.9, 50.4, 41.8,
38.3, 37.5, 32.2, 31.3, 26.8, 26.3, 26.2. Anal. Calcd. for C19H26N2O6: C,
60.30; H, 6.93; N, 7.40. Found: C, 60.02; H, 6.98; N, 7.21.
(6aS*,9S*,9aR*)-Trimethyl 9-Propyldihydro-1H-cyclopenta-
[c]isoxazolo[2,3-b]-isoxazole-2,8,8(2H,6H,9H)-tricarboxylate
1
(6g). 6gA. Pale yellow oil: H NMR (500 MHz, CDCl3) δ 4.75 (dd,
Preparation of (3S*,5R*,6S*,9S*)-Dimethyl 3-Hydroxy-9-
(hydroxymethyl)-6-isopropyl-2-oxo-1-azaspiro[4.4]nonane-
7,7-dicarboxylate 8. This conversion was performed according to a
method discussed in the literature.11 Raney Ni (1.5341 g) was added
to an aqueous solution of NaOH (1.2298 g in 15 mL of water), and
the resulting suspension was heated at 50 °C for 50 min. Saturated
NaHCO3 (5 mL) was added, and black precipitate was washed with
water (40 mL) eight times and with MeOH (40 mL) for four times.
The catalyst was added to MeOH solution of 6aA (107.0 mg, 0.29
mmol, 15 mL) under a hydrogen atmosphere, and the reaction mixture
was stirred vigorously for 24 h. Then, the reaction mixture was heated
at refluxing temperature for 24 h under a nitrogen atmosphere. Raney
Ni was filtered through a Celite pad and rinsed with MeOH. The
filtrate was concentrated, and the residue was purified by flash
chromatography (silica gel, hexane−EtOAc (20:1) then MeOH) to
J = 9.3, 6.9 Hz, 1 H), 4.22 (dd, J = 9.2, 6.6 Hz, 1 H), 3.84 (d, J = 9.2 Hz,
1 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.72 (s, 3 H), 2.92 (dd, J = 15.2, 8.7
Hz, 1 H), 2.73 (dd, J = 4.0, 10.0 Hz, 1 H), 2.72 (dd, J = 8.9, 12.9 Hz, 1
H), 2.47 (d, J = 6.5 Hz, 1 H), 2.46 (d, J = 10.0 Hz, 1 H), 1.81−1.70
(m, 1 H), 1.65 (dd, J = 13.2, 9.5 Hz, 1 H), 1.52−1.41 (m, 1 H), 1.41−
1.32 (m, 1 H), 1.31−1.22 (m, 1 H), 0.92 (t, J = 7.3 Hz, 3 H); 13C
NMR (126 MHz, CDCl3) δ 171.6, 170.7, 170.4, 90.0, 77.6, 76.1, 63.7,
52.7, 52.7, 52.5, 51.2, 49.5, 40.2, 37.8, 29.9, 20.7, 14.2; HRMS (ESI
M + H) m/z 372.1660. Calcd for C17H26NO8 372.1658. 6gB. Pale
1
yellow oil: H NMR (500 MHz, CDCl3) δ 4.57 (dd, J = 8.7, 6.6 Hz,
1 H), 4.54 (dd, J = 9.3, 4.3 Hz, 1 H), 3.81 (dd, J = 8.8, 1.2 Hz, 1 H),
3.76 (s, 3 H), 3.73 (s, 3 H), 3.71 (s, 3 H), 2.85 (ddd, J = 15.7, 9.0,
1.3 Hz, 1 H), 2.72 (dd, J = 13.4, 9.3 Hz, 1 H), 2.68 (dd, J = 13.1,
8.8 Hz, 1 H), 2.59 (dd, J = 9.4, 4.7 Hz, 1 H), 2.43 (dd, J = 13.6, 4.5 Hz,
1 H), 1.82−1.73 (m, 1 H), 1.66 (dd, J = 13.2, 9.2 Hz, 1 H), 1.49−1.39
(m, 1 H), 1.39−1.29 (m, 2 H), 0.92 (t, J = 7.1 Hz, 3 H); 13C NMR
(126 MHz, CDCl3) δ 171.5, 171.0, 170.9, 89.2, 76.3, 74.6, 63.6, 52.7,
52.6, 52.4, 51.1, 50.7, 40.3, 36.5, 29.9, 20.9, 14.3; HRMS (ESI M + H)
m/z 372.1653. Calcd for C17H26NO8 372.1658.
1,3-Dipolar Cycloaddition of 4c to Methyl Propiorate.
(7S*,7aR*) Dimethyl 1-(2-(tert-Butoxy)-2-oxoacetyl)-7-
isopropyltetrahydroazirino[1,2-b]cyclopenta[c]-isoxazole-
6,6(1H)-dicarboxylate (7a). General Procedure. Under a nitrogen
atmosphere, a mixture of 4c (328.3 mg, 1.15 mmol), MS4A (500 mg),
and methyl propiorate (0.8 mL) in dry toluene (4 mL) was heated at
refluxing temperature for 19 h. After cooling, filtration, and concen-
tration in vacuo, the crude product was purified by flash chromato-
graphy (silica gel/ethyl acetate−hexane 5:1) to give 7a in 90% yield
(427.4 mg). Pale yellow solid: mp 92.8−93.8 °C; 1H NMR (500 MHz,
CDCl3) δ 4.45 (dd, J = 13.5, 7.4 Hz, 1 H), 3.94−3.87 (m, 1 H), 3.75
(s, 3 H), 3.70 (s, 3H), 3.73−3.65 (m, 1 H), 3.45−3.34 (m, 1 H),
2.89−2.76 (m, 2 H), 2.30 (d, J = 14.5 Hz, 1 H), 1.78−1.69 (m, 1 H),
1.51 (s, 9 H), 0.98 (d, J = 6.9 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3 H). 13C
NMR (126 MHz, CDCl3) δ 186.7, 171.3, 169.5, 159.5, 84.7, 83.3, 71.7,
64.6, 53.3, 52.9, 52.8, 52.6, 43.5, 36.8, 28.7, 27.8, 22.9, 19.4. Anal.
Calcd. for C20H29NO8: C, 58.38; H, 7.10; N, 3.40. Found: C, 58.44; H,
7.14; N, 3.43.
1
give 8 in 79% yield (78.6 mg). White solid: mp 155.0−156.0 °C; H
NMR (500 MHz, CDCl3) δ 7.66 (br, 1 H), 5.06 (br, 1 H), 4.20 (d, J =
18.0 Hz, 1 H), 3.77 (s, 3 H), 3.71 (s, 3 H), 3.48 (br, 1 H), 2.66 (dd,
J = 14.5, 8.4 Hz, 1 H), 2.51 (dd, J = 12.7, 7.6 Hz, 1 H), 2.43 (d, J =
10.6 Hz, 1 H), 2.38−2.29 (m, 1 H), 2.27−2.15 (m, 1 H), 1.89 (dd, J =
12.7, 10.8 Hz, 1 H), 1.69 (dd, J = 14.6, 2.2 Hz, 1 H), 1.20 (br, 1 H),
0.94 (d, J = 6.4 Hz, 3 H), 0.86 (t, J = 5.7 Hz, 3 H); 13C NMR (126
MHz, CDCl3) δ 176.9, 173.3, 171.0, 70.5, 67.8, 61.8, 60.8, 60.8, 53.0,
52.6, 51.0, 40.6, 37.3, 27.4, 22.8, 22.6; HRMS (ESI M + H) m/z
344.1709. Calcd for C16H26NO7 344.1709.
ASSOCIATED CONTENT
* Supporting Information
■
S
Spectroscopic charts and preparation methods for compounds
1, 2, 3, 4, 5, 6, 7, and 8 and X-ray crystallographic data for 2d,
2h, 5, 6aA, 6eA, 6eB, and 7d. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ak10@yamaguchi-u.ac.jp.
■
(7S*,7aR*) Dimethyl 1-Benzoyl-7-isopropyltetrahydro-
azirino[1,2-b]cyclopenta[c]-isoxazole-6,6(1H)-dicarboxylate
(7b). White solid: mp 128.3−129.3 °C; 1H NMR (500 MHz, CDCl3)
δ 8.17 (d, J = 8.3 Hz, 2 H), 7.57 (t, J = 7.4 Hz, 1 H), 7.46 (dd, J = 11.1,
4.3 Hz, 2 H), 4.13 (t, J = 8.3 Hz, 1 H), 3.86 (dt, J = 9.5, 4.7 Hz, 1 H),
3.79 (s, 3 H), 3.74 (s, 3 H), 3.71 (dd, J = 4.4, 1.5 Hz, 1 H), 3.70 (s, 1
H), 3.69 (d, J = 7.9 Hz, 1 H), 2.99−2.90 (m, 1 H), 2.36 (dd, J = 14.6,
2.0 Hz, 1 H), 1.78 (dtd, J = 13.9, 7.0, 3.6 Hz, 1 H), 1.07 (d, J = 6.9 Hz,
3 H), 1.00 (d, J = 7.0 Hz, 3 H). 13C NMR (126 MHz, CDCl3) δ 192.3,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to Yamaguchi University for financial
aid from the The YU Strategic Program for Fostering Research
Activities (2010−2011).
2244
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Article
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision
D.02; Gaussian, Inc.: Wallingford, CT, 2004.
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