4,5-Unsubstituted 2,3-dihydroisoxazoles in the synthesis of racemic 4-substituted isoxazolidine-5-carbonitriles

Article abstract of DOI:10.1016/j.tet.2014.06.093

The synthesis of novel types of the 4-hydroxy- and 4-bromosubstituted isoxazolidines is described. Dihydroxylation reactions of 4,5-unsubstituted 2,3-dihydroisoxazoles proceed from the less hindered side and provide the major 3,4-trans-isoxazolidine-4,5-d

Full text of DOI:10.1016/j.tet.2014.06.093

Tetrahedron 70 (2014) 5585e5593
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4,5-Unsubstituted 2,3-dihydroisoxazoles in the synthesis of racemic
4-substituted isoxazolidine-5-carbonitriles
a
c
ꢁ a
ꢁ
ꢁ a
*
ꢁꢀ
ꢁ b
ꢁ
ꢀ
ꢀ
Daniela Benadikova , Julia Curillova , Tomas Lacek , Erik Rakovsky , Jan Moncol’ ,
a
,
ꢁꢀ ꢀ ꢁ d
Jana Dohanosova , Robert Fischer
a
ꢁ
Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovak Republic
Department of Inorganic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynska dolina, 842 15 Bratislava, Slovak Republic
Institute of Inorganic Chemistry, Technology and Materials, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovak Republic
Institute of Analytical Chemistry, Department of NMR Spectroscopy and Mass Spectrometry, Slovak University of Technology, Radlinskeho 9,
b
c
ꢁ
ꢁ
d
ꢁ
812 37 Bratislava, Slovak Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of novel types of the 4-hydroxy- and 4-bromosubstituted isoxazolidines is described.
Dihydroxylation reactions of 4,5-unsubstituted 2,3-dihydroisoxazoles proceed from the less hindered
side and provide the major 3,4-trans-isoxazolidine-4,5-diols in good yields. On the other hand, the hy-
droxybromination reaction of the model 3-phenyl-2,3-dihydroisoxazole predominantly proceeds with
3,4-cis selectivity. Isoxazolidine-5-carbonitriles have been prepared from isoxazolidines possessing
a good leaving group at C5 by treatment with TMSCN in the presence of TMSOTf.
Received 14 February 2014
Received in revised form 11 June 2014
Accepted 23 June 2014
Available online 27 June 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Isoxazolidines
2,3-Dihydroisoxazoles
Dihydroxylations
Cyanations
1. Introduction
It is well known that small five membered heterocyclic com-
pounds, such as isoxazolidines, pyrrolidines and pyrrazolidines
bearing hydroxyl groups are valuable building blocks in medicinal
chemistry.1 Therefore, our general effort has recently focused on
the preparation of 4-hydroxysubstituted isoxazolidine-5-
carbonitriles and their derivatives as a class of compounds bear-
ing a cyano group, so far not described in the literature, that is,
interesting for a versatile potential transformations.
Scheme 1. Reagents and conditions: (a) K2OsO4$2H2O, NMO, water/acetone, 10 ꢀC; (b)
NBS, water, THF, 0 ꢀC.
In this paper, we describe an extension of our studies on dihy-
droxylations and hydroxybrominations of 4,5-unsubstituted 2,3-
dihydroisoxazoles (A) as well as utilization of resulting iso-
xazolidine-4,5-diols (B) and 4-bromoisoxazolidin-5-ols (C) in the
synthesis of isoxazolidine-5-carbonitriles (D, E) (Scheme 2).
As a part of our continuous research in the field of isoxazolidinyl
nucleosides2 we observed that 4,5-unsubstituted 2,3-
dihydroisoxazoles are sometimes formed as byproducts in a pro-
3
€
cess of Vorbruggen nucleosidation. Based on this observation we
have recently developed a novel method for their preparation di-
rectly from 5-acetoxyisoxazolidines, which are readily available via
1,3-dipolar cycloaddition of nitrones with vinyl acetate.4 Recently,
we also reported optimal reaction conditions for the preparation
of isoxazolidine-4,5-diols
2 and 4-bromoisoxazolidin-5-ols 3
(Scheme 1).5
* Corresponding author. Tel.: þ421 2 59325 166; e-mail address: robert.fischer@
Scheme 2. General synthetic route to isoxazolidine-5-carbonitriles D and E from 4,5-
unsubstituted 2,3-dihydroisoxazoles A.
stuba.sk (R. Fischer).
http://dx.doi.org/10.1016/j.tet.2014.06.093
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

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D. Benadikova et al. / Tetrahedron 70 (2014) 5585e5593
Table 1
2. Results and discussion
Dihydroxylation reactions of 2,3-dihydroisoxazoles 1, 10 and 11
Entry Isoxazoles Conditions
Isoxazolidines a:b:c:db
47:47:6:d
Yield (%)d
84e
2.1. Synthesis of 2,3-dihydroisoxazoles
1
2
3
1
10 ꢀC, 1.5 h
rt, overnighta 12
ꢀCert, 6 h
13
2
10
11
75:25:d:d 29d
(84):(16)c 81f
At the beginning, we started with the preparation of initial 5-
acetoxyisoxazolidines. 1,3-Dipolar cycloaddition of nitrone 5 with
vinyl acetate provided non-separable mixture of 3,5-cis- and 3,5-
trans-5-acetoxyisoxazolidines 8a, b (8a/8b ratio 65:35) in total yield
of 69% (Scheme 3). Analogously to already reported 1,3-dipolar cy-
cloadditions of nitrones 4 and 6 with vinyl acetate,6,7 the reaction of
5 proceeded preferably through exo-TS providing predominantly
3,5-cis-isomer 8a. Subsequently, 2,3-dihydroisoxazole 10 was ob-
tained by reaction of 8a, b with BSTFA [N,O-bis(trimethylsilyl)tri-
fluoroacetamide] and TMSOTf in anhydrous NMP in very good yield
of 80% (Scheme 3). The isoxazoles 1 and 11 were prepared analo-
gously from respective mixtures of 3,5-cis- and 3,5-trans-isomers of
5-acetoxyisoxazolidines 7a, b6b and 9a, b7 according to procedure
we published earlier (Scheme 3).4 Compared to our results, 2,3-
dihydroisoxazole 10 has already been obtained using different
method from the corresponding 5-hydroxyisoxazolidine, however
in lower yield of 48%.8
2
a
The reaction was carried out with 0.03 equiv of K2OsO4$2H2O and 2.5 equiv of
NMO in neat acetone, the conversion of the initial 2,3-dihydroisoxazole 10 was 75%.
b
3,4-trans, 4,5-cis a; 3,4-trans, 4,5-trans b; 3,4-cis, 4,5-trans c; 3,4-cis, 4,5-cis d.
Ratio (aþb):(cþd) was determined from the mixture of 4,5-bis(acetoxy)
c
isoxazolidines.
d
Isolated yield.
The mixture of 2a, b.
The mixture of 13aed.
e
f
dihydroxylation of 10 turned to be more difficult. The presence of
water strongly inhibited the reaction and the reaction rate was
slightly improved when a higher amount of K2OsO4$2H2O and
NMO were used (Table 1, Entry 2). Despite the fact that the reaction
proceeded with incomplete conversion of 10 and with a disap-
pointingly low yield of isoxazolidine-4,5-diol 12, only the 3,4-trans-
isomers 12a, b were formed. The 4,5-cis/4,5-trans relative config-
uration of each diastereomer of isoxazolidine-4,5-diols 2, 12 and 13
was particularly assigned based on the coupling constant and the
multiplicity of the proton H-5 as follows. Either none or a small H-
4/H-5 coupling constant (J4,5e1.8 Hz) indicated 4,5-trans configu-
ration with a dihedral angle between H-4 and H-5 protons close to
w90ꢀ. A larger H-4/H-5 coupling constant (doublet or multiplet,
J4,5e4.5 Hz) occurred in 4,5-cis-isomers. The stereochemistry of
Scheme 3. Reagents and conditions: (a) vinyl acetate, sealed tube, 75 ꢀC; (b) BSTFA,
TMSOTf, NMP, 0 ꢀCert.
isoxazolidine-4,5-diols 12a, b as well as isoxazolidines 2a, b and
13a, b was later confirmed upon analysis of the NOESY 1D experi-
ments of the corresponding dibenzoates 14a, be16a, b, successfully
separated by preparative TLC.
2.2. Dihydroxylation reactions
In order to demonstrate utility of 4-unsubstituted 2,3-
dihydroisoxazoles in the synthesis of isoxazolidines, we focused
our interest on the dihydroxylation of their C4/C5 double bond
(Scheme 4).5 The reaction of 1 with K2OsO4$2H2O (0.01 equiv),
NMO (2 equiv, 50% w/w in water) in acetone/water (3:1, 0.2 M)
provided isoxazolidine-4,5-diol 2 in total yield of 84%. Dihydrox-
ylation afforded two major 3,4-trans-isoxazolidines 2a, b along
with traces of the minor 3,4-cis-4,5-trans-isomer 2c (Scheme 4,
Table 1). In the process of searching for the best reaction conditions
we found that the amount of K2OsO4$2H2O, the quantity of water in
the reaction mixture and the nature of the NMO removing agent are
crucial for successful dihydroxylation. Using more than 0.01 equiv
K2OsO4$2H2O decreased the yield. A large excess of water acceler-
ated the reaction at lower temperature (10 ꢀC) and avoiding the use
of sulfite in the work up improved the total yields. Dihydroxylation
reactions of 10 and 11 were carried out in the similar manner as
described for 1.
2.3. Hydroxybromination reactions
Earlier we have demonstrated, hydroxybromination of the 2,3-
dihydroisoxazole 1 with NBS (1 equiv) in THF in the presence of
water (2 equiv) at 0 ꢀC proceeds unselectively, providing mixture of
four diisomeric 4-bromoisoxazolidin-5-ols 3aed (3a/3b/3c/3d ratio
7:43:7:43) in total yield of 68% (Scheme 5, Table 2, Entry 1).5 Epi-
meric couples of 3a, b and 3c, d were separated by column chro-
matography on silica gel and their relative configuration was
confirmed based on NOE experiments. Now we explored various
reaction parameters and we showed that the amount of water, the
reaction temperature and the solvent have a significant effect on
the stereochemical outcome (Table 2). Interestingly, all reactions
performed at lower temperatures proceeded with 3,4-cis selectivity
(Table 2, Entries 2, 8e16) giving isoxazolidines 3c, d as major iso-
mers. Higher ratio of water in the mixture and substitution of THF
with more polar DMSO at ꢁ20 ꢀC significantly improved abundance
of 3c, d in the crude reaction mixture (Table 2, Entries 13, 15). It is to
be noted that the reaction in DMSO/water at ꢁ70 ꢀC did not further
improve the 3,4-cis/3,4-trans ratio, however other unidentified
byproducts were present in the crude mixture. We accordingly
performed hydroxybrominations of 1 at higher temperatures. Al-
though, the inversion of relative configuration could be expected to
favour formation of the 3,4-trans-isomers 3a, b, we achieved only
Scheme 4. Dihydroxylations of 2,3-dihydroisoxazoles 1, 10 and 11.
We observed that the reactions of 10 and 11 proceeded more
slowly and therefore required higher temperature. A mixture of
four isomers 13aed has been formed in the case of the EWG-
bearing dihydroisoxazole 11 in total yield of 81% (Table 1, Entry
3). The ratio between 13a, b and 13c, d was established after their
conversion into the corresponding acetates.5 Surprisingly, the
Scheme 5. Hydroxybromination reactions of 2,3-dihydroisoxazole 1.

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D. Benadikova et al. / Tetrahedron 70 (2014) 5585e5593
5587
Table 2
Table 3
Hydroxybromination reactions of 2,3-dihydroisoxazole 1
Preparation of 5-benzoyloxyisoxazolidines 14e18
Entry Solvent
T (ꢀC) 3a, b:3c, db Entry Solvent
T (ꢀC) 3a, b:3c, db
ꢁ20 25:75
Entry
Substrates
a:ba
Products
Yield (%)b
a:bc
1
2
3
4
5
6
7
8
THF/H2O
(2 equiv)a
THF/H2O
(9:1)
THF/H2O
(9:1)
THF/H2O
(9:1)
THF/H2O
(9:1)
THF/H2O
(2 equiv)a
DMSO/H2O
(9:1)
THF/H2O
(9:1)
0
50:50
9
10
11
12
13
14
15
16
NMP/H2O
(9:1)
DMF/H2O
(9:1)
DMA/H2O
(9:1)
1
2
3
4
5
2a, b
12a, b
13a, b
3a, b
3c, d
60:40
75:25
60:40
17:83
17:83
14a, b
15a, b
16a, b
17b
85
81
85
70
90
40:60
40:60
35:65
<5:>95
40:60
0
30:70
ꢁ20 20:80
ꢁ20 20:80
20 35:65
40 35:65
80 40:60
80 50:50
80 50:50
ꢁ20 35:65
18a, b
a
Ratio of a:b used in the reaction.
CH3CN/H2O ꢁ20 15:85
b
c
Isolated total yield.
(9:1)
Ratio of a:b determined from the crude reaction mixture by 1H NMR.
DMSO/H2O ꢁ20 15:85
(9:1)
CH3CN/H2O ꢁ20 15:85
(4:1)
DMSO/H2O ꢁ20 10:90
(4:1)
DMSO/H2O ꢁ70 10:90
(7:3)
a
The reaction was carried out in THF using 2 equiv of water.
4,5-cis a, c; 4,5-trans b, d.
b
equal ratios of 3a, b and 3c, d (Table 2, Entry 5e7). Reaction of 1 was
further optimized giving the best results in DMSO/water (4:1) at
ꢁ20 ꢀC. Finally, using these conditions, the mixture of iso-
xazolidines 3aed was obtained (3a, b/3c, d ratio 10:90) in total
yield of 82%.
Fig. 1. NOE enhancements observed in isoxazolidines 15a and 15b. Arrows show the
NOESY correlations.
These results strongly suggest the 3,4-trans, 4,5-cis-isomer. Ir-
radiation of proton H-4 of 15b resulted in similar enhancement for
the signals corresponding to H-3, and the protons of the methyl
group of the isopropyl substituent as described above, however
enhancement for the signal of H-5 was smaller in comparison with
15a. Moreover, the signal for H-5 was affected by irradiation of H-3.
These results confirmed 3,4-trans relative configuration in 15b and
showed that the protons H-4 and H-5 are in the trans relationship.
As in the above case concerning 15a, irradiation of H-3 of 15b led to
an increase in the signal for the methylene protons of the benzyl
group at N2. Along with the observed NOE enhancements, 4,5-cis/
4,5-trans relative configuration of 15a and 15b was assigned based
on analysis of the proton coupling constants between H-4 and H-5
nuclei. The minor 4,5-cis-isoxazolidine 15a showed a moderate
value of coupling constant between H-4 and H-5 (J4,5¼4.8 Hz),
whereas none H-4/H-5 coupling constant was observed in the
major isomer 15b, indicating its 4,5-trans configuration with a di-
hedral angle between H-4 and H-5 protons of w90ꢀ. The relative
configuration of each diastereomer of dibenzoates 14a, b and 16a,
b was assigned analogous with above mentioned results obtained
for isoxazolidines 15a and 15b. The stereochemistry of the iso-
xazolidines 17b and 18a was confirmed by X-ray crystallographic
analysis (Fig. 2).9
2.4. Preparation of 5-benzoyloxyisoxazolidines
With the aim to convert the 4-hydroxy- and 4-bromosubstituted
isoxazolidines in their corresponding isoxazolidine-5-carbonitriles,
isoxazolidine-4,5-diols 2a, b, 12a, b, 13a,
b
and 4-
bromoisoxazolidin-5-ols 3a, b and 3c, d were benzoylated using
standard conditions (Schemes 6 and 8). In all cases both the 4,5-cis-
14ae16a, 18a and 4,5-trans-isomers 14be16b, 18b were formed
with the exception of the reaction of 3a, b that afforded exclusively
a single 4,5-trans-isomer 17b. All isoxazolidines 14e18 were isolated
by flash column chromatography on silica gel. The total yields and
the ratios of 4,5-cis-a and 4,5-trans-b isomers are summarized in
Table 3. Their structure and relative stereochemistry were assigned
by NMR studies including NOESY 1D experiments. In accordance
with a work concerning determination of configuration and con-
formation of C5 O-ethyl and O-acetyl substituted isoxazolidines
reported by DeShong et al.,6a diastereomers 15a and 15b are most
stable in conformation where O-benzoyl group occupies pseu-
doaxial position on the five membered ring due to the stabilization
of an anomeric effect between a lone pair on the ring oxygen and the
pseudoaxial O-benzoyl substituent at C5 (Fig. 1). Analysis of the
NOESY 1D experiments of each diastereomers 15a and 15b un-
ambiguously determined their relative configuration (Fig. 1). Irra-
diation of proton H-4 of 15a resulted in enhancement of the signals
corresponding to H-5, and the protons of the methyl group of the
isopropyl substituent at C3. When H-3 was irradiated, a smaller NOE
was obtained for H-4, however a peak enhancement was observed
for the methylene protons of the benzyl group at N2.
2.5. SN-Reactions using TMSCN
Isoxazolidines 14e18 bearing benzoyloxy group at C5 are suit-
able precursors for the synthesis of 5-cyanoisoxazolidines using
TMSCN in the presence of TMSOTf (Schemes 7 and 8). Up to now,
only one example of preparation of 4-unsubstituted 5-
cyanoisoxazolidines is reported in the literature using this
method.10 To the best of our knowledge, we are the first to report
the cyanations of 4-hydroxy- and 4-bromosubstituted iso-
xazolidines. Hence, we focused our attention on the searching for
the suitable reaction conditions with regard to the yields and the
stereochemistry. We have found that the reaction of isoxazolidines
14a, b with 1.2 equiv of TMSCN in the presence of TMSOTf (1 equiv)
at 0 ꢀC in anhydrous CH2Cl2 (0.5 M) provides the mixture of two
isomers 4,5-cis-19a and 4,5-trans-19b (19a/19b ratio 20:80) in 74%
yield (Table 4, Entry 1). The cyanations of 15a, b and 16a, b pro-
ceeded with even higher diastereoselectivity in favour of 4,5-trans-
isomers 20b and 21b (Table 4, Entries 2, 3). The neighbouring effect
Scheme 6. Reagents and conditions: (a) BzCl, pyridine, DMAP, CH2Cl2, rt.

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D. Benadikova et al. / Tetrahedron 70 (2014) 5585e5593
5588
Fig. 2. Structures of 17b (left) and 18a (right).
Contrary to original conditions for isoxazolidines 14a, b and 15a, b,
the reactivity of 16a, b was improved when acetonitrile and lower
concentration were used (Table 4, Entry 3). All reaction conditions
and obtained results are summarized in Table 4. The substitution of
the C5 benzoyloxy group with cyano group was confirmed by1H
and 13C NMR experiments as follows.
Signals of the H-5 protons for both isomers 19a and 19b are
shifted to low field compared to H-5 protons of starting iso-
xazolidines 14a, b [14a:
¼4.80 ppm (d); 19b:
d
¼6.88 ppm (d); 14b:
d
¼6.63 ppm (s); 19a:
d
d
¼5.16 ppm (d)]. Moreover, the signal at
Scheme 7. Lewis acid-induced cyanations of 5-benzoyloxyisoxazolidines 14e17 using
TMSCN.
116.6 ppm in the 13C NMR (19b) is typical for the carbon atom of
a cyano group. Because, we were not able to separate each di-
astereomer of isoxazolidines 19a, b, the stereochemistry was
assigned from analysis of the NOESY 1D experiments obtained from
the corresponding mixture. The results showed that the major
isoxazolidine 19b has a 3,4-trans, 4,5-trans relative configuration
and the minor isoxazolidine 19a was assigned as 3,4-trans, 4,5-cis-
isomer. Irradiation of proton H-4 of 19a resulted in signal en-
hancement of two signals corresponding to H-5 (2.61%), and the
ortho protons of the phenyl ring (1.54%) while a smaller peak en-
hancement was observed for H-3 (0.55%). The signal for H-5 was
unaffected by irradiation of H-3. This can occur when phenyl sub-
stituent at C3 and the protons H-4 and H-5 are in the cis relation-
ship. Likewise as for 19a, irradiation of proton H-4 of the major 19b
resulted in similar enhancement of the signals corresponding to H-
3 (0.59%), and the ortho protons of the phenyl ring at C3 (1.59%),
however a smaller NOE was obtained for H-5 (0.98%) in comparison
with 19a. Additionally, irradiation of H-3 led to an increase in the H-
5 signal (0.28%). Thus, 3,4-trans relative configuration is consistent
with that for 19a, however benzoyloxy group and cyano group are
Scheme 8. Reagents and conditions: (a) BzCl, pyridine, DMAP, CH2Cl2, rt; (b) TMSCN,
TMSOTf, CH3CN, ꢁ20 ꢀC.
of the benzoyl group probably determines the 4,5-trans stereo-
selectivity. The type of solvent, temperature and the substrate
concentration are crucial for the successful progress of the reaction.
Whereas no cyanations of the isoxazolidines 14a, b and 15a, b oc-
curred in acetonitrile, the use of CH2Cl2 increased reactivity. All
reactions carried out in 0.1 M concentration were less clean then
those performed at higher concentrations. We have observed
a significant effect of the ester group at C3 in the case of iso-
xazolidines 16a, b. Herein, the reaction needed to be performed at
room temperature with 3 equiv of TMSCN to come to completion.
Table 4
Lewis acid-induced cyanations of 5-benzoyloxyisoxazolidines 14e18
Entry
Substrates
a:ba
Reaction conditions
Products
a:bb
Total yield (%)c
1
2
3
4
5
14a, b
15a, b
16a, b
17b
40:60
40:60
35:65
d
TMSCN (1.2 equiv), TMSOTf (1 equiv), 0 ꢀC, 3 h, CH2Cl2 (0.5 M)
TMSCN (1.2 equiv), TMSOTf (1 equiv), 0 ꢀC, 3 h, CH2Cl2 (0.5 M)
TMSCN (3 equiv), TMSOTf (1 equiv), rt, 24 h, CH3CN (0.1 M)
TMSCN (1.2 equiv), TMSOTf (1 equiv), 0 ꢀC, 1 h, CH2Cl2 (0.5 M)
TMSCN (1.2 equiv), TMSOTf (1 equiv), ꢁ20 ꢀC, 1 h, CH3CN (0.5 M)
19a, b
20a, b
21a, b
22a, b
23
20:80
10:90
10:90
70:30
<5:>95
74%
78%
83%
82%
82%
18a, b
40:60
a
Ratio of a:b used in the reaction.
b
c
Ratio of a:b determined from the crude reaction mixture by 1H NMR.
Isolated yield.

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D. Benadikova et al. / Tetrahedron 70 (2014) 5585e5593
5589
trans in the major isomer 19b. The 4,5-cis/4,5-trans relative con-
figuration of 19a and 19b could be assigned from analysis of H-5
proton coupling constant. The major 4,5-trans-isoxazolidine 19b
the substrate. The presence of an ester group at C3 decreased the
reaction rate of both dihydroxylation reaction and cyanation.
showed
a
small coupling constant between H-4 and H-5
4. Experimental section
(J4,5¼1.8 Hz), indicating that a dihedral angle between those two
protons is close to w90ꢀ, whereas a large H-4/H-5 coupling con-
stant was observed in the minor 4,5-cis-isomer 19a (J4,5¼6.6 Hz).
Similar results were obtained for cyanoisoxazolidines 20a, b and
21a, b. Subsequently, we have carried out cyanations of 4-
bromoisoxazolidines 17b and 18a, b (Table 4, Entries 4, 5). The re-
action of 17b proceeded with poor diastereoselectivity, even
afforded more 4,5-cis-isomer 22a (22a/22b ratio 70:30) to our
4.1. General
All melting points were measured on a Melting Point B-540
apparatus (Buchi) and are uncorrected. HRMS analyses were per-
€
formed on Orbittrap Velos Pro spectrometer (Thermo Fisher Sci-
entific). Infrared (IR) spectra were recorded on a Nicolet 5700 FT-IR
spectrometer with ATR Smart Orbit Diamond adapter (Thermo
Electron Corporation) and are reported as wavenumber (cmꢁ1).
NMR spectra were recorded on a Varian VRX-300 spectrometer (1H,
300 MHz and 13C, 75.4 MHz) and Varian INOVA-600 spectrometer
(1H, 600 MHz and 13C, 150.8 MHz) in CDCl3 using TMS as the in-
ternal standard. All MS analyses were performed on Agilent 1260B
LCMS system with multimode ion source (ESIþAPCI) in positive
mode, 50% scan and 50% SIM. TLC analysis was carried out using TLC
Silica gel 60 F254 (aluminium sheets, Merck) and visualized by UV
light or with permanganate solution followed by heating. Flash
surprise. Dichloromethane was again
acetonitrile.
a superior solvent to
On the other hand, the cyanation of the mixture 18a, b in ace-
tonitrile exclusively provided single 3,4-cis, 4,5-trans-5-
a
cyanoisoxazolidine 23 in very good yield (82%) (Scheme 8). In
analogy with the isoxazolidine-5-carbonitriles 19a, b, 4,5-cis/4,5-
trans relative configuration of each diastereomer of 4-
bromoisoxazolidines 22a and 22b was unambiguously assigned
from analysis of the NOESY 1D experiments for the protons H-3, H-
4 and H-5, respectively. In particular, irradiation of H-4 of the major
isomer 22a resulted in enhancement of the signal for H-5 (2.03%).
Likewise, when H-5 was irradiated, the signal corresponding to H-4
(2.23%) was enhanced, but no effect upon the intensity of H-3 was
observed. On the other hand, irradiation of H-4 of the minor isomer
22b produced much smaller enhancement of H-5 (0.58%). Similarly,
irradiation of H-5 led only to a small increase in H-4 (0.73%).
Moreover a peak enhancement was observed for H-3 (0.30%).
Above mentioned results clearly showed that the substituents at C4
and C5 of 22a occupied 4,5-cis relative configuration while in 22b
were in the trans relationship. These conclusions could be con-
firmed by analysis of the H-4/H-5 coupling constants. The major
4,5-cis-isoxazolidine 22a showed a large coupling constant be-
tween H-4 and H-5 (J4,5¼7.1 Hz), whereas a small H-4/H-5 coupling
constant was observed in the minor isomer 22b (J4,5¼2.8 Hz), in-
dicating its 4,5-trans configuration. The configuration of 5-
cyanoisoxazolidine 23 was also assigned from analysis of the
NOESY 1D experiments. The results were similar to those obtained
for 22b and confirmed the 3,4-cis, 4,5-trans configuration. Irradia-
tion of H-4 had a small effect upon the intensity of H-5 (0.35%),
however a large NOE was obtained for H-3 (2.43%). Irradiation of H-
3 resulted in a large enhancement of the signal for H-4 (2.50%).
€
column chromatography was performed on Buchi system (Pump
Manager C-615 and Fraction Collector C-660) using Normasil 60
silica gel (0.040e0.063 mm) (VWR). All solvents were dried and
distilled according to conventional methods. NMP, DCM and ace-
tonitrile were stored over molecular sieves and handled under inert
atmosphere. All reagents were purchased from Aldrich, Acros Or-
ganics, Alfa-Aesar, Merck and Mikrochem Trade and were used
without further purification.
4.2. 1,3-Dipolar cycloaddition of nitrone 5 with vinyl acetate
4.2.1. (ꢂ)-2-Benzyl-3-isopropylisoxazolidin-5-yl acetate (8a, b). A
solution of nitrone 511 (2.9 g, 16.36 mmol) in vinyl acetate (30 mL)
was stirred in sealed tube at 75 ꢀC for 24 h. When starting nitrone
had been consumed (TLC, ethyl acetate), vinyl acetate was evapo-
rated in vacuo and the products were isolated by flash column
chromatography (hexanes/ethyl acetate 80:20) to give the mixture
of two diastereoisomers 3,5-cis-8a and 3,5-trans-8b (2.98 g,
11.32 mmol, 69%, 8a/8b ratio 65:35) as a colourless oil. 1H NMR data
of each diastereomer were extracted from the corresponding
mixture. 8a: 1H NMR (300 MHz, CDCl3):
d
¼0.91 (d, 3H, J¼7.0 Hz),
0.93 (d, 3H, J¼7.0 Hz), 1.79e1.95 (m, 1H), 2.04 (s, 3H), 2.18 (ddd, 1H,
J¼13.6, 7.0, 1.8 Hz), 2.52 (ddd, 1H, J¼13.6, 8.4, 6.2 Hz), 2.71e2.78 (m,
1H), 3.92 (d, 1H, J¼13.9 Hz), 4.07 (d, 1H, J¼13.9 Hz), 6.30 (dd, 1H,
J¼6.2, 1.8 Hz), 7.22e7.39 (m, 5H); 8b: 1H NMR (300 MHz, CDCl3):
3. Conclusion
In conclusion, novel types of the 4-hydroxy- and 4-
bromosubstituted isoxazolidines were synthesized from 4,5-
unsubstituted 2,3-dihydroisoxazoles using dihydroxylation and
hydrobromination reactions. Dihydroxylation reactions with
K2OsO4$2H2O in the presence of NMO in acetone/water proceeded
from the less hindered side and provided the major 3,4-trans-iso-
xazolidine-4,5-diols in good yields with exception of 3-isopropyl-
2,3-dihydroisoxazole. On the other hand, the hydrobromination
reaction of the model 3-phenyl-2,3-dihydroisoxazole pre-
dominantly proceeded with 3,4-cis selectivity. In this case, the
amount of water, temperature and the type of solvent had a sig-
nificant effect on the stereochemical outcome of the reaction. In
order to prepare isoxazolidine-5-carbonitriles, 4-hydroxy- and 4-
bromosubstituted isoxazolidines were transformed into iso-
xazolidines possessing a good leaving group at C5. Substitution
reactions were carried out with TMSCN in the presence of TMSOTf
and proceeded with high 4,5-trans selectivity. Moreover, reaction of
3,4-cis-4-bromoisoxazolidines exclusively afforded single 3,4-cis,
4,5-trans-isoxazolidine-5-carbonitrile. In general, we observed
a strong solvent effect on the course of cyanations depending on
d
¼0.89 (d, 3H, J¼7.0 Hz), 0.94 (d, 3H, J¼7.0 Hz), 1.62e1.76 (m, 1H),
2.08 (s, 3H), 2.34 (ddd, 1H, J¼13.6, 8.4, 5.1 Hz), 2.44 (ddd, 1H, J¼13.6,
7.0, 1.1 Hz), 2.99e3.07 (m, 1H), 4.02 (d, 1H, J¼13.6 Hz), 4.19 (d, 1H,
J¼13.6 Hz), 6.33 (d, 1H, J¼5.1 Hz), 7.22e7.39 (m, 5H); 13C NMR data
are given for the mixture 8a, b. 13C NMR (75.4 MHz, CDCl3):
d
¼17.0,
18.4, 20.2, 20.7, 21.4, 21.5, 28.9, 31.6, 37.3, 39.1, 61.4, 65.1, 69.0, 69.4,
95.8, 98.2, 127.3 (ꢃ2), 128.2, 128.3, 129.1 (ꢃ2), 136.9, 137.6, 170.0,
170.6; MS (ESIþAPCI): m/z for C15H21NO3 (MþH)þ: 264.2.
4.3. Elimination reaction in the presence of TMSOTf
4.3.1. (ꢂ)-2-Benzyl-3-isopropyl-2,3-dihydroisoxazole (10). The re-
action flask was charged with 5-acetoxyisoxazolidines 8a, b (2.8 g,
10.63 mmol), sealed with a rubber septum and filled with argon.
Anhydrous NMP (53 mL) was added followed by BSTFA (3.4 mL,
12.76 mmol). The stirred solution was cooled in an ice/water-bath
(2e5 ꢀC) and TMSOTf (0.2 mL, 1.1 mmol) was added. Stirring was
continued at room temperature for 1.5 h with exclusion of the
moisture. When the initial 5-acetoxyisoxazolidines had been con-
sumed (TLC, hexanes/ethyl acetate 80:20), the reaction mixture

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D. Benadikova et al. / Tetrahedron 70 (2014) 5585e5593
5590
was cooled in an ice/water-bath, satd aqueous NaHCO3 (25 mL) and
Et2O (25 mL) were added and the mixture was vigorously stirred for
5 min. The precipitated solid was dissolved by addition of water
(25 mL). Water layer was removed and the organic layer was
washed three times with water (20 mL), dried with Na2SO4 and the
solvent was evaporated in vacuo (bath temperature bellow 35 ꢀC).
The product was isolated by flash column chromatography (hex-
anes/ethyl acetate 95:5) to give 2,3-dihydroisoxazole 10 (1.73 g,
8.51 mmol, 80%) as a colourless oil that becomes darker over time.
IR (thin film): 2956, 2870, 1622, 1454, 1123, 1049, 1029, 999, 729,
4.1 Hz), 4.67 (d, 1H, J¼3.5 Hz), 5.30 (s, 1H), 5.36 (d, 1H, J¼4.1 Hz),
7.23e7.37 (m, 10H); 13C NMR (75.4 MHz, CDCl3):
62.0, 62.8, 65.3, 71.4, 73.2, 78.1, 83.8, 95.0, 101.5, 127.8, 127.9, 128.3,
d
¼13.9, 14.0, 61.7,
128.4, 129.6, 129.8,135.3, 135.8,170.3, 170.6; MS (ESIþAPCI): m/z for
C
13H17NO5 (MþH)þ: 268.2; 13c, d: 1H NMR (300 MHz, CDCl3):
d
¼1.17e1.25 (m, 6H), 3.59 (d, 1H, J¼7.6 Hz), 3.98 (d, 1H, J¼4.1 Hz),
4.08e4.21 (m, 7H), 4.34 (d, 1H, J¼12.9 Hz), 4.60e4.68 (m, 2H),
5.31e5.38 (m, 2H), 7.28e7.39 (m, 10H); 13C NMR (75.4 MHz, CDCl3):
d
¼14.1 (ꢃ2), 61.6, 61.7, 61.8, 65.8, 69.4, 70.0, 75.8, 81.2, 94.4, 101.0,
127.9 (ꢃ2), 128.4 (ꢃ2), 129.6 (ꢃ2), 135.0, 135.7, 168.2, 168.8; MS
697 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
¼0.82 (d, 3H, J¼7.0 Hz), 0.83
(ESIþAPCI): m/z for C13H17NO5 (MþH)þ: 268.2.
(d, 3H, J¼7.0 Hz), 1.48e1.64 (m, 1H), 3.53e3.56 (m, 1H), 3.77 (d, 1H,
J¼12.9 Hz), 4.13 (d, 1H, J¼12.9 Hz), 4.86 (t, 1H, J¼2.9 Hz), 6.42e6.45
4.5. Hydroxybromination reactions
(m, 1H), 7.24e7.42 (m, 5H); 13C NMR (75.4 MHz, CDCl3):
d¼18.1,
18.5, 33.6, 63.9, 75.0, 97.6, 127.4, 128.3, 129.4, 136.9, 141.6; HRMS
4.5.1. (ꢂ)-Benzyl-4-bromo-3-phenylisoxazolidin-5-ol
(3aed). A
(ESI): calcd for C13H17NO (MþH)þ: 204.1388, found: 204.1379.
stirred solution of 2,3-dihydroisoxazole 14 (630 mg, 2.65 mmol) in
THF/water (53 mL, 9:1, v/v) or in DMSO/water (53 mL, 4:1, v/v) was
cooled to ꢁ20 ꢀC and solid NBS (460 mg, 2.60 mmol) was added by
portions over a period of 30 min. The stirring was continued at this
temperature until the initial 2,3-dihydroisoxazole disappeared
(30 min, TLC, hexanes/AcOEt 80:20). Thereafter, the mixture was
diluted with water (50 mL) and extracted with ether (50 mL). The
organic layer was washed with water (2ꢃ50 mL), dried with Na2SO4
and the solvent was evaporated in vacuo. Products were isolated by
flash column chromatography (hexanes/AcOEt 90:10) to provide
two couples of diastereoisomers 3,4-trans-3a, b and 3,4-cis-3c, d in
ratio and with the yield depending on the applied solvent: The re-
action carried out in THF/water (9:1, v/v) gave 3a, b (250 mg,
0.75 mmol, 28%) and 3c, d (470 mg, 1.41 mmol, 53%). The reaction
performed in DMSO/water (4:1, v/v) afforded 3a, b (70 mg,
0.21 mmol, 8%) and 3c, d (655 mg, 1.96 mmol, 74%). 3a, b, colourless
solid, mp 88e89 ꢀC (recrystallized from hexanes, 3a/3b ratio 17:83);
IR (thin film): 3460, 3032, 1454, 1070, 1025, 951, 760, 753, 699,
4.4. Dihydroxylation reactions
4.4.1. (ꢂ)-2-Benzyl-3-isopropylisoxazolidine-4,5-diol (12a, b). 2,3-
Dihydroisoxazole 10 (400 mg, 1.97 mmol) was dissolved in ace-
tone (10 mL), the solution was cooled to 2 ꢀC (ice/water bath) and
aqueous NMO (1.01 mL, 4.93 mmol, 50%, w/w) was added followed
by K2OsO4$2H2O (22.0 mg, 0.06 mmol). Afterwards, the mixture
was vigorously stirred at room temperature over night. Despite of
incomplete conversion of the starting 2,3-dihydroisoxazole (TLC,
hexanes/ethyl acetate 60:40), the reaction was quenched by di-
lution with water and repeatedly extracted with CH2Cl2. The
combined organic layers were dried with Na2SO4, filtered and the
solvent was evaporated in vacuo (bath temperature bellow 35 ꢀC).
The isoxazolidine-4,5-diols 12a, b were isolated by flash column
chromatography (hexanes/ethyl acetate 60:40) as a mixture of two
non-separable epimers 3,4-trans-4,5-cis-12a and 3,4-trans-4,5-
trans-12b (135 mg, 0.57 mmol, 29%, 12a/12b ratio 75:25) as a col-
ourless oil. NMR data of each diastereomer were extracted from the
corresponding mixture. 12a: 1H NMR (300 MHz, CDCl3):
532 cmꢁ1; (4,5-trans)-3b: 1H NMR (300 MHz, CDCl3):
d¼3.46 (br s,
1H), 3.76 (d, 1H, J¼14.8 Hz), 3.96 (d, 1H, J¼8.0 Hz), 4.03 (d, 1H,
J¼14.8 Hz), 4.20 (dd, 1H, J¼8.0, 1.8 Hz), 5.50 (d, 1H, J¼1.8 Hz),
d
¼0.97e1.00 (m, 6H), 1.72e1.86 (m, 1H), 2.75 (dd, 1H, J¼6.5, 6.1 Hz),
7.28e7.51 (m, 10H); 13C NMR (75.4 Hz, CDCl3):
d
¼59.5, 59.9, 80.1,
4.06 (d, 1H, J¼13.4 Hz), 4.16e4.22 (m, 1H), 4.26 (d, 1H, J¼13.4 Hz),
102.1, 127.5, 128.0, 128.3, 128.8, 128.9, 129.1, 134.5, 136.4. Partial 1H
5.16e5.21 (m, 1H), 7.25e7.39 (m, 5H); 13C NMR (75.4 MHz CDCl3):
NMR data extracted from the mixture of 3a, b for the minor (4,5-cis)-
d
¼18.6, 19.6, 30.4, 65.9, 75.0, 77.5, 95.6, 127.3, 128.3, 129.0, 137.8;
3a: 1H NMR (600 MHz, CDCl3):
d
¼4.05 (d,1H, J¼13.5 Hz), 4.10 (d,1H,
12b: 1H NMR (300 MHz, CDCl3):
d
¼0.97e1.00 (m, 6H), 1.87e1.99
J¼13.5 Hz), 4.24 (d, 1H, J¼10.6 Hz), 4.28 (dd, 1H, J¼10.0, 4.1 Hz), 5.41
(d, 1H, J¼4.1 Hz); MS (ESIþAPCI): m/z for C16H16BrNO2 (MþH)þ:
334.0/336.0; 3c, d, yellowish foam (3c/3d ratio 17:83); IR (thin film):
3288, 3032, 1454, 1228, 1049, 1015, 751, 717, 693, 517 cmꢁ1; (4,5-
(m, 1H), 2.55 (dd, 1H, J¼6.5, 3.8 Hz), 3.93 (d, 1H, J¼14.2 Hz),
4.25e4.28 (m, 1H), 4.26 (d, 1H, J¼14.2 Hz), 5.11 (s, 1H), 7.25e7.39
(m, 5H); 13C NMR (75.4 MHz, CDCl3):
d¼18.1, 20.4, 28.3, 62.1, 78.8,
82.4, 101.6, 127.5, 128.3, 129.2, 137.0; MS (ESIþAPCI): m/z for
trans)-3d: 1H NMR (300 MHz, CDCl3):
d¼3.54 (br s, 1H), 4.02 (d, 1H,
C
13H19NO3 (MþH)þ: 238.2.
J¼14.2 Hz), 4.23 (d,1H, J¼14.2 Hz), 4.49 (d,1H, J¼4.3 Hz), 4.57 (d,1H,
J¼4.3 Hz), 5.60 (s,1H), 7.28e7.49 (m,10H); 13C NMR (75.4 Hz, CDCl3):
4.4.2. (ꢂ)-Ethyl 2-benzyl-4,5-dihydroxyisoxazolidine-3-carboxylate
(13aed). 2,3-Dihydroisoxazole 114 (730 mg, 3.13 mmol) was dis-
solved in acetone/water (16 mL, 3/1, v/v), the solution was cooled to
2 ꢀC (ice/water bath) and aqueous NMO (1.3 mL, 6.26 mmol, 50%, w/
w) was added followed by K2OsO4$2H2O (11.5 mg, 0.03 mmol). The
mixture was vigorously stirred and the temperature was allowed to
rise to room temperature. When starting 2,3-dihydroisoxazole had
disappeared after 6 h (TLC, hexanes/ethyl acetate 67:33), the mix-
ture was diluted with water and repeatedly extracted with CH2Cl2.
The combined organic layers were dried with Na2SO4, filtered and
the solvent was evaporated in vacuo (bath temperature bellow
35 ꢀC). The isoxazolidine-4,5-diols 13aed were isolated by flash
column chromatography (hexanes/ethyl acetate 50:50) to give
epimeric couple 3,4-trans-13a, b (410 mg, 1.54 mmol, 49%) and
epimeric couple 3,4-cis-13c, d (270 mg, 1.01 mmol, 32%) as the
colourless oils. NMR data are given for the corresponding epimeric
d
¼59.4, 62.6, 69.7, 102.1, 127.5, 128.3 (ꢃ2), 128.4, 128.5, 129.1, 134.8,
136.6. Partial 1H NMR data extracted from the mixture of 3c, d for the
minor (4,5-cis)-3c: 1H NMR (600 MHz, CDCl3):
d
¼3.79 (d, 1H,
J¼14.7 Hz), 4.18 (d,1H, J¼14.7 Hz), 4.19 (d,1H, J¼6.5 Hz), 4.83 (dd,1H,
J¼6.5, 4.7 Hz), 5.46 (d, 1H, J¼4.7 Hz); MS (ESIþAPCI): m/z for
C
16H16BrNO2 (MþH)þ: 334.0/336.0.
4.6. Typical experimental procedure for the benzoylation of
isoxazolidine-4,5-diols
4.6.1. (ꢂ)-2-Benzyl-3-phenylisoxazolidine-4,5-diyl dibenzoate (14a,
b). The isoxazolidine-4,5-diols 2a, b5 (340 mg, 1.25 mmol) were
dissolved in anhydrous CH2Cl2 (13 mL), pyridine (0.42 mL,
5.20 mmol) and DMAP (30 mg, 0.26 mmol) were added followed by
benzoyl chloride (0.45 mL, 3.90 mmol). The reaction mixture was
stirred at room temperature for 24 h. When no starting iso-
xazolidine-4,5-diols had been detected by TLC (hexanes/ethyl
acetate¼60/40), the mixture was diluted with water and extracted
with CH2Cl2 (10 mL) two times. Combined organic layers were
couples. 13a, b: 1H NMR (300 MHz, CDCl3):
3.53 (d, 1H, J¼2.9 Hz), 3.64 (d, 1H, J¼7.0 Hz), 4.03e4.16 (m, 6H), 4.27
(d, 1H, J¼12.9 Hz), 4.38 (d, 1H, J¼12.3 Hz), 4.64 (dd, 1H, J¼7.0,
d
¼1.12e1.24 (m, 6H),

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D. Benadikova et al. / Tetrahedron 70 (2014) 5585e5593
5591
dried over Na2SO4 and the solvent was evaporated in vacuo.
Products were isolated by flash column chromatography (hexanes/
diethyl ether 85:15) to provide isoxazolidines 14a, b as a mixture of
two epimers 3,4-trans, 4,5-cis-14a and 3,4-trans, 4,5-trans-14b
(510 mg, 1.06 mmol, 85%, 14a/14b ratio 40:60) as a colourless oil.
With the aim of complete characterization of new compounds, the
analytical sample was used in preparative TLC (hexanes/CH2Cl2
33:67) to give pure isomers 14a and 14b. 14a, colourless solid, mp
111e113 ꢀC; IR (thin film): 2979, 1716, 1452, 1276, 1250, 1234, 1130,
68.1, 77.5, 94.3, 128.0, 128.5 (x 3), 128.6, 129.2, 129.7, 129.8 (ꢃ2),
133.6, 133.7, 135.0, 164.6, 164.9, 168.3; HRMS (ESI): calcd for
C
C
27H25NO7 (MþH)þ: 476.1709, found: 476.1692; calcd for
27H25NO7 (MþNa)þ: 498.1529, found: 498.1509; 16b, colourless
oil; IR (thin film): 2979, 1722, 1451, 1247, 1177, 1095, 1067, 1024, 945,
708 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d¼1.26 (t, 3H, J¼7.0 Hz), 3.83
(d, 1H, J¼3.8 Hz), 4.12e4.30 (m, 2H), 4.37 (s, 2H), 6.13 (d, 1H,
J¼3.8 Hz), 6.66 (s, 1H), 7.29e7.64 (m, 11H), 8.00 (d, 2H, J¼7.7 Hz),
8.10 (d, 2H, J¼7.7 Hz); 13C NMR (75.4 MHz, CDCl3):
¼14.0, 62.0,
d
1097, 1019, 695 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼4.19 (d, 1H,
62.1, 71.1, 84.3, 97.7, 127.8, 128.4 (ꢃ2), 128.6 (ꢃ2), 129.3, 129.7, 129.9,
130.1, 133.5, 133.8, 134.8, 165.2 (ꢃ2), 167.6; HRMS (ESI): calcd for
J¼14.1 Hz, NCH2Ph), 4.31 (d, 1H, J¼14.1 Hz, NCH2Ph), 4.51 (d, 1H,
J¼8.8 Hz, H-3), 5.70 (dd, 1H, J¼8.8, 4.1 Hz, H-4), 6.88 (d, 1H,
J¼4.1 Hz, H-5), 7.18e7.61 (m, 12H), 7.90e7.98 (m, 8H); 13C NMR
C
C
27H25NO7 (MþH)þ: 476.1709, found: 476.1690; calcd for
27H25NO7 (MþNa)þ: 498.1529, found: 498.1507.
(75.4 Hz, CDCl3):
d
¼62.7, 69.1, 80.3, 93.6, 127.5, 127.8, 128.3, 128.4
(ꢃ2), 128.6, 128.8, 128.9 (ꢃ2), 129.5, 129.7, 129.8, 133.4, 133.5 135.7,
135.9, 164.8, 165.0; HRMS (ESI): calcd for C30H25NO5 (MþH)þ:
480.1811, found: 480.1796; 14b, colourless oil; IR (thin film): 3032,
4.7. Typical experimental procedure for the benzoylation of
4-bromoisoxazolidin-5-ols
1721, 1451, 1248, 1105, 1095, 1059, 1023, 952, 695 cmꢁ1
;
1H NMR
4.7.1. (ꢂ)-2-Benzyl-4-bromo-3-phenylisoxazolidin-5-yl benzoate (18a,
b). 4-Bromoisoxazolidin-5-ols 3c, d (440 mg, 1.32 mmol) were dis-
solved in anhydrous CH2Cl2 (5 mL), pyridine (0.21 mL, 2.60 mmol)
and DMAP (30 mg, 0.25 mmol) were added followed by benzoyl
chloride (0.23 mL, 1.98 mmol). The reaction mixture was stirred at
room temperature 24 h. When no starting isoxazolidin-5-ols had
been detected by TLC (hexanes/ethyl acetate 80:20), the mixture was
diluted with water (10 mL) and extracted with CH2Cl2 (10 mL) two
times. Combined organic layers were dried over Na2SO4 and the
solvent was evaporated in vacuo. Products were isolated by flash
column chromatography (hexanes/ethyl acetate 95:5) to provide two
single isoxazolidines 4,5-cis-18a (220 mg, 0.50 mmol, 39%) and 4,5-
trans-18b (300 mg, 0.68 mmol, 51%) as colourless solids. 18a, mp
117e118 ꢀC; IR (thin film): 3032, 1712, 1452, 1261, 1064, 1039, 1014,
(300 MHz, CDCl3):
d
¼4.08 (d, 1H, J¼14.7 Hz, NCH2Ph), 4.17 (d, 1H,
J¼5.3 Hz, H-3), 4.21 (d, 1H, J¼14.7 Hz, NCH2Ph), 5.84 (d, 1H,
J¼5.3 Hz, H-4), 6.63 (s, 1H, H-5), 7.20e7.63 (m, 12H), 8.03e8.08 (m,
8H); 13C NMR (75.4 Hz, CDCl3):
d
¼60.0, 74.7, 88.4, 98.2, 127.3, 128.0,
128.2, 128.4, 128.5 (ꢃ2), 128.8, 128.9 (ꢃ2), 129.6, 129.8, 130.0, 133.4,
133.6, 136.0, 136.1, 165.2, 165.3; HRMS (ESI): calcd for C30H25NO5
(MþH)þ: 480.1811, found: 480.1798.
4.6.2. (ꢂ)-2-Benzyl-3-isopropylisoxazolidine-4,5-diyl
dibenzoate
(15a, b). The mixture of two epimers 3,4-trans, 4,5-cis-15a and 3,4-
trans, 4,5-trans-15b (15a/15b ratio 40:60); yield 81% (790 mg,
1.8 mmol) after flash column chromatography (hexanes/diethyl
ether 90:10), colourless oil. With the aim of complete character-
ization of new compounds, the analytical sample was used in
preparative TLC (hexanes/CH2Cl2 33:67) to give pure isomers 15a
and 15b. 15a, colourless solid, mp 91e92 ꢀC; IR (thin film): 2970,
754, 713, 697 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d¼3.96 (d, 1H,
J¼14.8 Hz), 4.25 (d,1H, J¼8.3 Hz), 4.27 (d,1H, J¼14.9 Hz), 4.98 (dd,1H,
J¼8.3, 5.4 Hz), 6.75 (d, 1H, J¼5.4 Hz), 7.18e7.64 (m, 13H), 8.10e8.17
1721, 1452, 1279, 1255, 1241, 1126, 1042, 1012, 713 cmꢁ1
;
1H NMR
(m, 2H); 13C NMR (75.4 MHz, CDCl3):
d¼55.0, 60.0, 71.3, 93.7, 127.6,
(300 MHz, CDCl3):
d
¼0.99e1.04 (m, 6H), 1.89e2.00 (m, 1H), 3.34 (t,
128.3, 128.4, 128.6, 128.7, 129.1, 129.5, 129.7, 130.3, 133.6, 135.9, 136.2,
165.4; HRMS (ESI): calcd for C23H20Br79NO3 (MþH)þ: 438.0705,
found: 438.0693; calcd for C23H20Br79NO3 (MþNa)þ: 460.0524,
found: 460.0513; 18b, mp 129e131 ꢀC; IR (thin film): 3008, 1719,
1H, J¼6.1 Hz), 4.25 (d, 1H, J¼14.4 Hz), 4.48 (d, 1H, J¼14.4 Hz), 5.73
(dd,1H, J¼6.1, 4.8 Hz), 6.84 (d,1H, J¼4.8 Hz), 7.26e8.17 (m, 15H); 13
C
NMR (75.4 MHz, CDCl3):
d
¼18.6, 19.3, 28.5, 65.6, 71.90, 82.8, 98.4,
127.6, 128.4 (ꢃ2), 128.5, 129.0, 129.3, 129.5, 129.7, 129.68, 129.8,
133.4, 133.6, 136.8, 164.7, 165.2; HRMS (ESI): calcd for C27H27NO5
(MþH)þ: 446.1967, found: 446.1957; calcd for C27H27NO5 (MþNa)þ:
468.1787, found: 468.1775; 15b, colourless oil; IR (thin film): 2960,
1450, 1237, 1058, 917, 742, 708, 694, 671 cmꢁ1
;
1H NMR (300 MHz,
CDCl3):
d
¼4.06 (d, 1H, J¼14.3 Hz), 4.36 (d, 1H, J¼14.3 Hz), 4.58 (d, 1H,
J¼4.2 Hz), 4.68 (d, 1H, J¼4.3 Hz), 6.71 (s, 1H), 7.13e7.72 (m, 12H),
7.90e7.97 (m, 2H), 8.12e8.20 (m, 1H); 13C NMR (75.4 MHz, CDCl3):
1720, 1451, 1257, 1106, 1079, 1062, 1024, 936, 706 cmꢁ1
;
1H NMR
d
¼57.8, 61.4, 68.6, 101.1, 127.5, 128.2, 128.4, 128.5 (ꢃ2), 128.7, 128.8,
(300 MHz, CDCl3):
d
¼0.99e1.04 (m, 3H), 1.18 (d, 3H, J¼6.5 Hz),
129.1, 129.7, 129.8, 130.5, 133.6, 133.8, 134.5,135.4,164.5; HRMS (ESI):
2.00e2.12 (m, 1H), 3.08 (dd, 1H, J¼6.5, 3.5 Hz), 4.23 (d, 1H,
J¼14.4 Hz), 4.28 (d, 1H, J¼14.4 Hz), 5.84 (d, 1H, J¼3.5 Hz), 6.60 (s,
calcd for C23H20Br79NO3 (MþH)þ: 438.0705, found: 438.0693.
1H), 7.25e8.09 (m, 15H); 13C NMR (75.4 MHz, CDCl3):
d
¼18.0, 20.2,
4.7.2. (ꢂ)-2-Benzyl-4-bromo-3-phenylisoxazolidin-5-yl
benzoate
30.5, 62.3, 75.2, 78.00, 95.6, 127.4, 128.3, 128.4, 128.5, 129.0, 129.7,
129.9, 133.3, 133.5, 129.1, 129.6, 136.5, 165.1, 165.3; HRMS (ESI):
calcd for C27H27NO5 (MþH)þ: 446.1967, found: 446.1951; calcd for
(17b). Yield 70% (405 mg, 0.92 mmol) after flash column chroma-
tography (hexanes/ethyl acetate 90:10), colourless solid, mp
117e119 ꢀC; IR (thin film): 3032, 1735, 1452, 1246, 1239, 1047, 1021,
C
27H27NO5 (MþNa)þ: 468.1787, found: 468.1768.
954, 754, 696 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼3.92 (d, 1H,
J¼15.0 Hz), 4.12 (s, 1H), 4.12 (d, 1H, J¼16.0 Hz), 4.51 (dd, 1H, J¼7.9,
4.6.3. (ꢂ)-2-Benzyl-3-(ethoxycarbonyl)isoxazolidine-4,5-diyl diben
zoate (16a, b). The mixture of two epimers 3,4-trans, 4,5-cis-16a
and 3,4-trans, 4,5-trans-16b (16a/16b ratio 35:65); yield 85%
(540 mg, 1.14 mmol) after flash column chromatography (hexanes/
diethyl ether 90:10), colourless oil. With the aim of complete
characterization of new compounds, the analytical sample was
used in preparative TLC (CH2Cl2) to give pure isomers 16a and 16b.
16a, colourless solid, mp 98e100 ꢀC; IR (thin film): 3032,1740,1724,
2.1 Hz), 6.64 (d, 1H, J¼2.0 Hz), 7.15e7.63 (m, 13H), 8.05e8.12 (m,
2H); 13C NMR (75.4 MHz, CDCl3):
d¼58.4, 59.6, 79.5, 101.4, 127.7,
128.3, 128.5, 128.8, 129.0, 129.4, 129.7, 130.3, 133.8, 134.8, 136.3,
165.7; HRMS (ESI): calcd for C23H20Br79NO3 (MþH)þ: 438.0705,
found: 438.0692; calcd for C23H20Br79NO3 (MþNa)þ: 460.0524,
found: 460.0511.
4.8. Typical experimental procedure for SN-reaction of iso-
xazolidinyl-4,5-dibenzoates with TMSCN
;
1450, 1244, 1200, 1112, 1065, 1019, 696 cmꢁ1 1H NMR (300 MHz,
CDCl3):
d
¼1.21 (t, 3H, J¼7.0 Hz), 4.12 (d, 1H, J¼7.3 Hz), 4.17 (q, 2H,
J¼7.0 Hz), 4.33 (d, 1H, J¼12.9 Hz), 4.52 (d, 1H, J¼12.9 Hz), 6.08 (dd,
1H, J¼7.3, 4.5 Hz), 6.90 (d, 1H, J¼4.5 Hz), 7.25e7.62 (m, 11H),
4.8.1. (ꢂ)-2-Benzyl-5-cyano-3-phenylisoxazolidin-4-yl benzoate (19a,
b). The reaction flask was charged with isoxazolidinyl-4,5-
dibenzoates 14a, b (340 mg, 0.71 mmol), sealed with a rubber
7.94e8.01 (m, 4H); 13C NMR (75.4 MHz, CDCl3):
d
¼14.0, 62.1, 65.1,

ꢀ
ꢁ
D. Benadikova et al. / Tetrahedron 70 (2014) 5585e5593
5592
septum and filled with argon. Anhydrous CH2Cl2 was added (1.4 mL)
followed by TMSCN (115 L, 0.85 mmol). The solution was cooled to
ꢀC with ice-bath, TMSOTf (130
L, 0.71 mmol) was added and the
3H, J¼7.0 Hz), 3.73 (d, 1H, J¼4.2 Hz), 4.18 (d, 1H, J¼14.6 Hz),
4.22e4.30 (m, 2H), 4.47 (d, 1H, J¼14.6 Hz), 4.84 (d, 1H, J¼1.4 Hz),
6.06 (dd, 1H, J¼4.2, 1.4 Hz), 7.30e7.65 (m, 8H), 7.98e8.01 (m, 2H);
m
0
m
stirring was continued at this temperature until no starting material
was detected (3 h, TLC, hexanes/CH2Cl2 33:67). Afterwards, the re-
action was quenched with satd aqueous NaHCO3 (5 mL). Sub-
sequently, the mixture was diluted with water (5 mL) and repeatedly
extracted with CH2Cl2 (2ꢃ5 mL). Combined organic layers were
washed with water (10 mL), dried with Na2SO4 and the solvent was
evaporated in vacuo. Products were isolated by flash column chro-
matography (hexanes/diethyl ether 85:15) to give the isoxazolidines
19a, b as a mixture of two non-separable isomers 3,4-trans-4,5-cis-
19a and 3,4-trans-4,5-trans-19b (205 mg, 0.53 mmol, 74%, 19a/19b
ratio 20:80) as a colourless solid. 1H NMR data of the major di-
astereomer 19b were extracted from the corresponding mixture. 19b:
13C NMR (75.4 MHz, CDCl3):
d
¼14.0, 60.7, 62.5, 70.3, 72.1, 83.6,
115.4, 127.9, 128.0, 128.4, 128.7, 128.9, 129.9, 134.1, 134.8, 165.5,
166.5; Partial 1H NMR data extracted from the mixture of 21a, b for
the minor 21a: 1H NMR (300 MHz, CDCl3):
d
¼4.02 (d, 1H, J¼2.8 Hz,
H-3), 5.18 (d,1H, J¼6.4 Hz, H-5), 6.10 (dd,1H, J¼6.4, 2.8 Hz, H-4); 13
C
NMR data are not presented because 20a was very minor; MS
(ESIþAPCI): m/z for C21H20N2O5 (MþH)þ: 381.0.
4.9. Typical experimental procedure for SN-reaction of 4-
bromoisoxazolidin-5-ols with TMSCN
4.9.1. (ꢂ)-2-Benzyl-4-bromo-3-phenylisoxazolidine-5-carbonitrile
(23). Reaction flask was charged with 4-bromoisoxazolidinyl-5-
benzoates 18a, b (200 mg, 0.46 mmol), sealed with a rubber sep-
tum and filled with argon. Anhydrous acetonitrile was added
1H NMR (300 MHz, CDCl3):
d
¼3.90 (d, 1H, J¼15.2 Hz), 4.02 (d, 1H,
J¼5.3 Hz), 4.18 (d, 1H, J¼15.2 Hz), 4.80 (d, 1H, J¼1.8 Hz), 5.65 (dd, 1H,
J¼5.3, 1.8 Hz), 7.27e7.65 (m, 13H, Ph), 8.01e8.05 (m, 2H, Ph); 13C NMR
(75.4 Hz, CDCl3):
d
¼58.7, 70.7, 75.3, 88.1,116.6,127.5,128.2 (ꢃ2),128.3,
(0.90 mL) followed by TMSCN (75
m
L, 0.55 mmol). The solution was
128.4, 128.6, 129.2, 129.3, 129.9, 134.0, 134.6, 135.8, 165.7; Partial 1H
cooled to ꢁ20 ꢀC. TMSOTf (85
mL, 0.46 mmol) was added and the
NMR data extracted from the mixture of 19a, b for the minor 19a: 1H
mixture was stirred at this temperature for 1 h until no starting
material was detected (TLC, hexanes/CH2Cl2 50:50). Afterwards, the
reaction was quenched with satd aqueous NaHCO3 (5 mL). Sub-
sequently, the mixture was diluted with water (5 mL) and re-
peatedly extracted with CH2Cl2 (2ꢃ5 mL). Combined organic layers
were washed with water (10 mL), dried with Na2SO4 and the sol-
vent was evaporated in vacuo. Product was isolated by flash column
chromatography (hexanes/CH2Cl2 50:50) to give exclusively single
3,4-cis, 4,5-trans-isoxazolidine 23 (130 mg, 0.38 mmol, 82%) as
a colourless sticky oil. IR (thin film): 3030, 1495, 1454, 1293, 1070,
NMR (300 MHz, CDCl3):
d
¼4.31 (d, 1H, J¼5.1 Hz, H-3); 5.16 (d, 1H,
J¼6.6 Hz, H-5); 5.75 (dd, 1H, J¼6.1, 5.1 Hz, H-4); 13C NMR data are not
presented because 19a was minor and 13C peaks were ambiguous; MS
(ESIþAPCI): m/z for C24H20N2O3 (MþH)þ: 385.0.
4.8.2. (ꢂ)-2-Benzyl-5-cyano-3-isopropylisoxazolidin-4-yl benzoate
(20a, b). The mixture of two non-separable isomers 3,4-trans,4,5-
cis-20a and 3,4-trans, 4,5-trans-20b (20a/20b ratio 10:90), yield
78% (220 mg, 0.63 mmol) after flash column chromatography
(hexanes/diethyl ether 90:10), colourless solid. 1H NMR data of the
major diastereomer 20b were extracted from the corresponding
1028, 996, 754, 697, 518 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼3.91
(d,1H, J¼14.5 Hz), 4.16 (d,1H, J¼14.5 Hz), 4.30 (d,1H, J¼6.5 Hz), 4.87
mixture. 20b: 1H NMR (300 MHz, CDCl3):
d
¼1.04 (d, 3H, J¼7.0 Hz),
(dd, 1H, J¼6.5, 4.7 Hz), 4.94 (d, 1H, J¼4.7 Hz), 7.29e7.46 (m, 10H);
1.13 (d, 3H, J¼7.0 Hz), 1.99e2.09 (m, 1H), 3.06 (t, 1H, J¼4.8 Hz), 4.00
(d,1H, J¼14.7 Hz), 4.27 (d,1H, J¼14.7 Hz), 4.70 (d,1H, J¼1.5 Hz), 5.64
(dd, 1H, J¼4.8, 1.5 Hz), 7.28e8.05 (m, 10H); 13C NMR (75.4 MHz,
13C NMR (75.4 MHz, CDCl3):
d
¼55.2, 60.4, 72.7, 72.9, 115.7, 128.0,
128.6, 128.7, 129.1, 129.2, 129.3, 134.1, 135.7; HRMS (ESI): calcd for
C
C
17H15Br79N2O (MþH)þ: 343.0446, found: 343.0431; calcd for
CDCl3):
d
¼17.1, 19.9, 27.5, 60.0, 70.6, 75.3, 81.9, 116.2, 127.5, 128.2,
17H15Br79N2O (MþNa)þ: 365.0265, found: 365.0250.
128.4, 128.5, 128.7, 129.8, 134.0, 136.2, 165.7; Partial 1H NMR data
extracted from the mixture of 20a, b for the minor 20a: 1H NMR
4.9.2. (ꢂ)-2-Benzyl-4-bromo-3-phenylisoxazolidine-5-carbonitrile
(22a, b). Reaction was performed in anhydrous CH2Cl2 at 0 ꢀC for
1 h according to the procedure described above. The products were
isolated by flash column chromatography (hexanes/CH2Cl2 50:50)
to give pure isomers 4,5-cis-22a (90 mg, 0.26 mmol, 56%) and 4,5-
trans-22b (40 mg, 0.12 mmol, 26%). 22a, colourless solid, mp
108e109 ꢀC; IR (thin film): 2985, 1493, 1451, 1190, 1003, 975, 763,
(300 MHz, CDCl3):
d
¼3.22 (dd, 1H, J¼6.6, 2.9 Hz, H-3), 5.02 (d, 1H,
J¼7.0 Hz, H-5), 5.79 (dd, 1H, J¼7.0, 2.9 Hz, H-4); 13C NMR data are
not presented because 20a was very minor; MS (ESIþAPCI): m/z for
C
21H22N2O3 (MþH)þ: 351.2.
4.8.3. (ꢂ)-Ethyl 4-(benzoyloxy)-2-benzyl-5-cyanoisoxazolidine-3-
carboxylate (21a, b). Reaction flask was charged with iso-
xazolidinyl-4,5-dibenzoates 16a, b (200 mg, 0.44 mmol), sealed
with a rubber septum and filled with argon. Anhydrous acetonitrile
746, 725, 694 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼4.00 (d, 1H,
J¼14.2 Hz), 4.07 (d, 1H, J¼14.2 Hz), 4.19 (d, 1H, J¼8.7 Hz), 4.43 (dd,
1H, J¼8.7, 7.1 Hz), 5.10 (d, 1H, J¼7.1 Hz), 7.26e7.49 (m, 10H); 13C
was added (4.5 mL) followed by TMSCN (180
m
L, 1.32 mmol). The
NMR (75.4 MHz, CDCl3):
d
¼51.6, 61.0, 70.4, 77.8, 115.2, 128.0 (ꢃ2),
solution was cooled to 0 ꢀC with ice-bath, TMSOTf (80
mL,
128.5, 129.1, 129.3, 129.6, 133.8, 135.9; HRMS (ESI): calcd for
0.44 mmol) was added, the mixture was allowed to warm to room
temperature and the stirring was continued at this temperature
24 h. Progress of the reaction was monitored by TLC (CH2Cl2). Af-
terwards, the mixture was cooled to 0 ꢀC with ice-bath and the
reaction was quenched with satd aqueous NaHCO3 (5 mL). Sub-
sequently, the mixture was diluted with water (5 mL) and the
solvent was partially evaporated under reduced pressure. The res-
idue was repeatedly extracted with CH2Cl2 (2ꢃ5 mL). Combined
organic layers were washed with water (10 mL), dried with Na2SO4
and the solvent was evaporated in vacuo. Products were isolated by
flash column chromatography (hexanes/ethyl acetate 80:20) to give
the isoxazolidines 21a, b as a mixture of two non-separable isomers
3,4-trans, 4,5-cis-21a and 3,4-trans, 4,5-trans-21b (135 mg,
0.36 mmol, 83%, 21a/21b ratio 10:90) as a pale yellow sticky oil. 1H
NMR data of the major diastereomer 21b were extracted from the
C
C
17H15Br79N2O (MþH)þ: 343.0446, found: 343.0434; calcd for
17H15Br79N2O (MþNa)þ: 365.0265, found: 365.0255; 22b, col-
ourless solid; mp 72e75 ꢀC; IR (thin film): 3035, 1495, 1455, 1188,
1051, 971, 758, 746, 696, 527 cmꢁ1
¼3.84 (d, 1H, J¼15.0 Hz), 4.01 (d, 1H, J¼7.0 Hz), 4.10 (d, 1H,
J¼15.0 Hz), 4.56 (dd, 1H, J¼7.0, 2.8 Hz), 4.90 (d, 1H, J¼2.8 Hz),
7.24e7.55 (m, 10H); 13C NMR (75.4 MHz, CDCl3):
;
1H NMR (300 MHz, CDCl3):
d
d¼56.3, 58.8, 72.8,
79.9,117.0,127.8,128.1, 128.4,128.5,129.5,129.6,133.8,135.7; HRMS
(ESI): calcd for C17H15Br79N2O (MþH)þ: 343.0446, found: 343.0437.
4.10. Crystallography
Data collection and cell refinement were carried out using a
axis diffractometer Kuma KM4 CCD at 293 K with graphite mono-
chromated Mo K radiation for both compounds. The diffraction
intensities were corrected for Lorentz and polarization factors. The
k-
a
corresponding mixture. 21b: 1H NMR (300 MHz, CDCl3):
d¼1.31 (t,

ꢀ
ꢁ
D. Benadikova et al. / Tetrahedron 70 (2014) 5585e5593
5593
structures were solved by direct methods using SIR-201112 (17b) or
References and notes
charge flipping method using SUPERFLIP13 (18a) and refined by the
full-matrix least-squares procedure with SHELXL-2014.14 Geo-
metrical analyses were performed with SHELXL-2014. Absolute
configuration of 18a has been confirmed using Flack15
(x¼ꢁ0.013(6)) and Hooft16 (y¼ꢁ0.006(2)) parameters, and the
chirality of carbon atoms has been confirmed using PLATON pro-
gram17 for C1(S), C2(R) and C3(S). The structures were drawn with
OLEX2 package.18 Crystal data and conditions of data collection and
refinement are reported in Table 5.
1. (a) LeFevre, G. N.; Crawford, R. J. J. Am. Chem. Soc. 1986, 108, 1019e1027; (b)
Monn, J. A.; Valli, M.; Johnson, B.; Salhoff, C.; Wright, R.; Howe, T.; Bond, A.;
Lodge, D.; Spangle, L.; Paschal, J.; Campbell, J.; Griffey, K.; Tizzano, J.; Schoepp,
D. J. Med. Chem. 1996, 39, 2990e3000; (c) Wang, C.; Zhen, Z.; Zhao, J.; Dowd, P.
Synth. Commun. 1999, 29, 631e643; (d) Goodman, M.; Del Valle, J. Angew. Chem.,
Int. Ed. 2002, 41, 1600e1602; (e) Laufersweiler, M. J.; Brugel, T.; Clark, M.; Go-
lebiowski, A.; Bookland, R.; Laughlin, S.; Sabat, M.; Townes, J.; VanRens, J.; De,
B.; Hsieh, L.; Heitmayer, S.; Juergens, K.; Brown, K.; Mekel, M.; Walter, R.; Ja-
nusz, M. Bioorg. Med. Chem. Lett. 2004, 14, 4267e4272; (f) Ganellin, C. R.; Bishop,
P.; Bambal, R.; Chan, S.; Leblond, B.; Moore, A.; Zhao, L.; Bourgeat, P.; Rose, C.;
Vargas, F.; Schwartz, J. J. Med. Chem. 2005, 48, 7333e7342; (g) Martin, B. P.;
Cooper, M. E.; Donald, D. K.; Guile, S. D. Tetrahedron Lett. 2006, 47, 7635e7639;
(h) Bekkali, Y.; Thomson, D.; Betageri, R.; Emmanuel, M.; Hao, M.; Hickey, E.;
Liu, W.; Patel, U.; Ward, Y.; Young, E.; Nelson, R.; Kukulka, A.; Brown, M.; Crane,
K.; White, D.; Freeman, D.; Labadia, M.; Wildeson, J.; Spero, D. Bioorg. Med.
Chem. Lett. 2007, 17, 2465e2469.
Table 5
Crystallographic data for compounds 17b and 18a
17b
18a
ꢁ
ꢀ
ꢁ
ꢁ
2. (a) Fischer, R.; Druckova, A.; Fisera, L.; Rybar, A.; Hametner, C.; Cyranski, M. K.
ꢁ
ꢀ
ꢁ
ꢁ
ꢀ
ꢁ
ꢀ
Synlett 2002, 1113e1117; (b) Fischer, R.; Hyrosova, E.; Druckova, A.; Fisera, L.;
Chemical formula
C23H20BrNO3
C23H20BrNO3
ꢁ
ꢀ
ꢁ
Hametner, C.; Cyraski, M. K. Synlett 2003, 2364e2368; (c) Fischer, R.; Hyrosova,
E.; Fisera, L.; Hametner, C. Chem. Pap. 2005, 59, 275e288; (d) Hyrosova, E.;
Mr
438.31
438.31
ꢀ
ꢁ
ꢁ
Cell setting, space group
Triclinic, P-1
293
Orthorhombic, Pna21
293
11.6470(3)
22.3036(5)
7.3826(1)
90
90
90
ꢀ
ꢁ
ꢁ
ꢀ
ꢁꢀ
Fisera, L.; Jame, R. M. A.; Pronayova, N.; Medvecky, M.; Koos, M. Chem. Heter-
T (K)
ꢁ
ꢀ
ꢁ
ꢀ ꢀ
ocycl. Compd. 2007, 43, 10e17; (e) Hyrosova, E.; Fisera, L.; Kozísek, J.; Fronc, M.
ꢂ
A (A)
9.2238(4)
10.4662(4)
11.4729(5)
76.889(3)
86.778(3)
70.195(4)
1014.64(8)
2
ꢁ
ꢀ
ꢁ
ꢀ
ꢁ
Synthesis 2008, 1233e1240; (f) Hyrosova, E.; Fisera, L.; Medvecky, M.; Reissig,
H. U.; Al-Harrasi, A.; Koos, M. Arkivoc 2009, 122e142.
3. Hyrosova, E.; Medvecky, M.; Fisera, L.; Hametner, C.; Frohlich, H.; Marchetti, M.;
ꢂ
B (A)
ꢁꢀ
ꢂ
C (A)
ꢁ
ꢀ
ꢁ
ꢁ
ꢀ
€
a
b
g
(ꢀ)
(ꢀ)
(ꢀ)
Allmaier, G. Tetrahedron 2008, 64, 3111e3118.
ꢀ
ꢁ
ꢀ
4. Fischer, R.; Lackovicova, D.; Fisera, L. Synthesis 2012, 44, 3783e3788.
ꢁ
ꢁ
5. Fischer, R.; Stanko, B.; Pronayova, N. Synlett 2013, 2132e2136.
6. (a) DeShong, P.; Dicken, C. M.; Staib, R. R.; Freyer, A. J.; Weinreb, S. M. J. Org.
Chem. 1982, 47, 4397e4403; (b) Keirs, D.; Moffat, D.; Overton, K.; Tomanek, R. J.
Chem. Soc., Perkin Trans. 1 1991, 1041e1051.
3
ꢂ
V (A )
1917.78(7)
4
Z
Radiation type
Mo K
2.049
a
Mo Ka
2.168
(mmꢁ1
)
7. Chiacchio, U.; Gumina, G.; Rescifina, A.; Romeo, R.; Uccella, N.; Casuscelli, F.;
Piperno, A.; Romeo, G. Tetrahedron 1996, 52, 8889e8898.
8. Ishikawa, T.; Kudoh, T.; Yoshida, J.; Yasuhara, A.; Manabe, S.; Saito, S. Org. Lett.
2002, 4, 1907e1910.
9. Crystallographic data for 17b and 18a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication numbers CCDC-
985723 and CCDC-985724, respectively.
m
Crystal size (mm)
Diffractometer
Abs correction
Tmin, Tmax
0.59ꢃ0.37ꢃ0.26
Kuma KM4 CCD
CrysAlisPro
0.512, 0.728
1.036
0.37ꢃ0.34ꢃ0.23
Kuma KM4 CCD
CrysAlisPro
0.495, 0.761
1.058
S
R1 [F2>2
s
(F2)], wR2(F2)
0.0399, 0.1142
4132/0/253
0.0247, 0.0630
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Acknowledgements
This work was supported by Slovak Grant Agencies (APVV,
Bratislava, project No. APVV-0203-10, VEGA, Bratislava project No.
1/0488/14 and ASFEU, Bratislava, ITMS projects No. 26240120001,
26240120025).
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