Optically active nitrile oxides: synthesis and 1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.1016/j.tetasy.2007.05.021

Baker's yeast-promoted reduction of the C{double bond, long}C bond in 2-aryl-1-nitropropenes gave the corresponding optically active (R)-2-aryl-1-nitropropanes of high enantiomeric purity (ee >90%). They were next converted with the aid of the Mukaiyama and Hoshino method into the optically active nitrile oxides, which were made to react in situ with ethyl propiolate, methylvinyl ketone and (R)-1-phenyl-2-(phenylsulfonyl)ethyl acrylate to yield the appropriate, enantiomerically enriched, isoxazoles or 4,5-dihydroisoxazoles as diastereomeric mixtures, respectively.

Full text of DOI:10.1016/j.tetasy.2007.05.021

Tetrahedron: Asymmetry 18 (2007) 1457–1464
Optically active nitrile oxides: synthesis and 1,3-dipolar
cycloaddition reactions
Marcin Zagozda and Jan Plenkiewicz*
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
Received 8 May 2007; accepted 17 May 2007
Available online 20 June 2007
Abstract—Baker’s yeast-promoted reduction of the C@C bond in 2-aryl-1-nitropropenes gave the corresponding optically active (R)-2-
aryl-1-nitropropanes of high enantiomeric purity (ee >90%). They were next converted with the aid of the Mukaiyama and Hoshino
method into the optically active nitrile oxides, which were made to react in situ with ethyl propiolate, methylvinyl ketone and (R)-1-phen-
yl-2-(phenylsulfonyl)ethyl acrylate to yield the appropriate, enantiomerically enriched, isoxazoles or 4,5-dihydroisoxazoles as diastereo-
meric mixtures, respectively.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Herein we report the results of the baker’s yeast-promoted
(Saccharomyces cerevisae) reduction of several 1-nitro-
2-arylpropenes to the corresponding optically active
1-nitro-2-arylpropanes, subsequently converted into the
optically active nitrile oxides. Cycloaddition of the nitrile
oxides to ethyl propiolate and methyl vinyl ketone yielded
the appropriate isoxazoles and isoxazolines.
D2-Isoxazolines (4,5-dihydroisoxazoles) are known as ver-
satile intermediates in the synthesis1 of various natural
products since the reductive cleavage of the isoxazoline
ring can lead to many synthetically important compounds,
such as b-hydroxy ketones, a,b-unsaturated ketones or c-
amino alcohols.2 The general and most frequently used
method for the synthesis of D2-isoxazolines depends on
the 1,3-dipolar cycloaddition of nitrile oxides to the acti-
vated double bond in alkenes; aliphatic nitrile oxides are
in most cases generated in situ from primary nitro com-
pounds in a Mukaiyama reaction,3 while their aromatic
counterparts are usually prepared by dehydrohalogenation
of hydroxamoyl chlorides.4 In most cases, 1,3-dipolar cyc-
loadditions (1,3-DC) of nitrile oxides to alkenes proceed
with high regioselectivity, with the relative configuration
on the 4- and 5-carbon atoms of the isoxazoline ring depen-
dent on the alkene geometry.
2. Results and discussion
Optically active nitrile oxides 8 were prepared from the
appropriate optically active nitroalkanes 7 with the aid of
the Mukaiyama and Hoshino method and used in situ as
reagents in the 1,3-DC reactions.3 The enantiomerically
enriched 7 was obtained by a dehydrogenase-catalyzed
reduction of the C@C bond in the corresponding nitroalk-
enes 5 synthesized from a-methylstyrene derivatives 3. The
retrosynthesis shown in Scheme 1 also includes the 1,3-
cycloaddition of the nitrile oxide to methyl vinyl ketone
yielding 2-isoxazoline 10.
Most of the literature data on the asymmetric 1,3-DC lead-
ing to isoxazolines refer to reactions between achiral nitrile
oxides and optically active alkenes.5 Since the preparation
of chiral nitrile oxides, usually from primary nitro com-
pounds6a,e or chloroaldoximes,6b–e is rather difficult, there
are only few reports on their use.6
In order to prepare the phenyl-substituted derivatives 3b–d
of a-methylstyrene, the appropriate acetophenones 1b–d
were made to react with methylmagnesium bromide7,8 to
give the corresponding dimethylphenylcarbinols 2b–d,
which were subjected to dehydration without purification8
with a catalytic amount of p-toluenesulfonic acid. The
yields of 3b–d were 34–68% (Scheme 2).
*
Corresponding author. Tel.: +48 22 234 75 70; fax: +48 22 628 27 41;
e-mail: plenki@ch.pw.edu.pl
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.021

1458
M. Zagozda, J. Plenkiewicz / Tetrahedron: Asymmetry 18 (2007) 1457–1464
N
O
O
+
N
O
O
10a
8a
7a
NO2
NO2
3a
5a
Scheme 1.
O
OH
CH3MgBr
Et2O
p-CH3PhSO3H x H2O
Toluene
R
R
R
1b-d
2b-d
c R=CH3,
3b-d
b R=Cl,
d R=OCH3
Scheme 2.
Table 1. The yields of nitroalkenes 5 and 6
The conversion of a-methylstyrenes 3a–d into 2-aryl-1-
nitropropenes 5a–d was accomplished by the two-step pro-
cedure described earlier.9 At first, b-nitro acetates 4a–d
were formed by the addition of acetyl nitrate (from acetic
anhydride and concentrated nitric acid) to the C@C bond
of 3a–d. In the second step, elimination of the acetic acid
with triethylamine yielded the desired 5a–d (Scheme 3).
However, it is noteworthy that the reaction with triethyl-
amine is not unidirectional and leads to two isomeric prod-
ucts in low-to-moderate yields. Although the desired 5a–d
predominated in the reaction products, substantial
amounts of 2-aryl-3-nitropropenes 6a–c were also formed.
As determined by 1H NMR spectra, the 5:6 ratio was
roughly 2:1. Polymerization side-reactions are presumably
responsible for low yields of the nitroalkene formation.
Crude products 5 and 6 were purified by distillation and
used in the bioreduction reactions as mixtures of isomers
(Table 1).
Entry Substrate
R
Yield (%) of 5 and 6 Ratio of 5 to 6a
1
2
3
4
3a
3b
3c
3d
–H
–Cl
–CH3
–OCH3
52
36
24
3
67:33
64:36
76:24
Pure 5d
a Ratio of diastereomers was determined by 1H NMR.
reduction product, namely (R)-1-nitro-2-phenylpropane
7a; a high enantiomeric excess was noted with either sub-
strate. Following the Ohta’s procedure with 5a–6a and
5b–6b mixtures and with growing cells of baker’s yeast
(S. cerevisiae) in a 2% glucose solution, we isolated the cor-
responding 1-nitro-2-arylpropanes 7a and 7b, but in very
low yields. However, since no substrates could be detected
after a 24 h incubation indicating their consumption must
have been complete. There are two possible reasons for
the failure. Firstly, we worked with a different brand of
yeast which possibly used the substrates as a source of car-
bon for the growing cells; and secondly, some problems
with product isolation might have arisen in spite of our
The baker’s yeast reduction of 2-phenyl-1-nitro-5a and 2-
phenyl-3-nitropropene 6a was investigated earlier by Ohta
et al.10 who reported that both isomers gave the same
AcO
NO2
NO2
NO2
Ac2O
HNO3
Et3N
CHCl3
+
R
R
R
R
3a-d
4a-d
5a-d
d R=OCH3
6a-c
a R=H b R=Cl,
c R=CH3,
Scheme 3.

M. Zagozda, J. Plenkiewicz / Tetrahedron: Asymmetry 18 (2007) 1457–1464
1459
strict observance of the Ohta’s procedure. This prompted
us to investigate the reduction with lyophylized yeast in
an organic solvent. A few solvents were investigated as
the reaction medium. In moisture-containing tert-butyl
methyl ether, the reduction of 5a and 6a was slower than
in water while the substrate conversion into 7a did not ex-
ceed 25% after 24 h. Satisfactory results were obtained in a
less polar solvent. Thus, in either hexane or petroleum
ether, the bioreduction of nitroalkenes 5 and 6 afforded
the corresponding (R)-nitroalkanes 7a–d in 41–82% yields,
which were substantially higher than those reported by
Ohta.10 The enantiomeric excesses of the prepared (R)-2-
aryl-1-nitropropanes 7a–d were high (91–99% ee) while
the (R) absolute configurations were established by com-
paring the signs of specific rotations with those reported
in the literature.10 The results of the experiments are pre-
sented in Table 2 (Scheme 4).
Unfortunately under these conditions, the reaction gave
a hardly definable mixture of products. When di-tert-
butyl-dicarbonate (Boc2O) and 4-dimethylaminopyridine
(DMAP) were used instead of phenyl isocyanate, the ex-
pected ethyl 3-[(1R)-1-phenylethyl]isoxazole-5-carboxylate
9a and ethyl 3-[(1R)-1-(4-chlorophenyl)-ethyl]-isoxazole-5-
carboxylate 9b were obtained in 72% and 64% yields,
respectively (Scheme 5). The reactions proceeded beside
the stereogenic centre and with full preservation of enantio-
merc purity. The obtained isoxazole derivatives 9a and 9b
showed the same enantiomeric excesses as the starting
nitroalkanes. That means that in both reaction steps the
enantiomeric purity of the substrates remained unaffected.
There were no such problems with the use of phenyl isocy-
anate as the dehydrating agent in the 1,3-DC reactions with
methyl vinyl ketone. However, the reactions with this
dipolarophile were not stereoselective and the in situ gener-
ated optically active nitrile oxides yielded diastereomeric
mixtures of 4,5-dihydroisoxazoles 10a–d in 35–55% yields,
relative to the nitroalkane substrate (Scheme 6). Detailed
results, including the diastereomeric ratios as determined
Our investigations on the use of optically active nitroalk-
anes 7a and 7b in the preparation of optically active nitrile
oxides started with the reaction of nitroalkane dehydration
with phenyl isocyanate according to the Mukaiyama proce-
dure. Ethyl propiolate was used as the dipolarophile.
1
by H NMR spectra, are presented in Table 3. As it may
Table 2. Reduction of nitroalkenes 5 and 6 to optically active nitroalkanes (R)-7a–d
Entry
Product
R
Reaction medium
Time (h)
Conv.a (%)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
7a
7a
7a
7a
7b
7b
7b
7c
7d
–H
–H
–H
–H
–Cl
–Cl
–Cl
–CH3
–OCH3
Water
24
48
20
24
24
48
24
48
24
59
83
2
90
90
64
55
59
80
25
70
—
82
12
41
47
47
45
>98
>98
—
>98
—
91
91
97
>99
Petroleum ether
t-Butyl methyl ether
Hexane
Water
Petroleum ether
Hexane
Hexane
Hexane
a Conversion of nitroalkenes was determined by GC analysis.
b Isolated yield of (R)-7a–d after purification by column chromatography.
c Enantiomeric excesses were determined by HPLC using Chiralcel OD-H column in comparison with racemic compounds.
NO2
NO2
NO2
Baker's
yeast
+
R
R
R
5a-d
6a-c
7a-d
a R=H b R=Cl,
c R=CH3,
d R=OCH3
Scheme 4.
O
O
N
O
Boc2O
DMAP
O
NO2
N
O
R
O
R
R
7a,b
8a,b
a R=H b R=Cl
9a,b
Yield: 9a 72%
9b 64%
Scheme 5.

1460
M. Zagozda, J. Plenkiewicz / Tetrahedron: Asymmetry 18 (2007) 1457–1464
O
N
PhNCO
NO2
O
Et3N
N
R
O
O
R
R
7a-d
8a-d
c R=CH3,
10a-d
a R=H b R=Cl,
d R=OCH3
Scheme 6.
several steps from a-chloroacetophenone. At first, ketone
11 was reduced by sodium borohydride to the racemic alco-
hol 12. A kinetic resolution of the racemate yielded the
optically active alcohol (R)-12 and its acetate (S)-13. The
reaction of (R)-12 with thiophenol gave b-hydroxysulfide
(R)-14 which was oxidized by OxoneÒ to the optically ac-
tive b-hydroxysulfone (R)-15. In the last step the optically
active (R)-1-phenyl-2-(phenylsulfonyl)ethyl acrylate (R)-16
was prepared from acryloyl chloride and sulfone (R)-15
(Scheme 7).
Table 3. 1,3-DC of chiral nitrile oxides 8a–d with methyl vinyl ketone
Entry Product
R
Time (h) Yielda (%) Ratio of
diastereomersb
1
2
3
4
10a
10b
10c
10d
–H
–Cl
–CH3
–OCH3
24
24
24
24
47
55
35
42
50:50
50:50
45:55
43:57
a Isolated yield of 10a–d after column chromatography.
b Ratio of diastereomers was determined by 1H NMR.
Using the optically active alkene (R)-16 as the dipolaro-
phile in the 1,3-DC with (R)-2-phenylpropionitrile oxide
we obtained, in 53% yield, a diastereomeric mixture of
the corresponding 4,5-dihydroisoxazoles 17 in the 65:35
ratio (de = 30%) (Scheme 8). That showed some improve-
ment in the reaction stereoselectivity when compared
with the earlier results with methyl vinyl ketone. Neverthe-
less, attempts to obtain complete stereoselectivity of the
cycloaddition proved unsuccessful.
be seen, low stereoselectivity was the case only in the reac-
tions of 4-methylphenyl- and 4-methoxyphenyl derivatives
7c and 7d; and the ratios of the 4,5-dihydroisoxazoles 10c
and 10d obtained were not equal (45:55 and 43:57, respec-
tively). The results presented in Table 3 indicate that the
configuration of the chiral centre in the optically active
nitrile oxides 8a–d did not affect the stereochemistry of
the cycloaddition reaction.
When in the reaction of 7a, and methyl vinyl ketone di-tert-
butyl-dicarbonate was used to replace phenyl isocyanate as
the dehydrating agent, the yield of 10a was increased (64%)
although there was no change in the diastereomeric ratio
(1:1).
3. Conclusion
The baker’s yeast-promoted reduction of the mixtures of 2-
aryl-1-nitro-1-propenes and 2-aryl-3-nitro-1-propenes gave
only the optically active (R)-2-aryl-1-nitropropanes. The
yields of the reduction carried out either in hexane or
petroleum ether were higher than those noted in water.
The enantiomeric excesses of the optically active nitroalk-
anes were high both in an organic solvent and in water
as the reaction medium.
In an attempt to improve the stereoselectivity of the cyclo-
addition reaction, we decided to use an optically active
bulky alkene instead of methyl vinyl ketone in 1,3-DC with
optically active nitrile oxide. Alkene (R)-16 was obtained in
O
OH
OAc
OH
NaBH4
MeOH
Novozym 435
Vinyl acetate
Cl
Cl
Cl
Cl
11
12
13
(R)-12
Et3N PhSH
OH
O
OH
O
O
O
acryloyl chloride
Et3N/CH2Cl2
oxone
MeOH/H2O
S
S
O
O
S
(R)-16
(R)-15
(R)-14
Scheme 7.

M. Zagozda, J. Plenkiewicz / Tetrahedron: Asymmetry 18 (2007) 1457–1464
1461
N
O
O
O
O
Boc2O
O
NO2
O
O
S
DMAP/CH2Cl2
O
O
S
(R)-16
7a
17
Scheme 8.
Conversion of the nitroalkanes into optically active nitrile
oxides proceeded with full preservation of the enantiomeric
excess but their further cycloaddition to methyl vinyl ke-
tone yielded the appropriate 4,5-dihydroisoxazoles of low
diastereoselectivity. It seems possible that the methyl and
phenyl substituents at the a-position to the 1,3 dipole of
chiral nitrile oxides are not bulky enough to constrain ste-
reoselectivity. For this reason the optically active alkene
(R)-16 possesing bulky substituents was prepared and sub-
jected to the 1,3-DC with (R)-2-phenylpropionitrile oxide.
Improved diastereoselectivity of this 1,3-dipolar cycloaddi-
tion reaction was then observed.
The mixture was stirred for 5 h and then poured into ice-
water. The content of the flask was acidified with 1 M
HCl and then aqueous layer was three times extracted with
ether. The combined organic layers were dried over magne-
sium sulfate. Removal of the solvent under reduced pres-
sure gave an oily crude carbinol, which was used without
purification in dehydration reaction.
A solution of the appropriate carbinol and catalytic
amount of p-toluenesulfonic acid in toluene was heated at
reflux and the liberated water was separated. The reaction
was usually complete after 2 h, and the mixture was washed
with water, dried and evaporated to dryness. The resulting
crude alkene was purified by distillation under reduced
pressure. The yields and properties of the propenes are
given below.
4. Experimental
4.1. General
4.2.1. 2-(4-Chlorophenyl)propene 3b. Yield: 68%; bp 95–
97 °C/19 mm Hg (lit.11 bp 93–95 °C/20 mm Hg).
1H (400 MHz) and 13C NMR (100 MHz) spectra were
recorded with Varian Mercury 400 MHz spectrometer in
CDCl3 solution, and chemical shifts (d) are reported in
ppm. Optical rotations were measured in CHCl3 using a
PolAAr 32 polarimeter. Enantiomeric excesses (ee%) were
determined by HPLC analysis on a Thermo-Separation
Products P-100 instrument with Chiralcel OD-H or
Whelk01 (S,S) column in n-hexane/iso-propanol as the elu-
ent in comparison with racemates. The course of the bio-
transformations were monitored by GC with Hewlett-
Packard Model 5890 II MSD 5972A chromatograph with
Helium as the carrier gas. Preparative chromatographic
separations were carried on Merck Silica Gel 60 (230–
400 mesh).
4.2.2. 2-(4-Methylphenyl)propene 3c. Yield: 62%; bp 84–
86 °C/20 mm Hg (lit.12 bp 82–83 °C/20 mm Hg).
4.2.3. 2-(4-Methoxyphenyl)propene 3d. Yield: 34%; bp
110–113 °C/21 mm Hg (lit.13 bp 107–110 °C/17 mm Hg).
4.3. Synthesis of 1-nitro-2-arylpropenes 5a–d and 3-nitro-2
arylpropenes 6a–c
The 2-arylnitropropenes were prepared from 2-arylprop-
enes and acetyl nitrate as described in the literature for 1-
nitro-2-phenylpropene.10
4.3.1. (E)-1-Nitro-2-phenylpropene 5a and 3-nitro-2-phenyl-
propene 6a. Yield 52%, the ratio of 5a to 6a 2:1,
bp = 107–112 °C/2.0 mm Hg. Anal. Calcd C: 66.12; H,
5.72; N, 8.49. Found: C, 66.25; H, 5.56; N, 8.58. Com-
pound 5a 1H NMR: 2.65 (d, J = 1.6 Hz, 3H), 7.31 (q,
J = 1.6 Hz, 1H), 7.43–7.47 (m, 5H); 13C NMR: 18.6,
4.2. General procedure for the synthesis of 2-arylpropenes
3b–d
a-Methylstyrene is commercially available. The phenyl ring
substituted derivatives of a-methylstyrene were obtained
by dehydration of the corresponding aryldimethylcarbinols
prepared from acetophenone derivatives and methylmag-
nesium bromide by a slightly modified literature method7,8
as follows.
1
126.8, 128.8, 129.0, 137.9, 138.3, 150.0. Compound 6a H
NMR: 5.67 (d, J = 0.8 Hz, 2H), 5.54 (s, 1H), 5.83 (s,
1H), 7.32–7.42 (m, 5H); 13C NMR: 79.5, 121.7, 125.7,
128.7, 130.3, 136.3, 136.8.
To a solution of methylmagnesium bromide in dry ether
(from methyl bromide 50.0 g, 0.53 mol and magnesium
12.88 g, 0.53 mol in 100 mL of dry ether), a solution of
the appropriate acetophenone derivative 0.30 mol in
100 mL of dry ether was added dropwise during 1 h at rt.
4.3.2. (E)-1-Nitro-2-(4-chlorophenyl)propene 5b and 3-nitro-
2-(4-chlorophenyl)propene 6b. Yield 36%, the ratio of 5b
to 6b: 1.8:1, bp = 124–130 °C/2.0 mm Hg. Anal. Calcd C,
54.84; H, 4.18; N, 6.95. Found: C, 54.70; H, 4.08; N,

1462
M. Zagozda, J. Plenkiewicz / Tetrahedron: Asymmetry 18 (2007) 1457–1464
1
7.09. Compound 5b H NMR: 2.62 (d, J = 1.6 Hz, 3H),
7.28 (q, J = 1.6 Hz, 1H), 7.38–7.44 (m, 4H); 13C NMR:
18.4, 128.1, 129.3, 136.4, 136.6, 147.7, 148.5. Compound
4.4.3. (R)-2-Nitro-1-(4-methylphenyl)propane 7c. Yield
47%; reaction time in hexane 48 h; ee = 97%.
27
½aꢀD ¼ þ39:2 (c 2.01 CHCl3). Anal. Calcd C, 66.92; H,
1
6b H NMR: 5.34 (d, J = 0.8 Hz, 2H), 5.56 (m, 1H), 5.81
7.29; N, 7.60. Found: C, 67.02; H, 7.31; N, 7.82. 1H
NMR: 1.36 (d, J = 7.2 Hz, 3H), 2.33 (s, 3H), 3.55–3.64
(m, 1H), 4.46 (dd, J = 12.0; 8.4 Hz, 1H), 4.53 (dd,
J = 12.0; 7.2 Hz, 1H), 7.10–7.17 (m, 5H); 13C NMR:
18.7, 21.0, 38.3, 81.9, 126.7, 129.6, 137.2, 137.8.
(s, 1H), 7.34–7.38 (m, 4H); 13C NMR: 79.4, 122.4, 127.1,
129.0, 134.7, 135.2, 136.9.
4.3.3. (E)-1-Nitro-2-(4-methylphenyl)propene 5c and 3-nitro-
2-(4-methylphenyl)propene 6c. Yield 24%, the ratio of 5c
to 6c: 3.1:1, bp = 126–132 °C/3.0 mm Hg. Anal. Calcd C,
67.91; H, 6.33; N, 7.78. Found: C, 67.78; H, 6.26; N,
7.90. Compound 5c 1H NMR: 2.40 (s, 3H), 2.64 (d,
J = 1.2 Hz, 3H), 7.22–7.27 (m, 2H), 7.31–7.39 (m, 3H);
13C NMR: 18.4, 21.3 126.7, 129.7, 135.2, 135.7, 140.9,
150.0. Compound 6c 1H NMR: 2.36 (s, 3H), 5.35 (d,
J = 0.8 Hz, 2H), 5.48 (s, 1H), 5.80 (s, 1H), 7.15–7.20 (m,
2H), 7.32–7.36 (m, 2H); 13C NMR: 21.1, 79.6, 120.8,
125.6, 129.5, 133.8, 137.7, 138.7.
4.4.4. (R)-2-Nitro-1-(4-methoxyphenyl)propane 7d. Yield
45%; reaction time in hexane 24 h; ee = 99%.
28
½aꢀD ¼ þ43:7 (c 1.02 CHCl3). Anal. Calcd C, 61.49; H,
6.63; N, 7.01. Found: C, 61.53; H, 6.71; N, 7.17. 1H
NMR: 1.35 (d, J = 6.8 Hz, 3H), 3.54–3.64 (m, 1H), 3.79
(s, 3H), 4.45 (dd, J = 12.0; 8.4 Hz, 1H), 4.51 (dd,
J = 12.0; 7.2 Hz, 1H), 6.85–6.89 (m, 2H), 7.13–7.17 (m,
2H); 13C NMR: 18.9, 38.1, 55.4, 114.2, 82.0, 127.9, 132.7,
158.7.
4.5. General procedure for the isoxazoles 9a,b synthesis
4.3.4. (E)-1-Nitro-2-(4-methoxyphenyl)propene 5d. Yield
3.2%, purification by column chromatography (hexane–
ethyl acetate 20:1). Anal. Calcd C, 62.02; H, 5.80; N,
7.19. Found: C, 62.17; H, 5.74; N, 7.25. Compound 5d
1H NMR: 2.64 (d, J = 1.6 Hz, 3H), 3.85 (s, 3H), 6.92–
6.98 (m, 2H), 7.34 (q, J = 1.6 Hz, 1H), 7.41–7.46 (m,
2H); 13C NMR: 18.3, 55.4, 114.4, 128.3, 130.0, 135.0,
149.8, 161.2.
To
a
stirred solution of di-tert-butyl-dicarbonate
(1.44 mmol), ethyl propiolate (1.98 mmol) and dimethyl-
aminopyridine (0.09 mmol) in acetonitrile (3.5 mL) at room
temperature, the acetonitrile solution of (R)-2-aryl-1-nitro-
propane (0.60 mmol) in 2.5 mL of acetonitrile was slowly
(over 2 h) added. The mixture was stirred for 48 h and then
concentrated under reduced pressure. The crude product
was purified by column chromatography (hexane–ethyl
acetate 15:1) affording optically active isoxazole.
4.4. General procedure for reduction of nitropropenes 5 and 6
by baker’s yeast
4.5.1. Ethyl 3-[(1R)-1-phenylethyl]isoxazole-5-carboxylate
28
9a. Yield 72%; ee = 98%. ½aꢀD ¼ ꢁ36:6 (c 0.63 CHCl3).
To a solution of 6.2 mmol of the appropriate nitropropene
mixture (5 and 6) in 370 mL of hexane (or petroleum ether)
38 g of Mauripan baker’s yeast and 25 mL of tap water
were added. The slurry was shaken at 30 °C and the con-
version monitored by GC. After an appropriate time the
mixture was filtered and the biomass was washed twice
with ethyl acetate. The combined filtrates were dried over
anhydrous sodium sulfate and the solvent evaporated
under reduced pressure. The crude mixture was purified
by column chromatography (hexane–ethyl acetate 20:1)
yielding the appropriate (R)-2-aryl-1-nitropropane.
Anal. Calcd C, 68.56; H, 6.16; N, 5.71. Found: C, 68.42;
1
H, 6.28; N, 5.96. H NMR: 1.37 (t, J = 7.2 Hz, 3H), 1.70
(d, J = 7.6 Hz, 3H), 4.29 (q, J = 7.2 Hz, 1H), 4.38 (q,
J = 7.2 Hz, 2H), 6.67 (s, 1H), 7.20–7.36 (m, 5H); 13C
NMR: 14.1, 20.0, 37.6, 62.1, 108.6, 127.1, 127.3, 128.8,
142.3, 156.8, 160.2, 168.0.
4.5.2. Ethyl 3-[(1R)-1-(4-chlorophenyl)ethyl]isoxazole-5-car-
28
boxylate 9b. Yield 64%; ee = 91%. ½aꢀD ¼ ꢁ27:7 (c
1.08 CHCl3). Anal. Calcd C, 60.11; H, 5.04; N, 5.01; Cl,
1
12.67. Found: C, 60.35; H, 5.10; N, 5.16; Cl, 12.82. H
NMR: 1.37 (t, J = 7.2 Hz, 3H), 1.67 (d, J = 7.2 Hz, 3H),
4.26 (q, J = 7.2 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 6.65 (s,
1H), 7.17–7.31 (m, 4H); 13C NMR: 14.1, 20.0, 37.0, 62.2,
108.4, 128.7, 128.9, 132.9, 140.8, 156.7, 160.4, 167.6.
4.4.1. (R)-2-Nitro-1-phenylpropane 7a.10 Yield 82%; reac-
tion time in hexane 24 h (in petroleum ether 48 h);
30
ee = 98%. ½aꢀD ¼ þ42:0 (c 1.91 CHCl3). Anal. Calcd C,
65.32; H, 6.58; N, 8.37. Found: C, 65.44; H, 6.71; N,
1
8.48. H NMR: 1.37 (d, J = 6.8 Hz, 3H), 3.59–3.68 (m,
4.6. General procedure of synthesis of 4,5-dihydroisoxazoles
10a–d
1H), 4.49 (dd, J = 12.0; 8.4 Hz, 1H), 4.56 (dd, J = 12.0;
7.2 Hz, 1H), 7.22–7.37 (m, 5H); 13C NMR: 18.7, 38.6,
81.8, 126.9, 127.5, 128.9, 140.8.
To a stirred solution of the appropriate (R)-2-aryl-1-nitro-
propane (1.5 mmol) and methyl vinyl ketone (1,5 mmol) in
dry benzene (7.5 mL), triethylamine (65 lL) and benzene
(1.0 mL) solution of phenyl isocyanate (3.8 mmol) were
added dropwise at 40 °C. The mixture was stirred for
24 h and then the precipitate was filtered off. The filtrate
was concentrated under reduced pressure and crude prod-
uct was purified by column chromatography (hexane–ethyl
acetate 5:1) affording the diastereomeric mixture of 4,5-
dihydroisoxazoles.
4.4.2. (R)-2-Nitro-1-(4-chlorophenyl)propane 7b. Yield
47%; reaction time in hexane 24 h (in petroleum ether
31
48 h); ee = 91%. ½aꢀD ¼ þ37:0 (c 2.11 CHCl3). Anal. Calcd
C, 54.07; H, 5.00; N, 6.95. Found: C, 54.15; H, 5.05; N,
1
7.02. H NMR: 1.37 (d, J = 7.2 Hz, 3H), 3.57–3.67 (m,
1H), 4.47 (dd, J = 12.4; 8.0 Hz, 1H), 4.52 (dd, J = 12.4;
7.6 Hz, 1H), 7.14–7.19 (m, 2H), 7.29–7.34 (m, 2H); 13C
NMR: 18.7, 38.0, 81.5, 128.3, 129.1, 133.3, 139.3.

M. Zagozda, J. Plenkiewicz / Tetrahedron: Asymmetry 18 (2007) 1457–1464
1463
4.6.1. 5-Acetyl-3-(1-phenylethyl)-4,5-dihydroisoxazole 10a.
Yield 47%; Anal. Calcd C, 71.89; H, 6.77; N, 6.52. Found:
C, 71.87; H, 6.96; N, 6.45. H NMR: 1.54 (d, J = 7.2 Hz,
3.6 Hz, 1H), 4.90 (dd, J = 8.8; 3.6 Hz, 1H), 7.32–7.41 (m,
5H).
1
2.85H), 1.55 (d, J = 7.2 Hz, 3H), 2.25 (s, 2.85H), 2.26 (s,
3H), 2.87–3.04 (m, 3.90H), 3.76–3.86 (m, 1.95H), 4.74–
3.82 (m, 1.95H), 7.19–7.36 (m, 9.75H); 13C NMR: d 18.5,
18.6, 26.1, 26.2, 37.9, 38.2, 38.9, 39.1, 83.5, 83.5, 127.1,
127.2, 127.3, 128.9, 140.9, 140.9, 161.6, 161.7, 207.1, 207.3.
4.8.2. (S)-2-Chloro-1-phenylethyl acetate (S)-13. Yield
50%, ee = 77%, 1H NMR: 2.15 (s, 3H), 3.73 (dd,
J = 11.6; 4.4 Hz, 1H), 3.80 (dd, J = 11.6; 8.0 Hz, 1H),
5.96 (dd, J = 8.0; 4.4 Hz, 1H), 7.34–7.40 (m, 5H).
4.9. (R)-1-Phenyl-2-(phenylthio)ethanol (R)-14
4.6.2. 5-Acetyl-3-[1-(4-chlorophenyl)ethyl]-4,5-dihydroisox-
azole 10b. Yield 55%; Anal. Calcd C, 62.11; H, 5.54; N,
5.66. Found: C, 62.03; H, 5.61; N, 5.56. H NMR: 1.51
(d, J = 6.8 Hz, 2.70H), 1.52 (d, J = 6.8 Hz, 3H), 2.25 (s,
2.70H), 2.26 (s, 3H), 2.85–3.04 (m, 3.80H), 3.74–3.83 (m,
1.90H), 4.75–3.82 (m, 1.90H), 7.12–7.17 (m, 3.80H), 7.27–
7.32 (m, 3.80H); 13C NMR: 18.5, 18.6, 26.2, 26.3, 37.6,
37.8, 38.4, 38.6, 83.5, 128.5, 128.6, 128.9, 129.0, 161.2,
161.3, 207.1, 207.3.
To a DMF (9.0 mL) solution of sodium hydroxide
1
(0.170 g;
4.25 mmol),
and
thiophenol
(0.42 mL;
4.10 mmol), a DMF (2.5 mL) solution of (R)-2-chloro-1-
phenylethanol (R)-12 (0.567 g; 3.62 mmol) was added.
The mixture was stirred at room temperature for 3 h. Next,
the flask contents were diluted with CH2Cl2 (15 mL), and
acidified with 1 M HCl. The organic layer was separated,
and aqueous layer extracted with CH2Cl2. The organic ex-
tracts were dried over magnesium sulfate and evaporated
under reduced pressure. The crude product was purified
by column chromatography (hexane–ethyl acetate 7:1)
4.6.3. 5-Acetyl-3-[1-(4-methylphenyl)ethyl]-4,5-dihydroisox-
azole 10c. Yield 35%; Anal. Calcd C, 72.56; H, 7.46; N,
1
5.93. Found: C, 72.70; H, 7.41; N, 6.06. H NMR: 1.52
yielding
(R)-1-phenyl-2-(phenylthio)ethanol
(R)-14
(d, J = 7.2 Hz, 3H), 1.53 (d, J = 7.2 Hz, 2.40H), 2.25 (s,
3H), 2.26 (s, 2.40H), 2.32 (s, 5.40H), 2.85–3.05 (m,
3.60H), 3.74–3.81 (m, 1.80H), 4.73–3.80 (m, 1.80H), 7.08–
7.15 (m, 7.20H); 13C NMR: 18.5, 18.7, 20.9, 26.1, 26.2,
38.0, 38.2, 38.5, 38.7, 83.5, 83.5, 126.9, 127.0, 128.3,
128.8, 128.9, 129.5, 136.9, 136.9, 161.8, 161.9, 207.6, 207.7.
(0.715 g; 86% yield) as colourless oil, ee = 95%. 1H
NMR: 2.85 (s, 1H), 3.10 (dd, J = 13.6; 9.4 Hz, 1H), 3.33
(dd, J = 13.6; 3.6 Hz, 1H), 4.73 (dd, J = 9.4; 3.6 Hz, 1H),
7.24–7.44 (m, 10H).
4.10. (R)-1-Phenyl-2-(phenylsulfonyl)ethanol (R)-15
4.6.4.
5-Acetyl-3-[1-(4-methoxyphenyl)ethyl]-4,5-dihydro-
Compound (R)-15 was obtained from (R)-1-phenyl-2-
(phenylthio)ethanol (R)-14 by oxidation with OxoneÒ
according to the method described in the literature.15 Yield
97%; mp 113–115 °C H NMR: 3.35 (dd, J = 14.4; 2.0 Hz,
1H), 3.51 (dd, J = 14.4; 10.4 Hz, 1H), 3.67 (d, J = 1.6 Hz,
1H), 5.29 (m, 1H), 7.29–7.35 (m, 5H), 7.58–7.62 (m, 2H),
7.67–7.72 (m, 1H), 7.95–7.99 (m, 2H).
isoxazole 10d. Yield 42%; Anal. Calcd C, 68.05; H, 6.73;
N, 5.78. Found: C, 68.00; H, 6.93; N, 5.66. 1H NMR:
1.51 (d, J = 7.2 Hz, 2.25H), 1.52 (d, J = 6.8 Hz, 3H), 2.25
(s, 2.25H), 2.25 (s, 3H), 2.86–3.05 (m, 3.50H), 3.72–3.81
(m, 1.75H), 3.78 (s, 5.25H), 4.73–3.80 (m, 1.75H), 6.86–
6.89 (m, 3.50H), 7.10–7.15 (m, 3.50H); 13C NMR: 18.6,
18.8, 26.1, 26.2, 38.0, 38.1, 38.2, 38.3, 55.2, 83.5, 114.2,
128.1, 128.2, 132.8, 132.9, 158.7, 161.9, 162.0, 207.6, 207.7.
1
4.11. (R)-1-Phenyl-2-(phenylsulfonyl)ethyl acrylate (R)-16
4.7. 2-Chloro-1-phenylethanol 12
To a CH2Cl2 (35.0 mL) solution of (R)-1-phenyl-2-(phen-
ylsulfonyl)ethanol (R)-15 (0.762 g; 2.90 mmol) and triethyl-
amine (0.82 mL; 5.87 mmol), a CH2Cl2 (5.0 mL) solution
of acryloyl chloride (0.24 mL; 2.95 mmol) was added. The
mixture was stirred at room temperature for 1.5 h. Next
20 mL of water was added and after separation of the or-
ganic layer, the aqueous layer was extracted with CH2Cl2.
The combined organic extracts were washed with brine and
dried over magnesium sulfate. The solvent was then re-
moved under reduced pressure. The crude product was
purified by column chromatography (hexane–ethyl acetate
Compound 11 was obtained by reduction of a-chloroaceto-
phenone by the method described in the literature.14
4.8. Kinetic resolution of racemic 2-chloro-1-phenylethanol
12
To a di-iso-propyl ether solution (300 mL) of 2-chloro-1-
phenylethanol 12 (2.00 g, 12.8 mmol) and vinyl acetate
(11.8 mL, 0.128 mol), Novozym 435Ò (from Candida antar-
tica, lipase B) (1.60 g) was added. The mixture was shaken
at 30 °C and the conversion was monitored by GC. After
11 days the enzyme was filtrated off, and washed with
di-iso-propyl ether. The solvent was evaporated under
reduced pressure, and crude mixture was separated by col-
umn chromatography (hexane–ethyl acetate 7:1) yielding
(R)-2-chloro-1-phenylethanol (R)-12 and (S)-2-chloro-1-
phenylethyl acetate (S)-13.
3:1) yielding (R)-1-phenyl-2-(phenylsulfonyl)ethyl acrylate
24
(R)-16 (0.506 g; 55% yield) ee = 94%. ½aꢀD ¼ ꢁ39:5 (c
1.09 CHCl3). Anal. Calcd C, 64.54; H, 5.10; S, 10.14.
1
Found: C, 64.60; H, 5.21; S, 10.19. H NMR: 3.47 (dd,
J = 15.0; 2.6 Hz, 1H), 3.88 (dd, J = 15.0; 9.8 Hz, 1H),
5.73 (dd, J = 10.4; 1.8 Hz, 1H), 5.81 (dd, J = 16.8;
10.4 Hz, 1H), 6.22 (dd, J = 16.8; 1.8 Hz, 1H), 6.28 (dd,
J = 9.8; 2.6 Hz, 1H), 7.25–7.32 (m, 5H), 7.51–7.56 (m,
2H), 7.61–7.66 (m, 1H), 7.88–7.91 (m, 2H); 13C NMR:
61.3, 70.3, 126.2, 127.4, 128.1, 128.9, 129.3, 131.7, 133.8,
137.6, 139.4, 164.2.
4.8.1. (R)-2-Chloro-1-phenylethanol (R)-12. Yield 31%;
23
1
ee = 95%. ½aꢀD ¼ ꢁ54:1 (c 1.02 CHCl3) H NMR: 2.78 (s,
1H), 3.65 (dd, J = 11.2; 8.8 Hz, 1H), 3.74 (dd, J = 11.2;

1464
M. Zagozda, J. Plenkiewicz / Tetrahedron: Asymmetry 18 (2007) 1457–1464
4. (a) Huisgen, R.; Mack, W. Tetrahedron Lett. 1961, 583–586;
(b) Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates
in Organic Synthesis; VCH: Weinheim, 1988.
4.12. [1-Phenyl-2-(phenylsulfonyl)ethyl] 3-(1-phenylethyl)-
4,5-dihydroisoxazole-5-carboxylate 17
5. (a) Kametani, T.; Nagahara, T.; Ihara, M. J. Chem. Soc.,
Perkin Trans. 1 1981, 3048–3052; (b) Kozikowski, A. P.;
Ghosh, A. K. J. Am. Chem. Soc. 1982, 104, 5788–5789; (c)
Houk, K. N.; Moses, S. R.; Wu, Y. D.; Rondan, N. G.; Jager,
V.; Schohe, R.; Fronczek, F. R. J. Am. Chem. Soc. 1984, 106,
3880–3882; (d) Wade, P. A.; Singh, S. M.; Pillay, K. M.
Tetrahedron 1984, 40, 601–611; (e) Curran, D. P.; Kim, B. H.
Synthesis 1986, 312–315; (f) Curran, D. P.; Kim, B. H.;
Piyasena, H. P.; Loncharich, R. J.; Houk, K. N. J. Org.
Chem. 1987, 52, 2137–2141; (g) Olsson, T.; Stern, K.; Sundell,
S. J. Org. Chem. 1988, 53, 2468–2472; (h) Annunziata, R.;
Cinquini, M.; Cozzi, F.; Raimondi, L. Tetrahedron 1988, 44,
4645–4652; (i) Curran, D. P.; Kim, B. H.; Daugherty, J.;
Heffner, T. A. Tetrahedron Lett. 1988, 29, 3555–3558; (j)
Curran, D. P.; Jeong, K.-S.; Heffner, T. A.; Rebek, J., Jr. J.
Am. Chem. Soc. 1989, 111, 9238–9240; (k) Brandi, A.;
Cannavo‘, P.; Pietrusiewicz, K. M.; Zablocka, M.; Wiecz-
orek, M. J. Org. Chem. 1989, 54, 3073–3077; (l) Curran, D.
P.; Heffner, T. A. J. Org. Chem. 1990, 55, 4585–4595; (m)
Olsson, T.; Stern, K.; Wastman, G.; Sundell, S. Tetrahedron
1990, 46, 2473–2482; (n) Akiyama, T.; Okada, K.; Ozaki, S.
Tetrahedron Lett. 1992, 33, 5763–5766; (o) Kim, Y. H.; Kim,
S. H.; Park, D. H. Tetrahedron Lett. 1993, 34, 6063–6066; (p)
Boa, A. N.; Dawkins, D. A.; Hergueta, A. R.; Jenkins, P. R.
J. Chem. Soc., Perkin Trans. 1 1994, 953–960; (q) Yang,
K.-S.; Lain, J.-C.; Lin, C.-H.; Chen, K. Tetrahedron Lett.
2000, 41, 1453–1456; (r) Tamai, T.; Asano, S.; Totani, K.;
Takao, K.; Tadano, K. Synlett 2003, 1865–1867; (s) Sibi, M.
P.; Itoh, K.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126,
5366–5367.
To a stirred acetonitrile (4.0 mL) solution of di-tert-butyl-
dicarbonate (0.174 g, 0.795 mmol), (R)-1-phenyl-2-(phen-
ylsulfonyl)ethyl acrylate (R)-16 (0.102 g, 0.321 mmol) and
dimethylaminopyridine (0.006 g, 0.047 mmol), an aceto-
nitrile (2.0 mL) solution of (R)-1-nitro-2-phenylpropane
(0.052 g, 0.312 mmol) was added dropwise at room temper-
ature within 3 h. The mixture was stirred at room temper-
ature for 48 h and then evaporated to dryness under
reduced pressure. The crude product was purified by col-
umn chromatography (hexane–ethyl acetate 3:1) yielding
isoxazole 17 (0.077 g, 53% yield). Anal. Calcd C, 67.37;
H, 5.44; N, 3.02; S, 6.92. Found: C, 67.45; H, 5.46; N,
1
2.93; S, 7.03. H NMR: 1.51 (d, J = 7.2 Hz, 3.0H), 1.58
(d, J = 7.2 Hz, 1.62H), 2.96–3.01 (m, 1.08H), 2.94 (ddd,
J = 17.2; 11.2, 0.4 Hz, 1H), 3.15 (ddd, J = 17.2; 6.0,
0.4 Hz, 1H), 3.39 (dd, J = 15.0; 2.8 Hz, 0.54H), 3.41 (dd,
J = 15.0; 2.8 Hz, 1H), 3.72 (dd, J = 15.0; 10.0 Hz,
0.54H), 3.79–3.86 (m, 2H), 3.82 (q, J = 7.2 Hz, 0.54H),
4.73 (dd, J = 11.2; 6.0 Hz, 1H), 4.73 (dd, J = 9.8; 7.8 Hz,
0.54H), 6.25 (dd, J = 10.0; 2.8 Hz, 1H), 6.27 (dd, J = 9.8;
2.6 Hz, 0.54H), 7.14–7.32 (m, 10H), 7.19–7.35 (m, 5.4H),
7.53–7.68 (m, 3H), 7.55–7.71 (m, 1.62H), 7.86–7.97 (m,
2H), 7.87–7.99 (m, 1.08H). 13C NMR: 18.72, 18.75,
38.63, 39.06, 39.14, 40.51, 60.95, 60.96, 70.32, 70.48,
76.83, 126.16, 126.18, 127.23, 127.26, 127.31, 128.12,
128.13, 128.83, 128.87, 128.88, 128.97, 128.98, 129.08,
129.09, 129.40, 129.45, 134.00, 134.06, 136.92, 136.96,
139.01, 139.06, 140.81, 141.11, 160.94, 161.23, 168.75,
168.76.
6. (a) Kozikowski, A. P.; Kitagawa, Y.; Springer, J. P. J. Chem.
Soc., Chem. Commun. 1983, 1460–1462; (b) Jones, R. H.;
Robinson, G. C.; Thomas, E. J. Tetrahedron 1984, 40, 177–
184; (c) Larsen, K. E.; Torssell, K. B. G. Tetrahedron 1984,
40, 2985–2988; (d) Kim, B. H.; Chung, Y. J.; Keum, G.; Kim,
J.; Kim, K. Tetrahedron Lett. 1992, 33, 6811–6814; (e)
Acknowledgements
We acknowledge the evaluation of this manuscript by
Professor Jerzy Lange and many valuable suggestions
provided by him. This work was financially supported by
the Warsaw University of Technology.
¨
´
Kudyba, I.; JoYwik, J.; Romanski, J.; Raczko, J.; Jurczak,
˜
J. Tetrahedron: Asymmetry 2005, 16, 2257–2262.
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1984, p 307; (b) Jun-ichi, T.; Akihiro, K.; Masaaki, T.; Sakae,
U. J. Chem. Soc., Perkin Trans. 1 1997, 2169–2173.
8. Thomas, A. F.; Egger, J.-C. Helv. Chim. Acta 1981, 64, 2393–
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