Ruthenium lewis acid catalyzed asymmetric 1,3-dipolar cycloadditions between N -methylnitrones and enals

Article abstract of DOI:10.1055/s-0029-1218788

N-Methylisoxazolidines are formed in good yields and high regio-, diastereo- and enantioselectivity via asymmetric 1,3-dipolar cycloaddition of nitrones with enals catalyzed by a chiral ruthenium Lewis acid. Electronic effects in the dipole are the key to activation of these substrates for efficient catalysis. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218788

PAPER
2207
Ruthenium Lewis Acid Catalyzed Asymmetric 1,3-Dipolar Cycloadditions
between N-Methylnitrones and Enals
A
symmetric 1, 3-D
n
ipolar Cyclo
d
additions rei Bădoiu, Gérald Bernardinelli, E. Peter Kündig*
Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland
Fax +41(22)3793215; E-mail: Peter.Kundig@unige.ch
Received 22 April 2010
Dedicated to Professor Rolf Huisgen on the occasion of his 90th birthday
in terms of nitrones and enals and demonstrated success-
fully ring opening of the isoxazolidine products.7m–o An
N-diphenylmethyl group on the nitrone afforded selec-
tively the 3,4-substituted isoxazolidine, an unique trait for
these transformations.7n,o
Abstract: N-Methylisoxazolidines are formed in good yields and
high regio-, diastereo- and enantioselectivity via asymmetric 1,3-di-
polar cycloaddition of nitrones with enals catalyzed by a chiral ru-
thenium Lewis acid. Electronic effects in the dipole are the key to
activation of these substrates for efficient catalysis.
Key words: asymmetric catalysis, Lewis acid, ruthenium, N-meth-
yl nitrones, 1,3-dipolar cycloaddition
Intrigued by these results, and by our observation of im-
portant changes in reactivity, regioselectivity and enanti-
oselectivity in the 1,3-DC reactions upon variation of the
para aryl-substituent in the nitrone,9,10 we decided to rein-
vestigate. This article reports our results with a-aryl,N-
methylnitrones.
Functionalized, chiral N,O-heterocyclic compounds hold
great synthetic value due to their high versatility either on
their own or, after the reductive cleavage of the N–O
bond, as acyclic chiral building blocks.1 In this class of
compounds, isoxazolidines stand out due to their ready
access through asymmetric catalytic 1,3-dipolar cycload-
dition (1,3-DC) reactions and the potential of this reaction
to generate up to three contiguous stereogenic centers.2
The nitrones were readily synthesized by condensation
of the corresponding substituted benzaldehydes with
N-methylhydroxylamine.11 Next, these dipoles were sub-
mitted to 1,3-DC reactions with methacrolein (2) in the
presence of the ruthenium complex (R,R)-1 (Table 1).12
With electron-poor substituted nitrones, the 3,5-substitut-
ed isoxazolidines were obtained selectively in good yields
and with excellent diastereo- and enantioselectivity (en-
tries 1–6). Despite long reaction times, nitrone 3g pro-
vides isoxazolidine 4g in poor yield and with decreased
diastereoselectivity (entry 7). Moreover, no product is
formed in the reaction of methacrolein (2) with the nitrile-
substituted nitrone 3h (entry 8). This is in agreement with
our previous finding that substrates bearing Lewis-basic
groups lead to competitive binding to the Lewis acid, thus
reducing efficiency or even shutting down the catalytic
cycle.9
Our work in the field of asymmetric Lewis acid catalysis
focused on the development of monocationic one-point
binding cyclopentadienyl complexes of iron and cyclo-
pentadienyl and indenyl complexes of ruthenium that
proved efficient and selective for the Diels–Alder reac-
tions of enals3,4 and enones5 with dienes.
We also detailed the first examples of chiral Lewis acid
catalyzed 1,3-DC of nitrones with enals.6 In the following,
several groups have reported other catalytic systems for
this reaction.7 We note that this transformation has also
been successfully carried out with organocatalysts.8 Re-
cently we reported more fully on the scope, regioselectiv-
ity, and enantioselectivity of reactions of diarylnitrones,9
and also extended the studies to nitrile oxides.10
N-Methyl,a-phenylnitrone (3i) affords the expected prod-
uct 4i with similar levels of selectivity as did 3a–e, but
with a reduced yield of 60% (entry 9). The moderate to
fair yields obtained in these cycloaddition reactions re-
flect the sensitivity of these adducts during isolation and
purification.13 No cycloaddition products were isolated
from reaction mixtures involving methacrolein (2) and
electron-rich substituted nitrones 3j–l (entries 10–12), re-
vealing the reactivity limits with this particular catalytic
system. Both the nitrones and the acetone precatalyst
could be recovered quantitatively at the end of the reac-
tion, suggesting low reactivity rather than catalyst inhibi-
tion.
Less reactive than cyclic or diarylnitrones, N-alkyl- and
N-benzylnitrones are synthetically more appealing in
view of the synthesis of chiral amino alcohols and amino
acids. Our initial attempts to extend reactions to alkylni-
trones failed to give the expected products in reasonable
yields. Subsequently, two groups reported the successful
use of N-methyl- and N-benzylnitrones in catalytic 1,3-
DC reactions. While Carmona et al. concentrated their ef-
forts on the synthesis and development of rhodium and iri-
dium Lewis acids,7g–l Maruoka, using titanium-based
catalysts, considerably expanded the substrate range both
A crystal of isoxazolidine 4d was analyzed by X-ray dif-
fraction (Figure 1). The compound crystallizes in the
orthorhombic system with no inclusion of solvent.
SYNTHESIS 2010, No. 13, pp 2207–2212
x
x.
x
x
.
2
0
1
0
Advanced online publication: 20.05.2010
DOI: 10.1055/s-0029-1218788; Art ID: C02310SS
© Georg Thieme Verlag Stuttgart · New York

2208
A. Bădoiu et al.
PAPER
Table 1 Ruthenium-Catalyzed Asymmetric 1,3-DC of Methacrolein (2) with a-Aryl, N-methylnitrones 3a–la
–
SbF6
+
Ru
(C6F5)2P
O
O
P(C6F5)2
Ph
O
(R,R)-1
Ph
Me
O–
+
N
CHO
CHO
CHO
Ar
Ar
(R,R)-1 (5 mol%)
N
O
N O
CH2Cl2, –5 °C, 50 h
R
Me
Me
3a–l
2
endo-4a–l
exo-4a–l
Entry
1
R
Yield (%)b
endo/exoc
>95:5
94:6
endo ee (%)d
2-F (3a)
74
73
79
73
85
60
43
–
93
91
90
97.7
92
78
92
–
2
4-F (3b)
3
4-Cl (3c)
94/6
4
4-Br (3d)
4-CF3 (3e)
pentafluoro (3f)
4-NO2 (3g)
4-CN (3h)
4-H (3i)
>95:5
94:6
5
6
91:9
7
80:20
e
8
–
9
60
–
94:6
94
–
e
10
11
12
4-Me (3j)
4-OMe (3k)
4-NMe2 (3l)
–
e
–
–
–
e
–
–
–
a Reaction conditions: (R,R)-1 (5 mol%), 2 (0.75 mmol), and 3 (0.5 mmol) in CH2Cl2 (1 mL).
b Isolated yield.
c Determined by 1H NMR spectroscopy.
d Determined by HPLC analysis of the corresponding primary alcohol.
e No reaction; quantitative recovery of unreacted nitrone.
The absolute configuration corresponds to C5 (S), C7 (S)
and is the one expected from an top-endo approach of the
Z-nitrone to the accessible Ca-SiC=C face of the double
bond of methacrolein (2) coordinated in the chiral pocket
of the [Ru(acetone)(R,R-BIPHOP-F)(Cp)][SbF6] com-
plex 1. This can be visualized by means of the X-ray-
based model shown below (Figure 2).14
This correlates perfectly with the previous results ob-
tained with the diarylnitrones6,9 and the nitrile oxides.10
Diastereo- and enantioselectivity are exclusively under
catalyst control.
Enantioselectivities were determined by HPLC analysis
of the isoxazolidine alcohols 5 obtained in high yields by
reduction of aldehydes 4 with sodium borohydride (see
experimental section).
In conclusion, we have developed an efficient and selec-
tive ruthenium-catalyzed 1,3-DC of N-methylnitrones
with enals. Electronic effects proved to be the key to acti-
vating the dipoles for the cycloaddition reaction. Synthet-
Figure 1 ORTEP representation of the X-ray structure of the isoxa-
zolidine 4d, obtained by ruthenium-catalyzed 1,3-DC of methacrolein
(2) with a-(4-bromophenyl)-N-methylnitrone (3d)
Synthesis 2010, No. 13, 2207–2212 © Thieme Stuttgart · New York

PAPER
Asymmetric 1,3-Dipolar Cycloadditions
2209
(Hdry = 5 cm, Fe = 1 cm) with CH2Cl2 gave viscous, clear oils that
1
solidified at –30 °C. Diastereomeric ratios were determined by H
NMR of the crude mixture.
Note: In all cases, partial data for the endo diastereomer is given (in
the mixture). Most isoxazolidines proved to be too unstable for MS
analysis (data is given for the corresponding primary alcohols).
(3S,5S)-3-(2-Fluorophenyl)-5-methyl-2-methylisoxazoline-5-
carbaldehyde (4a)
Obtained according to the general procedure in 74% yield (endo/exo =
95:5).
IR (film): 727, 757, 798, 816, 853, 895, 941, 978, 1034, 1091, 1135,
1179, 1231, 1277, 1376, 1455, 1473, 1489, 1519, 1587, 1617, 1733,
2876, 2963 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (s, 3 H, CH3), 2.18–2.23 (dd,
J = 9, 13 Hz, 1 H, H-C4), 2.65 (s, 3 H, NCH3), 3.01–3.06 (br dd,
J = 9, 13 Hz, 1 H, H-C4), 4.12 (br s, J = 9 Hz, 1 H, H-C3), 7.02–7.06
(m, 1 H, CHarom), 7.14–7.18 (m, 1 H, CHarom), 7.24–7.30 (m, 1 H,
CHarom), 7.51–7.54 (m, 1 H, CHarom), 9.68 (s, 1 H, CHO).
Figure 2 Model showing the approach of a-(4-bromophenyl),N-
methylnitrone (3d) to the accessible Ca-Si face of the C=C bond of
methacrolein (2) coordinated in the chiral pocket of the catalyst (R,R)-
114
13C NMR (100.6 MHz, CDCl3): d = 21.1, 43.9, 45.6, 85.5, 115.6,
115.8, 124.7, 125.8, 125.9, 128.5, 129.5, 159.7, 162.2, 201.0.
ically relevant isoxazolidines bearing the methyl group at
the nitrogen could thus be obtained in good yields and
with high regio-, diastereo-, and enantioselectivity.
(3S,5S)-3-(4-Fluorophenyl)-5-methyl-2-methylisoxazoline-5-
carbaldehyde (4b)
Obtained according to the general procedure in 73% yield (endo/exo =
94:6).
Complex (R,R)-1 was prepared by using our previously published
procedures.4 Reactions were carried out under a positive pressure of
N2, unless otherwise stated. Glassware was oven-dried at 70 °C. Pu-
rification of CH2Cl2 was carried out by using a Solvtek purification
system. All other solvents used were commercially available
synthesis grade. The nitrones 3a–l were synthesized by the conden-
sation of the appropriate substituted benzaldehyde with methyl-
hydroxylamine.11 Commercially available chemicals were used as
supplied, unless stated otherwise. Flash column chromatography
was carried out using silica gel (60L, 32–63 mesh, Brunschwig SA,
Basel). TLC was performed on precoated aluminum plates (Merck
silica 60F254), and visualized using UV light, aq KMnO4, or ceric
ammonium molybdate acidic solution. 1H, 31P, and 13C NMR spec-
tra were recorded on Bruker AMX 300, 400, and 500 spectrometers.
Chemical shifts are quoted relative to tetramethylsilane and refer-
enced to the residual solvent peaks as appropriate. IR spectra were
recorded on a PerkinElmer Spectrum One spectrophotometer as
neat liquids using a Golden Gate accessory. Polarimetry was per-
formed using a PerkinElmer 241 polarimeter with a Na lamp (589
nm, continuous). LRMS were acquired using a Varian CH4 or SM1
spectrometer with the ionizing voltage at 70 eV, whereas HRMS
were measured using a positive TOF mode in the ESI-MS mode us-
ing an Applied Biosystems/Scix (QSTA) spectrometer. HPLC anal-
yses were recorded on an Agilent HP 1100 Series instrument
(hexanes–propan-2-ol mixtures).
IR (film): 718, 761, 772, 837, 893, 979, 1015, 1091, 1134, 1158,
1223, 1295, 1378, 1473, 1509, 1606, 1640, 1733, 2850, 2963 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.46 (s, 3 H, CH3), 2.17–2.23 (dd,
J = 9, 13 Hz, 1 H, H-C4), 2.59 (s, 3 H, NCH3), 2.93–2.97 (br dd,
J = 9, 13 Hz, 1 H, H-C4), 3.65 (br s, J = 9 Hz, 1 H, H-C3), 7.02–7.06
(m, 2 H, CHarom), 7.31–7.34 (m, 2 H, CHarom), 9.67 (s, 1 H, CHO).
13C NMR (100.6 MHz, CDCl3): d = 19.1, 47.7, 72.8, 85.1, 128.1,
129.4, 129.7, 129.9, 161.5, 163.9, 205.0.
(3S,5S)-3-(4-Chlorophenyl)-5-methyl-2-methylisoxazoline-5-
carbaldehyde (4c)
Obtained according to the general procedure in 79% yield (endo/exo =
94:6).
IR (film): 700, 717, 825, 850, 893, 922, 979, 1015, 1089, 1134,
1174, 1296, 1376, 1411, 1474, 1491, 1519, 1599, 1640, 1733, 2849,
2962 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (s, 3 H, CH3), 2.15–2.20 (dd,
J = 9, 13 Hz, 1 H, H-C4), 2.59 (s, 3 H, NCH3), 2.94–2.98 (br dd,
J = 9, 13 Hz, 1 H, H-C4), 3.65 (br s, J = 9 Hz, 1 H, H-C3), 7.27–7.33
(m, 4 H, CHarom), 9.65 (s, 1 H, CHO).
13C NMR (100.6 MHz, CDCl3): d = 19.0, 47.6, 61.2, 85.2, 128.3,
128.5, 129.1, 129.4, 134.0, 137.0, 204.9.
Ruthenium-Catalyzed 1,3-DC Reaction of Nitrones 3 with
Methacrolein (2); General Procedure
(3S,5S)-3-(4-Bromophenyl)-5-methyl-2-methylisoxazoline-5-
carbaldehyde (4d)
In a 50 mL Schlenk tube equipped with a magnetic stirring bar, the
catalyst (R,R)-1 (36 mg, 0.025 mol, 5 mol%) was loaded and
CH2Cl2 (1 mL) was added. The mixture was stirred at the appropri-
ate temperature, methacrolein (2; 62 mL, 0.75 mmol, 1.5 equiv) was
added and the mixture stirred for further 20 min before addition of
the corresponding nitrone 3 (0.5 mmol, 1 equiv) in one portion as a
solid. The mixture was stirred at the appropriate temperature and the
extent of the reaction was followed by TLC analysis (SiO2, EtOAc–
cyclohexane, 2:3 or CH2Cl2) until no traces of nitrone were ob-
served. Pentane was added to precipitate the catalyst and any unre-
acted nitrone, and the mixture was passed through a plug of Celite
545 (P3-frit, Hdry = 1.5 cm, Fe = 2 cm) followed by in vacuo remov-
al of volatiles. Purification by a quick filtration through a SiO2 plug
Obtained according to the general procedure in 73% yield (endo/exo =
>95:5); [a]D20 –67.6 (c = 0.42, CH2Cl2).
IR (film): 822, 851, 893, 979, 1011, 1071, 1091, 1134, 1296, 1376,
1409, 1474, 1488, 1519, 1734, 2847, 2960 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.46 (s, 3 H, CH3), 2.16–2.21 (dd,
J = 9, 13 Hz, 1 H, H-C4), 2.60 (s, 3 H, NCH3), 2.95–3.00 (br dd,
J = 9, 13 Hz, 1 H, H-C4), 3.65 (br s, J = 9 Hz, 1 H, H-C3), 7.23–7.25
(d, J = 9 Hz, 2 H, CHarom), 7.47–7.49 (d, J = 9 Hz, 2 H, CHarom), 9.67
(s, 1 H, CHO).
13C NMR (100.6 MHz, CDCl3): d = 15.5, 21.2, 47.6, 66.1, 85.2,
122.2, 128.3, 129.1, 129.5, 132.1, 137.5, 200.2.
Synthesis 2010, No. 13, 2207–2212 © Thieme Stuttgart · New York

2210
A. Bădoiu et al.
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Crystallographic Data for 4d15
1H NMR (300 MHz, CDCl3): d = 1.38 (s, 3 H, CH3), 2.40–2.46 (br
dd, J = 9, 12 Hz, 1 H, H-C4), 2.61 (s, 3 H, NCH3), 2.66–2.71 (br dd,
J = 9, 12 Hz, 1 H, H-C4), 3.51–3.55 (br t, J = 8 Hz, 1 H, H-C3),
7.25–7.33 (m, 5 H, CHarom), 9.76 (s, 1 H, CHO).
13C NMR (100.6 MHz, CDCl3): d = 20.4, 34.6, 48.5, 85.6, 121.8,
125.8, 125.9, 128.1, 128.3, 130.9, 141.9, 200.5.
C12H14BrNO2; Mr = 284.2, orthorhombic, P212121, a = 6.0612(3),
b = 8.8059(5), c = 23.3962(10) Å, V = 1248.8(11) Å3; Z = 4,
m = 3.28 mm–1, dx = 1.511 g cm–3, MoKa radiation (l = 0.71073 Å);
7984 reflections measured at 150 K on a STOE IPDS diffractome-
ter, 2414 unique reflections of which 1839 with |Fo| > 4 s (Fo).
Data were corrected for Lorentz and polarization effects and for ab-
sorption (Tmin, Tmax = 0.5341, 0.7789). The structure was solved by
direct methods (SIR97).16 All calculations were performed with the
XTAL system.17 Full-matrix least-squares refinement based on F
using weights of 1/[s2 (Fo) + 0.0001(Fo2)] gave final values
R = 0.024, wR = 0.024, and S = 1.49(3) for 146 variables and 1839
contributing reflections. Flack parameter × = 0.005(4).
Reduction of Products 4; General Procedure
In a 10 mL round-bottomed flask equipped with a magnetic stirring
bar, the corresponding aldehyde 4 (50 mg, 1.35 equiv) was added to
EtOH (2 mL), followed by NaBH4 (5.3 mg, 1 equiv). The mixture
was stirred for 1–12 h at r.t. and then the excess NaBH4 was
quenched with H2O (2 mL). The mixture was extracted with Et2O
(3 × 10 mL), the combined Et2O layers were dried (MgSO4 or
Na2SO4), filtered, and concentrated to give a dense clear oil. Purifi-
cation by column chromatography (SiO2, Hdry = 15 cm, Fe = 1 cm),
gradient cyclohexane–EtOAc (9:1, 30 mL; 8:2, 20 mL; 7:3, 20 mL)
(Rf = 0.45 in 7:3 mixture) gave viscous, clear oils that solidified at
–30 °C.
(3S,5S)-5-Methyl-3-(4-trifluoromethylphenyl)-2-methylisox-
azoline-5-carbaldehyde (4e)
Obtained according to the general procedure in 85% yield (endo/exo =
94:6).
IR (film): 762, 839, 894, 979, 1019, 1068, 1123, 1165, 1324, 1378,
1421, 1474, 1520, 1620, 1735, 2853, 2963 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.46 (s, 3 H, CH3), 2.18–2.23 (dd,
J = 9, 13 Hz, 1 H, H-C4), 3.01–3.06 (br dd, J = 9, 13 Hz, 1 H, H-C4),
3.76 (br s, J = 9 Hz, 1 H, H-C3), 7.48–7.50 (d, J = 9 Hz, 2 H, arom-
CHm), 7.61–7.63 (d, J = 9 Hz, 2 H, arom-CHo), 9.68 (s, 1 H, CHO).
Note: In all cases, partial data for the endo diastereomer is given (in
the mixture).
(3S,5S)-3-(2-Fluorophenyl)-5-methyl-2-methylisoxazoline-5-
methanol (5a)
Obtained according to the general procedure in 92% yield. HPLC
(CHIRACEL OD-H, Grad. 99 + 1 to 90 + 10, 0.75 mL/min, 100
min, 254 + 340 nm): tR (min) = 25.13 (94.50%), 29.84 (3.45%).
13C NMR (100.6 MHz, CDCl3): d = 21.1, 33.5, 47.5, 85.4, 122.8,
125.5, 125.9, 128.1, 130.3, 130.6, 142.8, 201.5.
(3S,5S)-5-Methyl-3-(pentafluorophenyl)-2-methylisoxazoline-
5-carbaldehyde (4f)
IR (film): 756, 818, 857, 886, 931, 1054, 1130, 1231, 1277, 1367,
1455, 1492, 1587, 1617, 2872, 2965, 3403 cm–1.
Obtained according to the general procedure in 60% yield (endo/exo =
91:9).
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 3 H, CH3), 2.04–2.10 (m,
1 H, H-C4), 2.18 (br s, 1 H, OH), 2.59 (s, 3 H, NCH3), 2.78–2.83 (dd,
J = 8, 16 Hz, 1 H, H-C4), 3.47–3.50 (br d, J = 11 Hz, 1 H, CH2OH),
3.60–3.63 (br d, J = 11 Hz, 1 H, CH2OH), 3.87 (br s, 1 H, H-C3),
7.02–7.06 (m, 1 H, CHarom), 7.14–7.18 (m, 1 H, CHarom), 7.23–7.27
(m, 1 H, CHarom), 7.50–7.54 (m, 1 H, CHarom).
13C NMR (125.8 MHz, CDCl3): d = 22.7, 24.3, 29.7, 30.3, 31.2,
43.0, 45.8, 46.4, 47.8, 59.1, 59.5, 65.6, 70.7, 115.2, 115.3, 115.4,
115.5, 123.8, 123.9, 124.4, 124.5, 124.6, 128.2, 128.4, 129.0, 129.1,
129.2, 129.3, 129.4, 132.3.
IR (film): 736, 771, 842, 973, 1009, 1095, 1134, 1149, 1292, 1372,
1476, 1504, 1523, 1655, 1736, 2970 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.39 (s, 3 H, CH3), 2.37–2.43 (dd,
J = 9, 13 Hz, 1 H, H-C4), 2.64 (s, 3 H, NCH3), 2.83–2.89 (dd, J = 9,
13 Hz, 1 H, H-C4), 3.95–3.99 (t, J = 9 Hz, 1 H, H-C3), 9.74 (s, 1 H,
CHO).
13C NMR (100.6 MHz, CDCl3): d = 15.5, 19.6, 43.3, 62.4, 66.1,
85.0, 111.3, 136.8, 144.5, 146.9, 205.1.
MS (TS): m/z = 226.3 (M + 1), 222.3, 180.3, 176.3, 165.3, 161.3,
(3S,5S)-5-Methyl-3-(4-nitrophenyl)-2-methylisoxazoline-5-
152.3.
carbaldehyde (4g)
Obtained according to the general procedure in 43% yield (endo/exo =
80:20).
HRMS (ESI+): m/z calcd for C12H17FNO2 [M + H]+: 226.1233;
found: 226.1237.
IR (film): 751, 856, 981, 1016, 1092, 1292, 1347, 1382, 1474, 1520,
1601, 1641, 1734, 2929 cm–1.
(3S,5S)-3-(4-Fluorophenyl)-5-methyl-2-methylisoxazoline-5-
methanol (5b)
Obtained according to the general procedure in 96% yield. HPLC
(CHIRACEL OD-H, Grad. 99 + 1 to 90 + 10, 0.75 mL/min, 100
min, 254 + 340 nm): tR (min) = 19.42 (4.56%), 28.58 (95.43%).
1H NMR (300 MHz, CDCl3): d = 1.45 (s, 3 H, CH3), 2.16–2.21 (dd,
J = 9, 13 Hz, 1 H, H-C4), 2.64 (s, 3 H, NCH3), 3.07–3.12 (br dd,
J = 9, 13 Hz, 1 H, H-C4), 3.86 (br s, J = 9 Hz, 1 H, H-C3), 7.55–7.57
(d, J = 9 Hz, 2 H, CHarom), 8.21–8.24 (d, J = 9 Hz, 2 H, CHarom), 9.68
(s, 1 H, CHO).
IR (film): 718, 837, 859, 883, 929, 1056, 1131, 1158, 1225, 1297,
1367, 1458, 1509, 1607, 2870, 2965, 3413 cm–1.
13C NMR (125.8 MHz, CDCl3): d = 15.1, 18.6, 31.2, 42.7, 46.4,
46.9, 59.5, 61.3, 72.4, 77.2, 100.1, 123.4, 124.0, 127.7, 128.3,
128.7, 204.2.
1H NMR (300 MHz, CDCl3): d = 1.42 (s, 3 H, CH3), 2.02–2.07 (m,
1 H, H-C4), 2.12 (br s, 1 H, OH), 2.52 (s, 3 H, NCH3), 2.72–2.77 (dd,
J = 8, 16 Hz, 1 H, H-C4), 3.44–3.47 (br d, J = 11 Hz, 2 H, CH2OH
+ H-C3), 3.59–3.61 (br d, J = 11 Hz, 1 H, CH2OH), 7.01–7.05 (m, 2
H, CHarom), 7.32–7.35 (m, 2 H, CHarom).
(3S,5S)-5-Methyl-3-(phenyl)-2-methylisoxazoline-5-carbalde-
hyde (4i)
13C NMR (125.8 MHz, CDCl3): d = 15.3, 22.8, 29.7, 30.3, 31.2,
42.6, 47.3, 47.8, 59.5, 65.6, 65.8, 71.2, 73.6, 115.1, 115.2, 115.4,
115.5, 115.6, 115.7, 129.2, 129.3, 129.4, 129.5, 131.2, 131.3.
Obtained according to the general procedure in 84% yield (endo/exo =
93:7).
IR (film): 699, 753, 793, 845, 894, 914, 956, 973, 1025, 1073, 1091,
1139, 1177, 1290, 1307, 1361, 1374, 1455, 1494, 1604, 1732, 2808,
2849, 2963 cm–1.
MS (TS): m/z = 226.3 (M + 1), 203.3, 179.3, 177.3, 161.3, 152.3.
HRMS (ESI+): m/z calcd for C12H17FNO2 [M + H]+: 226.1230;
found: 226.1237.
Synthesis 2010, No. 13, 2207–2212 © Thieme Stuttgart · New York

PAPER
Asymmetric 1,3-Dipolar Cycloadditions
2211
(3S,5S)-3-(4-Chlorophenyl)-5-methyl-2-methylisoxazoline-5-
methanol (5c)
IR (film): 736, 771, 806, 837, 894, 956, 978, 1005, 1043, 1131,
1149, 1215, 1302, 1372, 1461, 1502, 1524, 1655, 2971, 3392 cm–1.
Obtained according to the general procedure in 90% yield. HPLC
(CHIRACEL OD-H, Grad. 99 + 1 to 90 + 10, 0.75 mL/min, 100
min, 254 + 340 nm): tR (min) = 21.28 (5.24%), 28.97 (91.48%).
1H NMR (300 MHz, CDCl3): d = 1.36 (s, 3 H, CH3), 2.05 (br s, 1 H,
OH), 2.25–2.30 (m, J = 8, 12 Hz, 1 H, H-C4), 2.56 (s, 3 H, NCH3),
2.66–2.72 (dd, J = 10, 16 Hz, 1 H, H-C4), 3.55–3.58 (d, J = 11 Hz,
2 H, CH2OH), 3.77–3.80 (br d, J = 11 Hz, 1 H, CH2OH), 3.95–4.00
(dd, J = 8, 10 Hz, 1 H, H-C3).
IR (film): 717, 804, 826, 858, 882, 929, 1015, 1055, 1090, 1131,
1216, 1298, 1368, 1411, 1458, 1492, 1599, 2869, 2964, 3409 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 3 H, CH3), 2.00–2.06 (m,
1 H, H-C4), 2.18 (br s, 1 H, OH), 2.52 (s, 3 H, NCH3), 2.73–2.78 (dd,
J = 8, 16 Hz, 1 H, H-C4), 3.44–3.47 (br d, J = 11 Hz, 2 H, CH2OH
+ H-C3), 3.58–3.61 (br d, J = 11 Hz, 1 H, CH2OH), 7.28–7.32 (m, 4
H, CHarom).
13C NMR (125.8 MHz, CDCl3): d = 15.3, 22.8, 29.7, 31.2, 42.7,
47.3, 47.9, 59.5, 65.6, 65.8, 71.1, 73.6, 128.5, 128.8, 128.9, 129.1,
129.2, 130.9.
13C NMR (125.8 MHz, CDCl3): d = 15.2, 22.7, 42.5, 43.2, 63.2,
65.8, 68.9.
MS (TS): m/z = 298.5 (M + 1), 226.3, 224.3, 211.3, 210.3, 208.1,
192.3, 190.3, 181.3, 179.1, 163.3.
HRMS (ESI+): m/z calcd for C12H13F5NO2 [M + H]+: 298.0864;
found: 298.0860.
(3S,5S)-5-Methyl-3-(4-nitrophenyl)-2-methylisoxazoline-5-
methanol (5g)
MS (TS): m/z = 242.5 (M + 1), 232.1, 205.1, 197.3, 175.5, 173.5,
168.3, 165.5, 156.1, 154.3.
HRMS (ESI+): m/z calcd for C12H17ClNO2 [M + H]+: 242.0940;
found: 242.0942.
Obtained according to the general procedure in 99% yield. HPLC
(CHIRACEL OD-H, Grad. 99 + 1 to 90 + 10, 0.75 mL/min, 100
min, 254 + 340 nm): tR (min) = 48.66 (67.49%), 51.32 (2.86%).
IR (film): 732, 804, 845, 884, 915, 1056, 1092, 1174, 1235, 1295,
1348, 1475, 1521, 1604, 2872, 2969, 3426 cm–1.
(3S,5S)-3-(4-Bromophenyl)-5-methyl-2-methylisoxazoline-5-
methanol (5d)
Obtained according to the general procedure in 93% yield. HPLC
(CHIRACEL OD-H, Grad. 99 + 1 to 90 + 10, 0.75 mL/min, 100
min, 254 + 340 nm): tR (min) = 22.71 (1.12%), 29.35 (96.14%).
1H NMR (300 MHz, CDCl3): d = 1.44 (s, 3 H, CH3), 2.02–2.08 (m,
1 H, H-C4), 2.18 (br s, 1 H, OH), 2.57 (s, 3 H, NCH3), 2.81–2.87 (m,
1 H, H-C4), 3.46–3.49 (br d, J = 11 Hz, 2 H, CH2OH + H-C3), 3.61–
3.64 (m, 1 H, CH2OH), 7.49–7.57 (m, 2 H, CHarom), 8.15–8.29 (m,
2 H, CHarom).
13C NMR (125.8 MHz, CDCl3): d = 15.1, 22.7, 24.4, 31.2, 43.0,
43.1, 47.6, 48.5, 61.3, 67.6, 70.8, 73.4, 77.2, 100.1, 123.4, 124.0,
127.7, 128.4, 128.6.
IR (film): 714, 822, 858, 881, 929, 1011, 1069, 1131, 1215, 1298,
1367, 1408, 1456, 1488, 1592, 2869, 2962, 3426 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 3 H, CH3), 2.00–2.06 (m,
1 H, H-C4), 2.15 (br s, 1 H, OH), 2.52 (s, 3 H, NCH3), 2.73–2.78 (dd,
J = 8, 16 Hz, 1 H, H-C4), 3.43–3.46 (br d, J = 11 Hz, 2 H, CH2OH
+ H-C3), 3.58–3.61 (br d, J = 11 Hz, 1 H, CH2OH), 7.24–7.26 (d,
J = 9 Hz, 2 H, CHarom), 7.46–7.48 (d, J = 9 Hz, 2 H, CHarom).
13C NMR (125.8 MHz, CDCl3): d = 22.8, 29.68, 30.30, 31.22, 42.7,
47.3, 48.0, 59.5, 65.7, 71.0, 73.7, 129.4, 129.5, 131.2, 131.4, 131.8,
131.9.
MS (TS): m/z = 253.1 (M + 1), 235.1, 219.1, 203.1, 188.1, 179.3,
168.1, 165.1, 162.3.
HRMS (ESI+): m/z calcd for C12H17N2O4 [M + H]+: 253.1182;
found: 253.1189.
(3S,5S)-5-Methyl-3-(phenyl)-2-methylisoxazoline-5-methanol
(5i)
MS (TS): m/z = 286.3 (M + 1), 214.3, 212.3, 200.3, 199.3, 198.3,
183.1, 171.3, 172.5, 169.3.
HRMS (ESI+): m/z calcd for C12H17ClNO2 [M + H]+: 286.3035;
found: 286.3029.
Obtained according to the general procedure in 90% yield. HPLC
(CHIRACEL OD-H, Grad. 99 + 1 to 90 + 10, 0.75 mL/min, 100
min, 254 + 340 nm): tR (min) = 21.32 (96.47%), 27.45 (3.53%).
IR (film): 763, 814, 825, 894, 930, 1005, 1016, 1086, 1142, 11683,
1323, 1379, 1481, 1453, 1621, 2875, 2974, 3458 cm–1.
(3S,5S)-5-Methyl-3-(4-trifluoromethylphenyl)-2-methylisox-
azoline-5-methanol (5e)
Obtained according to the general procedure in 90% yield. HPLC
(CHIRACEL OD-H, Grad. 99 + 1 to 90 + 10, 0.75 mL/min, 100
min, 254 + 340 nm): tR (min) = 23.74 (95.57%), 26.61 (4.43%).
1H NMR (300 MHz, CDCl3): d = 1.44 (s, 3 H, CH3), 2.09–2.14 (m,
1 H, H-C4), 2.50 (br s, 1 H, OH), 2.54 (s, 3 H, NCH3), 2.75–2.78 (dd,
J = 8, 16 Hz, 1 H, H-C4), 3.46–3.49 (br d, J = 11 Hz, 2 H, CH2OH
+ H-C3), 3.60–3.63 (br d, J = 11 Hz, 1 H, CH2OH), 7.30–7.45 (m, 5
H, CHarom).
13C NMR (125.8 MHz, CDCl3): d = 16.3, 23.3, 28.5, 32.2, 45.7,
48.5, 49.1, 59.5, 67.8, 68.5, 71.5, 74.3, 127.7, 127.9, 128.4, 128.5,
128.7, 130.5.
IR (film): 761, 804, 837, 860, 884, 931, 994, 1019, 1067, 1121,
1163, 1323, 1369, 1421, 1458, 1620, 2872, 2964, 3432 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42 (s, 3 H, CH3), 2.78–2.83 (dd,
J = 8, 16 Hz, 1 H, H-C4), 3.46–3.49 (m, 1 H, H-C4), 3.56 (br s, 1 H,
H-C3), 3.60–3.63 (m, 2 H, CH2OH), 7.49–7.51 (d, J = 8 Hz, 2 H,
CHarom), 7.60–7.62 (d, J = 8 Hz, 2 H, Carom).
MS (TS): m/z = 208.6 (M + 1), 190.6, 184.6, 161.6.
HRMS (ESI+): m/z calcd for C12H18NO2 [M + H]+: 208.1332;
found: 208.1333.
13C NMR (125.8 MHz, CDCl3): d = 22.7, 24.4, 29.7, 42.8, 43.1,
47.5, 48.5, 67.6, 71.0, 73.7, 125.5, 125.6, 125.7, 127.9, 128.1.
MS (TS): m/z = 276.3 (M + 1), 204.3, 202.3, 188.5, 186.5, 159.3.
HRMS (ESI+): m/z calcd for C13H17F3NO2 [M + H]+: 276.1209;
Acknowledgment
found: 276.1205l.
We wish to thank Dr. Bettina Bressel and Stephane Grass for help
with the manuscript and the experimental. We also acknowledge fi-
nancial support for this project from the Swiss National Science
Foundation and the University of Geneva.
(3S,5S)-5-Methyl-3-(pentafluorophenyl)-2-methylisoxazoline-
5-methanol (5f)
Obtained according to the general procedure in 94% yield. HPLC
(CHIRACEL OD-H, Grad. 99 + 1 to 90 + 10, 0.75 mL/min, 100
min, 254 + 340 nm): tR (min) = 18.53 (5.44%), 19.63 (44.68%).
Synthesis 2010, No. 13, 2207–2212 © Thieme Stuttgart · New York

2212
A. Bădoiu et al.
PAPER
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above were obtained with THF and EtOAc. Lower yields
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The approach of the nitrone is modeled.
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Synthesis 2010, No. 13, 2207–2212 © Thieme Stuttgart · New York