1,3-dipolar cycloaddition of chirally modified vinylboronic ester with nitrile oxides

Article abstract of DOI:10.1016/S0040-4020(00)00017-X

Chiral modified vinylboronic ester 1, derived from D-(+)-mannitol, reacted with nitrile oxides to afford optically active isoxazolines. The regioselectivity was excellent and moderate stereoselectivity (up to 60% d.e.) was achieved. The configuration of new chiral centres in all the isoxazoline products was established by NMR analysis or X-ray analysis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00017-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 965–970
1,3-Dipolar Cycloaddition of Chirally Modified Vinylboronic
Ester with Nitrile Oxides
*
Ao Zhang, Ying Kan, Gui-Ling Zhao and Biao Jiang
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, People’s Republic of China
Received 21 September 1999; revised 10 December 1999; accepted 23 December 1999
Abstract—Chiral modified vinylboronic ester 1, derived from d-(ϩ)-mannitol, reacted with nitrile oxides to afford optically active
isoxazolines. The regioselectivity was excellent and moderate stereoselectivity (up to 60% d.e.) was achieved. The configuration of new
chiral centres in all the isoxazoline products was established by NMR analysis or X-ray analysis. ᭧ 2000 Elsevier Science Ltd. All rights
reserved.
Introduction
Results and Discussion
Vinylboronic ester derivatives are accessible and widely
employed species for building a large number of important
molecules.1 Recently several groups have explored their
application in asymmetric reactions, especially in asym-
metric 1,3-dipolar cycloaddition reaction to prepare chiral
D2-isoxazolines, an important class of heterocycles.2–8
Wallace and others have shown boronic esters to be an
excellent group for inducing the regioselectivity of 1,3-
dipolar cycloaddition reactions of 1,2-disubstituted vinyl-
boronic esters with nitrile oxides.9,10 This was further
confirmed in our laboratory, but we also found that a
chirally modified vinylboronic ester, in which optically
active pinanediol was part of the boronic ester group, was
not effective to control the stereoselectivity in asymmetric
1,3-dipolar cycloaddition reactions.11
The chirally modified vinyl pinacol boronic ester 1 was
readily prepared by hydroboration of d-(ϩ)-mannitol
derived alkyne with dicyclohexylborane, selective oxidation
of the resulted alkenylborane with trimethylamine oxide,
and then transesterification of the intermediate dicyclo-
hexylboronate with pinacol (Scheme 1).12–14
The asymmetric 1,3-dipolar cycloaddition reaction of vinyl-
boronic ester 1 with aryl hydroximinoyl chloride 2 was
initially carried out in THF at 0ЊC, by using Et3N to generate
the nitrile oxide. As expected, the reaction proceeded
smoothly in a highly regioselective manner. Four isoxazo-
line products were obtained, comprising erythro- and threo-
D2-isoxazolines 3 and 30 as the major products, together
with (4S,5S,10R)- and (4R,5R,10R)-4-hydroxy-D2-isoxazo-
lines 4 and 40 as the minor products (Scheme 2, Table 1).
As part of our recent studies of the application of vinyl-
boronic esters in 1,3-dipolar cycloaddition reactions, we
synthesized optically active vinylboronic ester 1, and
carried out its asymmetric 1,3-dipolar cycloaddition
with nitrile oxides, which allow the preparation of chiral
isoxazolines, precursors for various classes of amino sugars.
From previous studies,3,4,11 we could conclude that D2-
isoxazolines 3 and 30 were the products which boronic
ester group was lost from the resulting 4-boronic ester
substituted D2-isoxazoline intermediates in the cyclo-
addition reaction, while the 4-hydroxy-D2-isoxazolines 4
Scheme 1.
Keywords: 1,3-dipolar cycloaddition; vinylboronic ester; D2-isoxazolines; 4-hydroxy-D2-isoxazolines.
* Corresponding author. Tel.: ϩ86-0-21-6416-3300; fax: ϩ860-21-6416-6128; e-mail: jiangb@pub.sioc.ac.cn
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00017-X

966
A. Zhang et al. / Tetrahedron 56 (2000) 965–970
Scheme 2.
Table 1. Results of cycloaddition of chirally modified vinylboronic ester 1
with aryl hydroximinoyl chloride 2
was known from d-(ϩ)-mannitol, the absolute configuration
0
¨
of C-5 was S in compound 3 and R in compound 3 . Jager and
others have also prepared erythro/threo-3a/30a and reported
their spectroscopic data.15,17 In their reports, the coupling
constant between H-5 and H-10 and other spectral data of
compounds 3a and 30a were completely in agreement with
our results. With respect to the oxidized products in the
regioselective 1,3-dipolar cycloaddition reaction, retention
of the configuration of the trans-1,2-disubstituted alkene 1
as the dipolarophile upon cycloaddition requires H-4 and H-5
in the cycloadducts should be in a trans relationship. So only
two diastereoisomers of trans-4,5-disubstituted-4-hydroxy-
D2-isoxazolines should result. The coupling constants in our
experiments, J4,5ˆ2.7 Hz in 4a and J4,5ˆ3.8 Hz in 40a, which
were indicative of a trans-stereochemistry between H-4 and
H-5, supported our analysis. The absolute configuration of the
major oxidized product 4a was inferred from the close agree-
ment of the chemical shift and coupling constants of the
Entry
R
Diastereomer ratioa (yield %b)
3/30
4/40
1
2
a; RˆPh
75/25(52)
77/23(50)
80/20(44)
70/30(45)
b; Rˆ4-ClC6H4
a Based on the isolated yields.
b Isolated yields.
and 40 were the products which 4-boronic ester substituted
D2-isoxazoline intermediates were oxidized. Moderate
stereoselectivity was obtained in each pair of diastereo-
isomers, the 4,5-erythro isomer was always dominant.
The diastereomers of erythro/threo-D2-isoxazoline 3/30 or
(4S,5S,10R)/(4R,5R,10R)-4-hydroxy-D2-isoxazoline 4/40 could
be separated by careful silica gel column chromatography.
The structures of D2-isoxazolines 3 and 30 were unambigu-
ously ascertained from their spectroscopic data. The
coupling constants between H-5 and H-10 in their 300 MHz
1
key H-4, H-5 and H-10signals in the 300 MHz H NMR
spectrum with the related compound 5, which J4,5ˆ2.7 Hz,
0
0
J5,1 ˆ8.1 Hz in compound 4a while J4,5ˆ2.7 Hz, J5,1 ˆ7.8 Hz
in compound 5. Further support for this assignment was
afforded by comparison of the specific rotation of compound
4a with compound 5 (Scheme 3).16 Further support for the
structure of (4S,5S,10R)-4a comes from the X-ray analysis
1H NMR were significantly different, J5,1 ˆ8.0 Hz in erythro-
0
D2-isoxazoline 3a while J5,1 ˆ4.5 Hz in threo-D -isoxazoline
2
0
30a. Because the configuration of C-10 in the cycloadducts
Scheme 3.

A. Zhang et al. / Tetrahedron 56 (2000) 965–970
967
Figure 1. X-ray analysis of 4a.
(Fig. 1). Since the structure of compound 4a has been well
established, according to our preliminary analysis, the minor
oxidized product must be compound 40a. The 1H NMR spec-
trum of this material was well resolved, and its analysis
confirmed the indicated stereochemistry. The coupling
constant between H-5 and H-10 in compound 40a
boronic ester 1 with aryl hydroximinoyl chloride 2, we
employed sodium percarbonate in place of triethylamine
to generate the cycloaddition. As expected, 4-hydroxy-D2-
isoxazolines 4 and 40 were obtained as the major products,
D2-isoxazolines 3 and 30 were not detected in the crude
reaction mixture by TLC analysis. The regioselectivity
was excellent, but the diastereoselectivity still fell in the
range of 52–58% (Table 2, Scheme 4).
0
(J5,1 ˆ6.5 Hz) was slightly smaller than that in compound
0
4a (J5,1 ˆ8.1 Hz), the other coupling constants and the chemi-
cal shifts for the key signals were very close. Another indica-
tion for this assignment was comparison of the specific
rotation of compound 40a with 4a.
In summary, chirally modified vinylboronic ester 1 was a
very reactive group to prepare optically active 4-hydroxy-
D2-isoxazolines via 1,3-dipolar cycloaddition reaction.
Compared with Wallace’s work, which achieved excellent
stereoselectivity by building camphorsultam into vinyl-
boronic ester.9,10 We obtained only moderate diastereo-
selectivity. But because of the ready accessibility of
optically active vinylboronic ester 1 from d-(ϩ)-mannitol
and all the isoxazalines in our system could be isolated in
optical purity, it provides a short and efficient method to
prepare these functionalized isoxazoline rings. These, after
reduction or suitable ring cleavage, may lead to interesting
chiral building blocks for synthesis of various important
amino sugars.15,16
4-Hydroxy-D2-isoxazolines 4 and 40 were obtained as the
major products when oxidizing agent tert-butyl hydro-
peroxide was added during the completion of the cyclo-
addition. In Wallace’s work and our previous paper,11
sodium percarbonate was found to be a good reagent to
generate the nitrile oxides and to oxidize the 4-substituted
boronic ester cycloaddition intermediate in 1,3-dipolar
cycloaddition reaction of 1,2-disubstituted vinylboronic
ester with nitrile oxide. So in the cycloaddition of vinyl-
Table 2. Results of cycloaddition reaction by using Na2CO3·1.5H2O2
a
Entry
R
Ratio of 4/40
Overall yield (%)b
Experimental
1
2
3
4
5
a; RˆPh
77:23
78:22
79:21
76:24
76:24
90
82
87
60
73
b; Rˆ4-ClC6H4
c; Rˆ4-MeC6H4
d; Rˆ4-MeOC6H4
e; Rˆ2,4-Cl2C6H4
Melting points were determined on a Digital Melting
Apparatus WRS-1A. NMR spectra were recorded as
CDCl3 solutions on a VXL-300 instrument. The H NMR
(300 MHz) chemical shifts are reported as d values in ppm
relative to tetramethylsilane as internal standard. Infrared
spectra were recorded on a Perkin–Elmer 983 FT-IR
1
a Based on the isolated yields.
b Isolated yields.
Scheme 4.

968
A. Zhang et al. / Tetrahedron 56 (2000) 965–970
spectrometer. Mass spectral measurements were performed
on a Fining 4021 or Fining MAT 8403 gas chromatography/
mass spectrometer at 70 eV. Elemental analyses were
carried out on a MOD-1106 elemental analyzer. All solvents
were purified and dried by standard techniques just before
use. All reactions were monitored by thin layer chromato-
graphy (TLC) using silica gel GF254. Products were puri-
fied by chromatography on silica gel manufactured in
Qingdao Marine Chemical Factory, eluting with the solvent
mixture of petroleum ether (bp 60–90ЊC) and ethyl acetate.
Optical rotations were measured using a Shanghai WZZ-1S
automatic polarimeter.
H-10, H-20 a), 4.66 (ddd, Jˆ6.9, 6.9, 9.9 Hz, 1H, H-5),
7.38 (m, 2H, ArH), 7.60 (m, 2H, ArH). HRMS: Calcd. for
C14H16NO335Cl: 281.0819, Found: 281.0832, Calcd. for
C14H16NO337Cl: 283.0790, Found: 281.0803.
30b: MS m/z: 284 (Mϩϩ 3, 11), 282 (Mϩϩ 1, 49), 281 (Mϩ,
1), 266 (26), 224 (25), 180 (14), 115 (16), 101 (100), 43
(69). IR (cmϪ1): 3060, 2989, 2926, 1598, 1492, 1382, 1372,
1
1257, 1094, 1077, 904, 836. 300 MHz H NMR (CDCl3):
1.36 (s, 3H, CH3), 1.45 (s, 3H, CH3), 3.23 (dd, Jˆ8.1,
16.8 Hz, 1H, H-4b), 3.38 (dd, Jˆ11.0, 16.8 Hz, 1H, H-
4a), 3.90 (dd, Jˆ6.3, 8.6 Hz, 1H, H-20 b), 4.10 (dd,
Jˆ6.85, 8.7 Hz, 1H, H-20 a), 4.34 (ddd, Jˆ4.5, 6.4,
6.4 Hz, 1H, H-10), 4.83 (ddd, Jˆ4.4, 7.9, 11.0 Hz, 1H, H-
5), 7.39 (m, 2H, ArH), 7.60 (m, 2H, ArH). HRMS: Calcd.
for C14H16NO335Cl: 281.0819, Found: 281.0835, Calcd. for
C14H16NO337Cl: 283.0790, Found: 281.0782.
General procedures
1,3-Dipolar cycloaddition reaction of vinylboronic ester
1 with nitrile oxides which initiated by Et3N. To a 0ЊC
cooled solution of vinylboronic ester
0.535 mmol) and aryl hydroximinoyl chloride
1
(136 mg,
4a: [a]2D0ˆϩ46.5 (c 0.60, CH2Cl2). MS m/z 265 (Mϩϩ 2, 9),
264 (Mϩϩ 1, 56), 248 (34), 160 (5), 115 (5), 104 (34), 101
(100), 73 (24), 43 (97). IR (cmϪ1): 3304, 3070, 2992, 1569,
1450, 1373, 1382, 1256, 1217.9, 1143, 1074.7, 1056, 904,
833. 300 MHz 1H NMR (CDCl3): 1.30 (s, 3H, CH3), 1.41 (s,
3H, CH3), 3.75 (s, OH), 3.88 (ddd, Jˆ4.38, 6.32, 8.14 Hz,
1H, H-10), 3.96 (dd, Jˆ4.3, 8.8 Hz, 1H, H-20 b), 4.08 (dd,
Jˆ6.9, 8.8 Hz, 1H, H-20 a), 4.38 (dd, Jˆ2.7, 8.1 Hz, 1H, H-
5), 5.45 (m, 1H, H-4), 7.30 (m, 3H, ArH), 7.77 (m, 2H,
ArH). 13C NMR (CDCl3): 24.97 (CH3), 26.80 (CH3),
67.01 (C-20), 73.49 (C-10), 78.95 (C-5), 88.60 (C-4),
110.08 (C-40), 127.21, 127.70, 128.86, 130.46 (Ar),
157.73 (C-3). Anal.: C14H17NO4 Calcd: C, 63.88; H, 6.46;
N, 5.32. Found: C, 63.81; H, 6.58; N, 5.10
2
(0.74 mmol) in THF (10 mL), was dropped slowly a solu-
tion of Et3N (760 mg, 0.75 mmol) by a syringe. The result-
ing mixture was stirred at 0ЊC to room temperature until the
starting material of vinylboronic ester 1 disappeared as
followed by TLC. The reaction suspension was filtered by
celite and the solid was washed with THF (2×10 mL). After
condensation of the combined organic phase, the residue
was subjected to flash chromatography on silica gel column.
The first elution (ethyl acetate: petroleum 1:15) afforded the
optically pure diastereoisomers D2-isoxazoline 3 and 30, the
optically pure diastereoisomers 4-hydroxy-D2-isoxazoline 4
and 40 were obtained after the second elution (ethyl acetate:
petroleum 1:4).
40a: [a]2D0ˆϪ48.8 (c 0.90, acetone). MS m/z 265 (Mϩϩ 2,
2), 264 (Mϩϩ 1, 12), 263 (Mϩ, 5), 248 (36), 162 (5), 145
(6), 131 (6), 104 (46), 101 (100), 73 (29), 43 (91). IR
(cmϪ1): 3311, 3061, 2991, 2921, 1600, 1451, 1372, 1263,
1215, 1155, 1090, 916, 838, 694. 300 MHz 1H NMR
(CDCl3): 1.32 (s, 3H, CH3), 1.39 (s, 3H, CH3), 3.24 (s,
OH), 3.93 (dd, Jˆ6.5, 8.6 Hz, 1H, H-20 b), 4.08 (dd,
Jˆ6.8, 8.6 Hz, 1H, H-20 a), 4.32 (ddd, Jˆ2.2, 4.2, 6.5 Hz,
1H, H-10), 4.50 (m, 1H, H-5), 5.45 (d, Jˆ3.8 Hz, 1H, H-4),
7.40 (m, 3H, ArH), 7.78 (m, 2H, ArH). 13C NMR (CDCl3):
25.26 (CH3), 26.09 (CH3), 65.28 (C-20), 75.39 (C-10), 79.14
(C-5), 87.72 (C-4), 110.16 (C-40), 127.14, 127.74, 128.83,
130.32 (Ar), 157.76 (C-3). Anal.: C14H17NO4 Calcd: C,
63.88; H, 6.46; N, 5.32. Found: C, 63.82; H, 6.71; N, 5.33
3a: MS m/z 249 (Mϩϩ2, 8), 248 (Mϩϩ1, 46), 247 (Mϩ, 1),
232 (26), 190 (22), 146 (20), 115 (18), 101 (100), 77 (28), 43
(96). IR (cmϪ1): 2986, 2920, 1594, 1565, 1448, 1371, 1356,
1264, 1204, 1153, 1049, 859, 764. 300 MHz 1H NMR
(CDCl3): 1.35 (s, 3H, CH3), 1.45 (s, 3H, CH3), 3.35 (dd,
Jˆ6.6, 16.9 Hz, 1H, H-4b), 3.45 (dd, Jˆ10.1, 16.8 Hz,
1H, H-4a), 3.95 (dd, Jˆ4.2, 8.0 Hz, 1H, H-20 b), 4.15 (m,
2H, H-10, H-20 a), 4.65 (ddd, Jˆ7.8, 8.0, 10.0 Hz, 1H, H-5),
7.44 (m, 3H, ArH), 7.70 (m, 2H, ArH). HRMS: C14H17NO3
Calcd 247.1209, Found: 247.1193
30a: MS m/z 249 (Mϩϩ 2, 10), 248 (Mϩϩ 1, 60), 247 (Mϩ,
1), 232 (30), 190 (29), 146 (22), 115 (19), 101 (100), 77
(27), 43 (94). IR (cmϪ1): 3030, 2987, 2932, 1599, 1569,
1448, 1372,1357, 1256, 1214, 1153, 1075, 862, 761.
4b: [a]2D0ˆϩ21.0 (c 0.65, CH2Cl2). MS m/z 299 (Mϩϩ 2, 6),
297 (Mϩ, 18), 281 (26), 240 (2), 138 (29), 111 (8), 102 (12),
101 (100.00), 73 (21). IR (cmϪ1): 3252, 2987, 2935, 1597,
1496, 1372, 1245, 1216, 1093, 1060, 1038, 1014, 901, 842.
300 MHz 1H NMR (CDCl3): 1.32 (s, 3H, CH3), 1.44 (s, 3H,
CH3), 3.08 (s, OH), 3.90 (ddd, Jˆ4.4, 6.3, 8.4 Hz, 1H, H-10),
4.00 (dd, Jˆ4.3, 8.9 Hz, 1H, H-20 b), 4.12 (dd, Jˆ6.3,
8.9 Hz, 1H, H-20 a), 4.41 (dd, Jˆ2.7, 8.2 Hz, 1H, H-5),
5.44 (d, Jˆ2.3 Hz, 1H, H-4), 7.35 (m, 2H, ArH), 7.71 (m,
2H, ArH). Anal.: C14H16NO4Cl Calcd: C, 56.47; H, 5.38; N,
4.70. Found: C, 56.17; H, 5.39; N, 4.53.
1
300 MHz H NMR (CDCl3): 1.38 (s, 3H, CH3), 1.48 (s,
3H, CH3), 3.26 (dd, Jˆ8.0, 16.7 Hz, 1H, H-4b), 3.42 (dd,
Jˆ11.1, 16.8 Hz, 1H, H-4a), 3.92 (dd, Jˆ6.3, 8.6 Hz, 1H,
H-20 b), 4.13 (dd, Jˆ7.0, 8.7 Hz, 1H, H-20 a), 4.36 (ddd,
Jˆ4.7, 6.4, 6.5 Hz, 1H, H-10), 4.83 (ddd, Jˆ4.5, 8.1,
11.0 Hz, 1H, H-5), 7.42 (m, 3H, ArH), 7.68 (m, 2H, ArH).
HRMS: C14H17NO3 Calcd: 247.1209, Found: 247.1194.
3b: MS m/z 284 (Mϩϩ 3, 10), 282 (Mϩϩ 1, 30), 281 (Mϩ,
9), 266 (19), 224 (15), 180 (11), 101 (94), 43 (100). IR
(cmϪ1): 3059, 2988, 2925, 1597, 1491, 1382, 1371, 1256,
1
1147, 1093, 1077, 903, 834. 300 MHz H NMR (CDCl3):
40b: [a]2D0ˆϪ46.6 (c 0.70, acetone). MS m/z 299 (Mϩϩ 2,
9), 297 (Mϩ, 27), 283 (10), 281 (28), 138 (22), 111 (9), 101
(100), 73 (20), 43 (77). IR (cmϪ1): 3243, 2987, 2935, 1597,
1.34 (s, 3H, CH3), 1.43 (s, 3H, CH3), 3.34 (dd, Jˆ6.8,
16.9 Hz, 1H, H-4b), 3.41 (dd, Jˆ10.2, 16.9 Hz, 1H, H-
4a), 3.95 (dd, Jˆ4.3, 8.2 Hz, 1H, H-20 b), 4.12 (m, 2H,

A. Zhang et al. / Tetrahedron 56 (2000) 965–970
969
1496, 1372, 1213, 1092, 1058, 1037, 901, 842. 300 MHz 1H
NMR (CDCl3): 1.31 (s, 3H, CH3), 1.37 (s, 3H, CH3), 3.21 (s,
OH), 3.92 (dd, Jˆ6.2, 8.2 Hz, 1H, H-20 b), 4.08 (dd, Jˆ6.9,
8.3 Hz, 1H, H-20 a), 4.34 (m, 1H, H-10), 4.50 (dd, Jˆ3.5,
7.2 Hz, 1H, H-5), 5.38 (d, Jˆ3.14 Hz, 1H, H-4), 7.34 (m,
2H, ArH), 7.70 (m, 2H, ArH). C14H16NO4Cl Calcd: C,
56.47; H, 5.38; N, 4.70. Found: C, 56.43; H, 5.42; N, 4.50.
(C-10), 79.40 (C-5), 88.39 (C-4), 110.08 (C-40), 114.30,
120.09, 128.85, 161.30 (Ar), 157.50 (C-3). Anal.:
C15H19NO5 Calcd C, 61.43; H, 6.48; N, 4.78. Found: C,
61.31; H, 6.52; N, 4.67.
40d: [a]2D0ˆϪ55.20 (c 0.65, acetone). MS m/z 294 (Mϩϩ1,
14), 293 (Mϩ, 62), 278 (29), 192 (5), 176 (10), 161 (3), 149
(10), 134 (82), 101 (100), 73 (32), 43 (99). IR (cmϪ1): 3473,
2998, 1607, 1595, 1514, 1382, 1253, 1183, 1051, 1012, 945,
874. 300 MHz 1H NMR (CDCl3): 1.33 (s, 3H, CH3), 1.40 (s,
3H, CH3), 3.10 (s, OH), 3.83 (s, 3H, OCH3), 3.92 (dd,
Jˆ6.5, 8.6 Hz, 1H, H-20 b), 4.10 (dd, Jˆ6.9, 8.6 Hz, 1H,
H-20 a), 4.35 (m, 1H, H-10), 4.50 (dd, Jˆ4.1, 8.1 Hz, 1H, H-
5), 5.44 (d, Jˆ3.6 Hz, 1H, H-4), 6.80 (m, 2H, ArH), 7.75 (m,
2H, ArH). 13C NMR (CDCl3): 25.25 (CH3), 26.13 (CH3),
55.36 (OCH3), 65.31 (C-20), 75.33 (C-10), 79.40 (C-5),
87.51 (C-4), 110.13 (C-40), 114.28, 120.10, 128.70,
161.20 (Ar), 157.30 (C3). Anal. C15H19NO5 Calcd C,
61.43; H, 6.48; N, 4.78. Found: C, 61.32; H, 6.63; N, 4.53.
1,3-Dipolar cycloaddition reaction of vinylboronic ester
1 with nitrile oxides initiated by sodium percarbonate.
To a solution of vinylboronic ester 1 (330 mg, 1.30 mmol)
and aryl hydroximinoyl chloride (1.8 mmol) in THF
(20 mL), was added sodium percarbonate (570 mg,
3.63 mmol) in one portion. The resulting suspension was
stirred at room temperature until the starting material of
vinylboronic ester 1 disappeared as followed by TLC. The
reaction mixture was filtered by celite and the solid was
washed with THF (2×20 mL). After condensation of the
combined organic phase, the residue was subjected to
flash chromatography on silica gel column with a mixture
of ethyl acetate and petroleum (1/4) as the eluent, the opti-
cally pure diastereoisomer 4-hydroxy-D2-isoxazoline 4 and
40 were obtained.
4e: [a]2D0ˆϩ74.5 (c 0.60, CH2Cl2). MS m/z 333 (7), 332
(Mϩ, 3), 331 (10), 315 (20), 273 (1), 172 (19), 136 (6),
101 (100), 73 (19), 43 (59). IR (cmϪ1): 3402, 3094, 2989,
2937, 1586, 1553, 1476, 1374, 1253, 1216, 1105, 1077,
4c: [a]2D0ˆϩ44.8 (c 1.87, CH2Cl2). MS m/z 278 (Mϩϩ 1, 6),
277 (Mϩ, 25), 262 (36), 176 (7), 118 (52), 101 (100), 91
(18), 73 (26). IR (cmϪ1): 3404, 3050, 2989, 2925, 1612,
1517, 1374, 1217, 1075, 1059, 892, 843. 300 MHz 1H
NMR (CDCl3): 1.31 (s, 3H, CH3), 1.42 (s, 3H, CH3), 2.35
(s, 3H, ArCH3), 3.62 (s, OH), 3.88 (ddd, Jˆ4.4, 6.3, 8.2 Hz,
1H, H-10), 3.96 (dd, Jˆ4.3, 8.8 Hz, 1H, H-20 b), 4.08 (dd,
Jˆ6.3, 8.8 Hz, 1H, H-20 a), 4.37 (dd, Jˆ2.7, 8.2 Hz, 1H,
H-5), 5.43 (d, Jˆ2.6 Hz, 1H, H-4), 7.14 (m, 2H, ArH), 7.64
(m, 2H, ArH). 13C NMR (CDCl3ϩacetone-d6): 21.57 (CH3),
25.26 (CH3), 26.99 (ArCH3), 67.19 (C-20), 74.14 (C-10),
78.91 (C-5), 88.73 (C-4), 110.09 (C-40), 125.87, 127.45,
129.71, 140.56 (Ar), 158.13 (C-3). Anal.: C15H19NO4
Calcd C, 64.98; H, 6.86; N, 5.05. Found: C, 64.54; H,
6.93; N, 5.00.
1050, 871, 842. 300 MHz H NMR (CDCl3): 1.37 (s, 3H,
1
CH3), 1.48 (s, 3H, CH3), 2.70 (s, OH), 4.05 (ddd, Jˆ4.13,
5.67, 7.93 Hz, 1H, H-10), 4.15 (m, 2H, H-20), 4.46 (dd,
Jˆ3.5, 7.7 Hz, 1H, H-5), 5.73 (d, Jˆ3.5 Hz, 1H, H-4),
7.32 (dd, Jˆ2.1, 8.4 Hz, 1H, ArH), 7.48 (d, Jˆ2.0 Hz, 1H,
ArH), 7.66 (dd, Jˆ8.4 Hz, 1H, ArH). Anal. C14H15NO4Cl2
Calcd C, 50.60; H, 4.52; N, 4.21. Found: C, 50.75; H, 4.74;
N, 4.18.
40e: [a]2D0ˆϪ97.0 (c 0.85, acetone). MS m/z 336 (2), 334
(12), 332 (Mϩ, 21), 331 (MϩϪ1, 100), 315 (34), 260 (58),
172 (6), 101 (68), 43 (21). IR (cmϪ1): 3402, 3094, 2989,
2937, 1586, 1553, 1476, 1374, 1253, 1216, 1105, 1077,
1
1050, 871, 842. 300 MHz H NMR (CDCl3): 1.36 (s, 3H,
CH3), 1.43 (s, 3H, CH3), 2.79 (s, OH), 3.97 (dd, Jˆ6.3,
8.7 Hz, 1H, H-20 b), 4.12 (dd, Jˆ6.8, 8.5 Hz, 1H, H-20 a),
4.39 (m, 1H, H-10), 4.54 (dd, Jˆ4.4, 4.4 Hz, 1H, H-5), 5.69
(d, Jˆ4.5 Hz, 1H, H-4), 7.30 (dd, Jˆ1.8, 8.4 Hz, 1H, ArH),
7.47 (d, Jˆ1.6 Hz, 1H, ArH), 7.63 (dd, Jˆ8.4 Hz, 1H, ArH).
Anal. C14H15NO4Cl2 Calcd C, 50.60; H, 4.52; N, 4.21.
Found: C, 50.54; H, 4.65; N, 4.30.
40c: [a]2D0ˆϪ57.3 (c 0.80, acetone). MS m/z 278 (Mϩϩ 1,
3), 277 (Mϩ, 15), 262 (27), 174 (3), 118 (43), 101 (100), 91
(19), 73 (24), 43 (64). IR (cmϪ1): 3270, 2990, 2920, 1517,
1455, 1381, 1370, 1265, 1211, 1084, 1056, 1022, 949, 857,
822. 300 MHz 1H NMR (CDCl3): 1.32 (s, 3H, CH3), 1.40 (s,
3H, CH3), 2.36 (s, 3H, ArCH3), 3.10 (s, OH), 3.92 (dd,
Jˆ6.6, 8.5 Hz, 1H, H-20b), 4.08 (dd, Jˆ6.9, 8.5 Hz, 1H,
H-20 a), 4.34 (m, 1H, H-10), 4.49 (dd, Jˆ4.0, 7.9 Hz, 1H,
H-5), 5.41 (m, 1H, H-4), 7.19 (m, 2H, ArH), 7.66 (m, 2H,
ArH). Anal.: C15H19NO4 Calcd C, 64.98; H, 6.86; N, 5.05.
Found: C, 64.84; H, 6.84; N, 4.78.
X-Ray diffraction study. X-Ray structure determination of
4a C14H17NO4: colourless crystal (0.20×0.20×0.30 mm,
grown from diethyl ether and n-hexane), C14H17NO4,
M263.29, orthorhombic, space group P212121(#19), aˆ
˚
˚
˚
˚
11.314(1) A,
bˆ12.707(2) A,
cˆ9.411(2) A,
Vˆ
3
1353.1(4) A , Zˆ4, Dˆ1.292 g cmϪ3
,
F(000)ˆ560.00,
4d: [a]2D0ˆϩ30.2 (c 1.25, CH2Cl2). MS m/z 294 (Mϩϩ 1,
24), 293 (Mϩ, 60), 278 (19), 192 (4), 176 (6), 149 (6), 134
(84), 101 (92), 73 (33), 43 (100). IR (cmϪ1): 3217, 2995,
2990, 2851 1609, 1518, 1375, 1263, 1181, 1076, 889, 834.
300 MHz 1H NMR (CDCl3): 1.32 (s, 3H, CH3), 1.45 (s, 3H,
CH3), 3.25 (s, OH), 3.82 (s, 3H, OCH3), 3.89 (ddd, Jˆ4.1,
6.0, 8.0 Hz, 1H, H-10), 4.00 (dd, Jˆ4.3, 8.8 Hz, 1H, H-20 b),
4.11 (dd, Jˆ6.3, 8.8 Hz, 1H, H-20 a), 4.38 (dd, Jˆ2.5,
8.3 Hz, 1H, H-5), 5.44 (d, Jˆ2.4 Hz, 1H, H-4), 6.89 (m,
2H, ArH), 7.72 (m, 2H, ArH). 13C NMR (CDCl3): 25.05
(CH3), 26.92 (CH3), 55.38 (OCH3), 67.18 (C-20), 73.53
Tˆ293 K. A Rigaku AFC7R diffractometer (CCD area
detector) and graphite monochromated Mo-Ka radiation,
˚
lˆ0.34 A, was used for all measurements. Cell constants
and an orientation matrix for data collection were obtained
from a least-squares refinement using the setting angles of
20 carefully centered reflections in the range
18.29Ͻ2uϽ21.79Њ. The data was collected using the
v-2u scan technique to a maximum 2u value of 55.0Њ.
The diameter of the incident beam collimator was
1.0 mm, the crystal to detector distance was 235 mm. A
total of 1808 reflections was collected. The intensities of

970
A. Zhang et al. / Tetrahedron 56 (2000) 965–970
6. Renard, P. Y.; Lallemand, J. Y. Tetrahedron Lett. 1997, 38,
6589.
7. Chataiguer, I.; Lebroton, J.; Zammattio, F.; Villiras, J.
Tetrahedron Lett. 1997, 38, 3719.
three representative reflection were measured after every
200 reflections. The structure was solved by direct methods
using SHELXS86 and expanded using DIRDIF92. The non-
hydrogen atoms were refined anisotropically. Hydrogen
atoms were refined isotropically.
´
8. Bertrand Carboni, B.; Ollivault, M.; Bouguenec, F.; Carrie, R.;
Mohamed Jazouli, M. Tetrahedron Lett. 1997, 38, 6665.
9. Wallace, R. H.; Liu, J.; Zong, K. K.; Eddings, H. Tetrahedron
Lett. 1997, 38, 6791.
10. Liu, J.; Eddings, H.; Wallace, R. H. Tetrahedron Lett. 1997,
38, 6795.
Atomic coordinates, thermal parameters and bond lengths
and angles have been deposited at the Cambridge Crystal-
lographic Data Centre (CCDC).
11. Jiang, B.; Zhang, A.; Kan, Y.; Chin, J. Chem. 1999, 17 (3),
293.
References
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¨
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¨
¨
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¨
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