Stereoselective formation of optically active 2-oxy-1,3-oxazolidin-4-ones from chiral O-acylmandelamides or lactamides

Article abstract of DOI:10.1016/S0040-4020(02)01057-8

(-)-O-Acyllactamides or mandelamides in the presence of TBSOTf underwent cyclization reaction to give optically active 2-oxy-1,3-oxazolidin-4-ones, a novel nitrogen analog of orthoesters, in good yields. An X-ray analysis and NOE studies indicated that the absolute configuration at the newly formed chiral carbon was S. For their synthetic application, the 1,3-dipolar cycloaddition of nitrile oxide was examined. The cycloadducts were obtained in a stereoselective manner. Subsequent treatment of the adduct with TBAF resulted in the one-step removal of mandelamide, giving optically active 4,5-dihydroisoxazole and mandelamide in good yields.

Full text of DOI:10.1016/S0040-4020(02)01057-8

Tetrahedron 58 (2002) 8763–8770
Stereoselective formation of optically active 2-oxy-1,3-oxazolidin-
4-ones from chiral O-acylmandelamides or lactamides
a
b
c
Akio Kamimura,a Yoji Omata, Akikazu Kakehi and Masashi Shirai
,
*
aDepartment of Applied Chemistry, Faculty of Engineering, Yamaguchi University, Ube 755-8611, Japan
bDepartment of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Nagano 380-8553, Japan
cUbe Laboratory, Ube Industries Ltd., Ube 755-8633, Japan
Received 25 June 2002; accepted 22 August 2002
Abstract—(2)-O-Acyllactamides or mandelamides in the presence of TBSOTf underwent cyclization reaction to give optically active
2-oxy-1,3-oxazolidin-4-ones, a novel nitrogen analog of orthoesters, in good yields. An X-ray analysis and NOE studies indicated that the
absolute configuration at the newly formed chiral carbon was S. For their synthetic application, the 1,3-dipolar cycloaddition of nitrile oxide
was examined. The cycloadducts were obtained in a stereoselective manner. Subsequent treatment of the adduct with TBAF resulted in the
one-step removal of mandelamide, giving optically active 4,5-dihydroisoxazole and mandelamide in good yields. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
(S)-lactic acid or (S)-mandelic acid derivatives. O-Acylation
of lactamide 1 was achieved by their esterification reaction
with acyl chloride or carboxylic acid in the presence of
DCC. Treatment of 2a with TBSOTf in the presence of
2,6-lutidine at 08C, for example, resulted in the rapid
disappearance of 2a and a new compound 4a was formed in
a spot-to-spot manner (Scheme 1). Product 4a was purified
through flash chromatography and isolated in a 90% yield as
the sole product (Table 1, entry 1). The results are
summarized in Table 1.
Acetals serve as a convenient protective group for carbonyl
compounds.1 They have also been recognized as a useful
chiral auxiliary for asymmetric synthesis and a number of
improvements have been achieved so far.2 Orthoseters, an
analog of acetals with a higher oxidation level, on the other
hand, have been rarely used for these purposes.3 One of the
reasons is their instability under acidic conditions; ortho-
esters usually decompose easily to give corresponding
esters.4 Some acyclic orthoesters, for example, are quickly
hydrolyzed during a chromatographic treatment. Addition-
ally, emergence of a new chiral center at the orthoester
carbon gives rise to formation of diastereomers so that a
facile stereocontrolling method has been desired.5 Recently,
we have found a simple method to prepare a novel nitrogen
analogue of chiral orthoesters, 2-oxy-1,3-oxazolidin-4-one,
in a highly diastereoselective manner. Here we report the
first practical and stereoselective synthesis of optically
active nitrogen analogues of cyclic orthoesters from readily
available chiral N-substituted lactamides or mandelamides.
We have also demonstrated its possibility as an auxiliary for
asymmetric synthesis.
The present reaction conditions were examined for various
lactamides 2 (entries 1–8). To our surprise, the reaction
product usually contained just a single diastereomer so that
the stereoselectivity of the reaction should be generally very
high. Acetate or substituted acrylate derivatives, for
example, underwent a smooth reaction to give a single
isomer of their corresponding 4 in good yields (entry 1 and
4–6). For some cases, the yield and the stereoselectivity
depended on the structure of lactamides 2; benzoate 2b and
isobutyrate 2c took many hours before finishing the reaction
and the yields of 4 remained at a poor level (entry 2 and 3).
2. Results and discussion
Optically active O-acyl-N-substituted lactamides 2 and
mandelamides 3, starting materials of 2-oxy-1,3-oxazolidin-
4-ones 4 and 5, were prepared from commercially available
Keywords: orthoesters; oxazolidinones; stereoselection; protecting groups.
*
Corresponding author. Tel.: þ81-836-85-9231; fax: þ81-836-85-9201;
Scheme 1. Reagents: (i) R1COCl, pyridine, DMAP; (ii) R1CO2H, DCC,
DMAP; (iii) TBSOTf, 2,6-lutidine, CH2Cl2, 08C.
e-mail: ak10@yamaguchi-u.ac.jp
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01057-8

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A. Kamimura et al. / Tetrahedron 58 (2002) 8763–8770
Table 1. Preparation of optically active 2-oxy-1,3-oxazolidin-4-ones 4 and 5
Entry
R1
R2
R
Amide 2 or 3; yield (%)a
[a]D
4 or 5; yield (%)a
Ratiob
[a]D
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Ph
2a; 95
2b; 84
2c; 95
2d; 88
2e; 67
2f; 74
2g; 59
2h; 91
3a; 79
3b; 95
3c; 98
3d; 91
3e; 57
3f; 40
4g; 41
2178.0
–
4a; 90
4b; 10
4c; 0
99:1
2153.9
–
c
c
84:16
–
92:8
94:6
95:5
63:37
99:1
.99:1
.99:1
.99:1
93:7
c
Me2CH–
CH2vCH–
MeCHvCH–
PhCHvCH–
EtO2CCHvCH–
Me
Me
Ph
Me2CH–
C6H13–
–
–
260.5
2156.5
2112.9
286.5
281.1
þ115.4
þ57.8
þ99.8
þ91.6
þ107.5
þ47.6
þ68.2
4d; 88
4e; 95
4f; 95
4g; 97
4h; 93
5a; 89
5b; 82
5c; 97
5d; 97
5e; 84
5f; 82
5g; 96
244.4
284.3
2144.0
286.7
239.0
þ57.2
213.5
þ42.4
þ54.2
þ19.0
þ95.9
þ64.3d
1-C10H7CH2
9
Bn
Bn
Bn
Bn
Bn
Bn
Bn
10
11
12
13
14
15
CH2vCH–
PhCHvCH–
EtO2CCHvCH–
97:3
.99:1
82:18
Ph
Ph
a
Isolated yield.
Determined by HPLC analyses (Chiral Pak-AD).
Racemic lactamide was used.
For major isomer. [a]D for minor isomer was þ30.6.
b
c
d
The reaction with fumaric ester 2g smoothly gave 4g in 97%
yield but the product contained two diastereomers in about a
2:1 ratio. N-1-Naphthylmethyllactamide 2h also gave a 93%
yield of 4h, which was subjected to X-ray crystallographic
analysis for structural elucidation (vide infra).
sition was observed for compound 5a in CDCl3 even after
more than several weeks.
The structures of 4 and 5 were determined in the following
way: 13C NMR spectrum for compound 4a, for example,
showed one carbonyl carbon and one quaternary carbon that
appeared at around 110 ppm. These observations reflected
that one of the two carbonyl carbons in 2a was lost during
the conversion to 4a. The 1H and 13C NMR spectra
suggested that 4a possessed the 2-oxy-1,3-oxazolidin-4-one
structure, which was also supported by microanalytical data
for 4a. The structure and the configuration at C2 of 4 were
finally confirmed by an X-ray crystallographic analysis for
compound 4h, which clearly indicated the two methyl
groups at C2 and C5 positions were located in cis.6 NOE
experiments for 4a and 4h showed that 5 and 4.5%,
respectively, of signal enhancement occurred at the methyl
group in TBS when either of the H5 was irradiated (Scheme
2). This observation suggested that 4a and 4h held the same
configuration at C2 and C5. A similar signal enhancement
was also seen in the NOE experiment for 5a. Based on these
results as well as the comparison of NMR and HPLC
behavior, the oxyoxazolidinone structure for other 4 and 5
was confirmed.
Although the formation of oxyoxazolidinones 4 from
lactamides 2 was accomplished stereoselectively, their
chemical stability was somewhat problematic. When stored
in CDCl3 solution, most of 4a decomposed into its starting
material 2a within 24 h. This could be serious setback for
the further synthetic use of 4, and so we examined
mandelamide to see if we could improve the stability.
Preparation of starting materials 3 was carried out in a
similar manner to the preparation of 2. The ring enclosure
reactions for 3 progressed again in a spot-to-spot manner
and the desired oxyoxazolidinones 5 were isolated in good
yields (entries 9–15). The stereoselectivity of the ring
formation was usually good to high. Acetate or substituted
acrylate as well as benzoate or other alkanoates gave 5 in an
excellent stereoselectivity which was in direct contrast to
the formation of 4 from lactamides 2. It should be remarked
that all of compounds 5 were stable enough for further
chemical treatment or storage. For example, no decompo-
The observed stereoselectivity was very high and it was
more than we had expected. If the ring enclosure had taken
place through the direct nucleophilic attack of the amide
nitrogen to the free-acyl carbonyl carbon, it would be hard
to imagine what factor would bring the current high
stereoselectivity. We assumed that some activation on the
carbonyl must take place before the actual ring enclosure
happened because both the acyl carbonyl and the amide
nitrogen generally showed very weak reactivity for the
nucleophilic addition. The present reaction was affected by
the electronic nature of acyl carbonyl carbon; an electron-
withdrawing group at the acyl carbon, that usually enhances
the nucleophilic addition to the carbonyl, lowered the yield
and made the selectivity poor. Additionally, other TBS
source such as TBSCl was quite inert to the reaction. Thus,
we assume the initial step of the reaction is likely the
coordination of the TBS group to the carbonyl group, which
Scheme 2. NOE experiments for 4A-a and 4A-b.

A. Kamimura et al. / Tetrahedron 58 (2002) 8763–8770
8765
Scheme 5. Reagents: (i) TBAF, THF, rt, 10 min; (ii) WSC·EtOH;
(iii) L-Selectiride, THF, rt; (iv) BH3·THF, THF, 2108C.
CH2Cl2 as the reaction solvent improved the stereoselec-
tivity to 82:18. Other aromatic nitrile oxides also gave chiral
4,5-dihydroisoxazoles 6b and 6c with good diastereo-
selectivity. The lactamide-derived oxyoxazolidinone 4d
also underwent the dipolar addition in a similar way.
To determine the absolute stereogenic center at C5 in the
4,5-dihydroisoxazole, the major isomer of 6a was separated
and treated with TBAF (Scheme 5). To our surprise,
mandelamide-free 4,5-dihydroisoxazole-5-carboxylic acid
7 was isolated in an 84% yield along with recovery of
mandelamide 1b. Esterification followed by reductive
treatment of 7 resulted in the formation of the corresponding
alcohol 9, which showed dextrorotatory. Comparison of the
optical rotation of known 9 unambiguously revealed the
absolute configuration at C5 was S.9 Treatment of 6d in a
similar way afforded 9 that also showed dextrorotatory.
Scheme 3.
is then activated to the nucleophilic attack by the secondary
amide nitrogen. Scheme 3 shows a plausible reaction
process. Due to the bulkiness of the TBS group coordinating
the carbonyl, intermediate B should be less favored than A,
which leads the 2S,5S isomers, the major isomer formed in
the actual reaction. The electron withdrawing substituent at
R position, on the other hand, reduces the Lewis basicity of
the carbonyl group so that the coordination of the TBS
group would be prevented. Thus, the reaction proceeds
through the interaction between the non-TBS coordinated
carbonyl group and the amide nitrogen and the stereo-
selectivity and/or reaction rates are spoiled.
Use of oxyoxazolidinone for asymmetric synthesis was
examined. The 1,3-dipolar cycloaddition of nitrile oxides is
regarded as a useful reaction to construct carbon backbones7
and its asymmetric modification has been developed so
far.8 The vinyl group in 5e, for example, underwent
cycloaddition with benzonitrile oxide in hexane, giving
4,5-dihydroisoxazole 6a in a 61% yield (Scheme 4). The
diastereomeric ratio of 6a was found to be 70:30. Use of
In conclusion, we have found the first convenient method to
prepare 2-oxy-1,3-oxazolidin-4-one, novel nitrogen analogs
of orthoesters, in a highly stereoselective manner. Use of
this preparation enables one to construct the orthoester
carbon in a stereochemically defined way. Recovery of
chiral mandelamide from 2-oxy-1,3-oxazolidin-4-one was
readily accomplished by treatment with TBAF. Further
investigation on the use of this structure for asymmetric
synthesis is now underway in our laboratory.
3. Experimental
3.1. General
All 1H and 13C NMR spectra were measured in CDCl3 and
recorded on JEOL EX-270 (270 MHz for 1H and 67.5 MHz
1
for 13C) or Brucker Advance 400 (400 MHz for H and
100 MHz for 13C) spectrometer. All the reactions in this
paper were performed under nitrogen atmosphere. Solvents
Scheme 4. Reagents: (i) R3CClvNOH, Et3N, hexane or CH2Cl2, 08C.

8766
A. Kamimura et al. / Tetrahedron 58 (2002) 8763–8770
used in the reaction described here were dried over CaH2
and distilled under nitrogen before use. Optically active
lactic acid and mandelic acid were from Aldrich and used
without further purification.
NMR (67.5 MHz, CDCl3) d 17.8, 42.9, 70.4, 116.8, 127.3,
127.3, 128.0, 128.5, 128.2, 130.5, 133.7, 137.8, 146.0,
165.4, 170.4. Exact mass determination: 309.1367 (Calcd
C19H19NO3: 309.1365).
3.1.1. Preparation of O-benzoyl-N-benzyllactamide (2b).
General procedure. To a mixture of 1a (0.5522 g,
3.08 mmol), Et3N (0.48 mL, 3.25 mmol), and DMAP
(0.1236 g, 1.01 mmol) in CH2Cl2 (20 mL) at 08C was
added benzoyl chloride (0.52 mL, 3.25 mmol) and the
reaction mixture was allowed to stir for 7 h. Aqueous dil
HCl was added to the reaction mixture and the resulting
biphasic mixture was extracted with CH2Cl2 (3£30 mL).
The combined organic phase was washed with sat. NaHCO3
and brine, and dried over Na2SO4. Filtration and removal of
solvent gave a crude product, which was purified through
flash chromatography (silica gel/hexane–ethyl acetate 10:1
v/v then 5:1) to give 2b in 84% yield. White solid. Mp 848C.
1H NMR (270 MHz, CDCl3) d 1.65 (d, 3H, J¼6.6 Hz), 4.51
(dd, 2H, J¼2.0, 5.9 Hz), 5.54 (q, 1H, J¼6.9 Hz), 6.46 (br,
1H), 7.24–8.05 (m, 10H). 13C NMR (67.5 MHz, CDCl3) d
17.9, 43.2, 71.1, 127.5, 127.5, 128.4, 128.6, 128.7, 130.1,
133.5, 137.8, 165.3, 170.4. Anal. Calcd for C17H17NO3: C,
72.07; H, 6.05; N, 4.94%. Found: C, 72.11; H, 6.05; N, 4.71.
3.1.6. (S)-N-Benzyl-O-(3-ethoxycarbonylacryloyl)lacta-
mide (2g). White solid. Mp 658C. [a]D¼286.58 (c 0.96,
1
CHCl3). H NMR (270 MHz, CDCl3) d 1.32 (t, 3H, J¼
7.1 Hz), 1.57 (d, 3H, J¼6.9 Hz), 4.27 (q, 2H, J¼7.2 Hz),
4.49 (d, 2H, J¼5.6 Hz), 5.37 (q, 1H, J¼6.8 Hz), 6.38 (br,
1H), 6.86 (d, 1H, J¼15.5 Hz), 6.93 (d, 1H, J¼15.8 Hz),
7.27–7.39 (m, 5H). 13C NMR (67.5 MHz, CDCl3) d 14.4,
18.2, 43.5, 61.9, 71.8, 127.9, 129.1, 132.7, 135.3, 138.0,
163.9, 164.9, 170.1. Exact mass determination: 305.1241
(Calcd C16H19NO5: 305.1263).
3.1.7. (S)-O-Acetyl-N-(1-naphtylmethyl)lactamide (2h).
1
White solid. Mp 1858C. [a]D¼281.18 (c 1.10, CHCl3). H
NMR (270 MHz, CDCl3) d 1.50 (d, 1H, J¼6.9 Hz), 2.03 (s,
1H), 4.88 (dd, 1H, J¼5.3, 14.5 Hz), 4.97 (dd, 1H, J¼5.3,
14.5 Hz), 5.24 (q, 1H, J¼6.8 Hz), 6.34 (br, 1H), 7.41–7.99
(m, 7H). 13C NMR (67.5 MHz, CDCl3) d 17.9, 21.0, 41.5,
70.7, 123.3, 125.4, 126.1, 126.7, 128.8, 131.3, 133.0, 133.9,
169.4, 170.0. Exact mass determination: 271.1224 (Calcd
C16H17NO3: 271.1208).
Other chiral or racemic O-acyl-N-benzyllactamides and
mandelamides were prepared in a similar procedure.
3.1.8. (S)-O-Acetyl-N-benzylmandelamide (3a). White
1
solid. Mp 758C. [a]D¼þ115.48 (c 1.03, CHCl3). H NMR
3.1.2. (S)-O-Acetyl-N-benzyllactamide (2a). White solid.
1
(270 MHz, CDCl3) d 2.17 (s, 1H), 4.45 (dd, 1H, J¼5.6,
14.8 Hz), 4.52 (dd, 1H, J¼5.6, 14.8 Hz), 6.12 (s, 1H), 6.40
(br, 1H), 7.22–7.47 (m, 10H). 13C NMR (67.5 MHz,
CDCl3) d 20.7, 43.0, 75.4, 127.2, 127.3, 127.3, 128.5,
128.5, 128.8, 135.4, 137.7, 168.3, 169.3. Anal. Calcd for
C17H17NO3: C, 72.07; H, 6.05; N, 4.94%. Found: C, 72.13;
H, 6.20; N, 4.95.
Mp 65–668C. [a]D¼2178.08 (c 1.00, CHCl3). H NMR
(270 MHz, CDCl3) d 1.51 (d, 3H, J¼6.6 Hz), 2.11 (s, 3H),
4.48 (d, 2H, J¼5.6 Hz), 5.25 (q, 1H, J¼6.8 Hz), 6.39 (br,
1H), 7.27–7.39 (m, 5H). 13C NMR (67.5 MHz, CDCl3) d
17.8, 20.9, 43.0, 70.5, 127.5, 128.6, 137.8, 169.4, 170.3.
Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33%.
Found: C, 65.43; H, 6.78; N, 6.26.
3.1.9. (S)-O-Benzoyl-N-benzylmandelamide (3b). White
1
3.1.3. (S)-O-Acryloyl-N-benzyllactamide (2d). Colorless
1
solid. Mp 104–1058C. [a]D¼þ57.88 (c 1.27, CHCl3). H
oil. [a]D¼260.58 (c 1.04, CHCl3). H NMR (270 MHz,
NMR (270 MHz, CDCl3) d 4.48 (dd, 1H, J¼5.9, 15.2 Hz),
4.56 (dd, 1H, J¼5.8, 15.2 Hz), 6.39 (s, 1H), 6.46 (br, 1H),
7.21–8.19 (m, 15H). 13C NMR (67.5 MHz, CDCl3) d 43.7,
76.4, 127.7, 127.9, 128.9, 129.1, 129.2, 129.4, 129.5, 129.8,
130.5, 134.0, 135.8, 138.0, 165.4, 168.9, 172.1. Anal. Calcd
for C22H19NO3: C, 76.50; H, 5.54; N, 4.06%. Found: C,
76.37; H, 5.54; N, 3.60.
CDCl3) d 1.55 (d, 3H, J¼6.6 Hz), 4.46 (d, 1H, J¼9.3 Hz),
4.51 (d, 1H, J¼9.8 Hz), 5.36 (q, 1H, J¼6.9 Hz), 5.91 (dd,
1H, J¼1.3, 10.6 Hz), 6.16 (dd, 1H, J¼10.6, 17.2 Hz), 6.40
(br, 1H), 6.48 (dd, 1H, J¼1.3, 17.2 Hz), 7.27–7.39 (m, 5H).
13C NMR (67.5 MHz, CDCl3) d 17.7, 43.0, 70.5, 127.4,
128.6, 132.1, 137.7, 164.6, 170.4. Exact mass determi-
nation: 233.1080 (Calcd C13H15NO3: 233.1052).
3.1.10. (S)-N-Benzyl-O-isobutyroylmandelamide (3c).
White solid. Mp 61–628C. [a]D¼þ99.88 (c 1.22, CHCl3).
1H NMR (270 MHz, CDCl3) d 1.17 (d, 3H, J¼6.9 Hz), 1.19
(d, 1H, J¼7.3 Hz), 2.66 (m, 1H, J¼7.0 Hz), 4.42 (dd, 1H,
J¼5.9, 15.2 Hz), 4.49 (dd, 1H, J¼5.9, 15.2 Hz), 6.11 (s,
1H), 6.46 (br, 1H), 7.19–7.46 (m, 10H). 13C NMR
(67.5 MHz, CDCl3) d 18.8, 33.8, 43.3, 75.2, 127.1, 127.5,
127.6, 128.7, 128.9, 135.6, 137.6, 168.4, 175.2. Anal. Calcd
for C19H21NO3: C, 73.29; H, 6.80; N, 4.50%. Found: C,
73.01; H, 6.81; N, 4.21.
3.1.4. (S)-N-Benzyl-O-crtonoyllactamide (2e). White
1
solid. Mp 508C. [a]D¼2156.58 (c 0.93, CHCl3). H NMR
(270 MHz, CDCl3) d 1.53 (d, 3H, J¼6.9 Hz), 1.90 (dd, 3H,
J¼1.7, 6.9 Hz), 4.48 (d, 2H, J¼6.6 Hz), 5.34 (q, 1H, J¼
6.8 Hz), 5.88 (qd, 1H, J¼1.7, 15.6 Hz), 6.42 (br, 1H), 7.05
(qd, 1H, J¼6.9, 15.5 Hz), 7.25–7.38 (m, 5H). 13C NMR
(67.5 MHz, CDCl3) d 17.9, 18.0, 43.0, 70.2, 121.7, 127.5,
128.6, 137.8, 146.5, 164.9, 170.5. Exact mass determi-
nation: 247.1232 (Calcd C14H17NO3: 247.1208).
3.1.5. (S)-N-Benzyl-O-cinnamoyllactamide (2f). White
solid. Mp 1018C. [a]D¼2112.98 (c 1.03, CHCl3). 1H
NMR (270 MHz, CDCl3) d 1.59 (d, 3H, J¼6.6 Hz), 4.47
(dd, 1H, J¼5.9, 14.9 Hz), 4.54 (dd, 1H, J¼5.9, 14.9 Hz),
5.42 (q, 1H, J¼6.8 Hz), 6.46 (d, 1H, J¼15.8 Hz), 6.47 (br,
1H), 7.27–7.56 (m, 10H), 7.74 (d, 1H, J¼16.2 Hz). 13C
3.1.11. (S)-N-Benzyl-O-heptanoylmandellactamide (3d).
Yellow oil. [a]D¼þ91.68 (c 1.01, CHCl3). 1H NMR
(270 MHz, CDCl3) d 0.85 (t, 3H, J¼6.8 Hz), 1.24–1.28
(m, 6H), 1.56–1.65 (m, 2H), 2.43 (t, 2H, J¼7.2 Hz), 4.49 (d,
2H, J¼5.9 Hz), 6.14 (s, 1H), 6.41 (br, 1H), 7.22–7.46 (m,
10H). 13C NMR (67.5 MHz, CDCl3) d 13.9, 22.3, 24.7,

A. Kamimura et al. / Tetrahedron 58 (2002) 8763–8770
8767
28.6, 31.3, 34.1, 43.2, 75.2, 127.2, 127.5, 128.5, 128.6,
128.9, 135.6, 137.6, 168.4, 172.0. Anal. Calcd for
C22H27NO3: C, 74.76; H, 7.70; N, 3.96%. Found: C,
74.70; H, 7.70; N, 3.96.
15.2 Hz), 4.39 (d, 1H, J¼15.2 Hz), 4.71 (q, 1H, J¼6.7 Hz),
6.99–7.48 (m, 10H). 13C NMR (100 MHz, CDCl3) d 23.7,
23.3, 17.7, 18.0, 25.9, 43.6, 73.3, 110.5, 125.8, 127.0,
128.1, 128.2, 128.3, 129.3, 136.9, 139.8, 172.1.
3.1.12. (S)-O-Acryroyl-N-benzylmandelamide (3e).
1
3.1.17. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
5-methyl-2-vinyl-1,3-oxazolidine-4-one (4d). Colorless
Colorless oil. [a]D¼þ107.18 (c 1.10, CHCl3). H NMR
1
(270 MHz, CDCl3) d 4.45 (dd, 1H, J¼5.8, 15.2 Hz), 4.53
(dd, 1H, J¼5.8, 15.2 Hz), 5.93 (dd, 1H, J¼1.3, 10.6 Hz),
6.22 (dd, 1H, J¼10.2, 17.2 Hz), 6.43 (br, 1H), 6.51 (dd,
1H, J¼1.3, 17.5 Hz), 7.22–7.49 (m, 10H). 13C NMR
(67.5 MHz, CDCl3) d 43.1, 75.5, 127.0, 127.2, 127.3,
127.4, 128.5, 128.6, 128.8, 132.4, 135.3, 137.6, 164.4, 168.2.
oil. [a]D¼244.48 (c 0.78, CHCl3). H NMR (270 MHz,
CDCl3) d 20.05 (s, 3H), 0.09 (s, 3H), 0.83 (s, 9H), 1.47 (d,
3H, J¼6.9 Hz), 4.31 (d, 1H, J¼15.5 Hz), 4.50 (d, 1H, J¼
15.2 Hz), 4.55 (q, 1H, J¼6.9 Hz), 5.18 (dd, 1H, J¼3.3,
8.6 Hz), 5.58 (d, 1H, J¼2.6 Hz), 5.59 (d, 1H, J¼8.6 Hz),
7.21–7.31 (m, 5H). 13C NMR (67.5 MHz, CDCl3) d 23.6,
23.5, 17.8, 18.2, 25.6, 43.2, 73.2, 108.5, 118.1, 127.2,
128.2, 128.3, 137.0, 137.6, 172.2. MS (FAB) m/z 348
[(MþH)þ, 55%].
3.1.13. (S)-N-Benzyl-O-cinnamoylmandelamide (3f).
1
White solid. Mp 1368C. [a]D¼þ47.68 (c 1.10, CHCl3). H
NMR (270 MHz, CDCl3) d 4.52 (dd, 1H, J¼6.2, 14.8 Hz),
4.56 (dd, 1H, J¼6.6, 14.8 Hz), 6.29 (s, 1H), 6.50 (br, 1H),
6.53 (d, 1H, J¼16.2 Hz), 7.24–7.54 (m, 15H), 7.77 (d, 1H,
J¼15.9 Hz). 13C NMR (67.5 MHz, CDCl3) d 43.4, 75.5,
116.6, 127.4, 127.6, 127.7, 128.2, 128.7, 128.8, 128.9,
129.9, 130.7, 133.9, 135.6, 137.7, 146.7, 165.2, 168.4. Anal.
Calcd for C24H21NO3: C, 77.61; H, 5.70; N, 3.77%. Found:
C, 77.45; H, 5.98; N, 3.32.
3.1.18. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
5-methyl-2-(1-propenyl)-1,3-oxazolidine-4-one
(4e).
Colorless oil. [a]D¼284.38 (c 1.37, CHCl3). 1H NMR
(270 MHz, CDCl3) d 0.04 (s, 3H), 0.08 (s, 3H), 0.82 (s, 9H),
1.46 (d, 3H, J¼6.9 Hz), 1.58 (dd, 3H, J¼1.7, 6.9 Hz), 4.26
(d, 1H, J¼15.2 Hz), 4.51 (d, 1H, J¼15.2 Hz), 4.52 (q, 1H,
J¼6.5 Hz), 5.21 (dd, J¼1.7, 15.2 Hz), 5.98 (qd, 1H, J¼6.7,
15.2 Hz), 7.20–7.30 (m, 5H). 13C NMR (100 MHz, CDCl3)
d 23.5, 23.4, 17.0, 18.0, 18.3, 25.8, 43.4, 73.2, 108.7,
127.2, 128.3, 128.4, 130.2, 131.4, 137.4, 172.2.
3.1.14. (S)-N-Benzyl-O-(3-ethoxycarbonylacryloyl)-
mandelmaide (3g). White solid. Mp 96–978C.
[a]D¼þ68.28 (c 1.14, CHCl3). 1H NMR (270 MHz,
CDCl3) d 1.31 (t, 3H, J¼7.1 Hz), 4.26 (q, 2H, J¼7.3 Hz),
4.45 (dd, 1H, J¼5.3, 14.9 Hz), 4.53 (dd, 1H, J¼5.6,
14.8 Hz), 6.21 (s, 1H), 6.37 (br, 1H), 6.93 (s, 2H), 7.21–
7.48 (m, 10H). 13C NMR (67.5 MHz, CDCl3) d 13.9, 43.3,
61.4, 76.1, 127.4, 127.5, 128.6, 128.8, 129.2, 132.2, 134.8,
135.0, 137.5, 163.4, 164.5, 167.8. Anal. Calcd for
C21H21NO5: C, 68.65; H, 5.76; N, 3.81%. Found: C,
68.33; H, 5.72; N, 3.77.
3.1.19. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
5-methyl-2-[1-(2-phenylethenyl)]-1,3-oxazolidine-4-one
(4f). Colorless oil. [a]D¼2144.48 (c 1.15, CHCl3). 1H NMR
(270 MHz, CDCl3) d 0.09 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H),
1.52 (d, 3H, J¼6.6 Hz), 4.30 (d, 1H, J¼15.2 Hz), 4.59 (q,
1H, J¼6.7 Hz), 4.63 (d, 1H, J¼15.2 Hz), 5.78 (d, 1H, J¼
15.5 Hz), 6.82 (d, 1H, J¼15.8 Hz), 7.10–7.29 (m, 10H). 13C
NMR (67.5 MHz, CDCl3) d 23.6, 23.5, 17.9, 18.2, 25.7,
43.3, 73.2, 108.9, 126.8, 126.9, 127.2, 128.3, 128.4, 128.5,
128.8, 132.7, 135.3, 137.2, 172.1.
3.1.15. Preparation of (2S,5S)-N-benzyl-2-(tert-butyldi-
methylsilyloxy)-2,5-dimethyl-1,3-oxazolidine-4-one (4a).
General procedure. 2,6-Lutidine (0.54 mL, 3.77 mmol),
DMAP (0.0834 g, 0.68 mmol), and TBSOTf (0.51 mL,
1.78 mmol) were added to a solution of lactamide 2a
(0.2251 g, 1.01 mmol) in CH2Cl2 at 08C in this order. After
23 h, pyridine was added and the solvent was removed in
vacuo. The residue was subjected through flash chroma-
tography (silica gel/hexane–ethyl acetate 10:1 v/v) to give
4a in 90% yield as colorless oil (0.3078 g). [a]D¼2153.98
(c 1.19, CHCl3). 1H NMR (270 MHz, CDCl3) d 0.05 (s, 3H),
0.11 (s, 3H), 0.82 (s, 9H), 1.39 (s, 3H), 1.43 (d, 3H, J¼
6.6 Hz), 4.15 (d, 1H, J¼15.2 Hz), 4.44 (q, 1H, J¼6.6 Hz),
4.75 (d, 1H, J¼15.6 Hz), 7.22–7.31 (m, 5H). 13C NMR
(67.5 MHz, CDCl3) d 23.7, 23.6, 17.7, 18.0, 25.6, 29.2,
43.3, 72.9, 110.2, 127.4, 127.8, 128.5, 137.4, 172.8. Anal.
Calcd for C18H29NO3Si: C, 64.44; H, 8.71; N, 4.17%.
Found: C, 64.15; H, 8.57; N, 4.15.
3.1.20. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
[1-(2-ethoxycarbonylethenyl)]-5-methyl-1,3-oxazolidine-
4-one (4g). Colorless oil. [a]D¼286.78 (c 1.54, CHCl3). For
1
major isomer H NMR (270 MHz, CDCl3) d 0.06 (s, 3H),
0.10 (s, 3H), 0.85 (s, 9H), 1.23 (t, 3H, J¼7.1 Hz), 1.50 (d,
3H, J¼6.9 Hz), 4.12 (q, 1H, J¼7.1 Hz), 4.25 (d, 1H, J¼
15.2 Hz), 4.57 (q, 1H, J¼6.8 Hz), 4.64 (d, 1H, J¼15.2 Hz),
6.07 (d, 1H, J¼15.2 Hz), 6.39 (d, 1H, J¼15.5 Hz), 7.21–
7.30 (m, 5H). 13C NMR (67.5 MHz, CDCl3) d 23.7, 23.5,
14.1, 18.2, 25.6, 43.3, 60.7, 73.6, 107.5, 123.1, 127.5, 128.3,
128.5, 136.5, 144.5, 165.4, 171.7.
1
For minor isomer H NMR (270 MHz, CDCl3) d 0.07 (s,
3H), 0.11 (s, 3H), 0.88 (s, 9H), 1.23 (t, 3H, J¼7.1 Hz), 1.54
(d, 3H, J¼6.9 Hz), 4.12 (q, 1H, J¼7.1 Hz), 4.31 (d, 1H,
J¼15.2 Hz), 4.50 (q, 1H, J¼6.8 Hz), 4.61 (d, 1H, J¼
14.8 Hz), 5.99 (d, 1H, J¼15.5 Hz), 6.42 (d, 1H, J¼15.2 Hz),
7.21–7.30 (m, 5H). 13C NMR (67.5 MHz, CDCl3) d 23.2,
23.2, 17.5, 17.9, 25.6, 43.3, 60.7, 74.2, 107.3, 121.7, 127.6,
128.3, 128.5, 136.5, 142.9, 165.4, 170.8. MS (FAB) m/z 420
[(MþH)þ, 90%].
Other chiral oxyoxazolidinones 4 and 5 were prepared in a
similar procedure. Their physical data are listed below.
3.1.16. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
5-methyl-2-phenyl-1,3-oxazolidine-4-one (4b). Colorless
1
oil. H NMR (400 MHz, CDCl3) d 20.07 (s, 3H), 0.07 (s,
3H), 0.83 (s, 9H), 1.63 (d, 3H, J¼6.8 Hz), 4.10 (d, 1H, J¼
3.1.21. (2S,5S)-2-(tert-Butyldimethylsilyloxy)-2,5-di-
methyl-N-(1-naphthylmethyl)-1,3-oxazolidine-4-one (4h).

8768
A. Kamimura et al. / Tetrahedron 58 (2002) 8763–8770
White plate. [a]D¼239.08 (c 1.10, CHCl3). Mp 82–838C.
1H NMR (270 MHz, CDCl3) d 0.07 (s, 3H), 0.10 (s, 3H),
0.81 (s, 9H), 1.25 (s, 3H), 1.46 (d, 3H, J¼6.6 Hz), 4.50 (q,
1H, J¼6.8 Hz), 4.71 (d, 1H, J¼15.5 Hz), 5.25 (d, 1H,
J¼15.5 Hz), 7.22–8.11 (m, 7H). 13C NMR (67.5 MHz,
CDCl3) d 23.7, 23.6, 17.6, 18.0, 25.5, 28.8, 41.5, 72.7,
110.3, 123.4, 125.0, 125.8, 126.5, 126.8, 128.5, 128.6,
131.4, 132.3, 133.7, 172.6. MS (FAB) m/z 386 [(MþH)þ,
50%].
C, 70.38; H, 7.63; N, 3.42%. Found: C, 70.13; H, 7.82; N,
3.37.
3.1.27. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
5-phenyl-2-[1-(2-phenylethenyl)]-1,3-oxazolidine-4-one
(5f). Colorless oil. [a]D¼þ95.98 (c 1.95, CHCl3). 1H NMR
(270 MHz, CDCl3) d 0.18 (s, 6H), 0.93 (s, 9H), 4.34 (d, 1H,
J¼15.2 Hz), 4.70 (d, 1H, J¼15.2 Hz), 5.46 (s, 1H), 5.91 (d,
1H, J¼15.5 Hz), 6.91 (d, 1H, J¼15.5 Hz), 7.13–7.53 (m,
15H). 13C NMR (67.5 MHz, CDCl3) d 23.7, 23.4, 17.9,
25.7, 43.6, 78.2, 109.3, 126.5, 126.9, 127.2, 127.4, 127.9,
128.1, 128.4, 128.5, 128.6, 128.9, 133.4, 135.2, 135.8,
137.1, 169.8. Anal. Calcd for C30H35NO3Si: C, 74.19; H,
7.26; N, 2.88%. Found: C, 73.85; H, 7.55; N, 2.79.
3.1.22. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
2-methyl-5-phenyl-1,3-oxazolidine-4-one (5a). White
solid. [a]D¼þ57.28 (c 1.27, CHCl3). Mp 87–888C. 1H
NMR (270 MHz, CDCl3) d 0.14 (s, 3H), 0.17 (s, 3H), 0.87
(s, 9H), 1.54 (s, 3H), 4.20 (d, 1H, J¼15.5 Hz), 4.68 (d, 1H,
J¼15.5 Hz), 5.33 (s, 1H), 7.22–7.46 (m, 10H). 13C NMR
(67.5 MHz, CDCl3) d 23.6, 17.7, 25.5, 28.8, 43.6, 78.0,
110.3, 126.3, 127.4, 127.8, 128.6, 128.6, 136.0, 137.3,
170.5. Anal. Calcd for C23H31NO3Si: C, 69.48; H, 7.86; N,
3.52%. Found: C, 69.39; H, 8.11; N, 3.49.
3.1.28. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
5-phenyl-2-[1-(2-ethoxycarbonylethenyl)]-1,3-oxazo-
lidine-4-one (5g). For major isomer: Colorless oil. [a]D¼
þ64.38 (c 0.69, CHCl3). 1H NMR (400 MHz, CDCl3) d 0.00
(s, 3H), 0.10 (s, 3H), 0.90 (s, 9H), 1.24 (t, 3H, J¼7.1 Hz),
4.13 (q, 2H, J¼7.2 Hz), 4.28 (d, 1H, J¼15.2 Hz), 4.68 (d,
1H, J¼15.2 Hz), 5.44 (s, 1H), 6.14 (d, 1H, J¼15.4 Hz), 6.51
(d, 1H, J¼15.4 Hz), 7.13–7.53 (m, 10H). 13C NMR
(67.5 MHz, CDCl3) d 23.5, 23.5, 14.1, 17.9, 25.7, 43.7,
60.7, 78.3, 107.8, 123.9, 126.4, 127.6, 128.2, 128.4, 128.5,
128.6, 135.2, 136.4, 143.8, 165.3, 169.6. Anal. Calcd for
C27H35NO5Si: C, 67.33; H, 7.32; N, 2.91%. Found: C,
67.09; H, 7.45; N, 2.93.
3.1.23. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
2,5-diphenyl-1,3-oxazolidine-4-one (5b). Colorless oil.
[a]D¼213.58 (c 1.24, CHCl3). 1H NMR (270 MHz,
CDCl3) d 0.02 (s, 3H), 0.15 (s, 3H), 0.88 (s, 9H), 4.21 (d,
1H, J¼15.2 Hz), 4.43 (d, 1H, J¼15.2 Hz), 5.60 (s, 1H),
7.00–7.61 (m, 15H). 13C NMR (67.5 MHz, CDCl3) d 23.7,
23.2, 18.0, 25.6, 25.8, 43.9, 77.7, 110.6, 126.8, 127.0,
127.2, 128.0, 128.1, 128.2, 128.3, 128.5, 129.3, 135.2,
136.6, 139.4, 169.8.
For minor isomer: colorless oil. [a]D¼þ30.68 (c 0.217,
CHCl3). 1H NMR (400 MHz, CDCl3) d 0.03 (s, 3H), 0.07 (s,
3H), 0.83 (s, 9H), 1.26 (t, 3H, J¼7.1 Hz), 4.13 (q, 2H,
J¼7.2 Hz), 4.45 (d, 1H, J¼15.2 Hz), 4.65 (d, 1H, J¼
15.2 Hz), 5.37 (s, 1H), 6.13 (d, 1H, J¼16.4 Hz), 6.56 (d, 1H,
J¼15.4 Hz), 7.21–7.49 (m, 10H). 13C NMR (67.5 MHz,
CDCl3) d 23.3, 23.1, 14.1, 17.9, 25.6, 43.6, 60.8, 79.4,
107.4, 121.8, 127.5, 127.7, 128.3, 128.5, 128.6, 128.9,
135.0, 136.6, 142.8, 165.5, 168.8.
3.1.24. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
2-isopropyl-5-phenyl-1,3-oxazolidine-4-one (5c). Color-
less oil. [a]D¼þ42.48 (c 1.00, CHCl3). 1H NMR (270 MHz,
CDCl3) d 0.12 (s, 3H), 0.22 (s, 3H), 0.41 (d, 3H, J¼6.9 Hz),
0.93 (s, 9H), 0.99 (d, 3H, J¼6.6 Hz), 2.00 (m, 1H, J¼
6.7 Hz), 4.17 (d, 1H, J¼14.8 Hz), 4.80 (d, 1H, J¼14.8 Hz),
5.43 (s, 1H), 7.21–7.58 (m, 10H). 13C NMR (67.5 MHz,
CDCl3) d 23.9, 23.2, 16.2, 16.9, 18.0, 25.7, 36.9, 44.2,
77.2, 114.5, 126.4, 127.5, 127.6, 128.2, 128.4, 128.7, 135.4,
136.9, 170.6.
3.2. 1,3-Dipolar cycloaddition to 5e
To a mixture of 5e (0.4320 g, 1.05 mmol) and benzo-
hydroximic chloride (0.2462 g, 1.58 mmol) in CH2Cl2
(1.1 mL) at 08C was added Et3N (0.23 mL, 1.58 mmol)
over 24 h. Water (20 mL) was added to the reaction mixture
and the resulting biphasic mixture was extracted with
CH2Cl2 (30 mL£3). The organic phase was combined and
dried over MgSO4. Removal of solvent gave the crude
product that was purified through flash chromatography
(silica gel/hexane–ether 30:1 v/v then 20:1 to 10:1) to give
4,5-dihydroisoxazole 6a in 63% yield (0.3513 g,
0.67 mmol) along with the recovery of the starting material
5e (0.0409 g, 0.1 mmol). The diastereomeric ratio of the
crude product was determined by HPLC analysis (chiral pak
AD, hexane/2-PrOH 92:8, v/v) to be 82:18. The two of
diastereomers were separated by careful chromatographic
treatment.
3.1.25. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
2-hexyl-5-phenyl-1,3-oxazolidine-4-one (5d). Colorless
1
oil. [a]D¼þ54.28 (c 1.11, CHCl3). H NMR (270 MHz,
CDCl3) d 0.15 (s, 3H), 0.20 (s, 3H), 0.80 (t, 3H, J¼6.3 Hz),
0.90 (s, 9H), 0.77–1.29 (m, 8H), 1.58–1.89 (m, 2H), 4.17
(d, 1H, J¼15.2 Hz), 4.82 (d, 1H, J¼15.2 Hz), 5.36 (s, 1H),
7.23–7.51 (m, 10H). 13C NMR (67.5 MHz, CDCl3) d 23.6,
23.3, 13.9, 17.8, 22.3, 23.6, 25.6, 28.6, 31.4, 40.2, 43.9,
77.7, 112.5, 126.6, 127.5, 128.3, 128.4, 128.5, 128.7, 135.6,
137.1, 170.9.
3.1.26. (2S,5S)-N-Benzyl-2-(tert-butyldimethylsilyloxy)-
5-phenyl-2-vinyl-1,3-oxazolidine-4-one (5e). Colorless
1
oil. [a]D¼þ19.08 (c 1.42, CHCl3). H NMR (270 MHz,
CDCl3) d 0.14 (s, 3H), 0.15 (s, 3H), 0.87 (s, 9H), 4.35 (d,
1H, J¼15.2 Hz), 4.57 (d, 1H, J¼15.2 Hz), 5.27 (dd, 1H,
J¼2.0, 9.6 Hz), 5.42 (s, 1H), 5.64 (dd, 1H, J¼1.7, 16.8 Hz),
5.76 (dd, 1H, J¼9.6, 16.8 Hz), 7.21–7.49 (m, 10H).
13C NMR (67.5 MHz, CDCl3) d 23.5, 23.4, 18.0, 25.7,
43.6, 78.2, 108.9, 118.9, 126.5, 127.3, 128.3, 128.6, 128.7,
135.9, 137.0, 137.1, 170.0. Anal. Calcd for C24H31NO3Si:
3.2.1. For major isomer of 6a. Colorless oil. [a]D¼
1
þ161.08 (c 0.55, CHCl3). H NMR (270 MHz, CDCl3) d
0.24 (s, 3H), 0.25 (s, 3H), 0.92 (s, 9H), 3.26 (dd, 1H,
J¼11.4, 17.0 Hz), 3.43 (dd, 1H, J¼7.9, 17.2 Hz), 4.37 (d,
1H, J¼15.2 Hz), 4.68 (dd, 1H, J¼8.1, 11.4 Hz), 4.88 (d, 1H,

A. Kamimura et al. / Tetrahedron 58 (2002) 8763–8770
8769
J¼15.2 Hz), 5.41 (s, 1H), 7.20–7.56 (m, 15H). 13C NMR
(67.5 MHz, CDCl3) d 24.0, 23.1, 17.8, 25.5, 35.9, 44.0,
79.9, 81.5, 110.5, 126.5, 127.1, 127.6, 128.2, 128.3, 128.4,
128.5, 128.6, 129.1, 130.0, 134.7, 135.9, 155.8, 170.4. Anal.
Calcd for C31H36N2O4Si: C, 70.42; H, 6.86; N, 5.30%.
Found: C, 70.32; H, 7.22; N, 4.90.
128.9, 129.1, 130.0, 135.9, 136.9, 155.7, 156.0, 172.4,
172.8. MS (FAB) m/z 467 [(MþH)þ, 80%].
3.2.5. Preparation of (S)-4,5-dihydroisoxazole-5-car-
boxylic acid (7). To a solution of 6a (0.320 g, 0.60 mmol)
in THF (1.1 mL) at room temperature was added TBAF
(1.0 M in THF, 0.7 mL). The reaction mixture was allowed
to stir at 08C for 30 min. Solvent was removed in vacuo and
the residue was subjected to flash chromatography (silica
gel/hexane–ethyl acetate 10:1 v/v then 1:1 to 1:2 and ethyl
acetate–acetic acid 96:4 v/v) to give carboxylic acid 7 in
85% yield (0.0969 g, 0.51 mmol) and mandelamide
(0.1247 g, 0.52 mmol).
For minor isomer of 6a: [a]D¼þ25.68 (c 0.68, CHCl3). 1H
NMR (270 MHz, CDCl3) d 0.09 (s, 3H), 0.16 (s, 3H), 0.77
(s, 9H), 2.70 (dd, 1H, J¼11.2, 17.5 Hz), 2.96 (dd, 1H, J¼
5.9, 17.2 Hz), 4.25 (d, 1H, J¼14.9 Hz), 4.53 (dd, 1H, J¼6.1,
11.4 Hz), 4.85 (d, 1H, J¼15.2 Hz), 5.33 (s, 1H), 7.04–7.38
(m, 15H). 13C NMR (67.5 MHz, CDCl3) d 23.8, 23.3,
18.0, 25.5, 37.0, 44.2, 77.3, 84.2, 109.9, 125.6, 126.6, 127.7,
128.4, 128.5, 128.6, 128.9, 130.0, 134.9, 136.7, 155.9,
170.4. Anal. Calcd for C31H36N2O4Si: C, 70.42; H, 6.86; N,
5.30%. Found: C, 70.46; H, 7.09; N, 5.10.
[a]D¼þ67.08 (c 0.41, CHCl3). 1H NMR (270 MHz, CDCl3)
d 3.70 (dd, 1H, J¼7.3, 17.4 Hz), 3.76 (dd, 2H, J¼10.2,
17.1 Hz), 5.24 (dd, 1H, J¼7.6, 9.9 Hz), 7.43–7.47 (m, 3H),
7.66–7.70 (m, 2H). 13C NMR (67.5 MHz, CDCl3) d 39.3,
77.2, 127.0, 128.5, 128.9, 130.2, 133.9, 156.5.
Other cycloadducts 6b, 6c and 6d were obtained in a similar
procedure. Their physical data are listed below.
3.2.6. Preparation of (S)-5-ethoxycarbonyl-3-phenyl-4,5-
dihydroisoxazole (8). To a solution of 7 (0.0969 g,
0.51 mmol), ethyl alcohol (0.07 mL, 1.23 mmol), and
DMAP (1 mg) in CH2Cl2 at room temperature was added
EDCI (0.1981 g, 1.04 mmol). The reaction mixture was
allowed to stir at room temperature for 24 h. The reaction
was quenched with dil HCl (1 M, 5 mL) and the mixture was
extracted with CH2Cl2 (20 mL£3). The organic phase was
combined and dried over MgSO4. Removal of solvent gave
the crude ethyl ester 8 in 87% yield. Yellow oil.
[a]D¼þ105.08 (c 0.49, CHCl3). 1H NMR (270 MHz,
CDCl3) d 1.33 (t, 3H, J¼7.1 Hz), 3.61 (dd, 1H, J¼10.6,
16.8 Hz), 3.68 (dd, 2H, J¼7.9, 17.1 Hz), 4.28 (q, 2H,
J¼7.2 Hz), 5.17 (dd, 1H, J¼7.9, 10.2 Hz), 7.41–7.43 (m,
3H), 7.67–7.71 (m, 2H). 13C NMR (67.5 MHz, CDCl3) d
14.0, 38.8, 61.9, 76.5, 126.8, 128.5, 128.7, 130.4, 155.9,
170.1.
3.2.2. Cycloadduct (6b). Colorless oil. [a]D¼þ117.08 (c
1
0.38, CHCl3). H NMR (270 MHz, CDCl3) d 0.16 (s, 3H),
0.25 (s, 3H), 0.93 (s, 9H), 3.21 (dd, 1H, J¼11.6, 17.2 Hz),
3.37 (dd, 1H, J¼7.9, 17.2 Hz), 4.34 (d, 1H, J¼15.5 Hz),
4.66 (dd, 1H, J¼7.9, 11.6 Hz), 4.90 (d, 1H, J¼15.5 Hz),
5.41 (s, 1H), 7.20–7.52 (m, 14H). 13C NMR (67.5 MHz,
CDCl3) d 24.1, 23.2, 17.8, 25.5, 35.7, 44.0, 78.7, 81.1,
110.4, 126.5, 127.1, 127.5, 127.6, 127.7, 128.2, 128.3,
128.5, 128.6, 128.8, 134.6, 135.8, 154.9, 170.4. Anal. Calcd
for C31H35ClN2O4Si: C, 66.11; H, 6.26; N, 4.97%. Found:
C, 65.95; H, 6.48; N, 4.77.
3.2.3. Cycloadduct (6c). Colorless oil. [a]D¼þ156.48 (c
1
0.20, CHCl3). H NMR (270 MHz, CDCl3) d 0.15 (s, 3H),
0.27 (s, 3H), 0.92 (s, 9H), 3.07 (dd, 1H, J¼11.5, 16.5 Hz),
3.29 (dd, 1H, J¼8.6, 16.8 Hz), 4.38 (d, 1H, J¼15.5 Hz),
4.65 (dd, 1H, J¼8.4, 11.4 Hz), 4.84 (d, 1H, J¼15.5 Hz),
5.41 (s, 1H), 6.60 (d, 1H, J¼16.5 Hz), 6.89 (d, 1H, J¼
16.5 Hz), 7.22–7.56 (m, 15H). 13C NMR (67.5 MHz,
CDCl3) d 24.0, 23.1, 17.8, 25.5, 34.4, 44.0, 78.8, 81.2,
110.3, 117.5, 126.9, 127.1, 127.6, 127.7, 128.2, 128.4,
128.7, 128.8, 128.9, 134.7, 135.6, 136.0, 136.3, 157.0,
170.5. Anal. Calcd for C33H38N2O4Si: C, 71.45; H, 6.90; N,
5.05%. Found: C, 71.43; H, 7.52; N, 4.49.
3.2.7. Preparation of (S)-5-hydroxymethyl-3-phenyl-4,5-
dihydroisoxazole (9). To a solution of 8 (0.0601 g,
0.27 mmol) in THF (2 mL) at room temperature was
added L-selectride (1.0 M in THF, 0.80 mL). Resulting
solution was allowed to stir at ambient temperature for
30 min. The reaction was quenched with water (0.5 mL),
KOH (20%, 0.5 mL) and H2O2 (30 wt%, 0.5 mL). The
mixture was concentrated and the residue was subjected to
flash chromatography (silica gel/hexane–ethyl acetate 1:1
v/v) to give 9 in 86% yield (0.0419 g, 0.24 mmol).
[a]D¼þ64.08 (c 1.04, CHCl3). 1H NMR (270 MHz,
CDCl3) d 3.28 (dd, 1H, J¼7.9, 16.8 Hz), 3.41 (dd, 1H,
J¼11.6, 17.5 Hz), 3.69 (dd, 1H, J¼5.0, 12.2 Hz), 3.89 (dd,
1H, J¼3.3, 12.2 Hz), 4.80 (m, 1H), 7.40–7.44 (m, 3H),
7.66–7.69 (m, 2H). 13C NMR (67.5 MHz, CDCl3) d 36.3,
63.5, 81.2, 126.6, 128.6, 129.2, 130.1, 157.0.
3.2.4. Cycloadduct (6d). Colorless oil. [a]D¼þ71.58 (c
1
0.39, CHCl3). H NMR (270 MHz, CDCl3) d 0.10 (s, 3H),
0.18 (s, 3H), 0.83 (s, 9H, for minor isomer), 0.91 (s, 9H, for
major isomer),1.43 (d, 3H, J¼6.9 Hz, for minor isomer),
1.48 (d, 3H, J¼6.9 Hz, for major isomer), 2.87 (dd, 1H,
J¼10.4, 16.7 Hz, for minor isomer), 3.11 (dd, 1H, J¼6.4,
17.3 Hz, for minor isomer), 3.23 (dd, 1H, J¼11.4, 17.0 Hz,
for major isomer), 3.39 (dd, 1H, J¼6.9, 17.2 Hz, for major
isomer), 4.24 (d, 1H, J¼15.5 Hz, for major isomer), 4.33 (d,
1H, J¼15.2 Hz, for minor isomer), 4.46 (dd, 1H, J¼7.1,
11.4 Hz, for major isomer), 4.52 (q, 1H, J¼6.8 Hz, for
major isomer), 4.55 (q, 1H, J¼6.1 Hz, for minor isomer),
4.85 (d, 1H, J¼15.5 Hz, for major isomer), 7.24–7.62 (m,
10H). 13C NMR (67.5 MHz, CDCl3) d 24.5, 24.1, 23.5,
23.3, 17.4, 17.7, 17.8, 18.0, 25.4, 25.5, 25.7, 35.7, 36.7,
43.3, 43.9, 73.2, 74.4, 80.2, 84.3, 109.5, 110.7, 126.4, 126.5,
126.6, 127.5, 127.6, 128.2, 128.3, 128.4, 128.5, 128.6,
Acknowledgements
The present work was partially supported by the Grant-in-
Aid (11640536) from the Ministry of Education, Science,
Sports and Culture, Japan. Financial support from Sasakawa
Scientific Research Grant (to Y. O.) is also appreciated.

8770
A. Kamimura et al. / Tetrahedron 58 (2002) 8763–8770
5. (a) Hiranuma, S.; Kanie, O.; Wong, C.-H. Tetrahedron Lett.
References
1999, 40, 6423. (b) Charette, A. B.; Chua, P. Tetrahedron Lett.
1997, 38, 8499. (c) Wipf, P.; Xu, W.; Kim, H.; Takahashi, H.
Tetrahedron 1994, 53, 16575. (d) Wipf, P.; Xu, W. J. Org.
Chem. 1993, 58, 5880. (e) Waldmu¨ller, D.; Braun, M.; Steigel,
A. Synlett 1991, 160. (f) Corey, E. J.; Raju, N. Tetrahedron Lett.
1983, 24, 5571. (g) Boss, G.; Gerlach, H. Helv. Chim. Acta
1983, 66, 2294.
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis. 3rd ed; Wiley: New York, 1999. (b) Kocienski, P. J.
Protective Groups; Thieme: Stuttgart, 1994.
2. Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161.
(b) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835. (c) Blaser, H. U. Chem. Rev. 1992, 92, 935. (d) Romo, D.;
Meyers, A. I. Tetrahedron 1991, 47, 9503. (e) Denmark, S. E.;
Almstead, N. G. J. Am. Chem. Soc. 1991, 113, 8089.
(f) Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry
1990, 1, 477. (g) Seebach, D.; Zimmermann, J.; Gysel, U.;
Ziegler, R.; Ha, T.-K. J. Am. Chem. Soc. 1988, 110, 4763.
(h) Seebach, D.; Imwinkelried, R.; Weber, T. In Modern
Synthetic Methods; Scheffold, R., Ed.; Springer: Berlin, 1986; p
125.
6. Crystallographic data for structure of 4h have been deposited
with Cambridge Crystallographic Data Centre (deposit No.
154167).
7. Padwa, A.; Schoffstall, A. M. Advances in Cycloaddition
Chemistry; Curran, D. P., Ed.; JAI: Greenwich, CT, 1990; Vol.
2, p 1. (b) Curran, D. P. Advances in Cycloaddition Chemistry;
Curran, D. P., Ed.; JAI: Greenwich, CT, 1988; Vol. 1, p 129.
(c) Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis; VCH: Weinheim, 1988. (d) Caramella, P.;
Gru¨nanger, P. 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Vol. 1, p 291.
´
ˆ
3. (a) Dube, D.; Deschenes, D.; Tweddell, J.; Gagnon, H.; Carlini,
R. Tetrahedron Lett. 1995, 36, 1827. (b) Longobardo, L.;
Mobbili, G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A.
Tetrahedron 1992, 48, 1299. (c) Basile, T.; Longobardo, L.;
Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Chem. Soc.,
Chem. Commun. 1991, 391.
8. Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
9. Ukaji, Y.; Sada, K.; Inomata, K. Chem. Lett. 1993, 1847.
(b) Akiyama, T.; Okada, K.; Ozaki, S. Tetrahedron Lett. 1992,
33, 5763. (c) Oppolzer, W.; Kingma, A. J.; Pillai, S. K.
Tetrahedron Lett. 1991, 32, 4893. (d) Curran, D. P.; Kim, B. H.;
Daugherty, J.; Haffner, T. A. Tetrahedron Lett. 1988, 29, 3555.
4. (a) DeWolfe, R. H. Synthesis 1974, 153. (b) DeWolfe, R. H.
Carboxylic Ortho Acid Derivatives; Academic: New York,
1970.