Diastereoselective 1,3-dipolar cycloaddition of ynolates with chiral nitrones

Article abstract of DOI:10.1055/s-2003-40189

Asymmetric inverse electron-demand 1,3-dipolar cycloaddition of ynolates with chiral nitrones produced 5-isoxazolidinones with good diastereoselectivity. These products were easily converted into optically pure β-amino acids and chiral γ-butyrolactones.

Full text of DOI:10.1055/s-2003-40189

SPECIAL TOPIC
1441
Diastereoselective 1,3-Dipolar Cycloaddition of Ynolates with Chiral Nitrones
D
iastereoselective 1,3-
i
Dipola
t
r
Cyclo
s
a
ddition o
u
f
Y
nolates
w
r
ith Chir
u
al
N
itrones Shindo,*a,b Kotaro Itoh,b Keiko Ohtsuki,a Chinatsu Tsuchiya,a Kozo Shishidoa
a
Institute for Medicinal Resources, University of Tokushima, Sho-machi 1, Tokushima 770-8505, Japan
Fax +81(88)6337294; E-mail: shindo@ph2.tokushima-u.ac.jp
b
PRESTO, Japan Science and Technology Corporation (JST),
Received 28 April 2003
ported.6 Lithium ynolate 1a reacted with nitrone 2
(Scheme 2) at –78 °C to give the desired 5-isoxazolidino-
nes 3 in 85% yield after quenching with aq NaHCO3, fol-
lowed by workup and column chromatography (Table 1,
entry 1). The diastereomeric ratio (3aA:3aB:3aC) turned
out to be 89:7:4 by 1H NMR and the configurations were
determined to be (3R,4S), (3R,4R), and (3S,4R),7 respec-
tively. Consequently, the diastereofacial selectivity (3R
vs. 3S) of addition to the nitrone was 92% de. Since the
addition of lithium enolate of ethyl propionate to 2 provid-
ed a 60:40 mixture of 5-isoxazolidinones (3aA:3aC)
(Scheme 3),8 the lithium ynolate showed much higher dia-
stereofacial selectivity than the lithium enolate. The Re
face attack of the lithium ynolate is in accordance with the
results obtained for the reactions of organolithiums with
the nitrone.6 To examine this generality, cycloadditions
using several kinds of lithium ynolates were attempted.
As shown in Table 1, in all cases, 3A was the predominant
product in good yield (Entries 1, 3, 5, and 7). The stereo-
chemistry was confirmed by NOE experiments on 3A and
the corresponding lactones 5 described below. The rela-
tive configuration of the minor isomers (3bB, 3bC, 3cB,
3cC), which were isolated in very small amounts by pre-
parative HPLC, were estimated by 1H NMR and NOE ex-
periments (cis-relationship of C3-H and C4-H in 3B).
Abstract: Asymmetric inverse electron-demand 1,3-dipolar cy-
cloaddition of ynolates with chiral nitrones produced 5-isoxazoli-
dinones with good diastereoselectivity. These products were easily
converted into optically pure -amino acids and chiral -butyrolac-
tones.
Key words: asymmetric synthesis, cycloadditions, diastereoselec-
tivity, nitrones, ynolates
Recently, we have found that the anionic inverse electron-
demand 1,3-dipolar cycloaddition of nitrones with yno-
lates affords trans-5-isoxazolidinones (Scheme 1).1 Since
the products can be easily converted to -amino acids,
which are important natural and unnatural components of
bioactive compounds, the asymmetric version of this di-
polar cycloaddition would be a valuable method for pro-
viding non-racemic -amino acids.2
The ratio of 3A to 3B should be dependent on the quench-
ing conditions. We attempted thermodynamically con-
trolled protonation reactions, which included addition of
t-BuOH to the reaction mixture at –78 °C and warming to
0 °C, but the selectivity (3A:3B) was not improved
(Table 1, Entry 2, 4, 6, and 8).
Scheme 1
Although we are continuing our investigation of ynolate
chemistry3 and revealing the versatility and functionality
of these interesting compounds,4 much of this chemistry
still remains unexplored, especially asymmetric reactions
using ynolates, which, as far as we know, have never been
published. Herein, we report the asymmetric 1,3-dipolar
cycloaddition of ynolates with chiral nitrones.
OLi
R
Bn
N+
R
O
–78 °C
O-
HX
+
N
1 h
O
O
Bn
OLi
O
+
O
2
1
We selected N-benzyl-2,3-O-isopropylidene-D-glyceral-
dehyde nitrone 25 as the chiral nitrone, since this nitrone
has an acetonide which can be easily converted to other
functionalities, and numerous examples of nucleophilic
additions of organometallics to the nitrone have been re-
O
O
O
H
H
H
H
R
R
R
4
O
O
O
3
+
N
N
N
H
O
H
Bn
Bn
Bn
O
O
O
O
O
3A
3B
(3R,4R)
3C
(3S,4R)
Synthesis 2003, No. 9, Print: 03 07 2003.
Art Id.1437-210X,E;2003,0,09,1441,1445,ftx,en;C01203SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
(3R,4S)
Scheme 2

1442
M. Shindo et al.
SPECIAL TOPIC
Table 1 Asymmetric 1,3-Dipolar Cycloaddition of Ynolates with
Chiral Nitrone 2
O
Me
Me
Me
–78 °C MeI
O
Entry
1
R
Protonationa Yield (%) 3A:3B:3Cb
(3R)
95%
+
2
N
–40 °C
2 h
(3R:3S = 94:6)
1 h
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
Me
Me
Bu
Bu
i-Pr
i-Pr
Ph
A
B
A
B
A
B
A
B
85
91
92
83
89
93
55
48
89:7:4
H
O
Bn
OLi
1a
O
84:10:6
3g
86:6:6
Scheme 5
81:5:14
most quantitatively. The amino group of 4 was protected
with CbzCl, and the resulting mixture was treated with hy-
drochloric acid to afford the trisubstituted -butyrolac-
tones 5, which would be useful chiral building blocks
bearing three contiguous chiral carbons. NOE experi-
ments with 5 revealed the all cis relationship of the sub-
stituents (Scheme 6). From these results, the
stereochemistry of the corresponding 5-isoxazolidinones
3 was determined to be (3R,4S).
84:11:5
90:5:5
85:(15:trace)c
84:(16:trace)c
Ph
a Method A: sat. NaHCO3 solution was added at –78 °C; Method B: t-
BuOH was added at –78 °C, followed by warming to 0 °C.
b The diastereomeric ratio was determined by 1H NMR.
c The configuration of the minor isomer is unknown.
O
R'
R'
-
CO2
R
R
H2, Pd-C
CO2Et
LDA
O
+
NH3
N
dioxane-H2O
H
O
H
O
Bn
O
O
–78 °C, 2 h then 0 °C
THF
OLi
4
3aA + 3aC
+
2
3
Me
OEt
42%
60 : 40
CbzCl; HCl
(R' = H)
Scheme 3
R = Me: 62% (5a)
Bu:73% (5b)
O
R'
R
i-Pr: 78% (5c)
Ph: 73% (5d)
R, R' = Me: 82% (5g)
(for 3 steps)
NOE
Since the silyl-substituted ynolate 1e furnished not only
3e but also the desilylated 5-isoxazolidinone 3f, the crude
mixture was treated with citric acid for complete conver-
sion into 3f, the diastereomeric ratio of which was 96:4
(Scheme 4).
O
NHCbz
H
HO
H
5
NOE
Scheme 6
O
Me3Si
In conclusion, we have found that diastereoselective 1,3-
dipolar cycloaddition of ynolates with the chiral nitrone
furnishes the optically active 5-isoxazolidinones leading
to -amino acids and trisubstituted -lactones. This is the
first example of an asymmetric reaction using ynolates,
and these results suggest that ynolates, like enolates, can
differentiate the asymmetric faces like enolates do and can
be applicable to other asymmetric reactions.
O
Me3Si
NaHCO3 aq
–78 °C
N
2
+
Bn
1e
O
O
OLi
O
3e
O
N
(3R)
citric acid
THF
72% for 2 steps
H
O
Bn
(3R:3S = 96:4)
O
1
THF was distilled from Na-benzophenone ketyl. H NMR (JNM
3f
AL-400, 400 MHz), 13C NMR (JNM AL-400, 75 MHz) spectra
were recorded in CDCl3, unless otherwise noted, and chemical
shifts ( ) are given in ppm relative to TMS (0.0 ppm). IR spectra
were obtained on a JASCO FTIR-410. Mass spectra were recorded
on a JEOL JMS-SX102A, JMS-DX303, JMS-AMSUN200. Col-
umn chromatography was performed using Kanto silica gel. Prepar-
ative HPLC was performed using Mightysil Si60, Kanto. Analytical
TLC was carried on Silica gel 60 F254 plates, Merck. Optical rota-
tions were recorded on a JASCO P-1010. Melting points were de-
termined on a Buchi 535. All reactions were performed under an Ar
atmosphere unless otherwise noted. The nitrone 2 was prepared by
Scheme 4
The enolate of 5-isoxazolidinone initially generated by
the cycloaddition was treated with MeI to give the 4,4-
dimethyl-5-isoxazolidinone 3g in excellent yield with a
diastereomeric ratio of 94:6 (Scheme 5)
After purification by column chromatography, the major
isomers of the 5-isoxazolidinones 3A were reduced by Pd/
C catalyzed hydrogenation to give the -amino acids 4 al- the procedure of Merino. , ,-Dibromo esters were prepared using
our procedure.9
Synthesis 2003, No. 9, 1441–1445 ISSN 1234-567-89 © Thieme Stuttgart · New York

SPECIAL TOPIC
Diastereoselective 1,3-Dipolar Cycloaddition of Ynolates with Chiral Nitrones
1443
(3R,4S,4 S)-2-Benzyl-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-me-
thyl-1,2-isoxazolidin-5-one (3a–d); Typical Procedure (Method
A)
1H NMR (CDCl3): = 0.99 (d, J = 6.8 Hz, 3 H, CH3CH), 1.13 (d, J
= 6.8 Hz, 3 H, CH3CH), 1.32 (s, 3 H, CH3), 1.42 (s, 3 H, CH3), 2.00
(m, 1 H, CHMe2), 2.71 (dd, 1 H, J = 8, 4.8 Hz, CHCO), 3.44 (dd, 1
H, J = 8, 6.4 Hz, CHN), 3.77 (dd, 1 H, J = 8.4, 6.4 Hz, OCHHCH),
4.01 (dd, 1 H, J = 8.4, 6.4 Hz, OCHHCH), 4.09 (ddd, 1 H, J = 6.4,
6.4, 6.4 Hz, OCHCHN), 4.21 (d, 1 H, J = 13.6 Hz, CHHPh), 4.25
(d, 1 H, J = 13.6 Hz, CHHPh), 7.26–7.36 (m, 5 H, Ph).
13C NMR (CDCl3): = 18.4 (CH3CH), 20.6 (CH3CH), 24.9
(CH3CO), 26.3 (OCCH3), 28.9 [CH(CH3)2], 49.2 (CHN), 63.8
(CH2Ph), 65.7 (OCH2CH), 66.8 (CHC = O), 76.6 (OCH), 109.7
(OCO), 128.2 (Ar-CH), 128.6 (Ar-CH), 129.6 (Ar-CH), 134.7 (Ar-
CH), 174.9 (C=O).
To a solution of ethyl 2,2-dibromopropanoate (312 mg, 1.2 mmol)
in anhyd THF (6 mL), cooled to –78 °C, was added dropwise a so-
lution of t-BuLi (3.3 mL, 4.8 mmol, 1.46 M in pentane). The yellow
solution was stirred for 3 h at –78 °C and allowed to warm to 0 °C.
After 30 min, the resulting colorless reaction mixture was cooled to
–78 °C, and a solution of nitrone 2 (235 mg, 1.0 mmol) in THF (2
mL) was added. After 1 h at –78 °C, a sat. NaHCO3 solution (20
mL) was added, and the mixture was stirred vigorously at r.t. The
resulting mixture was extracted with EtOAc (3 × 20 mL). The com-
bined organic phases were washed with brine (30 mL) and dried
(MgSO4). Removal of the solvent under reduced pressure and puri-
fication of the residue by column chromatography (SiO2; Et2O–hex-
ane, 3:7) afforded a mixture of 3aA, 3aB and 3aC (247 mg, 89:7:4
MS (EI): m/z = 319 (M+), 304 (M+ – CH3), 261 (M+ – Me2CO), 218
(M+ – Me2COCH2OCH).
HRMS (EI): m/z calcd for C18H25NO4, 319.1784; found, 319.1770.
1
by H NMR). Product 3aA was purified by recrystallization from
26
30% EtOAc–hexane to give colorless needles; mp 79–80 °C; [ ]D
(3R,4S,4 S)-2-Benzyl-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-phe-
nyl-1,2-isoxazolidin-5-one (3dA)
+161.0 (c 1, CHCl3). Further analytical data of 3aA and 3aB were
consistent with the literature data.7
Colorless prisms; mp 103.5–104.7 °C (EtOAc–hexane);
[ ]D24 +180.2 (c 1.04, CHCl3).
Method B
IR (CHCl3): 2966, 1768, 1605 cm–1.
To a solution of ethyl 2,2-dibromopropanoate (312 mg, 1.2 mmol)
in anhyd THF (6 mL), cooled to –78 °C, was added dropwise a so-
lution of t-BuLi (3.6 mL, 4.8 mmol, 1.34 M in pentane). The yellow
solution was stirred for 3 h at –78 °C and then allowed to warm to
0 °C. After 30 min, the resulting colorless reaction mixture was
cooled to –78 °C, and a solution of nitrone 2 (235 mg, 1.0 mmol) in
THF (2 mL) was added. After 1 h at –78 °C, t-BuOH (0.95 mL, 10
mmol) in THF (1 mL) was added, and the mixture was allowed to
warm to 0 °C. After 30 min, a sat. NaHCO3 solution was added and
the resulting mixture was extracted with EtOAc (3 × 20 mL). The
combined organic phases were washed with brine (30 mL) and
dried (MgSO4). Removal of the solvent under reduced pressure and
purification of the residue by column chromatography (SiO2; Et2O–
hexane 3:7) afforded a mixture of 3aA, 3aB and 3aC (266 mg,
84:10:6 by 1H NMR).
1H NMR (400 MHz, CDCl3): = 1.35 (s, 3 H, CH3), 1.37 (s, 3 H,
CH3), 3.10 (dd, J = 8.8, 7.6 Hz, 1 H, OCH2), 3.63 (dd, J = 11.6, 8.0
Hz, 1 H, CHN), 3.75 (dd, J = 8.8, 6.4 Hz, 1 H, OCH2), 3.89 (d,
J = 11.6 Hz, 1 H, CHC=O), 4.17 (d, J = 14.4 Hz, 1 H, CHHPh),
4.35 (ddd, J = 8.0, 7.6, 6.4 Hz, 1 H, OCH), 4.78 (d, J = 14.4 Hz, 1
H, CHHPh), 7.10–7.14 (m, 2 H, Ph), 7.31–7.44 (m, 8 H, Ph).
13C NMR (100 MHz, CDCl3): = 25.4 (CH3CH), 26.4 (CH3CH),
52.1 (CH3CO), 63.0 (CH2Ph), 66.1 (OCH2CH), 73.9 (CHN), 77.3
(OCH), 109.7 (OCO), 127.8 (Ar-CH), 128.3 (Ar-CH), 128.5 (Ar-
CH), 128.8 (Ar-CH), 129.2 (Ar-CH), 129.6 (Ar-CH), 133.4 (Ar-C),
135.0 (Ar-C), 172.9 (C=O).
MS (FAB): m/z = 354(M + H), 338 (M+ – CH3), 295 (M+ – Me2CO),
252 (M+ – Me2COCH2OCH).
Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C,
71.31; H, 6.65; N, 3.97.
(3R,4S,4 S)-2-Benzyl-4-butyl-3-(2,2-dimethyl-1,3-dioxolan-4-
yl)-1,2-isoxazolidin-5-one (3bA)
Colorless oil; purified by preparative HPLC (EtOAc–hexane, 3:7);
(3R,4 S)-2-Benzyl-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,2-isoxa-
zolidin-5-one (3f)
[ ]D26 +111.4 (c 1.06, CHCl3).
IR (neat): 1770, 1605 cm–1.
1H NMR (400 MHz, CDCl3):
To a solution of the crude mixture (3e) in THF (4.5 mL) and H2O
(1.7 mL) was added citric acid (384 mg, 2 mmol), and the mixture
was stirred for 12 h at r.t. Then, a sat. NaHCO3 solution was added
and the resulting mixture was extracted with EtOAc (3 × 20 mL).
The combined organic phases were washed with brine (30 mL) and
dried (MgSO4). Removal of the solvent under reduced pressure and
purification of the residue by column chromatography (SiO2;
EtOAc–hexane, 1:1) afforded (3R)-3f (192 mg, 69%) and (3S)-3f (9
mg, 3%). The analytical data were consistent with the literature da-
ta.7
= 0.89 (t, J = 7 Hz, 3 H,
CH3CH2CH2), 1.19–1.43 (m, 10 H, CH3CCH3, CH3CH2CH2CH),
1.56–1.67 (m, 2 H, CH3CH2CH2CH2CH), 2.76 (dt, J = 9.2, 5.6 Hz,
1 H, CHCO), 3.36 (dd, J = 9.2, 6.8 Hz, 1 H,CHN), 3.75 (dd, J = 8.4,
8.4 Hz, 1 H,OCH2CH), 4.04 (dd, J = 8.4, 6.4 Hz, 1 H, OCH2CH),
4.13 (d, J = 13.6 Hz, 1 H, CHHPh), 4.17 (ddd, J = 8.4, 6.8, 6.4 Hz,
1 H,OCHCHN), 4.43 (d, 1 H, J = 13.6 Hz, CHHPh), 7.27–7.36 (m,
5 H, Ph).
13C NMR (100 MHz, CDCl3): = 13.8 (CH3CH2), 22.6 (CH3CH2),
25.1 (CH3CCH3), 26.3 (CH3CCH3), 28.3 (CH3CH2CH2), 28.7
(CH3CH2CH2CH2), 43.6 (CHN), 63.6 (CH2Ph), 65.7 (OCH2CH),
68.6 (CHC=O), 76.7 (OCH), 109.6 (OCO), 127.8 (Ar-CH), 128.3
(Ar-CH), 129.4 (Ar-CH), 134.7 (Ar-C), 175.4 (C=O).
(3R,4 S)-2-Benzyl-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-4,4-dime-
thyl-1,2-isoxazolidin-5-one (3g)
To a solution of ethyl 2,2-dibromopropanoate (312 mg, 1.2 mmol)
in anhyd THF (6 mL), cooled to –78 °C, was added dropwise a so-
lution of t-BuLi (3.3 mL, 4.8 mmol, 1.46 M in pentane). The yellow
solution was stirred for 3 h at –78 °C and allowed to warm to 0 °C.
After 30 min, the resulting colorless reaction mixture was cooled to
–78 °C, and a solution of the nitrone 2 (235 mg, 1.0 mmol) in THF
(2 mL) was added. After 1 h at –78 °C, the temperature was in-
creased to –40 °C and MeI (0.31 mL, 5 mmol) was added. After the
mixture was stirred for 2 h at –40 °C, a sat. NaHCO3 solution (20
mL) was added. The resulting mixture was extracted with EtOAc
(3 × 20 mL). The combined organic phases were washed with brine
(30 mL) and dried (MgSO4). Removal of the solvent under reduced
MS (EI): m/z = 333 (M+), 318 (M+ – CH3), 275 (M+ – Me2CO), 232
(M+ – Me2COCH2OCH).
HRMS (EI): m/z calcd for C19H27NO4, 333.1940; found, 333.1937.
(3R,4S,4 S)-2-Benzyl-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-iso-
propyl-1,2-isoxazolidin-5-one (3cA)
Colorless oil; purified by preparative HPLC (EtOAc-hexane);
[ ]D26 +104.3 (c 0.87, CHCl3).
IR (neat): 1768, 1605 cm–1.
Synthesis 2003, No. 9, 1441–1445 ISSN 1234-567-89 © Thieme Stuttgart · New York

1444
M. Shindo et al.
SPECIAL TOPIC
pressure and purification of the residue by column chromatography
(SiO2; Et2O–hexane, 3:17) afforded a mixture of (3R)-3g and (3S)-
3g (291 mg, 93:7 determined by 1H NMR). After separation by pre-
parative HPLC, (3R)-3g was recrystallized from EtOAc–hexane.
Colorless needles; mp 94.3–94.7 °C; [ ]D26 +212.1 (c 1.05, CHCl3).
IR (CHCl3): 1769 cm–1.
IR (CHCl3): 3428, 1779, 1717, 1515 cm–1.
1H NMR (400 MHz, CDCl3): = 1.22 (d, J = 7.2 Hz, 3 H, CH3),
2.76 (br, 1 H, OH), 2.93 (dq, J = 7.2, 7.2 Hz, 1 H, CHCH3), 3.87 (br,
2 H, CH2OH), 4.55 (ddd, J = 4.8, 4.8, 4.8 Hz, 1 H, CHCH2OH),
4.71 (ddd, J = 8.4, 7.2, 4.8 Hz, 1 H, CHNH), 5.14 (s, 2 H, PhCH2),
5.62 (d, J = 8.4 Hz, 1 H, NH), 7.36 (m, 5 H, Ph).
NOE experiments: irradiation of CH at C-3 and C-4 produced an en-
hancement of CH at C-4 and C-5, respectively.
13C NMR (100 MHz, CDCl3): = 8.9 (CH3), 39.1 (CHC=O), 53.0
(CHNH), 59.8 (CH2OH), 67.5 (CH2Ph), 80.0 (CHOCO), 128.1 (Ar-
CH), 128.4 (Ar-CH), 128.6 (Ar-CH), 135.8 (Ar-C), 157.0 (CONH),
177.4 (COO).
1H NMR (400 MHz, CDCl3): = 1.23 (s, 3 H, CH3CC=O), 1.29 (s,
3 H, CH3CC=O), 1.41 (s, 3 H, OCCH3), 1.46 (s, 3 H, OCCH3), 3.06
(d, J = 8.8, Hz, 1 H, CHN), 3.65 (dd, J = 8.4, 8.4 Hz, 1 H,
OCHHCH), 3.99 (d, J = 15.2 Hz, 1 H, CHHPh), 4.13 (dd, J = 8.4,
5.6 Hz, 1 H, OCHHCH), 4.31 (ddd, J = 8.8, 8.4, 5.6 Hz, 1 H, OCH),
4.87 (d, J = 15.2 Hz, 1 H, CHHPh), 7.27–7.36 (m, 3 H, Ph), 7.41
(m, 2 H, Ph).
MS (EI): m/z = 279 (M+).
13C NMR (100 MHz, CDCl3):
= 19.2 (CH3CC=O), 23.2
Anal. Calcd for C14H17NO5: C, 60.21; H, 6.14; N, 5.02. Found: C,
59.95; H, 6.13; N, 4.91.
(CH3CC=O), 26.0 (CH3CO), 26.7 (CH3CO), 44.8 (CC=O), 62.8
(CH2Ph), 65.9 (OCH2CH), 75.0 (CHN), 75.4 (OCH), 109.4 (OCO),
127.5 (Ar-CH), 128.2 (Ar-CH), 129.5 (Ar-CH), 135.8 (Ar-C), 177.5
(C=O).
(3S,4R,5S)-4-Benzyloxycarbonylamino-5-hydroxymethyl-3-bu-
tyl-dihydrofuran-2-one (5b)
MS (EI): m/z = 305 (M+), 290 (M+ – CH3), 247 (M+ – Me2CO), 204
Colorless needles; mp 109.9 °C (EtOAc–hexane); [ ]D26 +83.5 (c
1.08, CHCl3).
(M+ – Me2COCH2OCH).
Anal. Calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C,
66.67; H, 7.59; N, 4.55.
IR (CHCl3): 3429, 1779, 1714, 1515 cm–1.
1H NMR (400 MHz, CDCl3): = 0.88 (t, J = 7.2 Hz, 3 H, CH3),
1.23–1.57 (m, 5 H, CH2CH2CHH), 1.82 (m, 1 H, CHCHH), 2.73 (m,
1 H, CHC=O), 2.84 (dd, J = 9.2, 5.2 Hz, 1 H, OH), 3.78 (ddd,
J = 12.4, 6.8, 4.8 Hz, 1 H, CHHOH), 3.87 (ddd, J = 12.4, 9.2, 4.8
Hz, 1 H, CHHOH), 4.49 (ddd, J = 7.0, 4.8, 4.8 Hz, 1 H,
CHCH2OH), 4.68 (ddd, J = 9.0, 7.0, 4.4 Hz, 1 H, CHNH), 5.15 (s,
2 H, PhCH2), 5.32 (d, J = 9.0 Hz, 1 H, NH), 7.32–7.39 (m, 5 H, Ph).
(3S,4R,5S)-4-Benzyloxycarbonylamino-5-hydroxymethyl-3-iso-
propyl-dihydrofuran-2-one (5c); Typical Procedure
The pure isoxazolidinone 3cA (33.8 mg, 0.11 mmol) in aq dioxane
(10%) was added to a suspension of 10% Pd/C in aq dioxane (10%).
H2 gas was added at ambient pressure, and the mixture was stirred
at 60 °C for 20 h. The solution was filtered, and the solvents were
removed in vacuo to afford 28.2 mg (>99%) of the -amino acid 4c.
To a solution of 4c in CH2Cl2 (10 mL) was added Et3N (0.05 mL,
0.36 mmol) and benzyloxycarbonyl chloride (0.03 mL, 0.21 mmol)
at r.t. After 12 h, the pH was adjusted to 1 by the addition of 3%
HCl–EtOH, and the mixture was stirred for a further 5 h. Removal
of the solvent under reduced pressure and purification of the residue
by column chromatography (SiO2; EtOAc–hexane, 3:7) afforded 5c
(26.5 mg, 78%) as colorless needles; mp 108.3–112.6 °C (EtOAc–
hexane); [ ]D24 +81.9 (c 0.44, CHCl3).
NOE experiments: irradiation of CH at C-3 and C-4 produced an en-
hancement of CH at C-4 and C-5, respectively.
13C NMR (100 MHz, CDCl3): = 13.9 (CH3), 22.5 (CH2CH3), 23.8
(CH2CH2CH3), 29.5 (CH2CH2CH2CH3), 44.5 (CHC=O), 52.3
(CHNH), 59.8 (CH2OH), 67.4 (CH2Ph), 80.9 (CHOCO), 127.8 (Ar-
CH), 128.2 (Ar-CH), 128.4 (Ar-CH), 135.7 (Ar-CH), 156.8
(CONH), 176.6 (COO).
MS (EI): m/z = 321 (M+)
Anal. Calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36; Found: C,
63.58; H, 7.21; N, 4.30.
IR (CHCl3): 3429, 1779, 1708, 1605, 1513 cm–1.
1H NMR (400 MHz, CDCl3): = 0.99 (d, J = 6.4, 3 H, CH3), 1.27
(d, J = 6.4, 3 H, CH3), 1.91 [m, 1 H, CH(CH3)2], 2.45 (dd, J = 6.4,
10 Hz, 1 H, CHC=O), 3.00 (dd, J = 9.2, 4.0 Hz, 1 H, OH), 3.65 (ddd,
J = 12, 7.6, 4.0 Hz, 1 H, CHHOH), 3.83 (ddd, J = 12, 9.2, 4.4 Hz, 1
H, CHHOH), 4.39 (ddd, J = 7.6, 4.4, 3.6 Hz, 1 H, CHCH2OH), 4.61
(ddd, J = 8.4, 6.4, 3.6 Hz, 1 H, CHNH), 5.12 (d, J = 12.4 Hz, 1 H,
PhCHH), 5.18 (d, J = 12.4 Hz, 1 H, PhCHH), 5.26 (d, J = 8.4 Hz, 1
H, NH), 7.36 (m, 5 H, Ph).
(3S,4R,5S)-4-Benzyloxycarbonylamino-5-hydroxymethyl-3-
phenyl-dihydrofuran-2-one (5d)
White powder; mp 127 °C (EtOAc–hexane); [ ]D24 +74.7 (c 0.73,
CHCl3).
IR (CHCl3): 3417, 1782, 1716, 1510 cm–1.
1H NMR (400 MHz, CDCl3): = 2.97 (br, 1 H, OH), 3.89 (m, 2 H,
CH2OH), 4.31 (d, J = 7.5 Hz, 1 H, CHC=O), 4.71 (ddd, J = 5, 5, 5
Hz, 1 H, CHCH2OH), 4.90 (d, J = 12.2 Hz, 1 H, PhCHH), 4.91 (m,
1 H, CHNH), 4.96 (d, J = 12.2 Hz, 1 H, PhCHH), 5.15 (d, J = 8.0
Hz, 1 H, NH), 7.15 (m, 2 H, Ph), 7.29–7.39 (m, 8 H, Ph).
NOE experiments: irradiation of CH at C-3 and C-4 produced an en-
hancement of CH at C-4 and C-5, respectively.
13C NMR (100 MHz, CDCl3): = 20.5 (CH3CH), 21.1 (CH3CH),
24.9 [CH(CH3)2], 50.6 (CHC=O), 52.8 (CHNH), 59.1 (CH2OH),
67.8 (CH2Ph), 80.3 (CHOCO), 128.1 (Ar-CH), 128.5 (Ar-CH),
128.7 (Ar-CH), 135.6 (Ar-C), 157.3 (CONH), 175.1 (COO).
NOE experiments: irradiation of CH at C-3 and C-4 produced an en-
hancement of CH at C-4 and C-5, respectively.
13C NMR (100 MHz, CDCl3): = 50.2 (CHC=O), 53.8 (CHNH),
59.7 (CH2OH), 67.3 (CH2Ph), 80.0 (CHOCO), 127.9 (Ar-CH),
128.3 (Ar-CH), 128.4 (Ar-CH), 128.5 (Ar-CH), 129.0 (Ar-CH),
129.5 (Ar-CH), 130.7 (Ar-C), 135.6 (Ar-C), 156.8 (CONH), 174.1
(COO).
MS (EI): m/z = 307 (M+).
Anal. Calcd for C16H21NO5: C, 62.53; H, 6.89; N, 4.56. Found: C,
62.35; H, 6.80; N, 4.52.
(3S,4R,5S)-4-Benzyloxycarbonylamino-5-hydroxymethyl-3-me-
thyl-dihydrofuran-2-one (5a)
MS (EI): m/z = 341 (M+).
HRMS (EI): m/z calcd for C19H19NO5, 341.1263; found, 341.1254.
Colorless needles; mp 105.9–106.0 °C (EtOAc–hexane);
[ ]D24 +53.0 (c 0.55, CHCl3).
Synthesis 2003, No. 9, 1441–1445 ISSN 1234-567-89 © Thieme Stuttgart · New York

SPECIAL TOPIC
Diastereoselective 1,3-Dipolar Cycloaddition of Ynolates with Chiral Nitrones
1445
(3S,4R,5S)-4-Benzyloxycarbonylamino-5-hydroxymethyl-3,3-
dimethyl-dihydrofuran-2-one (5g)
(2) For a recent review on -amino acids and -peptides see:
(a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem.
Rev. 2001, 101, 3219. (b) Abele, S.; Seebach, D. Eur. J.
Org. Chem. 2000, 1. (c) Cardillo, G.; Tomasini, C. Chem.
Soc. Rev. 1996, 117.
Colorless needles; mp 107–108 °C (EtOAc–hexane); [ ]D24 +59.4
(c 1.02, CHCl3).
IR (CHCl3): 3423, 1774, 1718, 1515 cm–1.
(3) For reviews see: (a) Shindo, M. Chem. Soc. Rev. 1998, 27,
367. (b) Shindo, M. J. Synth. Org. Chem. Jpn. 2000, 58,
1155. (c) Shindo, M. Yakugaku Zasshi 2000, 120, 1233.
(4) (a) Shindo, M. Tetrahedron Lett. 1997, 38, 4433.
(b) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron 1998, 54,
2411. (c) Shindo, M.; Koretsune, R.; Yokota, W.; Itoh, K.;
Shishido, K. Tetrahedron Lett. 2001, 42, 8357. (d) Shindo,
M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121,
6507. (e) Shindo, M.; Sato, Y.; Shishido, K. J. Org. Chem.
2001, 66, 7818. (f) Shindo, M.; Sato, Y.; Shishido, K.
Tetrahedron Lett. 2002, 43, 5039. (g) Shindo, M.;
Matsumoto, K.; Sato, Y.; Shishido, K. Org. Lett. 2001, 3,
2029. (h) Shindo, M.; Oya, S.; Murakami, R.; Sato, Y.;
Shishido, K. Tetrahedron Lett. 2000, 41, 5943. (i) Shindo,
M.; Sato, Y.; Shishido, K. Tetrahedron Lett. 1998, 39, 4857.
(j) Shindo, M.; Sato, Y.; Shishido, K. J. Org. Chem. 2000,
65, 5443. (k) Shindo, M.; Matsumoto, K.; Mori, S.;
Shishido, K. J. Am. Chem. Soc. 2002, 124, 6840.
(5) (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T.
Tetrahedron: Asymmetry 1997, 8, 3489. (b) Merino, P.;
Castillo, E.; Franco, S.; Merchan, F. L.; Tejero, T.
Tetrahedron: Asymmetry 1998, 9, 1759.
1H NMR (400 MHz, CDCl3): = 1.20 (s, 3 H, CH3), 1.38 (s, 3 H,
CH3), 2.65 (br, 1 H, OH), 3.82 (dd, J = 12.8, 3.2 Hz, 1 H, CHHOH),
3.99 (dd, J = 12.8, 3.2 Hz, 1 H, CHHOH), 4.47 (dd, J = 9.2, 7.6 Hz,
1 H, CHNH), 4.69 (ddd, J = 7.6, 3.2, 3.2 Hz, 1 H, CHCH2OH), 5.12
(s, 2 H, PhCH2), 5.84 (d, J = 9.2 Hz, 1 H, NH), 7.31 (m, 5 H, Ph).
NOE experiments: irradiation of CH at C-4 produced an enhance-
ment of CH at and C-5.
13C NMR (100 MHz, CDCl3): = 18.9 (CH3), 25.5 (CH3), 43.4
[C(CH3)2], 58.5 (CHNH), 60.4 (CH2OH), 67.3 (CH2Ph), 78.0
(CHOCO), 128.0 (Ar-CH), 128.3 (Ar-CH), 128.6 (Ar-CH), 136.0
(Ar-C), 156.6 (CONH), 180.6 (COO).
MS (EI): m/z = 293 (M+).
Anal. Calcd for C15H19NO5: C, 61.42; H, 6.53; N, 4.78. Found: C,
61.34; H, 6.46; N, 4.74.
Acknowledgment
This research was partially supported by a Grant in Aid for Scienti-
fic Research from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan.
(6) For a review see: Merino, P.; Franco, S.; Merchan, F. L.;
Tejero, T. Synlett 2000, 442.
(7) Moglioni, A. G.; Muray, E.; Castillo, J. A.; Alvarez-Larena,
A.; Moltrasio, G. Y.; Branchadell, V.; Ortuno, R. M. J. Org.
Chem. 2002, 67, 2402.
(8) Addition of the enolate of methyl acetate was reported: see
Merino, P.; Franco, S.; Garces, N.; Merchan, F. L.; Tejero,
T. Chem. Commun. 1998, 493.
References
(1) Shindo, M.; Itoh, K.; Tsuchiya, C.; Shishido, K. Org. Lett.
2002, 4, 3119.
(9) Shindo, M.; Sato, Y.; Koretsune, R.; Yoshikawa, T.;
Matsumoto, K.; Shishido, K. Chem. Pharm. Bull. 2003, 51,
477.
Synthesis 2003, No. 9, 1441–1445 ISSN 1234-567-89 © Thieme Stuttgart · New York