Asymmetric catalytic [4 + 1] annulations catalyzed by quinidine: Enantioselective synthesis of multi-functionalized isoxazoline N-oxides

Article abstract of DOI:10.1039/c2ob26165k

A highly regio-, chemo-, diastereo- and enantioselective organocatalytic [4 + 1] annulation of 2-halo-1,3-dicarbonyl compounds with Morita-Baylis-Hillman adducts catalyzed by commercially available, low cost quinidine for the preparation of synthetically

Full text of DOI:10.1039/c2ob26165k

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PAPER
Asymmetric catalytic [4 + 1] annulations catalyzed by quinidine:
enantioselective synthesis of multi-functionalized isoxazoline N-oxides†
Zhi-Wei Guo, Jian-Wu Xie,* Ce Chen and Wei-Dong Zhu*
Received 18th June 2012, Accepted 3rd September 2012
DOI: 10.1039/c2ob26165k
A highly regio-, chemo-, diastereo- and enantioselective organocatalytic [4 + 1] annulation of 2-halo-
1,3-dicarbonyl compounds with Morita–Baylis–Hillman adducts catalyzed by commercially available,
low cost quinidine for the preparation of synthetically unique and medicinally multi-functionalized
isoxazoline N-oxides with three stereogenic centers including adjacent quaternary and tertiary
stereocenters has been developed. Notably, the unexpected product ethyl 2-((tert-butyldimethylsilyl)oxy)-
2-(5,5-diacetyl-3-((methylsulfonyl)oxy)-4-phenylisoxazolidin-3-yl)acetate (8) bearing a quaternary
stereocenter and two tertiary stereocenters was obtained from the undocumented 5,5-diacetyl-3-(2-ethoxy-
1-hydroxy-2-oxoethyl)-4-phenyl-4,5-dihydroisoxazole 2-oxide (4ba).
quinidine and its direct application in the synthesis of optically
active multi-functionalized isoxazoline N-oxides. Notably, the
Introduction
Isoxazoline N-oxides are recognized as important precursors for
the synthesis of highly functionalized γ-hydroxy-α-amino acids
or γ-amino-α-hydroxy acids,1a,d–f,2 natural products,1c,3 and
several biologically active compounds.4 Owing to their impor-
tance in organic synthesis, different approaches towards the syn-
thesis of isoxazoline N-oxides have been reported.3,5 Chiral
isoxazoline N-oxides were often obtained from optically pure
starting materials5e–g,6 or stoichiometric quantities of chiral
reagents7 in the past few decades. However, a catalytic asym-
metric reaction for their synthesis is rare. Up to now, only a few
catalytic asymmetric strategies, such as [4 + 1] annulation and
the one-pot strategy to synthesize optically active isoxazoline
N-oxides have been reported.8 Especially, the methods to practi-
cally synthesize optically active multi-functionalized isoxazoline
N-oxides with high diastereoselectivity and enantioselectivity are
very limited. Therefore, it is of the utmost importance to develop
other strategies that can provide rapid access to these optically
active isoxazoline N-oxides with high atomic efficiency and,
more importantly, good feasibility to assemble various substi-
tution patterns. Herein, we present an efficient and highly enan-
designed reactions are highly regio-, chemo-, diastereo- and
enantioselective, and simultaneously give the desired multifunc-
tional products with up to three chiral carbon centers including
adjacent quaternary and tertiary stereocenters.
ð1Þ
The control of the regio- and stereochemistry in the synthesis
of optically active compounds containing many chiral centers
and various functional groups, such as hydroxyl, nitro, and car-
bonyl groups, is of particular interest because these optically
active compounds can be conveniently converted into other
various functional groups. Recently, our group has reported that
2-halo-1,3-dicarbonyl compounds bearing a leaving group could
act as versatile Michael donors in the synthesis of functionalized
2,3-dihydrobenzofurans [eqn (1)].9 On the other hand, Morita–
Baylis–Hillman adducts that posses nitro and hydroxyl groups
are useful synthons in organic synthesis. Moreover, guided by
our studies on the use of 2-halo-1,3-dicarbonyl compounds in
cascade transformations, we envisioned that multi-functionalized
cyclic products (e.g., tetrahydrofurans, isoxazoline N-oxides,
and nitrocyclopropanes) with up to four chiral carbon centers
would be obtained by the domino reaction of 2-halo-1,3-dicarbo-
nyl compounds with Morita–Baylis–Hillman adducts, as out-
lined in Scheme 1.
tioselective [4
+ 1] annulation of 2-halo-1,3-dicarbonyl
compounds with Morita–Baylis–Hillman adducts (MBH
adducts) catalyzed by the commercially available, low cost
Key Laboratory of the Ministry of Education for Advanced Catalysis
Materials, Department of Chemistry and Life Science, Zhejiang Normal
University, Jinhua 321004, P. R. of China. E-mail: xiejw@zjnu.cn,
weidongzhu@zjnu.cn; Fax: (+86) 579 82282610
†Electronic supplementary information (ESI) available. CCDC reference
number 887775. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c2ob26165k
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Table 1 Screening studies of the organocatalysts catalyzed [4 + 1]
annulation of Morita–Baylis–Hillman adducts 2a with 3-chloropentane-
2,4-dione 3aa
Yieldb (%)
eec (%)
drc
Scheme 1 [4 + 1]/[2 + 1] Cycloaddition of Morita–Baylis–Hillman
adducts.
Entry
Catalyst
1
2
3
4
5
6
7
8
DBU
1a
1b
1c
1d
1e
85
46
52
66
61
73
78
77
44
81
0
19
3
13
6
28
33
43
3
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
Results and discussion
Organocatalytic asymmetric reactions have been used as a
powerful tool for the synthesis of enantiopure molecules with
multiple stereocenters by employing either a single catalyst or a
combination of catalysts under mild, environmentally benign
conditions over the past few decades.10 To evaluate this hypo-
thesis, the Morita–Baylis–Hillman adduct 2a and 3-chloropen-
tane-2,4-dione 3a were first applied. Instead of finding
nitrocyclopropane and tetrahydrofuran, we identified the product
as 2-isoxazoline N-oxide 4aa when the reaction was carried out
in the presence of the organocatalysts in DCM at room tempera-
ture. A few representative results are shown in Table 1. It was
found that DBU [1,8-diazabicyclo (5, 4, 0) undec-7-ene] was a
highly active catalyst (Table 1, entry 1). The clean product,
2-isoxazoline N-oxide 4aa, was obtained with good yield.
Notably, excellent diastereoselectivity (>99 : 1) was observed.
Probably an internal OH group simultaneously activated the
nitro group and induced the high diastereoselectivity by the
formation of an internal H-bonding, as shown in Scheme 1
(path b). In fact, when the OH was protected, the reaction could
not proceed (see Scheme S1† in the ESI).
1f
1g
1h
1g
9
10d
50
a Unless otherwise noted, reactions were performed with 0.25 mmol of
2a, 0.10 mmol of 3a, and 20 mol% of catalyst in 2 mL of DCM at r.t.
under N2 for 24 h. b Isolated yield. c Determined by chiral HPLC
analysis. d −40 °C, 48 h.
As shown in Table 1, catalysts 1a–e (Fig. 1), with a cinchona
alkaloid skeleton, were screened first. We tended to activate both
donors and acceptors to promote this transformation and the
[4 + 1] annulation was catalyzed by the thiourea-tertiary amine
1a. A moderate yield and excellent diastereoselectivity were
obtained while the ee was very low (Table 1, entry 2). Other cat-
alysts derived from the cinchona alkaloids were then evaluated
and similar results were obtained. Cinchona alkaloids have
appeared as efficient organocatalysts in asymmetric transform-
ations since the basic tertiary nitrogen of cinchona alkaloids
could activate nucleophiles by deprotonation, whereas the sec-
ondary hydroxyl group would serve as a hydrogen-bonding
donor in the activation of electrophiles such as α,β-unsaturated
carbonyl compounds or nitroalkenes. As such, quinine 1f and
quinidine 1g were screened and better results were obtained
(Table 1, entries 7–8). A poor ee was observed in the presence of
Takemoto’s catalyst 1h (Table 1, entry 9). By lowering the reac-
tion temperature to −40 °C, we achieved a moderate enantios-
electivity (50% ee) and a good yield (81%) in the presence of
quinidine 1g, while the reaction time shouldbe extended
(Table 1, entry 10).
Fig. 1 Structures of organocatalysts 1a–h.
Table 2 Optimization of the [4 + 1] annulation conditionsa
Entry
Solvent
Yieldb (%)
eec (%)
drc
1
2
3
4
DCM
CH3CN
THF
Toluene
DMSO
1,4-Dioxane
DCM
81
58
88
74
76
66
76
50
41
14
40
31
29
80
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
5
6
7d
a Unless otherwise noted, reactions were performed with 0.25 mmol of
2a, 0.10 mmol of 3a, and 20 mol% of 1g in 2 mL of solvent at −40 °C
under N2 for 48 h. b Isolated yield. c Determined by chiral HPLC
analysis. d −78 °C, 72 h.
Subsequently, a series of commonly used solvents were
screened for the [4 + 1] annulation to obtain improved yields
and enantioselectivities (Table 2). The reaction proceeded
smoothly and afforded good yields (58%–88%) with excellent
8472 | Org. Biomol. Chem., 2012, 10, 8471–8477
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Table 3 Asymmetric [4 + 1] annulation of Morita–Baylis–Hillman adducts 2 with 3-chloropentane-2,4-diones 3a
Entry
Ar
R1
(2)
3
4
Yieldb (%)
eec (%)
drc
1
2
3
4
5
6
7
8
p-Cl–Ph
Ph
p-Me–Ph
p-MeO–Ph
p-Cl–Ph
Ph
p-Me–Ph
p-MeO–Ph
p-Br–Ph
p-F–Ph
o-Cl–Ph
p-CF3–Ph
2-Furanyl
Ph
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
H
(2a)
(2b)
(2c)
(2d)
(2a)
(2b)
(2c)
(2d)
(2e)
(2f)
(2g)
(2h)
(2i)
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
4aa
4ba
4ca
4da
4ab
4bb
4cb
4db
4eb
4fb
4gb
4hb
4ib
76
78
82
86
79
84
97
92
85
80
79
84
70
55
80
81
88
86
88
87
91
92
84
86
90
81
81
58
>99 : 1
>99 : 1
>99 : 1
>99 : 1
99 : 1
97 : 3
96 : 4
98 : 2
97 : 3
>99 : 1
95 : 5
96 : 4
94 : 6
97 : 3
9
10
11
12
13
14
(2j)
4jb
a Unless otherwise noted, reactions were performed with 0.25 mmol of 2, 0.10 mmol of 3, and 20 mol% of 1g in 2 mL of DCM at −78 °C under N2
for 72 h. b Isolated yield. c Determined by chiral HPLC analysis.
diastereoselectivities (>99 : 1) and varied enantioselectivities
(Table 2, entries 1–7) in the different solvents. Dichloromethane
turned out to be the optimal solvent to give the product in mod-
erate enantioselectivity and good yield (Table 2, entry 1). Thus,
quinidine 1g and DCM were chosen to further optimize the reac-
tion temperature. At a lower temperature (−78 °C), the best
result (76% yield, 80% ee, and >99 dr) was obtained (Table 2,
entry 7). Based on the above screened results, the optimal reac-
tion conditions: 2.5 equiv. 2 and 1.0 equiv. 3 in DCM with
20 mol% quinidine 1g at −78 °C were established.
Fig. 2 Molecular structure of enantiopure 4gb (ellipsoids with 50%
probability).
With the optimal reaction conditions in hand, the scope of the
present organocatalytic asymmetric [4 + 1] annulation using cat-
alyst 1g was extended to various MBH adducts 2 and 2-halo-
1,3-dicarbonyl compounds 3. As illustrated in Table 3, for the
reactions of 2-halo-1,3-dicarbonyl compounds 3a–b, the excel-
lent results were achieved with MBH adducts 2a–i bearing
various β-aryl substitutions or heteroaryl substitutions (Table 3,
entries 1–13). Several points are noteworthy: (1) the reaction
scope was proven to be quite broad with respect to MBH
adducts and the novel transformations were highly regio-,
chemo-, diastereo- and enantioselective, simultaneously giving
the highly substituted 2-isoxazoline N-oxides with up to three
chiral carbon centers and the products also possessed adjacent
quaternary and tertiary stereocenters. (2) It appeared that elec-
tronics of the substituents had a minimal impact on the
efficiency, enantioselectivity, and diastereoselectivity of the
[4 + 1] annulation. High yields and excellent enantioselectivities
were obtained in the [4 + 1] annulation of 3b with an electron-
donating substituent on the aryl ring of the MBH adducts 2
(Table 3, entries 7 and 8). On the contrary, an electron-withdraw-
ing substituent on the aryl ring of the MBH adducts 2 tended to
decrease the enantioselectivities and yields (Table 3, entries 9,
10 and 12). (3) The absolute configuration of the substituted
2-isoxazoline N-oxides were confirmed by the single-crystal
X-ray analysis of representative enantiopure 4gb that bears a
chlorine atom. As shown in Fig. 2, it composes of (C4S, C7R,
and C15R) configuration. (4) MBH adduct 2i with furanyl substi-
tution also exhibited good reactivity, and good results (81% ee
and 94 : 6 dr) were still obtained (Table 3, entry 13). (5) The
excellent diastereoselectivities were also achieved when the
COOEt (R1) on the MBH adduct was replaced with a hydrogen
atom, while the enantioselectivity and yield were only moderate
(Table 3, entry 14).
Having established the catalytic asymmetric formal [4 + 1]
annulation methodology of 2-halo-1,3-dicarbonyl compounds
and MBH adducts, the synthetic utilities of these previously
undocumented multi-functionalized isoxazoline N-oxides were
further explored (Scheme 2). The obtained isoxazoline N-oxides
are useful intermediates in organic synthesis and readily con-
verted to the corresponding oximes and isoxazolines
(Scheme 2). Chiral isoxazoline N-oxide 4ba was readily con-
verted to intermediate 5 by simple protection. Then isoxazoline
N-oxide 5 was treated with Pd/C in MeOH under H2 atmosphere
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plates. Column chromatography was performed using silica gel
(160–200 mesh) eluting with ethyl acetate and petroleum ether
(bp 60–90 °C). 1H NMR spectra were recorded at 400 MHz, and
13C NMR spectra were recorded at 100 MHz. Chemical shifts
(δ) are reported in ppm downfield from CDCl3 (δ = 7.27 ppm)
1
for H NMR and relative to the central CDCl3 resonance (δ =
77.0 ppm) for 13C NMR spectroscopy. Coupling constants (J)
are given in Hz. ESI-HRMS spectrometer was measured with a
Finnigan LCQDECA ion trap mass spectrometer. Optical rotations
were measured at 589 nm at 20 °C. Enantiomeric excess was
determined by HPLC analysis with Chiralpak columns. Com-
mercial grade solvents were dried and purified by standard pro-
cedures as specified in Purification of Laboratory Chemicals.12
The racemic Morita–Baylis–Hillman adducts 2 were prepared
according to the procedures reported in the literature.11
Asymmetric domino reaction of MBH substrate and chlorinated
1,3-dicarbonyl compounds
Scheme 2 Transformation of isoxazoline N-oxides (4ba and 4gb)
General procedure: 2a (0.25 mmol), 3a (0.1 mmol) and quini-
dine (0.02 mol) were stirred in CH2Cl2 (2 mL) at −78 °C under
N2 for 72 h. Then flash chromatography on silica gel (30% ethyl
acetate–petroleum ether) gave the product 4aa as a colorless oil
jelly (76% yield).
and oxime 6 was obtained in quantitative yield with complete
retention of stereochemistry. Interestingly, no isoxazoline 7 was
observed, but multifunctional isoxazolidine 8 bearing a quatern-
ary stereocenter and two tertiary stereocenters was isolated in
good yield without loss of optical purity when oxime 6 was
treated with methanesulfonyl chloride and triethylamine in
dichloromethane. Probably, isoxazoline 7 was protonated, and
then attacked by methanesulfonate anion to form isoxazolidine
8. In addition, chiral isoxazoline N-oxide 4gb was readily con-
verted to multi-functionalized isoxazoline N-oxide 9, which con-
tained four chiral carbon centers and two hydroxyl groups, in
excellent yield without any effect on the ee by simple reduction.
Synthesis of (R)-5,5-diacetyl-3-((S)-1-((tert-butyldimethylsilyl)-
oxy)-2-ethoxy-2-oxoethyl)-4-phenyl-4,5-dihydroisoxazole 2-oxide
(5). To a solution of 4ba (139.6 mg, 0.40 mmol) in DCM
(3 mL) was added imidazole (27.2 mg, 0.40 mmol) and TBSCl
(78.5 mg, 0.52 mmol). After stirring the reaction mixture at
room temperature for 8 h, excess solvent was removed in vacuo.
Purification of the residue by column chromatography on silica
gel (ethyl acetate–petroleum ether = 1 : 9 as eluent) gave the title
compound 5 as a white solid, mp 43–44 °C; 162.9 mg, yield
88%.
Conclusions
Synthesis of (2S,4R,Z)-ethyl 5-acetyl-2-((tert-butyldimethyl-
silyl)oxy)-5-hydroxy-3-(hydroxyimino)-6-oxo-4-phenylheptanoate
(6). To a solution of 5 (46.3 mg, 0.10 mmol) in MeOH (1 mL)
was stirred for 3 h in the presence of 5 wt% palladium on acti-
vated carbon (13.0 mg) at room temperature under H2 atmos-
phere. The resulting mixture was filtered to remove the catalyst,
and the filtrate was concentrated. Purification of the residue by
column chromatography on silica gel (ethyl acetate–petroleum
ether = 1 : 2 as eluent) gave the title compound 6 as a colorless
oil; 46.5 mg, yield 100%.
We have successfully demonstrated an efficient and highly enan-
tioselective [4 + 1] annulation of Morita–Baylis–Hillman
adducts 2 to 2-halo-1,3-dicarbonyl compounds 3 with excellent
regio-, chemo-, diastereo- and enantioselectivity, by employing a
commercially available, low cost quinidine as the organocatalyst.
This novel methodology provides facile access to various enan-
tioenriched multifunctional isoxazoline N-oxides with up to four
chiral carbon centers including adjacent quaternary and tertiary
stereocenters. Notably, an unexpected product, isoxazolidine 8,
bearing a quaternary stereocenter and two tertiary stereocenters
was obtained from the undocumented multi-functionalized iso-
xazoline N-oxide 4ba. Further investigations to expand the syn-
thetic utilities of this protocol, such as the synthesis of
structurally unique β-amino acids and amino alcohols as well as
the synthesis of pharmaceutically intriguing compounds, are
currently underway.
Synthesis of (2R)-ethyl 2-((tert-butyldimethylsilyl)oxy)-2-((4S)-
5,5-diacetyl-3-((methylsulfonyl)oxy)-4-phenylisoxazolidin-3-yl)-
acetate (8). To a solution of 6 (46.5 mg, 0.10 mmol) and Et3N
(21.2 mg, 0.21 mmol) in DCM (1 mL) was added MsCl
(11.4 mg, 0.10 mmol) dropwise at 0 °C under a nitrogen atmos-
phere, and the cooling bath was then removed. The reaction
mixture was stirred overnight at room temperature and poured
into water. After extraction with ethyl acetate, the organic layer
was washed with brine, dried over Na2SO4 and concentrated.
The resulting residue was purified by flash column chromato-
graphy on silica gel (ethyl acetate–petroleum ether = 3 : 1 as
eluent) to give the title compound 8 as a white solid; mp
104–106 °C; 36.4 mg, yield 67%.
Experimental section
General methods
NMR spectra were recorded with tetramethylsilane as the
internal standard. TLC was performed on glass-backed silica
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Synthesis of (4S,5R)-4-(2-chlorophenyl)-3-((S)-2-ethoxy-1-
hydroxy-2-oxoethyl)-5-(ethoxycarbonyl)-5-((R)-1-hydroxyethyl)-
4,5-dihydroisoxazole 2-oxide (9). To a solution of 4gb (82.6 mg,
0.2 mmol) in dried THF (2 mL) was added sodium borohydride
(10.0 mg, 0.3 mmol) in portions (TLC to monitor the reaction).
The reaction mixture was stirred for 5 h, quenched with water
(5 mL) and extracted with ethyl acetate (3 × 5 mL). The organic
phase was washed with brine and then dried. Solvent was
removed under reduced pressure. Flash chromatography (ethyl
acetate–petroleum ether = 1 : 3–1 : 2 as eluent) gave 9 as a color-
less oil; 76.4 mg, yield 92%.
26.1, 13.8. ESI-HRMS: calcd for C18H21NO8 + Na 402.1159,
found 402.1165; [α]2D0 = −165.8 (c = 0.63, CHCl3), ee = 86%, dr
> 99 : 1. The enantiomeric ratio was determined by HPLC on a
Chiralpak AS column (30% 2-propanol–hexane, 1 mL min−1),
tmajor = 14.54 min, tminor = 8.64 min.
(4R,5R)-5-Acetyl-4-(4-chlorophenyl)-3-((S)-2-ethoxy-1-hydroxy-
2-oxoethyl)-5-(ethoxycarbonyl)-4,5-dihydroisoxazole 2-oxide
1
(4ab). Colorless oil; 32.6 mg, yield 79%; H NMR (400 MHz,
CDCl3) δ 7.31 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H),
5.40 (s, 1H), 4.87 (d, J = 5.6 Hz, 1H), 4.14–4.06 (m, 1H),
3.96–3.88 (m, 1H), 3.87–3.78 (m, 2H), 3.51 (d, J = 5.9 Hz, 1H),
2.37 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 197.0, 169.2, 163.0, 135.4,
131.1, 130.2, 129.0, 114.6, 89.4, 65.2, 63.2, 62.9, 51.5, 25.4,
13.9, 13.4. ESI-HRMS: calcd for C18H20ClNO8 + Na 436.0770,
found 436.0774; [α]2D0 = −116.5 (c = 0.57, CHCl3), ee = 88%, dr
= 99 : 1. The enantiomeric ratio was determined by HPLC on a
Chiralpak AS column (30% 2-propanol–hexane, 1 mL min−1),
(R)-5,5-Diacetyl-4-(4-chlorophenyl)-3-((S)-2-ethoxy-1-hydroxy-
2-oxoethyl)-4,5-dihydroisoxazole 2-oxide (4aa). Colorless oil;
29.1 mg, yield 76%; 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J =
8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 5.31 (s, 1H), 4.88 (d, J =
6.0 Hz, 1H), 4.15–4.08 (m, 1H), 3.98–3.90 (m, 1H), 3.56 (d, J =
6.3 Hz, 1H), 2.35 (s, 3H), 1.92 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 199.5, 198.6, 169.0, 135.5,
130.7, 130.4, 129.4, 115.3, 95.2, 65.1, 63.2, 52.6, 27.9, 26.0,
13.8. ESI-HRMS: calcd for C17H18ClNO7 + Na 406.0664,
found 406.0662; [α]2D0 = −152.1 (c 0.47, CHCl3), ee = 80%, dr
>99 : 1. The enantiomeric ratio was determined by HPLC on a
Chiralpak AS column (30% 2-propanol–hexane, 1 mL min−1),
tmajor = 9.66 min, tminor = 6.51 min.
(4R,5R)-5-Acetyl-3-((S)-2-ethoxy-1-hydroxy-2-oxoethyl)-5-
(ethoxycarbonyl)-4-phenyl-4,5-dihydroisoxazole 2-oxide (4bb).
1
Colorless oil; 31.8 mg, yield 84%; H NMR (400 MHz, CDCl3)
δ 7.32–7.26 (m, 5H), 5.40 (s, 1H), 4.90 (d, J = 5.8 Hz, 1H),
4.09–4.01 (m, 1H), 3.87–3.80 (m, 1H), 3.78–3.73 (m, 2H), 3.54
(d, J = 5.9 Hz, 1H), 2.37 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H), 0.79
(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 197.2,
169.3, 163.2, 132.6, 129.3, 129.2, 128.7, 115.1, 110.0, 89.7,
65.2, 63.1, 62.7, 52.0, 25.4, 13.8, 13.3. ESI-HRMS: calcd for
C18H21NO8 + Na 402.1159, found 402.1153; [α]2D0 = −122.9 (c
= 0.83, CHCl3), ee = 87%, dr = 97 : 3. The enantiomeric ratio
was determined by HPLC on a Chiralpak AS column (30%
t
major = 9.34 min, tminor = 6.91 min.
(R)-5,5-Diacetyl-3-((S)-2-ethoxy-1-hydroxy-2-oxoethyl)-4-phenyl-
4,5-dihydroisoxazole 2-oxide (4ba). Colorless oil; 27.2 mg, yield
78%; 1H NMR (400 MHz, CDCl3) δ 7.35–7.34 (m, 3H),
7.26–7.24 (m, 2H), 5.32 (s, 1H), 4.92 (s, 1H), 4.09–4.01 (m,
1H), 3.89–3.81 (m, 1H), 3.63 (s, 1H), 2.35 (s, 3H), 1.86 (s, 3H),
1.21 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 199.8,
198.6, 169.1, 132.2, 129.4, 129.2, 129.0, 115.7, 95.4, 65.2, 63.1,
53.2, 27.7, 26.0, 13.8. ESI-HRMS: calcd for C17H19NO7 + Na
372.1054, found 372.1061; [α]2D0 = −154.3 (c 0.47, CHCl3), ee
= 81%, dr > 99 : 1. The enantiomeric ratio was determined by
HPLC on a Chiralpak AS column (30% 2-propanol–hexane,
1 mL min−1), tmajor = 9.23 min, tminor = 6.71 min.
2-propanol–hexane, 1 mL min−1), tmajor = 9.08 min, tminor
=
6.45 min.
(4R,5R)-5-Acetyl-3-((S)-2-ethoxy-1-hydroxy-2-oxoethyl)-5-
(ethoxycarbonyl)-4-(p-tolyl)-4,5-dihydro isoxazole 2-oxide (4cb).
1
Colorless oil; 38.1 mg, yield 97%; H NMR (400 MHz, CDCl3)
(R)-5,5-Diacetyl-3-((S)-2-ethoxy-1-hydroxy-2-oxoethyl)-4-(p-tolyl)-
4,5-dihydroisoxazole 2-oxide (4ca). Colorless oil; 29.8 mg, yield
82%; 1H NMR (400 MHz, CDCl3) δ 7.15–7.09 (m, 4H), 5.27 (s,
1H), 4.89 (s, 1H), 4.09–4.01 (m, 1H), 3.90–3.82 (m, 1H), 3.66
(s, 1H), 2.33 (s, 3H), 2.31 (s, 3H), 1.86 (s, 3H), 1.20 (t, J =
7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 199.9, 198.8,
169.1, 139.4, 129.9, 128.9, 115.9, 95.4, 65.2, 63.0, 52.9, 27.8,
26.0, 21.1, 13.8. ESI-HRMS: calcd for C18H21NO7 + Na
386.1210, found 386.1210; [α]2D0 = −156.7 (c 0.60, CHCl3), ee
= 88%, dr > 99 : 1. The enantiomeric ratio was determined by
HPLC on a Chiralpak AS column (30% 2-propanol–hexane,
1 mL min−1), tmajor = 10.52 min, tminor = 7.24 min.
δ 7.16–7.10 (m, 4H), 5.37 (s, 1H), 4.87 (d, J = 6.1 Hz, 1H),
4.11–4.03 (m, 1H), 3.91–3.83 (m, 1H), 3.82–3.72 (m, 2H), 3.52
(d, J = 6.3 Hz, 1H), 2.36 (s, 3H), 2.31 (s, 3H), 1.23 (t, J =
7.2 Hz, 3H), 0.83 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 197.3, 169.3, 163.2, 139.2, 129.4, 129.2, 115.2, 89.7,
65.3, 63.0, 62.6, 51.8, 25.4, 21.1, 13.8, 13.3. ESI-HRMS: calcd
for C19H23NO8 + Na 416.1316, found 416.1313; [α]2D0 = −117.1
(c = 1.37, CHCl3), ee = 91%, dr = 96 : 4. The enantiomeric ratio
was determined by HPLC on a Chiralpak AS column (30%
2-propanol–hexane, 1 mL min−1), tmajor = 8.80 min, tminor
=
5.96 min.
(4R,5R)-5-Acetyl-3-((S)-2-ethoxy-1-hydroxy-2-oxoethyl)-5-
(ethoxycarbonyl)-4-(4-methoxyphenyl)-4,5-dihydroisoxazole 2-
oxide (4db). Colorless oil; 37.6 mg, yield 92%; 1H NMR
(400 MHz, CDCl3) δ 7.19 (d, J = 8.6 Hz, 2H), 6.83 (d, J =
8.6 Hz, 2H), 5.36 (s, 1H), 4.87 (d, J = 6.3 Hz, 1H), 4.11–4.05
(m, 1H), 3.95–3.86 (m, 1H), 3.83–3.76 (m, 5H), 3.54 (d, J =
6.4 Hz, 1H), 2.36 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H), 0.87 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 197.3, 169.3,
163.3, 160.2, 130.6, 124.2, 115.2, 114.1, 89.7, 65.2, 63.1, 62.7,
(R)-5,5-Diacetyl-3-((S)-2-ethoxy-1-hydroxy-2-oxoethyl)-
4-(4-methoxyphenyl)-4,5-dihydroisoxazole 2-oxide (4da). Color-
1
less oil; 32.6 mg, yield 86%; H NMR (400 MHz, CDCl3) δ
7.15 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.26 (s, 1H),
4.89 (s, 1H), 4.09–4.03 (m, 1H), 3.92–3.85 (m, 1H), 3.77 (s,
4H), 2.33 (s, 3H), 1.87 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 200.0, 198.8, 169.2, 160.2, 130.3,
123.6, 115.9, 114.5, 109.9, 95.4, 65.2, 63.1, 55.2, 52.7, 27.8,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8471–8477 | 8475

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55.3, 51.5, 25.4, 13.9, 13.4. ESI-HRMS: calcd for C19H23NO9 +
Na 432.1265, found 432.1258; [α]2D0 = −136.8 (c = 0.83,
CHCl3), ee = 92%, dr = 98 : 2. The enantiomeric ratio was deter-
mined by HPLC on a Chiralpak AS column (30% 2-propanol–
hexane, 1 mL min−1), tmajor = 13.74 min, tminor = 7.92 min.
62.9, 51.7, 25.3, 13.8, 13.3. ESI-HRMS: calcd for C19H20F3NO8
+ Na 470.1033, found 470.1024; [α]2D0 = −101.4 (c = 1.23,
CHCl3), ee = 81%, dr = 96 : 4. The enantiomeric ratio was deter-
mined by HPLC on a Chiralpak IC column (30% 2-propanol–
hexane, 1 mL min−1), tmajor = 19.12 min, tminor = 11.64 min.
(4R,5R)-5-Acetyl-4-(4-bromophenyl)-3-((S)-2-ethoxy-1-hydroxy-
(4S,5R)-5-Acetyl-3-((S)-2-ethoxy-1-hydroxy-2-oxoethyl)-5-
2-oxoethyl)-5-(ethoxycarbonyl)-4,5-dihydroisoxazole
2-oxide
(ethoxycarbonyl)-4-(furan-2-yl)-4,5-dihydroisoxazole
2-oxide
1
(4ib). Brown oil; 25.8 mg; yield 70%;1H NMR (400 MHz,
CDCl3) δ 7.36 (s, 1H), 6.39–6.35 (m, 2H), 5.63 (s, 1H), 4.96 (d,
J = 5.5 Hz, 1H), 4.23–4.15 (m, 1H), 4.11–4.05 (m, 1H),
4.03–3.98 (m, 2H), 3.45 (d, J = 5.8 Hz, 1H), 2.36 (s, 3H), 1.28
(t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 196.5, 169.4, 163.3, 145.6, 143.5, 112.3,
111.4, 111.2, 77.3, 77.0, 76.7, 65.3, 63.3, 63.0, 45.7, 25.3, 13.9,
13.7. ESI-HRMS: calcd for C16H19NO9 + Na 392.0952, found
392.0950; [α]2D0 = −66.0 (c = 0.67, CHCl3), ee = 81%, dr =
94 : 6. The enantiomeric ratio was determined by HPLC on a
Chiralpak IC column (30% 2-propanol–hexane, 1 mL min−1),
(4eb). Colorless oil; 38.8 mg, yield 85%; H NMR (400 MHz,
CDCl3) δ 7.47 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H),
5.38 (s, 1H), 4.87 (d, J = 5.8 Hz, 1H), 4.15–4.04 (m, 1H),
3.95–3.87 (m, 1H), 3.85–3.79 (m, 2H), 3.54 (d, J = 6.0 Hz, 1H),
2.37 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 197.0, 169.2, 163.0, 131.9,
131.7, 131.0, 123.5, 114.5, 89.4, 65.2, 63.2, 62.9, 51.5, 25.3,
13.9, 13.4. ESI-HRMS: calcd for C18H20BrNO8 + Na 480.0265,
found 480.0261; [α]2D0 = −109.0 (c = 1.00, CHCl3), ee = 84%,
dr = 97 : 3. The enantiomeric ratio was determined by HPLC on
a Chiralpak IC column (30% 2-propanol–hexane, 1 mL min−1),
tmajor = 14.00 min, tminor = 9.38 min.
tmajor = 19.68 min, tminor = 14.15 min.
(4R,5R)-5-Acetyl-3-((S)-2-ethoxy-1-hydroxy-2-oxoethyl)-5-
(4R,5R)-5-Acetyl-5-(ethoxycarbonyl)-3-(hydroxymethyl)-4-phenyl-
(ethoxycarbonyl)-4-(4-fluorophenyl)-4,5-dihydroisoxazole 2-
oxide (4fb). Gray oil; 31.8 mg, yield 80%; 1H NMR (400 MHz,
CDCl3) δ 7.30–7.27 (m, 2H), 7.05–7.01 (m, 2H), 5.42 (s, 1H),
4.88 (d, J = 6.0 Hz, 1H), 4.13–4.08 (m, 1H), 3.94–3.90 (m, 1H),
3.85–3.78 (m, 2H), 3.53 (d, J = 6.1 Hz, 1H), 2.38 (s, 3H), 1.24
(t, J = 7.0 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 197.1, 169.2, 163.1, 131.3, 131.2, 128.1,
128.4, 115.9, 115.7, 114.8, 110.0, 89.5, 65.2, 63.2, 62.8, 51.4,
25.4, 13.9, 13.4. ESI-HRMS: calcd for C18H20FNO8 + Na
420.1065, found 420.1063; [α]2D0 = −115.9 (c = 0.73, CHCl3), ee
= 86%, dr > 99 : 1. The enantiomeric ratio was determined by
HPLC on a Chiralpak IC column (30% 2-propanol–hexane,
1 mL min−1), tmajor = 13.73 min, tminor = 9.05 min.
4,5-dihydroisoxazole 2-oxide (4jb). Colorless oil; 16.8 mg, yield
55%; 1H NMR (400 MHz, CDCl3) δ 7.38–7.32 (m, 3H),
7.29–7.24 (m, 2H), 5.46 (s, 1H), 4.42–4.35 (m, 1H), 4.24–4.19
(m, 1H), 3.76–3.21 (m, 2H), 2.44 (t, J = 7.0 Hz, 1H), 2.37 (s,
3H), 0.83 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
197.3, 163.7, 132.8, 129.2, 129.2, 129.0, 116.6, 89.1, 62.7, 55.8,
52.9, 25.6, 13.4. ESI-HRMS: calcd for C15H17NO6 + Na
330.0948, found 330.0950; [α]2D0 = −37.5 (c = 0.27, CHCl3), ee
= 58%, dr = 97 : 3. The enantiomeric ratio was determined by
HPLC on a Chiralpak IC column (20% 2-propanol–hexane,
1 mL min−1), tmajor = 19.30 min, tminor = 18.24 min.
(R)-5,5-Diacetyl-3-((S)-1-((tert-butyldimethylsilyl)oxy)-2-ethoxy-
2-oxoethyl)-4-phenyl-4,5-dihydroisoxazole 2-oxide (5). White
(4R,5R)-5-Acetyl-4-(2-chlorophenyl)-3-((S)-2-ethoxy-1-hydroxy-
1
solid; mp 43–44 °C; 162.9 mg, yield 88%; H NMR (400 MHz,
2-oxoethyl)-5-(ethoxycarbonyl)-4,5-dihydroisoxazole
2-oxide
(4gb). White solid; mp 81–84 °C; 32.6 mg, yield 79%; 1H
NMR (400 MHz, CDCl3) δ 7.42–7.37 (m, 1H), 7.36–7.34 (m,
1H), 7.30–7.22 (m, 2H), 6.16 (s, 1H), 4.89 (d, J = 6.4 Hz, 1H),
4.10–4.02 (m, 1H), 3.87–3.78 (m, 3H), 3.52 (d, J = 6.5 Hz, 1H),
2.39 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 196.3, 169.1, 162.8, 134.9,
130.9, 130.4, 130.2, 130.0, 127.0, 115.1, 89.4, 65.2, 63.1, 62.8,
47.6, 25.1, 13.8, 13.3. ESI-HRMS: calcd For C18H20ClNO8 +
Na 436.0770, found 436.0781; [α]2D0 = −120.0 (c = 0.73,
CHCl3), ee = 90%, dr = 95 : 5. The enantiomeric ratio was deter-
mined by HPLC on a Chiralpak IC column (30% 2-propanol–
hexane, 1 mL min−1), tmajor = 16.97 min, tminor = 14.93 min.
CDCl3) δ 7.28–7.22 (m, 3H), 7.19–7.17 (m, 2H), 5.18 (s, 1H),
5.05 (s, 1H), 3.73–3.65 (m, 1H), 3.53–3.45 (m, 1H), 2.30 (s,
3H), 1.81 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H), 0.84 (s, 9H), 0.01 (s,
3H), −0.01 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 200.2,
198.2, 167.4, 132.5, 129.1, 129.0, 128.9, 116.7, 96.0, 66.8, 61.6,
52.8, 27.8, 26.0, 25.4, 18.1, 13.7, −5.3, −5.4. ESI-HRMS: calcd
for C23H33NO7Si + Na 486.1919, found 486.1928; [α]D20
=
−86.9 (c = 2.63, CHCl3), ee = 75%, dr > 99 : 1. The enantio-
meric ratio was determined by HPLC on a Chiralpak IC column
(8% 2-propanol–hexane, 1 mL min−1), tmajor = 7.71 min, tminor
=
6.55 min.
(2S,4R,Z)-Ethyl 5-acetyl-2-((tert-butyldimethylsilyl)oxy)-5-
hydroxy-3-(hydroxyimino)-6-oxo-4-phenylheptanoate (6). Color-
(4R,5R)-5-Acetyl-3-((S)-2-ethoxy-1-hydroxy-2-oxoethyl)-5-
(ethoxycarbonyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydroisox-
1
less oil; 46.5 mg, yield 100%; H NMR (400 MHz, CDCl3) δ
1
azole 2-oxide (4hb). Yellow oil; 37.5 mg, yield 84%; H NMR
7.29–7.19 (m, 5H), 5.48 (s, 1H), 4.89 (s, 1H), 4.50 (s, 1H), 3.88
(d, J = 6.3 Hz, 2H), 2.19 (s, 3H), 1.80 (s, 3H), 1.14 (t, J =
6.9 Hz, 3H), 0.85 (s, 9H), 0.07 (s, 3H), 0.03 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 168.2, 132.5, 130.9, 127.9, 66.9, 61.5,
50.8, 27.0, 25.5, 21.2, 18.1, 13.8, −5.1, −5.3. ESI-HRMS: calcd
for C23H35NO7Si + Na 488.2075, found 488.2090; [α]2D0 = −77
(c = 1.00, CHCl3), ee = 77%, dr > 99 : 1. The enantiomeric ratio
(400 MHz, CDCl3) δ 7.60 (d, J = 8.1 Hz, 2H), 7.45 (d, J =
8.1 Hz, 2H), 5.48 (s, 1H), 4.88 (d, J = 5.6 Hz, 1H), 4.11–4.03
(m, 1H), 3.91–3.84 (m, 1H), 3.84–3.76 (m, 2H), 3.55 (d, J =
5.8 Hz, 1H), 2.39 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H), 0.80 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 197.0, 169.1,
162.9, 136.9, 129.8, 125.7, 125.6, 114.4, 109.9, 89.4, 65.2, 63.2,
8476 | Org. Biomol. Chem., 2012, 10, 8471–8477
This journal is © The Royal Society of Chemistry 2012

View Article Online
2 (a) V. Jäger and W. Schwab, Tetrahedron Lett., 1978, 19, 3133;
(b) E. P. Schreiner and H. Gstach, Synlett, 1996, 1131; (c) S. P. Ashburn
and R. M. Coater, J. Org. Chem., 1984, 49, 3127; (d) J. R. Manning and
H. M. L. Davies, J. Am. Chem. Soc., 2008, 130, 8602; (e) R. Annunziata,
M. Cinquini, F. Cozzi and L. Raimondi, Tetrahedron, 1986, 42, 2129.
3 B. M. Trost, L. Li and S. D. Guile, J. Am. Chem. Soc., 1992, 114, 8745.
4 (a) M. R. Barbachyn, G. J. Cleek, L. A. Dolak, S. A. Garmon, J. Morris,
E. P. Seest, R. C. Thomas, D. S. Toops, W. Watt, D. G. Wishka,
C. W. Ford, G. E. Zurenko, J. C. Hamel, R. D. Schaadt, D. Stapert,
B. H. Yagi, W. J. Adams, J. M. Friis, J. G. Slatter, J. P. Sams, N. L. Oien,
M. J. Zaya, L. C. Wienkers and M. A. Wynalda, J. Med. Chem., 2003,
46, 284; (b) D. Simoni, G. Grisolia, G. Giannini, M. Roberti,
R. Rondanin, L. Piccagli, R. Baruchello, M. Rossi, R. Romagnoli,
F. P. Invidiata, S. Grimaudo, M. K. Jung, E. Hamel, N. Gebbia, L. Crosta,
V. Abbadessa, D. A. Cristina, L. Dusonchet, M. Meli and M. Tolomeo,
J. Med. Chem., 2005, 48, 723.
was determined by HPLC on a Chiralpak AD column (5% 2-pro-
panol–hexane, 1 mL min−1), tmajor = 7.30 min, tminor = 7.97 min.
(2R)-Ethyl 2-((tert-butyldimethylsilyl)oxy)-2-((4S)-5,5-diacetyl-
3-((methylsulfonyl)oxy)-4-phenylisoxazolidin-3-yl)acetate
(8).
White solid; mp 104–106 °C; 36.4 mg, yield 67%; 1H NMR
(400 MHz, CDCl3) δ 7.31–7.20 (m, 5H), 5.45 (s, 1H), 5.36 (s,
1H), 4.78 (s, 1H), 3.66–3.49 (m, 2H), 3.20 (s, 3H), 2.34 (s, 3H),
1.99 (s, 3H), 1.04 (t, J = 7.1 Hz, 3H), 1.00 (s, 9H), 0.12 (s, 3H),
0.09 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 206.0, 205.3,
167.0, 164.4, 131.6, 130.5, 128.7, 127.9, 92.0, 66.8, 61.6, 50.0,
36.8, 25.6, 25.4, 25.3, 18.2, 13.6, −4.9, −5.5. ESI-HRMS: calcd
for C24H37NO9SSi + H 544.2031, found 544.2051; [α]D20
=
5 (a) M. Clagett, A. Gooch, P. Graham, N. Holy, B. Mains and J. Strunk,
J. Org. Chem., 1976, 41, 4033; (b) T. Sakakibara and R. J. Sudoh,
J. Chem. Soc., Chem. Commun., 1977, 7; (c) G. Rosini, R. Galarini,
E. Marotta and P. Righi, J. Org. Chem., 1990, 55, 781; (d) G. Kumaran
and G. H. Kulkarni, Synthesis, 1995, 1545; (e) E. Marotta,
L. M. Micheloni, N. Scardovi and P. Righi, Org. Lett., 2001, 3, 727;
(f) P. Righi, N. Scardovi, E. Marotta, P. Holte and B. Zwanenburg, Org.
Lett., 2002, 4, 497; (g) N. Scardovi, A. Casalini, F. Peri and P. Righi,
Org. Lett., 2002, 4, 965; (h) R. A. Kunetsky, A. D. Dilman, S. L. Loffe,
M. I. Struchkova, Y. A. Strelenko and V. A. Tartakovsky, Org. Lett.,
2003, 5, 4907; (i) M. A. Marsini, Y. Huang, R. W. Van De Water and
T. R. R. Pettus, Org. Lett., 2007, 9, 3229; ( j) D. Duan, X. Sun, W. Liao,
J. L. Petersen and X. Shi, Org. Lett., 2008, 10, 4113; (k) A. V. Chemagin,
N. V. Yashin, Y. K. Grishin, T. S. Kuznetsova and N. S. Zefirov, Syn-
thesis, 2010, 259; (l) Q. Zhang, J. Sun, F. Zhang and B. Yu, Eur. J. Org.
Chem., 2010, 3579.
6 (a) E. Marotta, M. Baravelli, L. Maini, P. Righi and G. Rosini, J. Org.
Chem., 1998, 63, 8235; (b) P. M. Khan, R. Wu and K. S. Bisht, Tetra-
hedron, 2007, 63, 1116.
7 (a) M. C. Maestro, M. C. Barquilla and M. R. Martín, Tetrahedron:
Asymmetry, 1999, 10, 3593; (b) C. Y. Zhu, X. M. Deng, X. L. Sun,
J. C. Zheng and Y. Tang, Chem. Commun., 2008, 738; (c) C. Y. Zhu,
X. M. Sun, X. M. Deng, J. C. Zheng and Y. Tang, Tetrahedron, 2008, 64,
5583; (d) C. Zhong, L. N. S. Gautam, J. L. Petersen, N. G. Akhmedov
and X. Shi, Chem.–Eur. J., 2010, 16, 8605.
−38.4 (c = 1.07, CHCl3), ee = 77%, dr > 99 : 1. The enantio-
meric ratio was determined by HPLC on a Chiralpak IC column
(3% 2-propanol–hexane, 1 mL min−1), tmajor = 13.39 min, tminor
= 17.23 min.
(4S,5R)-4-(2-Chlorophenyl)-3-((S)-2-ethoxy-1-hydroxy-2-
oxoethyl)-5-(ethoxycarbonyl)-5-((R)-1-hydroxyethyl)-4,5-dihydro-
isoxazole 2-oxide (9). Colorless oil; 76.4 mg, yield 92%; 1H
NMR (400 MHz, CDCl3) δ 7.41–7.38 (m, 1H), 7.33–7.20 (m,
3H), 5.38 (s, 1H), 4.93 (d, J = 5.9 Hz, 1H), 4.28–4.23 (m, 1H),
4.12–3.71 (m, 4H), 3.67–3.57 (m, 1H), 2.59 (d, J = 10.7 Hz,
1H), 1.44 (d, J = 6.5 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 0.91 (t, J
= 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 169.4, 166.5,
134.6, 131.8, 130.3, 129.9, 126.9, 115.1, 89.2, 71.0, 65.1, 63.1,
62.1, 49.0, 16.9, 13.9, 13.5. ESI-HRMS: calcd for C18H22ClNO8
+ Na 438.0926, found 438.0940; [α]2D0 = −26.7 (c = 0.30,
CHCl3), ee = 86%, dr = 69 : 31. The enantiomeric ratio was
determined by HPLC on a Chiralpak AD column (20% 2-propa-
nol–hexane, 1 mL min−1), tmajor = 10.22 min, tminor = 23.95 min.
8 (a) H. Jiang, P. Elsner, K. L. Jensen, A. Falcicchio, V. Marcos and
K. A. Jorgensen, Angew. Chem., Int. Ed., 2009, 48, 6844; (b) Z. G. Shi,
B. Tan, W. W. Y. Leong, X. F. Zeng, M. Lu and G. F. Zhong, Org. Lett.,
2010, 12, 5402; (c) T. Kano, A. Yamamoto, S. Song and K. Maruoka,
Chem. Commun., 2011, 47, 4358; (d) T. Kano, A. Yamamoto, S. Song
and K. Maruoka, Bull. Chem. Soc. Jpn., 2011, 84, 1057.
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (20902083), the Natural
Science Foundation of Zhejiang Province, China (R4080084),
and the Program for Changjiang Scholars and Innovative
Research Team in Chinese Universities (IRT0980).
9 Q. B. Li, F. T. Zhou, Z. G. Liu, X. F. Li, W. D. Zhu and J. W. Xie, J. Org.
Chem., 2011, 76, 7222.
10 Recent general reviews: (a) Y. Sohtome and K. Nagasawa, Synlett, 2010,
1; (b) L. W. Xu, J. Luo and Y. X. Lu, Chem. Commun., 2009, 1807;
(c) D. W. C. MacMillan, Nature, 2008, 455, 304; (d) J. T. Mohr,
M. R. Krout and B. M. Stoltz, Nature, 2008, 455, 323; (e) S. Mukherjee,
J. W. Yang, S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471;
(f) C. Chandler, P. Galzerano, A. Michrowska and B. List, Angew.
Chem., 2009, 121, 2012, (Angew. Chem., Int. Ed., 2009, 48, 1978);
(g) L. Albrecht, B. Richter, C. Vila, H. Krawczyk and K. A. Jørgensen,
Chem.–Eur. J., 2009, 15, 3093.
11 I. Deb, M. Dadwal, S. M. Mobin and I. N. N. Namboothiri, Org. Lett.,
2006, 8, 1201.
12 D. D. Perrin, W. L. F. Armarego, D. R. Perrin, Purification of Laboratory
Chemicals, Pergamon, New York, 1985.
Notes and references
1 (a) P. Righi, E. Marotta, A. Landuzzi and G. Rosini, J. Am. Chem. Soc.,
1996, 118, 9446; (b) M. Frederickson, Tetrahedron, 1997, 53, 403;
(c) B. M. Trost, L. S. Chupak and T. Lubbers, J. Am. Chem. Soc., 1998,
120, 1732; (d) F. Damkaci and P. Deshong, J. Am. Chem. Soc., 2003,
125, 4408; (e) A. R. Minter, A. A. Fuller and A. K. Mapp, J. Am. Chem.
Soc., 2003, 125, 6846; (f) A. A. Fuller, B. Chen, A. R. Minter and
A. K. Mapp, J. Am. Chem. Soc., 2005, 127, 5376.
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