Synthesis of isoxazoline N-oxides and its application in the formal synthesis of dehydroclausenamide

Article abstract of DOI:10.1016/j.tet.2008.03.075

A protocol for the synthesis of isoxazoline N-oxides and its application in the formal synthesis of dehydroclausenamide are described. Sulfonium salt 1 reacts with substituted nitroalkenes smoothly to generate isoxazoline N-oxides in high to excellent yields with dr higher than 99/1. Its asymmetric version has been developed by using cinchona alkaloid-derived ammonium salts 6a and 6b instead of sulfonium salt 1 and higher than 96% ee values are achieved. This method has also been successfully applied to the formal synthesis of dehydroclausenamide.

Full text of DOI:10.1016/j.tet.2008.03.075

Tetrahedron 64 (2008) 5583–5589
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of isoxazoline N-oxides and its application
in the formal synthesis of dehydroclausenamide
*
Chun-Yin Zhu, Xiu-Li Sun, Xian-Ming Deng, Jun-Cheng Zheng, Yong Tang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A protocol for the synthesis of isoxazoline N-oxides and its application in the formal synthesis of
dehydroclausenamide are described. Sulfonium salt 1 reacts with substituted nitroalkenes smoothly to
generate isoxazoline N-oxides in high to excellent yields with dr higher than 99/1. Its asymmetric version
has been developed by using cinchona alkaloid-derived ammonium salts 6a and 6b instead of sulfonium
salt 1 and higher than 96% ee values are achieved. This method has also been successfully applied to the
formal synthesis of dehydroclausenamide.
Received 27 February 2008
Received in revised form 21 March 2008
Accepted 21 March 2008
Available online 28 March 2008
Ó 2008 Elsevier Ltd. All rights reserved.
O
1. Introduction
EtO2C
Ph
O
N
Isoxazoline N-oxides and their derivatives are frequently used as
intermediates in the synthesis of complex molecules1 and are
found in several biologically active compounds.2 Although many
synthetic methods have been developed,3 practical protocols for
the enantioselective construction of isoxazoline N-oxides are very
limited. The development of asymmetric synthesis of isoxazoline
N-oxides with high diastereoselectivity and enantioselectivity
remains a challengeable task.
CO2Bn
CO2Bn
NO2
Br
CO2Et
3a
Cs2CO3
S
Ph
1
2a
O2N CO2Bn
Ph CO2Et
Scheme 1. Reaction of sulfonium salt 1 with nitroalkenes 2a.
In 1976, Holy reported that dimethylsulfoxonium methylide
could react with nitroolefin to afford isoxazoline N-oxides in the
presence of copper(I).3a Since this pioneering work, there have
been several other studies on this reaction3 but the product dis-
tribution (cyclopropane/isoxazoline N-oxide) was dependent on
ylide and nitroolefins. As our on-going research project on ylide
reaction4 and its applications in organic synthesis, we found very
recently that dimethylsulfonium salt 1 reacted with (Z)-benzyl
2-nitro-3-phenylacrylates 2 in the presence of K2CO3 leading to
isoxazoline N-oxides 3 in high to excellent yields and no cyclo-
propane derivatives were observed in the reaction (Scheme 1). We
communicated that, by using cinchonidine (cinchonine)-derived
ammonium salts instead of the sulfonium salt, nitroolefins could be
converted into optically active isoxazoline N-oxides with excellent
ees and high drs.5 This method has also been successfully applied to
the formal synthesis of dehydroclausenamide. In this paper, we
wish to report the results in details.
2. Results and discussion
2.1. Preparation of isoxazoline N-oxides through
sulfonium ylide
Initially, it was found that dimethylsulfonium salt 1, after
deprotonation by Cs2CO3, reacted with (Z)-benzyl 2-nitro-3-phe-
nylacrylate 2a, affording isoxazoline N-oxide 3a in 80% yield.
Further studies showed that bases influenced strongly the yields. As
shown in Table 1, K2CO3 gave the highest yield (91%), however, only
52% yield was obtained when KOtBu was employed as a base (entry
2, Table 1). In all the cases examined, the reaction proceeded well to
give isoxazoline N-oxides exclusively with excellent diaste-
reoselectivities in CH3CN in the presence of both inorganic bases
(Cs2CO3, K2CO3, KOH, and KOtBu) and organic base (iPr2NH). No
cyclopropane derivatives were detected.
Under the optimal conditions, we investigated the generality of
the current reaction by evaluating with various nitroalkenes. As
shown in Table 2, b-aryl, b-heteroaryl, and b-alkyl nitroalkenes
were good substrates for this reaction to afford the desired
* Corresponding author. Tel.: þ86 21 54925156; fax: þ86 21 54925078.
E-mail address: tangy@mail.sioc.ac.cn (Y. Tang).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.075

5584
C.-Y. Zhu et al. / Tetrahedron 64 (2008) 5583–5589
Table 1
Effects of bases on the cyclizationa
O
O
EtO2C
O
EtO2C
O
CO2Bn
NO2
N
N
Br
CO2Et
CH3CN, base
- 20 °C
S
Ph
Ph
CO2Bn
Ph
CO2Bn
rac-3'a
rac-3a
2a
1
Entry
Base
Yieldb (rac-3a, %)
rac-3a/rac-30ac
1
2
3
4
5
Cs2CO3
K2CO3
KOH
80
91
85
89
52
>99/1
>99/1
>99/1
>99/1
34/1
iPr2NH
KOtBu
a
Conditions: 2a (57 mg, 0.2 mmol), base (0.3 mmol), and 1 (50 mg, 0.22 mmol) in CH3CN (0.08 mol/L).
b
c
Isolated yield.
Determined by 1H NMR.
products with excellent diastereoselectivities (>99/1) in high
of the successful application of camphor-derived sulfonium ylides
in enantioselective ylide reactions,6,7 sulfonium salt 5 (Scheme 2)
was first chosen for this purpose. As shown in Table 3, un-
fortunately, the reactions of salt 5 with nitroolefin 2a only gave
isoxazoline N-oxide 3a with low ees and moderate des (entries 1–4)
although the yields were quite good. Further studies showed that
base influenced strongly the diastereoselectivities but did not
improve the enantioselectivities (Table 3).
Gaunt and co-workers reported that cinchonidine (cinchonine)-
derived ammonium salt 6a was a good reagent for the synthesis of
optical cyclopropane derivatives with high enantioselectivities.8
Thus, we tried the asymmetric cyclization reaction by employing
ammonium salt 6a instead of sulfonium salt 5. We are pleased to
find that nitroalkenes could be converted smoothly into the cor-
responding optically active isoxazoline N-oxides with excellent des
and ees when ammonium ylides derived from 6a or 6b was used. As
summarized in Table 4, various 3-aryl-2-nitro-a,b-unsaturated
esters prove to be good substrates for this cyclization. The O-sub-
stituent of the ester group influenced slightly the enantioselection
(entries 1 and 2). Both 3-aryl and 3-heteroaryl-2-nitro acrylates
worked smoothly, affording trans-isoxazoline N-oxides as single
diastereomers. The enantiomeric excesses are nearly independent
yields, providing an easy access to isoxazoline N-oxides. The
O-substituent of ester groups influenced the yields slightly. For
example, 2a and 2b gave the desired products in 91% and 99%
yields, respectively (entries 1 and 2). Both the electronic and the
steric properties of the aryl groups in nitroalkenes did not change
the diastereoselectivities at all (entries 1–8). b-Alkyl nitroalkenes
were also suitable substrates for this reaction with only a slight
decrease in the yield. For all substrates evaluated, only the trans-
isomers were obtained. Moreover, no cyclopropane derivatives
were observed.
The products isoxazoline N-oxides were characterized by 1H
NMR, 13C NMR, elemental analysis, and mass spectroscopic tech-
niques. Product 3a was further confirmed by X-ray analysis (Fig. 1).
The relative configuration of 3a was determined by 1H NMR as well
as X-ray analysis, in which the phenyl group and the ethyl ester are
located in trans-configuration.
2.2. Asymmetric synthesis of isoxazoline N-oxides
Encouraged by the aforementioned results, we are interested in
developing its asymmetric version of the present reaction. In view
Table 2
Reaction of salt 1 with nitroalkenes 2a
O
O
CO2R2
EtO2C
O
EtO2C
O
N
K2CO3
N
Br
CO2Et
S
MeCN, -20 °C
R1
NO2
R1
CO2R2
R1
CO2R2
rac-3'
rac-3
1
2
c
Entry
R1
R2
Yieldb (%)
rac-3/rac-30
1
2
3
4
5
6
7
Ph
Ph
Bn (2a)
Me (2b)
Me (2c)
Bn (2d)
Bn (2e)
Me (2f)
Me (2g)
91
99
88
99
94
92
98
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
o-MeOC6H4
p-MeOC6H4
p-MeC6H4
p-FC6H4
p-BrC6H4
8
9
Bn (2h)
Me (2i)
93
87
>99/1
>99/1
O
S
10
Me (2j)
Me (2k)
85
79
>99/1
>99/1
11
i-C3H7
a
Conditions: 2 (0.2 mmol), K2CO3 (42 mg, 0.3 mmol), and 1 (50 mg, 0.22 mmol) in CH3CN (0.08 mol/L).
b
c
Isolated yield of rac-3.
Determined by 1H NMR.

C.-Y. Zhu et al. / Tetrahedron 64 (2008) 5583–5589
5585
Table 3
Reaction of salt 5 with nitroalkenes 2a
O
O
EtO2C
O
EtO2C
O
CO2Bn
NO2
N
N
CH3CN, base
- 20 °C
5
Ph
Ph
CO2Bn
Ph
CO2Bn
3a
3'a
2a
Entry
Base
3a/30ab
Yieldc (%)
eed (%)
1e
2f
Cs2CO3
9/1
12/1
4/1
8/1
89
88
92
93
26
27
39
33
Cs2CO3
K2CO3
DBU
3e
4e
O
EtO2C
Ph
O
N
a
Conditions: 2a (57 mg, 0.2 mmol), base (0.22 mmol), and 5 (80 mg, 0.22 mmol)
CO2Bn
in CH3CN (0.08 mol/L).
b
Isolated total yield of 3a and 30a.
c
Determined by 1H NMR.
d
Determined by chiral HPLC for trans-isomer.
dr of 5 was 8.7/1.
dr of 5 was 12.4/1.
e
f
mechanism, we tried to develop single crystal of ylide derived from
6a but failed. X-ray analysis of salt 6a showed that quinolinyl group
shields one face of the ester group as well as the pre-ylidic carbon
Table 4
Reaction of ammonium salts 6 with nitroalkenes 2a
O
O
CO2R2
NO2
Figure 1. X-ray crystal structure of compound 3a.
EtO2C
O
EtO2C
O
N
N
Cs2CO3
THF, 0 °C
6
R1
R1
CO2R2
R1
CO2R2
on the substituents of the aryl and heteroaryl groups. In all cases
examined, trans-isomers of the desired products were obtained
with higher than 96% ee in good yields (entries 1–11), providing an
easy access to optically active isoxazoline N-oxides. Although both
the yield and diastereoselectivity decreased, aliphatic nitroalkene
2k was suitable for this cyclization and gave the desired product
with 99% ee (entry 12). Noticeably, the same cyclization underwent
smoothly using cinchonine-derived salt 6b instead of 6a, affording
the desired product in 99% ee with opposite configuration (entries
2 and 3). Thus, both enantiomers could be obtained easily just by
a simple choice of the ammonium salts. When salts 6c and 6d were
used, both the desired isoxazoline N-oxide and cyclopropanes were
not observed (entries 13–14).
Under basic conditions, the reactions of salts 6a and 6b with 2-
nitro-a,b-unsaturated esters afford trans-isoxazoline N-oxides
predominantly with excellent ees and diastereoselectivities. Gen-
erally, the selectivities of ylide cyclization depend on the degree of
the reversibility and the stereochemical course of the Michael ad-
dition reaction. Nitrogen ylide is regarded to be more active than
the corresponding sulfur ylide.9 Aggarwal and co-workers have
demonstrated that amine is a poorer leaving group than dimethyl
sulfide since C–N bond is stronger than C–S bond10 in a number of
elegant studies on ylide epoxidation.7c,e,11 Based on these mecha-
nism insights, together with the highly electron-deficient nature of
the substrate, it is envisaged that the intramolecular substitution
might be the rate-determining step (Scheme 3). Since the in-
termediate A is more stable than B due to steric effects, trans-
isomer is formed predominantly. To further understand the
2
3
3'
Entry
R1
R2
6
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Bn (2a)
Me (2b)
Me (2b)
Me (2c)
Bn (2d)
Bn (2e)
Me (2f)
Me (2g)
6a
6a
6b
6a
6a
6a
6a
6a
65
62
69
54
75e
77
79
74
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99
97
ꢀ99
o-MeOC6H4
p-MeOC6H4
p-MeC6H4
p-FC6H4
99
99
97
99
98
p-BrC6H4
9
Bn (2h)
Me (2i)
6a
6a
67
79
>99/1
>99/1
>99
>99
O
S
10
11
Me (2j)
6a
68
>99/1
96
12
13
14
i-C3H7
p-MeC6H4
p-MeC6H4
Me (2k)
Me (2l)
Me (2l)
6a
6c
6d
30f
0
80/20
d
99
d
0
d
d
a
Conditions: 2 (0.2 mmol), Cs2CO3 (72 mg, 0.22 mmol), 6 (0.22 mmol) in THF
(0.08 mol/L); and H2O (10 mL).
b
Isolated yield.
Determined by 1H NMR.
c
d
Determined by chiral HPLC for trans-isomer.
Cinchonidine-derived amine was recovered at the yield of 59%.
e
f
Total yield of 3k and 3k0.
N
MeO
N
MeO
H
H
S
S
EWG
Br
CO2Et
CO2Et
Br
OH
OH
Br
N
N
5
4
6a: EWG = CO2Et
6c: EWG = CONEt2
6d: EWG = CN
6b
Scheme 2. Precursors of chiral ylides in the asymmetric reactions with nitroalkenes.

5586
C.-Y. Zhu et al. / Tetrahedron 64 (2008) 5583–5589
H
group and the bicyclic ring, which forms stable intermediate A and
lead to (R,R)-isoxazoline N-oxides12 as the major products, which
are consistent with the observed result. A clear mechanistic
understanding waits for further investigation.
N+
H
Br-
CO2Et
MeO
2.3. Formal synthesis of dehydroclausenamide
6a
N
Dehydroclausenamide 1113
a potentially hepatoprotective
Cs2CO3
2
amide,14 was isolated from dry leaves of Chinese folk medicine
Clausena lansium. It was found that product ent-3b could be
employed for the formal synthesis of this compound. As shown in
Scheme 4, by exposure to trimethylphosphite, ent-3b was de-
oxygenated to isoxazoline 7 in 90% yield.15 The isoxazoline was
treated with Raney Ni under H2 atmosphere to form lactam 8.16
Methylation of the lactam, followed by reaction with PhLi17 gave
phenylketone 10, which could be easily transformed into dehy-
droclausenamide 11 in two steps according to literature.13b Com-
pound 10 was fully characterized by 1H, 13C NMR, and further
confirmed by an X-ray crystallographic analysis (Fig. 3).18 The
rotation [a]2D0 (c 0.97, CHCl3) of compound 10 was ꢀ116.5ꢁ, slightly
higher than that reported in literature [ꢀ111.7 (c 1.00, CHCl3)],13c
suggesting that there is almost no loss of optical purity in the
aforementioned transformations (Scheme 4). Thus, the enantiose-
lective total synthesis of dehydroclausenamide 11 could be finished
in seven steps using nitroolefin 2b as a starting material.
N+
N+
H
R
R
H
CO2Et
H
EtO2C
BnO2C
H
N
O
O-
N
O-
O-
BnO2C
O
B
A
slow
fast
O
O-
O
EtO2C
EtO2C
N+
CO2Bn
N+
R
R
CO2Bn
3'
3
Scheme 3. A proposed mechanism.
(Fig. 2). We assumed that the conformation of the corresponding
ylide in solution is similar to that of salt 6a and so a possible
stereochemical model was proposed to explain the enantiose-
lectivity. As shown in Figure 2, the nitroolefin can only approach to
the si-face of the ylide due to the steric hindrance by the quinolinyl
3. Conclusions
We have developed a highly efficient ylide cyclization for the
synthesis of optically active isoxazoline N-oxides by the reaction of
si-face
Figure 2. Molecular structures of salt 6a and a possible stereochemical model.
H
N
O
O
EtO2C
O
EtO2C
O
CO2Me
Ph
N
N
t
H2, rt
Raney Ni
53%
(1) KOBu , DME, rt
P(OMe)3
96%
(2) MeI 69%
Ph
CO2Me
Ph
CO2Me
HO
7
8
ent-3b
Ph
Me
N
Me
N
lit.13b
n
PhLi ( PhI + BuLi )
R
O
O
COPh
O
CO2Me
Ph
O
Ph
THF, -78 °C
66%
S
Ph
N
S
HO
HO
Me
)
10
11
Dehydroclausenamide
9
[α]D20 = -116.5 ( c = 1.00, CHCl3
lit.: [α]D20 = -111.7 ( c = 0.97, CHCl3
)
Scheme 4. Formal synthesis of dehydroclausenamide 11.

C.-Y. Zhu et al. / Tetrahedron 64 (2008) 5583–5589
5587
Compound 3a (solid): 46 h, 65% yield, dr >99/1. HPLC analysis
(Chiralcel OD-H, 30/70 iPrOH/hexanes, 0.8 mL/min, 238 nm; tR
(major)¼12.75 min, tR (minor)¼20.94 min) gave the isomeric
composition of the product: 99% ee. [a]2D0 ꢀ171.8 (c 1.11, CHCl3). Mp
82–85 ꢁC. IR (film) n/cmꢀ1 3064 (m), 3033 (m), 2983 (m), 1743 (s),
1708 (s), 1635 (s), 1207 (m), 1148 (m), 750 (s), 699 (s). 1H NMR
(300 MHz, CDCl3/TMS) d 7.36–7.38 (m, 3H), 7.25–7.30 (m, 5H), 7.04–
7.08 (m, 2H), 5.20 (ABd, J¼12.3 Hz, 1H), 5.06 (ABd, J¼12.3 Hz, 1H),
4.92 (d, J¼3.0 Hz, 1H), 4.85 (d, J¼3.0 Hz, 1H), 4.31 (q, J¼7.2 Hz, 2H),
1.32 (t, J¼7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 168.0, 157.8, 137.8,
134.5, 129.3, 128.7, 128.4, 128.3, 127.9, 127.0, 108.8, 78.7, 67.2, 62.6,
52.5, 14.0. MS (ESI, m/z) 424.1 (MþMeOHþNaþ), 392.0 (MþNaþ),
387.1 (MþNHþ4 ), 370.1 (MþHþ). Anal. Calcd for C20H19NO6: C, 65.03;
H, 5.18; N, 3.79. Found: C, 65.21; H, 5.19; N, 3.51.
Compound 3b (solid):3 36 h, 62% yield, dr >99/1. HPLC analysis
(Chiralcel OD-H, 30/70 iPrOH/hexanes, 0.8 mL/min, 238 nm; tR
(major)¼12.63 min, tR (minor)¼18.44 min) gave the isomeric
composition of the product: 97% ee. [a]2D0 ꢀ228.6 (c 1.00, CHCl3). 1H
NMR (300 MHz, CDCl3/TMS) d 7.27–7.43 (m, 5H), 4.93 (d, J¼3.6 Hz,
1H), 4.84 (d, J¼3.6 Hz,1H), 4.33 (q, J¼7.2 Hz, 2H), 3.75 (s, 3H),1.35 (t,
J¼6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 168.1, 158.6, 137.8, 129.4,
128.7, 126.9, 109.0, 78.7, 62.7, 52.7, 52.5, 14.0.
Compound ent-3b (solid): 36 h, 69% yield, dr >99/1. HPLC
analysis (Chiralcel OD-H, 30/70 iPrOH/hexanes, 0.6 mL/min,
238 nm; tR (minor)¼15.09 min, tR (major)¼19.74 min) gave the
isomeric composition of the product: ꢀ99% ee. [a]2D0 216.0 (c 0.50,
CHCl3).
Figure 3. Single-crystal X-ray diffraction analysis of compound 10.
sulfur or ammonium salts with nitroalkenes. By employing
cinchonidine (cinchonine)-derived ammonium salts instead of
sulfur ylide, excellent enantioselectivities and diastereoselectivities
could be achieved. Both enantiomers can be obtained just by
a choice of cinchonidine-derived and cinchonine-derived ylides
used. Although a stoichiometric amount of chiral reagent is used,
cinchonidine and cinchonine are quite cheap and recoverable. This
reaction has also been successfully applied to the formal synthesis
of dehydroclausenamide. The high diastereoselectivity, the excel-
lent enantioselectivity, the easily accessible, and the cheap starting
material make this reaction practically useful.
Compound 3c (solid): 36 h, 54% yield, dr >99/1. HPLC analysis
(Chiralcel AD-H, 10/90 iPrOH/hexanes, 0.4 mL/min, 238 nm; tR
(major)¼28.02 min, tR (minor)¼38.33 min) gave the isomeric
composition of the product: 99% ee. [a]2D0 ꢀ70.3 (c 1.13, CHCl3). IR
(film) n/cmꢀ1 2956 (m), 2843 (m), 1741 (s), 1708 (s), 1632 (s), 1494
(m), 1246 (m), 1026 (m), 757 (s). 1H NMR (300 MHz, CDCl3/TMS)
d 7.33–7.35 (m, 1H), 7.12–7.14 (m, 1H), 6.94–6.98 (m, 2H), 5.15 (d,
J¼3.6 Hz, 1H), 4.86 (d, J¼3.6 Hz, 1H), 4.30–4.34 (m, 2H), 3.88 (s, 3H),
3.74 (s, 3H), 1.35 (t, J¼7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 168.2,
158.8, 156.6, 129.9, 128.3, 125.2, 120.8, 111.0, 108.1, 78.0, 62.3, 55.5,
52.5, 47.9, 14.0. MS (ESI, m/z) 378.1 (MþMeOHþNaþ), 346.1
(MþNaþ), 324.1 (MþHþ). Anal. Calcd for C15H17NO7: C, 55.73; H,
5.30; N, 4.33. Found: C, 55.79; H, 5.27; N, 4.33.
4. Experimental section
4.1. General procedure for the reaction of sulfonium
salt 1 and nitroalkenes 2: (2a–2k)
Compound 3d (solid): 44 h, 65% yield, dr >99/1. HPLC analysis
(Chiralcel OD-H, 30/70 iPrOH/hexanes, 0.8 mL/min, 238 nm; tR
(major)¼17.28 min, tR (minor)¼26.61 min) gave the isomeric com-
position of the product: 99% ee. Mp 87–90 ꢁC. [a]D20 ꢀ163.0 (c 1.02,
CHCl3). Mp 87–90 ꢁC. IR (film) n/cmꢀ1 2979 (m), 2904 (m), 2837 (m),
1738 (s),1634 (s),1538 (s),1252 (m),1030 (m), 838 (m), 754 (m), 698
(m). 1H NMR (300 MHz, CDCl3/TMS) d 7.26–7.30 (m, 3H), 7.21 (ABd,
J¼9 Hz, 2H), 7.11–7.12 (m, 2H), 6.88 (ABd, J¼9.0 Hz, 2H), 5.22 (ABd,
J¼12 Hz, 1H), 5.09 (ABd, J¼12 Hz, 1H), 4.89 (d, J¼3.0 Hz, 1H), 4.80
(d, J¼3.0 Hz,1H), 4.31 (q, J¼6.9 Hz, 2H), 3.82 (s, 3H),1.33 (t, J¼7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3) d 168.1, 159.9, 158.0, 134.6, 129.9,
128.5,128.4,128.3,128.0,114.7,109.0, 79.0, 67.3, 62.6, 55.4, 52.0,14.1.
MS (ESI, m/z) 454.2 (MþMeOHþNaþ), 422 (MþNaþ), 417.3
(MþNHþ4 ), 400.2 (MþHþ). Anal. Calcd for C21H21NO7: C, 63.15; H,
5.30; N, 3.51. Found: C, 63.10; H, 5.12; N, 3.33.
A solution of salt 12 (51 mg, 0.22 mmol) and nitroalkene 2
(0.2 mmol) in MeCN (2.5 mL) was cooled to ꢀ20 ꢁC under N2. To the
solution was added K2CO3 (42 mg, 0.30 mmol) and then the
reaction mixture was stirred at ꢀ20 ꢁC for the desired time. After
the reaction was complete (monitored by TLC), the mixture was
passed rapidly through a glass funnel with a thin layer (20 mm) of
silica gel (300–400 mesh), washed with AcOEt (100 mL). The
filtrate was concentrated under reduced pressure and the residue
was purified by flash chromatography (EtOAc/petroleum ether/
Et3N, v/v/v, 100/500/1.8).
4.2. General procedure for the ammonium ylide annulation
reaction (substrates 2a–2k)
Compound 3e (solid): 37 h, 77% yield, dr >99/1. HPLC analysis
(Chiralcel OD-H, 30/70 iPrOH/hexanes, 0.8 mL/min, 238 nm; tR
(major)¼11.38 min, tR (minor)¼17.38 min) gave the isomeric com-
position of the product: 97% ee. [a]2D0 ꢀ137.7 (c 1.03, CHCl3). Mp 82–
83 ꢁC. IR (film) n/cmꢀ1 3032 (m), 2982 (s), 1738 (vs), 1709 (s), 1628
(vs), 1515 (m), 1456 (m), 1391 (m), 1361 (m), 1220 (s), 1024 (m), 818
(m), 751 (s), 698 (s). 1H NMR (300 MHz, CDCl3/TMS) d 7.25–7.27 (m,
3H), 7.17 (s, 4H), 7.06–7.09 (m, 2H), 5.20 (ABd, J¼12.0 Hz, 1H), 5.06
(ABd, J¼12.0 Hz, 1H), 4.89 (d, J¼3.0 Hz, 1H), 4.81 (d, J¼3.0 Hz, 1H),
4.31 (q, J¼6.9 Hz, 2H), 2.36 (s, 3H), 1.32 (t, J¼6.9 Hz, 3H). 13C NMR
(75 MHz, CDCl3) d 168.0,157.9,138.6,134.8,134.5,129.9,128.3,128.2,
A mixture of salt 1 (0.22 mmol), Cs2CO3 (0.22 mmol), and
nitroalkene 2 (0.2 mmol) was cooled to 0 ꢁC under N2. To the
mixture were then added H2O (10 mL) and THF (2.5 mL). The re-
action mixture was stirred at 0 ꢁC for the desired time. After the
reaction was complete (monitored by TLC), the mixture was passed
rapidly through a glass funnel with a thin layer (20 mm) of silica gel
(300–400 mesh), washed with AcOEt (100 mL). The filtrate was
concentrated under reduced pressure and the residue was purified
by flash chromatography (EtOAc/petroleum ether/Et3N, v/v/v, 100/
500/1.8).

5588
C.-Y. Zhu et al. / Tetrahedron 64 (2008) 5583–5589
127.9, 126.9, 108.9, 78.7, 67.2, 62.6, 52.2, 21.1, 14.0. MS (EI, m/z, rel
intensity) 383 (Mþ, 0.24), 91 (100.00). Anal. Calcd for C21H21NO6: C,
65.79; H, 5.52; N, 3.65. Found: C, 65.82; H, 5.70; N, 3.48.
(dd, J¼6.3, 6.6 Hz, 1H), 7.46 (t, J¼7.2 Hz, 1H), 7.32 (d, J¼6.6 Hz, 1H),
5.72 (d, J¼1.5 Hz, 1H), 4.88 (d, J¼1.8 Hz, 1H), 4.38–4.44 (m, 2H), 3.72
(s, 3H),1.41 (t, J¼7.2 Hz, 3H).13C NMR (75 MHz, CDCl3) d 168.4,158.7,
134.2,132.8,130.3,129.4,129.2,127.1,126.3,125.4,124.1,122.5,108.3,
78.5, 62.8, 52.8, 48.4, 14.0. MS (ESI, m/z) 398.1 (MþMeOHþNaþ),
366.1 (MþNaþ), 344.1 (MþHþ). Anal. Calcd for C18H17NO6: C, 62.97;
H, 4.99; N, 4.08. Found: C, 67.61; H, 4.94; N, 3.75.
Compound 3k (oil): 39 h, 30% yield, dr¼80/20. HPLC analysis
(Chiralcel OD-H, 1/15 iPrOH/hexanes, 0.5 mL/min, 238 nm; tR1
(major)¼28.16 min, tR1 (minor)¼39.40 min, tR2 (major)¼30.30 min,
tR2 (minor)¼33.59 min) gave the isomeric composition of the
product: trans, 93% ee; cis, 88% ee. For trans-isomer: 1H NMR
(300 MHz, CDCl3/TMS) d 4.76 (d, J¼2.7 Hz, 1H), 4.22 (dq, J¼2.1,
6.9 Hz, 2H), 3.82 (s, 3H), 3.58 (dd, J¼2.1 Hz, 3 Hz, 1H), 2.33 (hepta,
J¼3.9 Hz, 1H), 1.26 (t, J¼7.8 Hz, 3H), 1.02 (d, J¼7.2 Hz, 3H), 0.91 (d,
J¼7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 168.9, 159.0, 108.3, 72.5,
62.2, 53.5 52.6, 29.2, 19.5, 16.6, 13.9. MS (EI, m/z, rel intensity) 242
(MþꢀOH, 2.09),186 (45.42),144 (45.88),142 (42.86),100 (86.76), 85
(42.29), 59 (100.00), 43 (45.50), 41 (36.26). Anal. Calcd for
Compound 3f (solid): 34 h, 79% yield, dr >99/1. HPLC analysis
(Chiralcel OD-H, 30/70 iPrOH/hexanes, 0.6 mL/min, 238 nm; tR
(major)¼14.96 min, tR (minor)¼20.54 min) gave the isomeric
composition of the product: 99% ee. [a]2D0 ꢀ167.9 (c 0.94, CHCl3). Mp
85–87 ꢁC. IR (film) n/cmꢀ1 2986 (m), 2938 (m), 1742 (s), 1631 (s),
1511 (s), 1443 (m), 1373 (m), 1229 (m), 977 (w), 841 (m), 756 (s). 1H
NMR (300 MHz, CDCl3/TMS) d 7.31–7.35 (m, 2H), 7.10 (t, J¼8.4 Hz,
2H), 4.91 (d, J¼2.7 Hz, 1H), 4.85 (d, J¼2.7 Hz, 1H), 4.33 (q, J¼7.2 Hz,
2H), 3.76 (s, 3H), 1.35 (t, J¼7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d 167.9, 164.3 161.0, 158.5, 133.6, 133.5 (5), 128.8, 128.7, 116.5, 116.2,
108.8, 78.6 (5), 78.6 (3), 62.7, 52.7, 51.8, 14.0. MS (ESI, m/z) 366.2
(MþMeOHþNaþ), 334.2 (MþNaþ), 329.2 (MþNHþ4 ), 312.2 (MþHþ).
Anal. Calcd for C14H14FNO6: C, 54.02; H, 4.53; N, 4.50. Found: C,
54.06; H, 4.44; N, 4.40.
Compound 3g (solid): 34 h, 74% yield, dr >99/1. HPLC analysis
(Chiralcel OD-H, 30/70 iPrOH/hexanes, 0.6 mL/min, 238 nm; tR
(major)¼18.28 min, tR (minor)¼35.25 min) gave the isomeric
composition of the product: 98% ee. [a]2D0 ꢀ162.3 (c 1.20, CHCl3). Mp
88–90 ꢁC. IR (film) n/cmꢀ1 2978 (w), 2936 (w), 1740 (s), 1633 (s),
1442 (m), 1231 (s), 1011 (m), 756 (m). 1H NMR (300 MHz, CDCl3/
TMS) d 7.54 (ABd, J¼8.7 Hz, 2H), 7.23 (ABd, J¼8.7 Hz, 2H), 4.89 (d,
J¼2.7 Hz, 1H), 4.83 (d, J¼2.4 Hz, 1H), 4.33 (q, J¼6.9 Hz, 2H), 3.76 (s,
3H), 1.35 (t, J¼6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 167.7, 158.4,
136.7, 132.5, 128.6, 122.8, 108.5, 78.3, 62.8, 52.8, 51.9, 14.0. MS (ESI,
m/z) 428.1 (Mþ2þMeOHþNaþ), 426.1 (MþMeOHþNaþ), 396.0
(Mþ2þNaþ), 394.0 (MþNaþ), 391.0 (Mþ2þNH4þ), 389.0 (MþNH4þ),
374.0 (Mþ2þHþ), 372.0 (MþHþ). Anal. Calcd for C14H14BrNO6: C,
45.18; H, 3.79; N, 3.76. Found: C, 45.28; H, 3.82; N, 3.61.
Compound 3h (solid): 36 h, 67% yield, dr >99/1. HPLC analysis
(Chiralcel OD-H, 30/70 iPrOH/hexanes, 0.6 mL/min, 238 nm;
tR¼15.29 min, only one peak was observed) gave the isomeric
composition of the product: >99% ee. [a]2D0 ꢀ84.4 (c 1.00, CHCl3). IR
(film) n/cmꢀ1 3123 (w), 2983 (m), 1739 (s), 1633 (s), 1500 (m), 1456
(m), 1393 (m), 1224 (m), 747 (m), 698 (m), 598 (m). 1H NMR
(300 MHz, CDCl3/TMS) d 7.22–7.39 (m, 6H), 6.35 (dd, J¼1.5, 3.3 Hz,
1H), 6.27 (d, J¼3.0 Hz, 1H), 5.26 (ABd, J¼12.6 Hz, 1H), 5.14 (ABd,
J¼12.6 Hz, 1H), 5.04 (s, 2H), 4.30 (q, J¼7.2 Hz, 2H), 1.31 (t, J¼7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3) d 167.6, 157.7, 148.7, 143.1, 134.5,
128.4, 128.4, 128.0, 110.8, 108.4, 106.2, 76.0, 67.3, 62.7, 46.1, 13.9. MS
(EI, m/z, rel intensity) 341 (MþꢀH2O, 1.01), 91 (100.00). HRMS (ESI)
calcd for C18H17NO7Naþ (MþNaþ) 382.0901, found: 382.08973.
Compound 3i (solid): 41 h, 79% yield, dr >99/1. HPLC analysis
(Chiralcel OD-H, 30/70 iPrOH/hexanes, 0.6 mL/min, 238 nm; tR
(major)¼14.71 min, tR (minor)¼20.79 min) gave the isomeric
composition of the product: 99% ee. [a]2D0 ꢀ123.2 (c 1.10, CHCl3). Mp
119–121 ꢁC. IR (film) n/cmꢀ1 3113 (w), 2993 (w), 2909 (w), 1740 (s),
1633 (s), 1438 (m), 1230 (m), 982 (m), 751 (s), 732 (m), 546 (w). 1H
NMR (300 MHz, CDCl3/TMS) d 7.32 (dd, J¼0.9, 5.1 Hz, 1H), 7.09–7.10
(m, 1H), 7.02 (dd, J¼3.6, 5.4 Hz, 1H), 5.18 (d, J¼2.4 Hz, 1H), 5.05 (d,
J¼2.7 Hz, 1H), 4.33 (q, J¼7.2 Hz, 2H), 3.80 (s, 3H), 1.35 (t, J¼7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3) d 167.5, 158.3, 139.4, 127.4, 125.9 (9),
125.9 (6), 108.4, 78.8, 62.7, 52.7, 47.6, 13.9. MS (ESI, m/z) 354.1
(MþMeOHþNaþ), 322.1 (MþNaþ), 317.1 (MþNHþ4 ), 300.1 (MþHþ).
Anal. Calcd for C12H13NO6S: C, 48.16; H, 4.38; N, 4.68. Found: C,
48.58; H, 4.05; N, 4.63.
C11H17NO6: C, 50.96; H, 6.61; N, 5.40. Found: C, 51.40; H, 6.76; N,
5.20.
4.3. Procedure for the deoxygenation of ent-3b15
The starting material was dissolved in 4 mL/mmol of trimethyl
phosphite in a flask equipped with a condenser and a thermometer.
The mixture was stirred at 100 ꢁC for 5 h under nitrogen, then
diethyl ether was added (25 mL/mmol of starting material) and the
solution was cooled to ꢀ10 ꢁC, 1 N HCl (30 mL/mmol of starting
material) was added to the mixture dropwise, extracted with
diethyl ether (25 mL/mmol of starting material), washed with
water (10 mL/mmol) and brine (5 mL/mmol). The organic layer was
dried over sodium sulfate and concentrated in vacuo to give a crude
product, which was purified by flash chromatography.
Compound 7 (solid): 90% yield. [a]2D0 367.6 (c 0.95, CHCl3). Mp
52–54 ꢁC. IR (film) n/cmꢀ1 3032 (w), 2984 (m), 2957 (m), 1735 (s),
1592 (m),1497 (w),1442 (m),1456 (m),1366 (m),1230 (m),1123 (m),
1023 (m), 915 (m), 792 (m), 752 (m), 700 (m). 1H NMR (300 MHz,
CDCl3/TMS) d 7.20–7.37 (m, 5H), 5.07 (d, J¼4.8 Hz, 1H), 4.84 (d,
J¼4.8 Hz, 1H), 4.28 (q, J¼6.9 Hz, 2H), 3.78 (s, 3H), 1.32 (t, J¼7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3) d 168.4, 159.7, 153.1, 136.7, 129.4,
128.5, 127.3, 87.8, 62.4, 56.4, 52.9, 14.0. MS (ESI, m/z) 332.2
(MþMeOHþNaþ), 300.2 (MþNaþ), 278.2 (MþHþ). Anal. Calcd for
C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C, 60.43; H, 5.40; N,
4.83.
4.4. Procedure for the hydrogenation of 716
A mixture of 7 (0.2 mmol) and Raney Ni (20 mg wet) in MeOH
(2 mL) was subjected to H2 (1 atm) at room temperature for 48 h.
The catalyst was removed by filtration over Celite and the filtrate
was concentrated. The residue thus obtained was subjected to
column chromatography over silica gel (petroleum ether/AcOEt,
1:4) to afford 8.
Compound 8 (solid): 25 mg, 53% yield. [a]2D0 ꢀ184.5 (c 0.50,
CHCl3). Mp 161–164 ꢁC. IR (film) n/cmꢀ1 3331 (w), 2920 (w), 1969
(w), 1732 (s), 1691 (s), 1438 (m), 1376 (m), 1216 (s), 789 (s), 700 (s).
1H NMR (300 MHz, (CD3)2SO with the internal dimethylsulfoxide
signal at 2.5 ppm as a standard) d 7.24–7.30 (m, 5H), 4.29 (d,
J¼4.5 Hz, 1H), 4.20 (d, J¼7.2 Hz, 1H), 3.64 (s, 3H), 3.61 (d, J¼4.8 Hz,
1H). 13C NMR (75 MHz, (CD3)2SO with the internal dimethylsulf-
oxide signal at 39.5 ppm as a standard) d 175.5, 172.2, 137.2, 128.9,
128.0, 126.9, 69.8, 58.5, 52.3, 49.3. MS (ESI, m/z) 290.2
(MþMeOHþNaþ), 258.2 (MþNaþ), 236.2 (MþHþ). Anal. Calcd for
Compound 3j (solid): 39 h, 68% yield, dr >99/1. HPLC analysis
(Chiralcel OD-H, 30/70 iPrOH/hexanes, 0.6 mL/min, 238 nm; tR
(major)¼20.48 min, tR (minor)¼27.55 min) gave the isomeric
composition of the product: 96% ee. [a]2D0 ꢀ3.0 (c 1.23, CHCl3). IR
(film) n/cmꢀ1 3055 (w), 2981 (w), 2959 (w), 1759 (s), 1740 (s), 1633
(s), 1440 (s), 1227 (m), 1056 (w), 799 (m), 777 (m), 748 (m), 537 (m).
1H NMR (300 MHz, CDCl3/TMS) d 8.25 (d, J¼8.4 Hz, 1H), 7.92 (d,
J¼0.9 Hz,1H), 7.88 (d, J¼8.4 Hz,1H), 7.65 (dd, J¼6.3, 6.9 Hz,1H), 7.58
C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C, 61.00; H, 5.68; N,
5.47.

C.-Y. Zhu et al. / Tetrahedron 64 (2008) 5583–5589
5589
4.5. Procedure for the methylation of 8
References and notes
1. (a) Righi, P.; Marotta, E.; Landuzzi, A.; Rosini, G. J. Am. Chem. Soc. 1996, 118,
9446; (b) Frederickson, M. Tetrahedron 1997, 53, 403; (c) Trost, B. M.; Chupak,
L. S.; Lu¨bbers, T. J. Am. Chem. Soc. 1998, 120, 1732; (d) Damkaci, F.; Deshong, P.
J. Am. Chem. Soc. 2003, 125, 4408; (e) Minter, A. R.; Fuller, A. A.; Mapp, A. K.
J. Am. Chem. Soc. 2003, 125, 6846; (f) Fuller, A. A.; Chen, B.; Minter, A. R.;
Mapp, A. K. J. Am. Chem. Soc. 2005, 127, 5376.
2. (a) Barbachyn, M. R.; Cleek, G. J.; Dolak, L. A.; Garmon, S. A.; Morris, J.; Seest,
E. P.; Thomas, R. C.; Toops, D. S.; Watt, W.; Wishka, D. G.; Ford, C. W.; Zur-
enko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert, D.; Yagi, B. H.; Adams, W. J.;
Friis, J. M.; Slatter, J. G.; Sams, J. P.; Oien, N. L.; Zaya, M. J.; Wienkers, L. C.;
Wynalda, M. A. J. Med. Chem. 2003, 46, 284; (b) Simoni, D.; Grisolia, G.;
Giannini, G.; Roberti, M.; Rondanin, R.; Piccagli, L.; Baruchello, R.; Rossi, M.;
Romagnoli, R.; Invidiata, F. P.; Grimaudo, S.; Jung, M. K.; Hamel, E.; Gebbia, N.;
Crosta, L.; Abbadessa, V.; Cristina, A. D.; Dusonchet, L.; Meli, M.; Tolomeo, M.
J. Med. Chem. 2005, 48, 723.
To a solution of 8 (0.2 mmol) in DME (2 mL) at 0 ꢁC under
nitrogen, was added KOtBu (0.24 mmol). After 2 min, MeI
(0.3 mmol) was added. The resulting solution was stirred at room
temperature for 24 h, then was passed rapidly through a glass
funnel with a thin layer (20 mm) of silica gel (300–400 mesh),
washed with AcOEt (100 mL). The filtrate was concentrated under
reduced pressure and the residue was purified by flash chroma-
tography (petroleum ether/AcOEt, 1:2) to afford 9.
Compound 9 (solid): 69% yield. Mp 115–117 ꢁC. IR (film) n/cmꢀ1
3347 (m),1742(s),1714 (s),1700 (s),1684(s),1438 (w),1398 (w),1224
(m), 1085 (m), 765 (m), 735 (m), 700 (m). 1H NMR (300 MHz, CDCl3/
TMS) d 7.27–7.34 (m, 3H), 7.15–7.18 (m, 2H), 4.65 (dd, J¼4.8, 7.8 Hz,
1H), 4.21 (d, J¼2.1 Hz, 1H), 3.80 (s, 3H), 3.77–3.78 (m, 1H), 3.42 (d,
J¼4.8 Hz, 1H), 2.98 (s, 3H). 13C NMR (75 MHz, CDCl3) d 174.3, 170.7,
136.2, 128.8, 128.1, 127.9, 70.3, 65.9, 52.8, 47.8, 29.4. MS (ESI, m/z)
304.1 (MþMeOHþNaþ), 272.2 (MþNaþ), 250.1 (MþHþ). Anal. Calcd
for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C, 62.31; H, 6.09;
N, 5.47.
3. (a) Clagett, M.; Gooch, A.; Graham, P.; Holy, N.; Mains, B.; Strunk, J. J. Org. Chem.
1976, 41, 4033; (b) Sakakibara, T.; Sudoh, R. J. Chem. Soc., Chem. Commun. 1977,
7; (c) Kumaran, G.; KulKarni, G. H. Synthesis 1995, 1545; (d) Hubner, J.;
Liebscher, J.; Pa¨tzel, M. Tetrahedron 2002, 58, 10485.
¨
4. For selected recent examples on ylide cyclization, see: (a) Koep, S.; Gais, H.-J.;
Raabe, G. J. Am. Chem. Soc. 2003, 125, 13243; (b) Gais, H.-J.; Reddy, L. R.; Babu, G.
S.; Raabe, G. J. Am. Chem. Soc. 2004, 126, 4859; (c) Schomaker, J. M.; Pulgam, V.
R.; Borhan, B. J. Am. Chem. Soc. 2004, 126, 13600; (d) Kumarn, S.; Shaw, D. M.;
Longbottom, D. A.; Ley, S. V. Org. Lett. 2005, 7, 4189; (e) Kokotos, C. G.; Aggarwal,
V. K. Chem. Commun. 2006, 2156; (f) Unthank, M. G.; Hussain, N.; Aggarwal, V.
K. Angew. Chem., Int. Ed. 2006, 45, 7066; (g) Kumarn, S.; Shaw, D. M.; Ley, S. V.
Chem. Commun. 2006, 3211; (h) Tiwari, S. K.; Gais, H.-J.; Lindenmaier, A.; Babu,
G. S.; Raabe, G.; Reddy, L. R.; Ko¨hler, F.; Gu¨nter, M.; Koep, S.; Iska, V. B. R. J. Am.
Chem. Soc. 2006, 128, 7360; (i) Kokotos, C. G.; Aggarwal, V. K. Org. Lett. 2007, 9,
2099; (j) Schomaker, J. M.; Bhattacharjee, S.; Yan, J.; Borhan, B. J. Am. Chem. Soc.
2007, 129, 1996.
5. Zhu, C.-Y.; Deng, X.-M.; Sun, X.-L.; Zheng, J.-C.; Tang, Y. Chem. Commun. 2008, 738.
6. For examples on camphor-derived ylide reaction, see: (a) Li, A.-H.; Dai, L.-X.;
Huang, Y.-Z.; Li, F.-W. J. Org. Chem. 1996, 61, 489; (b) Li, A.-H.; Dai, L.-X.; Hou,
X.-L. Angew. Chem., Int. Ed.1997, 36,1317; (c) Ye, S.; Huang, Z. Z.; Xia, C. A.; Tang, Y.;
Dai, L. X. J. Am. Chem. Soc. 2002,124, 2432; (d) Aggarwal, V. K.; Hynd, G.; Picoul, W.;
Vasse, J.-L. J. Am. Chem. Soc. 2002, 124, 9964; (e) Li, X.-L.; Wang, Y.; Huang, Z.-Z.
Aust. J. Chem. 2005, 58, 749; (f) Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li,
K.; Tang, Y.; Wu, Y.-D.; Dai, L.-X. J. Am. Chem. Soc. 2006, 128, 9730.
7. For reviews on sulfur ylide in organic synthesis, see: (a) Li, A.-H.; Dai, L.-X.;
Aggarwal, V. K. Chem. Rev. 1997, 97, 2341; (b) Dai, L.-X.; Hou, X.-L.; Zhou, Y.-G.
Pure Appl. Chem. 1999, 71, 369; (c) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res.
2004, 37, 661; (d) Tang, Y.; Ye, S.; Sun, X.-L. Synlett 2005, 2720; (e) McGarrigle,
E. M.; Myers, E. L.; Illa, O.; Shaw, M. A.; Riches, S. L.; Aggarwal, V. K. Chem. Rev.
2007, 107, 5841.
8. For leading references on chiral nitrogen ylide in organic synthesis, see: (a)
Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2003, 42, 828;
(b) Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2004, 43, 4641; (c) Bremeyer, N.; Smith, S. C.; Ley, S. V.; Gaunt, M.
J. Angew. Chem., Int. Ed. 2004, 43, 2681; (d) Johansson, C. C. C.; Bremeyer, N.; Ley,
S. V.; Owen, D. R.; Smith, S. C.; Gaunt, M. J. Angew. Chem., Int. Ed. 2006, 45, 6024;
(e) Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596.
4.6. Procedure for the preparation of 1017
nBuLi (0.33 mmol, 2.5 M in hexane) was added to a stirred
solution of PhI (0.33 mmol) in THF (1 mL) at ꢀ78 ꢁC. The resulting
orange solution was then added dropwise to a solution of 6
(0.17 mmol) in THF (1 mL) at ꢀ78 ꢁC. After 1 h, HCO2Et (0.34 mmol)
was added. And after 3 min of stirring at ꢀ78 ꢁC, the reaction was
quenched by adding silica gel (300–400 mesh, 0.5 g). The resulting
mixture was passed through a glass funnel with a thin layer
(20 mm) of silica gel (300–400 mesh) and washed with AcOEt
(100 mL). The filtrate was concentrated under reduced pressure
and the residue was purified by flash chromatography (petroleum
ether/AcOEt, 1:1) to afford 10.
Compound 10 (solid): 66% yield. [a]2D0 ꢀ116.5 (c 1.00, CHCl3). 1H
NMR (300 MHz, CDCl3/TMS) d 7.86–7.89 (m, 2H), 7.64 (t, J¼7.5 Hz,
1H), 7.49 (t, J¼7.5 Hz, 2H), 7.37–7.40 (m, 3H), 7.20–7.36 (m, 2H), 5.09
(d, J¼1.2 Hz, 1H), 4.57 (dd, J¼4.8, 8.4 Hz, 1H), 3.73 (d, J¼8.4 Hz, 1H),
3.10 (d, J¼4.8 Hz,1H), 3.00 (s, 3H). 13C NMR (75 MHz, CDCl3) d 194.6,
174.5,136.5,134.4,133.7,129.0 (9),129.0 (8),128.5,128.2,128.1, 70.0,
69.0, 47.5, 29.6.
9. (a) Cheng, J. P.; Liu, B.; Zhao, Y.; Sun, Y.; Zhang, X.-M.; Lu, Y. J. Org. Chem. 1999,
64, 604; (b) Naito, T.; Nagase, S.; Yamataka, H. J. Am. Chem. Soc. 1994, 116, 10080.
10. Aggarwal, V. K.; Harvey, J. N.; Robiette, R. Angew. Chem., Int. Ed. 2005, 44, 5468.
11. (a) Robiette, R.; Conza, M.; Aggarwal, V. K. Org. Biomol. Chem. 2006, 4, 621; (b)
Aggarwal, V. K.; Charmant, J. P. H.; Fuentes, D.; Harvey, J. N.; Hynd, G.; Ohara, D.;
Picoul, W.; Robiette, R. I.; Smith, C.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc.
2006, 128, 2105.
Acknowledgements
We are grateful for the financial support from the Natural
Sciences Foundation of China, the Major State Basic Research
Development Program (Grant No. 2006CB806105), the Chinese
academy of Sciences, and the Science and Technology Commission
of Shanghai Municipality.
12. The absolute configuration of ent-3b was determined by chemical trans-
formations as shown in Scheme 4.
13. (a) Huang, D. F.; Huang, L. Tetrahedron 1990, 46, 3135; (b) Yan, Z. H.; Wang, J. Q.;
Tian, W. S. Tetrahedron Lett. 2003, 44, 9383; (c) Yan Z.-H. Application of Fluoro
Substituted Alkylsulfonyl Fluoride RfSO2F in the Organic Synthesis. Ph.D. Thesis,
Shanghai Institute of Organic Chemistry, CAS, Shanghai, China, 1999.
14. (a) Zhang, J. T. Acta Pharmacol. Sin. 1986, 21, 636; (b) Yang, M. H.; Cao, Y. H.; Li,
W. X.; Yang, Y. Q.; Huang, L. Acta Pharmacol. Sin. 1987, 22, 33; (c) Yang, M. H.;
Chen, Y. Y.; Huang, L. Acta Chimi. Sin., Engl. Ed. 1987, 267; (d) Duan, W. Z.; Zhang,
J. T. Acta Chimi. Sin. 1997, 32, 259.
Supplementary data
15. Marotta, E.; Micheloni, L. M.; Scardovi, N.; Righi, P. Org. Lett. 2001, 3, 727.
16. Singh, V.; Madapa, S.; Yadav, G. P.; Maulik, P. R.; Batra, S. Synthesis 1995, 1545.
General synthetic procedures and characterization and spectral
data for key compounds, CIF for compounds 3a, 6a and 10.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.03.075.
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17. Fernandez-Megıa, E.; Iglesias-Pintos Jose, M.; Javier Sardina, F. J. Org. Chem.
1997, 62, 4770.
18. For details, please see Supplementary data.