Total synthesis of (±)-camphorataimides and (±)-himanimides by NaBH4/Ni(OAc)2 or Zn/AcOH stereoselective reduction

Article abstract of DOI:10.1016/j.tet.2008.02.077

Maleic anhydride 1 of Antrodia camphorate, which can be isolated from Chinese herbal medicine, is achieved in which the longest linear sequence is only five steps, in 40% overall yield from commercially available succinic anhydride. The crucial antrodimid

Full text of DOI:10.1016/j.tet.2008.02.077

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4347e4353
www.elsevier.com/locate/tet
Total synthesis of (ꢀ)-camphorataimides and (ꢀ)-himanimides
by NaBH4/Ni(OAc)2 or Zn/AcOH stereoselective reduction
*
Chia-Fu Cheng, Zhen-Chang Lai, Yean-Jang Lee
Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan
Received 22 January 2008; received in revised form 19 February 2008; accepted 22 February 2008
Available online 4 March 2008
Abstract
Maleic anhydride 1 of Antrodia camphorate, which can be isolated from Chinese herbal medicine, is achieved in which the longest linear
sequence is only five steps, in 40% overall yield from commercially available succinic anhydride. The crucial antrodimides 3 and 2 can be
readily transformed by the chemoselective reduction with Zn/AcOH and NaBH4/Ni(OAc)2$4H2O to afford the naturally occurring camphora-
taimides, 4 and 5, in high yields as well, respectively. This synthetic strategy can also be modified to give access to a variety of different maleic
acid derivatives, himanimides 6e8.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Antrodia camphorate; Himanimides; NaBH4/Ni(OAc)2; Zn/AcOH; Stereoselective reduction
1. Introduction
carpacin3 and ailanthoidol,4 we became aware of the facile
conversion of p-alkoxyphenyl bromide to aryl stannanes and
the proceeding Stille5 coupling of bromomaleic acid deriva-
tives with stannanes to substituted maleiate skeleton. There-
fore, 1e3 are ideal synthetic target for the application of
these reactions. Although 1e3 have been synthesized by
Argade6a and Stewart,6b they were achieved with very time-
consuming and complicated synthetic approaches. To date,
no 4 and 5 have been synthesized and deficiently examined
the biological activity of the molecules, we undertook the first
total synthesis of (ꢀ)-camphorataimides, 4 and 5, the struc-
tural novelty of this family (Fig. 1).
Perhaps the easiest route to 1 would have been to sequen-
tially couple the known dibromomaleic anhydride 10,
i-BuMgBr, and the known7 bromo(prenyloxy)benzene. In
previous projects8 we have achieved such coupling by treating
a mixture of two aryl bromides with a bis(trialkyltin) in the
presence of a palladium catalyst. The reaction proceeds via
in situ conversion of one aryl bromide to the corresponding
stannane followed by coupling of the latter with the other
aryl bromide.8a In addition, although Stewart et al. have
achieved cross-coupling by the Negishi and Suzuki reactions,
we would still like to investigate the versatility of Stille cross-
As part of our research aims to uncover from natural prod-
ucts new compounds with improved biological activities,
including antioxidant, anti-human immunodeficiency virus
(HIV), and tumor growth inhibition activities, we attended
to the coumarin and benzofuran family. Recently, several
structurally interesting compounds with substituted maleic an-
hydride and maleimide moieties have been isolated as bioac-
tive natural products.1 Studies on the constituents of the
mycelium of Antrodia camphorate (Polyporaceae, Aphyllo-
phorales),1b which is used as a traditional Chinese medicine,
showed them to contain a number of pharmacological inter-
ests.2 Maleic anhydride 1, maleimide 2 and 3 together with
succinic acids 4 and 5 were isolated from the chloroform-
soluble fraction of the mycelium of A. camphorate and repeat-
edly chromatographed on silica gel with n-hexane/acetone and
CHCl3/MeOH. In addition, maleimides 2 and 3 showed appre-
ciable cytotoxic activity against Lewis lung carcinoma cell
lines. Recently, during the syntheses of the phytotoxins,
* Corresponding author. Tel.: þ886 4 7232105x3511; fax: þ886 4 7211190.
E-mail address: leeyj@cc.ncue.edu.tw (Y.-J. Lee).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.077

4348
C.-F. Cheng et al. / Tetrahedron 64 (2008) 4347e4353
OH
N
X
O
O
O
O
R
R
O
O
1 X=O, R=CH2CH(CH3)2 Camphorataanhydride A 4 R=CH2CH(CH3)2 Camphorataimide D
2 X=NH, R=CH2CH(CH3)2 Camphorataimide B
3 X=NOH, R=CH2CH(CH3)2 Camphorataimide C
6 X=O, R=Bn Himanimide A
8 R=Bn Himanimide D
OH
N
O
O
7 X=NOH, R=Bn Himanimide C
O
5 Camphorataimide E
Figure 1. Maleic anhydride and maleimide natural products of Antrodia camphorate and himanimide.
coupling reactions to provide 1, hence synthesizing the target
(ꢀ)-camphorataimides 4 and 5. Herein, we report the first syn-
thesis of the naturally occurring (ꢀ)-cis-camphorataimide D
and applied the Stille reaction and stereoselective reduction
with Zn/AcOH to achieve (ꢀ)-cis-himanimide D.
pyrroledione 11 appeared a competitive reactant in the 1,2-addi-
tion of carbonyl group. Fortunately, the expected 12 can be af-
forded with CuI instead of Pd-catalyst in moderate 61% yield.
Similarly, bromomaleimide 12 and the corresponding stannane
13 could also undergo the palladium-catalyzed cross-coupling
to give the key product 14 in an excellent yield (94%). The resul-
tant benzyl maleimide 14 was then transformed into the target
compound 1 under reflux in KOH/H2O/THF/MeOH. Finally,
the anhydride 1 was readily converted by heating at 85 ꢁC
in AcONH4 or NH2OH$HCl/pyridine to afford the natural
2. Results and discussion
In the beginning of our synthesis, although 10 has been
synthesized by several groups,9 it was achieved with very
time-consuming and complicated synthetic approaches. To
overcome these technical difficulties, we report our studies on
the synthesis of 10 from the commercially available succinic
anhydride with Br2 in a PTFE-vessel reactor in very good yield
(89%). In the case of 10 and 4-bromo(prenyloxy)benzene, how-
ever, the palladium-catalyzed reaction with (Me3Sn)2 to give 1
was unsuccessful. The major product was biphenyl, the product
from the homocoupling of 4-bromo(prenyloxy)benzene.
With the aim of developing a successful route to 1, an alter-
native method of construction was examined (Scheme 1).
Coupling of dibromide 11 with the commercially available
isobutyl magnesium bromide proceeded in dioxane by Pd(0)-
catalysis to give the desired 12 in very poor 12% yield. The
isolated yield might be low because Grignard reagent and
1
products, maleimides 2 and 3, respectively. H and 13C NMR
spectra of the synthetic products are in agreement with those
reported for the naturally derived materials.1
A further insight into the nature of NaBH4 with metallic
salts,10 it was envisioned that a chemoselective reduction of
3 could prove legible for the formation of the thermodynami-
cally more stable (ꢀ)-trans-camphorataimide E (5). With the
crucial intermediate 14 in hand, the chemoselective reduction
was smoothly testified with NaBH4/Ni(OAc)2$4H2O in mixed
solvent (THF/MeOH 1:1) to provide the expected (ꢀ)-trans-
succinimide 15 only in good yield 65%. Unfortunately, the
resultant 15 wasn’t then transformed into the corresponding
anhydride under reflux in KOH/H2O/THF/MeOH. Subse-
quently, the task turned to extend the original system with
a functioning prototype so that the variety of substrates was
evaluated by 1,4-reduction with the Luche’s reagent. For
instance, compound 2 was employed by the Luche’s method
to give the desired cis/trans-17 (1:2 ratio) in high yield 78%.
It is worth noting that the stereoselectivity preferentially
provided the trans-isomer with the Luche’s reagent, but the
mechanistic issues uncovered in the stereoselective process
as well as the scope and generality of this area will be probed
in detail in our continuing studies. In addition, the NeO bond
of 3 and 16 was first broken to provide 2, and then efficiently
reduced to afford the precedent 17 in high yield. Fortunately,
and to our greater satisfaction, we succeeded in obtaining
(ꢀ)-trans-isomer 18 only from 17, which epimerized the C-3
position to give the thermodynamically more stable trans
diastereomer as the major product in an excellent 94% yield,
suitable for further transformation to achieve the desired 5
(Scheme 2).
O
O
O
O
Br
Br
Br
Br
Br2
BnNH2
86%
i-BuMgBr
O
O
NBn
PTFE Vessel
89%
CuI
61%
NBn
O
Br
O
11
9
10
O
12
O
O
O
O
NBn
O
KOH/H2O
Pd(PPh3)4
13
THF/MeOH
92%
O
94%
14
O
1
O
AcONH4
88%
SnBu3
Br
n-BuLi
Bu3SnCl
96%
O
O
O
13
O
NH
NH2OH
82%
N
OH
O
1
2
O
O
3
O
With the aim of developing a successful route to (ꢀ)-cis-4,
Scheme 1.
an alternative method of construction, which was recently

C.-F. Cheng et al. / Tetrahedron 64 (2008) 4347e4353
4349
O
1. Pd(PPh3)4, BnMgCl
NH2OH
84%
KOH/H2O
81%
Ni(OAc)2-4H2O
O
O
N
Bn
71%
14
11
NaBH4, RT
THF/MeOH
65%
2. Pd(PPh3)4, 13
O
N
Bn
O
93%
15
(single diastereomer)
O
O
O
RO
RO
6 R=Prenyl
19 R=Prenyl
O
O
Ni(OAc)2-4H2O
(Boc)2O, DMAP
NH
N
R
O
NaBH4, RT
THF/MeOH
72~78%
O
Zn/AcOH
57%
CH3CN, RT
O
O
94%
N OH
O
O
O
N OH
2
R=H
17 (cis/trans 1:2)
BnBr/K2CO3
100%
3
R=OH
16 R=OBn
O
RO
7 R=Prenyl
RO
O
O
( ) -Himanimide D (8)
(single diastereomer)
NH2OH
N
Boc
N OH
CH3CN, RT
77%
Scheme 3.
O
O
18
O
O
( )-Camphorataimide E (5)
O
3. Conclusion
N OH
Zn, AcOH
RT, 80%
+ 5
In summary, a concise route to maleic anhydride 1, male-
imide 2 and 3 has been achieved in which the longest linear
sequence is only five or six steps from commercially available
materials in overall 40%, 36%, and 33% yield, respectively.
This synthesis is high yielding and easily modified to give
access to a variety of different (ꢀ)-cis-maleimide analogs
using Zn/AcOH stereoselective reduction, and (ꢀ)-trans-iso-
mers by NaBH4/Ni(OAc)2$4H2O as well. In addition, it dem-
onstrated the usefulness of the Stille coupling and Zn/AcOH
stereoselective reduction for substituted maleimide synthesis
of (ꢀ)-cis-himanimide D. The preparation of these compounds
is currently underway and their biological activities will be
investigated to evaluate the efficacy of these compounds as
anti-tumor agents.
3
O
O
( )-Camphorataimide D (4)
(2
Scheme 2.
:
1)
investigated by Comins et al.,11 was examined. As predicted,
chemoselective reduction of 3 with Zn/AcOH afforded the
desired (ꢀ)-cis-camphorataimide D (4) and the unexpected
(ꢀ)-trans-5 in high yield 80% (cis/trans 2:1). Although the
mechanism of obtaining the trans-isomer of herein is still
unknown, it is likely similar to catalytic hydrogenation to
produce the major cis-isomer, which is unstable under basic
and thermodynamic conditions, thus converting to trans-
isomer. The 1H and 13C NMR spectra of the synthetic products
are in agreement with those reported for the naturally derived
materials.1
4. Experimental
It is worth noting that our synthetic strategy can be
employed in the syntheses of himanimides 6e8 (Scheme 3).
Coupling of the dibromomaleimide 11 with sequent BnMgCl
and stannane 13 proceeded in dioxane by Pd(0)-catalysis to
obtain the predictable 19 in 66% yield over two steps. Simi-
larly, it involved removal of the benzyl-protected group with
KOH/H2O followed by heating at 85 ꢁC in NH2OH$HCl/pyr-
idine to afford the natural products, maleic anhydride 6 and
maleimide 7, respectively. Finally, 7 can readily transform
by the stereoselective reduction with Zn dust in acetic acid
to achieve the single diastereomer (ꢀ)-cis-himanimide (8) in
moderate 57% yield. In contrast, 8 was determined to be
cis-isomer from the coupling constant between H-3 and H-4
(4.0 and 8.0 Hz for trans and cis, respectively). In addition,
the appreciable NOE was observed between H-3 and H-4 in
the NOESY spectrum of 4, while no NOE was observed in
4.1. General
Melting points were determined on a Mel Temp II melting
1
point apparatus and are uncorrected. H NMR and 13C NMR
spectra were measured with a Bruker-200, Bruker-300, or
Varian-600 spectrometer. Chemical shifts are reported in parts
per million (d, ppm) using CHCl3 (dH 7.26) as an internal stan-
dard. Low-resolution mass spectra (MS) and high-resolution
mass spectra (HRMS) were determined on a JEOL JMS-HX
110 mass spectrometer from National Chung-Tsing Univer-
sity, Taichung. Elemental analyses were performed on
a Heracus CHN-OS Rapid spectrometer in the Taichung
Instrumentation Center, National Science Council, Taiwan.
Solvents were freshly distilled prior to use from phosphorus
pentoxide or CaH2. THF was distilled from sodium diphenyl
ketyl. All reactions were carried out under nitrogen atmo-
sphere unless otherwise stated. Silica gel (silica gel 60,
230e400 mesh, Merck) was used for chromatography.
Organic extracts were dried over anhydrous MgSO4.
1
that of 5. The other H and 13C NMR spectra of the synthetic
products are in agreement with those reported for the naturally
derived materials.12

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C.-F. Cheng et al. / Tetrahedron 64 (2008) 4347e4353
4.1.1. 2,3-Dibromomaleic anhydride (10)
for 12 h. After cooling, the solution was evaporated in vacuo
and the brown solid was subjected to flash chromatography
(SiO2, 5:1 hexane/diethyl ether) to obtain the known7 4-[(3-
methyl-2-butenyloxy)phenyl]bromide (13.88 g, 57.8 mmol)
A mixture of succinic anhydride (1.01 g, 10.1 mmol), and
bromine (3.70 g, 23.1 mmol) was stirred in a small autoclave
(PTFE-lined vessel)13 at 210 ꢁC (sand bath) for 3 h (Caution:
Don’t run over 2.00 g each time or raise temperature rapidly,
otherwise, it might appear explosion.). After cooling down
to room temperature, the mixture was dissolved in ethyl ether.
The solvent was then removed and the residue was purified by
chromatography (SiO2, 1:4 hexane/diethyl ether) to give 2,3-
dibromomaleic anhydride (2.30 g, 89%) as a white solid, mp
116e117 ꢁC (lit.9g mp 113e114 ꢁC). 13C NMR (CDCl3)
d 125.0, 163.0. Anal. Calcd for C4O3Br2: C, 18.78; O,
18.76. Found: C, 18.96; O, 18.90.
1
in 100% yield. H NMR (CDCl3) d 1.73 (s, 3H), 1.79 (s,
6H), 4.47 (d, J¼6.6 Hz, 2H), 5.46 (br t, J¼6.6 Hz, 1H), 6.78
(d, J¼9.0 Hz, 2H), 7.35 (d, J¼9.0 Hz, 2H); 13C NMR
(CDCl3) d 18.2, 25.8, 65.0, 112.7, 116.5, 119.3, 132.2,
138.5, 157.9.
4.1.5. 4-[(3-Methyl-2-butenyloxy)phenyl]tributyl-
stannane (13)
The stannane 13 was prepared, using the previous pro-
cedure,8f from 4-[(3-methyl-2-butenyloxy)phenyl]bromide.
4.1.2. N-Benzyl-3,4-dibromomaleimide (11)
A
solution of 4-[(3-methyl-2-butenyloxy)phenyl]bromide
This compound was prepared as a white solid from
anhydride 10 according to the procedure of Viaud-Massuard.9g
To a solution of 10 (4.62 g, 18.0 mmol) in acetic acid
(20.0 mL) was added benzylamine (2.0 mL, 18.0 mmol)
dropwise at room temperature. The mixture was stirred for
10 min and then heated at reflux for 2 h. After cooling down
to room temperature, the mixture was extracted with EtOAc
(3ꢂ30.0 mL). The solvent was then removed and the residue
was purified by chromatography (SiO2, 3:1 hexane/CH2Cl2)
to give 11 (5.32 g, 86%) as a white solid, mp 112e113 ꢁC
(1.02 g, 4.2 mmol) in 60.0 mL of dry THF was placed in
a dry, two-necked, 100-mL, round-bottomed flask under a nitro-
gen atmosphere with a small magnetic stir bar. The flask was
then immersed in an acetone/dry ice bath. n-Butyllithium solu-
tion (2.9 mL, 1.6 M in hexanes, 4.6 mmol) was introduced
slowly (1 drop/2 s) during which time the solution changed color
from pale yellow to dark orange. After the solution was stirred
for 15 min at ꢃ78 ꢁC, the reaction was treated at this tempera-
ture with neat tributyltin chloride (1.51 g, 4.6 mmol). The dry
ice bath was removed and the solution was allowed to reach
room temperature. The reaction was quenched with 0.5 mL of
H2O and the solution concentrated in vacuo. After removal of
the solvent, the residue was purified by chromatography
(SiO2, 3:1 hexane/CH2Cl2) to give 13 (1.82 g, 4.0 mmol) in
96% yield as colorless oil. 1H NMR (CDCl3) d 0.84e1.05 (m,
15H), 1.27e1.69 (m, 12H), 1.73 (s, 3H), 1.79 (s, 3H), 4.50 (d,
J¼6.6 Hz, 2H), 5.50 (br t, J¼6.6 Hz, 1H), 6.91 (d, J¼8.3 Hz,
2H), 7.35 (d, J¼8.3 Hz, 2H); 13C NMR (CDCl3) d 9.6, 13.7,
18.1, 25.8, 27.4, 29.1, 64.4, 114.6, 119.8, 129.4, 137.4, 138.0,
159.0; HRMS (EI) calcd for C23H40OSn (Mþ) 452.2101, found
452.2107.
1
(lit.14 mp 117e117.5 ꢁC). H NMR (CDCl3) d 4.75 (s, 2H),
7.31e7.35 (m, 5H); 13C NMR (CDCl3) d 43.1, 128.2, 128.7,
128.8, 129.4, 135.1, 163.5. Anal. Calcd for C11H7O2NBr2:
C, 38.30; H, 2.05; N, 4.06; O, 9.28. Found: C, 38.59; H,
1.74; N, 4.22; O, 9.23.
4.1.3. N-Benzyl-3-bromo-4-isobutylmaleimide (12)
A
solution of benzyldibromomaleimide 11 (1.04 g,
3.0 mmol) and CuI (0.02 g, 0.1 mmol) in anhydrous THF
(30.0 mL) was cooled down to 0 ꢁC under N2 pressure for
20 min. The commercially available Grignard reagent
(isobutyl magnesium bromide; 2 M, 2.2 mL) was added
dropwise at 0 ꢁC, and allowed to warm to room temperature.
After stirring for 8 h at room temperature, the reaction mixture
was quenched with saturated aqueous NH4Cl (1.2 mL) and
added MgSO4 for the removal of water. The resulting solution
was filtered and the filtrate evaporated. The product was
isolated by flash column chromatography (SiO2, 9:1 cyclohex-
4.1.6. N-Benzyl-3-isobutyl-4-[4-(3-methyl-2-butenyloxy)-
phenyl]maleimide (14)
Bromide 12 (0.52 g, 1.6 mmol), tetrakis(triphenylphos-
phine)palladium(0) (0.18 g, 10 mol %), and stannane 13
(0.73 g, 1.6 mmol) were introduced into a sealable tube con-
taining anhydrous dioxane (10.0 mL), and the reaction mixture
degassed. The tube was sealed and heated for 5 h at 145 ꢁC,
after cooling, and the solution was filtered and evaporated in
vacuo. The filtrate residue was subjected to flash chromatogra-
phy (SiO2, 1:3 CH2Cl2/diethyl ether) to provide the desired 14
1
ane/CH2Cl2) to give 12 (0.59 g, 61%) as an oil. H NMR
(CDCl3) d 0.95 (d, J¼7.2 Hz, 6H), 2.08 (sep, J¼7.2 Hz,
1H), 2.35 (d, J¼7.2 Hz, 2H), 4.69 (s, 2H), 7.27e7.36 (m,
5H); 13C NMR (CDCl3) d 22.6, 27.8, 34.1, 42.2, 125.5,
127.9, 128.4, 128.6, 135.8, 145.1, 165.1, 168.9; HRMS (EI)
calcd for C15H16O2NBr (Mþ) 321.0368, found 321.0363.
1
(0.61 g, 94%) as a light green-yellow oil. H NMR (CDCl3)
d 0.89 (d, J¼7.2 Hz, 6H), 1.87 (s, 3H), 1.88 (s, 3H), 2.07
(sep, J¼7.2 Hz, 1H), 2.51 (d, J¼7.2 Hz, 2H), 4.55 (d,
J¼6.6 Hz, 2H), 4.72 (s, 2H), 5.49 (br t, J¼6.6 Hz, 1H), 6.96
(d, J¼9.0 Hz, 2H), 7.49 (d, J¼9.0 Hz, 2H), 7.24e7.40 (m,
5H); 13C NMR (CDCl3) d 18.2, 22.7, 25.8, 28.1, 32.9, 41.7,
64.8, 114.7, 119.2, 121.4, 127.7, 128.4, 128.6, 130.9, 136.7,
137.7, 138.1, 138.6, 159.9, 171.1, 171.9; HRMS (EI) calcd
for C26H29O3N (Mþ) 403.2147, found 403.2149.
4.1.4. 4-[(3-Methyl-2-butenyloxy)phenyl]bromide
This compound was prepared as a colorless oil from
4-bromophenol according to the procedure of Bernard.7 To
a mixture of 4-bromophenol (10.0 g, 57.8 mmol), KI (0.58 g,
3.5 mmol), and K2CO3 (19.94 g, 144.5 mmol) in acetone
(100.0 mL) was added 3-methyl-2-butenyl bromide (11.20 g,
75.1 mmol) at room temperature, and then refluxed at 80 ꢁC

C.-F. Cheng et al. / Tetrahedron 64 (2008) 4347e4353
4351
4.1.7. 3-Isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]furan-
2,5-dione (1)
portion of NaBH4 (29 mg, 0.8 mmol) and stirred for 30 min,
followed by the other portion of NaBH4 (29 mg, 0.8 mmol) at
room temperature. The suspension was allowed to stir for 4 h
and then quenched with saturated aqueous NH4Cl, which was
extracted with CH2Cl2 (3ꢂ20.0 mL). After the removal of
solvent, the yellow residue was subjected to column chromatog-
raphy (SiO2, 10:1:0.005 hexane/diethyl ether/AcOH) to provide
15 (0.10 g, 65%) as a light yellow oil. 1H NMR (CDCl3) d 0.73
(d, J¼6.0 Hz, 3H), 0.81 (d, J¼6.0 Hz, 3H), 1.49e1.73 (m, 1H),
1.49e1.73 (m, 1H), 1.73 (s, 3H), 1.79 (s, 3H), 1.84 (sep,
J¼6.0 Hz, 1H), 2.91 (td, J¼5.4, 4.8 Hz, 1H), 3.55 (d, J¼
4.8 Hz, 1H), 4.48 (d, J¼6.9 Hz, 2H), 4.70 (ABq, J¼14.4 Hz,
2H), 5.47 (br t, J¼6.9 Hz, 1H), 6.86 (d, J¼8.7 Hz, 2H), 7.03
(d, J¼8.7 Hz, 2H), 7.27e7.39 (m, 5H); 13C NMR [(CD3)2CO]
d 17.4, 20.8, 22.6, 25.0, 25.3, 40.3, 42.0, 46.9, 52.3, 64.5,
114.8, 120.2, 127.5, 128.0, 128.5, 129.2, 129.9, 136.7, 136.8,
158.4, 176.8, 178.5; MS (EI) m/z 405 (Mþ, 4), 337 (16), 281
(100), 203 (27), 133 (99), 91 (56), 69 (27); HRMS (EI) calcd
for C26H31NO3 (Mþ) 405.2304, found 405.2300.
A mixture of benzyl maleimide 14 (0.45 g, 1.1 mmol) in
THF/MeOH (50.0/50.0 mL), water (50.0 mL), and KOH
(0.43 g) was refluxed for 3 h. After it was poured into water,
acidified with 1 N HCl, and then extracted with EtOAc. The
organic phase was washed with saturated aqueous NaHCO3
and brine, and then dried over MgSO4. After removal of the sol-
vent, the residue was purified by flash chromatography (SiO2,
7:3 EtOAc/cyclohexane) to provide 1 (0.32 g, 92%) as an oil.
1H NMR (CDCl3) d 0.94 (d, J¼7.2 Hz, 6H), 1.77 (s, 3H), 1.82
(s, 3H), 2.13 (sep, J¼7.2 Hz, 1H), 2.60 (d, J¼7.2 Hz, 2H),
4.55 (d, J¼6.6 Hz, 2H), 5.50 (br t, J¼6.6 Hz, 1H), 7.02 (d,
J¼9.0 Hz, 2H), 7.62 (d, J¼9.0 Hz, 2H); 13C NMR (CDCl3)
d 18.2, 22.7, 25.8, 27.9, 33.6, 65.0, 115.1, 118.9, 119.9, 131.1,
139.0, 139.8, 140.2, 160.9, 165.4, 166.4; HRMS (EI) calcd for
C19H22O4 (Mþ) 314.1518, found 314.1513.
4.1.8. 3-Isobutyl-4-[4-(3-methyl-2-butenyloxy)phenyl]-1H-
pyrrol-2,5-dione (2)
A solution of furandione 1 (0.22 g, 0.7 mmol) and ammo-
nium acetate (0.32 g, 4.2 mmol) in acetic acid (20.0 mL) was
heated at reflux for 24 h. After cooling, the solvent was removed
in vacuo and the resulting solid was subjected to column
chromatography (SiO2, 1:1 diethyl ether/CH2Cl2) to obtain 2
(0.19 g, 88%) as a white solid, mp 104.5e105 ꢁC (lit.1 mp
4.1.11. N-Benzyloxy-3-isobutyl-4-[4-(3-methylbutenyloxy)-
phenyl]-1H-pyrrol-2,5-dione (16)
To a mixture of 3 (0.15 g, 0.5 mmol) and K2CO3 (0.19 g,
1.4 mmol) in acetone (5.0 mL) was added BnBr (60.0 mL,
0.5 mmol) at room temperature, and then refluxed at 65 ꢁC for
12 h. After cooling, the solution was evaporated in vacuo, and
the brown solid was subjected to flash chromatography (SiO2,
1:15 EtOAc/hexane) to give 16 (0.19 g, 0.5 mmol) in 100%
1
110e111 ꢁC). H NMR (CDCl3) d 0.90 (d, J¼7.2 Hz, 6H),
1.76 (s, 3H), 1.81 (s, 3H), 2.06 (sep, J¼7.2 Hz, 1H), 2.51 (d,
J¼7.2 Hz, 2H), 4.56 (d, J¼6.9 Hz, 2H), 5.50 (br t, J¼6.9 Hz,
1H), 6.99 (d, J¼6.9 Hz, 2H), 7.51 (d, J¼6.9 Hz, 2H), 7.69 (br
s, NH); 13C NMR (CDCl3) d 18.2, 22.7, 25.8, 28.1, 32.8, 64.9,
114.8, 119.2, 121.1, 130.9, 138.6, 138.7, 139.1, 160.0, 171.3,
171.9; HRMS (EI) calcd for C19H23NO3 (Mþ) 313.1678, found
313.1676.
1
yield. H NMR (CDCl3) d 0.88 (d, J¼7.2 Hz, 6H), 1.75 (s,
3H), 1.81 (s, 3H), 2.00 (sep, J¼7.2 Hz, 1H), 2.47 (d,
J¼7.2 Hz, 2H), 4.55 (d, J¼6.6 Hz, 2H), 5.15 (s, 2H), 5.49 (br
t, J¼6.6 Hz, 1H), 6.97 (d, J¼8.7 Hz, 2H), 7.48 (d, J¼8.7 Hz,
2H), 7.36e7.53 (m, 5H); 13C NMR (CDCl3) d 18.2, 22.6, 25.8,
28.0, 32.9, 64.8, 79.5, 114.8, 119.1, 120.8, 128.5, 129.2, 129.8,
130.9, 134.0, 135.4, 135.7, 138.7, 160.1, 167.0, 167.7; HRMS
(EI) calcd for C26H29NO4 (Mþ) 419.2097, found 419.2099.
4.1.9. 1-Hydroxy-3-isobutyl-4-[4-(3-methyl-2-butenyloxy)-
phenyl]-1H-pyrrol-2,5-dione (3)
A mixture of furandione 1 (0.19 g, 0.6 mmol) and hydroxyl-
amine hydrochloride (0.10 g, 1.4 mmol) in pyridine (10.0 mL)
was heated at reflux for 2 h. After cooling, the solvent was
removed in vacuo and the resulting solid was subjected to
column chromatography (SiO2, 1:10 EtOAc/cyclohexane) to
4.1.12. (ꢀ)-trans-3-Isobutyl-4-[4-(3-methylbutenyloxy)-
phenyl]pyrrolidine-2,5-dione (17)
A solution of 2 (0.25 g, 0.8 mmol) in THF (8.0 mL) was
introduced into the pre-dissolved solution of Ni(OAc)2$4H2O
(0.20 g, 0.8 mmol) in MeOH (8.0 mL) and stirred for 30 min
at ambient temperature. To the resulting mixture was added
one portion of NaBH4 (58 mg, 1.6 mmol) and stirred for
30 min, followed by the other portion of NaBH4 (58 mg,
1.6 mmol) at ambient temperature. The suspension was allowed
to stir for 4 h and then quenched with saturated aqueous NH4Cl,
which was extracted with CH2Cl2 (3ꢂ20.0 mL). After the
removal of solvent, the yellow residue was subjected to column
chromatography (SiO2, 1:3 EtOAc/cyclohexane) to provide 17
1
obtain 3 (0.16 g, 82%) as a colorless oil. H NMR (CDCl3)
d 0.89 (d, J¼7.2 Hz, 6H), 1.76 (s, 3H), 1.81 (s, 3H), 2.04 (sep,
J¼7.2 Hz, 1H), 2.51 (d, J¼7.2 Hz, 2H), 4.56 (d, J¼6.6 Hz,
2H), 5.49 (br t, J¼6.6 Hz, 1H), 6.98 (d, J¼8.7 Hz, 2H), 7.51
(d, J¼8.7 Hz, 2H), 8.53 (br s, 1H); 13C NMR (CDCl3) d 18.2,
22.7, 25.8, 28.1, 33.0, 64.9, 114.9, 119.0, 120.7, 131.0, 135.8,
135.9, 138.9, 160.2, 168.2, 168.9; HRMS (EI) calcd for
C19H23NO4 (Mþ) 329.1627, found 329.1619.
1
(0.19 g, 78%, cis/trans 1:2) as a light yellow oil. H NMR
4.1.10. (ꢀ)-trans-1-Benzyl-3-isobutyl-4-[4-(3-methyl-2-but-
enyloxy)phenyl]pyrrolidine-2,5-dione (15)
A solution of 14 (0.16 g, 0.4 mmol) in THF (5.0 mL) was in-
troduced into the pre-dissolved solution of Ni(OAc)2$4H2O
(0.10 g, 0.4 mmol) in MeOH (5.0 mL) and stirred for 30 min
at room temperature. To the resulting mixture was added one
(CDCl3) d 0.73 (d, J¼6.3 Hz, 3H), 0.91 (d, J¼6.3 Hz, 3H),
1.53e1.89 (m, 1H), 1.53e1.89 (m, 1H), 1.74 (s, 3H), 1.77 (s,
3H), 1.86 (sep, J¼6.3 Hz, 1H), 2.98 (td, J¼5.4, 4.8 Hz, 1H),
3.60 (d, J¼4.8 Hz, 1H), 4.49 (d, J¼6.9 Hz, 2H), 5.49 (br t,
J¼6.9 Hz, 1H), 6.90 (d, J¼8.7 Hz, 2H), 7.12 (d, J¼8.7 Hz,
2H), 8.86 (br s, 1H); 13C NMR (CDCl3) d 18.2, 21.3, 23.0,

4352
C.-F. Cheng et al. / Tetrahedron 64 (2008) 4347e4353
25.5, 25.8, 40.5, 48.2, 53.7, 64.7, 115.3, 119.4, 128.5, 128.7,
138.4, 158.5, 178.1, 179.9; HRMS (EI) calcd for C19H25NO3
(Mþ) 315.1834, found 315.1837.
water (2.0 mL), and extracted with CH2Cl2 (3ꢂ5.0 mL). After
removal of the solvent, the residue was subjected to column
chromatography (SiO2, 1:2 EtOAc/cyclohexane) to provide 5
1
(0.035 g, 27%) and 4 (0.070 g, 53%) as a colorless oil. H
4.1.13. (ꢀ)-cis-3-Isobutyl-4-[4-(3-methylbutenyloxy)-
phenyl]pyrrolidine-2,5-dione (17)
NMR (CDCl3) d 0.67 (d, J¼6.0 Hz, 3H), 0.81 (d, J¼6.0 Hz,
3H), 1.03 (m, 1H), 1.44e1.48 (m, 1H), 1.44e1.48 (m, 1H),
1.73 (s, 3H), 1.79 (s, 3H), 3.09 (m, 1H), 4.08 (d, J¼8.4 Hz,
1H), 4.48 (d, J¼6.6 Hz, 2H), 5.47 (br t, J¼6.6 Hz, 1H), 6.85
(d, J¼8.4 Hz, 2H), 6.97 (d, J¼8.4 Hz, 2H); 13C NMR (CDCl3)
d 18.2, 21.7, 22.4, 25.2, 25.8, 35.3, 40.2, 47.4, 64.8, 115.0,
119.3, 125.3, 130.2, 138.3, 158.6, 174.1, 175.5; HRMS (EI)
calcd for C19H25NO4 (Mþ) 331.1784, found 331.1791.
1H NMR (CDCl3) d 0.67 (d, J¼6.3 Hz, 3H), 0.81 (d,
J¼6.3 Hz, 3H), 1.47e1.52 (m, 1H), 1.47e1.52 (m, 1H), 1.74
(s, 3H), 1.79 (s, 3H), 1.79 (sep, J¼6.3 Hz, 1H), 3.13 (dt, J¼9.0,
5.4 Hz, 1H), 4.11 (d, J¼9.0 Hz, 1H), 4.49 (d, J¼6.6 Hz, 2H),
5.48 (br t, J¼6.6 Hz, 1H), 6.88 (d, J¼8.7 Hz, 2H), 7.02 (d,
J¼8.7 Hz, 2H), 9.04 (br s, 1H); 13C NMR (CDCl3) d 18.1,
21.7, 22.5, 25.3, 25.8, 35.2, 44.1, 51.4, 64.8, 115.0, 119.4,
125.8, 130.0, 138.3, 158.4, 178.6, 180.4; MS (EI) m/z 315
(Mþ, 1), 247 (26), 191 (100), 176 (14), 133 (84), 69 (30);
HRMS (EI) calcd for C19H25NO3 (Mþ) 315.1834, found
315.1833.
4.1.17. N-Benzyl-3-benzyl-4-[4-(3-methyl-2-butenyloxy)-
phenyl]maleimide (19)
This compound was prepared as a colorless oil from 11
according to the procedure of Kelly.8f 1H NMR (CDCl3) d 1.74
(s, 3H), 1.80 (s, 3H), 3.95 (s, 2H), 4.53 (d, J¼6.6 Hz, 2H), 4.72
(s, 2H), 5.48 (br t, J¼6.6 Hz, 1H), 6.94 (d, J¼9.0 Hz, 2H),
7.53 (d, J¼9.0 Hz, 2H), 7.14e7.41 (m, 5H), 7.14e7.41 (m,
5H); 13C NMR (CDCl3) d 18.2, 25.8, 29.9, 41.8, 64.8, 114.8,
119.1, 121.0, 126.7, 127.7, 128.4, 128.5, 128.6, 128.8, 131.1,
135.9, 136.5, 137.3, 138.2, 138.7, 160.2, 171.0, 171.6; HRMS
(EI) calcd for C29H27NO3 (Mþ) 437.1991, found 437.1997.
4.1.14. (ꢀ)-trans-1-(tert-Butoxycarbonyl)-3-isobutyl-4-[4-
(3-methyl-2-butenyloxy)phenyl]pyrrolidine-2,5-dione (18)
To a mixture of 17 (0.19 g, 0.6 mmol) and DMAP (7.3 mg,
0.06 mmol) in CH3CN was added Boc2O (0.14 g, 0.7 mmol)
dropwise at 0 ꢁC. Stirring continued at 0 ꢁC for 30 min and at
room temperature for 1 h. Evaporation and chromatography
(SiO2, 1:9 EtOAc/hexane) gave 18 (0.23 g, 94%) as a yellow
oil. 1H NMR (CDCl3) d 0.74 (d, J¼6.3 Hz, 3H), 0.90 (d,
J¼6.3 Hz, 3H), 1.48e1.65 (m, 1H), 1.58 (s, 9H), 1.74 (s, 3H),
1.77 (s, 3H), 1.80e1.91 (m, 1H), 1.80e1.91 (m, 1H), 2.99 (m,
1H), 3.60 (d, J¼6.0 Hz, 1H), 4.50 (d, J¼6.6 Hz, 2H), 5.48 (br
t, J¼6.6 Hz, 1H), 6.91 (d, J¼8.7 Hz, 2H), 7.13 (d, J¼8.7 Hz,
2H); 13C NMR (CDCl3) d 18.2, 21.4, 22.9, 25.5, 25.8, 27.7,
40.4, 47.0, 52.9, 64.8, 86.2, 115.3, 119.4, 127.9, 128.9, 138.4,
146.5, 158.6, 173.3, 175.2; HRMS (EI) calcd for C24H23NO5
(Mþ) 415.2359, found 415.2360.
4.1.18. 3-Benzyl-4-[4-(3-methyl-2-butenyloxy)phenyl]furan-
2,5-dione (6)
A mixture of benzyl maleimide 19 (0.21 g, 0.5 mmol) in
THF/MeOH (20.0 mL/20.0 mL), water (20.0 mL), and KOH
(0.23 g) was refluxed for 3 h. After it was poured into water,
acidified with 1 N HCl, and then extracted with EtOAc, the
organic phase was washed with saturated aqueous NaHCO3
and brine and then was dried over MgSO4. After removal of
the solvent, the residue was purified by flash chromatography
(SiO2, 1:1 CH2Cl2/hexane) to provide 6 (0.14 g, 81%) as an
1
4.1.15. (ꢀ)-trans-1-Hydroxy-3-isobutyl-4-[4-(3-methyl-2-
butenyloxy)phenyl]pyrrolidine-2,5-dione (5)
oil. H NMR (CDCl3) d 1.75 (s, 3H), 1.81 (s, 3H), 4.03 (s,
2H), 4.57 (d, J¼6.9 Hz, 2H), 5.48 (br t, J¼6.9 Hz, 1H), 6.99
(d, J¼9.0 Hz, 2H), 7.63 (d, J¼9.0 Hz, 2H), 7.21 (d,
J¼7.4 Hz, 2H), 7.25e7.35 (m, 3H); 13C NMR (CDCl3)
d 18.2, 25.8, 30.5, 65.0, 115.2, 118.8, 119.5, 127.3, 128.3,
129.1, 131.3, 135.7, 137.4, 139.0, 140.6, 161.3, 165.3,
166.2; HRMS (EI) calcd for C22H20O4 (Mþ) 348.1362, found
348.1366.
Toa solutionof18(0.17 g, 0.4 mmol)inCH3CN was added an
excess (50 wt %) aqueous solution of NH2OH (0.2 mL,
3.4 mmol) at ambient temperature. The mixture was allowed to
stir for 1 h, and followed by removal of the solvent in vacuo
and the resulting solid was subjected to column chromatography
(SiO2, 6:1CH2Cl2/EtOAc)toobtain5(0.10 g,77%)asacolorless
oil. 1H NMR (CDCl3) d 0.69 (d, J¼6.0 Hz, 3H), 0.89 (d,
J¼6.0 Hz, 3H), 1.51 (m, 1H), 1.73 (s, 3H), 1.79 (s, 3H),
1.72e1.84 (m, 1H), 1.72e1.84 (m, 1H), 2.87 (m, 1H), 3.52 (d,
J¼4.2 Hz, 1H), 4.47 (d, J¼6.6 Hz, 2H), 5.47 (br t, J¼6.6 Hz,
1H), 6.87 (d, J¼8.4 Hz, 2H), 7.08 (d, J¼8.4 Hz, 2H); 13C NMR
(CDCl3) d 18.2, 21.3, 23.0, 25.3, 25.8, 40.3, 44.6, 49.8, 64.7,
115.3, 119.3, 128.0, 128.9, 138.4, 158.6, 173.4, 175.1; HRMS
(EI) calcd for C19H25NO4 (Mþ) 331.1784, found 331.1792.
4.1.19. 1-Hyroxy-3-benzyl-4-[4-(3-methyl-2-butenyloxy)-
phenyl]-1H-pyrrol-2,5-dione (7)
A mixture of furandione 6 (0.16 g, 0.5 mmol) and hydroxyl-
amine hydrochloride (0.13 g, 1.8 mmol) in pyridine (10.0 mL)
was heated at reflux for 2 h. After cooling, the solvent was
removed in vacuo and the resulting solid was subjected to col-
umn chromatography (SiO2, 1:3 EtOAc/hexane) to obtain 7
1
(0.14 g, 84%) as a colorless oil. H NMR (CDCl3) d 1.75 (s,
4.1.16. (ꢀ)-cis-1-Hydroxy-3-isobutyl-4-[4-(3-methyl-2-
butenyloxy)phenyl]pyrrolidine-2,5-dione (4)
To a solution of 3 (0.13 g, 0.4 mmol) in 5.0 mL of acetic acid
was added Zn dust (3.9 mmol) in one portion. The mixture was
stirred at room temperature for 2 h, quenched by addition of
3H), 1.80 (s, 3H), 3.94 (s, 2H), 4.54 (d, J¼6.6 Hz, 2H), 5.48
(br t, J¼6.6 Hz, 1H), 6.96 (d, J¼9.0 Hz, 2H), 7.54 (d,
J¼9.0 Hz, 2H), 7.16e7.30 (m, 5H), 8.15 (br s, 1H); 13C NMR
(CDCl3) d 18.2, 25.8, 29.9, 64.9, 115.0, 119.0, 120.3, 126.9,
128.3, 128.9, 131.1, 133.5, 136.2, 136.7, 138.8, 160.6, 167.9,

C.-F. Cheng et al. / Tetrahedron 64 (2008) 4347e4353
4353
168.5; HRMS (EI) calcd for C22H21NO4 (Mþ) 363.1471, found
363.1469.
References and notes
1. (a) Adlington, R. M.; Baldwin, J. E.; Cox, R. J.; Pritchard, G. J. Synlett
2002, 820 and references therein; (b) Nakamura, N.; Hirakawa, A.;
Gao, J. J.; Kakuda, H.; Shiro, M.; Komatsu, Y.; Sheu, C. C.; Hattori, M.
J. Nat. Prod. 2004, 67, 46.
4.1.20. (ꢀ)-cis-1-Hydroxy-3-benzyl-4-[4-(3-methyl-2-but-
enyloxy)phenyl]pyrrolidine-2,5-dione (8)
2. Tsai, Z. T.; Liaw, S. L. The Use and the Effect of Ganoderma; Sheng-Yun:
Taichung, Taiwan, 1982; p 116.
To a solution of 7 (0.079 g, 0.2 mmol) in 4.0 mL of acetic
acid was added Zn dust (1.6 mmol) in one portion. The mixture
was stirred at room temperature for 2 h, quenched by addition of
water (1.0 mL), and extracted with CH2Cl2 (3ꢂ5.0 mL). After
removal of the solvent, the residue was subjected to column
chromatography (SiO2, 1:2 EtOAc/cyclohexane) to provide
the single diastereomer 8 (0.045 g, 57%) as a colorless oil. 1H
NMR (CDCl3) d 1.59 (s, 3H), 1.62 (s, 3H), 2.43 (dd, J¼15.0,
10.5 Hz, 1H), 3.18 (dd, J¼15.0, 4.5 Hz, 1H), 3.48 (m, 1H),
4.02 (d, J¼8.7 Hz, 1H), 4.47 (d, J¼6.9 Hz, 2H), 5.47 (br t,
J¼6.9 Hz, 1H), 6.70e6.76 (br s, 2H), 6.84 (br s, 4H),
7.08e7.21 (br s, 3H); 13C NMR (CDCl3) d 18.2, 25.8, 31.6,
43.7, 47.0, 64.8, 114.9, 119.3, 124.8, 126.4, 128.2, 128.4,
130.3, 137.4, 138.4, 158.7, 173.4, 174.1; HRMS (EI) calcd for
C22H23NO4 (Mþ) 365.1627, found 365.1626.
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Acknowledgements
We thank the National Science Council of the Republic of
China for financial support (Research Grants NSC 94-2113-
M-018-003 and 95-2113-M-018-004). We also acknowledge
with appreciation to the former High School research participants
Mr. Xin-QuanChen,MissPei-XingLai, Yi-ChangLee, Lei-Ming
Kuo, Yi-Xun Xie, and M.S. Shun-Yu Lin for pioneer studies.
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Supplementary data
13. Autoclave, a PTFE-lined vessel No. 4749, was purchased from Parr
Instrument Company, USA.
14. Joyce, R. P.; Gainor, J. A.; Weinreb, S. M. J. Org. Chem. 1987, 52, 1177.
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.02.077.