Selective reduction of nitrocinnamoylfumagillols with α,β- unsaturated ester using Borohydride Exchange Resin (BER) - nickel acetate

Article abstract of DOI:10.3987/COM-05-10425

Borohydride Exchange Resin (BER) - nickel acetate system readily reduces nitrocinnamoylfumagillols to the corresponding amines in excellent yields, high chemoselectivity, and simple procedure. Especially, this system tolerates two epoxides (spiro-epoxide

Full text of DOI:10.3987/COM-05-10425

HETEROCYCLES, Vol. 65, No. 8, 2005
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HETEROCYCLES, Vol. 65, No. 8, 2005, pp. 1843 - 1856
Received, 8th April, 2005, Accepted, 13th May, 2005, Published online, 17th May, 2005
SELECTIVE REDUCTION OF NITROCINNAMOYLFUMAGILLOLS
WITH α,β-UNSATURATED ESTER USING BOROHYDRIDE
EXCHANGE RESIN (BER) - NICKELACETATE
Hong Woo Lee*, Joong Bok Ahn, Jung Hwa Lee, Sung Kwon Kang,
Soon Kil Ahn, and Sang Joon Lee
Chemical Process Development Labs, New Drug Research Labs,
Chong Kun Dang Research Institute
Cheonan P.O. Box 74, Cheonan, 330-831, South Korea
Abstract – Borohydride Exchange Resin (BER) – nickel acetate system readily
reduces nitrocinnamoylfumagillols to the corresponding amines in excellent
yields, high chemoselectivity, and simple procedure. Especially, this system
tolerates two epoxides (spiro-epoxide and the one on C4 alkene side chain) and
the α,β-unsaturated ester moiety at C6 on the fumagillol.
Fumagillin (1a), a natural product isolated from Aspergillius fumigatus, has been shown to inhibit the
growth of endothelial cell proliferation,1,2 and several analogues, especially including TNP-470 (1b)3 and
CKD-732 (1c),4 had been semi-synthesis and presently in clinical trials (Scheme 1). From the results of
the our biological tests, we found that the new aminocinnamoylfumagillol derivatives (8a-e) showed
excellent in vitro and in vivo activity than previous reported references.3,4 For further pharmacological
studies, we needed to hundreds grams scale of the new fumagillols. The selective reduction of nitro
compounds to corresponding amines is an important reaction in organic synthesis. Especially, our new

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HETEROCYCLES, Vol. 65, No. 8, 2005
aminofumagillol derivatives (8a-e), having two epoxides (spiro-epoxide and the one on C4 alkene side
chain) and the α,β-unsaturated ester at C6 position, were needed strict choice of reducing reagents.
OCH3
O
H
R
O
5
6
7
4
3
2
O
8
1O
1
O
1a Fumagillin R =
OH
N
H
N
1b TNP-470 R =
Cl
O
O
1c CKD-732 R =
Scheme 1
5
6
First, we tried on selective reduction with NaBH4 using NiCl2 or SnCl2 as catalysts, because, they were
reported that they exhibits enhanced reducing abilities when compared with NaBH4 itself. However, none
of these methods gave satisfied results in two requiring points, yields and selective reduction, although
these low yields of nitrofumagillols with α,β-unsaturated ester were improved substantially in the
presence of phase transfer catalysts.7 With the aim to obtain excellent selective reductions and high yields,
recently, our extensive efforts were focused on the borohydride exchange resin (BER) introduced by
Gibson and Baily8 in 1977, and further modified by Yoon et al.9 As a result, we found that borohydride
exchange resin (BER) - Ni(OAc)2 system was an excellent chemoselective reduction reagent for nitro
compounds to the corresponding amines10 compared with NaBH4 - NiCl2. In addition, another advantage
of this procedure was very simple workup, because BER - Ni(OAc)2 was easily removed by filtration.
Therefore, in this paper, we wish to report that BER - Ni(OAc)2 system chemoselectively reduced
nitrocinnamoylfumagillols to the corresponding aminocinnamoylfumagillols in excellent yields by
o
handling for 1-2.5 h at 0 C without any generating byproducts. First of all, in order to find optimal
conditions, we tried model studies with suitable nitrocinnamic acids methyl ester or coumarins having a
α,β-unsaturated ester system (Scheme 2). The procedure is very simple. For the nitro compounds with

HETEROCYCLES, Vol. 65, No. 8, 2005
1845
α,β-unsaturated ester system, BER (30 mmol, 3.0 equiv.) was added to Ni(OAc)2·4H2O (1.5 mmol, 0.15
equiv.) in methanol at 0 ℃. After five min, the nitro compounds (10 mmol, 1.0 equiv.) was added, and
whole was stirred at room temperature for 30 min. BER (30 mmol, 3.0 equiv.) was added once more and
stirring was continued for additional 30 min to 2 h in the same temperature. These reactions were
completed in 1-2.5 h at room temperature giving 90% to quantitative isolated yield.
O
O
R
R
R
R
OCH3
OCH3
BER - Ni(OAc)2, CH3OH
rt, 1-2.5 h, 96% - quantitative
NH2
NO2
3a-d
2a-d
NO2: o-, m-, p- position, R: H or OCH3
O
R
R
R
R
O
O
O
NH2
BER - Ni(OAc)2, CH3OH
rt, 1-2 h, 92%
NO2
OH
OH
R : H or OCH3
5a-b
4a-b
1
8
5
O
O
BER - Ni(OAc)2, CH3OH
rt, 1-2 h, 90%
O
O
2
3
7
H2N
R
O2N
R
6
4
OH
OH
O
O
R :
7a-b
or
6a-b
Scheme 2
As shown in Scheme 2, o-, m-, and p-nitrocinnamic acid methyl esters (2a-c) and 2-nitro-4,5-
dimethoxycinnamic acid methyl ester (2d) were converted to the corresponding aminocinnamic acid
methyl esters (3a-d) in 96% to quantitative yields by chemoselective reduction with BER - Ni(OAc)2 at
room temperature in methanol. We also found that BER - Ni(OAc)2 system was readily and effectively
reduced both 3-nitrocoumarins (4a-b) and 6-nitrocoumarins (6a-b) to the corresponding aminocoumarins
(5a-b, 7a and b) in excellent yields (90-95%) at room temperature without any generating byproducts
respectively. The results are summarized in Table 1. On the basis of our model studies, we next have
applied for a series of our novel fumagillol compounds, which have two epoxides (spiro-epoxide and the

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HETEROCYCLES, Vol. 65, No. 8, 2005
one on C4 alkene side chain) and the α,β-unsaturated ester moiety at C6 as depicted in Scheme 3.
Table 1. Reduction of nitro compounds to the corresponding amino compounds
with BER - Ni(OAc)2 in methanol at room temperature.
Reactionb)
Time (h)
Yield
(%)
Nitro Substrate
Amino Producta)
O
O
O
OCH
3
2a
2b
3a
3b
OCH
3
quantitative
96
1.0
1.5
NO
2
NH
2
O
OCH
3
OCH
3
NO
2
NH
2
O
O
O
OCH
OCH
OCH
3
3
quantitative
98
0.5
2.5
2c
2d
4a
4b
3c
3d
5a
5b
O N
2
H N
2
O
CH O
CH O
3
OCH
3
3
3
NO
CH O
NH
2
2
3
CH O
3
O
O
O
O
92
95
2.0
1.0
NO
NH
2
2
OH
O
OH
CH O
O
3
CH O
O
O
3
CH O
NO
2
3
CH O
NH
2
3
OH
OH
O
O
O
O
O
O
6a
6b
7a
7b
O N
2
1.0
2.0
90
90
H N
2
OH
O
OH
O
O
O
O
O
O N
2
H N
2
OH
OH
a) Reductions were monitored by HPLC or TLC. b) Nitro compounds (10 mmol, 1 equiv.) were added to
the reaction mixture of BER (60 mmol, 6 equiv.) and Ni(OAc)2 (1.5 mmol, 0.15 equiv.) in methanol at rt.
The reaction mixture was then stirred at room temperature for 0.5-2.5 h.
First, the same procedure was applied to the new fumagillol derivatives reduction. Against our
expectation, five nitrocinnamoylfumagillol derivatives (8a-e) gave a several byproducts showing low
yields relatively. Considering these results and the chemical property of fumagillols structure, first, we

HETEROCYCLES, Vol. 65, No. 8, 2005
1847
tried to control the reaction temperature range within room temperature to 0 ℃. As shown in Scheme 3,
BER (60 mmol, 6.0 equiv.) was added to Ni(OAc)2 (1.5 mmol, 0.15 equiv.) in methanol. After stirring for
30 min, the nitrocinnamoylfumagillol compound (10 mmol, 1.0 equiv.) was added and the mixture was
stirred at 0 oC for 1-2.5 h. After completion of the conversion to the corresponding amines monitoring by
HPLC and TLC, the resin was filtered off, and the methanol was removed under the reduced pressure to
give the nearly pure products.
O
O
OCH3
OCH3
H
H
R1
R1
O
O
O
O
O
O
9
8
a - ortho
b - meta
c - para
a - ortho
b - meta
c - para
R1 =
NH2
NO2
R1 =
NO2
Cl
NH2
Cl
d
d
e
OCH3
OCH3
OCH3
OCH3
e
NH2
NO2
Scheme 3
In the cases of o-, p-nitrocinnamoylfumagillol compounds, (8a) and (8c), and o-nitro-4,5-
dimethoxycinnamoylfumagillol compound (8e) were chemoselectively reduced to the corresponding
aminocinnamoylfumagillols in excellent yields (92-95%) (see Table 2). However, m-
nitrocinnamoylfumagillol (8b) and m-nitro-3-chlorocinnamoylfumagillol (8d) gave a slightly decreased
yield (85-88%), but exhibited good chemoselectivity (see Table 2). In the cases, by lowing the reaction
o
temperature to 0 C, it was possible to reduce nitrocinnamoylfumagillol compounds chemoselectively
without attacking two epoxides (spiro-epoxide and the one on C4 alkene side chain) and the α,β-
unsaturated ester moiety at C6 on the fumagillol compound. The results are summarized in Table 2. In

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HETEROCYCLES, Vol. 65, No. 8, 2005
conclusion, the nickel boride catalyst prepared on BER (BER - Ni(OAc)2) system in methanol is an
excellent reducing agent for the reduction of nitrocinnamoylfumagillols, possessing two epoxides (spiro-
epoxide and the one on C4 alkene side chain) and additionally having the α,β-unsaturated ester moiety at
C6, to the corresponding aminocinnamoylfumagillols because of its excellent yield (~ quantitative), high
chemoselectivity and simple work up procedure due to removal of BER – Ni(OAc)2 by filtration.
Table 2. Reduction of nitrocinnamoylfumagillols to the corresponding
aminocinnamoylfumagillols with BER - Ni (OAc)2 in methanol at 0 oC.
Reactionb)
Yield
Producta)
Substrate
(%)
Time (h)
OCH
OCH
O
O
O
O
3
3
H
H
H
H
O
O
8a
8b
9a
9b
92
1.5
O
O
O
O
NH
NO
2
2
O
O
O
O
OCH
OCH
3
3
O
O
NH
NH
NO
2.5
1.0
2.5
88
95
2
2
NO
2
2
2
OCH
OCH
O
O
O
O
3
3
H
H
H
H
O
O
9c
8c
O
O
O
O
O
O
O
O
NH
NO
Cl
2
OCH
OCH
3
3
O
O
9d
9e
Cl
85
92
8d
8e
OCH
OCH
3
3
OCH
OCH
3
3
OCH
OCH
O
O
3
3
H
H
1.0
O
O
O
O
NH
NO
2
2
O
O
a) All reactions were monitored by HPLC or TLC. b) Nitrofumagillol compounds (10 mmol, 1.0 equiv.) were added to
the reaction mixture of BER (60 mmol, 6.0 equiv.) and Ni(OAc)2 (1.5 mmol, 0.15 equiv.) in methanol at rt. The reaction
mixture was then stirred at 0 oC for 0.5-2.5 h.

HETEROCYCLES, Vol. 65, No. 8, 2005
1849
EXPERIMENTAL
Commercial available reagents were used without purification. Anion exchange resin (Amberlite IRA-
400) was used supporting the polymer of borohydride exchange resin (BER). All reactions were
conducted under anhydrous condition in solvents dried over molecular sieves type 4Å under nitrogen
atmosphere and performed using oven dried glassware. Melting points were determined on a Büchi 510
capillary apparatus and are uncorrected. IR spectra were recorded on a Bruker Vector 22 FT-IR
spectrophotometer. NMR spectra were recorded on a Bruker DPX 400 MHz instrument operating at 400
MHz for proton and 100 MHz for carbon and were performed in CDCl3 solution using tetramethylsilane
as the internal reference and chemical shift (δ) is reported in ppm downfield from internal
tetramethylsilane. The coupling constants (J) are reported in Hz. MS spectra were recorded on a HP
5989B instrument. Flash chromatography was performed using Merck silica gel 60 (230-400 mesh)
according to the published procedure.10 TLC was performed on glass backed plates pre-coated with silica
(0.2 mm, 60 F254) and developed using standard visualizing agents UV fluorescence (254 and 365 nm),
potassium permanganate and iodine. Nitrophenylacrylic acid methyl ester and nitrocinnamoylfumagillol
compounds were synthesized and purified according to in house procedures.11
General procedure: preparation of Borohydride Exchange Resin (BER).12,13 An aqueous solution of
sodium borohydride (37.8 g, 1.0 mol, 1.0 L) was stirred with wet chloride-form anion exchange resin
(Amberlite IRA-400 [20-50 mesh], 200 g) for 1 h. The resulting resin was washed thoroughly with
distilled water until free from excess NaBH4. The borohydride form anoin exchange resin was analyzed
for borohydride content by hydride evolution on acidification with 2.0 N HCl, and the average hydride
-
content of BER was found to be 3.3 mmol of BH4 per gram. The dried resin was stored under nitrogen in
refrigerator (around at 4 oC). The hydride content was constant over 6 weeks.
General Procedure: 3-(2-aminophenyl)acrylic acid methyl ester (3a). To a stirred suspension of BER
(9.68 g, 28.96 mmol) in dried methanol (50 mL) was added Ni(OAc)2 ·4H2O (0.18 g, 0.72 mmol) at 0 oC.

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HETEROCYCLES, Vol. 65, No. 8, 2005
The reaction mixture was stirred for 30 min. When black coating of nickel boride was observed, 3-(2-
nitrophenyl)acrylic acid methyl ester (1.0 g, 4.82 mmol) in dried methanol (20 mL) was added at the
o
same temperature. After stirring at 0 C for 2.5 h, BER- Ni(OAc)2 was removed by filtration, and the
filtrated was concentrated under the reduced pressure. The obtained residue was purified by column
chromatography on SiO2 with EtOAc-n-Hexane (1:2, v/v) as elution solvent to give 0.86 g (quantitative
yield) as yellowish solid. mp 112-115 oC (from EtOH). IR (KBr) νmax cm-1: 3414 (NH2), 3358, 1701 (CO),
1
1623, 1200. H NMR (400 MHz, CDCl3) δ: 3.78 (s, 3H, CH3), 6.37 (d, 1H, J = 16.0 Hz, -CH=CH-Ph),
6.84 (m, 2H), 7.21 (m, 1H), 7.42 (m, 1H), 7.88 (d, 1H, J = 16.0 Hz, -CH=CH-Ph). 13C NMR (100 MHz,
CDCl3) δ: 51.69, 117.11, 117.93, 119.43, 120.29, 128.13, 131.35, 140.25, 144.91, 167.69. HR-MS m/z
(M+) C10H11NO2 Requires, 177.0787; Found, 177.0786. Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N,
7.90. Found: C, 67.72; H, 6.31; N, 7.95.
3-(3-Aminophenyl)acrylic acid methyl ester (3b). Yield: 0.82 g, 96% as yellowish solid. mp 113-116 oC
(from EtOH). IR (KBr) νmax cm-1: 3446 (NH2), 3355, 1703 (CO), 1633, 1178. 1H NMR (400 MHz, CDCl3)
δ: 3.80 (s, 3H, CH3), 6.38 (d, 1H, J = 16.0 Hz, -CH=CH-Ph), 6.74 (m, 1H), 6.85 (s, 1H), 6.95 (d, 1H, J =
7.8 Hz, -CH=CH-Ph), 7.18 (t, 1H, J = 7.8 Hz), 7.60 (d, 1H, J = 16.0 Hz). 13C NMR (100 MHz, CDCl3) δ:
51.69, 114.14, 117.17, 117.61, 118.75, 129.81, 135.44, 145.19, 146.74, 167.55. HR-MS m/z (M+)
C10H11NO2 Requires, 177.0787; Found, 177.0795. Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90.
Found: C, 67.81; H, 6.22; N, 7.86.
3-(4-Aminophenyl)acrylic acid methyl ester (3c). Yield: 0.86 g, quantitative as yellowish solid. mp
o
1
122-125 C (from EtOH). IR (KBr) νmax cm-1: 3444 (NH2), 3355, 1687 (CO), 1593, 1174. H NMR (400
MHz, CDCl3) δ: 3.78 (s, 3H, CH3), 6.26 (d, 1H, J = 16.0 Hz, -CH=CH-Ph), 6.75 (m, 2H), 7.37 (m, 2H),
13
7.61 (d, 1H, J = 16.0 Hz, -CH=CH-Ph). C NMR (100 MHz, CDCl3) δ: 51.48, 113.33, 114.89, 124.78,
129.92, 145.11, 148.65, 168.12. HR-MS m/z (M+) C10H11NO2 Requires, 177.0787; Found, 177.0793. Anal.
Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.83; H, 6.30; N, 7.85.

HETEROCYCLES, Vol. 65, No. 8, 2005
1851
3-(2-Amino-4,5-dimethoxyphenyl)acrylic acid methyl ester (3d). Yield: 0.87 g, 98% as yellow solid.
o
mp 119-121 C (from EtOH). IR (KBr) νmax cm-1: 3449 (NH2), 3376, 1695 (CO), 1613, 1172. 1H NMR
(400 MHz, CDCl3) δ: 3.77 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.25 (d, 1H, J = 16.0
13
Hz, -CH=CH-Ph), 6.49 (s, 1H), 6.93 (s, 1H), 7.87 (d, 1H, J = 16.0 Hz, -CH=CH-Ph). C NMR (100
MHz, CDCl3) δ: 51.55, 55.85, 56.39, 100.85, 110.08, 111.37, 114.27, 139.66, 141.03, 142.78, 152.60,
168.08. HR-MS m/z (M+) C12H15NO4 Requires, 237.0997, Found, 237.0996. Anal. Calcd for C12H15NO4:
C, 56.75; H, 4.76; N, 6.62. Found: C, 56.82; H; 4.73; N, 6.59.
General Procedure: 3-amino-4-hydroxychromen-2-one (5a). To a stirred suspension of BER (9.59 g,
o
28.68 mmol) in dried methanol (50 mL) was added Ni(OAc)2·4H2O (0.18 g, 0.71 mmol) at 0 C. The
suspension was stirred for 30 min. When black coating of nickel boride was observed, 3-nitro-4-
hydroxychromen-2-one (1.0 g, 4.78 mmol) in dried methanol (20 mL) was added at the same temperature.
o
After stirring at 0 C for 2 h, BER- Ni2B was removed by filtration; and the filtrated was concentrated
under the reduced pressure. The obtained residue was purified by column chromatography on SiO2 with
EtOAc-n-Hexane (1:1, v/v) as elution solvents to give 0.79 g (92% yield) as pale yellowish solid. mp
o
192-196 C (from CH2Cl2/IPA, 5/1, v/v). IR (KBr) νmax cm-1: 3510 (OH), 3424 (NH2), 1757 (CO, ester),
1607. 1H NMR (400 MHz, CDCl3) δ: 7.25 (m, 3H), 7.71 (d, 1H, J = 9.2 Hz). 13C NMR (100 MHz,
CDCl3) δ: 102.67, 121.38, 125.20, 126.75, 127.61, 128.95, 145.62, 150.82, 162.07. HR-MS m/z (M+)
C9H7NO3 Requires, 177.0424; Found, 177.0420. Anal. Calcd for C9H7NO3: C, 61.02; H, 3.98; N, 7.91.
Found: C, 61.11; H, 4.02; N, 7.88.
3-Amino-4-hydroxy-6,7-dimethylchromen-2-one (5b). Yield: 0.84 g, 95% as pale yellowish solid. mp
o
240-243 C (from CH2Cl2/IPA, 5/1, v/v). IR (KBr) νmax cm-1: 3578 (OH), 3413 (NH2), 1760 (CO, ester),
1601. 1H NMR (400 MHz, CDCl3) δ: 2.35 (s, 3H, OCH3), 2.43 (s, 3H, OCH3), 7.01 (s, 1H), 7.46 (s, 1H).
13C NMR (100 MHz, CDCl3) δ: 14.85, 14.99, 102.61, 121.93, 124.74, 127.26, 135.16, 138.09, 145.33,
147.79, 162.06. HR-MS m/z (M+) C11H11NO3 Requires, 205.0736, Found, 205.0737. Anal. Calcd for

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HETEROCYCLES, Vol. 65, No. 8, 2005
C11H11NO3: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.45; H, 5.44; N, 6.81.
6-Amino-4-hydroxy-3-(2-oxopropyl)chromen-2-one (7a). Yield: 0.79 g, 90% as pale yellowish solid.
o
mp 294-297 C (from CH2Cl2/EtOH, 5/1, v/v). IR (KBr) νmax cm-1: 3503 (OH), 3428 (NH2), 1748 (CO,
1
ester), 1709 (CO), 1601. H NMR (400 MHz, CDCl3) δ: 2.21 (s, 3H, CH3), 3.35 (s, 2H, CH2), 6.68 (m,
3H). 13C NMR (100 MHz, CDCl3) δ: 25.12, 35.29, 91.67, 112.64, 114.75, 122.10, 129.32, 140.03, 143.56,
162.75, 165.98, 206.33. HR-MS m/z (M+) C12H11NO4 Requires, 233.0685; Found, 233.0689. Anal. Calcd
for C12H11NO4: C, 61.80; H, 4.75; N, 6.01. Found: C, 61.73; H, 4.73; N, 5.98.
6-Amino-4-hydroxy-3-(2-oxohex-3-enyl)chromen-2-one (7b). Yield: 0.81 g, 90% as pale yellowish
o
solid. mp 317-319 C (from CH2Cl2/EtOH, 5/1, v/v). IR (KBr) νmax cm-1: 3506 (OH), 3420 (NH2), 1751
1
(CO, ester), 1668 (CO), 1604. H NMR (400 MHz, CDCl3) δ: 1.12 (t, 3H, J = 7.56 Hz), 2.06 (m, 2H),
3.77 (s, 2H), 6.15 (d, 1H, J = 16.0 Hz), 6.58 (m, 1H), 6.89 (m, 3H). 13C NMR (100 MHz, CDCl3) δ: 13.78,
19.26, 33.08, 91.56, 113.26, 114.73, 122.15, 128.61, 129.54, 140.88, 142.03, 142.63, 143.47, 162.05,
165.95, 196.57. HR-MS m/z (M+) C15H15NO4 Requires, 273.0997; Found, 273.0992. Anal. Calcd for
C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C, 65.87; H, 5.50; N, 5.16.
General Procedure: 3-(2-aminophenyl)acrylic acid 5-methoxy-4-[2-methyl-3-(3-methylbut-2-enyl)-
oxiranyl]-1-oxaspiro[2.5]oct-6-yl ester (9a). To a stirred suspension of BER (4.38 g, 13.11 mmol) in
methanol (20 mL) was added Ni(OAc)2·4H2O (0.08 g, 0.32 mmol) at 0 oC. The suspension was stirred for
30 min. When black coating of nickel boride was observed, O-[4-(2-nitro)cinnamoyl]fumagillol (1.0 g,
o
2.19 mmol) in methanol (10 mL) was added at the same temperature. After stirring at 0 C for 1.5 h,
BER-Ni2B was removed by filtration; and the methanol was concentrated under the reduced pressure. The
obtained residue was purified by column chromatography on SiO2 as elution solvents EtOAc-n-Hexane
(1:1, v/v) to give 0.86 g (92% yield) as pale yellowish foam. mp 62-64 oC (from n-Hexane). IR (KBr) νmax
1
cm-1: 3453 (NH2), 2927, 1712 (CO), 1640, 1172. H NMR (400 MHz, CDCl3) δ: 1.07 (d, 1H, J = 13.1

HETEROCYCLES, Vol. 65, No. 8, 2005
1853
Hz), 1.23 (s, 3H), 1.62 (s, 3H), 1.71 (s, 3H), 1.89 (m, 2H), 2.00 (m, 2H), 2.15 (m, 3H), 2.37 (m, 1H), 2.58
(d, 2H, J = 4.2 Hz), 2.74 (t, 1H, J = 6.4 Hz)), 2.99 (d, 1H, J = 4.3 Hz), 3.49 (s, 3H), 3.72 (dd, 1H, J = 2.7,
11.3 Hz), 5.17 (t, 1H, J = 7.6 Hz), 5.75 (s, 1H), 6.44 (d, 1H, J = 16.0 Hz, -CH=CH-Ph), 6.97 (m, 1H),
7.04 (d, 1H, J = 7.6 Hz), 7.17 (m, 1H), 7.22 (t, 2H, J = 7.9 Hz), 7.50 (d, 1H, J = 16.0 Hz, -CH=CH-Ph).
13C NMR (100 MHz, CDCl3) δ: 19.21, 19.43, 22.77, 25.22, 26.03, 29.45, 42.37, 49.91, 51.52, 52.09,
53.71, 61.54, 65.78, 73.13, 115.11, 117.75, 118.42, 121.59, 125.88, 127.01, 128.52, 133.18, 142.86,
165.02. HR-MS m/z (M+) Requires C25H33NO5, 427.2350; Found, 427.2352. Anal. Calcd for C25H33NO5:
C, 70.72; H, 7.99; N, 3.17. Found: C, 70.65; H, 7.93; N, 3.15.
3-(3-Aminophenyl)acrylic acid 5-methoxy-4-[2-methyl-3-(3-methylbut-2-enyl)oxiranyl]-1-oxa-
spiro[2.5]oct-6-yl ester (9b). Yield: 0.84 g, 88% as pale yellowish foam. mp 59-62 oC (from n-Hexane).
IR (KBr) νmax cm-1: 3455 (NH2), 3367, 2927, 1708 (CO), 1635, 1168. 1H-NMR (400 MHz, CDCl3) δ: 1.12
(m, 1H), 1.25 (s, 3H), 1.66 (s, 3H), 1.74 (s, 3H), 2.19-1.88 (m, 5H), 2.38 (m, 1H), 2.56 (d, 1H, J = 4.1 Hz),
2.63 (t, 1H, J = 6.3 Hz), 3.00 (d, 1H, J = 4Hz), 3.47 (s, 3H), 3.72 (m, 1H), 5.21 (m, 1H), 5.75 (m, 1H),
6.45 (d, 1H, J = 16.0 Hz, -CH=CH-Ph), 6.75 (m, 1H), 6.88 (s, 1H), 6.93 (m, 1H), 7.20 (m, 1H), 7.66 (d,
1H, J = 16.0 Hz, -CH=CH-Ph). 13C NMR (100 MHz, CDCl3) δ: 19.32, 19.45, 22.73, 25.30, 26.16, 29.49,
42.37, 49.92, 51.88, 52.03, 53.76, 61.59, 65.72, 73.18, 112.8,1 114.33, 116.25, 117.64, 125.80, 129.21,
133.22, 135.73, 142.85, 146.64, 165.01. HR-MS m/z (M+) Requires C25H33NO5, 427.2350, Found,
427.2346. Anal. Calcd for C25H33NO5: C, 70.72; H, 7.99; N, 3.17. Found: C, 70.75; H, 7.95; N, 3.19.
3-(4-Aminophenyl)acrylic acid 5-methoxy-4-[2-methyl-3-(3-methylbut-2-enyl)oxiranyl]-1-oxa-
o
spiro[2.5]oct-6-yl ester (9c). Yield: 0.91 g, 95% as pale yellowish foam. mp 65-68 C (from n-Hexane).
IR (KBr) νmax cm-1: 3461 (NH2), 3365, 2927, 1702 (CO), 1599, 1160. 1H-NMR (400 MHz, CDCl3) δ: 1.11
(m, 1H), 1.24 (s, 3H), 1.65 (s, 3H), 1.74 (s, 3H), 1.88 (m, 1H), 2.17-2.01 (m, 4H), 2.36 (m, 1H), 2.56 (d,
1H, J = 4.2 Hz), 2.64 (t, 1H, J = 6.3 Hz), 3.00 (d, 1H, J = 4.2 Hz), 3.45 (s, 3H), 3.69 (m, 1H), 5.19 (m,
1H), 5.73 (m, 1H), 6.29 (d, 1H, J = 16.0 Hz, -CH=CH-Ph), 6.74 (m, 2H), 7.34 (m, 2H), 7.55 (d, 1H, J =

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HETEROCYCLES, Vol. 65, No. 8, 2005
13
16.0 Hz, -CH=CH-Ph). C NMR (100 MHz, CDCl3) δ: 19.32, 19.40, 22.71, 25.03, 26.38, 29.45, 42.38,
49.99, 51.67, 52.08, 53.71, 61.65, 65.78, 73.11, 115.09, 117.63, 124.90, 125.84, 127.03, 133.24, 142.86,
145.93, 165.08. HR-MS m/z (M+) Requires C25H33NO5: 427.2350; Found: 427.2360. Anal. Calcd for
C25H33NO5: C, 70.72; H, 7.99; N, 3.17. Found: C, 70.77; H, 8.06; N, 3.22.
3-(4-Amino-3-chlorophenyl)acrylic acid 5-methoxy-4-[2-methyl-3-(3-methylbut-2-enyl)oxiranyl]-1-
o
oxaspiro[2.5]oct-6-yl ester (9d). Yield: 0.79 g, 85% as pale yellowish foam. mp 67-70 C (from n-
1
Hexane). IR (KBr) νmax cm-1: 3460 (NH2), 3365, 2927, 1703 (CO), 1600, 1160. H NMR (400 MHz,
CDCl3) δ: 1.09 (m, 1H), 1.24 (s, 3H), 1.67 (s, 3H), 1.75 (s, 3H), 1.91 (m, 1H), 2.19-2.04 (m, 4H), 2.35 (m,
1H), 2.54 (d, 1H, J = 4.1 Hz), 2.66 (t, 1H, J = 6.4 Hz), 3.08 (d, 1H, J = 4.2 Hz), 3.47 (s, 3H), 3.71 (m, 1H),
5.19 (m, 1H), 5.73 (m, 1H), 6.31 (d, 1H, J = 16.0 Hz, -CH=CH-Ph), 6.76 (m, 1H), 7.41 (m, 2H), 7.57 (d,
1H, J = 16.0 Hz, -CH=CH-Ph). 13C NMR (100 MHz, CDCl3) δ: 19.16, 19.33, 21.56, 23.85, 26.84, 30.14,
43.21, 50.01, 51.63, 52.38, 53.77, 60.99, 65.91, 73.42, 116.85, 117.34, 120.43, 125.41, 125.80, 126.39,
127.43, 133.25, 142.86, 146.32, 165.41. HR-MS m/z (M+) Requires C25H32NO5Cl: 461.1959. Found:
461.1963. Anal. Calcd for C25H32NO5Cl: C, 65.60; H, 7.20; N, 2.94; Found: C, 65.31; H, 7.16; N, 3.00.
3-(2-Amino-4,5-dimethoxyphenyl)acrylic
acid
5-methoxy-4-[2-methyl-3-(3-methylbut-2-enyl)-
o
oxiranyl]-1-oxaspiro[2.5]oct-6-yl ester (9e). Yield: 0.84 g, 92% as pale yellowish foam. mp 65-68 C
1
(from n-Hexane). IR (KBr) νmax cm-1: 3367 (NH2), 2929, 2831, 1702 (CO), 1609, 1160. H NMR (400
MHz, CDCl3) δ: 1.07 (d, 1H, J = 13.6 Hz), 1.23 (s, 3H), 1.65 (s, 3H), 1.74 (s, 3H), 1.91 (m, 2H), 2.01-
2.18 (m, 4H), 2.35 (m, 1H), 2.56 (d, 2H, J = 4.2 Hz), 2.64 (m, 1H), 2.99 (d, 1H, J = 4.3 Hz), 3.46 (s, 3H),
3.72 (dd, 1H, J = 2.8, 11.2 Hz), 3.86 (s, 6H), 5.19 (t, 1H, J = 7.6 Hz), 5.72 (s, 1H), 6.30 (d, 2H, J = 16.0
Hz, -CH=CH-Ph), 6.91 (s, 1H), 7.81 (d, 1H, J = 16.0 Hz, -CH=CH-Ph). 13C NMR (100 MHz, CDCl3) δ:
20.56, 20.67, 22.78, 26.58, 26.68, 29.43, 43.30, 50.16, 51.69, 52.23, 53.70, 56.99, 62.12, 65.74, 73.14,
101.62, 113.66, 114.82, 118.23, 125.12, 133.64, 138.94, 133.15, 142.83, 147.64, 167.09. HR-MS m/z
(M+) Requires C27H37NO7: 487.2560; Found: 487.2583. Anal. Calcd for C27H37NO7: C, 67.04; H, 7.84; N,

HETEROCYCLES, Vol. 65, No. 8, 2005
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2.79. Found: C, 66.91; H, 7.80; N, 2.75.
ACKNOWLEDGEMENTS
The authors would like to thank for the Research Grant (HMP-01-PJ1-PG4-01PT01-0004) from Ministry
of Health and Welfare, Korea for financial support. The authors thank Dr. S. S. Lee for critical
proofreading and Miss K. H. Yang for typing of the manuscript.
REFERENCE AND NOTES
1. (a) J. Folkman, Adv. Cancer Res., 1974, 19, 331. (b) J. Folkman, Adv. Cancer. Res., 1985, 43, 175. (c) J.
Folkman, Nature Med., 1995, 1, 27.
2. J. Wang, P. Lou, and J. Henkin, J. Cell. Biochem., 2000, 77, 465.
3. D. Ingber, T. Fujita, S. Kishimoto, K. Sudo, T. Kanamaru, and J. Folkman, Nature, 1990, 348, 555.
4. C. K. Han, S. K. Ahn, N. S. Choi, R. K. Hong, S. K. Moon, H. S. Chun, S. J. Lee, J. W. Kim, C. I.
Hong, D. Kim, J. H. Yoon, and K. T. No, Bioorg. Med. Chem. Lett., 2000, 10, 39.
5. (a) A. Nose and T. Kudo, Chem. Pharm. Bull., 1981, 29, 1159. (b) J. O. Osby and B. Ganem,
Tetrahedron Lett., 1985, 26, 6413. (c) J. C. Sarma, M. Borbaruah, and R. P. Sharma, Tetrahedron Lett.,
1985, 26, 4657. (d) D. M. Sarma and R. P. Sharma, Tetrahedron Lett., 1985, 26, 2581. (e) Y. He, X.
Pan, H. Zhao, and S. Wang, Synth. Commun., 1989, 19, 3051.
6. T. Satoh, N. Sharma, and M. Nishiki, Chem. Pharm. Bull., 1981, 29, 1443.
7. (a) F. Rolla, J. Org. Chem., 1982, 47, 4327. (b) K. Soai, S. Yokoyama, and A. Okawa, Synthesis, 1987,
48. (c) J. Sarma and R. P. Sharma, Chem. Ind. (London), 1987, 764.
8. (a) H. W. Gibson and F. C. Baily, J. Chem. Soc., Chem. Commun., 1977, 24, 815.
9. (a) N. M. Yoon and J. Choi, Synlett., 1993, 135. N. M. Yoon and J. Choi, Tetrahedron Lett., 1996, 37,
1057. (b) N. M. Yoon, H. J. Lee, J. H. Ahn, and J. Choi, J. Org. Chem., 1994, 59, 4587. (c) T. B. Shim,
J. Choi, and N. M. Yoon, Tetrahedron Lett., 1996, 37, 3137. N. M. Yoon, J. Choi, and Y. S. Shon,
Synth. Commun., 1993, 23, 3047.

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HETEROCYCLES, Vol. 65, No. 8, 2005
10. W. C. Still, M. Khan, and A. Mitra, J. Org. Chem., 1978, 43, 2923.
11. Nitrocinnamoylfumagillol compounds were prepared as follows: To a stirred suspension of a
nitrocinnamic acid (2.5 equiv.) in toluene was added SOCl2 (5 equiv.) and the mixture was refluxed
for 2 h. Toluene was removed under vacuum evaporation, and the residue was used without further
purification for the next step. To the residue in DMF (10 mL) was added NaH (6 equiv.) at 0 ℃.
Fumagillol (1 equiv.) was added to the mixture, maintaining at that temperature. After addition, the
reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with sat.
NH4Cl and washed with ethyl acetate. The organic layer was washed with sat. NH4Cl twelve times,
and brine in sequence. The seperated organic layer was dried over MgSO4 and concentrated in
reduced pressure, giving a residue, which was subjected to column chromatography (SiO2, EtOAc : n-
Hexane = 1 : 1) to afford the desired product and the product was used without further purification in
the next step.
12. N. M. Yoon, K. B. Park, and Y. S. Gyoung, Tetrahedron Lett., 1983, 24, 5367.
13. G. W. Kabalka, P. P. Wadgaonkar, and N. Chatla, Synth. Commun., 1990, 20, 293 and references cited
therein.