Concise synthesis of fagaridine and decarine, phenolic benzo[c]phenanthridine alkaloids, using the palladium-assisted biaryl coupling reaction

Article abstract of DOI:10.3987/COM-02-S35

Total synthesis of fagaridine (5) and decarine (6), phenolic benzo[c]phenanthridine alkaloids, was accomplished via the aryl-aryl coupling reaction of bromo amides protected by an isopropyl group with palladium, followed by reduction with LiAlH₄

Full text of DOI:10.3987/COM-02-S35

HETEROCYCLES, Vol. 59, No. 1, 2003, pp. 293 - 301, Received, 30th July, 2002
CONCISE SYNTHESIS OF FAGARIDINE AND DECARINE,
PHENOLIC BENZO[c]PHENANTHRIDINE ALKALOIDS, USING
THE PALLADIUM-ASSISTED BIARYL COUPLING REACTION†
Takashi Harayama,* Tomonori Sato, Yuichiro Nakano, Hitoshi Abe, and Yasuo
Takeuchi
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1,
Okayama 700-8530, Japan
E-mail: harayama@pharm.okayama-u.ac.jp
Abstract—Total synthesis of fagaridine (5) and decarine (6), phenolic
benzo[c]phenanthridine alkaloids, was accomplished via the aryl-aryl coupling
reaction of bromo amides protected by an isopropyl group with palladium, followed
by reduction with LiAlH4 and treatment with conc. HCl
Palladium-assisted aryl-aryl coupling reactions have been used to synthesize many condensed aromatic
compounds.1 Recently, we reported that intramolecular coupling reactions between aromatic halides and
arenes using palladium reagents were a very versatile way to synthesize polycyclic heteroaromatic
compounds2-5 and
a
novel palladium reagent prepared from Pd(OAc)2, DPPP (1,3-
bis(diphenylphosphino)propane), and Bu3P was very effective for coupling reactions, not only between aryl
triflates and arenes, but also between aryl halides and arenes.6 Moreover, we succeeded in synthesizing the
benzo[c]phenanthridine alkaloids chelerythrine (1),2,7 nitidine (2),4,7 norchelerythrine (3), 3,7,12-
methoxydihydrochelerythrine (4),2a, 7 and others,3,6 by taking advantage of the palladium-assisted aryl-aryl
coupling reaction. Subsequently, in order to examine the generality of these methods, we designed a plan to
synthesize fagaridine (5) and decarine (6), phenolic benzo[c]phenanthridine alkaloids, as shown in Scheme 1.
This is the subject of this paper.
In 1973, Torto et al. identified a quaternary phenolic alkaloid, fagaridine, from Fagara xanthoxyloides, and
proposed its structure.8 However, Nakanishi and Suzuki revised the structure of fagaridine as 5 after
synthesizing it in 1998.9 A tertiary phenolic alkaloid, decarine (6), was isolated from Zanthoxylum decaryi
by Cave et al.10 and synthesized via the benzyne route by Kesser et al.11
We designed a common retorosynthetic plan for these phenolic alkaloids, as shown in Scheme 1. We
postulated that isopropyl or TBDMS group could be used to protect the phenol, because they are stable in the
hydride reduction and can be deprotected with hydrochloric acid, two steps that are very useful for
† Dedicated to Professor Yuichi Kanaoka for the celebration of his 75th birthday.

O
O
R1 = R2 = OMe, R3 = H
R1 = H, R2 =R3 = OMe
chelerythrine (1)
nitidine (2)
R3
R2
+
N
Me
R1 = OMe, R2 = OH, R3 = H fagaridine (5)
R1
OMe
O
O
O
O
N
R
NMe
MeO
OMe
OMe
R = OMe norchelerythrine (3)
R = OH decarine (6)
12-methoxydihydrochelerythrine (4)
CHO
COOH
19 : R = TBDMS
OMe
16 : R = H
17 : R = TBDMS
18 : R = Pr-i
OMe
20 : R = Pr-i
OR
OR
O
O
fagaridine (5)
or
decarine (6)
Pd
N
i-PrO
MeO O
R
7 : R = Me
8 : R = MOM
O
O
Br
NHR
COOH
Br
OMe
O
O
+
N
i-PrO
R
OR
O
MeO
12 : R = TBDMS
13 : R = Pr-i
14 : R = Me
15 : R = H
9 : R = Me
10 : R = H
11 : R = MOM
Scheme 1
transforming benzophenanthridone to base, as previously reported.2,3
First, the synthesis of bromo-acids (12) and (13) was investigated. Therefore, 1612 was treated with
TBDMS chloride and imidazole to afford the silyl ether (17), which was oxidized with NaClO2 and 31%
H2O2 to produce silyl acid (19) in 72% total yield. Bromination of 19 with dibromodimethylhydantoin
(DBDMH)13 was unfruitful. By contrast, oxidation of 1814 with NaClO2 and 31% H2O2 followed by
bromination with DBDMH successfully gave bromo acid (1 3) in 71% total yield. Then, bromo amides (9)
and (11), the starting materials for the coupling reaction, were synthesized as follows: 13 was successively
treated with oxalyl chloride followed by 14,7,15 to afford bromo amide (9) in 64% yield. Next, bromo
amide (1 1) possessing a MOM group, which was suitable for synthesizing the tertiary bases norchelerythrine
(3)3 and triphaeridine,3 was prepared from 1 3 and naphthylamine (1 5)4 via methoxymethylation in 59% total
yield.

Table 1. Results of coupling reaction of 6-bromo-3-isopropoxy-2-methoxy-N-methyl-N-(6,7-
methylenedioxy-1-naphthyl)benzamide (9) in DMF under refluxa)
O
O
O
O
O
O
Br
N
N
+
N
i-PrO
i-PrO
MeO
i-PrO
MeO
Me
Me
Me
O
MeO
O
9
O
7
21
time
(h)
yield(%)
run
Pd(OAc)2
L/Pdb)
base
ligand
9
7
21
DPPPc)
Ph3P
DPPP
(o-tol)3P
DPPPc)
n-Bu3P
n-Bu3P
(o-tol)3P
(o-tol)3P
1.0
1.0
1.0
1.0
0.2
0.2
0.2
0.2
0.2
–
–
14
–
11
–
6
10
26
–
1
2
3
4
5
6
7
8
9
1
2
1
2
1
3
3
2
2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
K2CO3
Ag2CO3
K2CO3
Ag2CO3
K2CO3
86
50
84
93
72
51
68
87
89
1
4
4
2
1
4
4
4
4
5
–
39
–
13
–
–
7
a) All reactions were carried out using 2 equivalents of base.
b) Molar ratio between ligand and Pd(OAc)2.
c) One eqivalent of n-Bu3P was added.
DPPP : 1,3-bis(diphenylphosphino)propane.
(o-tol)3P : tri-ortho-tolylphosphine
Table 2. Results of coupling reaction of 6-bromo-3-isopropoxy-2-methoxy-N-methoxymethyl-N-(6,7-
methylenedioxy-1-naphthyl)benzamide (11) in DMF under refluxa)
O
O
O
O
O
O
Br
N
+
N
i-PrO
MeO
N
i-PrO
MeO
i-PrO
MeO
MOM
R
O
O
MOM
O
11
8 : R = MOM
22 : R = H
23
time
(h)
yield(%)
L/Pdb)
run Pd(OAc)2 ligand
base
11
–
–
–
–
65
41
57
–
8
22
18
15
13
3
23
DPPPc)
DPPPc)
n-Bu3P
(o-tol)3P
DPPPc)
n-Bu3P
(o-tol)3P
(o-tol)3P
1.0
1.0
1.0
1.0
0.2
0.2
0.2
0.2
Ag2CO3
K2CO3
K2CO3
Ag2CO3
K2CO3
K2CO3
Ag2CO3
K2CO3
5
8
5
5
5
5
5
5
58
50
58
91
22
31
33
55
18
26
22
6
1
2
3
4
5
6
7
8
1
1
3
2
1
3
2
2
13
6
–
–
–
–
16
12
a) All reactions were carried out using 2 equivalents of base.
b) Molar ratio between ligand and Pd(OAc)2.
c) One eqivalent of n-Bu3P was added.

The results of the biaryl coupling reaction of bromo-amides (9) and (11) using the palladium reagent are
summarized in Tables 1 and 2, respectively. The coupling reactions proceeded in a good yield, especially
when using equimolar Pd(OAc)2, (o-tol)3P, and Ag2CO3 (See run 4 in Tables 1 and 2). The structure of
benzazepinone (2 3) was elucidated from 1H-NMR spectral data, in which 2 3 showed only one singlet signal
due to an aromatic proton in addition to the signals due to other aromatic protons16 (see EXPERIMENTAL).
The reduction of coupling products (9) and (11) with LiAlH4 followed by treatment with conc. HCl gave
fagaridine (5) and decarine (6), respectively. The spectral data for each synthetic sample were in good
agreement with those of the corresponding authentic sample.
EXPERIMENTAL
Melting points were measured on a micro melting point hot-stage apparatus (Yanagimoto) and are uncorrected.
IR spectra were recorded on a JASCO A-102 or JASCO FT/IR 350 spectrophotometer and 1H-NMR spectra
in deuteriochloroform on a Hitachi R-1500 (60 MHz) or a Varian VXR-200 (200 MHz) or -500 (500 MHz)
spectrometer unless otherwise stated. NMR spectral data are reported in parts per million downfield from
tetramethylsilane as an internal standard (δ 0.0) and coupling constants are given in Hertz. MS spectra were
obtained on a VG-70SE spectrometer. Column chromatography was carried out on Wako gel C-200. All
experiments were carried out in an argon atmosphere and the extract was washed with brine, dried over
anhydrous MgSO4, then filtered, and the filtrate was evaporated to dryness under reduced pressure, unless
otherwise noted. Pd(OAc)2 was treated with boiling benzene and the mixture was filtered while hot. The hot
filrate was then concentrated to dryness to give purified Pd(OAc)2.
3-[(tert-Butyldimethylsilyl)oxy]-2-methoxybenzaldehyde ( 17)
A solution of 16 (1.00 g, 6.57 mmol), TBDMS chloride (1.19 g, 7.89 mmol) and imidazole (1.34 g, 19.7
mmol) in dry DMF (15 mL) was stirred at 50˚C for 1 h. The reaction mixture was diluted with water and
extracted with AcOEt. The residue dissolved in CHCl3 was subjected to column chromatography on silica gel.
1
Elution with hexane : AcOEt (30 : 1) gave 17 (1.65 g, 95%) as an oil. IR (CHCl3) cm-1: 1687 (C=O). H-
NMR (200 MHz, CDCl3) δ: 0.21 (6H, s), 1.03 (9H, s), 3.93 (3H, s), 7.01－7.14 (2H, m), 7.44 (1H, dd,
J=7.2, 2.4 Hz),10.39 (1H, s). FAB-MS m/z: 265.1281 (Calcd for C14H21O3BrSi: 265.1259).
3-[(tert-Butyldimethylsilyl)oxy]-2-methoxybenzoic acid (1 9)
To a stirred mixture of 17 (1.00 g, 3.75 mmol), sodium phosphate monobasic dihydrate (146 mg, 0.94
mmol), and 31% hydrogen peroxide ( 0.63 mL, 5.63 mmol) in MeCN (30 mL) and water (1 mL) was added
a solution of sodium chlorite (80%; 636 mg, 5.63 mmol) in water (1 mL) and then the whole was stirred at
10˚C for 2 h. After the decomposition of excess hydrogen peroxide with aqueous 10% sodium sulfite
solution, the mixture was poured into water and acidified to pH 3 with 10% HCl, and then extracted with
AcOEt. The crystalline residue was recrystallized from hexane-ether to provide 19 (805 mg, 76 %) as
colorless needles, mp 109－110℃. IR (KBr) cm-1: 2929 (OH), 1675 (C=O).1H-NMR (200 MHz, CDCl3) δ:
0.22 (6H, s), 1.02 (9H, s), 4.03 (3H, s), 7.06－7.16 (2H, m), 7.73 (1H, dd, J=3.6, 2.5 Hz), 11.50 (1H,

br). Anal. Calcd for C14H22O4Si: C, 59.54; H, 7.85. Found: C, 59.41; H, 7.55.
3-Isopropoxy-2-methoxybenzoic acid (2 0)
To a stirred mixture of 18 (500 mg, 2.57 mmol), sodium phosphate monobasic dihydrate (100 mg, 0.64
mmol), and 31% hydrogen peroxide ( 0.42 mL, 3.86 mmol) in MeCN (15 mL) and water (0.5 mL) was
added a solution of sodium chlorite (80%; 436 mg, 3.86 mmol) in water (1 mL) and then the whole was
stirred at 10˚C for 8 h. After the decomposition of excess hydrogen peroxide with aqueous 10% sodium
sulfite solution, the mixture was poured into water and acidified with 10 % HCl and then, extracted with
AcOEt. The crystalline residue was recrystallized from hexane to provide 20 (483 mg, 89 %) as colorless
needles, mp 78－79.5℃. IR (KBr) cm-1: 2980 (OH), 1660 (C=O).1H-NMR (500 MHz, CDCl3) δ: 1.41 (6H,
d, J=6.1 Hz), 4.10 (3H, s), 4.61 (1H, septet, J=6.1 Hz), 7.14－7.19 (2H, m), 7.71 (1H, dd, J=7.0, 6.0
Hz), 11.49 (1H, br). Anal. Calcd for C11H14O4: C, 62.85; H, 6.71. Found: C, 62.96; H, 6.74.
6-Bromo-3-isopropoxy-2-methoxybenzoic acid (13)
Acid (2 0) (2.00 g, 9.52 mmol) was dissolved in a 0.7N NaOH solution (15 mL, 10.5 mmol) and the solution
was cooled to 0℃. After dibromodimethylhydantoin (1.50 g, 5.24 mmol) was added in portions over 5 min
and the solution was allowed to warm to rt and stirred for 40 min. The reaction was quenched by the addition
of sodium sulfite and filtered. The filtrate was acidified to pH 2 with conc. HCl under rapid stirring and the
whole was extracted with ether. The residue was recrystallized from benzene-hexane to afford 1 3 ( 2.21 g,
80%) as colorless needles, mp 108.5－110℃. IR (KBr) cm-1: 2980 (OH), 1700 (C=O). 1H-NMR (60 MHz,
CDCl3) δ: 1.35 (6H, d, J=6.1 Hz), 3.93 (3H, s), 4.56 (1H, septet, J=6.1 Hz), 6.85 (1H, d, J=8.6 Hz), 7.26
(1H, d, J=8.6 Hz). Anal. Calcd for C8H13O4Br: C, 45.70; H, 4.53. Found: C, 45.87; H, 4.80.
6-Bromo-3-isopropoxy-2-methoxy-N-methyl-N-(6,7-methylenedioxy-1-naphthyl)-
benzamide (9)
A few drops of dry DMF and oxalyl chloride (444 mg, 3.5 mmol) were added to a solution of 13 (500 mg,
1.73 mmol) in dry CH2Cl2 (5 mL) under ice-cooling and the mixture was stirred for 2 h. Then, the reaction
mixture was concentrated to dryness under reduced pressure. To this residue was added a solution of 1 4 (348
mg, 1.73 mmol) in dry CH2Cl2 (5 mL) and dry NEt3 (0.26 mL, 1.90 mmol) and the whole was stirred for 3 h
at rt. The reaction mixture was concentrated to dryness and diluted with CHCl3, then washed with 10% HCl,
aqueous 5% NaOH solution and brine. The residue dissolved in CHCl3 was subjected to column
chromatography on silica gel. Elution with hexane : AcOEt (5 : 1) gave 9 (520 mg, 64%) as colorless
1
prisms, mp 148－149℃ (from AcOEt-hexane). IR (KBr) cm-1: 1660 (C=O). H-NMR (200 MHz, CDCl3,
rotamers) δ: 1.21－1.56 (6H, m), 3.16－4.03 (6H, m ), 4.56－4.70 (1H, m), 6.04－6.06 (2H, m), 6.60
－7.70 (7H, m). Anal. Calcd for C23H22NO5Br: C, 58.49; H, 4.70; N, 2.97. Found: C, 58.40; H, 4.84; N,
2.93.
6-Bromo-3-isopropoxy-2-methoxy-N-(6,7-methylenedioxy-1-naphthyl)benzamide (10)
A few drops of dry DMF and oxalyl chloride (444 mg, 3.5 mmol)) were added to a solution of 1 3 (500 mg,

1.73 mmol) in dry CH2Cl2 (5 mL) and the stirred mixture was refluxed for 1 h. Then, the mixture was
concentrated to dryness under reduced pressure. To this residue was added a solution of 15 (324 mg, 1.73
mmol) in dry CH2Cl2 (5 mL) and dry NEt3 (0.27 mL, 1.90 mmol) and the whole was stirred for 5 h at rt. The
reaction mixture was concentrated to dryness and diluted with CHCl3, then washed with 10% HCl, aqueous
5% NaOH solution and brine. The residue was dissolved in CHCl3 and the solution was subjected to column
chromatography on silica gel. Elution with hexane : AcOEt (1 : 1) gave 10 (621 mg, 78%) as colorless
1
needles, mp 193－195℃ (from ether). IR (KBr) cm-1: 1655 (C=O). H-NMR (200 MHz, CDCl3) δ: 1.40
(6H, d, J=6.0 Hz), 3.97 (3H, s), 4.60 (1H, septet, J=6.0 Hz), 6.04 (2H, s), 6.60－7.70 (7H, m). Anal.
Calcd for C22H20NO5Br: C, 57.66; H, 4.40; N, 3.06. Found: C, 57.82; H, 4.31; N, 3.16.
6-Bromo-3-isopropoxy-2-methoxy-N-methoxymethyl-N-(6, 7-methylenedioxy-1-
naphthyl)benzamide (11)
A suspension of 10 (500 mg, 1.73 mmol) and NaH (380 mg, 63% dispersion in mineral oil, 6.3 mmol) in
dry DMF (20 mL) was stirred for 30 min at rt and then chloromethyl methyl ether (0.25 mL, 3.27 mmol) was
added to the reaction mixture. After stirring for 2 h at rt, the reaction mixture was diluted with ether and
washed with brine. The residue dissolved in CHCl3 was subjected to column chromatography on silica gel.
Elution with hexane : AcOEt (4 : 1) gave 11 (826 mg, 75%) as colorless prisms, mp 142－143˚C (from
AcOEt-hexane). IR (KBr) cm-1: 1662 (C=O). 1H-NMR (200 MHz, CDCl3, rotamers) δ: 1.21－1.45 (6H, m),
3.16－4.09 (6H, m), 4.38－4.98 (3H, m), 5.81－6.05 (2H, m), 6.48－7.70 (7H, m). Anal. Calcd for
C24H24NO6Br: C, 57.38; H, 4.82; N, 2.79. Found: C, 57.50; H, 4.94; N, 2.64.
General procedure for the biaryl coupling reaction of amide (9) by the Pd reagent
The reaction of amide (9) (0.3 mmol) in dry DMF (8 mL) was carried out using Pd(OAc)2 and phosphines in
a molar ratio of 1 : 1 and 2 mol equivalents of base under reflux and under the reaction conditions indicated in
Table 1. The reaction mixture was diluted with ether and the precipitate was removed by filtration. The
filtrate was washed with brine. The residue was dissolved in CHCl3 and subjected to column
chromatography on silica gel. Elution with hexane : AcOEt (4 : 1) gave the starting material (9) and
successive elution with the same solvent gave the debromo amide (2 1) and phenanthridone (7).
8-Isopropoxy-7-methoxy-N-methyl-2,3-methylenedioxybenzo[c]phenanthridin-6(5H)-one
(7) : colorless needles, mp 170－171℃ (from benzene). IR (KBr) cm-1: 1660 (C=O). 1H-NMR (500 MHz,
CDCl3) δ: 1.40 (1H, d, J=6.0 Hz, CH(CH3)2), 3.90 (3H, s, NCH3), 4.07 (3H, s, OCH3), 4.66 (1H, septet,
J=6.0 Hz, CH(CH3)2 ), 6.09 (2H, s, OCH2O), 7. 15 (1H, s, Ar-H), 7.38 (1H, d, J=8.8 Hz, Ar-H), 7.52
(1H, d, J=8.8 Hz, Ar-H), 7.53 (1H, s, Ar-H), 7.94 (1H, d, J=8.8 Hz, Ar-H), 7.98 (1H, d, J=8.8 Hz, Ar-
H). Anal. Calcd for C23H21NO5: C, 70.58; H, 5.41; N, 3.58. Found: C, 70.70; H, 5.59; N, 3.69.
3-Isopropoxy-2-methoxy-N-methyl-N-(6, 7-methylenedioxy-1-naphthyl)benzamide (21) :
colorless needles, mp 167－168℃ (from benzene-hexane). IR (KBr) cm-1: 1652 (C=O). 1H-NMR (60 MHz,
CDCl3, rotamers) δ: 1.13－1.48 (6H, m), 3.22-4.06 (6H, m), 4.25－4.70 (1H, m), 6.06 (2H, s), 6.46－

7.51 (8H, m). Anal. Calcd for C23H23NO5: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.48; H, 5.67; N,
3.43.
General procedure for the biaryl coupling reaction of amide (11) by the Pd reagent
The reaction of amide (1 1) (0.3 mmol) in dry DMF (8 mL) was carried out using Pd(OAc)2 and phosphines in
a molar ratio of 1 : 1, and 2 mol equivalents of base under reflux and under the reaction conditions indicated in
Table 2. The reaction mixture was diluted with ether and the precipitate was removed by filtration. The filtrate
was washed with brine. The residue was dissolved in CHCl3 and subjected to column chromatography on
silica gel. Elution with hexane : AcOEt (4 : 1) gave azepinone (23) and successive elution with the same
solvent gave the N-methylphenanthridone (8) and then NH-phenanthridone (2 2).
8-Isopropoxy-7-methoxy-N-methoxymethyl-2,3-methylenedioxybenzo[c]phenanthridin-
6(5H)-one (8) : colorless needles, mp 169－170℃ (from ether). IR (KBr) cm-1: 1664 (C=O).1H-NMR
(500 MHz, CDCl3) δ: 1.40 (6H, d, J=6.1 Hz), 3.88 (3H, s), 4.06 (3H, s), 4.65 (1H, septet, J=6.1 Hz),
5.36 (2H, s), 6.09 (2H, s), 7.14 (1H, s), 7.38 (1H, s), 7.38 (1H, d, J=9.0 Hz), 7.52 (1H, d, J=9.0 Hz),
7.93 (1H, d, J=9.0 Hz), 7.97 (1H, d, J=9.0 Hz) 8.02 (1H, s). FAB-MS m/z: 442 (M+1)+. Anal. Calcd for
C24H23NO6: C, 68.40; H, 5.50; N, 3.32. Found: C, 68.52; H, 5.63; N, 3.12.
8-Isopropoxy-7-methoxy-2, 3-methylenedioxybenzo[c]phenanthridin-6(5H)-one (22)
:
1
colorless prisms, mp ＞300℃ (from ether). IR (KBr) cm-1: 1647 (C=O). H-NMR (500 MHz, CDCl3) δ:
1.42 (6H, d, J=6.5 Hz), 4.07 (3H, s), 4.69 (1H, septet, J=6.5 Hz), 6.13 (2H, s), 7.18 (1H, s), 7.45 (1H, d,
J=9.0 Hz), 7.50 (1H, d, J=9.0 Hz), 7.81 (1H, s), 8.02 (1H, d, J=9.0 Hz), 8.05 (1H, d, J=9.0 Hz), 10.15
(1H, br s). Anal. Calcd for C22H19NO4・H2O: C, 69.65; H, 5.58; N, 3.69. Found: C, 69.51; H, 5.30; N,
3.68.
10-Isopropoxy-9-methoxy-7-methoxymethyl-1,2-methylenedioxynaphtho[1,8-cd][2]-
benzazepin-8(7H)-one (23) : colorless prisms, mp 153－154℃ (from ether). IR (KBr) cm-1: 1660
1
(C=O). H-NMR (200 MHz, CDCl3) δ: 1.36 (6H, d, J=6.0 Hz), 3.48 (3H, s), 4.04 (3H, s), 4.57 (1H,
septet, J=6.0 Hz), 6.11 (2H, br), 6.93 (1H, d, J=9.0 Hz), 6.97 (1H, s), 7.25 (1H, dt, J=7.8, 7.6 Hz), 7.34
(1H, d, J=9.0 Hz), 7.37 (1H, dd, J=7.8, 1.2 Hz), 7.57 (1H, dd, J=7.6, 1.2 Hz). Anal. Calcd for
C24H23NO6: C, 68.40; H, 5.50; N, 3.32. Found: C, 68.20; H, 5.74; N,3.21.
Fagaridine (5)
LiAlH4 (8.7 mg, 0.23 mmol) was added to a solution of 7 (30 mg, 0.077 mmol) in anhyd THF (2 mL) and
the mixture was stirred for 30 min at rt . Excess hydride was decomposed with wet ether and the organic layer
was decanted. The residue dissolved in concd HCl (3 mL) was refluxed for 4 h. The mixture was
concentrated to dryness under reduced pressure. The residue was recrystallized from MeOH-ether to give
fagaridine (5, 26.9 mg, 86%) as brown needles, mp 229－231℃ (lit.,9a 231－233℃). 1H-NMR (500
MHz, DMSO-d6) δ: 4.16 (3H, s, C7-OCH3), 4.99 (3H, s, C5-NCH3), 6.35 (2H, s, OCH2O), 7. 89 (1H, s,
C1-H), 8.15 (1H, d, J=9.0 Hz, C9-H), 8.31 (1H, d, J=9.0 Hz, C12-H), 8.34 (1H, s, C4-H), 8.73 (1H, d,
J=9.0 Hz, C10-H), 8.77 (1H, d, J=9.0 Hz, C11-H), 10.04 (1H, s, C6-H), 11.31 (1H, s, C8-OH). FAB-MS
m/z: 334 (M)+. Anal. Calcd for C20H16NO4Cl･2H2O: C, 59.19; H, 4.97; N, 3.45. Found: C, 59.05; H, 5.04;

N, 3.28.
Spectral data of synthetic sample were identical with those of authentic sample kindly provided with Dr. T.
Nakanishi, Nippon Kayaku Company.
Decarine (6)
LiAlH4 (27 mg, 0.71 mmol) was added to a solution of 8 (100 mg, 0.237 mmol) in anhyd THF (5 mL) and
the mixture was stirred for 30 min at rt . Excess hydride was decomposed with wet ether and the organic layer
was decanted. The residue dissolved in conc. HCl (5 mL) was refluxed for 4 h. The mixture was
concentrated to dryness under reduced pressure. The residue was recrystallized from MeOH-CHCl3 to give
1
decarine (6, 64 mg, 84%) as brown needles, mp 243－244.5℃ (lit.,10 243℃). H-NMR (500 MHz,
DMSO-d6) δ: 4.01 (3H, s, C7-OCH3), 6.20 (2H, s, OCH2O), 7. 50 (1H, s, C1-H), 7.57 (1H, d, J=9.0 Hz,
C9-H), 7.95 (1H, d, J=9.0 Hz, C12-H), 8.46 (1H, d, J=9.0 Hz, C10-H), 8.50 (1H, d, J=9.0 Hz, C11-H),
8.53 (1H, s, C4-H), 9.57 (1H, s, C6-H), 10.09 (1H, s, C8-OH). FAB-MS m/z: 320 (M+1)+. Anal. Calcd for
C19H13NO4・0.25 H2O: C, 70.47; H, 4.20; N, 4.33. Found: C, 70.22; H, 4.42; N, 4.12.
This sample was identified with the authentic sample of decarine provided with Professor T. Ishikawa,
Graduate School of Pharmaceutical Sciences, Chiba University.
ACKNOWLEDGEMENT
This research was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology. The authors are indebted to Dr. Nakanishi, Nippon Kayaku
Company and Professor Ishikawa, Graduate School of Pharmaceutical Sciences, Chiba University, for
providing us with copies of spectral data of the authentic sample and to the SC-NMR Laboratory of Okayama
University for the NMR experiments.
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