Isolation, structure elucidation, and total synthesis of two new Chimonanthus alkaloids, chimonamidine and chimonanthidine

Article abstract of DOI:10.1016/j.tet.2003.11.034

Two new tryptamine-related alkaloids, chimonamidine and chimonanthidine, were isolated from the seeds of Chimonanthus praecox Link. and their structures including absolute configuration were elucidated by spectroscopic analysis and biomimetic total synthesis from tryptamine.

Full text of DOI:10.1016/j.tet.2003.11.034

Tetrahedron 60 (2004) 893–900
Isolation, structure elucidation, and total synthesis of two new
Chimonanthus alkaloids, chimonamidine and chimonanthidine
*
Hiromitsu Takayama, Yohei Matsuda, Kyohei Masubuchi, Atsushi Ishida, Mariko Kitajima
and Norio Aimi
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 5 November 2003; revised 15 November 2003; accepted 17 November 2003
Abstract—Two new tryptamine-related alkaloids, chimonamidine and chimonanthidine, were isolated from the seeds of Chimonanthus
praecox Link. and their structures including absolute configuration were elucidated by spectroscopic analysis and biomimetic total synthesis
from tryptamine.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
2.1. Chimonamidine (1)
Recently, the potent antinociceptive activity of dimeric or
polymeric pyrrolidinoindoline alkaloids that interact with
opioid receptors has been reported by Elisabetsky–
Verotta’s group.1 In our continuous chemical and pharma-
cological studies of indole alkaloids possessing analgesic
activity,2 we have been interested in compounds of this
type, which have been isolated from plants belonging to
genera Calycanthaceae, Idiospermaceae, and Rubiaceae.3
Overman and co-workers have recently made several
important contributions to the synthesis of this family of
alkaloids.4 We started with the investigation of the
alkaloidal constituents in Chimonanthus praecox Link.,
which was used as folk medicine for the treatment of
rheumatic arthritis in China. (þ)-Calycanthine and (^)-
chimonanthine were isolated from the roots of this plant by
a Chinese group.5 In the present study, we were able to
isolate two new alkaloids, chimonamidine (1) and chimo-
nanthidine (2), together with (þ)-calycanthine, (2)-chimo-
nanthine (10), (2)-folicanthine (11), and (2)-
calycanthidine (12) from the MeOH extract of C. praecox
seeds. In this paper, we report the structure elucidation of
these new alkaloids by means of spectroscopic analysis and
biomimetic total syntheses.
The new compound 1, obtained as an amorphous powder,
exhibited [a]1D9¼212.6 (c 0.06, EtOH). High-resolution
FABMS analysis gave m/z 221.1290 (MþH)þ (D^0 mmu)
and established the molecular formula as C12H16N2O2. The
splitting mode of the protons in the aromatic region (d 6.74,
d J¼7.6 Hz; d 7.24, dd J¼7.6, 7.6 Hz; d 6.66, dd J¼7.6,
1
7.6 Hz; and d 6.85, d J¼7.6 Hz) in the H NMR spectrum
indicated the presence of an o-disubstituted benzene ring.
Further, the chemical shift of the carbon (d 148.3) on this
benzene ring as well as the HMBC cross-peak between that
carbon and the protons of the N-Me group (d 2.85, 3H, s)
suggested that 1 contained an N-Me aniline residue in the
molecule. In addition, 1H NMR, 13C NMR and COSY
spectra (Fig. 1) indicated the presence of one carbonyl
carbon (d 175.1), an isolated ethane fragment, one
oxygenated quaternary carbon (d 79.6), and an N-Me
group, all of which constituted a g-lactam ring having a
hydroxyl function. These two units could be connected by
HMBC cross-peaks between the aromatic proton at d 6.85
(H4) and the oxygenated quaternary carbon (d 79.6, C3) and
between the protons (d 2.41 and 2.73, H28) in the ethane
bridge and the aromatic quaternary carbon (d 124.6, C3a),
leading to the construction of the structure of the new
alkaloid, now named chimonamidine, to be formula 1.
To establish the above structure inferred by spectroscopic
analysis, we initially performed the total synthesis of (^)-1.
The synthetic strategy was based on the following
biogenetic speculation. As shown in Figure 1, a new alkaloid
is expected to be formed from tryptamine (3) through
conversion into an oxindole derivative, introduction of a
Keywords: Alkaloid; Chimonunthus; Isolation; Total synthesis.
*
Corresponding author. Tel./fax: þ81-432902902;
e-mail address: htakayam@p.chiba-u.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.034

894
H. Takayama et al. / Tetrahedron 60 (2004) 893–900
Figure 1. Selected 2D NMR correlations and hypothetical biogenetic route
for chimonamidine (1).
hydroxyl function to the benzylic position, and transannula-
tion of the lactam ring. Our biomimetic synthesis (Scheme 1)
started with the preparation of Na,Nb-dimethyl-Nb-carbo-
benzyloxytryptamine (5) from a known tryptamine deriva-
tive (4).6 The indole ring in 5 was then converted into
oxindole (6) in 71% yield by oxidation with dimethyl
sulfoxide and hydrochloric acid.7 Next, a hydroxyl group
was introduced to the benzylic position (C3) under oxygen
atmosphere to give the racemic a-hydroxyketone (7) in a
quantitative yield. Removal of the protecting group on the
nitrogen with trimethylsilyl iodide gave a secondary amine
that was gradually and spontaneously converted into the
target molecule over two days in 66% isolated yield. The
synthetic 1 (mp 213–215 8C) was found to be completely
identical with the natural product by comparison of their
chromatographic behavior and spectroscopic data including
1H and 13C NMR and MS spectra. Therefore, the structure
of chimonamidine was determined to be formula 1. Next,
we synthesized chiral chimonamidine to determine the
absolute configuration of the natural product, which
exhibited [a]D¼212.6. Initial attempts at the asymmetric
hydroxylation of 6 using Davis reagents8 gave chiral
hydroxyketone (7) up to 33% enantiomeric excess. Then,
we employed an alternative strategy that involved the
separation of the diastereomers of chiral ester derivatives.
After several attempts, a pair of diastereomeric esters
prepared from (þ)-MTPA chloride and racemic alcohol (7)
was found to be separable by SiO2 column chromatography,
and the more polar isomer (8) gave a crystal suitable for
X-ray crystallographic analysis, revealing that the absolute
stereochemistry at C3 in 8 had an R configuration. The ester
function in 8 and 9 was respectively hydrolyzed with
aqueous alkaline solution to afford chiral alcohols, (þ)-7
and (2)-7. Their optical purity was confirmed to be 100% ee
by chiral HPLC analysis and the CD spectra exhibited
antipodal curves, as shown in Figure 2.9 Finally, the pro-
tecting group on the nitrogen in (þ)-7 and (2)-7 was, respec-
tively, removed with TMSI to give chiral chimonamidines.
(R)-(2)-Chimonamidine (1) obtained from (R)-(þ)-7
showed [a]D¼2178, whereas the enantiomeric (S)-(þ)-
chimonamidine (1) from (S)-(2)-7 exhibited [a]D¼þ171.
As a result, we confirmed that natural chimonamidine
Scheme 1. Reagents and conditions: (a) Cbz–Cl, Na2CO3, H2O, CH2Cl2,
0 8C, quant. (b) conc. HCl, DMSO, phenol, AcOH, 0 8C, 71%. (c) 1 M
NaOH, THF, O2, rt, quant. (d) TMSI, CH3CN, 0 8C to rt, 66%. (e) (S)-
MTPA-Cl, DMAP, CH2Cl2, rt; 8, 43%; 9, 45%. (f) 0.5 M NaOH, MeOH, rt,
quant. (g) TMSI, CH3CN, 0 8C to rt; 55% from (þ)-7; 50% from (2)-7.
([a]D¼212.6) comprises a mixture slightly enriched with
the (R)-(2)-enantiomer.10
2.2. Chimonanthidine (2)
The new compound 2, obtained as an amorphous powder,
exhibited [a]2D0¼2285 (c 0.05, EtOH). High-resolution
FABMS analysis gave m/z 361.2392 (MþH)þ(D ^0 mmu)
and established the molecular formula as C23H28N4. The
1
UV, H and 13C NMR spectra strongly resembled those of
known dimeric pyrrolidinoindoline-type alkaloids, chimo-
nanthine (10),3b,11 folicanthine (11),6,12 and calycanthidine
(12),13 which were simultaneously isolated from this plant.
The 1H NMR spectrum showed the presence of three methyl
groups attached to nitrogen atoms. Their chemical shifts, d
2.36, 2.84, and 2.98, suggested that one methyl group

H. Takayama et al. / Tetrahedron 60 (2004) 893–900
895
total synthesis of chimonanthines.15 We utilized this method
for the synthesis of 2 as follows. Na-Methyl-Nb-2-
trimethylsilylethoxycarbonyl (Teoc) tryptamine (14), pre-
pared from known compound 13,16 was treated with
0.5 equiv. phenyliodine (III) bis(trifluoroacetate) (PIFA) in
CF3CH2OH at 240 8C to give two dimerization products
(15) and (16) in 16 and 21% yields, respectively. To
elucidate their relative stereochemistry, those two com-
pounds were transformed into known compounds. On
reduction with Red-Al in toluene, the less polar product
(16) gave rac-folicanthine (rac-12),6 whereas the more
polar one 15 produced meso-folicanthine (17), demonstrat-
ing the relative stereochemistry of the two dimerization
products. For the completion of the total synthesis of the
new alkaloid, rac-(16) was employed again for further
transformation. Elimination of one of two protecting groups
on the nitrogen atoms was carried out by treatment of 16
with 1.0 equiv. tetrabutyl ammonium fluoride in THF at
room temperature for 6 h to give the desired mono-
deprotected amine (18) in 33.4% yield together with
51.3% of the recovered starting material. Finally, the
remaining carbamate group in 18 was converted into the
N-methyl function by reduction with Red-Al to furnish
target molecule 2 in 73.4% yield. Synthetic 2 was
completely identical in all respects (chromatographic
Figure 2. CD spectra of (2)- and (þ)-3-hydroxyoxindoles (7).
existed on the aliphatic nitrogen atom and the other two
were on the nitrogen of aniline function. Therefore, the
structure of the new alkaloid, now named chimonanthidine,
was deduced to be formula 2 i.e. Nb-monodemethyl-
folicanthine (Fig. 3).
1
behavior; mass; IR; UV; H and 13C NMR) with natural
chimonanthidine except for the optical property. The CD
spectrum of natural 2 exhibited Cotton curves very similar
to those of (2)-folicanthine (11), the absolute configuration
of which was determined by chemical correlation with (2)-
chimonanthine (10).17 The absolute stereochemistry of (2)-
chimonanthine has been recently corrected by Overman
et al.18 Therefore, the structure including the absolute
configuration of (2)-chimonanthidine was determined to be
formula 2 (Scheme 2).
3. Experimental
3.1. General
UV: Recorded in MeOH on a JASCO V-560 instrument. IR:
recorded on a JASCO FT/IR-230 spectrophotometer. 1H and
13C NMR spectra: recorded on JEOL JNM A-400, JNM
A-500, JNM ECP-400, or JNM ECP-600 spectrometers, J
values are given in Hz. EI-MS: direct probe insertion at
70 eV recorded on a JEOL JMS GC-mate spectrometer.
FAB-MS: recorded on a JEOL JMS-HX110 mass spec-
trometer. Optical rotation: measured using a JASCO P-1020
polarimeter. CD: recorded on a JASCO J-720WI spec-
trometer. TLC: precoated Kieselgel 60 F254 plates (Merck,
0.25 mm thick). Column Chromatography: Kieselgel 60
[Merck, 70-230 (for open chromatography) and 230–400
mesh (for flash chromatography)], amino silica gel [Fuji
Silysia Chemical, NH-DM1020], medium pressure liquid
column chromatography: silica gel prepacked column
Kusano CPS-HS-221-05.
Figure 3. Structures and CD spectra of chimonanthidine (2) and
folicanthine (11).
To establish the above structure inferred by spectroscopic
analysis, we attempted the total synthesis of (^)-2.
Recently, we have developed a new synthetic procedure
that uses hypervalent iodine(III) reagents for the dimeriza-
tion of indole derivatives,14 and applied it to the concise
3.2. Plant material
The seeds of Chimonanthus praecox Link. were collected in
June at the medicinal plant garden in the Faculty of
Pharmaceutical Sciences, Chiba University, and identified

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H. Takayama et al. / Tetrahedron 60 (2004) 893–900
Scheme 2. Reagents and conditions: (a) Mel, NaH, DMF, 220 8C, 94%. (b) 0.5 equiv. PIFA, CF3CH2OH, 240 8C; 15, 16%; 16, 21%; 14, 5%. (c) Red-Al,
toluene, reflux; meso-17, 96%. rac-11, 95%; rac-2, 73.4%. (d) 1.0 equiv. TBAF, THF, rt, 6 h; 18, 33.4%; 16, 51.3%.
by Dr Fumio Ikegami, Graduate School of Pharmaceutical
Sciences, Chiba University, Japan. A voucher specimen was
deposited at the Herbarium of the Graduate School of
Pharmaceutical Sciences, Chiba University.
30.2 and 30.1 (N-Me£2); FABMS (NBA) m/z: 221
[MþH]þ; HRFABMS (NBA) m/z: 221.1290 (calcd for
C12H17N2O2, 221.1290).
3.3.2. Chimonanthidine (2). Amorphous powder;
[a]2D0¼2285 (c 0.05, EtOH); UV (MeOH) lmax 208, 245,
3.3. Extraction and isolation of alkaloids
1
300 nm; IR (neat) nmax 2938, 1603, 1495 cm20 1; H NMR
The dried powdered seeds (2.5 kg) of C. praecox were
macerated with MeOH (2.0 L) four times and filtered. The
combined filtrates were concentrated under reduced
pressure to give a crude extract (97.3 g), which was then
dissolved in 10% aqueous acetic acid (2.0 L). The solution
was washed with ethyl acetate (600 mL), alkalinized with
Na2CO3 (pH 10), and then exhaustively extracted with
CHCl3. The organic layer was washed with water, dried
over MgSO4, and evaporated to give a crude alkaloidal
fraction (15.37 g). From this fraction, crude crystalline
calycanthine (11.38 g) was directly obtained, a portion
(998 mg) of which was recrystallized from ethyl acetate to
give pure (þ)-calycanthine (632 mg). The mother liquid
(3.8 g) of the first crystallization was roughly separated by
silica gel flash column chromatography using a CHCl3–
MeOH/CHCl3 gradient to give twelve fractions. The 10%
MeOH/CHCl3 eluate was recrystallized from ethyl acetate
to give 352 mg of (2)-folicanthine (11). The 20% MeOH/
CHCl3 eluate was purified by SiO2 medium pressure liquid
chromatography (20% MeOH/ethyl acetate) to give 2.6 mg
of chimonamidine (1) and 22 mg of (2)-calycanthidine
(12). The 30% MeOH/CHCl3 eluate of the first column
chromatography was purified by reverse phase medium
pressure liquid chromatography (30% H2O/MeOH) to give
22 mg of (2)-chimonanthine (10) and 13 mg of chimo-
nanthidine (2).
(CDCl3, 600 MHz) d 2.03–2.07 (2H, m, H-3, 3 ), 2.24–2.31
(1H, m, H-30), 2.36 (3H, s, N1–CH3), 2.44–2.51 (3H, m,
0
0
H-2, 3, 2 ), 2.61–2.64 (1H, m, H-2), 2.84 (3H, s, N8 –CH3),
2.94–2.97 (1H, m, H-20), 2.98 (3H, s, N8–CH3), 4.18 (1H,
br-s, H-8a), 4.58 (1H, br-s, H-80a), 6.24 (1H, d, J¼8.1 Hz,
H-70), 6.34 0(1H, d, J¼7.8 Hz, H-7), 6.52 (1H, dd, J¼7.4,
7.4 Hz, H-5 ), 6.506 (1H, dd, J¼7.6, 7.6 Hz, H-5), 7.00–7.06
(4H, m, H-4, 6, 4 , 60); 13C NMR (CDCl3, 150 MHz) d 31.1
0
0
(N8 –CH3), 35.0 (C-3), 35.3 (N8–CH3), 38.2 (C-3 ), 38.3
(N1–CH3), 45.6 (C-20), 53.0 (C-2), 62.4 (C-3a, 30a), 87.2
(C-80a), 92.5 (C-8a), 1004.7 (C-70), 106.2 (C-7), 116.2 (C-50),
116.9 (C-5), 124.3 (C-4 ), 124.4 (C-4), 128.4 (C-6, 60), 131.8
(C-30b), 132.6 (C-3b), 152.5 (C-70a), 152.8 (C-7a); FABMS
(NBA) m/z: 361 [MþH]þ; HRFABMS (NBA) m/z:
361.2392 (calcd for C23H29N4, 361.2392).
1
3.3.3. Calycanthidine (12). The H and 13C NMR data of
the known alkaloid 12 have not been published so far. Thus,
1
we present them here; H NMR (CDCl3, 500 MHz, VT
50 8C) d 7.07 (1H, d, J¼7.3 Hz, H-4), 6.52 (1H, dd, J¼7.3,
7.3 Hz, H-5), 6.98 (1H, dd, J¼7.3, 7.6 Hz, H-6), 6.27 (1H, d,
J¼7.6 Hz, H-7), 7.002 (1H, d, J¼7.3 Hz, H-40), 6.59 (1H, d0d,
J¼7.3, 7.3 Hz, H-5 ), 6.92 (1H, dd, J¼7.3, 7.6 Hz, H-6 ),
6.48 (1H, d, J¼7.6 Hz, H-70), 4.38 (1H, br-s, 8a-H), 4.42
(1H, br-s, 8a0-H), 2.98 (3H, s, N8–CH3), 2.38 (3H, s,
0
N1–CH3), 2.33 (3H, s, N1 –CH3), 2.40–2.65 (6H, m, 2-H2,
20-H2, 3-H1, 30-H1), 1.95–2.05 (2H, m, 3-H1, 30-H1); 13C
NMR (CDCl3, 125 MHz, VT 50 8C) d 52.6 (C-2), 35.7
(C-3), 62.8 (C-3a), 132.7 (C-3b), 123.6 (C-4), 116.7 (C-5),
128.1 (C-6), 105.9 (C-7), 152.8 (C-7a0), 91.8 (C-8a), 37.9
(N1–CH3), 35.4 (N8–CH3), 52.6 (C-2 ), 35.7 (C-30), 63.2
(C-3a0), 133.3 (C-3b0), 124.4 (C-400), 118.2 (C-50), 127.9
(C-60), 109.0 (C-70), 150.8 (C-7a ), 85.0 (C-8a0), 37.0
(N1–CH3).
3.3.1. Chimonamidine (1). Amorphous powder;
[a]1D9¼212.6 (c 0.06, EtOH); UV (MeOH) lmax 202, 246,
300 nm; IR (neat) nmax 3378, 1695 cm21; 1H NMR (CDCl3,
500 MHz) d 7.24 (1H, dd, J¼7.6, 7.6 Hz, H-6), 6.85 (1H, d,
J¼7.6 Hz, H-4), 6.74 (1H, d, J¼7.6 Hz, H-7), 6.66 (1H, dd,
J¼7.6, 7.6 Hz, H-5), 3.88 (1H, br-s, N1–H), 3.31 (1H, ddd,
J¼9.8, 9.8, 1.2 Hz, H-9), 3.24 (1H, ddd, J¼9.8, 9.8, 6.4 Hz,
H-9), 2.97 (3H, s, N10–CH3), 2.85 (3H, s, N1–CH3), 2.73
(1H, ddd, J¼12.8, 6.4, 1.2 Hz, H-8), 2.41 (1H, ddd, J¼12.8,
9.8, 9.8 Hz, H-8); 13C NMR (CDCl3, 125 MHz) d 175.1
(C-2), 148.3 (C-7a), 129.4 (C-6), 125.4 (C-4), 124.6 (C-3a),
116.7 (C-5), 111.7 (C-7), 79.6 (C-3), 45.7 (C-9), 33.0 (C-8),
3.4. Synthesis of chimonamidine
3.4.1. Na,Nb-Dimethyl-Nb-carbobenzyloxytryptamine
(5). Under argon atmosphere, a solution of benzyl

H. Takayama et al. / Tetrahedron 60 (2004) 893–900
897
chloroformate (2.0 mL, 13.86 mmol) in dry dichloro-
methane (25 mL) and a solution of Na2CO3 (1.336 g) in
water (40 mL) were simultaneously added dropwise to a
stirred solution of 4 (2.36 g, 12.55 mmol) in dichloro-
methane (40 mL) at 0 8C. After being stirred at the same
temperature for 1 h, the reaction mixture was transferred
into a separatory funnel. The organic layer was drawn off
and the aqueous layer was extracted with dichloromethane.
The combined organic layer was washed with brine, dried
over MgSO4, and concentrated to give a residue that was
purified by pre-packed silica gel column chromatography
(10% acetone/chloroform) to give 3.48 g (86%) of 5 as a
colorless oil; IR nmax (CHCl3) cm21: 1692; UV lmax
(MeOH) nm: 209, 225.5, 289.5; 1H NMR (DMSO-d6,
400 MHz, VT 100 8C) d 2.87 (3H, s), 2.93 (2H, m), 3.51
(2H, m), 3.70 (3H, s), 5.05 (2H, s), 6.98 (1H, ddd, J¼7.9,
7.0, 1.0 Hz), 7.03 (1H, s), 7.12 (1H, ddd, J¼7.9, 7.0,
1.0 Hz), 7.30–7.37 (6H, m), 7.49 (1H, d, J¼7.9 Hz); 13C
NMR (DMSO-d6, 100 MHz, VT 100 8C) d 22.8, 31.6, 33.7,
49.0, 65.7, 108.9, 110.5, 117.8, 120.6, 126.6, 126.8, 126.9,
127.1, 127.2, 127.8, 136.5, 136.7, 155.0; FABMS
(NBAþKI) m/z: 361 [MþK]þ; HRFABMS (NBAþKI)
m/z: 361.1309 (calcd for C20H22N2O2K [MþK]þ,
361.1318).
J¼12.8 Hz), 4.99 (1H, d, J¼12.8 Hz), 5.69 (1H, s), 6.93
(1H, dd, J¼8.1, 0.9 Hz), 7.02 (1H, ddd, J¼7.5, 7.5, 0.9 Hz),
7.26–7.36 (7H, m); 13C NMR (DMSO-d6, 100 MHz, VT
100 8C) d 25.2, 33.2, 35.0, 43.0, 65.6, 73.5, 107.8, 118.6,
121.6, 122.9, 126.7, 127.0, 127.7, 128.5, 136.6, 142.7,
154.7, 176.4; FABMS (NBA) m/z: 355 [MþH]þ. Anal.
calcd for C20H22N2O4: C, 67.78; H, 6.26; N, 7.90. Found: C,
67.48; H, 6.29; N, 7.83.
3.4.4. (6)-Chimonamidine (1). To a stirred solution of
(^)-7 (37.4 mg, 0.11 mmol) in dry CH3CN (3 mL) was
added trimethysilyl iodide (60 mL, 0.42 mmol) at 0 8C and
the mixture was stirred at the same temperature for 6 h and
then at room temperature for 13 h. The reaction mixture was
poured into 10% aqueous HCl solution and then extracted
with ether. The acidic aqueous layer was alkalinized with
10% aqueous KOH solution and then extracted three times
with chloroform. The combined extract was washed with
water, dried over solid K2CO3, and concentrated to give a
residue that was allowed to stand for two days in a
desiccator. The thus obtained crude product was recrystal-
lized from ethyl acetate to give 15.4 mg (66%) of (^)-
chimonamidine as colorless needles; mp 213–215 8C
(AcOEt). Anal. calcd for C12H16N2O2: C, 65.43; H, 7.32;
N, 12.72. Found: C, 65.21; H, 7.32; N, 12.55. The synthetic
compound was found to be completely identical with the
natural product by comparison of their chromatographic
behavior and spectroscopic data (1H and 13C NMR, UV, IR
and MS spectra).
3.4.2. Preparation of oxindole (6). To a stirred mixture of
conc. HCl (3.20 mL), DMSO (0.81 mL, 11 mmol), and
phenol (0.16 mL, 1.9 mmol) in acetic acid (40 mL) was
added dropwise a solution of 5 (3.05 g, 9.49 mmol) in acetic
acid (10 mL) at 0 8C. Stirring was continued for 10 min at
the same temperature. The reaction mixture was poured into
chilled water and then alkalinized with saturated aqueous
Na2CO3 solution. The whole mixture was extracted three
times with chloroform. The combined extract was washed
with brine, dried over MgSO4, and concentrated to give a
residue that was purified by silica gel flash column
chromatography (40% ethyl acetate in n-hexane) to give
3.4.5. Preparation and separation of MTPA-esters (8 and
9). A mixture of (^)-7 (51.9 mg, 0.147 mmol), (S)-MTPA-
chloride (41 mL, 0.22 mmol), and DMAP (36.4 mg,
0.29 mmol) in dry dichloromethane (1 mL) was stirred for
1.5 h at room temperature under argon atmosphere. Water
was added to the reaction mixture, which was then extracted
three times with chloroform. The combined extract was
washed with brine, dried over MgSO4, and concentrated
to give a residue that was purified by pre-packed silica
gel column chromatography (acetone/chloroform/n-
hexane¼1:9:10) to give 37.9 mg (y. 45%) of less polar 9
and 35.7 mg (y. 43%) of more polar 8. 8; colorless prisms,
mp 130–131 8C (MeOH); [a]2D4¼þ9.2 (c 0.152, CHCl3); IR
2.27 g (71%) of 6 as a colorless oil; IR nmax (CHCl3) cm21
:
1
1695, 1613; UV lmax (MeOH) nm: 208, 254; H NMR
(DMSO-d6, 400 MHz, VT 100 8C) d 2.06 (2H, m), 2.81 (3H,
s), 3.10 (3H, s), 3.29 (1H, m), 3.43 (2H, m), 5.00 (1H, d,
J¼12.8 Hz), 5.02 (1H, d, J¼12.8 Hz), 6.93 (1H, d,
J¼7.5 Hz), 6.99 (1H, dd, J¼7.5, 7.5 Hz), 7.23–7.36 (7H,
m); 13C NMR (DMSO-d6, 100 MHz, VT 100 8C) d 25.3,
27.6, 33.4, 42.2, 45.2, 65.7, 107.6, 121.3, 123.0, 125.9,
126.9, 127.1, 127.2, 127.4, 127.7, 128.0, 136.6, 143.7,
154.9, 176.0; FABMS (NBA) m/z: 339 [MþH]þ;
HRFABMS (NBA) m/z: 339.1704 (calcd for C20H23N2O3
[MþH]þ, 339.1709).
n
max (KBr) cm21: 1729, 1697; UV lmax (MeOH) nm: 214.5,
1
259; H NMR (DMSO-d6, 600 MHz, VT 100 8C) d 2.20
(2H, m), 2.69 (3H, s), 3.19 (3H, s), 3.25 (2H, m), 3.48 (3H,
s), 4.98 (1H, d, J¼12.6 Hz), 4.99 (1H, d, J¼12.6 Hz), 7.07–
7.12 (2H, m), 7.26–7.49 (12H, m); 13C NMR (DMSO-d6,
150 MHz, VT 100 8C) d 26.9, 34.3, 43.1, 55.8, 66.8, 81.3,
84.8, 109.7, 123.3, 123.5, 124.6, 126.0, 127.85, 127.92,
128.2, 128.8, 129.0, 130.4, 131.1, 131.9, 137.5, 144.4,
155.7, 164.3, 172.8; FABMS (NBA) m/z: 571 [MþH]þ;
HRFABMS (NBA) m/z: 571.2103 (calcd for C30H30N2O6F3
[MþH]þ, 571.2056); CD (c 0.195 mmol/L, MeOH, 23 8C)
l nm (D1): 206 (þ12.6), 218 (0), 231 (215.1), 249 (0), 258
(þ2.9), 274 (0). 9; colorless oil, [a]2D4¼25.2 (c 0.39,
CHCl3); IR nmax (KBr) cm21: 1728, 1696; UV lmax
3.4.3. Preparation of (6)-3-hydroxyoxindole (7). Under
oxygen atmosphere, a solution of 6 (992 mg, 3.0 mL) in
THF (2 mL) and 1 M aqueous NaOH (3.0 mL) was stirred
for 4 h at room temperature. The reaction mixture was
diluted with water and then extracted three times with
chloroform. The combined extract was washed with brine,
dried over MgSO4, and concentrated to give a residue that
was purified by silica gel column chromatography (60%
ethyl acetate in n-hexane) to give 1.21 g (y. quant) of (^)-7
as colorless prisms; mp 128–129 8C (AcOEt); IR nmax
1
(MeOH) nm: 214.5, 259; H NMR (DMSO-d6, 600 MHz,
VT 100 8C) d 2.20 (2H, m), 2.71 (3H, s), 3.20 (3H, s), 3.28
(2H, m), 3.47 (3H, s), 4.97 (1H, d, J¼12.6 Hz), 4.98 (1H, d,
J¼12.6 Hz), 7.07–7.13 (3H, m), 7.25–7.34 (5H, m), 7.41–
7.52 (6H, m); 13C NMR (DMSO-d6, 150 MHz, VT 100 8C)
d 26.9, 34.4, 43.1, 55.7, 66.8, 81.3, 84.9, 109.7, 123.2,
1
(KBr) cm21: 3290; UV lmax (MeOH) nm: 209, 258.5; H
NMR (DMSO-d6, 400 MHz, VT 100 8C) d 2.04 (2H, m),
2.73 (3H, s), 3.08 (3H, s), 3.20 (2H, m), 4.96 (1H, d,

898
H. Takayama et al. / Tetrahedron 60 (2004) 893–900
123.3, 124.6, 125.9, 127.7, 127.9, 128.2, 128.8, 129.0,
130.5, 131.1, 132.0, 137.5, 144.5, 155.7, 164.2, 172.9;
FABMS (NBA) m/z: 571 [MþH]þ; HRFABMS (NBA) m/z:
571.2048 (calcd for C30H30N2O6F3 [MþH]þ; 571.2056);
CD (c 0.195 mmol/L, MeOH, 23 8C) l nm (D1): 206
(221.7), 218 (0), 231 (þ24.0), 250 (0), 259 (-5.7), 274 (0).
silica gel column chromatography (50% ethyl acetate in
n-hexane) to give 64 mg (y. 55%) of (2)-chimonamidine 1
as a colorless amorphous powder. [a]2D3¼2177.8 (c 0.17,
EtOH); CD (c 0.582 mmol/L, MeOH, 23 8C) l nm (D1): 201
(227), 215 (0), 224 (22.9), 234 (0), 246 (þ3.6), 257 (0),
297 (23.7), 321 (0); HRFABMS (NBA) m/z: 221.1308
(calcd for C12H17N2O2, 221.1290). The synthetic com-
pound was found to be identical with the natural product
by comparison of their chromatographic behavior and
spectroscopic data (1H and 13C NMR, IR, UV, and MS
spectra).
3.4.6. X-ray crystallographic analysis of 8. All measure-
ments were conducted on a Quantum CCD area detector
coupled with a CCD diffractometer with graphite mono-
˚
chromated Mo Ka radiation (l¼0.71069 A). Crystal
data: orthorhombic, C30H29N2O6F3 (Mw: 570.56), space
˚
˚
group P21212 with a¼9.318(2) A, b¼10.628(2) A, c¼
3.4.10. Preparation of (S)-(1)-Chimonamidine. (2)-7
(10 mg, 0.029 mmol) was treated according to the pro-
cedure described above. The residue obtained by work-up
was allowed to stand for ten days in a desiccator and then
purified by pre-packed silica gel column chromatography
(50% ethyl acetate in n-hexane) to give 3.2 mg (y. 50%) of
(þ)-chimonamidine 1 as a colorless amorphous powder.
[a]2D3¼þ170.7 (c 0.18, EtOH); CD (c 0.582 mmol/L,
MeOH, 23 8C) l nm (De): 202 (þ24.4), 215 (0), 226
(þ3.1), 237 (0), 251 (23.2), 257 (0), 298 (þ3.5), 321 (0);
HRFABMS (NBA) m/z: 221.1296 (calcd for C12H17N2O2,
221.1290). The synthetic compound was found to be
identical with the natural product by comparison of their
chromatographic behavior and spectroscopic data (1H and
13C NMR, IR, UV, and MS spectra).
3
˚
˚
27.933(5) A, V¼2766.1(9) A , Z¼4, and Dcalc¼1.370 g/
cm3. The structure was solved by direct methods (SIR97)
and expanded using Fourier techniques (DIRDIF94). The
non-hydrogen atoms were refined anisotropically. Hydro-
gen atoms were included but not refined. The final cycle of
full-matrix least-squares refinement was based on 6504
reflections (I.0.00s(I), 2u,57.358) and 371 variable
parameters and converged with unweighted and weighted
agreement factors of R¼0.091 and Rw¼0.111.
3.4.7. Alkaline hydrolysis of 8. Under argon atmosphere, a
mixture of 8 (15.8 mg, 0.028 mmol) in 0.5 M aqueous
NaOH solution (0.5 mL) and MeOH (0.5 mL) was stirred at
room temperature for 20 h and then heated under reflux for
1.5 h. The reaction mixture was diluted with water and
extracted three times with chloroform. The combined
extract was washed with brine, dried over MgSO4, and
concentrated to give a residue that was purified by silica gel
short column chromatography (AcOEt) to give 10.6 mg (y.
quant) of (þ)-7 as a colorless amorphous powder;
[a]2D5¼þ21.3 (c 0.67, CHCl3); CD (c 0.458 mmol/L,
MeOH, 23 8C) l nm (D1): 208 (þ23.6), 222 (0), 238
(220.7), 253 (0), 263 (þ7.4), 308 (0). This compound
was found to be identical with racemate described above
by comparison of their chromatographic behavior and
spectroscopic data (1H and 13C NMR, IR, UV, and MS
spectra).
3.5. Synthesis of chimonanthidine
3.5.1. Na-Methyl-Nb-2-trimethylsilylethoxycarbonyl-
tryptamine (14). To a stirred solution of 13 (2.2 g,
7.24 mmol) in dry DMF (31 mL) was added sodium hydride
(377 mg, 60% dispersion in mineral oil) by portions at
220 8C and the mixture was stirred at the same temperature
for 10 min. Iodomethane (0.6 mL, 9.63 mmol) was added to
the reaction mixture and stirring was continued for 60 min at
0 8C. The reaction mixture was poured into chilled water
and then extracted three times with chloroform. The
combined extract was washed with brine, dried over
MgSO4, and concentrated to give a residue that was purified
by silica gel column chromatography (66% ethyl acetate in
n-hexane) to give 2.16 g (94%) of 14 as a colorless oil; IR
nmax (neat) cm21: 3341, 2951, 1698, 1250, 740; UV lmax
(MeOH) nm: 205.5, 225.5, 289.5; 1H NMR (CDCl3,
400 MHz) d 0.03 (9H, s), 0.96 (2H, dd, J¼8.5, 8.5 Hz),
2.95 (2H, dd, J¼6.8, 6.8 Hz), 3.49 (2H, d-like, J¼6.8 Hz),
3.75 (3H, s), 4.15 (2H, dd, J¼8.5, 8.5 Hz), 4.69 (1H, br-s),
6.88 (1H, s), 7.11 (1H, ddd, J¼7.8, 7.8, 1.1 Hz), 7.23 (1H,
ddd, J¼7.8, 7.8, 1.1 Hz), 7.30 (1H, d, J¼7.8 Hz), 7.59 (1H,
d, J¼7.8 Hz); 13C NMR (CDCl3, 100 MHz) d 21.5, 17.7,
25.7, 32.5, 41.3, 62.8, 109.2, 111.4, 118.9, 121.7, 126.8,
127.7, 130.7, 156.7; EIMS m/z (%): 318 (Mþ, 32), 157
(100), 144 (69), 73 (26); HRFABMS (NBA) m/z: 318.1755
(calcd for C17H26N2O2Si, 318.1764).
3.4.8. Alkaline hydrolysis of 9. Under argon atmosphere, a
mixture of 9 (6.9 mg, 0.012 mmol) in 0.5 M aqueous NaOH
solution (0.5 mL) and MeOH (0.5 mL) was stirred at room
temperature for 90 h. The reaction mixture was diluted with
water and extracted three times with chloroform. The
combined extract was washed with brine, dried over
MgSO4, and concentrated to give a residue that was purified
by silica gel short column chromatography (AcOEt) to give
4.7 mg (y. quant) of (2)-7 as a colorless amorphous
powder; [a]2D5¼221.3 (c 0.58, CHCl3); CD (c
0.432 mmol/L, MeOH, 23 8C) l nm (D1): 208 (221.8),
222 (0), 238 (þ19.6), 253 (0), 263 (27.1), 308 (0). This
compound was found to be identical with racemate
described above by comparison of their chromatographic
behavior and spectroscopic data (1H and 13C NMR, IR, UV,
and MS spectra).
3.5.2. Dimerization of 14. To a stirred solution of 14
(988 mg, 3.11 mmol) in trifluoroethanol (12.5 mL) was
added PIFA (95% purity, 669 mg, 1.55 mmol) at 240 8C
and the reaction mixture was stirred at the same temperature
for 8 h under argon atmosphere. Aqueous sat. NaHCO3
solution was added to the reaction mixture, which was then
extracted three times with chloroform. The combined
3.4.9. Preparation of (R)-(2)-Chimonamidine. (þ)-7
(185 mg, 0.52 mmol) was treated according to the pro-
cedure described above for the synthesis of (^)-1. The
residue obtained by work-up was allowed to stand for
three days in a desiccator and then purified by pre-packed

H. Takayama et al. / Tetrahedron 60 (2004) 893–900
899
extract was washed with brine, dried over MgSO4, and
concentrated to give a residue that was purified by silica gel
column chromatography (5% acetone in n-hexane) and then
by pre-packed silica gel column chromatography (7%
acetone in n-hexane) to give 159 mg (16%) of 15, 209 mg
(21%) of 16, and 48 mg (5%) of 14. 15; colorless oil, IR
0.026 mmol) in dry toluene (3 mL) was added a solution of
Red-Al (65% solution of sodium bis(2-methoxyethoxy)-
aluminum hydride in toluene, 0.08 mL) at room temperature
under argon atmosphere. The reaction mixture was refluxed
at 130 8C for 2 h. After cooling, 5% aqueous NaOH solution
was added and the mixture was filtered using Celite. The
filtrate was extracted three times with chloroform and the
combined extract was washed with brine, dried over
MgSO4, and concentrated to give a residue that was purified
by amino silica gel column chromatography (50% ethyl
acetate in n-hexane) to give 9.2 mg (95%) of rac-
folicanthine 11 as pale yellow crystals: mp 172–174 8C
n
max (neat) cm21: 2952, 1700, 1698, 746; UV lmax (MeOH)
1
nm: 208.0, 253.0, 309.5; H NMR (CDCl3, 400 MHz, VT
50 8C) d 0.05 (18H, s), 1.02 (4H, br-s), 2.16–2.20 (4H, m),
2.71 (6H, br), 2.87–2.98 (2H, m), 3.81–3.91 (2H, br), 4.21
(4H, br), 5.17–5.28 (2H, br), 6.31 (2H, d, J¼8.1 Hz), 6.52
(4H, m), 7.08 (2H, dd, J¼7.6, 7.6 Hz); 13C NMR (CDCl3,
100 MHz, VT 50 8C) d 21.5 (CO2CH2CH2Si(CH3)3), 17.9
(CO2CH2CH2Si(CH3)3), 33.1 (N8–CH3), 34.7 (br, C-3),
45.1 (C-2), 61.7 (br, CO2CH2CH2Si(CH3)3), 63.5 (C-3a),
83.4 (br, C-8a), 106.4, 117.1, 123.7, 129.1, 129.6, 152.5
(C-3b, 4, 5, 6, 7, 7a), 155.3 (br, CO2CH2CH2Si(CH3)3);
EIMS m/z (%): 634 (Mþ, 25), 318 (9.5), 144 (65), 73 (100);
HRFABMS (NBA) m/z: 634.3380 (calcd for
C34H50N4O4Si2, 634.3371). 16; colorless oil, IR nmax
(CHCl3) cm21: 2955, 1687, 766; UV lmax (MeOH) nm:
208.5, 253.5, 310.0; 1H NMR (CDCl3, 400 MHz, VT 50 8C)
d 0.06 (18H, s), 0.96 (4H, dd, J¼7.8, 7.8 Hz), 2.01 (2H, dd,
J¼5.6, 5.6 Hz), 2.32 (2H, m), 2.82 (2H, br-s), 2.94 (6H,
br-s), 3.78–3.88 (2H, br), 4.14 (4H, m), 5.14-5.28 (2H, br),
6.31 (2H, d, J¼7.6 Hz), 6.59 (2H, dd-like, J¼7.1, 7.1 Hz),
7.06 (4H, m); 13C NMR (CDCl3, 100 MHz, VT 50 8C) d
21.5 (CO2CH2CH2Si(CH3)3), 17.8 (CO2CH2CH2-
Si(CH3)3), 32.1 (br, C-3), 33.6 (N8–CH3), 45.0 (C-2),
61.0, 62.0 (br, CO2CH2CH2Si(CH3)3), 63.3 (C-3a), 83.8 (br,
C-8a), 105.7, 116.8, 124.0, 129.0, 129.1, 151.9 (C-3b, 4, 5,
6, 7, 7a), 155.0 (br, CO2CH2CH2Si(CH3)3); EIMS m/z (%):
634 (Mþ, 11), 318 (7), 144 (57), 73 (100); HRFABMS
(NBA) m/z: 634.3315 (calcd for C34H50N4O4Si2, 634.3371).
1
(n-hexane/AcOEt). The H and 13C NMR and MS spectra
were identical with those reported in the literature.6
3.5.5. Partial deprotection of carbamates in 16. To a
solution of 16 (42 mg, 0.066 mmol) in dry THF (2.5 mL)
was added 1.0 M solution of tetrabutylammonium fluoride
in THF (66 mL, 0.066 mmol) at 0 8C and the mixture was
stirred at room temperature for 6 h. The reaction mixture
was poured into chilled water and then extracted three times
with chloroform. The combined extract was washed with
brine, dried over MgSO4, and concentrated to give a residue
that was purified by silica gel column chromatography (3%
methanol in chloroform) to give 11 mg (33.4%) of 18 as a
colorless oil and 21.5 mg (51.3%) of starting material 16.
18. IR nmax (neat) cm21: 2951, 1697, 1492, 744; UV lmax
1
(MeOH) nm: 212.0, 254.0, 310.5; H NMR (Pyridine-d5,
400 MHz, VT 90 8C) d 0.08 (9H, s), 1.06 (2H, dd, J¼8.2,
8.2 Hz), 2.12 (1H, dd, J¼11.7, 5.2 Hz), 2.18 (1H, dd,
J¼12.3, 5.7 Hz), 2.42 (1H, ddd, J¼11.2, 11.2, 7.5 Hz), 2.58
(1H, ddd, J¼10.8, 10.8, 5.5 Hz), 2.67 (1H, ddd, J¼11.9,
11.9, 8.1 Hz), 2.86 (3H, s), 2.96–3.03 (2H, m), 3.12 (3H, s),
4.33 (2H, dd, J¼8.2, 8.2 Hz), 4.81 (1H, s), 5.67 (1H, br-s),
6.40 (1H, d, J¼7.5 Hz), 6.49 (1H, d, J¼7.5 Hz), 6.68 (1H,
dd, J¼7.5, 7.5 Hz), 6.77 (1H, dd, J¼7.4, 7.4 Hz), 7.14 (1H,
dd, J¼7.5, 7.5 Hz), 7.18–7.21 (1H, m), 7.32 (1H, d,
J¼7.5 Hz), 7.36 (1H, d, J¼7.4 Hz); 13C NMR (Pyridine-d5,
100 MHz, VT 90 8C) d 21.5, 18.2, 30.9, 32.5, 35.0,
38.3, 45.4, 46.0, 62.8, 63.4, 79.3, 85.0, 87.8, 105.5,
106.2, 116.6, 117.4, 124.5, 124.6, 129.0, 129.3, 131.1,
131.8, 152.8, 153.3, 155.4; EIMS m/z (%): 490 (Mþ, 26),
316 (100), 272 (46), 244 (49), 173 (55), 144 (91);
HRFABMS (NBA) m/z: 491.2807 (calcd for
C28H39N4O2Si, 491.2842).
3.5.3. Red-Al reduction of 15. To a solution of 15 (17 mg,
0.027 mmol) in dry toluene (3 mL) was added a solution of
Red-Al (65% solution of sodium bis(2-methoxyethoxy)-
aluminum hydride in toluene, 0.08 mL) at room temperature
under argon atmosphere. The reaction mixture was refluxed
at 130 8C for 1.5 h. After cooling, 5% aqueous NaOH
solution was added and the mixture was filtered using
Celite. The filtrate was extracted three times with chloro-
form and the combined extract was washed with brine, dried
over MgSO4, and concentrated to give a residue that was
purified by amino silica gel column chromatography (50%
ethyl acetate in n-hexane) to give 9.7 mg (96%) of meso-
folicanthine 17 as pale yellow crystals: mp 176–178 8C
(n-hexane/AcOEt); IR nmax (CHCl3) cm21: 2933, 1602,
3.5.6. Red-Al reduction of 18. To a solution of 18 (36 mg,
0.073 mmol) in dry toluene (5 mL) was added a solution of
Red-Al (65% solution of sodium bis(2-methoxyethoxy)-
aluminum hydride in toluene, 0.13 mL) at room temperature
under argon atmosphere. The reaction mixture was refluxed
at 130 8C for 2 h. After cooling, 5% aqueous NaOH solution
was added and the mixture was filtered using Celite. The
filtrate was extracted three times with chloroform and the
combined extract was washed with brine, dried over
MgSO4, and concentrated to give a residue that was purified
by amino silica gel column chromatography (75% ethyl
acetate in n-hexane) to give 19.3 mg (73.4%) of rac-
chimonanthidine 2 as a colorless amorphous powder. The
synthetic compound was found to be completely identical
with the natural product by comparison of their chromato-
graphic behavior and spectroscopic data (1H and 13C NMR,
UV, IR and MS spectra).
1
1491, 669; UV lmax (MeOH) nm: 207.5, 253.5, 308.0; H
NMR (Pyridine-d5, 600 MHz, VT 90 8C) d 2.01 (2H, dd,
J¼4.4, 4.4 Hz), 2.43 (10H, m), 2.53 (2H, m), 2.76 (2H, dd,
J¼8.5, 8.5 Hz), 4.37 (2H, br-s), 6.45 (2H, d, J¼7.7, 7.7 Hz),
6.60 (2H, br-s), 7.12 (2H, dd, J¼7.7, 7.7 Hz), 7.16 (2H, s);
13C NMR (Pyridine-d5, 150 MHz, VT 90 8C) d 36.0 (N8–
CH3)p, 36.3 (C-3), 36.6 (N1–CH3)p, 52.5 (C-2), 63.6 (C-3a),
91.9 (C-8a), 107.3, 117.4, 124.2, 128.4, 133.8, 155.0 (C-3b,
4, 5, 6, 7, 7a) (pinterchangeable); EIMS m/z: (%): 374
(Mþ, 42), 188 (38), 187 (100), 186 (88), 144 (87);
HRFABMS (NBA) m/z: 375.2560 (calcd for C24H31N4,
375.2549).
3.5.4. Red-Al reduction of 16. To a solution of 16 (16 mg,

900
H. Takayama et al. / Tetrahedron 60 (2004) 893–900
9. (a) Takayama, H.; Shimizu, T.; Sada, H.; Harada, Y.;
Acknowledgements
Kitajima, M.; Aimi, N. Tetrahedron 1999, 55, 6841–6846.
(b) Monde, K.; Taniguchi, T.; Miura, N.; Nishimura, S.;
Harada, N.; Dukor, R. K.; Nafie, L. A. Tetrahedron Lett. 2003,
44, 6017–6020.
The authors thank to Professor Dr. Kentaro Yamaguchi,
Analysis Center of Chiba University, for X-ray crystal-
lographic analysis.
10. Some examples of enantiomerically not pure natural alkaloids
have been found in our laboratory. (a) Takayama, H.;
Kurihara, M.; Kitajima, M.; Said, I. M.; Aimi, N. J. Org.
Chem. 1999, 64, 1772–1773. (b) Takayama, H.; Kurihara, M.;
Kitajima, M.; Said, I. M.; Aimi, N. Tetrahedron 2000, 56,
3145–3151. (c) Takayama, H.; Ichikawa, T.; Kuwajima, T.;
Kitajima, M.; Seki, H.; Aimi, N.; Nonato, M. G. J. Am. Chem.
Soc. 2000, 122, 8635–8639.
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