Divergent total synthesis of (-)-aspidophytine and its congeners via Fischer indole synthesis

Article abstract of DOI:10.1016/j.tet.2012.10.060

A total synthesis of (-)-aspidophytine and the first total syntheses of its congeners, (+)-cimicidine and (+)-cimicine, were accomplished in a divergent manner. Construction of the aspidosperma skeleton was executed by Fischer indole synthesis between substituted phenylhydrazines and tricyclic aminoketone. The regiochemistry of the Fischer indole synthesis was strongly dependent on the choice of acid, and a weak acid, such as acetic acid provided the desired indolenine isomer in high selectivity.

Full text of DOI:10.1016/j.tet.2012.10.060

Tetrahedron 69 (2013) 89e95
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Divergent total synthesis of (ꢀ)-aspidophytine and its congeners via
Fischer indole synthesis
*
Hitoshi Satoh, Hirofumi Ueda, Hidetoshi Tokuyama
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2012
Received in revised form 17 October 2012
Accepted 20 October 2012
Available online 30 October 2012
A total synthesis of (ꢀ)-aspidophytine and the first total syntheses of its congeners, (þ)-cimicidine and
(þ)-cimicine, were accomplished in a divergent manner. Construction of the aspidosperma skeleton was
executed by Fischer indole synthesis between substituted phenylhydrazines and tricyclic aminoketone.
The regiochemistry of the Fischer indole synthesis was strongly dependent on the choice of acid, and
a weak acid, such as acetic acid provided the desired indolenine isomer in high selectivity.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Alkaloid
Aspidophytine
Fischer indole synthesis
Indolenine
1. Introduction
(3), have been reported.11 While the total synthesis of haplophytine
(1) had not been reported for about a half century since its isolation,
Aspidosperma alkaloids have attracted long-standing interest as
synthetic targets in the area of alkaloid synthesis due to its densely
fused polycyclic structure and fascinating biological activities.1-3
Furthermore, these compounds constitute medicinally important
dimeric indole alkaloids, some of which are currently used in
clinical practice. In 1952, Snyder et al. isolated the alkaloid
(þ)-haplophytine (1) from dried leaves of Haplophyton cimicidum.4
Structural determination of this compound revealed a highly
unique dimeric structure consisting of an aspidosperma skeleton
we recently achieved the first total synthesis,12 which was followed
by a total synthesis by Nicolaou and Chen.13
Our successful total synthesis of 1 depended on establishment of
a facile assembly of tricyclic aminoketone 6 via stereoselective
intramolecular Mannich reaction,12b and construction of the aspi-
dosperma skeleton by Fischer indole synthesis14 using 6 and phe-
nylhydrazine derivative 7 at the later stage of the synthesis
(Scheme 1). Taking advantage of the high convergence, we
possessing a g
-lactone ring.5 In addition, a number of related di-
meric and monomeric aspidosperma alkaloids, such as cimilophy-
tine (2),6 cimicidine (4),7,8 and cimicine (5)7,8 were found in H.
cimicidum (Fig. 1).
In addition to the characteristic structure, these compounds
possess intriguing biological activities, such as inhibitory activity
against acetylcholine esterase9 and insecticidal activity for
cockroaches.4
Because of its unusual polycyclic structure, haplophytine (1),5
a
representative compound isolated from H. cimicidum, has
attracted considerable attention from the synthetic community and
tremendous efforts have been made to construct this molecule.10 To
date, five total syntheses of the left-half segment, aspidophytine
* Corresponding author. E-mail address: tokuyama@mail.pharm.tohoku.ac.jp
(H. Tokuyama).
Fig. 1. Aspidosperma alkaloids isolated from Haplophyton cimicidum.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.060

90
H. Satoh et al. / Tetrahedron 69 (2013) 89e95
envisioned that our synthetic strategy would be a powerful tool for
divergent synthesis of (ꢀ)-aspidophytine (3) and its congeners
simply by switching of phenylhydrazine segment 9 (Scheme 2). Our
strategy should be particularly suited for divergent synthesis be-
cause all of the previously established syntheses of aspidophytine
(3) were based on construction of the aspidosperma skeleton on
the initially-formed indole segment. Thus, it is inefficient to apply
to the diversity-oriented synthesis regarding structural diversity on
the indoline moiety. In this paper, we reported a total synthesis of
aspidophytine (3) and the first total syntheses of its congeners,
(þ)-cimicidine (4) and (þ)-cimicine (5) in a divergent manner,
featuring construction of the aspidosperma skeleton by Fischer
indole synthesis.
find the regiochemical outcome was strongly dependent on the
acidity. Thus, the ratio of the desired indolenine 14 increased as
acidity decreased. Eventually, we succeeded in obtaining the de-
sired indolenine 14 in 48% associated with 5% of indole 15 when
reaction was executed in acetic acid at 100 ꢁC (entry 4).14
Table 1
Fischer indole synthesis with various acids
Scheme 1. The key Fischer indole synthesis in the first total synthesis of (þ)-hap-
lophytine (1).
Entry
Acid
Solvent
Temp
Yield (2 steps)
14
15
1
2
3
4
TsOH (3 equiv)
TsOH (3 equiv)
TFA (30 equiv)
AcOH
t-BuOH
t-BuOH
t-BuOH
None
rt
15%
32%
39%
48%
12%
22%
10%
5%
80 ꢁC
80 ꢁC
100 ꢁC
With pentacyclic indolenine 14 in hand, we proceeded to ad-
vance 14 toward (ꢀ)-aspidophytine (3) (Scheme 3). The literature
protocol11b,c including oxidation of imine 14 to conjugated imine 16
and one-pot transformation including 1,2-reduction of the conju-
gated imine and reductive methylation to 17 resulted in low yield.
Thus, it was necessary to reinvestigate these steps. After extensive
optimization, we found that the appropriate choice of solvent was
crucial to conduct the oxidation of imine smoothly at a lower
temperature. Thus, treatment of 14 with benzeneseleninic anhy-
dride in dichloromethane at 0 ꢁC gave the desired conjugated imine
16 in good yield. Since one-pot 1,2-reduction and reductive meth-
ylation of imine 16 based on the previously established conditions
unexpectedly promoted the retro-Mannich type reaction to give
a ring-opening side product.16 This side reaction was successfully
suppressed by execution of this one-pot reaction under a weakly
acidic condition. As a result, we succeeded in improving the yield of
the desired amine 17 in 89% yield. Finally, saponification of the ester
and subsequent formation of the lactone ring with potassium fer-
ricyanide11a furnished (ꢀ)-aspidophytine (3).11
Scheme 2. Synthetic strategy for divergent synthesis of (ꢀ)-aspidophytine (3) and its
congerners.
2. Results/discussion
First, we chose 2,3-dimethoxyphenylhydrazine (11),15 which is
required for synthesis of aspidophytine (3), and investigated
Fischer indole synthesis. The optically active tricyclic aminoketone
6 was prepared from commercially available ketoester 12 according
to our protocol12b and condensed with 12 in refluxing benzene. The
resultant hydrazone 13 was subjected to various acidic conditions
(Table 1). Disappointingly, the conditions established in our total
synthesis of haplophytine (1)12b using TsOH in t-BuOH at room
temperature resulted in formation of the desired indolenine 14 and
indole by-product 15 with poor regioselectivity and low chemical
yields (entry 1). Elevating the reaction temperature up to 80 ꢁC
improved yield of indolenine 14, though the regioselectivity was
still low (entry 2). Interestingly, exploration of other acids led us to
Next, we moved to synthesis of (þ)-cimicidine (4) from the
common intermediate 14 (Scheme 4). After reduction of imine 14,
the resultant secondary amine was acylated with propionic anhy-
dride to afford amide 18. Oxidative lactonization11a proceeded
smoothly to provide lactonic compound 19 in high yield. Finally,
regioselective demethylation was effected with a combination of
BCl3 and TBAI17 to complete the first total synthesis of (þ)-cimici-
dine (4).8

H. Satoh et al. / Tetrahedron 69 (2013) 89e95
91
Scheme 3. Reagents and conditions; (i) benzeneseleninic anhydride, CH2Cl2, 0 ꢁC to rt,
83%; (ii) HCHO (37%), NaBH3CN, AcOH, MeOH, e78 ꢁC to rt, 89%; (iii) 1 M NaOH, MeOH,
60 ꢁC; (iv) K3Fe(CN)6, NaHCO3, t-BuOH/H2O, rt, 46% (2 steps).
Scheme 5. Reagents and conditions; (i) benzene, reflux; (ii) AcOH, 95 ꢁC, 22 41% (2
steps), 23 6% (2 steps); (iii) NaBH4, MeOH, e78 to 0 ꢁC; (iv) propionic anhydride,
pyridine, rt, 81% (2 steps); (v) 1 M NaOH, MeOH, 50 ꢁC; (vi) K3Fe(CN)6, NaHCO3, t-
BuOH/H2O, rt, quant. (2 steps); (vii) BCl3, TBAI, CH2Cl2, e78 to rt, 75%.
(þ)-cimicine (5). The utility of our synthetic strategy for synthe-
sizing highly functionalized aspidosperma alkaloids was fully
demonstrated by the divergent synthesis of these three aspido-
sperma alkaloids from the common tricyclic aminoketone in-
termediate. In addition, we have found that the regiochemistry of
Fischer indole synthesis using unsymmetrical ketone was strongly
influenced by acidity of acids. The synthetic methodology estab-
lished in this work would be applicable to synthesis of not only
monomeric and dimeric indole alkaloids found in H. cimicidum,
such as cimilophytine (2), but also to a range of natural and un-
natural aspidosperma-type compounds.
Scheme 4. Reagents and conditions; (i) NaBH4, MeOH, e78 to 0 ꢁC; (ii) propionic
anhydride, pyridine, rt, 92% (2 steps); (iii) 1 M NaOH, MeOH, 60 ꢁC; (iv) K3Fe(CN)6,
NaHCO3, t-BuOH/H2O, rt, 94% (2 steps); (v) BCl3, TBAI, CH2Cl2, e78 to 0 ꢁC, 79%.
4. Experimental section
4.1. General remarks
The utility of the convergent synthetic strategy was also dem-
onstrated by accomplishment of the first total synthesis of
(þ)-cimicine (5) (Scheme 5). Thus, Fischer indole synthesis with 2-
methoxyphenylhydrazine (20)18 afforded the desired indolenine
compound 22 in high regioselectivity. Then, 1,2-reduction of imine
22 with NaBH4 and acylation of the resultant secondary amine gave
amide 24. Finally, basic hydrolysis of ester, oxidative lactoniza-
tion,11a and demethylation of the methyl group17 on the phenolic
hydroxyl group furnished (þ)-cimicine (5).8
Materials were obtained from commercial suppliers and used
without further purification unless otherwise mentioned. All re-
actions were carried out in oven-dried glasswares under a slight
positive pressure of argon unless otherwise noted. CH2Cl2 was
purchased from Kanto Chemical Co. Inc. Anhydrous benzene, t-
BuOH, AcOH, and pyridine were dried and distilled according to the
standard protocols. Column chromatography was performed on
Silica Gel 60N (Kanto, spherical neutral, 40e50 mm) and NH Silica
3. Conclusion
Gel (Fuji Silysia) using the indicated eluent. Preparative TLC was
performed on Merck 60 F254 glass plates pre-coated with a 0.50 or
a 0.25 mm thickness of silica gel and preparative NH TLC was
performed on Fuji Silysia glass plates pre-coated with the NH Silica
In conclusion, we have achieved a total synthesis of (ꢀ)-aspi-
dophytine (3), and the first total syntheses of (þ)-cimicidine (4) and

92
H. Satoh et al. / Tetrahedron 69 (2013) 89e95
Gel. Analytical TLC was performed on Merck 60 F254 glass plates
pre-coated with a 0.25 mm thickness of silica gel. All melting points
(mp) were determined on a Yanaco micro melting point apparatus
and uncorrected. IR spectra were measured on a SHIMADZU
FTIRe8300 spectrometer. NMR spectra were recorded on a JNM-
AL400 spectrometer, a GX500 spectrometer, and a JEOL ECA600
spectrometer with tetramethylsilane (0 ppm) or chloroform
(7.24 ppm) or MeCN (1.93 ppm) as an internal standard. Mass
spectra were recorded on a JEOL JMS-DX-303 or a JMS-700 or a JMS-
T100GC or a MS-50070BU spectrometers. Optical rotations were
measured on a Horiba SEPA-300 and a JASCO P-2200.
reaction mixture was diluted with CH2Cl2, basified with saturated
aqueous Na2CO3, and extracted with CH2Cl2 five times. The com-
bined organic extracts were dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (meth-
anoledichloromethane¼1:99 to 3:97, gradient) to afford pure
conjugated imine 16 (55.9 mg, 0.146 mmol, 83%) as an orange foam;
27
[a
]
þ258 (c 0.48, CHCl3); IR (neat, cmꢀ1) 2937, 1734, 1493, 1255,
D
1138, 1080; 1H NMR (400 MHz, CDCl3)
d
6.97 (d, J¼8.0 Hz, 1H), 6.84
(d, J¼8.0 Hz,1H), 6.72 (d, J¼10.0 Hz,1H), 6.52 (d, J¼10.0 Hz,1H), 4.19
(s, 3H), 3.89 (s, 3H), 3.50 (s, 3H), 3.15 (br d, J¼11.2 Hz, 1H), 3.08 (dd,
J¼7.2, 7.6 Hz, 1H), 2.65 (s, 1H) 2.72e2.61 (m, 1H), 2.43 (ddd, J¼11.2,
10.8, 3.6 Hz, 1H), 2.33e2.29 (m, 1H), 2.20 (ddd, J¼11.2, 10.8, 6.4 Hz,
1H), 1.82 (d, J¼15.6 Hz, 1H), 1.73 (d, J¼15.6 Hz, 1H), 1.74e1.65 (m,
3H), 1.35 (ddd, J¼13.6, 13.2, 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
4.2. Pentacyclic indolenine 14
A stirred solution of aminoketone 6 (438 mg, 1.74 mmol), 2,3-
ꢀ
dimethoxyphenylhydrazine (11) (310 mg, 1.84 mmol), and MS3A
d 183.1, 170.8, 151.9, 149.1, 145.5, 141.9, 139.4, 124.2, 113.9, 109.5,
(610 mg) in benzene (6.0 mL) was heated at reflux for 6 h. After
cooling to room temperature, the mixture was filtered through
a pad of Celite and the filtrate was concentrated under reduced
pressure. The residue was diluted with benzene (12 mL), and the
resulting solution was stirred at reflux with a DeaneStark trap for
2.5 h. The organic solvents were removed under reduced pressure
to afford a crude phenylhydrazone 13 (779 mg), which was sub-
jected to the next reaction without further purification. A solution
of the crude phenylhydrazone 13 (779 mg) in acetic acid (20 mL)
was heated at 100 ꢁC for 80 min. After cooling to room temperature,
the reaction mixture was basified with saturated aqueous Na2CO3
and extracted with CH2Cl2 five times. The combined organic ex-
tracts were washed with brine, dried over anhydrous sodium sul-
fate, filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (hex-
aneseethyl acetate¼1:4) to afford a mixture of indole and indole-
nine products. These products were separated by silica gel column
chromatography (methanolechloroform¼3:97) to afford the de-
sired indolenine 14 (323 mg, 1.90 mmol, 48% over 2 steps) as red
crystals and the undesired indole 15 (35.1 mg, 0.0914 mmol, 5%
69.0, 62.4, 61.8, 56.5, 52.6, 51.3, 50.6, 45.1, 39.7, 38.1, 34.1, 22.9;
HRMS (EI) calcd for C22H26N2O4 [Mþ] 382.1893, found 382.1881.
4.4. N-Methyl indoline 17
To
a
stirred solution of conjugated imine 16 (127 mg,
L, 6.58 mmol) in MeOH
0.332 mmol) and HCHO (37% solution, 490
m
(7.2 mL) were added NaBH3CN (104 mg, 1.65 mmol) and AcOH
(13.3
m
L, 0.232 mmol) at ꢀ78 ꢁC. The resulting solution was allowed
warm up to room temperature, and stirred for 5 h. The reaction
mixture was diluted with CH2Cl2, poured into saturated aqueous
NaHCO3 and brine, and the resulting mixture was concentrated
under reduced pressure. The residue was extracted with CH2Cl2
four times. The combined organic extracts were dried over anhy-
drous sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (methanoledichloromethane¼3:97) to afford indoline 17
28
(118 mg, 0.296 mmol, 89%); [
a]
þ64.6 (c 0.54, CHCl3); IR (neat,
D
cmꢀ1) 2934, 2835, 2783, 1732, 1611, 1475, 1265, 1163, 1070; 1H NMR
(400 MHz, CDCl3)
d
6.72 (d, J¼8.0 Hz,1H), 6.24 (d, J¼8.0 Hz,1H), 6.10
over 2 steps).
(dd, J¼10.0, 5.2 Hz, 1H), 5.96 (d, J¼10.0 Hz, 1H), 3.81 (s, 3H), 3.71 (s,
3H), 3.62 (d, J¼5.2 Hz, 1H), 3.50 (s, 3H), 3.09 (s, 3H), 3.13e3.05 (m,
2H), 2.39 (d, J¼15.2 Hz, 1H), 2.32 (dd, J¼9.4, 8.4 Hz, 1H), 2.21 (s, 1H),
2.14e1.97 (m, 3H), 2.01 (d, J¼15.2 Hz, 1H), 1.91 (d, J¼13.2 Hz, 1H),
1.63e1.56 (m, 2H), 1.37 (ddd, J¼13.2, 12.8, 5.6 Hz, 1H); 13C NMR
27
Indolenine 14: [
a]
þ209 (c 3.00, CHCl3); mp 115e118 ꢁC; IR
D
(neat, cmꢀ1) 2937, 2779, 1732, 1493, 1258, 1080; 1H NMR (400 MHz,
CDCl3)
d
6.91 (d, J¼8.0 Hz, 1H), 6.70 (d, J¼8.0 Hz, 1H), 4.16 (s, 3H),
3.88 (s, 3H), 3.43 (s, 3H), 3.27e3.06 (m, 3H), 2.86 (ddd, J¼14.2, 10.6,
3.6 Hz, 1H), 2.63e2.50 (m, 2H), 2.43 (s, 1H), 2.29e2.11 (m, 2H),
1.96e1.80 (m, 2H),1.78 (d, J¼14.8 Hz,1H), 1.72e1.50 (m, 3H),1.60 (d,
J¼14.8 Hz, 1H), 1.29 (ddd, J¼13.6, 13.2, 4.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d 171.9, 153.5, 143.4, 137.6, 133.7, 130.8, 125.4,
118.2, 101.9, 75.8, 72.9, 60.5, 55.9, 53.1, 52.4, 51.7, 50.9, 45.1, 44.9,
37.7, 36.2, 34.8, 22.8; HRMS (EI) calcd for C23H30N2O4 [Mþ]
398.2206, found 398.2203.
(100 MHz, CDCl3)
d 190.9, 171.6, 151.9, 145.9, 141.3, 140.9, 114.7,
109.2, 78.7, 61.8, 60.7, 56.4, 54.3, 51.8, 50.9, 41.4, 36.3, 35.4, 33.8,
27.7, 23.5, 21.8; HRMS (EI) calcd for C22H28N2O4 [Mþ] 384.2049,
found 384.2028.
4.5. (L)-Aspidophytine (3)
Indole 15: [
a
]
27 þ258 (c 0.48, CHCl3); IR (neat, cmꢀ1) 3371, 2934,
To a stirred solution of indoline 17 (35.5 mg, 89.1 mmol) in MeOH
D
2785, 1732, 1510, 1463, 1234, 1090, 754; 1H NMR (400 MHz, CDCl3)
(1.8 mL) was added 1 M NaOH (1.8 mL) at room temperature. The
resulting solution was heated at 60 ꢁC for 1 h. After cooling to 0 ꢁC,
the resulting mixture was acidified with 1 M HCl until the pH 6e7
and concentrated under reduced pressure to afford a crude car-
boxylic acid. To a stirred solution of the crude carboxylic acid in
a mixture of t-BuOH (1.0 mL) and H2O (2.0 mL) were added
K3Fe(CN)6 (440 mg, 1.34 mmol) and NaHCO3 (225 mg, 2.67 mmol)
at 0 ꢁC. After stirring for 15 min, the resulting solution was allowed
warm up to room temperature and stirred for 20 min. Then, the
reaction mixture was poured into H2O. The resulting mixture was
extracted with CH2Cl2 four times. The combined organic extracts
were washed with brine, dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. The residue was
purified by preparative TLC (methanolechloroform¼3:97) to afford
d
7.76 (br s, 1H), 7.06 (d, J¼8.5 Hz, 1H), 6.76 (d, J¼8.5 Hz, 1H), 3.96 (s,
3H), 3.90 (s, 3H), 3.54 (s, 3H), 3.48e3.42 (m, 1H), 3.17e3.10 (m, 2H),
2.97 (dd, J¼15.5, 1.5 Hz, 1H), 2.58 (d, J¼15.5 Hz, 1H), 2.36 (d,
J¼14.0 Hz,1H), 2.27 (d, J¼14.0 Hz,1H), 2.24e2.12 (m, 2H), 2.02e1.79
(m, 5H), 1.67e1.62 (m, 1H), 1.54 (ddd, J¼13.0, 12.5, 4.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3)
d 172.3, 146.7, 134.9, 134.2, 131.0, 124.9,
113.0, 107.3, 106.4, 71.1, 60.8, 57.3, 54.9, 53.5, 51.1, 42.8, 36.8, 34.0,
33.7, 27.9, 25.2, 22.0; HRMS (EI) calcd for C22H28N2O4 [Mþ]
384.2049, found 384.2043.
4.3. Conjugated imine 16
To a stirred solution of indolenine 14 (67.5 mg, 0.176 mmol) in
CH2Cl2 (880
m
L) was added benzeneseleninic anhydride (70% con-
pure (ꢀ)-aspidophytine (3) (15.8 mg, 41.3
m
mol, 46% over 2 steps) as
23
tent, 94.9 mg, 0.184 mmol) at 0 ꢁC. The resulting solution was
allowed to warm up to room temperature and stirred for 1 h. The
a white solid; [
a
]
e117 (c 0.37, CHCl3) (lit.11a
[a]
D
ꢀ121 (c 0.37,
D
CHCl3)); mp 199e202 ꢁC (lit.5 201e203); IR (neat, cmꢀ1) 2943,

H. Satoh et al. / Tetrahedron 69 (2013) 89e95
93
2839, 1751, 1609, 1495, 1466, 1418, 1265, 1169; 1H NMR (400 MHz,
CDCl3)
J¼10.4, 2.4 Hz, 1H), 5.51 (dd, J¼10.4, 1.2 Hz, 1H), 3.79 (s, 3H), 3.75 (s,
3H), 3.17 (q, J¼8.4 Hz,1H), 3.15 (s, 3H), 3.10e3.06 (m,1H), 2.93e2.87
(m, 1H), 2.76e2.71 (m, 1H), 2.36 (d, J¼16.4 Hz, 1H), 2.29 (ddd,
J¼12.4, 8.8, 3.2 Hz, 1H), 2.23 (d, J¼16.4 Hz, 1H), 2.08 (ddd, J¼13.2,
10.8, 7.2 Hz, 1H), 1.72e1.50 (m, 4H); 13C NMR (100 MHz, CDCl3)
chromatography on silica gel (hexaneseethyl acetate¼1:1 to
methanoledichloromethane¼1:9, gradient) to afford pure hemi-
aminal 19 (26.1 mg, 0.0612 mmol, 94% over 2 steps) as a white solid;
d
6.96 (d, J¼8.4 Hz, 1H), 6.19 (d, J¼8.4 Hz, 1H), 5.83 (dd,
[a]
24 e66.3 (c 0.395, CHCl3); mp 148e154 ꢁC; IR (neat, cmꢀ1) 2936,
D
2855, 1771, 1749, 1651, 1495, 1456, 1254, 752; 1H NMR (500 MHz,
CDCl3)
d
7.21 (d, J¼8.3 Hz, 1H), 6.65 (d, J¼8.3 Hz, 1H), 4.53e4.45 (m,
1H), 3.86 (s, 3H), 3.75 (s, 3H), 3.14 (ddd, J¼8.9, 8.9, 5.7 Hz, 1H), 3.04
(ddd, J¼10.4, 8.4, 4.9 Hz, 1H), 2.92 (ddd, J¼11.9, 11.9, 2.3 Hz, 1H),
2.82e2.70 (m, 2H), 2.38 (d, J¼16.0 Hz, 1H), 2.35 (dq, J¼15.4, 7.7 Hz,
1H), 2.09e1.74 (m, 5H), 1.93 (d, J¼16.0 Hz, 1H), 1.63e1.50 (m, 4H),
1.36 (ddd, J¼15.0, 15.0, 4.0 Hz, 1H), 1.14 (t, J¼15.4 Hz, 3H); 13C NMR
d
175.8,153.8,143.6,133.7,130.4,125.5,125.4,120.1,107.1,102.1, 71.8,
61.1, 57.0, 55.7, 47.7, 47.2, 43.3, 41.4, 35.3, 35.2, 34.5, 21.6; HRMS (EI)
calcd for C22H26N2O4 [Mþ] 382.1893, found 382.1887.
4.6. Anilide 18
(125 MHz, CDCl3) d 176.1, 175.0, 152.8, 139.4, 134.2, 132.1, 119.7,
109.3, 107.9, 67.9, 60.0, 59.1, 56.0, 48.5, 43.5, 42.6, 40.4, 34.1, 34.0,
27.7, 25.2, 24.4, 20.3, 9.8; HRMS (EI) calcd for C24H30N2O5 [Mþ]
426.2155, found 426.2159.
To a stirred solution of indolenine 14 (27.3 mg, 0.0708 mmol) in
MeOH (0.70 mL) was added NaBH4 (13.4 mg, 0.354 mmol) at
ꢀ78 ꢁC. After 5 min, the resulting mixture was allowed to warm up
to 0 ꢁC. After stirring for 100 min, NaBH4 (2.7 mg, 0.071 mmol) was
added to the reaction mixture. After stirring for an hour, the re-
action was quenched with saturated aqueous NaHCO3 and the re-
action mixture was concentrated under reduced pressure. The
residue was poured into saturated aqueous Na2CO3 and the
resulting mixture was extracted with CH2Cl2 five times. The com-
bined organic extracts were dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (meth-
anoledichloromethane¼1:49) to afford secondary amine com-
pound (27.1 mg). To a stirred solution of the secondary amine
(27.1 mg) in pyridine (0.17 mL) was added propionic anhydride
(0.17 mL) at room temperature. The resulting mixture was stirred
for 6.5 h. After cooling to 0 ꢁC, the reaction was quenched with 28%
aqueous ammonia solution and the mixture was extracted with
CH2Cl2 four times. The combined organic extracts were dried over
anhydrous sodium sulfate, filtered, and concentrated under re-
duced pressure. The residue was purified by column chromatog-
raphy on silica gel (methanoledichloromethane¼1:49) to afford
anilide 18 (28.8 mg, 0.0651 mmol, 92% over 2 steps) as a yellow
4.8. (D)-Cimicidine (4)
To a stirred solution of hemiaminal 19 (12.4 mg, 0.0291 mmol)
and tetrabutylammonium iodide (35.2 mg, 0.0952 mmol) in CH2Cl2
(0.29 mL) was added BCl3 (1 M in CH2Cl2, 58 mL, 0.058 mmol) at
ꢀ78 ꢁC. After 10 min, the resulting solution was allowed to warm up
to 0 ꢁC. After stirring for 2.5 h, BCl3 (1 M solution in CH2Cl2, 58
mL,
0.058 mmol) was added to the reaction mixture. After stirring for
additional 45 min, the reaction was quenched with saturated
aqueous NaHCO3 and the mixture was extracted with CH2Cl2 five
times. The combined organic extracts were dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(methanoledichloromethane¼1:4), column chromatography on
NH Silica Gel (acetoneehexanes¼2:3) and preparative TLC (meth-
anoledichloromethane¼1:9) to afford (þ)-cimicidine (4) (9.5 mg,
0.023 mmol, 79%) as a white solid, associated with a recovery of the
26
starting compound 19 (0.4 mg, 0.9
mmol, 3%); [
a
]
D
þ120 (c 0.47,
CHCl3) (lit.4a
[
a
]
D
25 þ123.0 (CHCl3)); mp 262e265 ꢁC (lit.8 266e268);
IR (neat, cmꢀ1) 2937, 2855, 2800 (br), 1771, 1747, 1634, 1599, 1456,
foam; [
1495, 1454, 1385, 1335, 1275, 1225, 1177, 1088, 754; 1H NMR
(600 MHz, CD3CN, 65 ꢁC)
6.93 (d, J¼8.4 Hz, 1H), 6.75 (d, J¼8.4 Hz,
a
]
D
27 e95.9 (c 0.345, CHCl3); IR (neat, cmꢀ1) 2937, 1732, 1651,
1254, 752; 1H NMR (500 MHz, CDCl3)
d 10.6 (s, 1H), 6.98 (d,
J¼8.3 Hz, 1H), 6.69 (d, J¼8.3 Hz, 1H), 3.94 (dd, J¼11.3, 4.8 Hz, 1H),
3.85 (s, 3H), 3.13 (ddd, J¼8.8, 8.8, 5.5 Hz, 1H), 3.06 (ddd, J¼10.5, 8.5,
5.0 Hz, 1H), 2.92 (ddd, J¼11.9, 11.9, 2.7 Hz, 1H), 2.81e2.75 (m, 1H),
2.61 (dq, J¼15.2, 7.6 Hz, 1H), 2.53 (dq, J¼15.2, 7.6 Hz, 1H), 2.49 (d,
J¼16.3 Hz, 1H), 2.12 (ddd, J¼13.9, 8.9, 5.1 Hz, 1H), 1.98e1.90 (m, 3H),
1.97 (d, J¼16.3 Hz, 1H), 1.86e1.70 (m, 2H), 1.65e1.52 (m, 3H), 1.44
(ddd, J¼14.5, 3.8, 3.8 Hz, 1H), 1.29 (t, J¼7.6 Hz, 3H); 13C NMR
d
1H), 4.33 (dd, J¼11.1, 6.3 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.54 (s,
3H), 3.09 (ddd, J¼9.0, 9.0, 3.8 Hz, 1H), 3.02e2.97 (m, 1H), 2.65 (dq,
J¼15.3, 7.7 Hz, 1H), 2.46 (s, 1H), 2.37 (dq, J¼15.3, 7.7 Hz, 1H),
2.31e2.25 (m, 1H), 2.23e2.15 (m, 1H), 2.18 (d, J¼14.4 Hz, 1H),
2.07e1.89 (m, 5H),1.75 (dddd, J¼26.1,13.1, 4.1, 4.1 Hz,1H),1.66e1.60
(m, 1H), 1.56e1.45 (m, 2H), 1.37 (ddd, J¼13.7, 13.7, 4.6 Hz, 1H),
1.28e1.22 (m, 1H), 1.12 (t, J¼7.7 Hz, 3H); 13C NMR (150 MHz, CD3CN,
(125 MHz, CDCl3) d 175.8,172.3,150.1,137.4,129.6,128.1,114.7,110.4,
106.3, 67.9, 58.2, 56.3, 48.4, 43.6, 42.5, 40.5, 35.0, 33.9, 28.4, 25.07,
25.06, 20.3, 9.7; HRMS (EI) calcd for C23H28N2O5 [Mþ] 412.19982,
found 412.19923.
65 ꢁC)
d 174.9, 173.0, 154.2, 142.0, 135.8, 135.3, 118.8, 111.2, 70.4, 70.1,
60.4, 57.5, 54.5, 54.3, 53.0, 51.8, 43.2, 39.0, 37.1, 36.0, 28.9, 26.7, 25.6,
22.7, 10.5; HRMS (EI) calcd for C25H34N2O5 [Mþ] 442.2468, found
442.2455.
4.9. Indolenine 22
4.7. Hemiaminal 19
A mixture of ketone 6 (47.1 mg, 0.187 mmol) and 2-methox-
yphenylhydrazine 20(27.2 mg, 0.197 mmol) in benzene(0.94 mL)was
heated at reflux for a day. After cooling to room temperature, the re-
action mixture was concentrated under reduced pressure to afford
a crude phenylhydrazone derivative 21, which was subjected to the
next reaction without further purification. A stirred solution of the
crude phenylhydrazone 21 in acetic acid (2.3 mL) was heated at 95 ꢁC
for 90 min. After cooling to room temperature, the reaction mixture
was basified with saturated aqueous Na2CO3 and extracted with
CH2Cl2 three times. The combined organic extracts were washed with
brine, dried overanhydrous sodiumsulfate, filtered, andconcentrated
under reduced pressure. The residue was purified sequentially by
column chromatography on NH silica gel (hexaneseethyl
acetate¼1:9), column chromatography on silica gel (hexaneseethyl
acetate¼7:3 and then methanolechloroform¼1:99), and preparative
To a stirred solution of anilide 18 (28.8 mg, 0.0651 mmol) in
MeOH (0.3 mL) was added 1 M NaOH (0.3 mL) at room temperature.
The resulting solution was heated at 60 ꢁC for 3.5 h. After cooling to
room temperature, the resulting mixture was acidified with 1 M
HCl until pH 6e7 and concentrated under reduced pressure to af-
ford a crude carboxylic acid. To a stirred solution of the crude car-
boxylic acid in a mixture of t-BuOH (0.22 mL) and H2O (0.43 mL)
were added K3Fe(CN)6 (214 mg, 0.651 mmol) and NaHCO3 (109 mg,
1.30 mmol) at room temperature. After stirring for 1.5 h, the re-
action mixture was poured into H2O and the resulting mixture was
extracted with CH2Cl2 seven times. The combined organic extracts
were dried over anhydrous sodium sulfate, filtered, and concen-
trated under reduced pressure. The residue was purified by column

94
H. Satoh et al. / Tetrahedron 69 (2013) 89e95
TLC coated by NH Silica Gel (hexaneseethyl acetate¼1:1) to afford the
desired indolenine product 22 (28.8 mg, 0.813 mmol, 41% over 2
steps) as a yellow foam and the undesired indole product 23 (3.9 mg,
143.8, 131.2, 127.4, 116.8, 113.3, 70.4, 70.0, 56.6, 54.9, 54.2, 53.0,
51.7, 43.1, 38.6, 37.1, 36.0, 28.9, 26.5, 25.4, 22.6, 10.5; HRMS (EI)
calcd for C24H32N2O4 [Mþ] 412.2362, found 412.2355.
0.011 mmol, 6% over 2 steps) as red crystals.
25
Indolenine 22: [
a]
þ241 (c 0.82, CHCl3); IR (neat, cmꢀ1) 2937,
D
4.11. Hemiaminal 25
2779, 1732, 1487, 1281, 1254, 748; 1H NMR (400 MHz, CDCl3)
d 7.13
(dd, J¼7.8, 7.8 Hz, 1H), 6.93 (dd, J¼7.8, 0.6 Hz, 1H), 6.84 (d, J¼7.8 Hz,
1H), 3.96 (s, 3H), 3.42 (s, 3H), 3.20e3.14 (m, 2H), 3.08 (ddd, J¼14.3,
11.9, 4.7 Hz, 1H), 2.91 (ddd, J¼14.3, 10.3, 3.9 Hz, 1H), 2.65e2.56 (m,
2H), 2.47 (s, 1H), 2.27e2.13 (m, 2H), 1.95e1.83 (m, 2H), 1.80 (d,
J¼14.4 Hz, 1H), 1.68e1.51 (m, 4H), 1.27 (ddd, J¼13.5, 13.5, 4.9 Hz,
To a stirred solution of anilide 24 (4.7 mg, 0.011 mmol) in
MeOH (0.12 mL) was added 1 M NaOH (0.12 mL) at room tem-
perature. After stirring for 6.5 h, the reaction mixture was heated
at 50 ꢁC for an hour. After cooling to 0 ꢁC, the resulting mixture
was acidified with 1 M HCl until pH 6e7 and concentrated under
reduced pressure to afford a crude carboxylic acid. To a stirred
solution of the crude carboxylic acid in a mixture of t-BuOH
(0.12 mL) and H2O (0.25 mL) were added K3Fe(CN)6 (38 mg,
0.11 mmol) and NaHCO3 (19 mg, 0.23 mmol) at room tempera-
ture. After stirring for 40 min, the reaction mixture was poured
into H2O and the resulting mixture was extracted with CH2Cl2
three times. The combined organic extracts were dried over an-
hydrous sodium sulfate, filtered, and concentrated under reduced
pressure. Pure hemiaminal 25 (4.3 mg, 0.011 mmol, quant. over 2
1H); 13C NMR (100 MHz, CDCl3)
d 189.7, 171.4, 151.0, 148.5, 142.0,
126.4, 113.5, 110.3, 78.2, 61.7, 55.7, 54.3, 51.7, 50.9, 41.5, 36.4, 35.0,
33.7, 27.6, 23.4, 21.9; HRMS (EI) calcd for C21H26N2O3 [Mþ]
354.1943, found 354.1941.
25
Indole 23: [
a
]
e105 (c 0.32, CHCl3); mp 146e152 ꢁC; IR (neat,
D
cmꢀ1) 3377, 2932, 2851, 2785, 1732, 1574, 1470, 1339, 1256, 756; 1H
NMR (600 MHz, CDCl3)
(dd, J¼8.0, 8.0 Hz, 1H), 6.58 (d, J¼8.0 Hz, 1H), 3.93 (s, 3H), 3.54 (s,
3H), 3.58e3.46 (m, 1H), 3.20e3.12 (m, 2H), 3.07e2.98 (m, 1H), 2.60
(d, J¼15.6 Hz, 1H), 2.34 (d, J¼13.8 Hz, 1H), 2.30e2.22 (m, 2H),
2.20e2.12 (m, 1H), 2.10e1.80 (m, 4H), 1.69e1.51 (m, 3H); 13C NMR
d
7.89 (br s, 1H), 7.05 (d, J¼8.0 Hz, 1H), 6.96
steps) was obtained as a white solid without further purification;
25
[
a
]
e88.5 (c 0.93, CHCl3); IR (neat, cmꢀ1) 2932, 2849, 1773,
D
(150 MHz, CDCl3)
d 172.4, 145.6, 129.4, 126.9, 119.4, 111.3, 106.7,
1643, 1493, 1447, 1387, 1252, 1188, 881, 754; 1H NMR (500 MHz,
CDCl3)
101.6, 71.1, 55.3, 55.0, 53.5, 51.2, 42.8, 36.9, 33.9, 33.6, 29.7, 28.2,
25.5, 22.0; HRMS (EI) calcd for C21H26N2O3 [Mþ] 354.1943, found
354.1950.
d
7.19 (d, J¼8.1 Hz, 1H), 7.08 (dd, J¼8.1, 8.1 Hz, 1H), 6.84 (d,
J¼8.1 Hz, 1H), 4.53e4.44 (m, 1H), 3.86 (s, 3H), 3.14 (ddd, J¼8.8, 8.8,
5.5 Hz, 1H), 3.04 (ddd, J¼10.4, 8.1, 4.9 Hz, 1H), 2.92 (ddd, J¼11.9,
11.9, 2.8 Hz, 1H), 2.81e2.75 (m, 1H), 2.64 (dq, J¼15.1, 7.5 Hz, 1H),
2.33 (d, J¼16.5 Hz, 1H), 2.27 (dq, J¼15.1, 7.5 Hz, 1H), 2.08 (ddd,
J¼13.5, 9.0, 4.8 Hz, 1H), 2.04e1.74 (m, 4H), 1.91 (d, J¼16.5 Hz, 1H),
1.63e1.49 (m, 4H), 1.34 (ddd, J¼14.5, 4.0, 4.0 Hz, 1H), 1.15 (t,
4.10. Anilide 24
To a stirred solution of indolenine 22 (16.4 mg, 0.0463 mmol)
in MeOH (0.46 mL) was added NaBH4 (5.3 mg, 0.14 mmol) at
ꢀ78 ꢁC. After 10 min, the resulting mixture was allowed to warm
up to 0 ꢁC. After stirring for an hour, NaBH4 (1.6 mg, 0.042 mmol)
was added to the reaction mixture. After stirring for 50 min,
another portion of NaBH4 (1.3 mg, 0.034 mmol) was added to the
reaction mixture and the mixture was stirred for 10 min. After
quenching with saturated aqueous NaHCO3 and saturated aque-
ous Na2CO3, the reaction mixture was concentrated under re-
duced pressure. The residue was poured into water and the
resulting mixture was extracted with CH2Cl2 three times. The
combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and concentrated under reduced pressure. The
J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 176.1, 174.9, 149.5,
140.4, 129.7, 127.1, 117.2, 111.7, 107.8, 67.9, 59.7, 55.5, 48.6, 43.5,
42.6, 40.6, 34.1, 33.7, 28.0, 25.2, 24.3, 20.4, 10.0; HRMS (EI) calcd
for C23H28N2O4 [Mþ] 396.2049, found 396.2030.
4.12. (D)-Cimicine (5)
To a stirred solution of hemiaminal 25 (11.8 mg, 0.0298 mmol)
and tetrabutylammonium iodide (14.3 mg, 0.0387 mmol) in CH2Cl2
(0.3 mL) was added BCl3 (1 M solution in CH2Cl2, 74 mL, 0.074 mmol)
at ꢀ78 ꢁC. After 15 min, the resulting solution was allowed warm up
to 0 ꢁC, and stirred for 135 min. Then, the resulting solution was
allowed to warm up to room temperature, and the mixture was
stirred for 130 min. After cooling to 0 ꢁC, the reaction was quenched
with saturated aqueous NaHCO3 and the mixture was extracted
with CH2Cl2 three times. The combined organic extracts were dried
over anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified sequentially by column
chromatography on silica gel (methanoledichloromethane¼1:9 to
2:8, gradient), preparative TLC (methanoledichloromethane¼1:9),
reverse-phase preparative TLC (MeOH), and preparative TLC coated
with NH Silica Gel (acetoneehexanes¼3:7) to afford (þ)-cimicine
residue
was
purified
by
preparative
TLC
(meth-
anolechloroform¼1:19) to afford secondary amine product
(18.2 mg). To a stirred solution of the secondary amine (18.2 mg)
in pyridine (0.12 mL) was added propionic anhydride (0.12 mL) at
room temperature. The resulting mixture was stirred for 7 h.
After cooling to 0 ꢁC, the reaction was quenched with 28%
aqueous ammonia solution and the resulting mixture was
extracted with CH2Cl2 three times. The combined organic ex-
tracts were dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (dichloromethaneeethyl
acetate¼1:1 to methanoledichloromethane¼3:97, gradient) to
(5) (8.6 mg, 0.022 mmol, 75%) as a white solid, associated with
22
afford anilide 24 (15.4 mg, 0.0373 mmol, 81% over 2 steps) as
a recovery of the starting compound 25 (0.4 mg, 1 mmol, 3%); [a]
D
a yellow foam; [
a
]
e91.2 (c 0.77, CHCl3); IR (neat, cmꢀ1) 2939,
þ81.3 (c 0.37, CHCl3) (lit.8
[
a
]
D
þ82 (CHCl3)); mp 220e223 ꢁC (lit.8
24
D
2787, 1732, 1651, 1487, 1454, 1393, 1385, 1227, 746; 1H NMR
(600 MHz, CD3CN, 65 ꢁC)
7.13 (dd, J¼8.0, 8.0 Hz, 1H), 6.95 (d,
229e231); IR (neat, cmꢀ1) 2937, 2856, 2800 (br), 1771, 1747, 1632,
d
1599, 1470, 1454, 1435, 1261, 1198, 748; 1H NMR (500 MHz, CDCl3)
J¼8.0 Hz, 2H), 4.42 (dd, J¼11.1, 6.3 Hz, 1H), 3.89 (s, 3H), 3.55 (s,
3H), 3.13 (ddd, J¼9.2, 9.2, 3.4 Hz, 1H), 3.05e3.01 (m, 1H), 2.65 (dq,
J¼15.0, 7.5 Hz, 1H), 2.51 (s, 1H), 2.35e2.29 (m, 1H), 2.33 (dq,
J¼15.0, 7.5 Hz, 1H), 2.22 (ddd, J¼13.8, 13.8, 2.8 Hz, 1H), 2.15 (d,
J¼14.1 Hz, 1H), 2.08e1.90 (m, 4H), 1.92 (d, J¼14.1 Hz, 1H), 1.78
(dddd, J¼26.2, 13.2, 4.1, 4.1 Hz, 1H), 1.71e1.66 (m, 1H), 1.60e1.44
(m, 2H), 1.40 (ddd, J¼13.5, 13.5, 4.6 Hz, 1H), 1.28e1.23 (m, 1H), 1.13
d
10.5 (s, 1H), 7.09e7.03 (m, 2H), 6.85 (dd, J¼7.0, 2.0 Hz, 1H), 3.95
(dd, J¼11.3, 4.8 Hz, 1H), 3.14 (ddd, J¼8.9, 8.9, 5.2 Hz, 1H), 3.06 (ddd,
J¼9.6, 9.6, 5.2 Hz, 1H), 2.93 (ddd, J¼11.8, 2.5, 2.5 Hz, 1H), 2.82e2.76
(m, 1H), 2.60 (dq, J¼15.3, 7.7 Hz, 1H), 2.53 (dq, J¼15.3, 7.7 Hz, 1H),
2.46 (d, J¼16.5 Hz, 1H), 2.13 (ddd, J¼13.6, 8.9, 4.9 Hz, 1H), 2.01e1.90
(m, 4H), 1.87e1.70 (m, 2H), 1.66e1.53 (m, 3H), 1.45 (ddd, J¼14.5, 3.8,
3.8 Hz,1H),1.29 (t, J¼7.7 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 175.6,
(t, J¼7.5 Hz, 3H); 13C NMR (150 MHz, CD3CN)
d
; 175.3, 172.8, 151.6,
172.2, 147.2, 137.8, 128.7, 127.4, 118.7, 115.3, 106.1, 67.3, 58.8, 48.4,

H. Satoh et al. / Tetrahedron 69 (2013) 89e95
95
9. Mroue, M. A.; Euler, K. L.; Ghuman, M. A.; Alam, M. J. Nat. Prod. 1996, 59, 890.
10. For a recent account on the total synthesis of haplophytine, see: Doris, E. An-
gew. Chem., Int. Ed. 2009, 48, 7480.
43.6, 42.4, 40.5, 34.6, 33.8, 28.4, 25.1, 24.9, 20.3, 9.6; HRMS (EI) calcd
for C22H26N2O4 [Mþ] 382.1893, found 382.1891.
11. (a) He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 6771; (b)
Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5, 1891; (c)
Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2003, 59,
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Cao, G. F. Tetrahedron Lett. 2006, 47, 7711; (f) Nicolaou, K. C.; Stephen, M. D.;
Majumder, U. J. Am. Chem. Soc. 2008, 130, 14942.
12. (a) Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Synlett 2007, 3137; (b) Ueda, H.;
Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew.
Chem., Int. Ed. 2009, 48, 7600.
13. (a) Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y. K. Angew.
Chem., Int. Ed. 2009, 48, 7616 formal synthesis of haplophytine, see: (b)
Tian, W.; Chennamaneni, L. R.; Suzuki, T.; Chen, D. Y. K. Eur. J. Org. Chem.
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Acknowledgements
This work was financially supported by the Cabinet Office,
Government of Japan through its ‘Funding Program for Next Gen-
eration World-Leading Researchers’ (LS008), the Grant-in aid for
Young Scientists (B) (24790003) (for H.U.), An Emergency Fund
from Astellas Foundation for Research on Metabolic Disorders to
support researchers suffered from 3.11 earthquake and tsunami,
Tohoku University G-COE program ‘IREMC’, and the JSPS pre-
doctoral fellowship to H.S.
14. (a) Stork, G.; Dolfini, E. J. Am. Chem. Soc. 1963, 85, 2872; (b) Stevens, R. V.;
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