Synthesis of pyrrolophenanthridine alkaloids based on C(sp3)-H and C(sp2)-H functionalization reactions

Article abstract of DOI:10.1002/asia.201402490

Assoanine, pratosine, hippadine, and dehydroanhydrolycorine belong to the pyrrolophenanthridine family of alkaloids, which are isolated from plants of the Amaryllidaceae species. Structurally, these alkaloids are characterized by a tetracyclic skeleton that contains a biaryl moiety and an indole core, and compounds belonging to this class have received considerable interest from researchers in a number of fields because of their biological properties and the challenges associated with their synthesis. Herein, a strategy for the total synthesis of these alkaloids by using C-H activation chemistry is described. The tetracyclic skeleton was constructed in a stepwise manner by C(sp ³)-H functionalization followed by a Catellani reaction, including C(sp²)-H functionalization. A one-pot reaction involving both C(sp³)-H and C(sp²)-H functionalization was also attempted. This newly developed strategy is suitable for the facile preparation of various analogues because it uses simple starting materials and does not require protecting groups.

Full text of DOI:10.1002/asia.201402490

FULL PAPER
DOI: 10.1002/asia.201402490
3
À
Synthesis of Pyrrolophenanthridine Alkaloids Based on C
G
2
À
C
U
Chihiro Tsukano, Nobusuke Muto, Iderbat Enkhtaivan, and Yoshiji Takemoto*[a]
Abstract: Assoanine, pratosine, hippa-
dine, and dehydroanhydrolycorine
belong to the pyrrolophenanthridine
family of alkaloids, which are isolated
from plants of the Amaryllidaceae spe-
cies. Structurally, these alkaloids are
characterized by a tetracyclic skeleton
that contains a biaryl moiety and an
indole core, and compounds belonging
to this class have received considerable
interest from researchers in a number
of fields because of their biological
properties and the challenges associat-
ed with their synthesis. Herein, a strat-
egy for the total synthesis of these al-
followed by a Catellani reaction, in-
2
À
cluding C
G
one-pot reaction involving both C-
3
À
À
kaloids by using C H activation
ACHUTGTNREN(UNG sp ) H and CACHTUGNTREN(NUGN sp ) H functionaliza-
chemistry is described. The tetracyclic
skeleton was constructed in a stepwise
tion was also attempted. This newly de-
veloped strategy is suitable for the
facile preparation of various analogues
because it uses simple starting materi-
als and does not require protecting
groups.
3
À
manner by C
N
À
Keywords: alkaloids · C H activa-
tion · natural products · synthesis
design · total synthesis
Introduction
Pyrrolophenanthridine alkaloids, which can be biogeneti-
cally produced by the dehydration and aromatization of ly-
corine, belong to the Amaryllidaceae family of alkaloids
(Figure 1),[1] and assoanine (1), which was originally isolated
from Narcissus pseudonarcissus by Wildman et al.[2a] in 1956,
is representative of this class alkaloid.[2] More than ten con-
geners, including pratosine (2),[3] hippadine (3),[4] and dehy-
droanhydrolycorine (4),[5] have been isolated from plants be-
longing to the Amaryllidaceae species. Pyrrolophenanthri-
dine alkaloids exhibit various biological properties, including
acetylcholinesterase inhibitory activity,[6] anticancer activi-
ty,[7] and anti-tripanosomal activity,[8] and have consequently
received considerable attention from both chemists and bio-
logical scientists.[1] A variety of total syntheses have been re-
ported, to date, for the preparation of pyrrolophenanthri-
dine alkaloids, and these strategies have generally focused
on the use of an indole derivative as the starting material
for the construction of the biaryl moiety of the alkaloid.[9]
For example, Snieckus and Siddiqui reported the Suzuki
coupling reaction of 7-iodoindoline with 2-formylphenyl bor-
onic acid in the presence of a palladium catalyst to give
a pyrrolophenanthridine skeleton, which was subsequently
converted into hippadine (3).[9y] Palladium-catalyzed cross-
Figure 1. Structures of lycorine and pyrrolophenanthridine alkaloids dis-
cussed herein.
coupling reactions have also been used to construct the
biaryl moiety of pyrrolophenanthridine alkaloids.[9d,e,i,s,t,w]
Diels–Alder,[9q,aa] ring expansion,[9t] anion coupling,[9r,u] and
radical cyclization[9n,o,s,x] reactions have also been used as key
transformations for the construction of the biaryl moiety or
the phenanthridine skeleton of pyrrolophenanthridine alka-
loids.
À
C H functionalization chemistry has received considera-
ble attention as an innovative method in organic chemistry
during the last decade, because it has the potential to simpli-
[10]
À
fy synthesis by allowing the use of ubiquitous C H bonds.
[a] Dr. C. Tsukano, N. Muto, I. Enkhtaivan, Prof. Y. Takemoto
Graduate School of Pharmaceutical Sciences
Kyoto University, 46-29 Yoshida, Sakyo-ku
Kyoto 606-8501 (Japan)
À
The popularity of C H functionalization reactions has
grown considerably in recent years, with various groups re-
porting the concise total syntheses of natural products based
Fax : (+81)75-753-4569
E-mail: takemoto@pharm.kyoto-u.ac.jp
À
on transition-metal-catalyzed C H functionalization strat-
egies.[11] As part of their work towards the total synthesis of
pyrrolophenanthridine alkaloids, Black et al. achieved the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402490.
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Yoshiji Takemoto et al.
À
Scheme 1. a) Reported synthesis of biaryl systems obtained by using a C
3
À
H functionalization reaction. b) Oxindole formation through a C
functionalization reaction. Ad=1-adamantyl, Piv=pivaloyl.
G
Scheme 2. Retrosynthesis of pyrrolophenanthridine alkaloids based on C-
3
2
2
À
À
ACHUTNGREN(NUG sp ) H and CACHTUNGTRENN(UGN sp ) H functionalization reactions.
À
total synthesis of 2 and 3 in 1989 by using a C
G
tionalization reaction for the construction of the biaryl
moiety in these compounds, although
a stoichiometric
amount of Pd
G
tion require similar conditions in terms of their Pd0/PdII cat-
alytic cycles, the tetracyclic skeleton of 5 could be construct-
ed from carbamoyl chloride 6, according to a one-pot reac-
tion (Scheme 2, route A). In contrast, we could use a step-
wise strategy for the construction of the lactam ring and the
dihydrophenanthridine skeleton from iodotoluene 10 and
years later, Miki et al. reported a palladium(0)/palladiu-
2
À
m(II)-catalyzed C
G
started with the oxidative addition of an aryl halide to palla-
dium(0),[9c,l] and several groups went on to adopt this
method in their own work (Scheme 1a,B).[9g,h,k] In 2012,
2
2
3
À
À
À
Bisai et al. developed a KOtBu-promoted C
N
benzylaniline 11 through CACTHNGUTREN(UNG sp ) H and CACHTUGNERTN(NUNG sp ) H function-
tionalization reaction for the construction of biaryl com-
pounds, which was applied to total synthesis of several pyr-
rolophenanthridine alkaloids.[9a,b] There have, however, been
no reports in the literature concerning the total synthesis of
alization reactions. In this case, the lactam ring would have
to be constructed during the later stages of the process be-
3
À
cause the
C
(sp ) H functionalization reaction requires
2
À
higher temperatures than the C
(sp ) H reaction.
3
À
alkaloids belonging to this class through a C
N
tionalization reaction. We recently developed a series of
synthetic methods for the construction of several heterocy-
clic systems, including oxindoles, spirooxindoles, 2-aryl in-
Results and Discussion
3
À
doles, and benzocarbazoles, by using a C
N
We focused our initial efforts on investigating route A
(Scheme 2), which would provide a concise, few-step synthe-
sis involving the challenging double cyclization of carbamoyl
chlorides 15 or 21. o-Toluidine (12) was coupled with 6-bro-
moveratraldehyde (13), according to McDonaldꢁs reductive
amination procedure[14] (Scheme 3). The resulting amine 14
was treated with triphosgene and pyridine to give carbamoyl
chloride 15. The other carbamoyl chloride 21 was also pre-
pared by the same two-step sequence from 18 and 19. The
zation reaction (Scheme 1b).[12,13] To evaluate the scope and
À
generality of our newly developed C
N
tion method for the construction of oxindoles, we investigat-
ed its application to total synthesis of Amaryllidaceae alka-
loids.[12a] Herein, we report a concise synthesis of 1, 2, 3, and
4 from simple, commercially available starting materials
3
À
based on C
G
used to prepare various analogues of these compounds.
3
À
double cyclization reaction involving the C
(sp ) H and C-
2
À
(sp ) H functionalization reactions was attempted by the
Synthetic Plan
treatment of 15 with Pd
(OAc)2 (5 mol%), Ad2PnBu
Retrosynthetically, it was envisioned that compound 5 could
be used as a common intermediate for the synthesis of pyr-
rolophenanthridine alkaloids, and that this compound could
(10 mol%), Cs2CO3 (1.1 equiv), and PivNHOH (0.3 equiv)
in mesitylene (0.2m) at 1208C under an atmosphere of
carbon monoxide.[12a] Unfortunately, however, this reaction
gave lactam 17 in 49% yield instead of the desired product
16. Byproduct 17 was most likely derived from amine 14,
which would have been produced by the oxidative addition
of carbamoyl chloride 15 followed by the elimination of CO.
Indeed, treatment of amine 14 under the same conditions
3
2
À
À
be synthesized by using CACTHNUTRGENNG(U sp ) H and CAHCTUNGTERNN(UGN sp ) H functionali-
zation reactions (Scheme 2). For example, the oxindole and
3
À
phenanthridine rings could be constructed through C
N
2
À
H and C
(sp ) H functionalization reactions of the methyl
and phenyl groups, respectively. Because both of these reac-
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Yoshiji Takemoto et al.
Scheme 3. Attempted one-pot formation of the tetracyclic skeleton.
Scheme 4. Formation of isooxindole 17.
Scheme 5. Total synthesis of assoanine (1) and pratosine (2). TFA=tri-
fluoroacetic acid, THF=tetrahydrofuran, DMF=N,N-dimethylforma-
mide, DIBAL=diisobutylaluminum hydride.
gave compound 17 quantitatively through the oxidative ad-
dition of the aryl bromide followed by insertion of CO
(Scheme 4). It was assumed that oxidative addition of the
aryl bromide would be favorable and that the resulting pal-
ladium intermediate would assist in the elimination of CO
from the carbamoyl chloride. This sequence would allow for
the formation of isooxindole 17 following sequential CO in-
sertion and cyclization reactions.
yl moiety (Scheme 2). This particular synthesis started from
the reductive amination of 6-bromoveratraldehyde (22), fol-
lowed by hydrolysis of the resulting carbamate to give ben-
zylamine 23 in 83% yield over two steps (Scheme 5).[15]
Compound 23 was then coupled with 2-iodotoluene 12 by
using a Catellani reaction with PdACTHNUTRGEN(UNG OAc)2 (5 mol%), PPh3
The carbon–bromide bond was moved from one aryl ring
to the other in an attempt to avoid decomposition of the
carbamoyl moiety. However, treatment of carbamoyl chlo-
ride 21 under the same conditions gave aniline 20 as the
major product (31%), which was formed through the elimi-
nation of CO, together with small amounts of several un-
identified byproducts (Scheme 3). Although compound 21
did not give rise to a four-membered lactam ring, the C-
(10 mol%), Cs2CO3 (2.1 equiv), and 2-norbornene
(0.5 equiv) in DMF (0.2m) at 1308C under an argon atmos-
phere, according to Malacriaꢁs procedure.[16,17] Although our
initial attempts to isolate dihydrophenathridine 25 resulted
in low yields because the material was readily oxidized
under the purification conditions, phenanthridine 24 was ob-
tained in 66% yield after purification.[18] Subsequent reduc-
tion of compound 24 with NaCNBH4,[19] followed by treat-
ment of the resulting amine with triphosgene, gave carbamo-
yl chloride 26 in 79% yield over two steps.
3
À
G
by the oxidative addition of the aryl bromide followed by
the elimination of CO. Based on this result, it was concluded
that it would be difficult to suppress the undesired reaction
because the oxidative addition reactions of the carbamoyl
chloride and aryl bromide were competitive, and the activa-
We then turned our attention to the cyclization of carba-
3
À
moyl chloride 26 through the C
action. Treatment of 26 with Pd
N
(OAc)2 (5 mol%), Ad2PnBu
(10 mol%), Cs2CO3 (1.1 equiv), and PivNHOH (0.3 equiv)
in mesitylene (0.2m) under an atmosphere of CO at 1008C
gave the desired tetracyclic compound 16 (30%) together
with a significant amount of the compound 24 (60%), which
was presumably derived from the elimination of CO and
aerobic oxidation.[20] Although an extensive period of reac-
tion of the C
ture than those required for the side reactions.
Based on these limitations, we decided to focus our atten-
tion on route B, which would avoid possible complications
arising from the unfavorable decomposition of the carbamo-
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Yoshiji Takemoto et al.
tion screening (i.e., palladium sources, ligands, bases, and
additives) did not lead to an improvement in the yield of
the product, compound 24 could be recycled following its
separation from the product by column chromatography on
silica gel. Because the carbamoyl moiety was fixed by the
by treatment of the resulting amine with triphosgene gave
carbamoyl chloride 32 in 82% yield over two steps. In a simi-
lar manner to the synthesis of 1, the cyclization of carbamo-
yl chloride 32 proceeded smoothly following activation of
3
À
the C
N
À
rigid tricyclic skeleton, the C H bond of the methyl group
33 and phenanthridine 30, which was recyclable, in 32 and
34% yield, respectively. Tetracyclic compound 33 was con-
verted into 3 by reduction with DIBAL followed by the oxi-
dation of 4. The spectroscopic data for the synthetic materi-
als 3 and 4 were in good agreement with the previously re-
ported data for these compound.[4,5,9f,r,s] The established syn-
thetic route, which is short and concise because it does not
require the use of protecting groups, could be used to pro-
vide facile access to various analogues from simple starting
materials.
became distant from the palladium center compared with
the corresponding derivatives of phenyl carbamoyl chloride,
and the elimination of CO consequently became competi-
tive.
With the common intermediate 16 in hand, we investigat-
ed the formation of the natural products by adjustment of
oxidation level. The reduction of 16 with DIBAL gave dehy-
droassoanine 27 in 57% yield, which was oxidized with
BaMnO4 to give 2 in 72% yield.[9m] In contrast, compound
1 was synthesized in 40% yield by the reduction of 27 with
NaCNBH3 in AcOH.[9g] The spectroscopic data for these
compounds, including the high-resolution mass spectra of
synthetic 1 and 2, were in agreement with the previously re-
ported data for these compounds.[2,3,9f,h,r,u]
Conclusion
We have accomplished the total synthesis of 1, 2, 3, and 4
À
The established synthetic route was applied to the synthe-
sis of 3 and 4. Commercially available 6-bromopiperonal
(28) was converted into benzylamine 29 in 84% yield over
two steps (Scheme 6). Compound 29 was then coupled to 2-
iodotoluene 12 through a Catellani reaction followed by an
oxidation reaction to give phenanthridine 30 in 51% yield.
Because dihydrophenanthridine 31 was not readily oxidized
in the presence of air in the same way as 25, it was necessary
to expose this compound to an oxygen atmosphere to affect
the one-pot procedure. Reduction with NaCNBH3 followed
through C H activation chemistry. Tetracyclic skeleton 5
3
À
was constructed in a stepwise manner by using a C
N
functionalization reaction for the oxindole skeleton and
a Catellani reaction, including a C
2
À
N
reaction, to complete the system. Our newly developed
route is suitable for the facile preparation of related ana-
logues because it uses simple starting materials and does not
require the use of protecting groups. Our synthesis is com-
parable in many ways to those previously reported in this
area because it allows for the rapid preparation of analogues
related to the target compounds and represents a new area
3
À
of C
(sp ) H functionalization chemistry.
Experimental Section
General
All nonaqueous reactions were carried out under a positive atmosphere
of argon in oven-dried glassware. Analytical TLC was performed with
Silica gel 60 TLC plates (Merck). Column chromatography on silica gel
was performed with Kanto silica gel 60 (particle size, 63–210 mm) and
Fuji silysia Chromatorex BW-300. 1H NMR spectra were recorded on
a JEOL JNM-ECA 500 spectrometer at 500 MHz or a JEOL JNM-AL
400 spectrometer at 400 MHz. Chemical shifts are reported relative to
Me4Si (d=0.00 ppm) in CDCl3, and CHDCl2 (d=5.32 ppm) in CD2Cl2.
The multiplicities of the signals are indicated by one or more of the fol-
lowing: s (singlet); d (doublet); t (triplet); q (quartet); m (multiplet); br
(broad). 13C NMR spectra were recorded on a JEOL JNM-ECA 500 at
126 MHz or a JEOL JNM-AL 400 spectrometer at 100 MHz. The chemi-
cal shifts are reported relative to residual CDCl3 and CD2Cl2 (d=77.0
and 53.8 ppm, respectively). IR spectra were recorded on a FT/IR-4100
Fourier-transform infrared ATR attenuated total reflectance spectrome-
ter (JASCO). Low and high-resolution mass spectra were recorded on
a JEOL MS700 mass spectrometer.
Compound 23
Methyl carbamate (310 mg, 4.12 mmol), TFA (625 mL, 8.16 mmol), trie-
thylsilane (1.65 mL, 10.3 mmol) were added to a solution of 6-bromovar-
atraldehyde (500 mg, 2.04 mmol) in acetonitrile (20 mL) under an argon
atmosphere. The mixture was stirred at 808C for 5 h and cooled to room
temperature. The mixture was concentrated under reduced pressure and
Scheme 6. Total synthesis of hippadine (3) and dehydroanhydrolycorine
(4).
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Yoshiji Takemoto et al.
the residue was dissolved in THF, MeOH, and a 2m aqueous solution of
LiOH (1:1:1; 30 mL). The reaction mixture was stirred at 808C for 2 days
and cooled to room temperature. The reaction mixture was then diluted
with AcOEt and a 1m aqueous solution of HCl. The organic phase was
extracted with a 1m aqueous solution of HCl. The aqueous extracts were
combined and basified with a 1m aqueous solution of NaOH. The aque-
ous phase was extracted with AcOEt. The organic extracts were com-
bined, washed with brine, and dried over Na2SO4. Concentration under
reduced pressure afforded 23 as a white solid (419 mg, 83%, 2 steps).
1H NMR (400 MHz, CDCl3): d=7.02 (s, 1H), 6.92 (s, 1H), 3.89 (s, 3H),
3.87 (s, 3H), 3.85 ppm (s, 2H); 13C NMR (101 MHz, CDCl3): d=148.4,
148.3, 133.9, 115.5, 113.1, 112.0, 56.1, 55.9, 46.4 ppm; IR (ATR): n˜ =3386,
then added to the reaction and the resulting mixture was stirred at 1008C
for 1 h. The mixture was then filtered through a pad of Celite and the fil-
trate was collected and concentrated under reduced pressure to give a res-
idue that was purified by column chromatography on silica gel (hexane/
AcOEt=1/1 (v/v) then CH2Cl2/AcOEt=9/1 to 8/2 (v/v)) to give oxindole
16 (15.7 mg, 30%) as a white solid and phenanthridine 24 (28.5 mg,
60%). 1H NMR (400 MHz, CDCl3): d=7.48 (d, J=7.6 Hz, 1H), 7.24 (s,
1H), 7.08 (d, J=7.6 Hz, 1H), 7.01 (t, J=7.0 Hz, 1H), 6.63 (s, 1H), 5.01
(s, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 3.54 ppm (s, 2H); 13C NMR (101 MHz,
CD2Cl2): d=174.7, 149.9, 149.3, 140.2, 123.7, 123.5, 122.6, 122.0, 121.6,
119.9, 117.3, 110.8, 105.9, 56.3, 56.2, 43.2, 36.6 ppm; IR (ATR): n˜ =3021,
2986, 2836, 1696, 1627, 1521, 1495, 1482, 1467, 1443, 1359, 1242,
1212 cmÀ1; HRMS (FAB): m/z calcd for C17H16NO3: 282.1130 [M+H]+;
found: 282.1135.
3323, 3012, 2900, 2842, 1598, 1497, 1382, 1256, 1206, 1150, 1030 cmÀ1
;
HRMS (FAB): m/z calcd for C9H1381BrNO2: 248.0109 [M+H]+; found:
248.0113.
Compound 27
Compound 24
Oxindole 16 (86.4 mg, 0.307 mmol) was dissolved in CH2Cl2 (3.6 mL)
under an atmosphere of argon and the resulting solution was cooled to
08C before being treated with a 1m solution of DIBAL in toluene
(1.95 mL, 1.95 mmol). The reaction mixture was stirred at 08C for 2 h
and then quenched by the addition of a 2m aqueous solution of NaOH.
The resulting mixture was extracted with CHCl3 and the combined or-
ganic layers were washed with brine and dried over Na2SO4 before being
filtered and concentrated under reduced pressure to give a residue that
was purified by column chromatography on silica gel (hexane/CHCl3 =1/
1) to give 27 as a yellow solid (46.1 mg, 57%). 1H NMR (400 MHz,
CDCl3): d=7.44 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.6 Hz, 2H), 7.14 (d, J=
3.6 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 6.65 (s, 1H), 6.53 (d, J=2.8 Hz,
1H), 5.52 (s, 2H), 3.99 (s, 3H), 3.92 ppm (s, 3H); 13C NMR (101 MHz,
CDCl3): d=148.9, 148.7, 133.0, 125.9, 125.7, 122.7, 122.5, 120.3, 119.9,
118.6, 112.6, 109.8, 105.5, 102.4, 56.0, 56.0, 47.6 ppm; IR (ATR): n˜ =2933,
2854, 1673, 1608, 1525, 1464, 1392, 1337, 1254, 1212 cmÀ1; HRMS (FAB):
m/z calcd for C17H16NO2: 266.1181 [M+H]+; found: 266.1161.
Under an argon atmosphere, Cs2CO3 (4.66 g, 14.3 mmol); triphenylphos-
phine (190 mg, 0.724 mmol);
(0.92 mL, 7.23 mmol), benzylamine 23 (1.97 g, 6.97 mmol), and 2-norbor-
nene (346 mg, 3.67 mmol) in DMF (20 mL); and Pd(OAc)2 (86.0 mg,
a solution containing 2-iodotoluene
AHCTUNGTRENNUNG
0.383 mmol) were added to a flask. The reaction mixture was stirred at
1308C for 1 day and cooled to room temperature. The resultant mixture
was filtered through Celite and concentrated under reduced pressure.
The reaction mixture was diluted with diethyl ether, washed with H2O,
brine, and dried over Na2SO4. After filtration and concentration under
reduced pressure, the obtained residue was purified by column chroma-
tography on silica gel (hexane/ethyl acetate=3/1) to give 24 as a yellow
solid (1.21 g, 66%). 1H NMR (400 MHz, CDCl3): d=9.16 (s, 1H), 8.29
(dd, J=1.6, 7.6 Hz, 1H), 7.85 (s, 1H), 7.55–7.50 (m, 2H), 7.33 (s, 1H),
4.12 (s, 3H), 4.06 (s, 3H), 2.87 ppm (s, 3H); 13C NMR (101 MHz, CDCl3):
d=152.7, 150.3, 149.8, 142.7, 137.6, 128.5, 128.4, 126.1, 123.6, 121.5, 119.6,
107.6, 101.9, 56.08, 56.06, 18.7 ppm; IR (ATR): n˜ =2990, 2925, 1615, 1593,
1505, 1474, 1442, 1403, 1375, 1263 cmÀ1; HRMS (FAB): m/z calcd for
C16H16NO2: 254.1181 [M+H]+; found: 254.1180.
Pratosine (2)
BaMnO4 (209 mg, 0.814 mmol) was added to a solution of 27 (21.6 mg,
0.0814 mmol) in CH2Cl2 (1.9 mL) under an atmosphere of argon and the
resulting mixture was stirred at room temperature for 2.5 h. The mixture
was then filtered through a pad of Celite and the filtrate was collected
and concentrated under reduced pressure to give a residue that was puri-
fied by column chromatography on silica gel (CH2Cl2 and then CH2Cl2/
AcOEt=20/1) to give 2 as a white solid (16.4 mg, 72%). 1H NMR
(400 MHz, CDCl3): d=8.07 (d, J=4.0 Hz, 1H), 8.02 (s, 1H), 7.99 (d, J=
7.6 Hz, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.67 (s, 1H), 7.49 (t, J=7.4 Hz,
1H), 6.91 (d, J=3.2 Hz, 1H), 4.13 (s, 3H), 4.07 ppm (s, 3H); 13C NMR
(101 MHz, CDCl3): d=158.4, 153.7, 149.7, 131.1, 129.5, 128.5, 123.9,
123.5, 122.4, 120.8, 118.0, 116.7, 110.7, 110.1, 103.8, 56.29, 56.25 ppm; IR
(ATR): n˜ =3010, 2837, 1665, 1602, 1526, 1507, 1440, 1362, 1308, 1270,
1216 cmÀ1; HRMS (FAB): m/z calcd for C17H14NO3: 280.0974 [M+H]+;
found: 280.0965.
Compound 26
AcOH (326 mL, 5.70 mmol) was added to a solution of phenanthridine 24
(1.45 g, 5.70 mmol) in EtOH (10 mL). The mixture was heated at reflux
for 1 h and then NaCNBH3 (681 mg, 10.8 mmol) was added. The reaction
mixture was stirred for 1.5 h and cooled to room temperature. The reac-
tion mixture was basified with a saturated aqueous solution of Na2S2O3
containing 10% NH3 and extracted with CHCl3. The organic phases were
combined, washed with brine, and dried over Na2SO4. The organic resi-
due was filtered and concentrated under reduced pressure. The residue
was dissolved in CH2Cl2 (30 mL), cooled to À788C under an argon at-
mosphere, and then triphosgene (861 mg, 2.89 mmol) and pyridine
(0.9 mL, 11.1 mmol) were added. The reaction mixture was stirred at
room temperature for 3 h, diluted with CHCl3 and H2O, and extracted
with CHCl3. The organic phases were combined, washed with brine, and
dried over Na2SO4. After filtration and concentration under reduced
pressure, the obtained residue was purified by column chromatography
on silica gel (CHCl3) to give 26 as a yellow amorphous solid (1.43 g,
79%, 2 steps). 1H NMR (400 MHz, CDCl3): d=7.55 (d, J=7.2 Hz, 1H),
7.33–7.30 (m, 2H), 7.20 (d, J=7.2 Hz, 1H), 6.83 (s, 1H), 5.35–5.30 (m,
1H), 4.38–4.15 (m, 1H), 4.01–3.93 (m, 6H), 2.46–2.35 ppm (m, 3H);
13C NMR (101 MHz, CDCl3): d=149.7, 149.4, 149.2, 147.2, 135.8, 134.3,
131.2, 130.4, 129.9, 129.7, 127.8, 127.6, 126.5, 125.0, 124.8, 121.6, 121.5,
109.2, 108.6, 107.4, 56.22, 56.17, 52.2, 50.1, 18.7, 18.5 ppm (mixture of two
rotamers); IR (ATR): n˜ =3017, 2960, 2933, 2850, 1728, 1609, 1517, 1470,
1442, 1398, 1348 cmÀ1; HRMS (FAB): m/z calcd for C17H16NO3: 317.0819
[M]+; found: 317.0817.
Assoanine (1)
AcOH (0.3 mL) and NaCNBH3 (0.72 mmol) were added to a solution of
27 (20.7 mg, 0.078 mmol) in THF (1.0 mL) and the resulting mixture was
stirred at room temperature for 6 h. The reaction mixture was then neu-
tralized with a 1m aqueous solution of NaOH and extracted with AcOEt.
The combined organic phases were washed with brine and dried over
Na2SO4 before being filtered and concentrated under reduced pressure to
give a residue that was purified by column chromatography on silica gel
1
(hexane/AcOEt=5/1) to give 1 as a yellow solid (8.4 mg, 40%). H NMR
(400 MHz, CDCl3): d=7.33 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 7.01 (d, J=
6.8 Hz, 1H), 6.77 (t, J=7.6 Hz, 1H), 6.66 (s, 1H), 4.12 (s, 2H), 3.95 (s,
3H), 3.90 (s, 3H), 3.35 (t, J=8.2 Hz, 2H), 3.03 ppm (t, J=7.8 Hz, 2H);
13C NMR (101 MHz, CDCl3): d=149.6, 148.6, 148.4, 128.5, 124.7, 124.3,
123.3, 119.6, 119.3, 119.0, 110.3, 105.4, 56.03, 56.01, 55.4, 53.2, 29.0 ppm;
IR (ATR): n˜ =2924, 1609, 1520, 1472, 1406, 1346, 1250 cmÀ1; HRMS
(FAB): m/z calcd for C17H18NO2: 268.1338 [M+H]+; found: 268.1329.
Oxindole 16
Carbamoyl chloride 26 (59.4 mg, 0.19 mmol) was mixed with PdACTHNUTRGNEUNG(OAc)2
(2.3 mg, 0.010 mmol), Ad2PnBu (6.7 mg, 0.019 mmol), Cs2CO3 (67.1 mg,
0.21 mmol), and PivNHOH (6.6 mg, 0.056 mmol), and the resulting mix-
ture was purged under an atmosphere of CO. Mesitylene (1 mL) was
Chem. Asian J. 2014, 9, 2628 – 2634
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Yoshiji Takemoto et al.
Compound 29
Oxindole 33
Carbamoyl chloride 32 (179 mg, 0.59 mmol) was mixed with PdACHTUNGTRENNUNG(OAc)2
Methyl carbamate (1.33 g, 17.8 mmol), TFA (2 mL, 26.2 mmol), and trie-
thylsilane (4.2 mL, 26.2 mmol) were added to a solution of 6-bromopi-
peronal (2.01 g, 8.78 mmol) in acetonitrile (80 mL) under an argon at-
mosphere. The mixture was stirred at 808C for 12 h and then cooled to
room temperature. The mixture was concentrated under reduced pres-
sure and the residue was dissolved in THF, MeOH, and a 2m aqueous so-
lution of LiOH (1:1:1; 150 mL). The reaction mixture was stirred at 808C
for 1 day and then cooled to room temperature. The reaction mixture
was diluted with AcOEt and a 1m aqueous solution of HCl. The organic
phase was extracted with a 1m aqueous solution of HCl. The aqueous ex-
tracts were combined and basified with a 1m aqueous solution of NaOH.
The aqueous phase was extracted with AcOEt. The organic extracts were
combined, washed with brine, and dried over Na2SO4. Concentration
under reduced pressure afforded 29 as a white solid (1.69 g, 84%,
2 steps). 1H NMR (400 MHz, CDCl3): d=7.00 (s, 1H), 6.89 (s, 1H), 5.96
(s, 2H), 3.81 ppm (s, 2H); 13C NMR (101 MHz, CDCl3): d=147.3, 147.1,
135.3, 113.4, 112.7, 109.0, 101.5, 46.6 ppm; IR (ATR): n˜ =3318, 3037,
2907, 1587, 1503, 1474, 1415, 1347, 1244 cmÀ1; HRMS (FAB): m/z calcd
for C8H9BrNO2: 229.9817 [M+H]+; found: 229.9815.
(6.6 mg, 0.029 mmol), Ad2PnBu (21 mg, 0.059 mmol), Cs2CO3 (213 mg,
0.65 mmol), and PivNHOH (21 mg, 0.18 mmol), and the resulting mix-
ture was purged under an atmosphere of CO. Mesitylene (3 mL) was
then added to the reaction and the resulting mixture was stirred at 1208C
for 1.5 h before being filtered through a pad of Celite. The filtrate was
collected and concentrated under reduced pressure to give a residue that
was purified by column chromatography on silica gel (hexane/AcOEt=3/
1 then CH2Cl2/AcOEt=9/1) to give oxindole 33 (49.9 mg, 32%) as
a
yellow solid and phenanthridine 30 (53.8 mg, 34%). 1H NMR
(500 MHz, CD2Cl2): d=7.41 (d, J=7.0 Hz, 1H), 7.22 (s, 1H), 7.07 (d, J=
7.0 Hz, 1H), 6.96 (t, J=7.7 Hz, 1H), 6.64 (s, 1H), 5.99 (s, 2H), 4.92 (s,
2H), 3.47 ppm (s, 2H); 13C NMR (126 MHz, CD2Cl2): d=174.6, 148.4,
148.3, 140.2, 123.7, 123.6, 123.4, 123.2, 122.7, 120.1, 117.3, 107.9, 102.8,
102.1, 43.7, 36.6 ppm; IR (ATR): n˜ =3042, 2922, 1698, 1632, 1510, 1474,
1351, 1255, 1231, 1209 cmÀ1; HRMS (FAB): m/z calcd for C16H12NO3:
266.0817 [M+H]+; found: 266.0817.
Dehydroanhydrolycorine (4)
Oxindole 33 (43.8 mg, 0.165 mmol) was dissolved in CH2Cl2 (2 mL)
under an atmosphere of argon, and the resulting solution was cooled to
08C before being treated with a 1m solution of DIBAL in toluene
(0.99 mL, 0.99 mmol). The reaction mixture was then stirred at 08C for
3 h before being quenched by the addition of a 2m aqueous solution of
NaOH. The residue was extracted with CHCl3 and the combined organics
were washed with brine and dried over Na2SO4, before being filtered and
concentration under reduced pressure to give a residue that was purified
by column chromatography on silica gel (hexane/CHCl3 =1/1) to give 4
as a red solid (19.9 mg, 48%). 1H NMR (400 MHz, CDCl3): d=7.44 (d,
J=8.0 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.12 (d, J=3.2 Hz,
1H), 7.05 (t, J=7.4 Hz, 1H), 6.65 (s, 1H), 6.52 (d, J=3.2 Hz, 1H), 6.00
(s, 2H), 5.50 ppm (s, 2H); 13C NMR (101 MHz, CDCl3): d=147.6, 147.5,
133.0, 125.9, 125.7, 124.2, 123.8, 120.4, 120.0, 118.6, 112.9, 107.1, 102.9,
102.5, 101.3, 48.1 ppm; IR (ATR): n˜ =2902, 1730, 1657, 1502, 1485, 1461,
Compound 30
Cs2CO3 (493 mg, 1.51 mmol); triphenylphosphine (37.7 mg, 0.144 mmol);
a solution containing 2-iodotoluene (92 mL, 0.723 mmol), benzylamine 29
(166 mg, 0.719 mmol), and 2-norbornene (34.3 mg, 0.364 mmol) in DMF
(3.6 mL); and PdACHTUNGTRENNUNG(OAc)2 (16.3 mg, 0.0726 mmol) were added to a flask
under an argon atmosphere. The reaction mixture was stirred at 1308C
for 1 day. Oxygen was added to the reaction mixture through a balloon
for 1 h, and then cooled to room temperature. The resultant mixture was
filtered through Celite and concentrated under reduced pressure. After
the reaction mixture was diluted with AcOEt, the organic layer was
washed with a saturated aqueous solution of K2CO3 and brine and dried
over Na2SO4. After filtration and concentration under reduced pressure,
the obtained residue was purified by column chromatography on silica
gel (hexane/ethyl acetate=5/1) to give 30 as a red solid (87.2 mg, 51%).
1H NMR (400 MHz, CDCl3): d=9.13 (s, 1H), 8.25 (d, J=7.6 Hz, 1H),
7.93 (s, 1H), 7.56–7.52 (m, 2H), 7.35 (s, 1H), 6.17 (s, 2H), 2.86 ppm (s,
3H); 13C NMR (101 MHz, CDCl3): d=151.2, 150.4, 148.0, 142.9, 137.6,
130.5, 128.7, 126.2, 124.1, 122.8, 119.9, 105.2, 101.8, 100.0, 18.7 ppm; IR
(ATR): n˜ =2918, 1463, 1257, 1220, 1036 cmÀ1; HRMS (FAB): m/z calcd
for C15H12NO2: 238.0868 [M+H]+; found: 238.0872.
1339, 1242 cmÀ1
; HRMS (FAB): m/z calcd for C16H12NO2: 250.0868
[M+H]+; found: 250.0855.
Hippadine (3)
BaMnO4 (126 mg, 0.493 mmol) was added to a solution of oxindole 33
(12.3 mg, 0.0493 mmol) in CH2Cl2 (1.4 mL) under an atmosphere of
argon, and the resulting mixture was stirred at room temperature for
2.5 h. The reaction mixture was then filtered through a pad of Celite and
the filtrate was collected and concentrated under reduced pressure to
give a residue that was purified by column chromatography on silica gel
(hexane/CH2Cl2 2/1) to give 3 as a white solid (10.0 mg, 77%). 1H NMR
(400 MHz, CDCl3): d=8.05 (d, J=3.6 Hz, 1H), 7.99 (s, 1H), 7.93 (d, J=
7.6 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.48 (t, J=7.8 Hz,
1H), 6.90 (d, J=3.2 Hz, 1H), 6.17 ppm (s, 2H); 13C NMR (101 MHz,
CDCl3): d=158.2, 152.6, 148.5, 131.6, 130.9, 128.4, 124.0, 123.5, 122.6,
122.5, 118.4, 116.7, 110.8, 108.0, 102.3, 101.7 ppm; IR (ATR): n˜ =3152,
2922, 1670, 1618, 1526, 1477, 1457, 1392, 1366, 1347, 1310, 1286,
1244 cmÀ1; HRMS (FAB): m/z calcd for C16H10NO3: 264.0661 [M+H]+;
found: 264.0647.
Compound 32
AcOH (68 mL, 1.18 mmol) was added to a solution of phenanthridine 30
(280 mg, 1.18 mmol) in EtOH (2.4 mL). The mixture was heated at reflux
for 1 h and then NaCNBH3 (142 mg, 2.25 mmol) was added. The reaction
mixture was stirred for 2 h and cooled to room temperature. The reaction
mixture was basified with a saturated aqueous solution of Na2S2O3 con-
taining 10% NH3 and extracted with CHCl3. The organic phases were
combined, washed with brine, and dried over Na2SO4. The organic resi-
due was filtered and concentrated under reduced pressure. The residue
was dissolved in CH2Cl2 (6 mL), cooled to À788C under an argon atmos-
phere, and then triphosgene (177 mg, 0.593 mmol) and pyridine (190 mL,
2.36 mmol) were added. The reaction mixture was stirred at room tem-
perature for 2.5 h. The reaction mixture was diluted with CHCl3 and
H2O, and extracted with CHCl3. The organic phases were combined,
washed with brine, and dried over Na2SO4. After filtration and concen-
tration under reduced pressure, the obtained residue was purified by
column chromatography on silica gel (CHCl3) to give 32 as a yellow oil
(290 mg, 82%, 2 steps). 1H NMR (400 MHz, CDCl3): d=7.47 (d, J=
7.6 Hz, 1H), 7. 30 (d, J=7.2 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.80 (s,
1H), 6.00 (s, 2H), 5.30–5.24 (m, 1H), 4.31–4.08 (m, 1H), 2.44–2.33 ppm
(m, 3H); 13C NMR (101 MHz, CDCl3): d=149.6, 148.2, 147.5, 147.2,
135.7, 135.4, 135.0, 134.2, 131.1, 130.4, 130.0, 129.8, 128.9, 127.9, 127.7,
126.5, 126.3, 121.8, 121.6, 106.7, 106.1, 104.7, 101.4, 52.4, 50.7, 50.3, 18.6,
18.4 ppm (mixture of two rotamers); IR (ATR): n˜ =2902, 1739, 1503,
1469, 1348, 1247, 1221 cmÀ1; HRMS (FAB): m/z calcd for C16H13ClNO3:
302.0584 [M+H]+; found: 302.0574.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research on
Innovative Areas “Molecular Activation Directed toward Straightfor-
ward Synthesis” and Platform for Drug Discovery, Informatics, and
Structural Life Science from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT) of Japan.
Chem. Asian J. 2014, 9, 2628 – 2634
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Yoshiji Takemoto et al.
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À
[18] Compound 25 might be directly accessed by intramolecular C H ac-
tivation from compound 14. However, we have not attempted the
route because it would require a protecting group on the secondary
amine.
[19] L. Matesic, J. M. Locke, K. L. Vine, M. Ranson, J. B. Bremner, D.
Skropeta, Tetrahedron 2012, 68, 6810–6819.
[20] When the reaction was performed at 1208C, very similar results
were obtained (16: 29%, 26: 70%).
Received: May 7, 2014
Revised: May 30, 2014
Published online: July 14, 2014
Chem. Asian J. 2014, 9, 2628 – 2634
2634
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