Total Synthesis of (+)-Chimonanthine, (+)-Folicanthine, and (-)-Calycanthine

Article abstract of DOI:10.1021/acs.joc.5b01907

Facile, straightforward, and asymmetric total syntheses of (+)-chimonanthine (1), (+)-folicanthine (2), and (-)-calycanthine (3) were accomplished in four to five steps from commercially available tryptamine. The synthesis features copper-mediated asymmet

Full text of DOI:10.1021/acs.joc.5b01907

Article
pubs.acs.org/joc
Total Synthesis of (+)-Chimonanthine, (+)-Folicanthine, and
(−)-Calycanthine
Ming Ding,†,‡,§ Kangjiang Liang,‡,§ Rui Pan,‡ Hongbin Zhang,*,† and Chengfeng Xia*,†,‡
†Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education, School of Chemical Science and Technology,
Yunnan University, Kunming 650091, China
‡State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of
Sciences, Kunming 650201, China
§University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: Facile, straightforward, and asymmetric total
syntheses of (+)-chimonanthine (1), (+)-folicanthine (2), and
(−)-calycanthine (3) were accomplished in four to five steps
from commercially available tryptamine. The synthesis features
copper-mediated asymmetric cyclodimerization of chiral trypt-
amine derivative, which established a new entry into
constructing the sterically hindered vicinal quaternary stereo-
genic carbon centers of dimeric hexahydropyrroloindole
alkaloids in one procedure. An unprecedented base-induced
isomerization from the chimonanthine skeleton to the
calycanthine skeleton was observed and facilitated the
synthesis of (−)-calycanthine (3).
INTRODUCTION
■
In nature, hexahydropyrroloindole skeletons are very important
moieties that are widespread in a large family of natural
products with wide range of attractive bioactivities.1 Dimeric or
oligomeric hexahydropyrroloindole derivatives, bearing vicinal
quaternary stereogenic carbon centers at C3a and C3a′, have
attracted significant interest for both synthetic and biological
studies. As the representative models of these alkaloids,
(+)-chimonanthine (1), (+)-folicanthine (2), and (−)-calycan-
thine (3) (shown in Figure 1) have continuously received
considerable synthetic efforts from the community of synthetic
chemists, especially in the past few years.2
With respect to the instability of the C3a−C3a′ bond, as well
as the difficulties in construction of the sterically hindered
vicinal stereogenic quaternary centers, efficient methods toward
the enantioselective synthesis of dimeric hexahydropyrroloin-
dole alkaloids were still challenging.3 In 1999, Overman
uncovered the first stereocontrolled total synthesis of
(−)-chimonanthine (1) and (+)-calycanthine (3) (Scheme
1). In this method, the contiguous quaternary carbon centers,
induced from the tartrate-derived diiodide compound, were
established efficiently via double-intramolecular Heck cycliza-
tion.3a Movassaghi and co-workers developed an efficient
Co(I)-mediated reductive homodimerization of chiral 3-
bromohexahydropyrroloindole in 2007 and completed the
concise enantioselective total synthesis of (+)-chimonanthine
(1), (+)-folicanthine (2), and (−)-calycanthine (3).3b In 2013,
Ma and co-workers developed a chiral anionic phase-transfer
catalytic enantioselective bromocyclization of tryptamine. By
Figure 1. Representative hexahydropyrroloindole-derived family of
alkaloids with C3a−C3a′ bond.
employing Movassghi’s dimerization conditions, the enantiose-
lective total synthesis of (−)-chimonanthine(1) was achieved
from 3-bromohexahydropyrrolo[2,3,-b]indole.3e Movassaghi’s
coupling methodology was also frequently utilized by several
other research groups toward the total synthesis of other
dimeric hexahydropyrroloindole alkaloids.3e,4 A novel enantio-
Received: August 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01907
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Scheme 1. Summary of the Previous Reports on Total
Synthesis of Chiral Dimeric Hexahydropyrroloindole
Natural Products
Scheme 2. Retrosynthetic Analysis of (+)-Chimonanthine
(1), (+)-Folicanthine (2), and (−)-Calycanthine (3)
The (+)-menthyl group was utilized as a chiral source to
induce the global chirality (Scheme 3). The chiral carbamate 12
Scheme 3. Synthesis of Chiral Carbamate 17
selective nucleophilic substitution reaction of 3-hydroxyox-
indoles with enecarbamates for C3a and C3a′ coupling for the
synthesis of disubstituted oxindoles was developed by Gong
and co-workers in 2012.3d This methodology was strategically
utilized for the total synthesis of (+)-folicanthine (2) with
several additional steps. Soon afterward, a catalytic asymmetric
double-Michael addition of bisoxindole was developed by
Kanai’s research group, which provided alternative choice for
the synthesis of (+)-chimonanthine (1), (+)-folicanthine (2),
and (−)-calycanthine (3).3c Very recently, a copper catalyzed
sequential arylation−oxidative dimerization reaction as the key
step for the synthesis of (+)-chimonanthine (1), (+)-folican-
thine (2) and (−)-calycanthine (3) was developed with
sulfonamide as chiral auxiliary.5 Herein, we disclosed a concise,
straightforward, and asymmetric total synthesis of (+)-chimo-
nanthine (1), (+)-folicanthine (2), and (−)-calycanthine (3)
via an oxidative cyclodimerization method.
was easily synthesized on a multigram scale by treating
commercially available tryptamine 10 with (+)-menthyl
chloroformate 11 in the presence of excessive DIPEA. The
enantiomerically pure carbamate 12 was obtained in 92% yield
by crystallization from the crude residue in a mixture of
petroleum ether and CH2Cl2 at low temperature.
Having a sufficient amount of dimeric precursor 12 in hand,
we then focused on the study of the crucial homodimeric
coupling step. During the application of the previously reported
cyclodimerization conditions (CuCl2 (1.1 equiv) and DBU (2.5
equiv) in CH3CN under anaerobic conditions),6 we encoun-
tered difficulties with low conversion rate (<10% yield). We
then turned our attention to diverse metal oxidants to improve
the efficiency of the cyclodimerization reaction. A wide range of
metal salts (1.1 equiv), such as CoCl2, FeCl3, MgCl2,
Mn(OAc)3, ZnCl2, CeCl3, ZrCl4, and NiCl2, were screened in
the presence of DBU (2.5 equiv), but none of them were found
to proceed effectively. Furthermore, other copper sources, such
as Cu(OAc)2, Cu(acac)2, Cu(OTf)2, CuSO4, Cu(NO3)2, and
Cu(2-ethylhexanoate)2, were also tested but failed. It was
noticed that this cyclodimerization reaction could be initiated
by none of them except CuCl2, which revealed the importance
of the counterpart anion in copper salt. We reasoned that
CuCl2 was superior for the oxidation of N1-anion comparing to
other copper salts, while without a strong coordination effect.
In this case, we thus returned to the CuCl2/base protocol. As
illustrated in Table 1, no significant improvements were
achieved after intensive survey of various reaction temperatures,
concentrations, times, bases, and the amounts of base. To our
delight, the reaction was effectively promoted as the amount of
CuCl2 was increased to 1.5 equiv in association with t-BuOK,
which was far beyond our knowledge. According to our
previous results, the dimeric hexahydropyrroloindole analogues
RESULTS AND DISCUSSION
■
To start with the synthesis of the target compounds, a general
and convergent retrosynthetic approach for (+)-chimonanthine
(1), (+)-folicanthine (2), and (−)-calycanthine (3) was
designed. As outlined in Scheme 2, (+)-chimonanthine (1)
was envisioned as the common intermediate for both
(+)-folicanthine (2) and (−)-calycanthine (3) by a later stage
of N1-methylation or isomerization. We inferred that
(+)-chimonanthine (1) could be prepared from dimer 7 with
all the stereogenic centers located close together. A powerful
homodimeric coupling reaction would be strategically involved
in the construction of the 3a,3a′-bispyrrolidino[2,3-b]indoline
framework via intermediate 8, establishing the vicinal
quaternary stereogenic carbon centers at the C3a and C3a′
positions from readily available chiral monomer 9 or its
analogues.
B
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deprotonated, followed by a single-electron oxidation process,
to generate the corresponding indole N1 free radical species,
which then delocalized to indole C3. Then two indole C3
radicals dimerized first, and the 5-exo-trig annulation occurred
afterward. In this manner, the C3 free-radical species, consisting
of the auxiliary located remotely, underwent the frequent
conformational inversion process (TS-1 and TS-2), leading to
poor final diastereoselectivity. In addition, the meso dimeriza-
tion process (TS-3 and TS-4) was unfavorable owing to the
steric interaction between the two side chains. .
With this key intermediate 13a in hand, we then focused on
accomplishing the total synthesis of this family of natural
products, which seems easily obtained. Thus, several promising
reagents for the reduction of (+)-menthyl group in 13a, such as
lithium aluminum hydride (LiAlH4),10 diisobutyl aluminum
hydride (DIBAL-H),11 or bis(2-methoxyethoxy)aluminum
hydride (Red-Al), were explored under various conditions
with different temperatures or solvents. However, the
straightforward transformation of compound 13a to (+)-chi-
monanthine (1) turned out to be highly challenging under
reductive conditions. Notably, after compound 13a was treated
with LiAlH4 either in THF or Et2O, the corresponding
monomer or its derivatives were isolated. This experimental
evidence indicated that an unexpected anionic fragmentation
process of the C3a−C3a′ bond predominated.3b Moreover, if
Red-Al was utilized as reducing reagent, a major product was
obtained and further identified as compound 14 wherein a
pyrrole ring-opening process occurred. As depicted in Scheme
5, we proposed that the Al(III)-mediated ring opening
occurred, followed by reduction of the imine intermediate,
affording mono-ring-opening product 14.
Table 1. Studies on the Cyclodimerization Reaction
a
c
CuCl2
(equiv)
conc
(M)
yield
(%)
brsm
(%)
entry
base (equiv)
13a:13b
b
1
2
3
1.1
1.1
1.1
DBU (2.5)
NaH (2.5)
0.1
0.1
0.1
<10
b
t-BuOK
(2.5)
b
4
5
6
7
8
1.5
1.5
2.0
1.5
1.5
t-BuOK
0.1
39
40
25
45
42
60
59
33
59
56
3:2
3:2
3:2
3:2
(2.5)
t-BuOK
(2.5)
0.05
0.05
0.05
0.05
t-BuOK
(2.5)
t-BuOK
(1.1)
d
t-BuOK
(1.1)
3:2
a
b
0.3 mmol of substrate was used unless otherwise mentioned. A low
c
conversion rate was observed by TLC analysis. Based on recovered
starting material. Gram scale.
d
were liable to decompose rapidly with excess CuCl2 (1.5
equiv).6 With further optimization, we disclosed that the
amounts of both CuCl2 and t-BuOK were very critical for this
cyclodimerization reaction. Two diastereomers, 13a and 13b,
were identified as homodimeric coupling products in 45% yield
(59% brsm). At this stage, we were unable to confirm the
relative configurations at all newly formed stereocenters of
these two diastereomers. However, the diastereomeric ratio of
them was measured to be 3:2 after isolation by reversed-phase
preparative HPLC. The relative configurations of these two
isomers 13a and 13b were confirmed at the end of the
To verify the proposed decomposition mechanism, the N1
was protected with methyl groups by reductive methylation to
give compound 15. Thus, compound 15 would not form the
nitrogen anion intermediate under reductive conditions,
consequently preventing the ring-opening reaction. As
expected, after compound 15 was treated with Red-Al,
(+)-folicanthine (2) was achieved in high yield without the
detection of ring-opening byproducts (Scheme 6). These
experimental results confirmed our proposed mechanism as
depicted in Scheme 5.
synthesis. We found that the spectroscopic data (1H NMR, 13
C
NMR, and specific rotation) of 13a-derived synthetic material
matched those of the isolated natural products (+)-chimonan-
thine (1), and the 13b-derived synthetic material had the same
1H NMR and 13C NMR, while with the opposite specific
rotation. Most importantly, the C2-symmetry was predominant
in this reaction, and no meso-isomers or any other regioisomers
were detected.2f,7 It should also be noted that the process of
this tandem sequence was highly efficient (four stereogenic
centers, three chemical bonds, and two heterocycles were
simultaneously constructed in a single step). In particular, even
when the reaction was scaled up to 1 g, the combined yield was
still well maintained. This was highly helpful from a practical
point of view, in particular for large-scale preparation of each
diastereomer.
To investigate the copper-mediated oxidization process, a
nitrogen-masking experiment was designed and explored. The
reaction was completely suppressed by a large excess of Et3B,
which usually served as a deactivator of indole N1 to inhibit its
functionality.8 We also discovered that no reactions occurred
when N1 was protected with a methyl or sulfonyl group.9
These experiments demonstrated that the radical species
oxidized by CuCl2 was originated from indole N1.
For the preparation of another two natural products,
(+)-chimonanthine (1) and (−)-calycanthine (3), which have
no methyl groups at the N1 position, the bulky menthyl groups
in 13a were globally removed by KOH in heated EtOH
(Scheme 7). The reaction mixture was then treated with
ClCO2Me to successfully deliver the desired carbamate 16
along with isomerized product 17. Pleasingly, the C3a−C3a′
bond fragmentation occurred even at temperatures up to 155
23
°C under basic conditions. The specific rotation [[α]D
=
22.3
+414.1 (c 0.41, CH3Cl); lit. [α]D = +437.0 (c 1.47, CH3Cl)
by Kanai’s group3c and [α]D = +474.0 (c 1.00, CH2Cl2) by
22
Movassaghi’s group3b] of carbamate 16 was in agreement with
the values published for the title compound. Notably, rather
than employing acidic conditions like many research groups to
date,2b,c,i,3a−c,12 it was first time that this kind of skeleton
isomerization process was achieved under basic conditions. The
ratio between desired product 16 and isomerized product 17
depended on the duration of the deprotecting step, and it was
convenient to control the ratio between the two intermediates
by verifying the reaction duration. The ratio between product
17 and 16 could reach up to 8.3:1 in 70% overall yield with a
deprotection duration of 80 h. Then, reducing the two
On the basis of the experimental results above, a plausible
mechanism is proposed in Scheme 4. The indole N1 was
C
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Scheme 4. Plausible Mechanism for the Cyclodimerization Reaction
achieved in the presence of excessive K2CO3 and MeI, affording
(−)-calycanthine (3) in 54% yield over two steps. More
interestingly, (+)-chimonanthine (1) and other overmethyla-
tion products were not observed. Finally, carbamate 16 was
transformed to (+)-chimonanthine (1) also via a large excess of
Red-Al and gave (+)-chimonanthine (1) in 83% yield. All of the
spectroscopic data of (+)-chimonanthine (1), (+)-folicanthine
(2), and (−)-calycanthine (3) for the synthetic samples were
identical to those reported in the literature.
Scheme 5. Attempts at Reducing the (+)-Menthyl Auxiliary
of Dimer 13a
CONCLUSIONS
■
In summary, we have developed a facile asymmetric synthetic
route to the total synthesis of three representative C2-
symmetric bispyrrolidinoindoline-derived natural products,
(+)-chimonanthine (1), (+)-folicanthine (2), and (−)-calycan-
thine (3), with the shortest steps so far. The key steps of this
synthesis featured a novel and efficient copper-mediated
asymmetric homodimeric coupling reaction from readily
available chiral tryptamine derivative. Additionally, other new
discoveries in this synthesis included an unprecedented base-
induced skeleton isomerization and a direct chemoselective
methylation. This straightforward strategy could be applied to
synthesize other high-order hexahydropyrroloindole alkaloids
and derivatives, which also holds great potential for the
methoxycarbonyl groups of 17 with a large excess of Red-Al
smoothly gave (−)-calycanthine (3) in 84% yield. Competitive
with this three-step sequence, direct N-methylation of the crude
mixture of intermediate 16a and 17a was chemoselectively
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Scheme 6. Total Synthesis of (+)-Folicanthine (2)
Scheme 7. Total Synthesis of (+)-Chimonanthine (1) and (−)-Calycanthine (3)
a KBr pellet. High-resolution ESI mass spectra were recorded on a
triple-quadrupole mass spectrometer operating in positive-ion mode.
(1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl (2-(1H-Indol-3-
yl)ethyl) Carbamate (12). To a stirred solution of tryptamine 10
(5.00 g, 31.3 mmol) and DIPEA (10.9 mL, 62.7 mmol) in 150 mL of
CH2Cl2 was added (+)-menthyl chloroformate 11 (7.3 mL, 34.4
mmol) dropwise at 0 °C. Then the reaction mixture was warmed to
room temperature and stirred for 2 h before it was quenched with
saturated aqueous NH4Cl (120 mL). The resulting mixture was
extracted with CH2Cl2 (2 × 100 mL), and the organic phase was
washed with brine (1 × 100 mL), dried (Na2SO4), filtered and
concentrated under reduced pressure. The crude product was
crystallized three times in a mixture of CH2Cl2 and petroleum ether
at 4 °C to afford 9.8 g (92%) of 12 as an amorphous solid: Rf = 0.4
discovery of leading drug candidates containing the poly
hexahydropyrroloindole substructure.
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed under argon
atmosphere using oven-dried glassware unless otherwise noted.
CH3CN, CH2Cl2, and DMSO were distilled over CaH2. THF and
toluene were distilled over Na/benzophenone. All other reagents were
commercially available and used without further purification unless
indicated otherwise. Thin-layer chromatography (TLC) was carried
out on GF254 plates (0.25 mm layer thickness). Flash chromatog-
raphy was performed with 300−400 mesh silica gels. Visualization of
the developed chromatogram was performed by fluorescence
quenching, ceric ammonium molybdate, or KMnO4 stain. Yields
reported were for isolated, spectroscopically pure compounds. 1H
NMR and 13C NMR experiments were recorded on a 400 MHz
instrument at ambient temperature unless otherwise noted. The
residual solvent protons (1H) or the solvent carbons (13C) were used
as internal standards. 1H NMR data are presented as follows: chemical
shift in ppm downfield from tetramethylsilane (multiplicity, coupling
constant, integration). The following abbreviations are used in
reporting NMR data: s, singlet; br s, broad singlet; d, doublet; dd,
doublet of doublets; t, triplet; q, quartet; m, multiplet. Optical
rotations were measured with a polarimeter at ambient temperature
using a 1 mL capacity cell with 1 dm path length. Infrared (IR) spectra
were recorded using a thin film supported on KBr disks or dispersed in
1
(EtOAc/petroleum ether, 1/4); H NMR (400 MHz, CDCl3) δ 8.22
(s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.21 (t, J =
7.4 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.00 (s, 1H), 4.72 (s, 1H), 4.58
(dd, J = 10.1, 6.8 Hz, 1H), 3.52 (d, J = 6.0 Hz, 2H), 2.98 (t, J = 6.4 Hz,
2H), 2.06 (d, J = 11.7 Hz, 1H), 1.92 (s, 1H), 1.67 (d, J = 4.3 Hz, 2H),
1.56−1.42 (m, 1H), 1.28 (t, J = 10.6 Hz, 1H), 1.13−1.00 (m, 1H),
0.98−0.85 (m, 8H), 0.81 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 156.5, 136.4, 127.3, 122.1, 119.3, 118.8, 113.0, 111.2, 74.4,
47.3, 41.5, 41.2, 34.3, 31.3, 26.2, 25.8, 23.5, 22.0, 20.8, 16.4; IR (KBr) ν
3413, 2915, 2869, 1690, 1531, 1454, 1263, 1142, 1017, 740 cm−1;
23
[α]D = +43.9 (c 1.10, CH3Cl); HRMS (ESI) m/z calcd for
C21H30N2O2Na [M + Na]+ 365.2199, found 365.2198.
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Bis((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl) (3aR,3′a-
R,8aR,8′aR)-2,2′,3,3′,8,8a,8′,8′a-Octahydro-1H,1′H-[3a,3′a-
bipyrrolo[2,3-b]indole]-1,1′-dicarboxylate (13a) and bis-
((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl) (3aS,3′aS,-
8aS,8′aS)-2,2′,3,3′,8,8a,8′,8′a-octahydro-1H,1′H-[3a,3′a-
bipyrrolo[2,3-b]indole]-1,1′-dicarboxylate (13b). To a stirred
solution of 12 (103 mg, 0.30 mmol) in 6 mL of degassed CH3CN was
added t-BuOK (37 mg, 0.33 mmol) in one portion at room
temperature. The reaction mixture was stirred at the same temperature
for 1 h. Then CuCl2 (61 mg, 0.45 mmol) was added at the same
temperature in one portion successively and the mixture stirred for 10
h. The reaction mixture was quenched with aqueous HCl (1M, 10
mL), extracted with EtOAc (3 × 20 mL), washed with brine (1 × 20
mL), dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue was subjected to flash column chromatography
to afford a mixture of 13a and 13b and combined with 22 mg of 12.
The mixture of 13a and 13b was further purified by reversed-phase
preparative HPLC (Agilent Zorbax SB-C18 column, MeOH/H2O =
95/5) to afford 28 mg (27%) of 13a as an amorphous solid and 19 mg
(19%) of 13b as an amorphous solid with a ratio of 3:2. On a larger
scale, reaction of 12 (1.00 g, 2.90 mmol) provided 251 mg of 13a, 170
mg of 13b, and 249 mg of recovered 12. Dimeric product 13a: Rf = 0.5
1154, 1102, 742 cm−1; [α]D23 = +190.3 (c 0.60, CH3Cl); HRMS (ESI)
m/z calcd for C22H29N4 [M + H]+ 349.2387, found 349.2382.
Bis((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl) (3aR,3′aR,-
8aR,8′aR)-8,8′-Dimethyl-2,2′,3,3′,8,8a,8′,8′a-octahydro-
1H,1′H-[3a,3′a-bipyrrolo[2,3-b]indole]-1,1′-dicarboxylate (15).
To a stirred solution of 13a (36 mg, 0.05 mmol) in 3 mL of CH3CN
were added formalin (37%, 52 μL, 0.64 mmol), HOAc (15 μL, 0.26
mmol), and NaBH3CN (17 mg, 0.27 mmol) successively at room
temperature. The reaction mixture was stirred at the same temperature
for 1 h before it was quenched with saturated aqueous NaHCO3 (10
mL) and extracted with EtOAc (3 × 10 mL), and the organic phase
was washed with brine (1 × 10 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The obtained residue was
subjected to flash column chromatography on silica gel (EtOAc/
petroleum ether, 1/12) to afford 37 mg (100%) of 15 as a colorless oil:
Rf = 0.3 (EtOAc/petroleum ether, 1/9); 1H NMR (400 MHz, CDCl3)
δ 7.22−6.96 (m, 4H), 6.74−6.51 (m, 2H), 6.35 (d, J = 7.8 Hz, 2H),
5.53−4.62 (m, 2H), 4.58−4.25 (m, 2H), 3.96−3.63 (m, 2H), 3.03−
2.68 (m, 8H), 2.56−2.28 (m, 2H), 2.21−1.88 (m, 4H), 1.85−1.20 (m,
6H), 1.53−1.14 (m, 6H), 1.11−0.37 (m, 26H); 13C NMR (100 MHz,
CDCl3) δ 154.1, 151.6, 129.4, 129.2, 128.6, 124.2, 123.9, 117.3, 116.8,
106.0, 105.7, 83.7, 82.9, 75.1, 61.6, 61.1, 60.4, 47.4, 45.2, 44.9, 41.6,
41.1, 34.3, 33.0, 32.8, 32.5, 32.2, 31.9, 31.2, 29.7, 26.4, 25.9, 25.5, 23.7,
23.2, 22.7, 22.0, 21.2, 20.6, 16.6, 15.9; IR (KBr) ν 2954, 2870, 1702,
1605, 1493, 1406, 1227, 1099, 994, 890, 744 cm−1; [α]D23 = +390.5 (c
0.82, CH3Cl); HRMS (ESI) m/z calcd for C44H63N4O4 [M + H]+
711.4844, found 711.4850.
1
(EtOAc/petroleum ether, 1/4); H NMR (400 MHz, CDCl3) δ 7.22
(d, J = 9.1 Hz, 1.5H), 7.13 (br s, 2.5H), 6.77 (d, J = 7.2 Hz, 2H), 6.63
(d, J = 6.7 Hz, 2H), 5.22 (br s, 1H), 4.85 (d, J = 6.3 Hz, 1H), 4.61 (br
s, 2H), 4.47 (d, J = 9.9 Hz, 2H), 3.71 (d, J = 7.6 Hz, 1H), 3.55 (br s,
1H), 2.86 (br s, 2H), 2.70−2.48 (m, 2H), 2.28−1.85 (m, 4H), 1.78−
1.34 (m, 9H), 0.97−0.45 (m, 24 H); 13C NMR (100 MHz, CDCl3) δ
154.7, 154.6, 153.6, 150.7, 150.6, 150.3, 150.1, 129.3, 129.2, 129.1,
129.0, 128.6, 128.4, 128.3, 125.5, 124.9, 124.8, 124.4, 119.2, 118.9,
118.5, 118.1, 109.7, 109.6, 109.5, 79.3, 78.8, 78.1, 77.9, 75.3, 75.2, 75.1,
61.84, 61.77, 61.1, 60.8, 47.34, 47.26, 47.2, 45.2, 41.7, 41.6, 34.3, 31.8,
31.7, 31.4, 26.3, 26.2, 23.6, 22.0, 20.8, 20.72, 20.69, 16.5, 16.4; IR
(KBr) ν3415, 2955, 2927, 1691, 1608, 1469, 1412, 1202, 1109, 741
(+)-Folicanthine (2). To a stirred solution of product 15 (13 mg,
0.02 mmol) in 2 mL of toluene was added Red-Al (65% in toluene, 57
uL, 0.18 mmol) dropwise at room temperature. Then the reaction
mixture was heated at reflux and stirred for 1 h. After being allowed to
cool to room temperature, the reaction mixture was quenched by the
slow addition of MeOH/CH2Cl2 (1/20) saturated with ammonia. The
resulting mixture was concentrated under reduced pressure, and the
residue was subjected to flash column chromatography on silica gel
(MeOH/CH2Cl2 saturated with ammonia, 1/60) to afford 6 mg
(88%) of (+)-folicanthine (2) as a colorless solid: Rf = 0.3 (MeOH/
23
cm−1; [α]D = +420.0 (c 1.05, CHCl3); HRMS (ESI) m/z calcd for
C42H59N4O4 [M + H]+ 683.4531, found 683.4534. Dimeric product
1
13b: Rf = 0.5 (EtOAc/petroleum ether, 1/4); H NMR (400 MHz,
1
CH2Cl2, 1/9); H NMR (400 MHz, CDCl3, 50 °C) δ 6.97 (t, J = 7.8
CDCl3) δ 7.22−7.07 (m, 4H), 6.85−6.72 (m, 2H), 6.62 (m, 2H), 5.26
(s, 1.2H), 5.26−5.10 (br s, 0.8H), 5.09−4.81 (m, 1.5H), 4.67−4.46
(m, 2.5H), 3.76−3.61 (m, 0.8H), 3.53 (t, J = 9.2 Hz, 1.2H), 2.94−2.80
(m, 2H), 2.50−2.70 (m, 2H), 2.18−1.99 (m, 1H), 1.99−1.80 (m, 5H),
1.74−1.52 (m, 4H), 1.44 (br s, 3.5H), 1.35−1.21 (m, 1.5H), 1.12−
0.73 (m, 24H); 13C NMR (100 MHz, CDCl3) δ 154.7, 154.6, 153.9,
153.8, 150.6, 150.5, 150.2, 150.1, 129.3, 129.1, 129.0 128.6, 128.5,
128.4, 125.7, 125.3, 125.1, 119.1, 118.8, 118.4, 118.1, 109.7, 109.6,
79.4, 79.0, 78.5, 78.4, 75.1, 74.9, 62.0, 61.1, 60.8, 47.4, 47.3, 47.2, 45.5,
45.3, 45.2, 41.6, 41.5, 41.4, 34.2, 31.9, 31.6, 31.39, 31.35, 29.6, 29.3,
26.72, 26.65, 26.2, 26.1, 23.3, 23.2, 22.7, 22.0, 21.0, 20.9, 16.4, 16.2,
Hz, 2H), 6.93 (d, J = 7.3 Hz, 2H), 6.50 (t, J = 7.4 Hz, 2H), 6.26 (d, J =
7.8 Hz, 2H), 4.35 (s, 2H), 2.99 (s, 6H), 2.63−2.61 (m, 2H), 2.50−2.33
(m, 10H), 2.02−1.90 (m, 2H); 13C NMR (100 MHz, CDCl3, 50 °C) δ
153.0, 132.9, 128.1, 123.7, 116.7, 105.8, 92.1, 62.8, 52.7, 38.0, 35.29,
35.26; IR (KBr) ν 3045, 2926, 1602, 1491, 1346, 1257, 1158, 1019,
23
919, 739 cm−1; [α]D = +213.1 (c 0.15, MeOH); HRMS (ESI) m/z
calcd for C24H31N4 [M + H]+ 375.2543, found 375.2539.
Dimethyl (3aR,3′aR,8aR,8′aR)-2,2′,3,3′,8,8a,8′,8′a-Octahy-
dro-1H,1′H-[3a,3′a-bipyrrolo[2,3-b]indole]1,1′-dicarboxylate
(16) and Dimethyl (4bR,5R,10bR,11S)5,6,11,12-tetrahydro-
5,10b:11,4b-bis(epiminoethano)dibenzo[c,h][2,6]-
naphthyridine-13,18-dicarboxylate (17). To a stirred solution of
13a (100 mg, 0.15 mmol) in 4 mL of EtOH was added KOH (2 M in
EtOH, 5.9 mL, 11.8 mmol) dropwise at room temperature. Then the
reaction mixture was heated to 155 °C in a sealed tube and stirred for
48 h. After being allowed to cool to room temperature, the reaction
mixture was quenched with saturated NH4Cl and extracted with
CHCl3 (5 × 10 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude product was directly used in the next step without further
purification.
To a stirred solution of the above crude product in 8 mL of CH2Cl2
were added Et3N (62 μL, 0.45 mmol) and ClCO2Me (25 μL, 0.33
mmol) dropwise at 0 °C successively. After being stirred at the same
temperature for 5 min before it was quenched with saturated aqueous
NH4Cl (10 mL) and extracted with CH2Cl2 (3 × 10 mL), the organic
phase was washed with brine (1 × 10 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure. The obtained residue was
subjected to flash column chromatography on silica gel (acetone/
CH2Cl2, 1/60) to afford 37 mg (58%, over two steps) of 17 as
colorless oil and 12 mg (19% over two steps) of 16 as a colorless oil.
Carbamate 17: Rf = 0.4 (EtOAc/petroleum ether, 2/3); 1H NMR (400
23
14.1; [α]D = +291.8 (c 0.60, CH3Cl); HRMS (ESI) m/z calcd for
C42H59N4O4 [M + H]+ 683.4531, found 683.4530.
N-Methyl-2-((R)-3-((3aS,8aR)1-methyl-2,3,8,8a-
tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)indolin-3-yl)ethan-1-
amine (14). To a stirred solution of 13a (73 mg, 0.11 mmol) in 11
mL of toluene was added Red-Al (65% in toluene, 0.33 mL, 1.06
mmol) dropwise at room temperature. The reaction mixture was
heated at 90 °C, stirred for 1 h, cooled to room temperature, and
quenched by the slow addition of MeOH/CH2Cl2 (1/19) saturated
with ammonia. The resulting mixture was concentrated under reduced
pressure, and the residue was purified by flash column chromatography
(MeOH/CH2Cl2 saturated with ammonia, 1/19) to afford 20 mg
1
(55%) of 14 as a colorless oil: Rf = 0.3 (MeOH/CH2Cl2, 1/9); H
NMR (400 MHz, CDCl3) δ 7.25−7.17 (t, J = 8.5, 2H), 7.06 (dd, J =
17.6, 7.8 Hz, 2H), 6.72 (q, J = 7.3 Hz, 2H), 6.60 (t, J = 7.6 Hz, 2H),
4.28 (s, 1H), 4.15 (s, 1H), 3.39 (d, J = 10.1 Hz, 1H), 3.26 (d, J = 10.1
Hz, 1H), 2.70−2.59 (m, 1H), 2.52−2.45 (m, 1H), 2.45−2.36 (m, 2H),
2.36−2.26 (m, 5H), 2.26−2.13 (m, 5H), 2.07−1.96 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 152.6, 151.1, 132.7, 130.4, 128.2, 125.7,
125.6, 118.5, 118.2, 109.7, 109.2, 85.4, 65.8, 53.8, 53.5, 53.1, 48.5, 37.6,
36.5, 35.4, 34.6; IR (KBr) ν 3419, 2925, 1631, 1604, 1484, 1463, 1249,
F
DOI: 10.1021/acs.joc.5b01907
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
MHz, CDCl3) δ 7.22−7.09 (m, 2H), 6.88 (t, J = 7.5 Hz, 2H), 6.64 (t, J
= 7.4 Hz, 2H), 6.29 (d, J = 7.9 Hz, 2H), 5.92 (2br s, 2H), 4.20−3.89
(m, 2H), 3.74 (s, 6H), 2.96 (d, J = 9.8 Hz, 2H), 2.48 (td, J = 13.2, 5.8
Hz, 2H), 1.42 (d, J = 9.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
156.8, 143.2, 127.4, 124.8, 122.3, 117.6, 112.6, 63.1, 52.8, 36.7, 35.9,
30.1, 29.7; IR (KBr) ν 3411, 2937, 2856, 1606, 1477, 1323, 1055, 745
126.5, 124.9, 124.4, 116.4, 112.0, 71.0, 46.5, 42.5, 35.9, 31.6; IR (KBr)
23
ν 3420, 2924, 2852, 1604, 1495, 1311, 1039, 1023, 743 cm−1; [α]D
=
−599.9 (c 0.50, EtOH); HRMS (ESI) m/z calcd for C22H27N4 [M +
H]+ 347.2230, found 347.2229.
ASSOCIATED CONTENT
23
cm−1; [α]D = −589.7 (c 0.81, CH3Cl); HRMS (ESI) m/z calcd for
■
C24H27N4O4 [M + H]+ 435.2027, found 435.2030. Carbamate 16: Rf =
S
* Supporting Information
1
0.3 (EtOAc/petroleum ether, 2/3); H NMR (400 MHz, CDCl3) δ
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01907.
7.23−7.08 (m, 4H), 6.86−6.74 (m, 2H), 6.67 (t, J = 8.6 Hz, 2H),
5.12−4.86 (m, 2H), 3.69−3.62 (m, 7H), 3.55 (t, J = 9.1 Hz, 1H), 2.88
(td, J = 10.7, 6.0 Hz, 2H), 2.66−2.52 (m, 2H), 2.17−1.97 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 155.2, 154.3, 150.6, 150.2, 129.3,
129.2, 128.3, 128.1, 125.3, 118.9, 118.8, 118.5, 109.93, 109.87, 79.2,
79.0, 78.4, 61.7, 60.8, 60.7, 52.5, 52.3, 45.5, 45.3, 31.6, 31.5, 31.3; IR
(KBr) ν 3358, 2951, 1691, 1605, 1451, 1383, 1244, 1072, 901, 744
1H and 13C NMR spectra of all new compounds
described in the Experimental Section (PDF)
AUTHOR INFORMATION
■
23
cm−1; [α]D = +414.1 (c 0.41, CH3Cl); HRMS (ESI) m/z calcd for
Corresponding Authors
C24H27N4O4 [M + H]+ 435.2027, found 435.2023.
*E-mail: xiachengfeng@mail.kib.ac.cn.
*E-mail: zhanghb@ynu.edu.cn.
Notes
(+)-Chimonanthine (1). To a stirred solution of 16 (38 mg, 0.09
mmol) in 9 mL of toluene was added Red-Al (65% in toluene, 0.27
mL, 0.88 mmol) dropwise at room temperature. Then the reaction
mixture was heated at reflux and stirred for 1 h. After being allowed to
cool to room temperature, the reaction mixture was quenched by the
slow addition of MeOH/CH2Cl2 (1/20) saturated with ammonia. The
resulting mixture was concentrated under reduced pressure, and the
residue was subjected to flash column chromatography on silica gel
(MeOH/CH2Cl2 saturated with ammonia, 1/20) to afford 25 mg
(83%) of (+)-chimonanthine (1) as a colorless solid: Rf = 0.2
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21272242 and 21572236),
Yunnan High-End Technology Professionals Introduction
Program (2010CI117), and National Basic Research Program
of China (2011CB915500).
1
(MeOH/CH2Cl2, 1/9); H NMR (400 MHz, CDCl3, 50 °C) δ 7.18
(d, J = 7.4 Hz, 2H), 6.98 (t, J = 7.5 Hz, 2H), 6.65 (t, J = 7.4 Hz, 2H),
6.53 (d, J = 7.8 Hz, 2H), 4.41 (s, 2H), 4.24 (s, 2H), 2.61−2.51 (m,
6H), 2.32 (s, 6H), 2.05 (dd, J = 10.8, 4.8 Hz, 2H); 13C NMR (100
MHz, CDCl3, 50 °C) δ 150.8, 133.4, 128.1, 124.4, 118.6, 109.2, 85.3,
63.6, 52.7, 37.1, 35.7; IR (KBr) ν 3424, 2930, 1605, 1484, 1465, 1354,
1317, 1251, 1158, 747 cm−1; [α]D23 = +228.1 (c 0.27, EtOH); HRMS
(ESI) m/z calcd for C22H27N4 [M + H]+ 347.2230, found 347.2228.
(−)-Calycanthine (3). Reduction of Nb-methoxycarbonyl. To a
stirred solution of 17 (24 mg, 0.06 mmol) in 6 mL of toluene was
added Red-Al (65% in toluene, 0.17 mL, 0.55 mmol) dropwise at
room temperature. Then the reaction mixture was heated at 90 °C and
stirred for 1 h. After being allowed to cool to room temperature, the
reaction mixture was quenched by the slow addition of MeOH/
CH2Cl2 (1/20) saturated with ammonia. The resulting mixture was
concentrated under reduced pressure,, and the residue was purified by
flash column chromatography (MeOH/CH2Cl2 saturated with
ammonia, 1/60) to afford 16 mg (84%) of (−)-calycanthine (3).
Direct N-Methylation. To a stirred solution of 13a (100 mg, 0.15
mmol) in 4 mL of EtOH was added KOH (2 M in EtOH, 5.9 mL, 11.8
mmol) dropwise at room temperature. Then the reaction mixture was
heated to 155 °C in a sealed tube and stirred for 48 h. After being
allowed to cool to room temperature, the reaction mixture was
quenched with saturated NH4Cl and extracted with CHCl3 (5 × 10
mL). The combined organic layers were dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude product was directly
used in the next step without further purification.
To a stirred solution of above crude product in 6 mL of CH3CN/
CH2Cl2 (2/1) were added K2CO3 (81 mg, 0.59 mmol) and MeI (55
μL, 0.91 mmol) at 0 °C succcessively. After being stirred at room
temperature for 4 h, the reaction mixture was quenched with saturated
aqueous NH4Cl (10 mL) and extracted with CH2Cl2 (5 × 10 mL),
and the organic phase was dried (Na2SO4), filtered, and concentrated
under reduced pressure. The obtained residue was subjected to flash
column chromatography on silica gel (MeOH/CH2Cl2 saturated with
ammonia, 1/60) to afford 27 mg (54%, over two steps) of
(−)-calycanthine (3) as a colorless solid: Rf = 0.5 (MeOH/CH2Cl2,
1/15); 1H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 7.7 Hz, 2H), 6.81
(t, J = 7.5 Hz, 2H), 6.54 (t, J = 7.4 Hz, 2H), 6.27 (d, J = 7.9 Hz, 2H),
4.58 (br s, 2H), 4.32 (s, 2H), 3.13 (td, J = 13.2, 5.5 Hz, 2H), 2.63 (dd,
J = 11.3, 5.0 Hz, 2H), 2.42 (s, 6H), 2.26 (td, J = 12.9, 4.0 Hz, 2H),
1.29 (dd, J = 13.4, 3.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 145.2,
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J. Org. Chem. XXXX, XXX, XXX−XXX