Asymmetric Total Synthesis of (+)-Winchinine B

Article abstract of DOI:10.1021/acs.joc.9b02462

The first asymmetric total synthesis of aspidosperma alkaloid (+)-winchinine B was achieved in 12 steps from commercially available materials. A new synthetic strategy which features an efficient aza-Michael addition, a ruthenium-catalyzed transfer dehydrogenation, and an intramolecular palladium-catalyzed oxidative coupling was adopted to install the ABC tricycle system. A one-pot process involving carbonyl reduction/iminium formation/intramolecular conjugate addition developed by our group was utilized to construct the D ring moiety.

Full text of DOI:10.1021/acs.joc.9b02462

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Note
Asymmetric Total Synthesis of (+)-Winchinine B
Zaimin Liu, Xiaolin Ju, Shiqiang Ma, Chenglong Du, Weiwei
Zhang, Huilin Li, Xiaolei Wang, Xingang Xie, and Xuegong She
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Oct 2019
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Asymmetric Total Synthesis of (+)-Winchinine B
Zaimin Liu, Xiaolin Ju, Shiqiang Ma, Chenglong Du, Weiwei Zhang, Huilin Li, Xiaolei Wang, Xingang
Xie and Xuegong She*
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State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, Peo-
ple’s Republic of China.
Supporting Information Placeholder
ABSTRACT: The first asymmetric total synthesis of aspidosperma alkaloid (+)-winchinine B was achieved in 12 steps from com-
mercially available materials. A new synthetic strategy which features an efficient aza-Michael addition, a ruthenium-catalyzed
transfer dehydrogenation and an intramolecular palladium-catalyzed oxidative coupling was adopted to install the ABC tricycle
system. And a one-pot process involving carbonyl reduction/iminium formation/intramolecular conjugate addition developed by
our group was utilized to construct the D ring moiety.
The aspidosperma alkaloids are a class of structurally
complex compounds isolated from various biological natural
sources. Currently, more than 250 members in the
aspidosperma family have been discovered, and many of them
exhibit significant biological activities.1 Remarkably, bisindole
alkaloids vinblastine (1f) and vincristine (1g) have already
been used for chemotherapy medication to treat various types
of cancers.2 Other members including vincadifformine (1c,
cytotoxic effect against KB and jurkat cells),3 jerantinine E (1d,
cytotoxicity against KB (VJ300) cells, IC50 = 0.78 ug/mL and
and tabersonine (1e) (Figure 1). Recently, a new member of
this family, (+)-winchinine B (1b) containing a rare cyano
group was isolated from the twigs and leaves of Winchia
calophylla by Ye and co-workers.7
Due to their intriguing structures and biological profiles, as-
pidosperma alkaloids have long been attractive targets for
synthetic chemists. Early in 1963, Stork and Dolfini have
acomplished the syntheses of aspidospermidine (1a) and que-
brachamine.8 Following that, a variety of other members in-
cluding aspidospermidine (1a)9, vincadifformine (1d)10 and
tabersonine (1e)11 have been finished. Among the established
syntheses, the main strategies to access the key structure are
Fischer indolization of a tricyclic ketone with phenyl-
4,
5
A549 lung cancer cell line, IC50 = 0.4 ug/mL)
and ta-
bersonine (1e, cytotoxicity against SK-BR-3 human cancer
cell lines stronger than cisplatin)6 were known to be pharma-
cologically important alkaloids. The typical structure of
aspidosperma alkaloids is the ABCDE pentacyclic framework
embeded with two nitrogen atoms like aspidospermidine (1a),
vincadifformine (1c), jerantinine E (1d)
Scheme 1. Methods for the Preparation of the Key β-
Enaminone Precursor
Figure 1. Structures of the representative aspidosperma
alkaloids
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Scheme 2. Retrosynthetic Analysis of (+)-Winchinine B Scheme 3. Synthesis of the Key β-enaminone Intermediate
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catalyzed dehydrogenation and an intramolecular palladium-
catalyzed oxidative coupling.
hydrazine8, rearrangement of an indoloquinolizidine12, intra-
molecular Diels−Alder reaction of indole derivatives13 and
dearomatization of indoles to construct the E ring14.
As shown in Scheme 2, we envisioned that (+)-winchinine
B
(1b) can be obtained from its precursor (+)-1,2-
dehydroaspidospermidine (2). Then, (+)-1,2-
dehydroaspidospermidine (2) could be derived from alcohol 3
via an intramolecular alkylation, which could arise from
lactam 4 through a N-alkylation reaction. In turn, the lactam 4
might be obtained from ketoamide 5 through our strategic one-
pot process involving carbonyl reduction/ iminium
formation/intramolecular conjugate addition. As for
preparation of the ABC tricycle skeleton 5, it could be
synthesized from β-enaminone 6 via an intramolecular
palladium-catalyzed oxidative coupling, while 6 could be
synthesized through an efficient aza-Michael addition and an
oxidation. The chiral enone 7 would arise from an asymmetric
Michael addition of 2-ethylcyclohexanone 8 with acrylonitrile.
Owing to their common structural features, constructing of
the common ABC tricycle framework via a Heck-type
coupling might be a powerful synthetic strategy. Thus, devel-
opment of an efficient strategy to approach the key β-
enaminone precursor still invites great interest, and some ele-
gant syntheses had been reported (Scheme 1). In 1994,
Desmaële and d’Angelo had reported the synthesis of (+)-
aspidospermidine using condensation of 1,3-diketone with
aniline.15 In 2013, Qiu had accomplished the synthesis of (-)-
aspidophytine through the same condensation method.16
Recently, Magauer had developed
a
one-pot β-C−H
bromination of enones and a Buchwald-Hartwig amination
approaching ABC ring system of jerantinine E.17 Herein, we
report the first asymmetric total synthesis of (+)-winchinine B
utilizing a highly efficient aza- Michael addition, a ruthenium-
Our synthesis commenced with preparation of ketone 10
and installing the quaternary carbon stereocenter using asym-
metric Michael addition (Scheme 3). According to the litera-
ture, Pfau and d’Angelo had developed an asymmetric
Table 1. Conditions Screened for the Oxidation of 11
Entrya
Oxidative
Solvent
DCM
DCM
DCM
PhMe
DCM
PhMe
DMSO
DMSO
AcOH
PhMe
PhMe
PhMe
T(oC)
-78 to rt
rt
Time(h)
4
Yield(%)b
N.R.
1
2
DMSO /(COCl)2/Et3N
DMP
12
12
12
12
12
12
2
N.R.
3
PCC
rt
N.R.
4
DDQ
reflux
reflux
reflux
120
N.R.
5
PhIO
N.R.
6
PhIO
N.R.
7
I2
IBX
N.R.
8
80
Decomposed
Decomposed
30, (26c)
20
9
Pd(TFA)2/ DMSO/O2
12, 13a
rt
5
10
11
12
110
36
36
36
110
12, 13b
12, 13c
110
22
[a] All reactions were performed in freshly distilled solvent. [b] Isolated yields. [c] Carried on 500 mg scale.
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chiral enamine intermediate
Michael addition, using
a
through the method developed by Glorius,23d treatment of
6with a mixture of Pd(OAc)2/Cu(OAc)2/K2CO3 in DMF at 140
oC afforded the desired indole intermediate 14 in 53% yield.
Exposure of nitrile 14 to anhydrous formic acid smoothly
generated corresponding amide, which was easily transformed
into its N-benzyl derivative 5 with BnBr in 80% yield. Then
our previously developed method was performed24: when
amide 5 was treated with LiAlH4 at -20 °C, the carbonyl group
could be selectively reduced to alcohol. Then in presence of
aqueous hydrochloric acid, iminium ions could be formed in
situ, which was trapped intramolecularly by the amide,
affording the desired lactam 4 as a single diastereoisomer in
73% yield (90% brsm).
derivative obtain the corresponding ketoester in 86% ee.15 Zu
had reported the similar asymmetric Michael addition using 2-
ethylcyclopentanone to afford the desired addition product in
90% ee.18 Accordingly, treatment of 2-ethylcyclohexanone 8
with (R)-1-(1-naphthyl)ethylamine 9 in toluene in the presence
of p-TSA·H2O at reflux temperature generated thermodynami-
cally more stable enamine, followed by reaction with
acrylonitrile at rt to furnish ketone 10 in 72% yield and 95%
ee. Subsequently, 10 was oxidized to enone 7 by IBX in
DMSO at 85 oC in 70% yield.19
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With enone 7 in hand, we set our sights on accessing the
key β-enaminone intermediate. Unfortunately, our initial at-
tempts to use various bases, such as K2CO3, Cs2CO3, Et3N,
DBU, NaH and t-BuOK to promote the aza-Michael addition
failed to give desired products under typical conditions. In
addition, several Bronsted and Lewis acid such as HOAc,
TsOH·H2O and BF3.Et2O, was also proved to be ineffective.
Having achieved
4 efficiently, we next focused on
accomplishing the total synthesis of (+)-winchinine B.
Reduction of lactam 4 with LiAlH4 afforded the corresponding
amine. Then, removement of Bn protection group with
Na/NH3(liq) at -78 °C successfully gave 15 in 93% yield over
two steps.25 Alkylation with excess amount of 2-bromoethanol
in the presence of K2CO3 afforded the desired amino alcohol 3
in 83% yield. Subsequently, treatment of the amino alcohol
with t-BuOK and TsCl in THF resulted in (+)-1,2-
dehydroaspidospermidine (2) in 51% yield.9a, 9b In the end, a
cyanation reaction was taken by treating the imine 2 with a
cyanide reagent.26 We found that solvent effect was critical to
the reaction outcome. Initially, when aprotic solvent like THF
or DCM was used, no desired product was detected. When it
was changed into protic solvent MeOH, the desired cyanation
product (+)-winchinine B (1b) was gratifyingly obtained albeit
the yield was only 46% yield. The hydrogen bond might
activate the imine moiety of 2, which can further accelerate
addition of cyano group. Then, we screened other protic
solvents including EtOH, i-PrOH and t-BuOH to realize a
better result. Finally, EtOH was found to be the optimal
solvent with 64% yield (82% brsm). Up to this stage, we have
successfully achieved the first asymmetric total synthesis of
(+)-winchinine B. All the physical data of the synthetic sam-
ples are identical with those reported in literature.
o
To our delight, when heated with aniline at 70 C in a sealed
vessel, enone 7 was smoothly converted into amine 11 in
excellent yield as an 1:1 diastereoisomeric mixture.20
Subsequent oxidation of the aromatic amine 11 was proved to
be extremely difficult (Table 1). Commonly employed
reagents such as DMSO/(COCl)2/Et3N, DMP, PCC, DDQ,
PhIO and I2 were ineffective with only starting material
recovered (entries 1-7), while IBX oxidation and
Pd(TFA)2/DMSO/O221 resulted in decomposition of 11 (entries
8-9). Finally, inspired by Bäckvall’s work, a ruthenium-
catalyzed transfer dehydrogenation was carried out.22 11 was
subjected to the Ru catalysis 13a and benzoquinone 12 in
o
toluene at 110 C, giving the desired -enaminone 6 success-
fully (entry 10). The Ru catalysis 13b and 13c were also
screened, but they didn’t provide better results than 13a did
(entries 11-12).
With a reliable supply of 6 being secured, formation of the
ABC tricycle framework was executed. At this stage, C-H
bond activation has been considered as an efficient pathway
for the construction of the indole moiety (Scheme 4). 23 Thus,
In summary, the first asymmetric total synthesis of aspido-
sperma alkaloids (+)-winchinine B was achieved in 12 steps
from commercially available 2-ethylcyclohexanone. The
synthetic route features several key transformations, including
a highly efficient aza-Michael addition, a ruthenium-catalyzed
dehydrogenation, an intramolecular palladium-catalyzed
oxidative coupling to approach the ABC tricycle framework
and a one-pot process involving carbonyl reduction/iminium
formation/intramolecular conjugate addition to construct the D
ring system. Study on syntheses of other indole alkaloids using
our developed strategy is in progress and will be reported in
due course.
Scheme 4. Completion of the Total Synthesis of (+)-
Winchinine B (1b)
EXPERIMENTAL SECTION
General information: All reactions sensitive to air or mois-
ture were carried out under argon atmosphere in dry and fresh-
ly distilled solvents under anhydrous conditions, unless other-
wise noted. An oil bath was used as the heating source for the
reactions that require heating. Column chromatography was
performed on silica gel (200–300 mesh). Optical rotations
were measured on a precision automated polarimeter. Infrared
spectra were recorded on a 670 FT-IR spectrometer. High-
resolution mass spectra (HRMS) were measured by the elec-
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Page 4 of 8
1
trospray ionization (ESI) technique on an Orbitrap Elite mass
ml/min, t1 = 10.7 min, t2 = 14.0 min). H NMR (300 MHz,
CDCl3) δ 7.37 – 7.29 (m, 5H), 5.10 (s, 2H), 2.41 – 2.09 (m,
4H), 2.00 – 1.40 (m, 10H), 0.76 (t, J = 7.5 Hz, 3H). 13C{1H}
NMR (75 MHz, CDCl3) δ 214.70, 173.53, 135.88, 128.46,
128.13, 128.11, 66.19, 50.91, 39.01, 35.67, 28.84, 28.81,
27.00, 26.95, 20.60, 7.61. IR (neat) vmax 2935.2, 2865.5,
1736.3, 1702.1, 1455.1, 1164.6, 751.8 cm-1. HRMS (ESIMS):
1
analyzer. H NMR and 13C{1H} NMR spectra were recorded
1
2
3
4
5
6
7
on 400 MHz and 300 MHz spectrometers. Chemical shifts are
reported as δ values relative to internal chloroform (δ 7.26 for
1H NMR and 77.0 for 13C{1H} NMR). Melting points were
measured on a melting point apparatus and are uncorrected.
Analysis with HPLC was performed using Waters 1100 series
chromatograph with JASCO PU-980 pump and Agilent 1100
Series detection system.
calcd for C18H25O3 [M+H]+ 289.1804, found 289.1798. []D
22.6
+11.3 (CHCl3, c=1.1).
8
9
(S)-3-(1-ethyl-2-oxocyclohex-3-en-1-yl)propanenitrile (7).
To a stirred solution of 10 (3.40 g, 18.97 mmol) in DMSO
(150 ml) was added IBX (3 eq., 15.9 g, 59.90 mmol). The
mixture was stirred at 85 °C and additional IBX (4 eq., 21.2 g,
75.88 mmol) was added in portions. After stirring for 24 h,
aqueous saturated sodium bicarbonate (200 ml) and diethyl
ether (300 ml) were added to the reaction mixture at room
temperature, which was filtered through a Celite pad. The
organic layer was separated and the aqueous layer was ex-
tracted with diethyl ether. The combined organic phases were
washed with brine, dried over anhydrous sodium sulfate, fil-
tered and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography
(eluted with petroleum/EtOAc = 50:1 to 10:1) to give 7 (2.32 g,
70%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.85 (dt, J
= 9.9, 3.9 Hz, 1H), 5.86 (dt, J = 9.9, 1.9 Hz, 1H), 2.46 – 2.18
(m, 4H), 1.99 (ddd, J = 13.9, 9.4, 6.7 Hz, 1H), 1.87 (t, J = 6.0
Hz, 2H), 1.75 (ddd, J = 14.0, 9.7, 6.3 Hz, 1H), 1.62 – 1.43 (m,
2H), 0.80 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 201.9, 148.8, 128.4, 120.0, 46.9, 29.9, 29.5, 26.2,
22.6, 12.1, 7.8. IR (neat) vmax 3487.3, 2969.8, 2936.1, 2881.3,
2246.9, 1667.5, 1447.1, 1427.8 cm-1. HRMS (ESIMS): calcd
Experimental Procedures
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(S)-3-(1-ethyl-2-oxocyclohexyl)propanenitrile (10). To a
stirred solution of 8 (3.80 g, 30.11 mmol) in toluene (120 mL)
were added (R)-(+)-1-(1-Naphthyl)ethylamine 9 (1.1 eq., 5.42
mL, 33.12 mmol) and p-TsOH.H2O (0.01 eq., 57 mg, 0.30
mmol) at rt. After stirring under reflux for overnight with aze-
otropic removal of water, the reaction mixture was concentrat-
ed under reduced pressure to give a crude enamine as yellow
oil, which was then treated with acrylonitrile (1.8 eq., 3.60 mL,
54 mmol) in the presence of hydroquinone (10 mg). The mix-
ture was stirred at rt for 7 days. Aqueous acetic acid (20%, 40
mL) and THF (60 mL) were added to the reaction mixture, and
the reaction was stirred for 5 h at rt. The solvents were re-
moved under reduced pressure to afford the crude residue,
which was treated with 1 N aqueous HCl (40 mL). The mix-
ture was saturated with NaCl and extracted with EtOAc three
times, and the combined organic phases were washed with
water and brine, dried over anhydrous sodium sulfate and con-
centrated under reduced pressure. The crude product was puri-
fied by silica gel column chromatography (eluted with petro-
leum/EtOAc = 100:1 to 20:1) to give 10 (3.90 g, 72%, 95%
24.5
for C11H16NO [M+H]+ 178.1232, found 178.1226. []D
1
ee27) as yellow oil. H NMR (400 MHz, CDCl3) δ 2.47 – 2.16
+32.0 (CHCl3, c=1.0).
(m, 4H), 2.01 – 1.89 (m, 2H), 1.82 – 1.45 (m, 8H), 0.76 (t, J =
7.5 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 213.9, 120.1,
51.0, 38.9, 35.2, 29.9, 27.1, 26.9, 20.5, 12.1, 7.5. IR (neat) vmax
3383.7, 2939.6, 2870.1, 2246.4, 1701.8, 1460.8, 1448.5,
1426.3 cm-1. HRMS (ESIMS): calcd for C11H18NO [M+H]+
180.1388, found 180.1383. []D24.2 +67.0 (CHCl3, c=1.0).
3-((1S)-1-ethyl-2-oxo-4-(phenylamino)cyclohexyl)-
propanenitrile (11). A mixture of 7 (590 mg, 3.329 mmol)
and aniline (1.5 eq., 0.46 mL, 4.993 mmol) in a sealed vessel
was heated at 70 oC for 48 h. After consumption of the starting
material, the resulting mixture was cooled to rt. The crude
product was purified by silica gel column chromatography
(eluted with petroleum/EtOAc = 10:1 to 5:1) to give 11 (665
mg, 74%, d.r. 1:1) as a brown oil. 1H NMR (400 MHz, CDCl3)
δ 7.18 (t, J = 7.8 Hz, 4H), 6.73 (td, J = 7.3, 0.9 Hz, 2H), 6.63 –
6.57 (m, 4H), 3.88 (dd, J = 9.1, 4.9 Hz, 1H), 3.60 (ddd, J =
10.8, 9.6, 4.1 Hz, 1H), 2.89 – 2.73 (m, 2H), 2.43 – 1.71 (m,
20H), 1.69 – 1.47 (m, 4H), 0.84 – 0.76 (m, 6H). 13C{1H} NMR
(100 MHz, CDCl3) δ 212.1, 211.1, 146.0, 145.8, 129.4, 129.3,
120.1, 119.9, 118.2, 118.0, 113.4, 113.4, 52.5, 51.7, 50.4, 50.3,
45.5, 44.8, 31.1, 30.2, 29.6, 29.3, 27.4, 27.1, 26.8, 25.3, 12.1,
12.0, 7.8, 7.5. IR (neat) vmax 3379.9, 2967.1, 2939.2, 2878.9,
2246.5, 1701.2, 1665.5, 1602.6, 1509.0, 1449.4, 751.9, 695.2
cm-1. HRMS (ESIMS): calcd for C17H23N2O [M+H]+ 271.1810,
found 271.1805.
(S)-benzyl 3-(1-ethyl-2-oxocyclohexyl)propanoate (S-1).
To the solution of 10 (85 mg, 0.474mmol) in EtOH/H2O (2
mL) was added NaOH (1.0 eq., 19 mg, 0.474 mmol) at room
temperature. After stirring at reflux for 17 h, the reaction was
cooled to rt. After removal of EtOH under reduce pressure, the
aqueous mixture was extracted with Et2O. Then the aqueous
layer was adjusted by 6 N HCl to attain the target of pH (1–2)
and the mixture was extracted with DCM three times. The
combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure to
afford a crude carboxylic acid as a colorless oil. The crude
carboxylic acid was directly subjected to the next reaction
without further purification. The solution of the crude carbox-
ylic acid (36 mg) in DMF (1.5 mL) was added K2CO3 (126 mg)
and BnBr (26 μL) at room temperature. After stirring at the
same temperature for 5 h, the reaction was poured into brine
and the mixture was extracted with EtOAc three times. The
combined organic extracts were washed with water and brine,
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography (eluted with petroleum/EtOAc = 10:1 to 5:1)
to give S-1 (50 mg, 96%, 95% ee) as colorless oil. The enanti-
omeric excess was determined by HPLC (DAICEL-
CHIRALPAK-AY-H, hexane-EtOH = 90/10, flow rate = 1
(S)-3-(1-ethyl-2-oxo-4-(phenylamino)cyclohex-3-en-1-
yl)propanenitrile (6). Ruthenium complex 13a28 (5 mol%, 2
mg, 0.004 mmol) and dry quinone 12 (1.2 eq., 15 mg, 0.089
mmol) were dissolved under an argon atmosphere in toluene
(2 mL) in a round bottomed flask equipped with a condenser
and a stirring bar. Amine 11 (20 mg, 0.074 mmol) was added
o
and the reaction mixture was heated to 110 C for 36 h. The
resulting mixture was cooled to rt, and poured into saturated
aqueous Na2S2O3. After stiring for 5 h, the mixture was ex-
tracted with EtOAc three times. The combined organic ex-
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tracts were washed with water and brine then dried over
Na2SO4. The solution was concentrated to dryness in vacuo
and was purified by column chromatography (eluted with pe-
troleum/acetone = 10:1 to 5:1) to give 6 (6 mg, 30 %) as a
yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.7 Hz,
2H), 7.17 – 7.10 (m, 3H), 6.81 (br s, 1H), 5.43 (s, 1H), 2.68 –
2.41 (m, 2H), 2.37 – 2.24 (m, 2H), 2.00 (ddd, J = 17.8, 12.0,
7.9 Hz, 1H), 1.94 – 1.84 (m, 2H), 1.84 – 1.73 (m, 1H), 1.70 –
1.47 (m, 2H), 0.85 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 200.1, 160.5, 137.9, 129.3, 125.6, 123.9, 120.5,
98.7, 45.2, 30.6, 29.1, 27.4, 25.7, 12.4, 8.1. IR (neat) vmax
3268.1, 2964.8, 2931.3, 2264.5, 1604.0, 1580.4, 1534.6,
gel column chromatography (eluted with DCM/MeOH =
100:1) to give 5 (659 mg, 80 % two steps) as a white solid. H
1
1
2
3
4
5
6
7
8
NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.4 Hz, 1H), 7.33 –
7.19 (m, 6H), 7.02 (d, J = 6.5 Hz, 2H), 6.02 (br s, 1H), 5.60
(br s, 1H), 5.27 (s, 2H), 2.98 – 2.81 (m, 2H), 2.37 – 2.18 (m,
2H), 2.16 – 2.07 (m, 3H), 1.88 (ddd, J = 13.7, 11.0, 5.7 Hz,
1H), 1.68 (dtd, J = 21.5, 14.1, 7.3 Hz, 2H), 0.90 (t, J = 7.5 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 197.9, 176.1, 150.3,
137.4, 135.8, 129.0, 127.9, 126.0, 125.3, 123.2, 122.6, 121.6,
112.0, 109.7, 47.6, 46.9, 31.2, 31.0, 29.8, 27.6, 19.1, 8.5. IR
(neat) vmax 3445.7, 3202.2, 3054.9, 2967.2, 2933.9, 1664.3,
1656.2, 1637.0, 1457.7, 736.0, 700.8 cm-1. HRMS (ESIMS):
calcd for C24H27N2O2 [M+H]+ 375.2067, found 375.2062.
[]D24.0 -10.0 (CHCl3, c=1.0); m.p. 66-68 °C.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1496.2, 1447.3, 757.8, 695.4 cm-1. HRMS (ESIMS): calcd for
24.4
C17H21N2O [M+H]+ 269.1654, found 269.1648. []D
(CHCl3, c=1.0); m.p. 137-140 °C.
+3.0
(4aS,11cR)-7-benzyl-4a-ethyl-1,3,4,4a,5,6,7,11c-
Performed on 500 mg scale: Ruthenium complex 13a (8 mol%,
93 mg, 0.187 mmol) and dry quinone 12 (1.5 eq., 588 mg,
3.500 mmol) were dissolved under an argon atmosphere in
toluene (20 mL) in a round bottomed flask equipped with a
condenser and a stirring bar. Amine 11 (630 mg, 2.333 mmol)
octahydro-2H-pyrido[3,2-c]carbazol-2-one (4). To a solu-
tion of the amide 5 (653 mg, 1.746 mmol) in anhydrous THF
(20 mL) at -20 °C was added LiAlH4 (265 mg, 6.984 mmol,
4.0 equiv) slowly over 3 min and the resulting mixture was
stirred at -20°C for 4 h. The reaction was quenched by water
and then adjusted by 2 N HCl to attain the target of pH (1–2).
After removal of THF under reduced pressure, the aqueous
layer was extracted with DCM three times. The combined
organic extracts were washed with saturated aqueous NaHCO3
and brine then dried over Na2SO4. The solution was concen-
trated to dryness in vacuo and was purified by column chro-
matography on silica gel (eluted with petroleum/acetone = 2:1)
to give pure lactam 4 (456 mg, 73% yield) as a white solid,
o
was added and the reaction mixture was heated to 110 C for
40 h. The resulting mixture was cooled to rt, and poured into
saturated aqueous Na2S2O3. After stiring for 5 h, the mixture
was extracted with EtOAc three times. The combined organic
extracts were washed with water and brine then dried over
Na2SO4. The solution was concentrated to dryness in vacuo
and was purified by column chromatography (eluted with pe-
troleum/acetone = 10:1 to 5:1) to give 6 (160 mg, 26 %) as a
yellow solid.
1
along with 119 mg recovered amide 5. H NMR (400 MHz,
CDCl3) δ 7.51 (dd, J = 5.6, 3.0 Hz, 1H), 7.31 – 7.21 (m, 4H),
7.17 – 7.10 (m, 2H), 6.95 (d, J = 7.0 Hz, 2H), 5.90 (s, 1H),
5.27 (s, 2H), 4.49 (s, 1H), 2.69 (ddd, J = 16.7, 6.0, 2.0 Hz, 1H),
2.59 (ddd, J = 16.8, 11.0, 5.6 Hz, 1H), 2.52 – 2.34 (m, 2H),
2.13 – 2.02 (m, 1H), 1.94 – 1.81 (m, 2H), 1.62 (dt, J = 13.4,
6.8 Hz, 1H), 1.54 (dt, J = 14.9, 7.5 Hz, 1H), 1.35 – 1.24 (m,
2H), 0.91 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 171.0, 137.3, 137.0, 135.7, 128.8, 127.4, 126.0,
125.9, 121.6, 119.8, 116.9, 109.6, 108.8, 53.6, 46.4, 34.1, 29.6,
27.9, 27.8, 24.8, 18.8, 8.0. IR (neat) vmax 3391.3, 3216.3,
3052.1, 2962.6, 2933.8, 2862.6, 1658.2, 1614.0, 1465.0,
(S)-3-(3-ethyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)propanenitrile (14). A mixture of compound 6 (1.33 g,
4.978 mmol), Pd(OAc)2 (10 mol%, 112 mg, 0.498 mmol),
.
Cu(OAc)2 H2O (3 eq., 2.98 g, 14.934 mmol), and K2CO3 (3 eq.,
2.06 g, 14.934 mmol) in DMF (30mL) was stirred for 2 h at
o
140 C under an atmosphere of argon. After cooling to room
temperature, the solution was filtered through a pad of Celite,
and the residue was washed with ethyl acetate. The solution
was washed with aqueous ammonia (10%), brine, dried over
MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatog-
raphy (eluted with DCM/EtOAc = 200:1) to give 14 (698 mg,
53%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.11 (br
s, 1H), 8.22 – 8.15 (m, 1H), 7.38 – 7.32 (m, 1H), 7.26 – 7.21
(m, 2H), 3.10 – 2.95 (m, 2H), 2.53 – 2.34 (m, 2H), 2.27 – 2.11
(m, 3H), 1.92 – 1.86 (m, 1H), 1.81 – 1.60 (m, 2H), 0.93 (t, J =
7.5 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 196.8, 149.5,
136.1, 125.1, 123.5, 122.6, 121.3, 120.4, 112.1, 111.1, 47.5,
31.2, 30.3, 27.3, 20.0, 12.6, 8.4. IR (neat) vmax 3265.9, 2966.4,
2935.8, 2247.9, 1627.1, 1614.0, 1470.4, 753.8, 737.4 cm-1.
1454.3, 737.6 cm-1. HRMS (ESIMS): calcd for C24H27N2O
24.0
[M+H]+ 359.2118, found 359.2114. []D
c=1.0); m.p. 119-121 °C.
-77.0 (CHCl3,
(4aR,11cR)-4a-ethyl-2,3,4,4a,5,6,7,11c-octahydro-1H-
pyrido[3,2-c]carbazole (15). To a solution of the lactam 4
(440 mg, 1.229 mmol) in THF (15 mL) was added LiAlH4
(280 mg, 7.374 mmol, 6.0 equiv) at 0 °C. After stirring at re-
flux temperature for 10 h, water (0.28 mL), 10% aqueous so-
dium hydroxide (0.56 mL) and water (0.84 mL) were sequen-
tially added. Then, the mixture was filtrated through a pad of
Celite, and the filtrate was evaporated under reduced pressure.
The resulting crude amine (419 mg) was immediately used for
the following step without further purification. Freshly cut Na
(280 mg) was added to liquid ammonia at -78 °C. Then a solu-
tion of crude 4 (419 mg) in THF (10 mL) was added to the
blue ammonia solution. After 30 min, the reaction was
quenched with solid NH4Cl and ammonia was allowed to
evaporate at 0 °C. After removal of the solvent in vacuo, the
resultant residue was taken up in water and the mixture was
extracted with CHCl3. The combined organic extracts were
washed with brine and dried over anhydrous Na2SO4. The
solution was concentrated to dryness in vacuo and was puri-
fied by flash column chromatography on silica gel (eluted with
HRMS (ESIMS): calcd for C17H19N2O [M+H]+ 267.1497,
22.9
found 267.1492. []D
157 °C.
+34.4 (CHCl3, c=1.0); m.p. 154-
(S)-3-(9-benzyl-3-ethyl-4-oxo-2,3,4,9-tetrahydro-1H-
carbazol-3-yl)propanamide (5). The nitrile 14 (588 mg,
2.211 mmol) was dissolved in anhydrous formic acid (20 mL)
and the resulting solution was stirred at room temperature for
20 h. After removal of the solvent in vacuo, the resultant resi-
due and excess amount of K2CO3 (5 eq., 1.52 g, 11.0 mmol)
was dissolved in acetone (20 mL) and added dropwise BnBr
o
(1.1 eq., 0.30 mL, 2.42 mmol) at 0 C. After refluxing for 8 h,
the reaction mixture was cooled to room temperature and con-
centrated in vacuo. The crude product was purified by silica
ACS Paragon Plus Environment

The Journal of Organic Chemistry
DCM/MeOH = 5:1) to give the product 15 (290 mg, 93% yield
Page 6 of 8
125.0, 120.9, 120.0, 79.0, 61.2, 54.5, 52.0, 36.4, 35.1, 33.1,
29.7, 27.1, 23.7, 22.0, 7.2. IR (neat) vmax 2936, 2776, 1577,
1454, 1323, 1249, 1193, 1123, 1013, 750 cm-1. HRMS
(ESIMS): calcd for C19H25N2 [M+H]+ 281.2012, found
281.2018. []D24.3 +146.0 (CHCl3, c=1.0).
over two steps) as a white solid. 1H NMR (400 MHz, CDCl3) δ
8.60 (s, 1H), 7.58 (dd, J = 5.6, 2.7 Hz, 1H), 7.19 (dd, J = 6.0,
2.6 Hz, 1H), 7.14 – 7.02 (m, 2H), 3.71 (s, 1H), 3.02 (d, J =
12.0 Hz, 1H), 2.75 (td, J = 11.9, 2.8 Hz, 1H), 2.52 (dd, J = 8.6,
3.8 Hz, 2H), 2.27 (dt, J = 17.8, 8.9 Hz, 1H), 1.81 (d, J = 13.3
Hz, 1H), 1.72 – 1.51 (m, 2H), 1.49 – 1.34 (m, 4H), 1.15 – 0.98
(m, 1H), 0.83 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 136.1, 134.6, 127.1, 120.7, 119.0, 117.4, 111.1,
110.6, 56.5, 46.0, 34.4, 34.0, 29.3, 23.9, 22.3, 19.8, 7.5. IR
(neat) vmax 3398, 3290, 3150, 3105, 3055, 2930, 2876, 2859,
2744, 1623, 1590, 1465, 1452, 1434, 1379, 1305, 1230, 1167,
1
2
3
4
5
6
7
8
(+)-Winchinine B (1b). To a solution of imine (+)-1,2-
dehydroaspidospermidine 2 (23 mg, 0.082 mmol) in EtOH (1
mL) was added TMSCN (5.0 eq., 0.05 mL, 0.411 mmol). The
mixture was allowed to stir 1.5 h at 30 °C before the solvent
was evaporated under reduced pressure. The residue was puri-
fied by column chromatography on silica gel (eluted with pe-
troleum/EtOAc 20:1 to 10:1) afforded (+)-winchinine B (1b)
(16 mg, 64% yield) as a white solid, along with 5 mg recov-
ered imine 2. The synthetic (+)-winchinine B (1b) matched the
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1114, 1012, 738 cm-1. HRMS (ESIMS): calcd for C17H23N2
24.1
[M+H]+ 255.1856, found 255.1857. []D
c=1.0); m.p. 171-173 °C.
-30.0 (CHCl3,
analytical data of natural sample.7 1H NMR (400 MHz, CDCl3)
δ 7.05 (m, 2H), 6.80 (dd, J = 7.4 Hz, 1H), 6.63 (d, J = 7.7 Hz,
1H), 3.93 (s, 1H), 3.26 (td, J = 9.0, 4.3 Hz, 1H), 3.04 (br d, J =
10.7 Hz, 1H), 2.67 (m, 1H), 2.36 (s, 1H), 2.29 (m, 1H),
2.24(m,1H), 1.97 (m, 2H), 1.77 (m, 2H), 1.62 (d, J = 13.6 Hz,
1H), 1.49 (m, 2H), 1.39 (dd, J = 14.4, 7.4 Hz, 1H), 1.13 (m,
1H), 1.08 (m, 1H), 0.92 (m, 1H), 0.64 (t, J = 7.5 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 146.5, 133.2, 128.2, 123.3,
122.2, 120.8, 111.0, 69.7, 64.8, 57.9, 53.4, 51.8, 36.7, 36.0,
34.3, 32.7, 29.9, 22.1, 21.6, 7.0. IR (neat) vmax 3332, 2935,
2788, 2374, 1687, 1545, 1510, 1466, 1377, 1330, 1181, 1141,
734 cm-1. HRMS (ESIMS): calcd for C20H26N3 [M+H]+
308.2121, found 308.2123. []D24.5 +35.0 (MeOH, c=1.0); m.p.
154-156 °C.
2-((4aR,11cR)-4a-ethyl-2,3,4,4a,5,6,7,11c-octahydro-1H-
pyrido[3,2-c]carbazol-1-yl)ethan-1-ol (3). To a solution of
15 (280 mg, 1.102 mmol) in absolute ethanol (10 mL) were
sequentially added anhydrous potassium carbonate(8 eq., 1.22
g, 8.819 mmol) and 2-bromoethanol (8 eq., 0.64 mL, 8.819
mmol) in a sealed-vessel. The resulting suspension was heated
to 100 °C for 6 h. The reaction mixture was cooled to room
temperature. After removal of EtOH, the residue was purified
by flash chromatography on silica gel (eluted with EtOAc with
2% Et3N) to afford the alkylated product 3 (270 mg, 83% yield)
1
as a yellow solid. H NMR (400 MHz, CDCl3) δ 8.59 (br s,
1H), 7.46 (d, J = 7.5 Hz, 1H), 7.29 (t, J = 10.5 Hz, 1H), 7.21 –
7.06 (m, 2H), 4.50 (s, 1H), 3.73 (ddd, J = 14.3, 7.1, 3.0 Hz,
1H), 3.63 (ddd, J = 14.4, 5.8, 2.9 Hz, 1H), 3.57 – 3.49 (m, 1H),
3.47 (s, 1H), 3.31 – 3.23 (m, 1H), 2.84 – 2.63 (m, 3H), 2.56 –
2.48 (m, 2H), 2.07 (ddd, J = 13.7, 10.4, 6.9 Hz, 1H), 1.99 –
1.88 (m, 1H), 1.65 (dt, J = 13.5, 6.7 Hz, 2H), 1.39 – 1.20 (m,
3H), 0.87 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 174.6, 136.2, 136.1, 128.1, 121.7, 120.1, 117.5,
111.0, 106.8, 63.6, 59.1, 48.1, 37.0, 29.7, 29.5, 28.0, 26.3,
20.0, 8.1. IR (neat) vmax 3397, 3217, 3185, 3109, 3058, 2937,
2877, 2794, 1620, 1585, 1461, 1377, 1331, 1308, 1265, 1233,
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Full spectroscopic data for all new compounds (PDF).
1169, 1141, 1120, 1041, 739 cm-1. HRMS (ESIMS): calcd for
AUTHOR INFORMATION
Corresponding Author
24.3
C19H27N2O [M+H]+ 299.2118, found 299.2117. []D
(CHCl3, c=1.0); m.p. 86-88 °C.
-3.0
(+)-1,2-dehydroaspidospermidine (2). To a solution of
primary alcohol 3 (74 mg, 0.248 mmol) in THF (12 mL) was
added dropwise a 1 M solution of t-BuOK in THF (3.34 eq.,
0.83 mL, 0.829 mmol) at 0 °C. After stirring for 10 min, TsCl
(1.48 eq., 70 mg, 0.367 mmol) was added and the reaction
mixture was allowed to warm to room temperature. After stir-
ring for 1 h, the reaction was diluted with Et2O and quenched
* E-mail:shexg@lzu.edu.cn. Fax: +86-931-8912582
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Science Foundation of
China (21732001, 21871118 and 21572088) and PCSIRT
(IRT_15R28).
o
with water at 0 C. Then the mixture was saturated with NaCl
and extracted with EtOAc three times. The combined organic
layers were dried over MgSO4, filtered and concentrated. The
crude product was purified by column chromatography on
silica gel (eluted with petroleum/EtOAc = 4:1 with 2% Et3N)
to afford (+)-1,2-dehydroaspidospermidine (2) as a pale yel-
low oil (35 mg, 51% yield), which matched the previously
reported analytical data.9a 1H NMR (400 MHz, CDCl3) δ 7.52
(d, J = 7.6 Hz, 1H), 7.35 – 7.26 (m, 2H), 7.17 (dd, J = 10.8,
4.0 Hz, 1H), 3.21 – 3.15 (m, 2H), 3.14 – 3.07 (m, 1H), 2.76
(ddd, J = 14.0, 10.4, 3.4 Hz, 1H), 2.59 (ddd, J = 11.5, 8.5, 5.7
Hz, 1H), 2.45 (td, J = 12.7, 3.2 Hz, 1H), 2.40 (s, 1H), 2.23 –
2.12 (m, 2H), 1.91 – 1.78 (m, 1H), 1.64 (dd, J = 12.4, 5.6 Hz,
1H), 1.61 – 1.52 (m, 2H), 1.51 – 1.44 (m, 1H), 1.00 (td, J =
13.5, 4.9 Hz, 1H), 0.71 – 0.56 (m, 2H), 0.49 (t, J = 7.3 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 192.3, 154.4, 147.1, 127.4,
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configuration of 10 was determined by comparing the optical rotation
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