The effect of carbonyl on the isomerization of a galanthan ring system and total synthesis of (±)-β-lycorane

Article abstract of DOI:10.1039/d0ob02398a

Lycorine-type alkaloids are privileged structures in drug development due to their attractive biological activities. In this paper, the carbonyl on the C ring was proved to have played a critical role in stereoselectivity during the synthesis process, and the galanthan skeleton with acis-B/C ring is more thermodynamically stable in its presence. Furthermore, the total synthesis of (±)-β-lycorane was successfully completed by employing the Michael addition reaction to construct the galanthan skeleton with atrans-B/C ring. This system might be applied to other structural types with similar stereochemistry setting.

Full text of DOI:10.1039/d0ob02398a

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PAPER
The effect of carbonyl on the isomerization of a
galanthan ring system and total synthesis of
( )-β-lycorane†
Cite this: Org. Biomol. Chem., 2021,
19, 2767
b
Leilei Liang,‡a Ji Li,‡a Baochun Shen,a Yili Zhang,a Jianping Liu,b Jingbo Chen
*
a
and Dandan Liu
*
Lycorine-type alkaloids are privileged structures in drug development due to their attractive biological
activities. In this paper, the carbonyl on the C ring was proved to have played a critical role in stereo-
selectivity during the synthesis process, and the galanthan skeleton with a cis-B/C ring is more thermo-
dynamically stable in its presence. Furthermore, the total synthesis of ( )-β-lycorane was successfully
completed by employing the Michael addition reaction to construct the galanthan skeleton with a trans-
B/C ring. This system might be applied to other structural types with similar stereochemistry setting.
Received 2nd December 2020,
Accepted 2nd March 2021
DOI: 10.1039/d0ob02398a
rsc.li/obc
such invaluable molecules. With the aim of developing
efficient and flexible synthesis strategies for bioactive natural
Introduction
Amaryllidaceae plants have a rich history as herbal remedies products and their analogues, our group has previously accom-
since ancient Greece. To date, over 300 different alkaloids have plished total synthesis of putative ( )-amarbellisine and
been isolated from the amaryllidaceae plants. These amarylli- ( )-γ-lycorane by a palladium-catalyzed carbonyl α-site aryla-
daceae alkaloids have attracted considerable attention due to tion reaction.8 Interestingly, the intramolecular arylation reac-
their biological activities such as anti-Alzheimer, anticholiner- tions have exhibited excellent stereoselectivities, and only the
gic, antifungal, antibacterial, and antitumor activities.1 Among products with the galanthan skeleton of the cis-B/C ring were
them, lycorine-type alkaloids, especially lycorine, show antitu- detected (Fig. 2A and B). Therefore, we recently have ques-
mor activity against human cancer cell lines and inhibit cell tioned whether the carbonyl on the C ring plays an important
growth and cell division.2 These alkaloids are isoquinoline role in the determination of stereoselectivity. In this paper, our
chemotypes characterized by a unique tetracyclic galanthan speculation was confirmed by the oxidation reaction of TBS-
skeleton (Fig. 1). Amarbellisine and γ-lycorane share the protected natural lycorine with
a trans-B/C ring, which
galanthan skeleton with cis-B/C ring galanthan, whereas lycor- afforded the oxidation product with a cis-B/C ring by isomeri-
ine, α-lycorane and β-lycorane feature trans-B/C ring zation (Fig. 2C). In order to develop an efficient alternative syn-
galanthan.
thesis method for amaryllidaceae alkaloids, the construction
Owing to the preeminent biological activities of lycorine- of the galanthan skeleton via the Michael addition was
type alkaloids and the infeasibility of isolation in larger quan- explored, resulting in total synthesis of β-lycorane (Fig. 2D),
tity from plants, many research groups such as those of which differs from ( )-γ-lycorane in the stereochemistry of the
Tsuda,3 Hudlicky,4 Gong,5 Ojima6 and Booker-Milburn7 have central hydrogen adjacent to the ring nitrogen.
demonstrated their elegant studies on the total synthesis of
aSchool of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for
Natural Products, Kunming Medical University, Kunming, Yunnan 650500,
P. R. China. E-mail: liudandan1017@qq.com
bKey Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education;
Yunnan Provincial Center for Research & Development of Natural Products; School of
Chemical Science and Technology, Yunnan University, Kunming, 650091,
P. R. China. E-mail: chenjb@ynu.edu.cn
†Electronic supplementary information (ESI) available. CCDC 2009154. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0ob02398a
‡These authors contributed equally.
Fig. 1 Lycorine-type alkaloids.
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Scheme 2 Isomerization of 11.
firmed by frequency analysis, which showed no imaginary fre-
quency for each energy minimum.
Fig. 2 Different stereoselectivities of arylation and Michael addition.
Based on our findings described above, avoiding the ketone
intermediate is crucial for the synthesis of lycorine-type alka-
loids. Therefore, we anticipated that the ( )-β-lycorane with the
trans-B/C ring could be synthesized from the intramolecular
reductive aminocyclization of 14, which was prepared though
the Michael addition of 17 and AcOEt (Scheme 3). The inter-
mediate 17 could be synthesized from 18 and nitroolefin 19
via another Michael addition reaction.
Our synthetic routes started from the preparation of 18 and
19 (Scheme 4). The reaction of piperonyl aldehyde 20 with
bromine afforded the bromide 21, which was then converted
to glycol acetal 18 according to the related literature studies.10
The nitroolefin 19 was prepared from 2-nitrocyclohexane-1,3-
diol 24 studied through the double Henry reaction of nitro-
methane with glutaraldehyde.11 Then, the hydroxyl groups in
24 were protected by careful treatment with acetic anhydride,
Results and discussion
Initially, the speculation that the carbonyl on the C ring may
determine the stereoselectivity was confirmed (Scheme 1). The
hydroxyl group at the C2 position of natural lycorine (pur-
chased) was selectively protected to give 15, and subsequent
hydrogenation and Swern oxidation afforded the product 12 as
the only stereoisomer. To our delight, 12 was confirmed with
the cis-B/C ring by two-dimensional 1H NMR analysis and
X-ray analysis of its derivative 16.9
The keto–enol tautomerization should be responsible for
the isomerization process (Scheme 2). Firstly, 11 was trans-
formed into its oxidation product 11a. Subsequently, 11b was
formed by the keto–enol tautomerization. Then, 11b attracted
a proton from both faces but only gave 12 as a thermo-
dynamically stable product. Finally, the quantum mechanics
calculation showed that 12 has 2.15 kcal mol−1 lower free
energy than its thermodynamically unfavorable counterpart
12′. DFT calculations were carried out with the Gaussian 09
program package using Becke’s three-parameter hybrid func-
tional (B3LYP) method and the 6-31G* basis set. The full geo-
metry optimization computations were carried out. The stabi-
lity of the optimized conformation of the compounds was con-
Scheme 3 Retrosynthetic analysis of ( )-β-lycorane.
Scheme 4 Synthesis of intermediates 18 and 19. Reagents and con-
ditions: (a) Br2, MeOH, r.t., 88%; (b) HOCH2CH2OH, p-TsOH, toluene,
reflux, 96%; (c) Na2CO3, MeOH, r.t., 89%; (d) Ac2O, DMAP, Al2O3, DCM, r.
t., 87%; and (e) NaHCO3, 1,4-dioxane, 110 °C, 93%.
Scheme 1 Isomerization of the B/C ring.
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and the product 25 was next converted to nitroolefin 19 under
heating in the presence of NaHCO3.
Conclusions
With 18 and nitroolefin 19 in hand, major efforts were In conclusion, it has been verified that the carbonyl on the C
made to the Michael addition–elimination reaction (Table 1).12 ring plays an important role in the determination of stereo-
The initially tested lithium hexamethyldisilazide (LiHMDS) at selectivity, and the galanthan skeleton with the cis-B/C ring is
−78 °C failed to promote the reaction (Table 1, entry 1). By more thermodynamically stable in its presence. The mecha-
using n-butyllithium (n-BuLi), a trace amount of the Micheal nism of the isomerization was proposed with the keto–enol
addition product 17 was detected (Table 1, entry 2). It was tautomerization process, which was confirmed by quantum
found that the reaction accelerated remarkably at elevated chemistry calculations. The total synthesis of β-lycorane was
temperature and the aimed product was obtained in 86% yield successfully completed in 8 steps with 24% overall yield by
when the reaction mixture was allowed to warm slowly to room employing the Michael addition reaction to construct the
temperature and was stirred overnight (Table 1, entry 3). To galanthan skeleton with the trans-B/C ring.
our delight, the addition of CuI as an additive has further pro-
moted the reaction to 91% yield within 6 hours (Table 1, entry
4).
The Michael addition reaction of 17 with AcOEt furnished
Experimental section
14 in 81% yield. The reaction exhibited excellent stereo-
General
selectivity, and no diastereoisomer was observed. The follow-
All reactions were conducted in dried glassware under positive
pressure of dry nitrogen. THF was dried over Na-benzophe-
none ketyl. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded on a Bruker Avance 300, 400 or 600
spectrometer at 300, 400 or 600 MHz. Carbon-13 nuclear mag-
netic resonance (13C NMR) spectra were recorded on a Bruker
Avance 300, 400 or 600 spectrometer at 75, 100 or 150 MHz.
Chemical shifts are reported as δ values in parts per million
(ppm) relative to tetramethylsilane (TMS) for all recorded NMR
spectra. The starting materials and reagents used in the reac-
tions were obtained commercially from Acros, Aldrich, Fluka
and were used without further purification, unless otherwise
indicated. All reactions were conducted in dried glassware
under positive pressure of dry nitrogen. Silica gel (Qingdao,
200–300 mesh) was used for column chromatography.
ing treatment of 14 with zinc in acetic acid successfully
afforded the reductive aminocyclization product 26 in a single
step. After the MeONa-mediated intramolecular amidation of
26, the tetracyclic framework of β-lycorane was constructed
successfully and it afforded 27. The relative configuration of 27
was confirmed by two-dimensional NMR spectroscopy; H(11b)
and H(11c) were trans, and H(11c) and H(3a) were also trans,
in complete agreement with the reported spectra.13 Finally,
( )-β-lycorane was synthesized by the reduction of 27 with
LiAlH4 (Scheme 5). The NMR spectra of our synthetic sample
were in complete agreement with the reported data.7,14
Table 1 Reaction condition screening for the synthesis of 17a
(1S,2S,3a1S,12bS)-2-((tert-Butyldimethylsilyl)oxy)-2,3a1,4,5,7,
12b-hexahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]
phenanthridin-1-ol (15)
A mixture of imidazole (48 mg, 0.7 mmol), t-butyl dimethyl
chlorosilane (63 mg, 0.42 mmol) and lycorine (100 mg,
0.35 mmol) in dry N,N-dimethylformamide (10 mL) was stirred
at 60 °C for 24 h. Then, the reaction mixture was quenched
with saturated aqueous sodium bicarbonate and extracted with
ethyl acetate. The combined organic layers were washed with
brine; the organic solvent was dried (sodium sulfate), filtered,
and evaporated. 15 (140 mg, 99%) was obtained as a yellow oil.
1H NMR (CDCl3, 600 MHz) δ (ppm): 6.82 (1H, s), 6.58 (1H, s),
5.91 (2H, d, J = 2.4 Hz), 5.41 (1H, s), 4.41 (1H, s), 4.27 (1H, s),
4.14–4.11 (1H, d, J = 14.1 Hz), 3.49–3.47 (1H, d, J = 13.9 Hz),
3.34–3.31 (1H, m), 2.94–2.86 (1H, d, J = 43.7 Hz), 2.80–2.79
(1H, d, J = 10.6 Hz), 2.71–2.69 (1H, d, J = 10.5 Hz), 2.61–2.56
(2H, m), 2.36–2.31 (1H, m), 0.89 (9H, s), 0.14 (3H, s), 0.12 (3H,
s). 13C NMR (CDCl3, 150 MHz) δ (ppm): 146.7, 146.4, 142.0,
130.6, 128.1, 118.5, 107.9, 104.6, 101.1, 72.6, 72.4, 61.1, 57.3,
54.1, 41.2, 28.7, 26.0, 18.3, −4.3, −4.6. HRMS (ESI) calcd for
C22H31NO4Si (M + H)+ 402.2101, found 402.2095.
Entry
Base
Temperature (°C)
Time (h)
Yieldb (%)
1
2
LiHMDS
n-BuLi
n-BuLi
n-BuLi
−78
−78
−15 to rt
−15 to rt
12
12
12
6
0
5
86
91
3
4c
a Reaction conditions: reactions were conducted with 18 (2 mmol), 19
(2 mmol) and base (2.2 mmol) in THF (5.0 mL) under a N2 atmo-
sphere. b Isolated yield. c 0.2 mmol of CuI was added.
Scheme 5 Completion of the total synthesis of ( )-β-lycorane.
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(1S,2S,3a1R,12bR)-2-((tert-Butyldimethylsilyl)oxy)-
2,3,3a,3a1,4,5,7,12b-octahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo
[3,2,1-de]phenanthridin-1-ol (11)
(2S,3a1R,12bR)-2-Hydroxy-2,3,3a,3a1,4,5,7,12b-octahydro-1H-
[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridin-1-one (16)
To a solution of 12 (100 mg, 0.25 mmol) in EtOH (10 mL) was
To a solution of 15 (0.1 g, 0.25 mmol) in glacial acetic acid added 2 M hydrochloric acid (2 mL) slowly. After being stirred
(10 mL) was added 10% palladium on carbon (10 mg). The at room temperature for 3 h, the reaction mixture was
device was vacuumized, hydrogen was introduced 3 times, and quenched with saturated aqueous sodium bicarbonate and
then the reaction mixture was stirred at room temperature for extracted with ethyl acetate. The combined organic layers were
24 h. The solid was collected by suction filtration and then washed with brine; the organic solvent was dried (sodium
washed with ethyl acetate. The filtrate was evaporated, and the sulfate), filtered, and evaporated. The residue was purified by
pH was adjusted to neutral with saturated aqueous sodium flash chromatography (elution with petroleum ether/ethyl
1
bicarbonate. The solution was extracted with ethyl acetate. The acetate: 1/1) to give 16 (67 mg, 93%) as a white solid. H NMR
combined organic layers were washed with brine; the organic (CDCl3, 400 MHz) δ (ppm): 6.53 (1H, s), 6.50 (1H, s), 5.93–5.92
solvent was dried (sodium sulfate), filtered, and evaporated. (2H, dd, J = 2.1, 1.4 Hz), 4.37–4.32 (1H, qd, J = 6.0, 1.2 Hz),
The residue was purified by flash chromatography (elution 4.03–4.00 (1H, d, J = 14.6 Hz), 3.75–3.73 (1H, d, J = 4.7 Hz),
with petroleum ether–ethyl acetate: 1/1) to give 11 (80 mg, 3.38–3.32 (1H, td, J = 9.3, 5.1 Hz), 3.31–3.27 (1H, d, J = 14.6
79%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ (ppm): Hz), 2.99–2.96 (1H, t, J = 4.7 Hz), 2.72–2.69 (1H, m), 2.33–2.27
6.92 (1H, s), 6.73 (1H, s), 5.86–5.85 (2H, d, J = 3.8 Hz), (2H, m), 2.10–2.07 (1H, m), 1.89–1.80 (1H, q, J = 12.6 Hz),
4.45–4.41 (1H, d, J = 13.8 Hz), 4.27 (1H, s), 3.96 (1H, s), 1.62–1.56 (1H, m). 13C NMR (CDCl3, 100 MHz) δ (ppm): 208.7,
3.91–3.88 (1H, d, J = 13.9 Hz), 3.46–3.41 (2H, m), 3.30–3.25 146.1, 145.1, 127.6, 121.3, 109.7, 105.2, 100.0, 72.0, 65.6, 54.7,
(1H, m), 3.19–3.18 (2H, d, J = 1.4 Hz), 3.07–3.04 (1H, d, J = 11.8 51.5, 49.4, 38.6, 34.3, 26.9. HRMS (ESI) calcd for C16H17NO4 (M
Hz), 2.52–2.41 (2H, m), 2.17–2.12 (1H, m), 2.01–1.98 (1H, m), + H)+ 288.1236, found 288.1228.
0.80 (9H, s), 0.04 (3H, s), 0.02 (3H, s). 13C NMR (CD3OD,
2-Nitrocyclohexane-1,3-diol (24)
100 MHz) δ (ppm): 149.8, 147.9, 133.0, 124.7, 108.6, 106.8,
102.7, 71.7, 69.8, 64.4, 56.5, 54.0, 37.1, 33.0, 30.5, 28.2, 26.3,
18.9, −4.8, −4.9. HRMS (ESI) calcd for C22H33NO4Si (M + H)+
404.2257, found 404.2252.
To a solution of 50% aqueous glutaraldehyde (0.4 mL,
2 mmol) in dry methanol (5 mL) was added nitromethane
(120 mg, 2 mmol) and 5% aqueous sodium carbonate (1 mL).
The reaction mixture was stirred at room temperature for 24 h.
The solvents were evaporated to remove methanol, then
extracted with ethyl acetate and washed with brine. The
organic layer was dried (sodium sulfate) and evaporated. The
residue was purified by flash chromatography (elution with
petroleum ether–ethyl acetate: 2/1) to give 24 (290 mg, 89%) as
a white powder. 1H NMR (CD3OD, 300 MHz) δ (ppm):
4.31–4.24 (1H, t, J = 9.8 Hz), 4.05–3.97 (2H, m), 2.10–2.05 (2H,
m), 1.87–1.82 (1H, m), 1.51–1.35 (3H, m). 13C NMR (CD3OD,
75 MHz) δ (ppm): 99.7, 71.9, 33.9, 20.8.
(2S,3a1R,12bR)-2-((tert-Butyldimethylsilyl)oxy)-2,3,3a,3a
1,4,5,7,12b-octahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]
phenanthridin-1-one (12)
To a solution of oxalyl chloride (0.17 mL, 2 mmol) in dry di-
chloromethane (10 mL) under a N2 atmosphere was added
dropwise dimethyl sulfoxide (0.18 mL, 2.5 mmol) in dry di-
chloromethane (5 mL) at −78 °C for 40 min. Then, a solution
of 11 (200 mg, 0.5 mmol) in dry dichloromethane (10 mL) was
added dropwise. After being stirred at −78 °C for 1.5 h, tri-
ethylamine (0.7 mL, 5 mmol) was added slowly, and the solu-
tion was kept at the same temperature for another 30 min. The
reaction mixture was then warmed to room temperature,
quenched with saturated aqueous sodium bicarbonate and
extracted with ethyl acetate. The combined organic layers were
washed with brine, and the organic solvent was dried (sodium
sulfate), filtered, and evaporated. The residue was purified by
flash chromatography (elution with petroleum ether–ethyl
2-Nitrocyclohexane-1,3-diyl diacetate (25)
To a solution of 24 (3.3 g, 20 mmol) in dry dichloromethane
(20 mL) was added acetic anhydride (1.9 mL, 20 mmol). After
adding DMAP (12 mg, 0.1 mmol) and basic aluminum oxide
(4.1 g, 40 mmol), the reaction mixture was stirred at room
temperature for 36 h. The solvents were filtered and evapor-
ated. The residue was purified by flash chromatography
(elution with petroleum ether–ethyl acetate: 5/1) to give 25
(4.2 g, 87%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ
(ppm): 5.21–5.14 (2H, td, J = 10.8, 4.8 Hz), 4.60–4.55 (1H, t, J =
10.4 Hz), 2.26–2.21 (2H, dd, J = 13.0, 3.7 Hz), 2.01 (6H, s),
1.85–1.81 (1H, m), 1.53–1.45 (1H, m), 1.39–1.29 (2H, m). 13C
NMR (CDCl3, 100 MHz) δ (ppm): 169.5, 91.0, 71.9, 29.5, 20.8,
19.4.
1
acetate: 5/1) to give 12 (150 mg, 75%) as a yellow oil. H NMR
(CDCl3, 400 MHz) δ (ppm): 6.50 (1H, s), 6.49 (1H, s), 5.92–5.89
(2H, dd, J = 9.6, 1.4 Hz), 4.43–4.38 (1H, m), 4.01–3.98 (1H, d, J
= 14.5 Hz), 3.63–3.62 (1H, d, J = 4.4 Hz), 3.36–3.25 (2H, m),
2.93–2.90 (1H, t, J = 4.4 Hz), 2.70–2.66 (1H, m), 2.32–2.26 (1H,
m), 2.14–1.98 (3H, m), 1.61–1.54 (1H, m), 0.89 (9H, s), 0.10
(3H, s), 0.03 (3H, s). 13C NMR (CDCl3, 100 MHz) δ (ppm):
207.2, 146.9, 145.9, 128.6, 123.4, 110.8, 106.1, 100.9, 75.0, 66.4,
55.8, 52.5, 51.2, 40.4, 36.1, 28.1, 25.8, 18.6, −4.4, −5.3. HRMS
2-Nitrocyclohex-2-en-1-yl acetate (19)
H)+ 402.2101, found A solution of 25 (2.58 g, 10 mmol) and sodium bicarbonate
(ESI) calcd for C22H31NO4Si (M
+
402.2095.
(6.72 g, 80 mmol) in 1,4-dioxane (20 mL) was refluxed for 3 h.
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The reaction mixture was filtered, extracted with ethyl acetate Ethyl 2-(1,2,3,4,4a,5,6,11b-octahydro-[1,3]dioxolo[4,5-j]
and washed with brine. The organic solvent was dried (sodium phenanthridin-4-yl)acetate (26)
sulfate) and evaporated, and a yellow oil was obtained. The
To a solution of diisopropylamine (0.17 mL, 1.2 mmol) in dry
residue was purified by flash chromatography (elution with
tetrahydrofuran (5 mL) under a N2 atmosphere was added 2.5
petroleum ether–ethyl acetate: 10/1) to give compound 19
M n-BuLi (0.48 mL, 1.2 mmol) at −78 °C for 0.5 h and then
dry ethyl acetate (0.1 mL, 1 mmol) was added. After being
(1.73 g, 93%) as a light yellow oil. 1H NMR (CDCl3, 400 MHz) δ
(ppm): 7.59–7.57 (1H, m), 6.01 (1H, s), 2.56–2.49 (1H, m),
stirred for 0.5 h, 17 (160 mg, 0.5 mmol) was added. The reac-
2.34–2.27 (1H, m), 2.10–2.07 (1H, d, J = 11.2 Hz), 2.03 (3H, s),
tion mixture was stirred for 3 h, quenched with pure water,
extracted with ethyl acetate, washed with brine, dried (sodium
sulfate), and evaporated. The residue was purified by flash
1.76–1.68 (3H, m). 13C NMR (CDCl3, 100 MHz) δ (ppm): 169.8,
147.4, 140.4, 63.2, 28.4, 25.1, 21.0, 16.1.
chromatography (elution with petroleum ether/ethyl acetate:
10/1) to give 14 (170 mg, 81%) as a white solid. To a solution
5-Bromo-6-(1,3-dioxolan-2-yl)benzo[d][1,3]dioxole (18)
of 14 (110 mg, 0.28 mmol) and acetic acid (6 mL) was added
A solution of piperonal (2 g, 13 mmol) in dry methanol
activated zinc powder (1 g), and then stirred at room tempera-
(20 mL) was stirred at 0 °C, and liquid bromine (1 mL, 20 mol)
ture for 16 h. The reaction mixture was diluted with dichloro-
was dripped slowly through a constant pressure funnel. After
methane and neutralized with potassium carbonate solid until
being stirred at room temperature for 10 h, the excess bromine
alkaline. After being filtered and evaporated, the residue was
was removed from the reaction mixture with saturated sodium
purified by flash chromatography (elution with petroleum
bisulfite. The solid was collected by suction filtration and then
washed with cold water. The residue was recrystallized from
ether/ethyl acetate: 3/1) to give 26 (76 mg, 86%) as a white
solid. 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.78 (1H, s), 6.45
ethyl acetate to afford compound 21 (2.7 g, 88%) as white crys-
(1H, s), 5.88 (2H, d, J = 0.9 Hz), 4.17–4.10 (2H, m), 3.94–3.92
tals. To a solution of 21 (2.5 g, 11 mmol) and ethylene glycol
(2H, d, J = 7.5 Hz), 2.86–2.79 (1H, dd, J = 15.3, 5.1 Hz),
(1.3 g, 22 mmol) in dry toluene (20 mL) was added p-toluene-
sulfonic acid (95 mg, 0.55 mmol), and then the solution was
refluxed and water was segregated over 24 h. The reaction
mixture was cooled to room temperature, potassium carbonate
2.35–2.29 (2H, m), 2.16–2.09 (2H, m), 2.06–2.04 (1H, d, J = 6.6
Hz), 1.91–1.84 (4H, m), 1.53–1.48 (1H, m), 1.31–1.26 (3H, t, J =
7.2 Hz). 13C NMR (CDCl3, 75 MHz) δ (ppm): 173.8, 146.1,
145.5, 131.8, 129.4, 105.9, 105.6, 100.6, 63.1, 60.1, 49.1, 43.4,
was added, and then the solution was stirred for 0.5 h, filtered,
40.2, 38.6, 32.3, 30.4, 25.6, 14.3. HRMS (ESI) calcd for
and evaporated. The residue was purified by flash chromato-
C18H23NO4 (M + H)+ 318.1705, found 318.1696.
graphy (elution with petroleum ether–ethyl acetate: 10/1) to
give 18 (2.9 g, 96%) as a white solid. 1H NMR (CDCl3,
2,3,3a,4,7,12b-Hexahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-
300 MHz) δ (ppm): 7.09 (1H, s), 7.01 (1H, s), 6.07–5.98 (3H, m),
de]phenanthridin-5(3a1H)-one (27)
4.18–4.01 (4H, m). 13C NMR (CDCl3, 75 MHz) δ (ppm): 149.0,
A solution of sodium methylate (54 mg, 1 mmol) in dry metha-
147.5, 130.0, 114.0, 112.8, 107.7, 102.6, 101.9, 65.4.
nol (5 mL) was stirred until being cooled. 26 (50 mg,
0.16 mmol) was added and then stirred at room temperature
5-(1,3-Dioxolan-2-yl)-6-(2-nitrocyclohex-2-en-1-yl)benzo[d] [1,3]
dioxole (17)
for 3 h. The reaction mixture was evaporated and dissolved
with ethyl acetate. After being filtered and evaporated, the
residue was purified by flash chromatography (elution with
petroleum ether/ethyl acetate: 1/1) to give 27 (31 mg, 73%) as a
To a solution of 18 (550 mg, 2 mmol) in dry tetrahydrofuran
(5.0 mL) under a N2 atmosphere was added 2.5 M n-BuLi
(0.88 mL, 2.2 mmol) at −78 °C for 0.5 h, and then cuprous
iodide (38 mg, 0.2 mmol) was added. After being stirred at
−78 °C for 1 h, the reaction mixture was warmed in an ice
bath. 19 (370 mg, 2 mmol) was added, and the reaction
mixture was stirred at room temperature for 6 h. The solution
was quenched with saturated aqueous ammonium chloride,
extracted with ethyl acetate, washed with brine, dried (sodium
sulfate), and evaporated. The residue was purified by flash
chromatography (elution with petroleum ether/ethyl acetate: 5/
1) to give 17 (580 mg, 91%) as a light yellow oil. 1H NMR
(CDCl3, 300 MHz) δ (ppm): 7.14 (1H, s), 6.50 (1H, s), 6.13 (1H,
s), 5.91 (2H, d, J = 1.8 Hz), 4.53 (1H, s), 4.20–4.01 (4H, m),
1
white solid. H NMR (CDCl3, 600 MHz) δ (ppm): 6.69 (1H, s),
6.60 (1H, s), 5.93–5.92 (2H, dd, J = 5.2, 1.3 Hz), 4.46–4.38 (2H,
q, J = 17.0 Hz), 2.72–2.69 (1H, t, J = 10.2 Hz), 2.53–2.49 (1H, td,
J = 10.9, 3.3 Hz), 2.48–2.44 (1H, dd, J = 15.4, 6.5 Hz), 2.41–2.38
(1H, m), 2.18–2.13 (1H, dd, J = 14.8, 12.9 Hz), 2.04–2.01 (1H,
m), 1.98–1.92 (2H, m), 1.63–1.58 (1H, ddd, J = 17.2, 13.1, 9.1
Hz), 1.41–1.29 (2H, m). 13C NMR (CDCl3, 150 MHz) δ (ppm):
175.0, 146.7, 146.2, 130.6, 125.0, 107.2, 104.7, 101.0, 64.7, 42.9,
42.8, 40.5, 38.2, 27.8, 27.8, 25.8. HRMS (ESI) calcd for
C16H17NO3 (M + H)+ 272.1287, found 272.1281.
( )-β-Lycorine
2.55–2.35 (2H, m), 2.12–2.01 (1H, m), 1.90–1.81 (1H, m), To a solution of 27 (20 mg, 0.074 mmol) in dry THF (5 mL)
1.70–1.60 (3H, m). 13C NMR (CDCl3, 75 MHz) δ (ppm): 151.7, was added LiAlH4 (4.2 mg, 0.11 mmol) at 0 °C for 1 h. The
147.9, 146.4, 136.2, 134.6, 128.8, 107.1, 106.7, 101.2, 100.8, reaction mixture was quenched with saturated aqueous
65.3, 65.2, 35.1, 31.3, 25.0, 17.4. HRMS (ESI) calcd for ammonium chloride, extracted with ethyl acetate, washed with
C16H17NO6 (M + Na)+ 342.0954, found 342.0948.
brine, dried (sodium sulfate), and evaporated. The residue was
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Organic & Biomolecular Chemistry
purified by flash chromatography (elution with petroleum
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1
white solid. H NMR (CDCl3, 300 MHz) δ (ppm): 6.72 (1H, s),
6.51 (1H, s), 5.90–5.89 (2H, d, J = 3.3 Hz), 4.10–4.05 (1H, d, J =
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2.36–2.25 (2H, m), 2.06–1.91 (3H, m), 1.67–1.57 (4H, t, J = 14.5
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Conflicts of interest
There are no conflicts to declare.
9 X-ray crystallographic data of 16 have been deposited in the
Cambridge Crystallographic Data Centre database ( http://
www.ccdc.cam.ac.uk/) under accession code CCDC
2009154.†
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21907044 and 81860632). D. Liu is
thankful for the grants from the Yunnan Provincial Science
and Technology Department (2019FB124). L. Liang is thankful
for the support from Yunnan Provincial Department of
Education (2018JS158). J. Li and Y. Zhang thank the Basic
Research Plan of Yunnan Provincial Science and Technology
Department–Kunming Medical University (2019FE001(-301)
and 2018FE001(-192)). J. Chen is thankful for the grants from
Yunnan Provincial Science and Technology Department
(2018FA045).
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