Synthesis of phenanthridine skeletal Amaryllidaceae alkaloids

Article abstract of DOI:10.1016/j.tet.2016.07.065

Strategies for the synthesis of Amaryllidaceae alkaloids, including crinasiadine, trisphaeridine, bicolorine, N-methylcrinasiadine, 5,6-dihydrobicolorine, galanthindole, lycosinine A and lycosinine B were reported. Investigation of optionally synthetic routes to approach bicolorine, 5,6-dihydrobicolorine, trisphaeridine and N-methylcrinasiadine were demonstrated as well. In addition, three structurally related alkaloids galanthindole, lycosinine A and lycosinine B were concisely prepared by using Suzuki coupling reaction as the key step.

Full text of DOI:10.1016/j.tet.2016.07.065

Accepted Manuscript
Synthesis of phenanthridine skeletal Amaryllidaceae alkaloids
Tai-Ting Fan-Chiang, Hung-Kai Wang, Jen-Chieh Hsieh
PII:
S0040-4020(16)30723-2
10.1016/j.tet.2016.07.065
TET 27961
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 June 2016
Revised Date: 25 July 2016
Accepted Date: 26 July 2016
Please cite this article as: Fan-Chiang T-T, Wang H-K, Hsieh J-C, Synthesis of phenanthridine skeletal
Amaryllidaceae alkaloids, Tetrahedron (2016), doi: 10.1016/j.tet.2016.07.065.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthesis of Phenanthridine Skeletal
Amaryllidaceae Alkaloids
Leave this area blank for abstract info.
Tai-Ting Fan-Chiang, Hung-Kai Wang and Jen-Chieh Hsieh*

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of Phenanthridine Skeletal Amaryllidaceae Alkaloids
Tai-Ting Fan-Chiang, Hung-Kai Wang and Jen-Chieh Hsieh*
Department of Chemistry, Tamkang University, New Taipei City, 25137, Taiwan (R.O.C.)
ARTICLE INFO
ABSTRACT
Article history:
Received
Strategies for the synthesis of Amaryllidaceae alkaloids, including crinasiadine, trisphaeridine,
bicolorine, N-methylcrinasiadine, 5,6-dihydrobicolorine, galanthindole, lycosinine and
A
Received in revised form
Accepted
Available online
lycosinine B were reported. Investigation of optionally synthetic routes to approach bicolorine,
5,6-dihydrobicolorine, trisphaeridine and N-methylcrinasiadine were demonstrated as well. In
addition, three structurally related alkaloids galanthindole, lycosinine A and lycosinine B were
concisely prepared by using Suzuki coupling reaction as the key step.
Keywords:
2009 Elsevier Ltd. All rights reserved.
Amaryllidaceae alkaloid
DNA topoisomeraseⅠ
Suzuki coupling
Ullmann coupling
SNAr
1. Introduction
O
N
O
O
O
O
O
O
N
N
H
O
H
O
Plants of the Amaryllidaceae family, containing ca. 85 genera
and 1100 species, distribute widely on the tropical to temperate
regions around the world. Many of them have been cultivated as
ornamental plants for a long time because of their colorful and
beautiful flowers; thus, making a big market and great economic
values. Not only as ornaments, but Amaryllidaceae plants have
also been applied on the pharmaceutical purpose. For example,
lycorine1 (Figure 1), a well-known Amaryllidaceae alkaloid,
which can be found in Lycoris’ bulb and various Amaryllidaceae
species, possesses multi-medicinal functions.
N
H
HO
OH
OH
Anhydrolycorine
OH
Lycorine
Vittatine
Graciline
O
O
O
O
H
O
O
O
O
O
O
O
NH
N
O
O
OH
OH
OH
OH
O
OMe
H
N
HO
N
O
OMe
OH
Lycoranine A
Pancratistatin
Hippeastrine
Galasine
OMe
O
O
O
O
N
O
O
OH
Amaryllidaceae alkaloids, consisted of a nitrogen-containing
polycyclic structure, often possess significantly pharmaceutical
activities, including antitumor, antimalarial, antivirus, antifungal
and antibacterial etc.2–5 Recent studies have also reported that
some derivatives could be used as the treatments for Alzheimer's
N
O
N
O
O
O
O
N
O
Ungeremine
Rhoifline A
Asiaticumine B
Galanthindole
Figure 1. Selected examples of Amaryllidaceae alkaloids
and Parkinson's diseases.6, Because of the wide applications,
7
considerable attention have been paid by chemists toward the
isolations, preparations and bioactivities of these Amaryllidaceae
alkaloids and their analogs. 2–9
It was reported that bicolorine (8) and its derivatives exhibit
apparent function to inhibit human DNA topoisomerase Ⅰ.15
This important bioactivity makes us explore other possibility to
reduce its synthetic steps and to synthesize alkaloids with related
structures. Herein, we organize our preliminary studies and report
various pathways to approach bicolorine and other structurally
related alkaloids.
Structures of many Amaryllidaceae alkaloids are with some
degree of similarity, generally containing an o-dioxygenated aryl
group (e.g. benzodioxole) with heterocyclic rings fused on it
(Figure 1).11 This structural similarity can be found in various
types of Amaryllidaceae alkaloids, and allows the complicated
structures to be afforded through a series of semisyntheses from
the simple scaffolds. In our preliminary results,11 we have shown
that the copper catalysis could be applied to be a key step for the
synthesis of crinasiadine (5).12 Other two alkaloids, trisphaeridine
(7)13 and bicolorine (8),14 can be obtained by subsequent steps
(Scheme 1).
2. Results and Discussion
Our strategy started from the preparation of substrate 4 (Scheme
1), which was described in our previously developed method.11 It
started from a cyanation of the commercial available compound 1,
the subsequent Miyaura borylation of compound 2 with diboron
converted bromide to boronic ester (3).
* Corresponding Author.
Tel: 886-2-26215656ext2545; Fax: 886-2-26209924;
E-mail: jchsieh@mail.tku.edu.tw (J.-C. Hsieh)

ACCEPTED MANUSCRIPT
2
Tetrahedron
Scheme 1. Synthesis of Amaryllidaceae alkaloids
A Suzuki coupling reaction by 3 with 1-bromo-2-iodobenzene
afforded compound 4 in 67% yield. Compound 4 was able to be
transformed to the crinasiadine (5) by our previously developed
Cu-catalyzed coupling reaction in 72% yield (36% overall yield,
4 steps).11a Crinasiadine is the key intermediate for the further
semisyntheses to approach other four alkaloids. Treatment of
crinasiadine with Tf2O and pyridine provided compound 6 in
75% yield with only 10 minutes reaction time. The following Pd-
catalyzed hydrogenation provided trisphaeridine (7) in 91% yield
(25% overall yield, 6 steps). A methylation of trisphaeridine with
exchange of the counter anion gave bicolorine (8) (chloride as the
counter anion) in 86% yield (21% overall yield, 8 steps).
Moreover, the alkaloid N-methylcrinasiadine (9)16 was obtained
in 86% yield simply by a methylation of crinasiadine (5). Further
reduction of 9 by LiAlH4 afforded alkaloid 5,6-dihydrobicolorine
(10)14 in 74% yield.
suggested by a reduction of bicolorine in 78% yield.9d Both of the
two transformations performed very well, and the purifications
could be carried out simply by the filtration of salts.
Furthermore, the bicolorine could be also obtained by a synthetic
shortcut from the commercial available compound 1 with shorter
steps and higher overall yield (Scheme 3).9e This strategy starts
from a Miyaura borylation of compound 1. A resulted compound
11 underwent the Suzuki coupling reaction, providing compound
12. The subsequent Cu-catalyzed annulation reaction converted
12 to bicolorine with bromide as the counter anion (13). Through
this synthetic sequence, bicolorine (bromide as the counter anion)
could be synthesized in 58% overall yield from the commercial
compound 1 with only three steps. To the best of our knowledge,
this is the shortest way to approach bicolorine and its analogues.
In addition, compound 11 could be also utilized to synthesize the
5,6-dihydrobicolorine (10) through a combined Suzuki coupling
reaction/reduction step in 67% yield (64% overall yield, 3 steps).
However, without the second reduction step, we could only
detect very few amount of bicolorine in crude NMR spectrum.
CN
O
O
O
O
N
Li(Et)3BH/THF
100 oC, 48 h, 58%
Br
Trisphaeridine (7)
4
O
O
N
K3[Fe(CN)6]/KOH
O
MeOH/toluene/H2O
0 to 45 oC, 13 h, 80%
O
O
N
Cl
N-Methylcrinasiadine (9)
O
N
LiAlH4/THF
Bicolorine (8)
O
r.t., 40 min, 78%
5,6-Dihydrobicolorine (10)
Scheme 2. Alternative pathways to approach trisphaeridine, N-
methylcrinasiadine and 5,6-dihydrobicolorine
Scheme 3. Alternative pathways to approach bicolorine and 5,6-
dihydrobicolorine
After achievement of this synthetic strategy, we paid some effort
in reducing the synthetic steps for the synthesis of bioactive
alkaloid bicolorine. Therefore, a direct synthesis of trisphaeridine
from substrate 4 was accessible by treating the super hydride
Li(Et)3BH with 4 (Scheme 2).9d This step provided only 58%
yield after isolation; however, it reduced two steps from the
commercial compound 1 to the trisphaeridine and gave higher
overall yield (4 steps, 29% overall yield). Additionally, an
alternative route to N-methylcrinasiadine (9) could be proposed
by an addition/oxidation combined step via K3[Fe(CN)6] with
KOH. And the formation of 5,6-dihydrobicolorine (10) could be
The Suzuki coupling reaction is able to be utilized in providing
galanthindole-type17 alkaloids with switching the structures of
coupling partners. Thus, we prepared substrates 15 and 16 for the
synthesis of other three Amaryllidaceae alkaloids galanthindole,
lycosinine A and B18 with similar structures. Compound 14 was
prepared according to the Bartoli reaction19 in the presence of o-
bromonitrobenzene with vinyl Grignard reagent in THF at -45 °C
for only 30 minutes. Longer reaction time was not helpful to
improve the reaction yield. Further methylation and reductive

ACCEPTED MANUSCRIPT
3
methylation provided substrates 15 and 16 in 84% and 53%
bicolorine, 5,6-dihydrobicolorine, galanthindole, lycosinine A,
yields, respectively (Scheme 4).
and lycosinine B. The copper and palladium-mediated coupling
reactions were used as the key steps to construct the skeleton of
these alkaloids. Further studies for the evaluation of medicinal
properties of these alkaloids and their derivatives are currently
underway.
4. Experimental Section
4.1. General
All reagents were purchased from Sigma-Aldrich, Alfa-Aesar,
TCI and Fisher-Acros, which were used without further
purification unless otherwise noted. THF and Et2O were distilled
from sodium, and CH3CN was distilled from CaH2. Flash column
chromatography was performed using silica gel (230-400 mesh).
Analytical thin layer chromatography (TLC) was performed on
60 F254 (0.25 mm) plates and visualization was accomplished
with UV light (254 and 354 nm) and/or an aqueous alkaline
KMnO4 solution followed by heating. Proton and carbon nuclear
magnetic resonance spectra (1H NMR and 13C NMR) were
recorded on Bruck 300 or Bruck 600 spectrometer with Me4Si or
solvent resonance as the internal standard (1H NMR, Me4Si at 0
ppm, CDCl3 at 7.26 ppm, d6-DMSO at 2.49 ppm; 13C NMR,
Me4Si at 0 ppm, CDCl3 at 77.0 ppm, d6-DMSO at 39.7 ppm). 1H
NMR data are reported as follows: chemical shift, multiplicity (s
= singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext
= sextet, br = broad, m = multiplet), coupling constants (Hz), and
integration. IR spectral data were recorded on Brucker TENSOR
37 spectrometer. Melting points (mp) were determined using
SRS OptiMelt MPA100. High resolution mass spectral data were
obtained from MAT-95XL HRMS by using EI method and from
Varian 901-MS TQ-FT by using ESI or FAB methods.
Scheme 4. Synthesis of bromoindole and bromoindoline
Although a one-step reductive methylation to afford compound
16 is concise, the low yield of 16 still made us find an alternative
pathway to replace this conversion. A two-step synthesis, which
contained a sequence of reduction and methylation was carried
out. This synthetic sequence performed very well and provided
excellent yields for compound 17 and 16. The combined yield is
much higher than the single-step transformation.
After getting substrate 15, we tried to synthesize galanthindole
(18) via a Suzuki coupling reaction (Scheme 5). However, the
present reaction conditions can not smoothly proceed a coupling
reaction with heterocyclic compounds. With further optimization
of the conditions, we found that PdCl2 with additional bidentate
°
ligand dppf in acetonitrile at 100 C is able to carry out this
coupling reaction with only 5 h. Thus, we combined this protocol
with a further reduction to furnish the galanthindole (18) in 79%
combined yield. In addition, two other Amaryllidaceae alkaloids
lycosinine B (20) and lycosinine A (21) with related structures to
galanthindole could be also obtained by a similar condition with
increasing the reaction temperature and modifying the bidentate
ligand. Compound 19, a coupling partner for lycosinine B, was
prepared through a Miyaura coupling reaction. The following
Suzuki coupling reaction afforded lycosinine B (20) in 74% yield.
A reduction of the aldehyde to alcohol led to lycosinine A (21) in
92% yield.
4.2. Experimental procedures and data for compounds 2–21
Synthetic procedures and experimental data of compounds 2–8,
please check our preliminary results for the detail.11 Synthetic
procedures of compounds 7 (Scheme 2), compounds 9–21 as well
as the experimental data of compounds 9–21 were recorded as
below:
Trisphaeridine (7): Synthesis from 4 (Scheme 2): 6-(2-Bromo-
phenyl)benzo[d][1,3]dioxole-5-carbonitrile (181 mg, 0.6 mmol,
1.0 equiv) was dissolved in dry THF (3 mL) under N2 and kept
stirring at r.t., then Li(Et)3BH (lithium triethylborohydride, 1.0 M
in THF, 0.66 mmol, 1.1 equiv) was slowly injected into the
solution. After injection, the reaction temperature was increased
to 100 °C and kept stirring for 48 h. Work-up by filtration of slats,
then purification through a column chromatography [(Rf = 0.4 (30
% ethyl acetate in hexane)] to afford 7 as a yellow solid (78 mg,
58%).
O
OH
.
(1) PdCl2/dppf/K3PO4 nH2O
CH3CN, 100 oC, 5 h
O
11
+
15
(2) LiAlH4/THF, r.t., 3 h, 79% (2 steps)
N
Galanthindole (18)
MeO
MeO
MeO
O
O
O
O
O
O
O
PdCl2(dppf)/KOAc
B
B
+
1,4-dioxane, 80 o
C
MeO
B
N-Methylcrinasiadine (9): Synthesis from crinasiadine (Scheme
1): crinasiadine (120 mg, 0.5 mmol, 1.0 equiv), Cs2CO3 (815 mg,
2.5 mmol, 5.0 equiv) and CH3I (1.42 g, 10 mmol, 20 equiv) were
stirred in dry THF (5 mL) at r.t. for 24 h. Work-up through an
extraction (CH2Cl2/H2O), then purification by wash with hexane
and ethyl acetate for several times to afford 9 as a white solid
(109 mg, 86%). Synthesis from bicolorine (Scheme 2): bicolorine
(71 mg, 0.3 mmol, 1.0 equiv), K3[Fe(CN)6] (1.09 g, 3.3 mmol, 11
equiv) and KOH (236 mg, 4.2 mmol, 14 equiv) were stirred in
MeOH (3 mL) at 0 °C for 1 h. The co-solvent (6 mL, toluene/H2O
Br
O
36 h, 95%
19
MeO
MeO
MeO
MeO
OH
O
16
7-bromo-1-methylindoline (
)
.
LiAlH4/THF
PdCl2/dppp/K3PO4 nH2O
CH3CN, 120 oC, 24 h, 74%
r.t., 2 h, 92%
N
N
Lycosinine B (20)
Lycosinine A (21)
Scheme 5. Synthesis of galanthindole, lycosinine B and lycosinine A
°
= 1/1) was added into the solution and kept stirring at 45 C for
3. Conclusion
12 h. Work-up and purification by filtration of slat to afford 9 as
a white solid (61 mg, 80%), mp: 240–242 ℃; IR (KBr): 2976,
In conclusion, we have developed concisely synthetic pathways
for the efficient synthesis of a series of Amaryllidaceae alkaloids,
including crinasiadine, N-methylcrinasiadine, trisphaeridine,
1
2921, 1651, 1467, 1346, 1033, 936, 752 cm-1; H NMR (600
MHz, CDCl3): δ 8.07 (dd, J = 7.8, 1.2 Hz, 1H), 7.90 (s, 1H), 7.60
(s, 1H), 7.50 (td, J = 7.8, 1.2 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H),

ACCEPTED MANUSCRIPT
4
Tetrahedron
7.29 (td, J = 7.8, 1.2 Hz, 1H), 6.12 (s, 2H), 3.79 (s, 3H); 13C
128.8, 127.2, 124.1, 110.3, 105.9, 102.2; HRMS [(ESI),
NMR (150 MHz, CDCl3): δ 161.0, 152.2, 148.4, 137.4, 130.4,
128.9, 122.9, 122.3, 121.3, 119.2, 115.0, 107.0, 101.9, 100.4,
30.0; HRMS [(FAB), M+]: 253.0741 (cal. for C15H11NO3
253.0739).
(M+H)+]: 304.9815 (cal. for C14H10BrO3 304.9813).
Bicolorine (bromide as counter anion, 13): CuCl2 (3 mg, 0.025
mmol, 5 mol %), compound 12 (153 mg, 0.5 mmol, 1.0 equiv)
and CH3NH2 (19 mg, 0.6 mmol, 1.2 equiv) were stirred in
ethylene glycol (5 mL) at 100 °C for 24 h. Work-up by filtration
of slats, then purification through a column chromatography [Rf =
0.2 (10% methanol in CH2Cl2)] to afford 13 as a yellow solid (99
mg, 83%), mp: 252–254 ℃; IR (KBr): 3434, 2983, 2840, 1643,
5,6-Dihydrobicolorine (10): Synthesis from 9 (Scheme 1):
LiAlH4 (lithium aluminum hydride, 76 mg, 2.0 mmol, 4.0 equiv)
was added into the solution of 9 (127 mg, 0.5 mmol, 1.0 equiv) in
THF (5 mL) at r.t.. The solution was then allowed to stir at 40 °C
for 4 h. Work-up by adding excess ethyl acetate to quench the
reaction. Extraction (Et2O/H2O) then purification through a
column chromatography [Rf = 0.75 (10 % ethyl acetate in
hexane)] to afford 10 as a yellow solid (89 mg, 74%). Synthesis
from 8 (Scheme 2): LiAlH4 (30 mg, 0.8 mmol, 4.0 equiv) was
added into the solution of 8 (48 mg, 0.2 mmol, 1.0 equiv) in THF
(2 mL) at r.t. and allowed to stir for 40 min. Work-up, extraction
then purification to afford 10 as a yellow solid (37 mg, 78%).
Synthesis from 11 (Scheme 3): Pd(PPh3)4 (23 mg, 0.02 mmol, 2
mol %), K3PO4·nH2O (345 mg, 1.5 mmol, 1.5 equiv), compound
11 (276 mg, 1.0 mmol, 1.0 equiv) and 2-iodo-N-methylaniline
(291 mg, 1.25 mmol, 1.25 equiv) were stirred in co-solvent (6
mL, toluene/EtOH/H2O = 1/1/1) under N2 at 80 °C for 4 h. The
co-solvent of the reaction mixture was removed under vacuum,
and THF (12.5 mL) was added into the residue. LiAlH4 (42 mg,
1.1 mmol, 1.1 equiv) was added into the solution and kept
stirring at r.t. for 3 h. Work-up, extraction then purification to
afford 10 as a yellow solid (160 mg, 67%), mp: 80–81 °C; IR
(KBr): 3452, 2894, 2796, 1510, 1487, 1287, 1236, 1033, 748 cm-
1271, 1041, 1010 cm-1; H NMR (600 MHz, d6-DMSO): δ 9.89
1
(s, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.63 (s, 1H), 8.42 (d, J = 9.0
Hz, 1H), 8.07 (t, J = 7.2 Hz, 1H), 8.00 (t, J = 7.2 Hz, 1H), 7.87
(s, 1H), 6.47 (s, 2H), 4.56 (s, 3H); 13C NMR (150 MHz, d6-
DMSO): δ 157.2, 151.9, 150.0, 134.4, 133.7, 131.5, 129.5, 124.9,
120.4, 119.6, 107.2, 104.2, 101.3, 62.7, 45.2; HRMS [(ESI), (M-
Br)+]: 238.0864 (cal. for C15H12NO2 238.0868).
7-Bromo-1H-indole (14): Vinylmagnesium bromide (30 mL, 1.0
M in THF, 30 mmol, 3.0 equiv) was slowly injected into the 1-
bromo-2-nitrobenzene/THF solution (2.02 g, 10 mmol, 1.0 equiv
in 60 mL) under N2 at -45 °C. The resulted solution mixture was
kept stirring at -45 °C for 30 min. Work-up by adding a saturated
brine solution. Extraction (Et2O/H2O) then purification through a
column chromatography [Rf = 0.6 (10% ethyl acetate in hexane)]
to afford 14 as a white solid (1.18 g, 60%), mp: 41–43 ℃; IR
(KBr): 3431, 1330, 784, 719, 574 cm-1; H NMR (600 MHz,
1
CDCl3): δ 8.34 (br, s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.36 (d, J =
7.8 Hz, 1H), 7.27 (dd, J = 5.4, 2.4 Hz, 1H), 7.01 (t, J = 7.8 Hz,
1H), 6.64 (t, J = 1.8 Hz, 1H); 13C NMR (150 MHz, CDCl3): δ
134.6, 129.0, 124.7, 124.3, 121.0, 119.9, 104.6, 103.9; HRMS
[(EI), M+]: 194.9681 (cal. for C8H6BrN 194.9684).
1; H NMR (600 MHz, CDCl3): 7.57 (dd, J = 7.8, 1.8 Hz, 1H),
1
7.24–7.21 (m, 2H), 6.88 (td, J = 7.2, 0.6 Hz, 1H), 6.75 (d, J = 8.4
Hz, 1H), 6.63 (s, 1H), 5.97 (s, 2H), 4.09 (s, 2H), 2.91 (s, 3H); 13C
NMR (150 MHz, CDCl3): δ 147.5, 146.7, 146.4, 128.3, 127.1,
126.2, 123.5, 122.9, 118.6, 112.1, 106.0, 103.1, 100.9, 55.0, 38.5;
HRMS [(EI), M+]: 239.0949 (cal. for C15H13NO2 239.0946).
7-Bromo-1-methyl-1H-indole (15): 7-Bromo-1H-indole (196 mg,
1.0 mmol, 1.0 equiv), NaOH (224 mg, 5.6 mmol, 5.6 equiv) and
CH3I (284 mg, 2.0 mmol, 2.0 equiv) were stirred in THF (12.5
mL) at r.t. for 4 h. Work-up by filtration of salts and extraction
(Et2O/H2O). Purification through a column chromatography [Rf =
0.8 (10% ethyl acetate in hexane)] to afford 15 as a white solid
(176 mg, 84%), mp: 52–54 ℃; IR (KBr): 3101, 3061, 2949,
2919, 1607, 1557, 1487, 1445, 1381, 1297, 1103, 918, 781, 711,
6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d][1,3]-
dioxole-5-carbaldehyde (11): Bis(pinacolato)diboron (1.22 g, 4.8
mmol, 1.2 equiv), 6-bromobenzo[d][1,3]dioxole-5-carbaldehyde
(916 mg, 4.0 mmol, 1.0 equiv), PdCl2(dppf) (88 mg, 0.12 mmol,
3 mol %) and KOAc (1.18 g, 12 mmol, 3.0 equiv) were stirred in
dry 1,4-dioxane (15 mL) under N2 at 80 °C for 36 h. Work-up by
filtration of salts and extraction (CH2Cl2/H2O). Purification
through a column chromatography [Rf = 0.5 (20% ethyl acetate in
hexane)] to afford 11 as a white solid (1.05 g, 95%), mp: 105–
107 ℃; IR (KBr): 3446, 2978, 2928, 2903, 1684, 1603, 1433,
1252 cm-1; 1H NMR (600 MHz, CDCl3): δ 10.50 (s, 1H), 7.46 (s,
1H), 7.31 (s, 1H), 6.05 (s, 2H), 1.36 (s, 12H); 13C NMR (150
MHz, CDCl3): δ 192.9, 151.7, 150.3, 138.1, 114.7, 106.7, 101.9,
84.4 (2C), 24.8 (4C), C‒B signal was not observed due to
quadruplolar relaxation; HRMS [(EI), M+]: 276.1169 (cal. for
C14H17BO5 276.1169).
577 cm-1; H NMR (600 MHz, CDCl3): δ 7.54 (d, J = 7.8 Hz,
1
1H), 7.35 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 3.0 Hz, 1H), 6.92 (t, J
= 7.8 Hz, 1H), 6.47 (d, J = 3.0 Hz, 1H), 4.17 (s, 3H); 13C NMR
(150 MHz, CDCl3): δ 133.1, 131.7, 131.7, 126.5, 120.5, 120.3,
103.9, 101.2, 36.8; HRMS [(EI), M+]: 208.9839 (cal. for
C9H8BrN 208.9840).
7-Bromo-1-methylindoline (16): Synthesis form 14: 7-Bromo-
1H-indole (980 mg, 5.0 mmol, 1.0 equiv) dissolved in formic
acid (HCO2H, 20 mL) at r.t.. The resulted solution was then
allowed to stir at 0 °C. NaBH4 (sodium borohydride, 3.78 g, 100
mmol, 20 equiv) was slowly added into the solution and kept
stirring at r.t. for 4 h. Work-up by extraction (ethyl acetate/H2O),
then purification through a column chromatography [(Rf = 0.8 (10
% ethyl acetate in hexane)] to afford 16 as a yellow liquid (562
mg, 53%). Synthesis from 17: 7-Bromoindoline (99 mg, 0.5
mmol, 1.0 equiv) and NaH (95%, 38 mg, 1.5 mmol, 3.0 equiv)
were stirred in THF (6 mL) at r.t. for 1 h. CH3I (142 mg, 1.0
mmol, 2.0 equiv) was injected into the solution and kept stirring
at 50 °C for 15 h. Work-up by filtration of salts, then purification
through a column chromatography to afford 16 as a yellow liquid
(91 mg, 86%). IR (KBr): 3448, 2949, 1633, 1414, 1268, 1086,
6-(2-Bromophenyl)benzo[d][1,3]dioxole-5-carbaldehyde (12):
PdCl2(PPh3)2 (42 mg, 0.06 mmol, 2 mol %), K3PO4·nH2O (1.04
g, 4.5 mmol, 1.5 equiv), 6-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzo[d][1,3]dioxole-5-carbaldehyde
(828
mg, 3.0 mmol, 1.0 equiv) and o-bromoiodobenzene (1.06 g, 3.75
mmol, 1.25 equiv) were stirred in dry toluene (10 mL) under N2
at 100 °C for 12 h. Work-up by filtration of salts, then
purification through a column chromatography [Rf = 0.4 (10%
ethyl acetate in hexane)] to afford 12 as a yellow solid (677 mg,
74%), mp: 86–88 ℃; IR (KBr): 3059, 2857, 2745, 1683, 1257,
1036, 546 cm-1; 1H NMR (600 MHz, CDCl3): δ 9.52 (s, 1H), 7.66
(d, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.30–
7.26 (m, 2H), 6.71 (s, 1H), 6.09 (s, 2H); 13C NMR (150 MHz,
CDCl3): δ 189.6, 152.0, 148.2, 141.8, 138.3, 132.7, 131.7, 129.8,
1050, 562 cm-1; H NMR (600 MHz, CDCl3): δ 7.20 (d, J = 7.8
1
Hz, 1H), 7.00 (dd, J = 7.2, 0.6 Hz, 1H), 6.55 (t, J = 7.8 Hz, 1H),
3.38 (t, J = 8.4 Hz, 2H), 3.11 (s, 3H), 2.95 (t, J = 8.4 Hz, 2H); 13C
NMR (150 MHz, CDCl3): δ 149.8, 133.9, 132.7, 123.4, 120.1,

ACCEPTED MANUSCRIPT
5
103.2, 57.2, 39.4, 28.5; HRMS [(EI), M+]: 210.9994 (cal. for
C9H10BrN 210.9997).
3H); 13C NMR (150 MHz, CDCl3): δ 191.6, 153.5, 151.2,
148.7, 139.8, 131.6, 130.8, 127.6, 124.3, 119.0, 118.2, 113.1,
108.0, 56.9, 56.3, 56.1, 39.1, 28.6; HRMS [(EI), M+]: 297.1368
(cal. for C18H19NO3 297.1365).
7-Bromoindoline (17): 7-Bromo-1H-indole (980 mg, 5.0 mmol
1.0 equiv) and NaBH3CN (Sodium cyanoborohydride, 471 mg,
7.5 mmol, 1.5 equiv) were stirred in AcOH (10 mL) under N2
from 0 °C to r.t. for 12 h. Work-up by adding excess ethyl acetate
to quench the reaction. Extraction (Et2O/H2O) then purification
through a column chromatography [(Rf = 0.6 (10 % ethyl acetate
in hexane)] to afford 17 as a yellow liquid (891 mg, 90%), IR
Lycosinine A (21): LiAlH4 (21 mg, 0.55 mmol, 1.1 equiv) was
added into the solution of 20 (149 mg, 0.5 mmol, 1.0 equiv) in
THF (6 mL) at r.t. and kept stirring for 2 h. Work-up by adding
excess ethyl acetate to quench the reaction, then purification
through a column chromatography [Rf = 0.2 (30 % ethyl acetate
in hexane)] to afford 21 as a colorless liquid (138 mg, 92%), IR
(KBr): 3454, 2935, 2843, 1635, 1515, 1243, 1148, 1061 cm-1; 1H
NMR (600 MHz, CDCl3): δ 7.15 (dd, J = 7.2, 1.2 Hz, 1H), 7.00
(s, 1H), 6.94 (dd, J = 7.8, 1.2 Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H),
6.85 (s, 1H), 4.22 (s, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.60 (td, J =
7.8, 2.4 Hz, 1H), 3.13–3.08 (m, 1H), 3.01–2.91 (m, 2H), 2.20 (s,
3H); 13C NMR (150 MHz, CDCl3): δ 151.0, 148.6, 148.5, 132.2,
132.1, 131.8, 129.7, 126.2, 123.9, 120.9, 112.9, 112.6, 64.6, 56.7,
56.0, 55.9, 41.0, 28.9; HRMS [(EI), M+]: 299.1525 (cal. for
C18H21NO3 299.1521).
1
(KBr): 3382, 3070, 2956, 2845, 1461, 1054, 573 cm-1; H NMR
(600 MHz, CDCl3): δ 7.17 (d, J = 7.8 Hz, 1H), 7.03 (dd, J = 7.2,
1.2 Hz, 1H)), 6.57 (t, J = 7.8 Hz, 1H), 3.98 (br, s, 1H), 3.61 (t, J
= 9.0 Hz, 2H), 3.15 (t, J = 9.0 Hz, 2H); 13C NMR (150 MHz,
CDCl3): δ 150.1, 130.4, 129.7, 123.3, 119.5, 103.1, 46.6, 30.8;
HRMS [(EI), M+]: 196.9844 (cal. for C8H8BrN 196.9840).
Galanthindole (18): PdCl2 (18 mg, 0.1 mmol, 10 mol %), dppf (6
mg, 0.1 mmol, 10 mol %), K3PO4·nH2O (691 mg, 3.0 mmol, 3.0
equiv), compound 11 (483 mg, 1.75 mmol, 1.75 equiv) and
compound 15 (210 mg, 1.0 mmol, 1.0 equiv) were stirred in dry
CH3CN (6 mL) under N2 at 100 °C for 5 h. After completion of
the reaction, the solvent was removed under vacuum, and THF
(12.5 mL) was added into the residue. LiAlH4 (42 mg, 1.1 mmol,
1.1 equiv) was then added into the solution and kept stirring at r.t.
for 3 h. Work-up by adding excess ethyl acetate to quench the
reaction. Extraction (CH2Cl2/H2O) then purification through a
column chromatography [Rf = 0.5 (30 % ethyl acetate in hexane)]
to afford 18 as a white solid (222 mg, 79%), mp: 127–129 ℃; IR
(KBr): 3353, 2917, 1482, 1227, 1042 cm-1; 1H NMR (600 MHz,
CDCl3): δ 7.62 (d, J = 7.8 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.04
(s, 1H), 6.95 (d, J = 3.0 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.82
(s, 1H), 6.52 (d, J = 3.0 Hz, 1H), 6.04 (d, J = 1.2 Hz, 1H), 6.02
(d, J = 1.2 Hz, 1H), 4.30 (s, 2H), 3.29 (s, 3H); 13C NMR (150
MHz, CDCl3): δ 147.4, 146.3, 134.1, 133.7, 132.1, 130.8, 129.7,
123.8, 123.7, 120.6, 119.1, 110.9, 107.9, 101.2, 101.1, 63.1, 35.8;
HRMS [(EI), M+]: 281.1055 (cal. for C17H15NO3 281.1052).
Acknowledgments
We thank the Ministry of Science and Technology of Republic
of China (MOST-103-2113-M-032-009-MY2) for the financial
support of this research.
Supplementary data
Experimental procedure, H and 13C NMR spectra and spectral
1
data for all compounds are available in the online version.
References and notes
1. (a) Ringer, S.; Morshead, E. A. J. Physiol. 1879, 6, 437. (b) Nakagawa,
Y.; Uyeo, S.; Yayima, H. Chem. Ind. 1956, 1238. (c) Ieven, M.;
Vlietinck, A. J.; Berghe, D. A. V.; Totte, J.; Dommisse, R.; Esmans, E.;
Alderweireldt, F. J. Nat. Prod. 1982, 45, 564.
4,5-Dimethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
benzaldehyde (19): Bis(pinacolato)diboron (1.22 g, 4.8 mmol, 1.2
equiv), 2-bromo-4,5-dimethoxybenzaldehyde (980 mg, 4.0
mmol, 1.0 equiv), PdCl2(dppf) (88 mg, 0.12 mmol, 3 mol %) and
KOAc (1.18 g, 12 mmol, 3.0 equiv) were stirred in dry 1,4-
dioxane (15 mL) under N2 at 80 °C for 36 h. Work-up by
filtration of salts and extraction (CH2Cl2/H2O). Purification
through a column chromatography [Rf = 0.4 (20% ethyl acetate in
hexane)] to afford 19 as a white solid (1.11 g, 95%), mp: 107–
109 ℃; IR (KBr): 3493, 2978, 2936, 2845, 1681, 1586, 1514,
1269 cm-1; 1H NMR (600 MHz, CDCl3): δ 10.58 (s, 1H), 7.55 (s,
1H), 7.35 (s, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 1.37 (s, 12H); 13C
NMR (150 MHz, CDCl3): δ 193.7, 152.8, 151.2, 136.3, 117.2,
108.6, 84.3 (2C), 56.1, 56.0, 24.9 (4C), C‒B signal was not
observed due to quadruplolar relaxation; HRMS [(ESI),
(M+H)+]: 293.1562 (cal. for C15H22BO5 293.1560).
2. For selected papers: (a) Chmura, S. J.; Dolan, M. E.; Cha, A.; Mauceri,
H. J.; Kufe, D. W.; Weichselbaum, R. R. Clin. Cancer Res. 2000, 6, 737.
(b) Lamoral-Theys, D.; Andolfi, A.; Goietsenoven, G. V.; Cimmino, A.;
Calvé, B. L.; Wauthoz, N.; Mégalizzi, V.; Gras, T.; Bruyère, C.;
Dubois, J.; Mathieu, V.; Kornienko, A.; Kiss, R.; Evidente, A. J. Med.
Chem. 2009, 52, 6244. (c) Slaninová, I.; Pĕnčíková, K.; Urbanová, J.;
Slanina, J.; Táborská, E. Phytochem Rev 2014, 13, 51. (d) Hatae, N.;
Fujita, E.; Shigenobu, S.; Shimoyama, S.; Ishihara, Y.; Kurata, Y.;
Choshi, T.; Nishiyama, T.; Okada, C.; Hibino, S. Bioorg. Med. Chem.
Lett. 2015, 25, 2749.
3. (a) Toriizuka, Y.; Kinoshita, E.; Kogure, N.; Kitajima, M.; Ishiyama,
A.; Otoguro, K.; Yamada, H.; Ōmura, S.; Takayama, H. Bioorg. Med.
Chem. 2008, 16, 10182. (b) Parhi, A.; Kelley, C.; Kaul, M.; Pilch, D. S.;
LaVoie, E. J. Bioorg. Med. Chem. Lett. 2012, 22, 7080.
4. Gabrielsen, B.; Monath, T. P.; Huggins, J. W.; Kefauver, D. F.; Pettit,
G. R.; Groszek, G.; Hollingshead, M.; Kirsi, J. J.; Shannon, W. M.;
Schubert, E. M.; Dare, J.; Ugarkar, B.; Ussery, M. A.; Phelan, M. J. J.
Nat. Prod. 1992, 55, 1569.
5. Rivaud, M.; Mendoza, A.; Sauvain, M.; Valentin, A.; Jullian, V. Bioorg.
Med. Chem. 2012, 20, 4856.
Lycosinine B (20): PdCl2 (18 mg, 0.1 mmol, 10 mol %), dppp (4
mg, 0.1 mmol, 10 mol %), K3PO4·nH2O (691 mg, 3.0 mmol, 3.0
equiv), compound 19 (511 mg, 1.75 mmol, 1.75 equiv) and
compound 16 (212 mg, 1.0 mmol, 1.0 equiv) were stirred in dry
CH3CN (6 mL) under N2 at 120 °C for 24 h. Work-up by
6. (a) Heinrich, M.; Teoh, H. L. J. Ethnopharmacol. 2004, 92, 147. (b)
Marco-Contelles, J.; do Carmo Carreiras, M.; Rodríguez, C.; Villarroya,
M.; García, A. G. Chem. Rev. 2006, 106, 116. (c) Unver, N. Phytochem.
Rev. 2007, 6, 125. (d) Evidente, A.; Kornienko, A. Phytochem. Rev.
2009, 8, 449.
filtration of salts, then purification through
a
column
chromatography [Rf = 0.4 (30% ethyl acetate in hexane)] to
7. Cheng, P.; Zhou, J.; Qing, Z.; Kang, W.; Liu, S.; Liu, W.; Xie, H.;
Zeng, J. Bioorg. Med. Chem. Lett. 2014, 24, 2712.
afford 20 as a yellow liquid (220 mg, 74%), IR (KBr): 3457,
1
2927, 2849, 1683, 1596, 1509, 1353, 1266, 1137, 1061 cm-1; H
8. For selected papers: (a) Viladomat, F.; Bastida, J.; Tribo, G.; Codina,
C.; Rubiralta, M. Phytochemistry 1990, 29, 1307. (b) Suau, R.; Gómez,
A. I.; Rico, R. Phytochemistry 1990, 29, 1710. (c) Wang, L.; Zhang, X.-
Q.; Yin, Z.-Q.; Wang, Y.; Ye, W.-C. Chem. Pharm. Bull. 2009, 57, 610.
(d) Wang, L.; Yin, Z.-Q.; Cai, Y.; Zhang, X.-Q.; Yao, X.-S.; Ye, W.-C.
Biochem. Syst. Ecol. 2010, 38, 444. (e) Chen, C.-K.; Lin, F.-H.; Tseng,
NMR (600 MHz, CDCl3): δ 9.77(s, 1H), 7.48 (s, 1H), 7.13 (d, J =
7.2 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.87 (s, 1H), 6.76 (t, J =
7.2 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.35 (dd, J = 16.2, 8.4 Hz,
1H), 3.25 (dd, J = 17.4, 9.0 Hz, 1H), 3.05–2.96 (m, 2H) , 2.25(s,

ACCEPTED MANUSCRIPT
6
Tetrahedron
L.-H.; Jiang, C.-L.; Lee, S.-S. J. Nat. Prod. 2011, 74, 411.
14. Viladomat, F.; Bastida, J.; Tribo, G.; Codina, C.; Rubiralta, M.
9. (a) Stark, L. M.; Lin, X.-F.; Flippin, L. A. J. Org. Chem. 2000, 65, 3227.
(b) Boger, D. L.; Wolkenberg, S. E. J. Org. Chem. 2000, 65, 9120. (c)
Lv, P.; Huang, K.; Xie, L.; Xu, X. Org. Biomol. Chem. 2011, 9, 3133.
(d) Chen, W.-L.; Chen, C.-Y.; Chen, Y.-F.; Hsieh, J.-C. Org. Lett. 2015,
17, 1613. (e) Jhang, Y.-Y.; Fan-Chiang, T.-T.; Huang, J.-M.; Hsieh, J.-
C. Org. Lett. 2016, 18, 1154.
Phytochemistry 1990, 29, 1307.
15. Baechler, S. A.; Fehr, M.; Habermeyer, M.; Hofmann, A.; Merz, K.-H.;
Fiebig, H.-H.; Marko, D.; Eisenbrand, G. Bioorg. Med. Chem. 2013, 21,
814.
16. Suau, R.; Gómez, A. I.; Rico, R.; Phytochemistry 1990, 29, 1710.
17. Unver, N.; Kaya, G. I.; Werner, C.; Verpoorte, R.; Gözler, B. Planta
10. For selected reviews: (a) Jin, Z. Nat. Prod. Rep. 2009, 26, 363. (b) Jin,
Z. Nat. Prod. Rep. 2011, 28, 1126. (c) Jin, Z. Nat. Prod. Rep. 2013, 30,
849. (d) He, M.; Qu, C.; Gao, O.; Hu, X.; Hong, X. RSC Adv. 2015, 5,
16562.
Med. 2003, 69, 869.
18. Yang, Y.; Huang, S.-X.; Zhao, Y.-M.; Zhao, Q.-S.; Sun, H.-D. Helv.
Chim. Acta 2005, 88, 2550.
19. (a) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett.
1989, 30, 2129. (b) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.;
Marcantoni, E. J. Chem. Soc., Perkin Trans. 1 1991, 2757.
11. (a) Chen, Y.-F.; Wu, Y.-S.; Jhan, Y.-H.; Hsieh, J.-C. Org. Chem. Front.
2014, 1, 253. (b) Chen, Y.-F.; Hsieh, J.-C. Org. Lett. 2014, 16, 4642.
12. Ghosal, S.; Saini, K.; Razdan, S.; Kumar, Y. J. Chem. Res. (S) 1985,
100.
13. Warren, F. L.; Wright, W. G. J. Chem. Soc. 1958, 4696.