Rapid synthesis of ismine, a bioactive amaryllidaceae alkaloid

Article abstract of DOI:10.3184/174751917X14894997017496

Ismine (6-[2-(methylamino)phenyl]-1,3-benzodioxole-5-methanol, 1), a biologically active alkaloid, has been synthesised by a rapid and simple four-step sequence. This synthesis involved a consecutive aryl-aryl and N-aryl coupling, leading to a phenanthridine derivative in a one-pot sequence, which employed a palladium catalyst and trifurylphosphine as the ligand. This synthesis gave an overall yield of 23%.

Full text of DOI:10.3184/174751917X14894997017496

202 RESEARCH PAPER
VOL. 41 APRIL, 202–204
JOURNAL OF CHEMICAL RESEARCH 2017
Rapid synthesis of ismine, a bioactive amaryllidaceae alkaloid
Jing-jing Guoa,b, Bi-juan Yangb,c, Chen-xu Jingb, Duo-zhi Chenb* and Xiao-jiang Haob
aCollege of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming 650500, P.R. China
bState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, P.R. China
cSchool of Chemical Science and Technology, Yunnan University, Kunming 650000, P.R. China
Ismine (6-[2-(methylamino)phenyl]-1,3-benzodioxole-5-methanol, 1), a biologically active alkaloid, has been synthesised by a rapid and
simple four-step sequence. This synthesis involved a consecutive aryl–aryl and N–aryl coupling, leading to a phenanthridine derivative in
a one-pot sequence, which employed a palladium catalyst and trifurylphosphine as the ligand. This synthesis gave an overall yield of 23%.
Keywords: amaryllidaceae alkaloid, palladium catalyst, aryl–aryl coupling, N–aryl coupling
Ismine (6-[2-(methylamino)phenyl]-1,3-benzodioxole-5-methanol,
1, Fig. 1) is a natural bioactive alkaloid that was first isolated from
an Ismene species in 1961.1 During the ensuing 50 years, ismine
was found to have neuroprotective, antibacterial, antifungal and
cytotoxicity activities.2–6 We have previously identified ismine as an
activator of the Wnt signalling pathway that targets the DIX domain
of the Axin protein and potentiates the Axin–LRP6 association,
7
promoting Wnt signalling transduction.
In the light of these results, structural modification of ismine
Fig. 1 The structure of ismine (1).
is needed and larger amounts of material are required to confirm
and further explore the potential activities of ismine compounds
in bioassays, including in vivo assays. However, ismine cannot
be readily isolated from plants. Therefore, we have designed a
totally synthetic route for the production of ismine.
the key intermediate 5, which can be rapidly transformed into
the target compound, ismine, by hydrolysis of lactam and
hydrogenation (Fig. 2).
As shown in Fig. 3, ismine was synthesised from 2-bromo-
4,5-(methylenedioxy)benzoic acid (2) in four steps. First,
compound 2 was amidated with methylamine to obtain
N-methyl-2-bromo-4,5-(methylenedioxy)benzamide (3), which
was then coupled with iodobenzene (4) using a palladium
catalyst to afford 5-methyl-[1,3]dioxolo-phenanthridin-6-one
(5). This was followed by hydrolysis of the lactam group in
35% aqueous HCl to afford 6. Finally, ismine (1) was obtained
by reduction of 6 in the presence of lithium aluminium hydride
(LAH).
Results and discussion
According to the retrosynthetic analysis of compound 1, we
concluded that ismine could be obtained by reduction of
6-[2-(methylamino)phenyl]benzo[1,3]dioxole-5-carboxylic
acid (6), which is the lactam ring-opening product of
5-methyl-[1,3]dioxolo-phenanthridin-6-one (5). We have
previously developed a rapid synthetic method for obtaining
phenanthridine compounds from halogenated benzamide
analogues and iodobenzene by an efficient and consecutive
aryl–aryl and N–aryl coupling process.8 Therefore, this simple
phenanthridine synthetic method could be employed to prepare
Reagents and conditions: (a) SOCl2, DMF, THF, 50 °C, 2 h;
(b) CH3NH2 (30%), 5 °C, 1 h, 78% yield; (c) K2CO3, norbornene,
Fig. 2 The retrosynthetic analysis of ismine.
* Correspondent. E-mail: chenduozhi@mail.kib.ac.cn

JOURNAL OF CHEMICAL RESEARCH 2017 203
Fig. 3 Total synthesis of ismine (1).
5-Methyl-[1,3]dioxolo-phenanthridin-6-one (5)
Pd(OAc)2, TFP, MeCN, 95 °C, 12 h, 60% yield; (d) 35% HCl, 120
°C, 48 h, 75% yield; (e) LAH, CH2Cl2, −40 °C, 4 h, 65% yield.
An efficient and convenient synthetic route to ismine was
developed for the production of sufficient quantities to enable its
use in further bioassays. This new route hinges on an efficient
palladium-catalysed coupling reaction involving consecutive
aryl–aryl and N–aryl coupling. This relatively simple procedure,
utilisation of cheap and readily available reagents, and overall
yield (23%) of products are the main advantages of the present
approach.
A flask was charged under nitrogen with Pd(OAc)2 (5.0 mg,
0.02 mmol), tri-2-furylphosphine (10 mg, 0.035 mmol), K2CO3
(72.3 mg, 0.52 mmol), the amide 3 (0.26 mmol), a solution of
norbornene (40 mg, 0.4 mmol) in anhydrous solvent (7 mL), and
iodobenzene (4, 0.26 mmol). The mixture was heated with stirring at
95 °C for 12 h and then cooled to room temperature. After the addition
of saturated NH4Cl (30 mL) and extraction with EtOAc (3 × 20 mL),
the combined organic extracts were washed with brine (50 mL) and
dried over Na2SO4. Removal of the solvent under reduced pressure
gave the crude product, which was purified by flash chromatography
on silica gel to furnish 5 as: Colourless powder; m.p. 237–239 °C;
Experimental
1
yield 52 mg (80%); H NMR (500 MHz, CDCl3): δ 8.10 (dd, J = 8.7,
ESI and HREIMS were recorded using a Finnigan MAT 90 instrument
and VG Auto Spec-3000 spectrometer, respectively. Melting points were
measured using X-4 apparatus (Yingyu Yuhua Instrument Factory,
Gongyi, Henan Province, China). NMR experiments were carried out on
a Bruker AM-400 spectrometer, a DRX-500 spectrometer or an Avance
III 600 spectrometer with the solvents CDCl3, DMSO-d6 and Me4Si as
internal standard. Column chromatography was performed on silica
gels (60–80 mesh, 200–300 mesh, 300–400 mesh, Qingdao Haiyang
Chemical Co. Ltd., Qingdao, China). Pre-coated silica gel 60 F254
(Merck, Darmstadt, Germany) was used for TLC. Semi-preparative
HPLC was performed on a Hypersil Gold RP-C18 column (i.d. 10 × 250
mm; Thermo Fisher Scientific Inc., Waltham, Massachusetts, USA)
eluted with CH3CN–H2O at room temperature. All regular solvents and
reagents were reagent grade and were purchased from Aldrich-Sigma
Chemical Co., Acros Organics or J&K Scientific. The purities of all
compounds were over 95% as determined by HPLC. All yields reported
are for dry compounds that require no further purification for use in
other reactions.
1.5 Hz, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.45–7.36 (m, 2H), 7.30 (t, J =
7.3 Hz 1H), 6.15 (s, 2H), 3.13 (s, 3H); 13C NMR (500 MHz, CDCl3): δ
160.8 (C), 152.2 (C), 148.3 (C), 137.3 (C), 130.5 (C), 128.7 (CH), 122.8
(CH), 122.3 (CH), 121.1 (C), 119.1 (C), 115.2 (CH), 106.9 (CH), 101.8
(CH2), 100.3 (CH), 30.2 (CH3); HREIMS m/z: 253.0731 [M]+ (calcd
for C15H11NO3, 253.0739).
6-(2-(Methylamino)phenyl)benzo[d][1,3]dioxole-5-carboxylic acid
(6)
Compound 5 (29 mg, 0.1 mmol) was dissolved in DMF (1 mL). The
solution was then cooled to −5 °C and aqueous HCl (35%, 5 mL) was
added. The mixture was then heated to 120 °C and stirred for 48 h. It
was then diluted with saturated NaHCO3 (10 mL). The solution was
extracted with CH2Cl2 (2 × 25 mL), and the organic layer was washed
with brine, concentrated and then purified by column chromatography
using chloroform:methanol (30:1) as the eluent to give 6 as: Pale yellow
1
powder; m.p. 197–199 °C; yield 21 mg (75%); H NMR (500 MHz,
CDCl3): δ 8.02 (dd, J = 8.1, 1.5 Hz, 1H), 7.82 (s, 1H), 7.60 (s, 1H),
7.36–7.32 (m, 2H), 7.26 (t, J = 7.7 Hz, 1H), 6.07 (s, 2H), 3.05 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 163.2 (C), 152.3 (C), 148.5 (C), 142.3
(C), 137.0 (C), 133.0 (CH), 131.8 (C), 130.6 (C), 127.3 (CH), 122.4
(CH), 121.9 (CH), 106.7 (CH), 102.2 (CH2), 100.8 (CH), 29.7 (CH3);
HREIMS m/z: 271.0839 [M]+ (calcd for C15H13NO4, 271.0845).
N-Methyl-2-bromo-4,5-(methylenedioxy)benzamide (3)
Compound 2 (260 mg, 1 mmol) was dissolved in THF (20 mL), to
which DMF (0.1 mL) and SOCl2 (0.5 mL, 4mmol) were added. The
solution was stirred for 2 h at 50 °C and then concentrated to remove
THF. The residue was then added to a 30% solution of methylamine in
water (20 mL) at 5 °C and filtered. The cake was purified by column
chromatography to give 3 as: Pale yellow solid; m.p. 184–185 °C; yield
6-[2-(Methylamino)phenyl]-1,3-benzodioxole-5-methanol (ismine)
(1)
1
200 mg (78%); H NMR (500 MHz, CDCl3): δ 7.03 (s, 1H), 6.98 (s,
A solution of 6 (30 mg, 0.1 mmol) in THF (5 mL) and CH2Cl2 (10 mL)
was added to LAH (30 mg) at −5 °C. The reaction was stirred for 6 h at
room temperature and then quenched using H2O (5 mL). The mixture
was then extracted with Et2O (2 × 20 mL). The organic phase was
washed with brine and concentrated, and the residue was purified by
1H), 6.01 (s, 2H), 2.99 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 167.7
(C), 149.7 (C), 147.5 (C), 131.0 (C), 113.2 (CH), 110.6 (C), 109.7 (CH),
102.3 (CH2), 26.8 (CH3); HREIMS m/z: 256.9684 [M]+ (calcd for
C9H8BrNO3, 256.9688).

204 JOURNAL OF CHEMICAL RESEARCH 2017
column chromatography to give 1 as: Colourless solid; m.p. 98–99 °C;
yield 17 mg (65%); 1H NMR (400 MHz, CDCl3): δ 7.29 (t, J = 1.5 Hz,
1H), 7.02 (s, 1H), 7.00 (dd, J = 7.5, 1.4 Hz, 1H), 6.83 (dd, J = 14.8, 7.6
Hz, 1H), 6.75 (d, J = 8.2Hz, 1H), 6.69 (s, 1H), 6.01 (s, 2H), 4.27 (d,
J = 12.0, 1H), 4.21 (d, J = 12.0, 1H), 2.75 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 147.6 (C), 147.5 (C), 146.6 (C), 133.9 (C), 131.1 (C), 129.9
(CH), 129.0 (CH), 127.4 (C), 118.4 (CH), 111.0 (CH), 110.2 (CH), 109.9
(CH), 101.3 (CH2), 63.8 (CH2), 30.8 (CH3); HREIMS m/z: 257.1055
[M]+ (calcd for C15H15NO3, 257.1052).9
Received 9 October 2016; accepted 18 February 2017
Paper 1604366
https://doi.org/10.3184/174751917X14894997017496
Published online: 29 March 2017
References
1
2
R.J. Highet, J. Org. Chem., 1961, 26, 4767.
C. Iannello, J. Bastida, F. Bonvicini, F. Antognoni, G.A. Gentilomi and F.
Poli, Nat. Prod. Res., 2014, 28, 704.
3
4
T. Morikawa, K. Ninomiya, H. Kuramoto, I. Kamei, M. Yoshikawa and O.
Muraoka, J. Nat. Med., 2016, 70, 89.
L. Cahlikova, M. Hrabinova, A. Kulhankova, N. Benesova, J. Chlebek, D.
Jun, Z. Novak, K. Macakova, J. Kunes, K. Kuca and L. Opletal, Nat. Prod.
Commun., 2013, 8, 1541.
Z. Luo, F. Wang, J. Zhang, X. Li, M. Zhang, X. Hao, Y. Xue, Y. Li, F.D.
Horgen, G. Yao and Y. Zhang, J. Nat. Prod., 2012, 75, 2113.
J.E. Ortiz, S. Berkov, N.B. Pigni, C. Theoduloz, G. Roitman, A .Tapia, J.
Bastida and G.E. Feresin, Molecules, 2012, 17, 13473.
S. Wang, J.L. Yin, D.Z. Chen, F. Nie, X.M. Song, C. Fei, H.F. Miao, C. Jing,
B.W. Ma, J.L. Wang, S.C. Xie, C. Li, R. Zeng, W.J. Pan, X.J. Hao and L. Li,
Nat. Chem. Biol., 2013, 9, 579.
Acknowledgements
This research was supported financially by the national Natural
Science Foundation of China (81402828 and 21432010), the
“Light of Western” foundation of the Chinese Academy of
Sciences, the Natural Science Fund of Yunnan Province
(2016FB015) and the Foundation of State Key Laboratory of
Phytochemistry and Plant Resources in West China (P2015-
ZZ14).
5
6
7
Electronic Supplementary Information
8
9
C.X. Jing, J.Y. Cai, Y. Zhang, D.Z. Chen and X.J. Hao, J. Chem. Res., 2015,
39, 247.
D.T.A. Youssef, J. Nat. Prod., 2001, 64, 839
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