Total synthesis of 60-hydroxyjusticidin A

Article abstract of DOI:10.1080/10286020.2011.653561

The first total synthesis of 6′-hydroxyjusticidin A, isolated from Justicia procumbens L. with good inhibitory activity against cancer cells, has been accomplished. The structure was confirmed by ¹H NMR, ¹³C NMR, and HR-ESI-MS. The key steps involved a Diels-Alder cycloaddition reaction and a reduction in NaBH₄.

Full text of DOI:10.1080/10286020.2011.653561

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Total synthesis of 6′-hydroxyjusticidin A
Lu Xiong a , Ming-Gang Bi b , Song Wu a & Yuan-Feng Tong a
a State Key Laboratory of Bioactive Substance and Function
of Natural Medicines, Department of New Drug Research and
Development, Institute of Materia Medica, Chinese Academy
of Medical Sciences and Peking Union Medical College, Beijing,
100050, China
b Institute of Medicinal Plant Development, Research Center
for Pharmacology and Toxicology, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing, 100193, China
Published online: 01 Mar 2012.
To cite this article: Lu Xiong , Ming-Gang Bi , Song Wu & Yuan-Feng Tong (2012): Total synthesis of
6′-hydroxyjusticidin A, Journal of Asian Natural Products Research, 14:4, 322-326
To link to this article: http://dx.doi.org/10.1080/10286020.2011.653561
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Journal of Asian Natural Products Research
Vol. 14, No. 4, April 2012, 322–326
Total synthesis of 60-hydroxyjusticidin A
Lu Xionga, Ming-Gang Bib, Song Wua* and Yuan-Feng Tonga*
aState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of
New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing 100050, China; bInstitute of Medicinal Plant
Development, Research Center for Pharmacology and Toxicology, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing 100193, China
(Received 18 July 2011; final version received 22 December 2011)
The first total synthesis of 60-hydroxyjusticidin A, isolated from Justicia procumbens
L. with good inhibitory activity against cancer cells, has been accomplished.
The structure was confirmed by 1H NMR, 13C NMR, and HR-ESI-MS. The key steps
involved a Diels–Alder cycloaddition reaction and a reduction in NaBH4.
Keywords: total synthesis; 60-hydroxyjusticidin A; anticancer
1. Introduction
hydroxyjusticidin A. The synthetic strategy
was outlined in Scheme 1 starting from
sesamol 2 and vertraldethyde 5. The key
steps involved a Diels–Alder reaction
between alcohol 8 and diethyl acetylenedi-
carboxylate to construct the highly sub-
stituted naphthalene and a selective
reduction of diester 9 by NaBH4. In the
process of reduction, several solvents were
tried such as methanol, ethanol, isopropa-
nol, and THF [7–9]. Because of low
solubility for diester 9 in alcohols, we
attempted to improve the yield through
enlarging the volume of solvent, improving
the temperature, or adding more NaBH4,
but the yield of the reduction was not more
than 65%. Subsequently, taking THF as
solvent, the diester 9 was reduced by
NaBH4 under refluxing for 3 h, and the
mixture was acidified by 3 mol/l hydro-
chloric acid to afford five-membered ring
inner ester 10. The yield of reduction
reaction summed up to 97.7%.
60-Hydroxyjusticidin A (Figure 1), an
arylnaphthalene lignan lactone first isolated
from Justicia procumbens L. by Yang et al.,
has been reported to exhibit good cytotox-
icity against human colon cancer cells
(HCT-8 and HT-29), human hepatoma
carcinoma cells (Bel-7402), human carci-
noma of urinary bladder cells (EJ), and
human mammary cancer cells (MCF-7).
Compared with normal cells, tumor cells are
more susceptible to 60-hydroxyjusticidin A
[1]. Moreover, the arylnaphthalene lignan
lactones have stimulated interest in the
synthetic community for their diverse
biological activities, such as phosphodi-
esterase inhibition; leukotriene biosynthesis
inhibition; hypolipidemic, antitumoral, anti-
fungal, and antiviral activities [2,3]. Herein,
we first report the total synthesis of
60-hydroxyjusticidin A.
2. Results and discussion
The yield of the total synthesis of the
natural product 1 had been achieved in
Based on the related Refs [4–7], we design
a reasonable route to synthesize 60-hydro-
*Corresponding authors. Email: ws@imm.ac.cn; tongyuanf@imm.ac.cn
ISSN 1028-6020 print/ISSN 1477-2213 online
q 2012 Taylor & Francis
http://dx.doi.org/10.1080/10286020.2011.653561
http://www.tandfonline.com

Journal of Asian Natural Products Research
323
lane as an internal standard. Electrospray
ionization (ESI) mass spectra and HR-ESI-
MS were obtained on an AutoSpec Ultima-
TOF mass spectrometer (Agilent, Santa
Clara, CA, USA). TLC was carried out on
silica gel layers and detected by UV at
254 nm (provided by Yantai Chemical
Industry Research Institute, Yantai,
China).
OCH3
4
5
3
12
13
H3CO
H3CO
11
6
2
O
7
1
10
9
8
O
1′
6′
HO
2′
3′
5′
O
4′
O
3.2 5-(Benzyloxy)benzo[d][1,3]
dioxole (3)
Figure 1. Structure of 60-hydroxyjusticidin A (1).
5-(Benzyloxy)benzo[d][1,3]dioxole (3)
was prepared via a method similar to the
literature [10], with a yield of 92.8%, mp
46.5–46.78C. 1H NMR (300 MHz, CDCl3)
d: 7.29–7.42 (m, 5H), 6.78 (d, J ¼ 8.0 Hz,
1H), 6.68 (d, J ¼ 3.0 Hz, 1H), 6.42 (dd,
J ¼ 8.0 and 3.0 Hz, 1H), 5.93 (s, 2H), and
4.99 (s, 2H). HR-ESI-MS: m/z 229.0849
[M þ H]þ (calculated for C14H13O3,
229.0865).
nearly 38.5%, and the structure of the
1
synthetic compound was confirmed by H
NMR, 13C NMR, and HR-MS, which were
identical to those of the natural product
(Table 1).
3. Experimental
3.1 General experimental procedures
Melting points were determined on YRT-3
precision melting point apparatus and are
uncorrected (Tianjin University Precision
Apparatus Factory, Tianjin, China). 1H
NMR spectra were determined on a Varian
Mercury 300 MHz spectrometer (Varian,
Palo Alto, CA, USA) using tetramethylsi-
3.3 6-(Benzyloxy)benzo[d][1,3]dioxole-
5-carbaldehyde (4)
In a 250-ml round-bottomed flask, N,
N-dimethylformamide (52 ml, 0.66 mol)
was cooled to 08C. Phosphoroxytrichloride
O
OBn
OH
OBn
O
O
O
O
O
O
b
a
O
O
O
CHO
OH
f
e
2
3
4
O
O
BnO
O
CHO
O
O
O
O
CHO
Br
c
d
O
O
Br
O
5
6
7
8
OH
OH
O
O
O
O
O
O
CO2Et
CO2Et
O
O
O
O
O
O
O
g
i
h
O
O
O
BnO
BnO
HO
BnO
O
O
O
O
O
O
O
O
9
10
11
1
Scheme 1. The synthetic route of 60-hydroxyjusticidin A. Reagents and conditions: (a) BnCl,
K2CO3, DMF, rt, 12 h, 93%; (b) POCl3, DMF, 258C, 3 h, rt, 12 h, 89.1%; (c) Br2, CH3OH, ,408C,
12 h, 92.5%; (d) ethanediol, TsOH·H2O, toluene, reflux, 3 h, 96%; (e) n-BuLi, THF, 2788C, 3 h,
100%; (f) DEADC, AcOH, CH2Cl2, 1408C, 1 h, 60.9%; (g) (1) NaBH4, THF, reflux, 3 h; (2) 3 mol/l
HCl, 97.7%; (h) CH3I, K2CO3, acetone, reflux, 1 h, 95.5%; and (i) H2, Pd/C, CH3OH, 408C, 3 h, 85.9%.

324
L. Xiong et al.
Table 1. 1H and 13C NMR spectral data of 60-hydroxyjusticidin A (300 MHz for 1H and 75 MHz for
13C NMR in DMSO-d6).
Sample prepared by synthesis
Yang et al. [14]
dH (ppm)
Atom
dH (ppm)
dC
dC
1
3
4
5
6
7
8
9
10
169.0
66.7
169.6
67.1
5.68, s
7.49, s
5.67, br s
7.49, s
147.1
100.5
149.8
151.1
105.9
130.3
119.7
123.8
129.7
124.8
113.1
110.6
139.6
147.4
97.6
147.6
101.0
150.3
151.6
106.4
130.7
120.2
124.4
130.1
125.4
113.6
111.0
140.1
147.7
98.1
6.92, s
6.91, s
11
12
13
10
20
6.59, s
6.56, s
6.59, s
6.57, s
30
40
50
60
149.7
150.0
60-OH
30-OCH2O-40
5.98, s
5.98, br s
4-OCH3
7-OCH3
6-OCH3
8.96, s
5.99, s
100.9
5.99, br s
101.3
4.11, s
3.92, s
3.64, s
59.0
55.6
55.2
4.11, s
3.92, s
3.65, s
59.6
56.1
55.7
(23.3 ml, 0.248 mol) was slowly added via
syringe under continuous stirring. The
reaction mixture was stirred for 2 h at the
same temperature and then allowed to
warm to room temperature. After 10 min,
compound 3 (37.7 g, 0.147 mol) in 20 ml
dry N, N-dimethylformamide was added
via syringe, and the resultant mixture was
stirred overnight at room temperature. The
reaction mixture was poured into 250 ml
ice water at 08C and produced a light
yellow solid. The reaction mixture was
then extracted with EtOAc (3 £ 100 ml),
and the organic layers were collected,
combined, dried over anhydrous Na2SO4,
and concentrated. The crude product 4 was
purified by recrystallization in EtOAc
[11]. Yield: 37.7 g (89.1%), mp 95.8–
96.08C. 1H NMR (300 MHz, DMSO-d6) d:
10.19 (s, 1H), 7.30–7.48 (m, 5H), 7.08
(s, 1H), 6.10 (s, 1H), and 5.23 (s, 2H).
HR-ESI-MS: m/z 257.0851 [M þ H]þ
(calculated for C15H13O4, 257.0814).
3.4 6-Bromoveratraldehyde (6)
6-Bromoveratraldehyde (6) was prepared
via a method similar to the literature [12]
with a yield of 96%, mp 150.5–150.68C.
1H NMR (300 MHz, DMSO-d6) d: 10.06
(s, 1H), 7.31 (s, 2H), 3.89 (s, 3H), and 3.81
(s, 3H). HR-ESI-MS: m/z 244.9799
[M þ H]þ (calculated for C9H10BrO3,
244.9813).
3.5 2-(2-Bromo-4,5-dimethoxyphenyl)
-1,3-dioxolane (7)
2-(2-Bromo-4,5-dimethoxyphenyl)-1,3-
dioxolane (7) was prepared via a method
similar to the literature [7] with a yield of

Journal of Asian Natural Products Research
325
96%. The crude product was purified by
recrystallization in EtOAc, mp 108.5–
After work-up as above, the crude product
was recrystallized from 95% ethanol to
afford a colorless solid 9 (10.3 g, 60.9%),
1
108.78C. H NMR (300 MHz, DMSO-d6)
1
d: 7.12 (s, 1H), 7.03 (s, 1H), 5.83 (s, 1H),
4.11 (t, J ¼ 7.2 Hz, 2H), 3.99 (t, J ¼
7.2 Hz, 2H), 3.89 (s, 3H), and 3.81 (s, 3H).
HR-ESI-MS: m/z 289.0156 [M þ H]þ
(calculated for C11H14BrO4, 289.0075).
mp 173.8–173.98C. H NMR (300 MHz,
DMSO-d6) d: 11.93 (s, 1H), 7.63 (s, 1H),
7.13–7.16 (m, 3H), 6.64–6.95 (m, 3H),
6.63 (s, 2H), 6.03 (d, J ¼ 6.0 Hz, 2H), 4.92
(s, 2H), 4.31 (q, J ¼ 6.0 Hz, 2H), 3.95–3.93
(m, 5H), 3.59 (s, 3H), 1.25 (t, J ¼ 6.0 Hz,
3H), and 0.93 (t, J ¼ 6.0 Hz, 3H). HR-ESI-
MS: m/z 575.1895 [M þ H]þ (calculated
for C32H31O10, 575.1917).
3.6 (2-(1,3-Dioxolan-2-yl)-4,
5-dimethoxyphenyl)-(6-(benzyloxy)
benzo[d][1,3]dioxol-5-yl) methanol (8)
Compound 7 (9.04 g, 31.4 mmol) was
dissolved in dry THF (200 ml) under
nitrogen, cooled to 2788C, and n-BuLi
(1.6 M in hexanes, 20.0 ml, 32.1 mmol)
was added dropwise over 15 min. The
mixture was stirred for another 15 min,
followed by the addition of the THF
(50 ml) solution of compound 4 (8.04 g,
31.4 mmol) dropwisely. After stirring for
30 min, the solution was gradually warmed
to room temperature and was stirred for
2.5 h, followed by the addition of H2O
(170 ml). The resulting mixture was
extracted with EtOAc (3 £ 150 ml), dried
(Na2SO4), and concentrated to give a
colorless solid 8 (14.6 g, 100%) [13]. The
crude product immediately reacted in the
following Diels–Alder reactions without
3.8 60-Benzyloxydiphyllin (10)
Compound 9 (9.8 g, 17.1 mmol), NaBH4
(3.2 g, 85.6 mmol), and THF (200 ml) were
refluxed for 3 h. The solution gradually
increased to room temperature, HCl
(3 mol/l) was added cautiously to adjust
the pH to 2–3, and the mixture was stirred
for 1 h, followed by extraction with EtOAc
(3 £ 50 ml) [12–14]. The solution was
concentrated to give a yellow solid which
was then recrystallized from 95% EtOH to
afford pure 60-benzyloxydiphyllin 10
(8.1 g, 97.7%), mp 228.1–228.88C. 1H
NMR (300 MHz, DMSO-d6) d: 10.33 (s,
1H), 7.61 (s, 1H), 7.14 (m, 4H), 6.72–6.93
(m, 4H), 6.05 (s, 2H), 5.34 (s, 2H), 4.90
(d/d, J ¼ 12.0, 12.0 Hz, 2H), 3.93 (s, 3H),
and 3.61 (s, 3H). HR-ESI-MS: m/z 487.
1390 [M þ H]þ (calculated for C28H23O8,
487.1393).
1
purification. H NMR (300 MHz, DMSO-
d6) d: 7.29–7.35 (m, 5H), 7.01 (s, 1H),
6.96 (s, 1H), 6.78 (s, 1H), 6.31 (s, 1H),
5.92 (d, J ¼ 5.4 Hz, 2H), 5.85 (s, 1H), 5.50
(s, 1H), 5.08 (d/d, J ¼ 12.0 and 12.0 Hz,
2H), 3.95 (t, J ¼ 8.7 Hz, 2H), and 3.74–
3.65 (m, 8H). HR-ESI-MS: m/z 489.1513
[M þ Na]þ (calculated for C26H26NaO8,
489.1525).
3.9 60-Benzyloxyjusticidin A (11)
Compound 10 (4.4 g, 9.1 mmol), dry
acetone (300 ml), MeI (2.3 ml), and anhy-
drous K2CO3 (3.9 g, 27.3 mmol) were
refluxed for 1 h. The mixture was concen-
trated to give a yellow solid, washed with
water and extracted with EtOAc, concen-
trated, to give a light yellow solid
3.7 Diethyl-1-(6-(benzyloxy)
benzo[d][1,3]dioxol-5-yl)-4-hydroxy-
6,7-dimethoxynaphthalene-2,
3-dicarboxylate (9)
60-benzyloxyjusticidin
A (11, 4.4 g,
Compound 8 (14.6 g, 31.4 mmol), diethyl
acetylenedicarboxylate (DEADC, 5.9 g,
34.5 mmol), CH2Cl2 (14.7 ml), and acetic
acid (10 ml) were heated at 1008C for 1 h.
95.5%), mp 213.8–213.98C.1H NMR
(300 MHz, DMSO-d6) d: 7.51 (s, 1H),
7.14 (m, 3H), 6.95 (s, 1H), 6.85 (m, 3H),
6.73 (s, 1H), 6.06 (s, 2H), 5.71 (s, 2H), 4.88

326
L. Xiong et al.
Special Scientific Project for the Ministry of
Health of China (200802038).
(d/d, J ¼ 12.0 and 12.0 Hz, 2H), 4.14
(s, 3H), 3.94 (s, 3H), and 3.61 (s, 3H).
HR-ESI-MS: m/z 501.1528 [M þ H]þ
(calculated for C29H25O8, 501.1549).
References
[1] P. Zhang, W.Q. Zhou, and X.Z. Dong,
Chin. J. Pharmacol. Toxicol. 24, 207
(2010).
3.10 60-Hydroxyjusticidin A (1)
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palladium on carbon (wet, 65% water) in
THF (50ml) was stirred under 1atm of
hydrogen at room temperature for 3 h. The
reaction mixture was filtered through a pad
of Cellite, and concentrated under reduced
pressure. The resulting crude product was
recrystallized from DMSO and H2O (1:5) to
afford the target conpound 1 (0.76 g, 85.9%)
1
as a light yellow powder, mp . 2608C. H
NMR spectral data were identical to those
reported in the literature [14]. HR-ESI-MS:
m/z 411.1057 [M þ H]þ (calculated for
C22H19O8, 411.1080).
[9] S.P. Adams and H.W. Whitlock, J. Org.
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Acknowledgements
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Financial support was provided by the Basic
Research Special Fund of Institute of Materia
Medica, Chinese Academy of Medical Sciences
(2011CHX16); Major Scientific and Techno-
logical Special Project for ‘Significant New
Drugs Innovation’ (2009ZX09301-003); and