An efficient total synthesis of chrysophanol and the sennoside C aglycon

Article abstract of DOI:10.1016/j.tetlet.2005.08.154

A rapid synthetic approach to the naturally occurring chrysophanol and the sennoside C aglycon is reported. The method involves a three-step protocol starting with commercially available aloin-A to give the two title compounds.

Full text of DOI:10.1016/j.tetlet.2005.08.154

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7571–7573
An efficient total synthesis of chrysophanol
and the sennoside C aglycon
*
Nikolai Kuhnert and Hoshiar Y. Molod
Chemistry, School of Biomedical and Molecular Sciences, The University of Surrey, Guildford GU2 7XH, UK
Received 26 May 2005; revised 19 August 2005; accepted 26 August 2005
Available online 16 September 2005
Abstract—A rapid synthetic approach to the naturally occurring chrysophanol and the sennoside C aglycon is reported. The method
involves a three-step protocol starting with commercially available aloin-A to give the two title compounds.
Ó 2005 Published by Elsevier Ltd.
Sennosides A–D 1A–D and chrysophanol 2 are a family
strong criticism and require pure synthetic material.
5
of polyphenolic compounds isolated from Senna plants
Chrysophanol 2 has been extracted from Cassia siamea
1
6
including Cassia acutifolia or Cassia angustifolia. C.
and Senna rugosa plants and synthesised biochemically
7
8
acutifolia is native to Egypt and Sudan, while C. angus-
tifolia is native to Somalia and Arabia. These plants
have been used for centuries as an effective herbal laxa-
tive. They are clinically used to treat constipation and to
from an octaketide, and from emodin. A multi-step
chemical synthesis of chrysophanol 2 has also been
9
reported. The compound was shown to exhibit anti-
1
0,11
fungal activity.
2
clean bowels. Despite the frequent use of cassia extracts
it is so far unknown, which of the naturally occurring
sennosides A–D (the sennosides A–D differ in their aro-
matic substitution pattern as well as in their C10–C10
stereochemistry) is responsible for their biological activ-
ity, hence a reliable synthesis is required for their full
biological evaluation.
A synthesis of the sennoside C aglycon 1 has not been
attempted previously. The original structure of the sen-
nosides was reported in 1950 based on elegant chemical
0
1
2,13
degradation procedures.
In this letter, we report a short total synthesis of
chrysophanol and the sennoside C aglycon. Starting
from commercially available aloe emodin 3 oxidative
Furthermore, the sennosides are currently under close
scrutiny due to their reported tumour promoting activi-
cleavage using aqueous FeCl afforded dianthron 4 in
3
3
,4
ties. The data, however, are inconclusive and under
good yield. Reduction with SnCl in HOAc produced
2
β-D-Glc-O
O
OH
β-D-Glc-O
O
OH
1
OH
O
O
OH
1
0
10
COOH
R
COOH
R
H
H
H
H
1
0'
10'
O
1A,C
1B,D
β-D-Glc-O
O
OH
β-D-Glc-O
OH
Chrysophanol 2
C 10-C10' cis (meso)
Sennoside B R = COOH
Sennoside D R = CH OH
C10-C10' trans:
Sennoside A R = COOH
Sennoside C R = CH OH
2
2
*
0
Corresponding author. E-mail: n.kuhnert@surrey.ac.uk
040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.08.154

7572
N. Kuhnert, H. Y. Molod / Tetrahedron Letters 46 (2005) 7571–7573
OH
O
OH
OH
O
OH
OH
O
O
OH
OH
O
OH
SnCl2
FeCl3
+
OH H O
2
OH
OH HOAc
O
OH
OAc
2
5%
H
3
OH
O
5
52%
4
74%
Chrysophanol 2
HO
OH
O
OH
OH
O
OH
OH
OH
8%
1
2
. Pd/O2
H
H
. NaOAc
OAc
7
5
OH
O
OH
6
a 30:70 mixture of chrysophanol 2 and anthron 5 as
judged from the H NMR spectrum of a crude reaction
References and notes
1
mixture. The two compounds could be separated by
column chromatography yielding chrysophanol 2 in a
1. Martindale, The Extra Pharmacopoeia, 25th ed.; The
Pharmaceutical Press, Department of Parmaceutical Sci-
ence, 1967; pp 1266–1268; The Review of Natural Products,
2nd ed.; Facts & Comparisons, 2002; pp 588–589.
1
4
2
5% isolated yield and anthron 5 in a 52% isolated
1
5
yield. Similar selective reduction of the C-9 carbonyl
as opposed to the C-1 carbonyl has been reported by
Alexander et al. and was attributed to a protected
Sn-chelate complex being formed between C-10 (C@O)
and the neighbouring phenolic OH (either C-4 or
2
. Iijima, O. T.; Kondo, K.; Itakura, H.; Yoshie, F.;
Miyamoto, H.; Kubo, M.; Higuchi, M.; Takeda, H.;
Matsumiya, T. J. Ethnopharmacol. 2004, 91, 89–94.
3
. Mascolo, N.; Capasso, R.; Capasso, F. Phytother. Res.
1
998, 12, 143–145.
1
6,17
C-5).
4. Kleibeuker, J. H.; Cats, A.; Zwart, N.; Mulder, N. H.;
Hardonk, M. G.; De Vries, E. G. E. J. Nat. Cancer Inst.
1995, 87, 452–453.
The chrysophanol obtained showed identical spectro-
8
5
6
7
. Singh, V.; Singh, J.; Sharma, J. P. Phytochemistry 1992,
scopic data to those reported in the literature.
3
1, 2176–2177.
. Barbosa, F. G.; De Oliveira, M. D. D. F.; Braz, R.;
Silveira, E. R. Biochem. Syst. Ecol. 2004, 32, 363–365.
. Inouye, H.; Leistner, E. In Chemistry of the Quinoid
Compounds; Patai, S., Rappaport, Z., Eds.; Wiley: New
York, 1988; Vol. 2, Chapter 22, p 1293.
Surprisingly, the SnCl is able to act as a reducing agent
2
for the benzylic alcohol functionality in 4. We are not
aware of any precedents for using SnCl in the reduction
2
of benzylic alcohols. This synthetic procedure allows the
synthesis of large quantities of chrysophanol in only two
synthetic steps.
8
. Anderson, J. A. Phytochemistry 1985, 25(1), 103–106.
9. Ahmed, S. A.; Bardshiri, E.; Simpson, T. J. J. Chem. Soc.,
Chem. Commun. 1987, 883–884; Ahmed, S. A.; Bardshiri,
E.; McIntyre, C. R.; Simpson, T. J. Aust. J. Chem. 1992,
The second major product of the reaction, anthron 5,
could be oxidatively coupled using palladium on char-
coal in the presence of atmospheric oxygen to give
the sennoside aglycon 6 as a single diastereoisomer
4
5, 249–274.
1
0. Agarwal, S. K.; Singh, S. S.; Verma, S.; Kumar, S. J.
Ethnopharmacol. 2000, 72, 43–46.
11. Choi, G. J.; Lee, S. W.; Jang, K. S.; Kim, J. S.; Cho, K. Y.;
1
13
as judged by H and C NMR spectroscopy. The sur-
prisingly high diastereoselectivity can be tentatively
explained by assuming p–p stacking between the two
Kim, J. C. Crop Prot. 2004, 1–7.
1
1
2. Stoll, A.; Becker, B.; Helfenstein, A. Helv. Chim. Acta
950, 33, 313–328.
3. Stoll, A.; Becker, B. Fort. Chem. Org. Nat. 1950, 7, 248.
1
1
8
reacting anthrons 5 .The analytical data confirms that
the C -symmetric sennoside C aglycon is the product of
the reaction as opposed to the meso-diastereomer.
14. A typical procedure for the preparation of 2 is as follows:
To a solution of 0.8 g (2.96 mmol) aloe-emodin in a
mixture of 6 ml of concentrated HCl and 24 ml of acetic
acid was added 1.1 g (5.92 mmol) tin chloride and the
resulting mixture was heated to 120 °C for 1 h. The
reaction was cooled to room temperature, 50 ml of water
was added to the mixture whereupon an orange solid
precipitated. The solid precipitate was filtered and dried to
recover 0.72 g of a mixture of products. The product was
2
1
2,13,19
In conclusion, we have succeeded in developing a novel
and rapid synthetic route to the naturally occurring sen-
noside C aglycon and chrysophanol from commercially
available aloin A.
purified by column chromatography (SiO
Lp (40–60 °C) 1:1) to give the title compound 2 as an
orange solid (0.19 g, 25%); R 0.36 [ether–Lp (bp 40–
2
, diethyl ether–
Acknowledgements
f
Funding by EPSRC (project GR/R17751/01) is thank-
fully acknowledged.
60 °C) (1:1)]; dH (300 MHz, CDCl ): 12.11 (1H, s, ArOH),
3
12.00 (1H, s, ArOH), 7.81 (1H, s, Ar), 7.64–7.67 (2H, m,

N. Kuhnert, H. Y. Molod / Tetrahedron Letters 46 (2005) 7571–7573
7573
Ar), 7.28 (1H, d, J 8.5, Ar), 7.09 (1H, s, Ar), 2.46 (3H, s,
ArCH ); d (75 MHz, CDCl ) 199.5 (CO), 193.1 (CO),
63.0, 162.7, 140.7, 138.6, 137.3, 135.4, 124.8, 124.7, 122.1,
21.7, 121.0, 120.2 (Ar), 30.1 (ArCH ). MS (ESI, negative
18. A typical procedure for the preparation of 6 is as follows:
To a solution of 0.05 g (0.15 mmol) anthrone 8 in 30 ml
aqueous sodium hydroxide was added 25 mg of Pd on
charcoal. Oxygen was bubbled through the solution for
2 h. at room temperature. Ten millilitres of hydrochloric
acid (3 M) was added to the solution and the crude
product was precipitated. The crude solid was filtered and
dried to give the title compound 6 as an orange solid
3
C
3
1
1
3
ion mode), m/z 253 [MꢀH].
5. The analytical data of 5 are as follows: R
ether–Lp (bp 40–60 °C) (1:1)]; mp 95–98 °C; m
1
f
0.8 [diethyl
(Nujol)/
max
ꢀ1
cm 1667 (CO ketone), 1584 (C@C aromatic), 1242 (C–
O); d (300 MHz, CDCl ) 12.29 (1H, s, OH), 12.28 (1H, s,
OH), 7.48 (1H, t, J 7.4, Ar), 6.80–6.90 (4H, m, Ar), 4.73
2H, s, Ar–CH –Ar), 4.34 (2H, s, CH COOCH ), 2.16 (3H,
s, COCH ); d (125 MHz, CDCl ) 193.8 (CO ketone),
70.8 (CO ester), 150.3, 145.9, 142.4, 142.0, 136.1, 135.4,
25.1, 121.6, 118.8, 116.5, 115.7, 113.1 (Ar), 65.3 (CH O),
H
3
H 3
(0.03 g 78%); d (500 MHz, CDCl ): 7.81 (2H, d, J 7.4,
Ar), 7.64–7.69 (4H, m, Ar), 7.28 (2H, d, J 8.4, Ar), 7.09
(2H, s, Ar), 4.81 (2H, s, ArCHCHAr), 4.46 (4H,
2 C 3
CH OH); d (125 MHz, CDCl ) 193.2 (CO), 162.5,
(
2
2
3
3
C
3
1
1
3
150.1, 137.8, 133.9, 124.6, 124.3, 121.2, 121.1, 119.9,
118.1, 117.8, 116.5 (Ar), 78.1 (C–O), 74.5 (OCH ), 63.1
2
2
+
2.9 (ArCH
2
Ar), 22.34 (COCH
3
); Found (CI) 299.0918
(ArCHCHAr); m/z (CI) 511 (100%, M +H), 477 (10,
[
M+H], C17
H
15
O
5
requires 299.0914; m/z (EI) 299 (80%,
Mꢀ2OH), 420 (50, 477ꢀCO), 390 (477ꢀCOC
6 4
H OH),
+
+
+
M ), 255 (20, M ꢀCOCH
3
), 241 (100, M ꢀCH
2
COCH
3
).
120 (5, COC OH).
6 4
H
n
1
6. Alexander, J.; Bhatia, A. V.; Mitscher, L. A.; Omoto, S.;
Suzuki, T. J. Org. Chem. 1980, 45, 20–24.
19. The synthetic material is identical by LC–MS to material
assigned as sennoside C aglycone on comparison to
authentic natural material (spiking of natural extract).
For conditions see: Duez, P. J. Chromatogr. 1984, 303,
391–395.
1
7. Alexander, J.; Bhatia, A. V.; Clark, G. W., II; Leutzow,
A.; Mitscher, L. A.; Omoto, S.; Suzuki, T. J. Org. Chem.
1
980, 45, 24–28.