Total synthesis of (±)-paeonilide

Article abstract of DOI:10.1021/ol060382z

The total synthesis of paeonilide, a natural anti-PAF (platelet-activating factor) new skeleton monoterpenoid with an IC₅₀ value of 8 μg/mL, was achieved in 16 steps with 15% overall yield from commercially available 2-hydroxy-4-methylacetophenone.

Full text of DOI:10.1021/ol060382z

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2479-2481
Total Synthesis of (±)-Paeonilide
Chenying Wang,†,‡ Jikai Liu,† Yanhua Ji,‡ Jingfeng Zhao,‡ Liang Li,‡ and
Hongbin Zhang*,‡
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming
Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650204, Graduate
School of Chinese Academy of Sciences, Beijing 100039, PRC, and Key Laboratory of
Medicinal Chemistry for Natural Resources, Ministry of Education, Research School of
Pharmacy, Yunnan UniVersity, Kunming, Yunnan 650091, PRC
zhanghb@ynu.edu.cn
Received February 14, 2006
ABSTRACT
The total synthesis of paeonilide, a natural anti-PAF (platelet-activating factor) new skeleton monoterpenoid with an IC50 value of 8
achieved in 16 steps with 15% overall yield from commercially available 2-hydroxy-4-methylacetophenone.
µg/mL, was
Paeonia root bark is used in traditional Chinese medicine
for treatment of abdominal pain and syndromes such as
stiffness of abdominal muscles.1 Phytochemical research has
generated a number of structurally related monoterpenes from
paeony roots.2 Representative compounds are shown in
Figure 1. In 2000, a novel monoterpenoid, paeonilide (4)
(Figure 1), was isolated from the roots of Paeonia delaVayi.3
Its new skeleton was established by a combination of
spectroscopic and X-ray crystallographic analyses. Because
of its ginkgolide-like ring structure, paeonilide was screened
against platelet-activating factors (PAFs).4 The bioassay
indicated that paeonilide selectively inhibited the platelet
aggregation induced by PAFs with an IC50 value of 8 µg/
mL (25 µM), with no inhibitory effect on adenoside
diphosphate-induced or arachidonic acid-induced platelet
aggregation. Because of the scarcity of available samples,
however, further biological study of this compound was
suspended. Paeonilide represents a new monoterpene skel-
eton. Synthesis of paeonilide and its derivatives is of interest
in terms of medicinal chemistry as well as synthetic
chemistry. In this paper, we describe the total synthesis of
paeonilide.
As shown in Figure 1, paeonilide is a highly oxygenated
monoterpenoid featured with an acetonyl moiety attached
to the ketal function. We drafted a synthetic plan starting
from the readily available 2-hydroxy-4-methylacetophenone.
The key to the synthesis of paeonilide was the construction
of a disubstituted acetylacetone 6 as indicated in the
retrosynthetic analysis in Scheme 1.
A synthetic study was initiated from commercially avail-
able 2-hydroxy-4-methylacetophenone.5 The phenol group
† Graduate School of Chinese Academy of Sciences.
‡ Yunnan University.
(1) (a) Kimura, M.; Kimura, I.; Nojima, H.; Takahashi, K.; Hayashi, T.;
Shimizu, M.; Morita, N. Jpn. J. Pharmacol. 1984, 35, 61. (b) Hatakeyama,
S.; Kawamura, M.; Shimanuki, E.; Takano, S. Tetrahedron Lett. 1992, 33,
333.
(2) (a) Shimizu, M.; Hayashi, T.; Morita, N.; Kimura, I.; Kimura, M.;
Kiuchi, F.; Noguchi, H.; Iitaka, Y.; Sankawa, U. Tetrahedron Lett. 1981,
22, 3069. (b) Hayashi, T.; Shinbo, T.; Shimizu, M.; Arisawa, M.; Morita,
N.; Kimura, M.; Matsuda, S.; Kikuchi, T. Tetrahedron Lett. 1985, 26, 3699.
(3) Liu, J. K.; Ma, Y. B.; Wu, D. G.; Lu, Y.; Shen, Z. Q.; Zheng, Q. T.;
Chen, Z. H. Biosci. Biotechnol. Biochem. 2000, 64, 1511.
(4) Bazan, N. G.; Zorumski, C. F.; Clark, G. D. J. Lipid Mediators 1993,
6, 421.
Figure 1. Paeonilactone A, C, and paeonilide.
10.1021/ol060382z CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/09/2006

Phenol 14 was thus protected with TBDMS chloride. After
Birch reduction, the resulting diene was treated with boric
acid in the presence of n-Bu4NF in THF at 10 °C. To our
delight, the desired nonconjugated enone was isolated in 87%
yield (Scheme 3).
Scheme 1. Retrosynthetic Analysis of Paeonilide
Scheme 3. Synthesis of â,γ-Unsaturated Ketone 7 and Its
Related Reactions
was protected by reaction with benzyl chloride in the
presence of base. Rubutom oxidation6 followed by protection
of the hydroxyl group provided compound 11 in 65% yield
over two steps.
A Wittig reaction followed by hydroboration led to 1,3-
diol 13 (Scheme 2). The benzyl protecting group was
Scheme 2. Synthesis of an Intermediate for Paeonilide
With the ketone in hand, oxidative cleavage of the double
bond was conducted. It was expected that an ozonolysis
followed by further oxidation of the resultant aldehyde would
lead to disubstituted acetylacetone 6, which was expected
to undergo cyclization and provide the target compound 5.
To our surprise, ozonolysis of ketone 7 in dichloromethane
at -78 °C led to ozonide 18 which could not be decomposed
by a usual workup procedure such as dimethyl sulfide and
triphenyl phosphine. Treatment of the ozonide with zinc
powder in acetic acid resulted in a complex mixture. When
ozonolysis was carried out in the presence of methanol at
-78 °C, peroxide 19 was obtained in high yield. The
peroxide structure was confirmed by COSY, HMBC, HMQC,
and HRMS spectra.
removed by hydrogenolysis with palladium on carbon. After
protection of the 1,3-diol systems, phenol 14 was protected
initially by formation of the corresponding methyl ether. The
next Birch reaction gave the diene intermediate in good
isolated yield; unfortunately, we failed to effect the conver-
sion of methyl enol ether to â,γ-unsaturated ketone 7. An
R,â-unsaturated ketone was formed instead, upon treatment
of diene 15a with oxalic acid or a Lewis acid such as ZnBr2
or ZnCl2. Careful survey of the literature revealed that a
TBDMS ether-protected diene system could be converted
to a nonconjugated ketone system with high selectivity.7
To access the key intermediate, we decided to conduct a
cis dihydroxylation using osmium tetroxide on â,γ-unsatur-
ated ketone 7. To our delight, only one diastereomer was
isolated in 92% yield. The relative stereochemistry of
compound 20 was initially deduced by small coupling
constants observed for proton H-C(4) (3.84 ppm, brs)
toward the two adjacent protons at C(3). If the H-C(4) was
in an axial position, a large (10∼12 Hz) coupling constant
between the axial H-C(4) and the axial H-C(3) would be
expected. The relative stereochemistry of diol 20 was finally
established by ROESY spectrum, in which significant NOE
correlation peaks between He-C(4) and Me-C(5) (1.16
(5) Hydroxy-4-methylacetophenone can also be prepared by Fries
rearrangement: Bensari, A.; Zaveri, N. T. Synthesis 2003, 267.
(6) Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1978, 43, 1599.
(7) Donaldson, R. E.; Fuchs, P. L. J. Org. Chem. 1977, 42, 2032.
Org. Lett., Vol. 8, No. 12, 2006
2480

ppm); He-C(4) and Ha-C(3) (1.57 ppm, ddd, J ) 2.5, 14.5,
14.6 Hz); He-C(4) and He-C(3) (2.24 ppm, m); Ha-C(3)
and Me-C(5); and He-C(6) (2.34 ppm, d, J ) 12.3 Hz)
and Me-C(5) were observed (see Scheme 4). The diol
isolate the UV active key intermediate, which underwent
intramolecular cyclization in ethyl acetate to afford alcohol
5 as the only isolated product. The two hydroxyl groups in
compound 6 are constitutionally identical but topologically
different groups (diastereotopic groups). We obtained the
required relative stereochemistry which might be a conse-
quence of a diastereotopic group differentiation reaction.9
After esterification with benzoyl chloride in the presence of
triethylamine in dichloromethane, paeonilide was obtained
in 46% yield over four steps (see Scheme 4). Spectroscopic
data of synthetic paeonilide were completely identical to
those of authentic samples isolated from the roots of Paeonia
delaVayi.10
Scheme 4. Total Synthesis of (()-Paeonilide
In summary, the first total synthesis of paeonilide was
achieved in 16 steps with 15% overall yield. Flexibility is a
notable feature of our synthetic strategy, and synthesis of
representative monoterpenes isolated from paeony roots could
be expected by this strategy. Assembly of a chiral center in
a later stage is also a good tactic that greatly facilitates
experimental practice. Synthesis of analogues as well as other
highly oxygenated monoterpenes from paeony roots is
currently underway in our laboratory.
Acknowledgment. This work was supported by a grant
(20272049) from the National Natural Science Foundation
of China and a grant from the foundation of the Chinese
Ministry of Education for the promotion of Excellent Young
Scholars. We would like to thank the International Coopera-
tion Division of Yunnan Provincial Science & Technology
Department for partial financial support (2002GH04).
1
Supporting Information Available: H NMR, 13C NMR,
MS, as well as HRMS spectra of all key intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
compound 20 was then oxidized with IBX8 in ethyl acetate
to afford diketone 21 in 94% yield (see Scheme 4).
At the final stage of our journey, diketone 21 was
deprotected and cleaved with periodic acid in ethyl acetate
to give the key intermediate 6. No attempt was made to
OL060382Z
(9) (a) Hoffmann, R. W. Synthesis 2004, 2075. (b) Studer, A.; Schleth,
F. Synlett 2005, 3033.
(10) Authentic natural paeonilide was provided by Professor Liu Ji-Kai.
A few typing errors were found for the assignment of protons at the C13
position in the original paper published in Biosci. Biotechnol. Biochem.
(see ref 3). It should be corrected to 3.34 (1H, dd, J ) 10.5, 18.5 Hz) and
2.55 (1H, dd, J ) 2.8, 18.5 Hz).
(8) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
Org. Lett., Vol. 8, No. 12, 2006
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