for the further biological investigation of paeonilide. We were
attracted by its both interesting chemical structure and potential
medicinal use, and initiated a project aimed at the total synthesis
of paeonilide.4
Our approach involves the synthesis of the key intermediate
ketone-ester 3 by the intermolecular radical addition of 3-(eth-
ylenedioxy)butanal (4)5 and (E)-2-(ethoxycarbonyl)ethenyl-2,2-
dimethyl-1,3-dioxane (5) as shown in Scheme 1. Intermediate
5 can be prepared from 5-(hydroxymethyl)-2,2-dimethyl-1,3-
dioxane (6) and ethyl (triphenylphosphoranylidene)acetate
through Swern oxidation and Wittig olefination.
Facile Synthesis of (()-Paeonilide
Yuguo Du,*,† Jun Liu,† and Robert J. Linhardt‡
State Key Laboratory of EnVironmental Chemistry and
Ecotoxicology, Research Center for Eco-EnVironmental
Sciences, Chinese Academy of Sciences, Beijing 100085, China,
and Departments of Chemistry, Biology, and Chemical and
Biological Engineering, Rensselaer Polytechnic Institute, Troy,
New York 12180
Alcohol 6 (Scheme 2) was subjected to a one-pot sequential
Swern oxidation and Wittig olefination to afford trans-ester E-5
in a 84% overall yield from the starting triol.6 However, the
attempted two-step procedure,7 i.e., pyridinium dichromate
(PDC) oxidation of 6 followed by Wittig reaction with ethyl
(triphenylphosphoranylidene)acetate in methanol, gave a sepa-
rable mixture of Z-8 (64%) and E-5 (27%).8 Benzoyl peroxide-
promoted radical addition9 of 4 to 5 in benzene under reflux
conditions furnished the critical ketone-ester 3 in 79% yield
(Scheme 3). The neat reaction of 4 (10 equiv) and 5, and the
same reaction in toluene under reflux, were sluggish. It is also
worth noting that the same radical reaction of Z-8 and 4 afforded
3 in only 47% yield. These results are in contrast to those
observed for the addition of butanal to ethyl maleate and
fumarate, but parallel the results obtained for crotonate and
cinnamate.10 Treatment of 3 with aqueous 1 N HCl in EtOAc
afforded bicycliclactone 2 in a one-pot yield of 91% through
the sequential in situ deacetalation, hemiacetal formation, and
lactonization. The relative stereochemistry in compound 2,
postulated based on the Felkin-Ahn model, is supported by
identical, recently published spectra data.4a Benzoylation of 2
with BzCl in pyridine completed the total synthesis of (()-
paeonilide 1. Our strategy provides the efficient total synthesis
of (()-paeonilide 1 in five steps with 59% overall yield,
compared to the recently reported4a synthesis of compound 1
in 16 steps with 15% overall yield.
ReceiVed January 22, 2007
(()-Paeonilide, a novel monoterpenoid metabolite from the
roots of Paeonia delaVayi showing anti-platelet activating
factor activity, is convergently synthesized in five steps with
59% overall yield. The application of benzoyl peroxide-
promoted radical addition of unsaturated ester to aldehyde
and subsequent topologically favored cyclization greatly
simplified the synthesis.
Paeony root, having a Chinese name of “mu-dan-pi” or “dan-
pi”, is widely used as crude drugs in several Chinese medicinal
prescriptions for treatment of abdominal pain and syndromes
such as stiffness of abdominal muscles.1 Studies on the
biologically active components of the paeony root have resulted
in the discovery of a variety of monoterpenes, and their chemical
structures have been established based on spectroscopy and/or
X-ray crystallography.2 In the year of 2000, Liu and co-workers
discovered an active compound with a novel monoterpenoid
skeleton from the roots of Paeonia delaVayi and named it
paeonilide.3 The biossay indicated that paeonilide selectively
inhibited platelet aggregation induced by the platelet activating
factor (PAF) with an IC50 value of 8 µg/mL, with no inhibitory
effect on adenoside diphosphate (ADP) or arachidonic acid
(AA)-induced platelet aggregation. However, 1.13 kg of Paeonia
delaVayi root methanol extract afforded only 8 mg of paeonilide.
The scarcity of the pure compound has become a bottleneck
In summary, the convergent synthesis of paeonilide was
achieved in five steps with 59% overall yield. The application
of benzoyl peroxide-promoted radical addition of unsaturated
ester to aldehyde and subsequent topologically favored cycliza-
tion greatly simplified the synthesis. The current strategy
provides a suitable approach for the large-scale preparation of
(4) During our efforts, two papers were published regarding the total
synthesis of paeonilide: (a) Wang, C.; Liu, J.; Ji, Y.; Zhao, J.; Li, L.; Zhang,
H. Org. Lett. 2006, 8, 2479-2481. (b) Wang, C.; Zhang, H.; Liu, J.; Ji, Y.;
Shao, Z.; Li, L. Synlett 2006, 1051-1054.
(5) Kelly, T. R.; Ananthasubramanian, L.; Borah, K.; Gillard, J. W.;
Goerner, R. N., Jr.; Patrick, F. K.; Judith, M. L.; Wen, G. T.; Jacob, V.
Tetrahedron 1984, 40, 4569-4577.
(6) (a) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198-
2200. (b) Maezaki, N.; Murakami, M.; Soejima, M.; Tanaka, T.; Imanishi,
T.; Iwata, C. Chem. Pharm. Bull. 1996, 44, 1146-1151.
(7) Yadav, J. S.; Raju, A. K.; Rao, P.; Rajaiah, G. Tetrahedron:
Asymmetry 2005, 16, 3283-3290.
* Author to whom correspondence should be addressed. Phone: 86-10-
62849126. Fax: 86-10-62923563.
† Chinese Academy of Sciences.
‡ Rensselaer Polytechnic Institute.
(1) Harada, M. J. Trad. Sino-Japanese Med. 1985, 6, 45-50.
(2) (a) Hatakeyama, S.; Kawamura, M.; Shimanuki, E.; Takano, S.
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M.; Arisawa, M.; Morita, N.; Kimura, M.; Matsuda, S.; Kikuchi, T.
Tetrahedron Lett. 1985, 31, 3699-3702. (c) Shimizu, M.; Hayashi, T.;
Morita, N.; Kimura, I.; Kimura, M.; Kiuchi, F.; Noguchi, H.; Iitaka, Y.;
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(3) Liu, J.; Ma, Y.; Wu, D.; Lu, Y.; Shen, Z.; Zheng, Q.; Chen, Z. Biosci.
Biotechnol. Biochem. 2000, 64, 1511-1514.
(8) House, H. O.; Jones, V. K.; Frank, G. A. J. Org. Chem. 1964, 29,
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(9) (a) Gunther, C.; Mosandl, A. Liebigs Ann. Chem. 1986, 2112-2122.
(b) Kharasch, M. S.; Urry, W. H.; Kuderna, B. M. J. Org. Chem. 1949, 14,
248-253. (c) Benedetti, F.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin, E.;
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10.1021/jo0701278 CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/06/2007
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J. Org. Chem. 2007, 72, 3952-3954