Studies towards the biomimetic synthesis of bisesquiterpene lactones

Article abstract of DOI:10.1016/S0040-4039(03)01172-9

A possible biomimetic connection between atractylolide, hydroxyatractylolide and biatractylolide and biepiasterolide has been demonstrated by efficiently generating the biatractylolide and biepiasterolide core structures from atractylolide and hydroxyatra

Full text of DOI:10.1016/S0040-4039(03)01172-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4993–4996
Studies towards the biomimetic synthesis of
bisesquiterpene lactones
Sharanjeet K. Bagal,a Robert M. Adlington,a Rodolfo Marquez,b Andrew R. Cowleyc and
Jack E. Baldwina,*
aDyson Perrins Laboratory, Department of Chemistry, Oxford University, South Parks Road, Oxford OX1 3QY, UK
bDepartment of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
cChemical Crystallography, Oxford University, South Parks Road, Oxford OX1 3QR, UK
Received 26 March 2003; revised 1 May 2003; accepted 9 May 2003
Abstract—A possible biomimetic connection between atractylolide, hydroxyatractylolide and biatractylolide and biepiasterolide
has been demonstrated by efficiently generating the biatractylolide and biepiasterolide core structures from atractylolide and
hydroxyatractylolide model butenolides via a radicaloid intermediate in a single step in good yield. © 2003 Elsevier Science Ltd.
All rights reserved.
Biatractylolide 1 and biepiasterolide 2 are novel bis-
esquiterpenoids recently isolated from the Chinese
medicinal plant Atractylodes macrocephala.1–3 Biologi-
cally, biatractylolide 1 has shown powerful negative
inotropic and chronotropic effects, making it a poten-
tial blood pressure lowering agent.4
crucial dimerisation step takes place between two units
of atractylolide 3 or hydroxyatractylolide 4 through the
captodative stabilised radical 76 (or its equivalent).7
Furthermore, Hikino has reported the aerial autoxida-
tion of atractylon 6 into atractylolides 3 and 4.8 Thus,
atractylolides 3 and 4 could emanate from atractylon 6
in vivo (Scheme 1).
Structurally both biatractylolide 1 and biepiasterolide 2
are dimeric sesquiterpenic lactones joined at the C8–C8a
bridgehead positions as proven by X-ray analysis.1–3
Biosynthetically, it is believed that both biatractylolide
1 and biepiasterolide 2 originate from the naturally
occurring sesquiterpene lactones atractylolide 3 or
hydroxyatractylolide 4, which are closely related to the
sesquiterpenes peroxyatractylolide 5, and atractylon 6
(Fig. 1).5
In order to test our biomimetic hypothesis, we decided
to synthesise simplified atractylolide model systems and
to explore their oxidative dimerisation chemistry. We
now report the synthesis of the model butenolides 8 and
9 and their potential for a biomimetic synthesis of
biatractylolide 1 and biepiasterolide 2 (Scheme 2).
In order to synthesise model butenolide 8, pyrrolidine
enamine 11 was alkylated to give ester 12, which after
saponification gave acid 13. The crude acid 13 was
converted into butenolide 8 with acetic anhydride and
It is possible to propose a biomimetic synthesis for both
biatractylolide 1 and biepiasterolide 2 in which the
Figure 1. Naturally occurring sesquiterpenes isolated from Atractylodes macrocephala.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01172-9

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S. K. Bagal et al. / Tetrahedron Letters 44 (2003) 4993–4996
Scheme 1.
recovered starting material. We then turned our attention
to the resonance stabilised anion 14. Oxidation of this
anion with a 1-electron oxidant would then furnish the
captodative stabilised butenolide radical 15 (Scheme 4).11
Unfortunately, a wide variety of base and 1-electron
oxidant combinations, failed to give any of the desired
dimeric product 10.
We next examined DTBP (di-tert-butyl peroxide) due to
its use as a model for hydrogen atom abstraction
reactions in biological systems,12 as well as its known
ability to effect dehydrodimerisations of polyhaloalka-
nes, alcohols, ethers, amides and esters.13 Thus, a mixture
of butenolide 8, acetone and a stoichiometric amount of
DTBP (0.5 mol equiv.) in the absence of oxygen, was
placed in a sealed tube and heated to 140°C overnight.
This procedure afforded the desired dimers 10a/10b in an
isolated yield of 34% after purification by column chro-
matography (Scheme 5).
Scheme 2.
sodium acetate in reasonable yield after careful isolation
and purification, by minor modification of the general
method of Minato (Scheme 3).9
Initially, treatment of butenolide 8 with Tollens reagent
was attempted under a variety of conditions based upon
literature precedent.10 However, butenolide 8 failed to
oxidise to the desired dimer 10, affording instead only
Scheme 3. Reagents and conditions: (i) Ethyl a-bromo-propionate, dioxane, reflux, 16 h; (ii) water, reflux, 1 h; (iii) KOH–MeOH
(5% w/v), rt, 2 h; (iv) NaOAc, Ac2O, reflux, 3 h.
Scheme 4.
Scheme 5.

S. K. Bagal et al. / Tetrahedron Letters 44 (2003) 4993–4996
4995
NMR indicated the presence of two diastereomeric
dimers in a 6:1 ratio. Separation of the major
diastereomer 10a was successfully achieved by recrys-
tallisation from a 20% mixture of EtOAc in Et2O.
However, despite our success using DTBP in obtaining
model dimer 10, we were unable to optimise the reac-
tion yield further. This prompted us to consider alter-
native radical formation methods, which might afford
the dimer. We were particularly intrigued by the
reported ability of metals and metal salts to couple
allylic and benzylic halides. We believed that such an
approach might be successful in the dimerisation of a
halobutenolide 16 (Scheme 6).
With the chlorobutenolide readily available, we focused
our attention on improving the dimerisation yields.
Thus, treatment of chlorobutenolide 9 with either
zinc,17 copper bronze,10 or activated copper bronze
(Vogel’s method),18 failed to afford the dimerised
adduct 10 in higher than 2% yield. However, treatment
of chlorobutenolide
9
with freshly prepared
Co(PPh3)3Cl under Yamada’s conditions afforded the
desired dimer 10 in excellent yield (56%) as a (>98:2)
mixture of dl:meso 10a:10b diastereomers at room tem-
perature (Scheme 8, Table 1).19,20
X-Ray analysis of this newly formed dl-bis-butenolide
10a unambiguously demonstrated that the major
diastereomer has the same relative stereochemistry at
both C8 and C8a as that of biatractylolide 1 and biepias-
terolide 2.21 Furthermore, the X-ray structure corrobo-
rates the natural product assignment by showing that
the C8 and C8a bond is the longest in the molecule
Thus, reduction of lactone 8 followed by silylation of
the resulting furan 17, afforded the desired silylfuran 18
in reasonable yield.14 Singlet oxygen oxidation of furan
18 then yielded the expected hydroxybutenolide 19 in
excellent yield.15 Finally, treatment of hydroxybuteno-
lide 19 with excess thionyl chloride afforded the desired
chlorobutenolide 9 in good yield (Scheme 7).16
,
,
at 1.57 A, compared to 1.59 A in biatractylolide 1 and
,
1.58 A in biepiasterolide 2 (Fig. 2).
Scheme 6.
t
Scheme 7. Reagents and conditions: (i) Dibal-H, THF, −25°C; (ii) BuLi, pentane, THF, −50°C; (iii) TMSCl, THF, 0°C to rt; (iv)
satd aq. NH4Cl, −78°C; (v) O2, cat. Rose Bengal, 150 W tungsten lamp, MeOH, −78°C; (vi) SOCl2, DCM, rt.
Scheme 8.
Table 1. Metal-mediated coupling of chlorolactone 9 to afford dimer 10
Coupling agent
Temperature (°C)
Reaction time (h)
Solvent
Yield of 10 (%)
Copper
Activated copper
Zinc
90–100
90–100
20–25
1
1
24
2
Benzene
Benzene
EtOAc
2
2
No reaction
56
Co(PPh3)3Cl
20–25
Benzene

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S. K. Bagal et al. / Tetrahedron Letters 44 (2003) 4993–4996
5. (a) Wang, Y. S.; Chang, J. C.; Li, K. K.; Wu, C. H.; Liu,
Y. H. Shan-his Hsin I Yao 1980, 9, 47; (b) Zhang, Q. F.;
Luo, S. D.; Wang, H. Y. Chin. Chem. Lett. 1998, 9, 1097.
6. Janousek, Z.; Merenyi, R.; Viehe, H. G. Acc. Chem. Res.
1985, 18, 148.
7. For example, a pinacol type dimerisation of the keto
form of 4, followed by bis-lactonisation.
8. Hikino, H.; Hikino, Y.; Yosioka, I. Chem. Pharm. Bull.
1962, 10, 641.
9. Minato, H.; Nagasaki, T. J. Chem. Soc. (C) 1966, 1866.
10. (a) Lutz, R. E.; Couper, M. J. Org. Chem. 1941, 6, 91; (b)
Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis;
Wiley: London, 1967; Vol. 1, p. 1171.
11. Rio, G.; Masure, D. Bull. Soc. Chim. Fr. 1972, 12, 4604.
12. Tanko, J. M.; Friedline, R.; Suleman, N. K.; Castagnoli,
N. J. Am. Chem. Soc. 2001, 123, 5808.
Figure 2. X-Ray crystal structure of 10a. Hydrogen atoms
and the minor disorder component are omitted.
13. Paquette, L. A. Encyclopedia of Reagents for Organic
Synthesis; Wiley: Chichester, 1995; Vol. 3, p. 1616.
14. Wu, H. J.; Yen, C. H.; Chuang, C. T. J. Org. Chem.
1998, 63, 5064.
15. Shikari, R.; Tadano, K.; Ogawa, S. J. Org. Chem. 1996,
61, 2845.
16. Ro¨hrig, S.; Hennig, L.; Findeisen, M.; Welzel, P. Tetra-
hedron 1998, 54, 3439.
17. Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757.
18. Vogel, Vogel’s Textbook of Practical Organic Chemistry,
5th ed.; Wiley: New York, 1989; p. 426.
In conclusion, we have demonstrated
a possible
biomimetic connection between atractylolide 3 or
hydroxyatractylolide 4 and biatractylolide 1 and biepi-
asterolide 2 by efficiently generating the core structure
10a from the model butenolides 8 and 9 in a single step
and high diastereoselectivity via a radicaloid intermedi-
ate 15. We are currently working on ways to optimise
our radical dimerisation strategy and to apply it to a
biomimetic synthesis of biatractylolide 1 and biepias-
terolide 2.
19. Aresta, M.; Rossi, M.; Sacco, A. Inorg. Chim. Acta 1969,
3, 227.
20. (a) Yamada, Y.; Momose, D.; Iguchi, K.; Sugiyama, T.
Tetrahedron Lett. 1983, 24, 921; (b) Yamada, Y.;
Momose, D. Chem. Lett. 1981, 1277.
21. The atomic coordinates for 10a are available on request
from the Cambridge Crystallographic Data Centre, Uni-
versity Chemical Laboratory, Lensfield Road, Cambridge
CB2 1EW (Deposition No. CCDC 201013). The crystal-
lographic numbering system differs from that used in the
test; therefore any request should be accompanied by the
full literature citation of this paper.
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