Unified synthesis of eudesmanolides, combining biomimetic strategies with homogeneous catalysis and free-radical chemistry

Article abstract of DOI:10.1021/ol034510k

(Matrix presented) A general procedure for the synthesis of both 12,6- and 12,8-eudesmanolides has been developed. The key step is the titanocene-catalyzed radical cyclization of accessible epoxygermacrolides. The novel reagent 2,4,6-trimethyl-1-trimethylsilylpyridinium chloride, both compatible with oxiranes and capable of regenerating Cp₂TiCl ₂ from Cp₂Ti(Cl)H and Cp₂Ti(Cl)OAc, played an important role in the catalytic cycle leading to exocyclic alkenes.

Full text of DOI:10.1021/ol034510k

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1935-1938
Unified Synthesis of Eudesmanolides,
Combining Biomimetic Strategies with
Homogeneous Catalysis and
Free-Radical Chemistry
Alejandro F. Barrero, Antonio Rosales, Juan M. Cuerva, and J. Enrique Oltra*
Department of Organic Chemistry, Faculty of Sciences, Campus FuentenueVa s/n,
UniVersity of Granada, E-18071 Granada, Spain
joltra@ugr.es
Received March 24, 2003
ABSTRACT
A general procedure for the synthesis of both 12,6- and 12,8-eudesmanolides has been developed. The key step is the titanocene-catalyzed
radical cyclization of accessible epoxygermacrolides. The novel reagent 2,4,6-trimethyl-1-trimethylsilylpyridinium chloride, both compatible
with oxiranes and capable of regenerating Cp2TiCl2 from Cp2Ti(Cl)H and Cp2Ti(Cl)OAc, played an important role in the catalytic cycle leading
to exocyclic alkenes.
General methods for the synthesis of large families of natural
products might be more productive than specific procedures
restricted to the preparation of just one or a few compounds.
Eudesmanolides constitute one of the main groups of natural
sesquiterpenoids, with more than 500 members described to
date.1 These compounds have been classified into two
subfamilies: 12,6-eudesmanolides such as (+)-tuberiferine
(1) and 12,8-eudesmanolides such as (+)-â-cyclopyrethrosin
(2).1 Their pharmacological properties include antifungal,
antiinflammatory, and antitumoral activities and the capacity
to inhibit human topoisomerase II, among others.2 Neverthe-
less, many of them are scarce in nature and so chemists have
developed several synthetic processes.3 The methods de-
scribed to date, however, are specific for a few products,
require numerous steps, and generally provide low overall
yields. A general procedure for the effective synthesis of
eudesmanolides therefore seemed desirable.
(1) (a) Fischer, N. H.; Olivier, E. J.; Fischer, H. D. Prog. Chem. Org.
Nat. Prod. 1979, 38, 134-165. (b) Connolly, J. D.; Hill, R. A. Dictionary
of Terpenoids; Chapman and Hall, London, 1991; Vol. 1, pp 340-371. (c)
Fraga, B. M. Nat. Prod. Rep. 2002, 19, 650-672 and previous issues in
this series.
(2) (a) Hehner, S. P.; Heinrich, M.; Bork, P. M.; Vogt, M.; Ratter, F.;
Lehmann, V.; Schulze-Osthoff, K.; Dro¨ge, W.; Schmitz, M. L. J. Biol. Chem.
1998, 273, 1288-1297. (b) Dirsch, V. M.; Stuppner, H.; Ellmerer-Mu¨ller,
E. P.; Vollmar, A. M. Bioorg. Med. Chem. 2000, 8, 2747-2753. (c) Skaltsa,
H.; Lazari, D.; Panagouleas, C.; Georgiadou, E.; Garc´ıa, B.; Sokovic, M.
Phytochemistry 2000, 55, 903-908
As germacrolides are the biogenetic precursors of
eudesmanolides,1a and some of them such as (+)-dihydro-
10.1021/ol034510k CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/09/2003

costunolide (3), (+)-costunolide (4), (+)-stenophyllolide (5),
and (+)-salonitenolide (6) are accessible in (multi)gram
quantities,4 we planned to employ these raw materials in a
biomimetic synthesis of eudesmanolides. The results obtained
using carbocationic chemistry, however, were quite discour-
aging because of product mixtures, and only poor yields were
obtained;4b,5 therefore, we assayed free-radical chemistry.6
Thus, we achieved the synthesis of some eudesmanolides
applying the stoichiometric version of the method reported
by RajanBabu and Nugent,7 but we required considerable
amounts of Cp2TiCl2 to obtain acceptable yields.4b These
observations prompted us to develop a novel procedure for
the synthesis of eudesmanolides catalyzed by titanocene.
Our initial hypothesis was based on the assumption that a
single electron transfer between Cp2TiIIICl generated in situ8
and an epoxygermacrolide such as 7 should promote a
rearrangement process giving tertiary radical 8 (Scheme 1).
OH. So far, only two types of reagents have been described
to regenerate Cp2TiCl2 from species of oxygen-bonded
titanium: chlorosilanes and protic compounds closely related
with collidine hydrochloride (15).9 The former are strong
Lewis acids incompatible with oxiranes, while the weak acid
15 is not suitable for regenerating Cp2TiCl2 from acetoxy-
titanium derivatives. Acidic reagents, moreover, easily
promote the carbocationic rearrangement of epoxygermac-
rolides, giving rise to undesirable byproducts and a con-
comitant decrease in the yield from the radical process.4b
Fortunately, the acid-promoted rearrangement of epoxyger-
macrolides can be prevented by adding pyridine or related
bases,5a and therefore we chose the combination of 15 plus
collidine used by Gansa¨uer et al. to regenerate Cp2TiCl2.9b
Finally, Cp2TiCl2 should be transformed back into Cp2TiCl
by the surplus of Mn in the medium, and thus the catalytic
cycle would be completed. To check our hypothesis, we
stirred 7, prepared from 3,4b with a substoichiometric quantity
of Cp2TiCl2 (20 mol %), Mn dust, H2O, 15, and collidine
for 7 h at 25 °C. In this manner, we obtained the desired
eudesmanolide 11 (only the (4S)-epimer 11a4b) accompanied
by a small amount of 1210 but no detectable carbocationic
rearrangement products (e.g., 13 and 14) (Table 1, entry 1).
Scheme 1. Hypothetical Catalytic Cycle in Aqueous Medium;
Base: 2,4,6-Collidine
Table 1. Relative Proportionsa (%) of Compounds Obtained
via Cyclization of 7b
c
entry Cp2TiCl2
additives (equiv)
11a 12 13 14
1
2
3
4
5
6
20
20
20
10
5
H2O (5), 15 (5), col.d (5) 82
18
40
74
20
15 (5), col. (5)
60
18
80
50
Me3SiCl (4), col. (7)
H2O (5), 15 (5), col. (5)
H2O (5), 15 (5), col. (5)
H2O (5), 15 (5), col. (5)
8
27 23
34 31 35
a Determined by 1H NMR spectroscopy. b Cyclizations performed by
stirring 7 with or without Cp2TiCl2, Mn dust (excess), and different additives
in THF at 25 °C. c Proportions in mol %. d Col. ) 2,4,6-collidine.
Flash chromatography provided 11a (72% yield) supporting
the concepts outlined in Scheme 1.
Subsequent C-Ti coupling between 8 and a second Cp2-
TiIIICl species would lead to the alkyl-TiIV complex 9,
which, after hydrolysis, would provide 10 and Cp2Ti(Cl)-
(5) (a) Barrero, A. F.; Oltra, J. E.; Morales, V.; AÄ lvarez, M. J. Nat. Prod.
1997, 60, 1034-1035. (b) Barrero, A. F.; Oltra, J. E.; AÄ lvarez, M.
Tetrahedron Lett. 1998, 39, 1401-1404.
(6) For a recent overview on contemporary free-radical chemistry, see:
Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; VCH:
Weinheim, Germany, 2001; Vols. 1 and 2.
(7) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116, 986-
997.
(8) Cp2TiCl can be generated in situ by stirring commercially available
Cp2TiCl2 and Mn dust; see: (a) Sekutowski, D.; Jungst, R.; Stucky, G. D.
Inorg. Chem. 1978, 17, 1848-1855. (b) Enemaerke, R. J.; Hjollund, G.
H.; Daasbjerg, K.; Skrydstrup, T. Compt. Rend. Acad. Sc. II 2001, 4, 435-
438.
(3) Some selected examples: (a) Schultz, A. G.; Godfrey, J. D. J. Am.
Chem. Soc. 1980, 102, 2414-2428. (b) Blay, G.; Cardona, L.; Garc´ıa, B.;
Pedro, J. R. J. Org. Chem. 1993, 58, 7204-7208. (c) Watson, F. C.; Kilburn,
J. D. Tetrahedron Lett. 2000, 41, 10341-10345.
(4) Compounds 3 and 4 can be obtained from commercially available
Costus Resinoid, while 5 and 6 can be isolated from Centaurea calcitrapa
and C. malacitana by simply immersing these weeds in Cl3CH; see: (a)
Barrero, A. F.; Oltra, J. E.; Barraga´n, A.; AÄ lvarez, M. J. Chem. Soc., Perkin
Trans. 1 1998, 4107-4113. (b) Barrero, A. F.; Oltra, J. E.; Cuerva, J. M.;
Rosales, A. J. Org. Chem. 2002, 67, 2566-2571. (c) Barrero, A. F.; Oltra,
J. E.; AÄ lvarez, M.; Rosales, A. J. Org. Chem. 2002, 67, 5461-5469.
1936
Org. Lett., Vol. 5, No. 11, 2003

The stereoselectivity observed might well be ascribed to
equatorial attack by the bulky Cp2TiCl species against 8 to
give 9a (Scheme 2). The intermediate 9a should then undergo
any case, the minor amount of 1314 obtained (8%) indicated
that the participation of a carbocationic process was con-
siderably restricted.15 Thus, 16 becomes the first example
of a new type of reagent that is both compatible with
epoxides and capable of regenerating Cp2TiCl2 from Cp2-
Ti(Cl)H and (as we will see later) acetoxy-titanium deriva-
tives. The above results reveal the versatile nature of the
catalytic procedure, which can be controlled to afford either
reduction products or alkenes by adding or excluding water
and using the additives 15 or 16, respectively. We subse-
quently diminished the catalyst proportions to determine the
minimum required to guarantee the radical nature of the
process. With 0.05 equiv (entry 5), 11a was still the main
product, while in the complete absence of Cp2TiCl2 (entry
6), the mixture containing diol 1414 obtained was character-
istic of a purely carbocationic process, confirming the crucial
role played by the titanium catalyst.
Scheme 2. Proposed Mechanism for the Formation of 10a and
12a
a R ) OTi(Cl)Cp2; (a) hydrolysis, (b) â-hydrogen elimination.
To explore the synthetic usefulness of the method, we
chose as targets two eudesmanolides belonging to different
subfamilies: (+)-9â-hydroxyreynosin (17) and (+)-â-cy-
clopyrethrosin (2). 12,6-Eudesmanolide 17 and its derivative
19 were isolated from Inula heterolepis and Artemisia herba-
alba, respectively, and their structures were established by
spectroscopic techniques.16 We started their synthesis with
5, which, after selective hydrogenation and treatment with
MCPBA, afforded oxirane 18 (Scheme 3). Subsequent
hydrolysis to produce 10a, which would in turn give 11a
after acidic quenching. The alkyl-TiIV complex 9a could
also account for the minor quantity of alkene 12 derived from
a relatively slow â-hydrogen elimination or any other process
generating Cp2Ti(Cl)H.11 This possibility led us to take
advantage of this process to synthesize eudesmanolides with
an exocyclic ∆4,15 double bond.12 Treatment of 7 in the
absence of water, however, gave a mixture containing a
relatively high proportion (60%) of the reduction product
11a (Table 1, entry 2), presumably due to the protonolysis
of the C-Ti bond of 9a by the hydrochloride 15 employed.13
Therefore, we assayed a novel reagent, the aprotic derivative
16 (prepared in situ by mixing collidine and Me3SiCl), to
regenerate Cp2TiCl2 and prevent protonolysis.
Scheme 3. Biomimetic Synthesis of 17 and 19
Treatment of 7 under these new conditions (entry 3) gave
a substantially increased proportion of the exocyclic alkene
12 (74%) and a significant decrease (down to 18%) in the
hydrolysis product 11a (which might derive from adventi-
tious water). The regeneration of the catalyst might be
rationalized by reaction between 16 and the â-elimination
product Cp2Ti(Cl)H, giving Cp2TiCl2 together with collidine
and gaseous Me3SiH, but in the absence of experimental
evidence, alternative explanations cannot be discarded. In
(9) (a) Fu¨rstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468-
4475. (b) Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998,
120, 12849-12859. (c) Hansen, T.; Daasbjerg, K.; Skrydstrup, T. Tetra-
hedron Lett. 2000, 41, 8645-8649.
titanocene-catalyzed cyclization of 18 gave alkene 19. In this
case, the â-elimination of the C-15 hydroxyl group was much
faster than â-hydrogen elimination from 9a, and neither
anhydrous conditions nor 16 were required. Finally, the
conjugated double bond was restored in a single-pot reaction
applying a slight modification of Grieco’s method.17 Thus,
we obtained 17 in four steps at an overall yield of 31%. The
spectroscopic properties of synthetic compounds 17 and 19
were in agreement with those of the natural products.16
The 12,8-eudesmanolide 2 was isolated from pyrethrum
flowers, and its structure was established by spectroscopic
(10) Ogura, M.; Cordell, G. A.; Farnsworth, N. R. Phytochemistry 1978,
17, 957-961.
(11) Despite the fact that we could not isolate Cp2Ti(Cl)H, previous
results suggest that it might be formed from certain alkyl-TiIV complexes
and possibly displays reductive properties similar to those of Cp2Zr(Cl)H
(the Schwartz reagent).4b For a theoretical study on the reactivity of Cp2-
Ti(Cl)H, see: Sakai, S. J. Mol. Struct.: THEOCHEM 2001, 540, 157-
169.
(12) There are more than 170 natural eudesmanolides described contain-
ing a ∆4,15 double bond.1
(13) As 15 is more acidic than H2O, the different results summarized in
entries 1 and 2 of Table 1 might seem somewhat anomalous. To rationalize
these results and the counterintuitive sequence given in Scheme 1, one of
the referees suggested that water could act as a very good ligand for Ti
that would increase the reduction potential and diminish the tendency toward
â-elimination.
(16) (a) Bohlmann, F.; Ates, N.; Grenz, M. Phytochemistry 1982, 21,
1166-1168. (b) Ahmed, A. A.; Abou-El-Ela, M.; Jakupovic, J.; Seif-El-
Din, A. A.; Sabri, N. Phytochemistry 1990, 29, 3661-3663.
(17) For the two-step original method, see: Grieco, P. A.; Nishizawa,
M. J. Org. Chem. 1977, 42, 1717-1720.
(14) Ando, M.; Takase, K. Tetrahedron 1977, 33, 2785-2789.
(15) Compound 13 derives from the acid-induced cyclization of 7.4b
Org. Lett., Vol. 5, No. 11, 2003
1937

methods and some chemical correlations.18 We began its
synthesis with 6, which, after alkaline isomerization, provided
the 12,8-germacrolide 20 (Scheme 4). Selective epoxidation
and has been shown to inhibit cell growth, regulate plant
development, and help control crop diseases.22c The most
recent synthesis of 1 started from (-)-R-santonin (22) and
was achieved in nine steps, an improvement over previous
procedures.22c When we started its synthesis with 11a, we
obtained 1 after only six steps (see Supporting Information).
Along the same line, compounds 2, 17, and 19 might be
employed to obtain other natural eudesmanolides with
practically every functionality pattern.
Scheme 4. Biomimetic Synthesis of 2
In summary, here we describe a novel method for the
synthesis of both 12,6- and 12,8-eudesmanolides via free-
radical chemistry by combining titanocene catalysis with a
biomimetic strategy starting from accessible germacrolides.
This procedure uses inexpensive reagents, works at room
temperature under mild conditions compatible with several
functional groups, and employs titanium quantities an order
of magnitude lower than those required for the stoichiometric
version. At the moment, we are applying this method to
obtain potent antifungal eudesmanolides and more complex
terpenoids.
of 20 followed by the titanocene-catalyzed cyclization of 21
gave eudesmanolide 2, thus obtained in four steps in an
overall yield of 13%. The spectroscopic data for synthetic
2, including optical rotation, were in agreement with those
of (+)-â-cyclopyrethrosin,18 confirming the structure and
absolute stereochemistry of the natural product.19 In this case,
we used the novel additive 16, confirming the utility of this
reagent for regenerating Cp2TiCl2 from Cp2Ti(Cl)OAc.
The synthesis of eudesmanolides 2, 17, and 19 proved the
utility of our method. It also occurred to us that in addition
to this, the synthetics 2, 11a, 17, and 19 could well be used
as raw materials for the enantiospecific synthesis of many
other eudesmanolides.20 To test our idea, we set about (+)-
tuberiferine (1), one of the most significant examples of
bioactive eudesmanolides. Tuberiferine, found in Sonchus
tuberifer SVent,21 has been synthesized by various groups22
Acknowledgment. This work was supported by the
Spanish DGICYT (PB98-1365) and by a graduate fellowship
from the Spanish MEC to A.R. We thank our English
colleague Dr. J. Trout for his revision of our English text.
Supporting Information Available: Titanocene-cata-
lyzed cyclization of 7 (model experimental procedure) and
a scheme of the synthesis of 1 from 11a. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL034510K
(20) Reported methods for transforming R-santonin (22) into other
terpenoids might be advantageously applied to obtain eudesmanolides from
2, 11a, 17, and 19. For a review on chemical transformations of 22, see:
Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J. R. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 2000; Vol. 24, pp
53-129.
(21) Bermejo-Barrera, J.; Breto´n, J. L.; Fajardo, M.; Gonza´lez, A. G.
Tetrahedron Lett. 1967, 8, 3475-3476.
(22) (a) Yamakawa, K.; Nishitani, K.; Tominaga, T. Tetrahedron Lett.
1975, 16, 2829-2832. (b) Grieco, P. A.; Nishizawa, M. J. Chem. Soc.,
Chem. Commun. 1976, 582-583. (c) Ando, M.; Wada, T.; Kusaka, H.;
Takase, K.; Hirata, N.; Yanagi, Y. J. Org. Chem. 1987, 52, 4792-4796.
(18) (a) Doskotch, R. W.; El-Feraly, F. S. Can. J. Chem. 1969, 47, 1139-
1142. (b) Cardona, M. L.; Ferna´ndez, I.; B. Garc´ıa, J. R. Pedro, J. Nat.
Prod. 1990, 53, 1042-1045.
(19) Absolute configuration of 6 is known; see: Barrero, A. F.; Oltra, J.
E.; Rodr´ıguez-Grac´ıa, I.; Barraga´n, A.; AÄ lvarez, M. J. Nat. Prod. 2000,
63, 305-307.
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