General approach to polycyclic meroterpenoids based on Stille couplings and titanocene catalysis

Article abstract of DOI:10.1021/jo049253r

We describe a novel convergent procedure that has proved useful in the synthesis of a wide range of meroterpenoid-related structures containing a mono-, sesqui-, or diterpenoid moiety linked to a nonfused aromatic subunit with various substitution pattern

Full text of DOI:10.1021/jo049253r

Gen er a l Ap p r oa ch to P olycyclic
Mer oter p en oid s Ba sed on Stille Cou p lin gs
a n d Tita n ocen e Ca ta lysis
J ose´ J usticia, J . Enrique Oltra, and J uan M. Cuerva*
Department of Organic Chemistry, Faculty of Sciences,
University of Granada, E-18071 Granada, Spain
jmcuerva@platon.ugr.es
Received May 3, 2004
Abstr a ct: We describe a novel convergent procedure that
has proved useful in the synthesis of a wide range of
meroterpenoid-related structures containing a mono-, ses-
qui-, or diterpenoid moiety linked to a nonfused aromatic
subunit with various substitution patterns. The key steps
were the Stille-type coupling of aryl stannanes and allylic
carbonates, followed by the titanocene-catalyzed domino
cyclization of aryl epoxypolyprenes. The coupling reaction
was perfectly compatible with preformed epoxides, while the
sequential cyclization, which presumably proceeded via alkyl
radicals inert to benzene derivatives, selectively provided
exocyclic alkenes.
F IGURE 1. Various fungal and marine meroterpenoids.
by the acid-induced epoxide opening used by these
authors. In fact, the tertiary carbocation formed at the
end of epoxypolyprene cyclization is effectively trapped
by one of the nucleophilic oxygen atoms of the hydro-
quinone moiety,3a,b thus facilitating the preparation of
taondiol (7) but at the same time seriously hindering the
potential synthesis of other meroterpenoids, including
zonarol (2), K-76 (3), and stypoldione (6), with stronger
biological activity. Moreover, tertiary carbocations are
electrophilic enough to attack accessible positions of the
The word “meroterpenoids” is generally used to denote
a wide range of natural products of mixed (polyketide-
terpenoid) biogenesis.1 Among the meroterpenoids there
occur both marine and fungal metabolites that share a
common structural feature: their molecules are formed
by a quinone, hydroquinone, or closely related subunit
linked to a cyclic terpenoid moiety by at least one C-C
bond. As relevant examples we might cite marine natural
products such as cyclocymopol (1), zonarol (2), pelorol (5),
stypoldione (6), and taondiol (7) or fungal metabolites
such as K-76 (3) and kampanol A (4) (Figure 1).2 Several
of these products have attracted the attention of synthetic
chemists3 because of their interesting pharmacological
properties such as antifungal,2b antiinflammatory,2c or
ras farnesyl-protein transferase inhibitory activity2d or
severe ichthyotoxic effects.2g
Two different strategies have generally been employed
for the chemical synthesis of polycyclic meroterpenoids:
(a) the biomimetic4 sequential cyclization of prenylated
hydroquinones, as used by Gonzalez et al.3a,b for the
synthesis of taondiol (7), and (b) a two-synthon strategy
(Scheme 1) introduced by Corey and Das3c for the
synthesis of K-76 (3), which has subsequently been used
by several other chemists despite the often troublesome
procedure required for the preparation of the polycyclic
terpenoid synthon.3d-i
(2) Isolation: (a) Cyclocymopol: Ho¨gberg, H.-E.; Thomson, R. H.;
King, T. J . J . Chem. Soc., Perkin Trans. 1 1976, 1696. (b) Zonarol:
Fenical, W.; Sims, J . J .; Squatrito, D.; Wing, R. M.; Radlick, P. J . Org.
Chem. 1973, 38, 2383. (c) K-76: Kaise, H.; Shinohara, M.; Miyazaki,
W.; Izawa, T.; Nakano, Y.; Sugawara, M.; suwagara, K. Chem.
Commun. 1979, 726. (d) Kampanol A: Singh, S. B.; Zink, D. L.;
Willians, M.; Polishook, J . D.; Sanchez, M.; Silverman, K. C.; Lingham,
R. B. Biorg. Med. Chem. Lett. 1998, 8, 2071. (e) Taondiol: Gonzalez,
A. G.; Darias, J .; Mart´ın, J . D. Tetrahedron Lett. 1971, 2729. (f)
Pelorol: Kwak, J . H.; Schmitz, J .; Kelly, M. J . Nat. Prod. 2000, 63,
1153. (g) Stypoldione: Gerwick, W. H.; Fenical, W.; Fritsch, N.; Clardy,
J . Tetrahedron Lett. 1979, 14, 145.
(3) For some selected reports on synthesis of fungal and marine
meroterpenoids, see: (a) Gonzalez, A. G.; Mart´ın, J . D.; Rodr´ıguez, M.
L. Tetrahedron Lett. 1973, 14, 3657. (b) Gonzalez, A. G.; Martin, J . D.;
Rodriguez, M. L. An. Quim. 1976, 72, 1004. (c) Corey, E. J .; Das, J . J .
Am. Chem. Soc. 1982, 104, 5551. (d) McMurry, J . E.; Erion, M. D. J .
Am. Chem. Soc. 1985, 107, 2712. (e) Begley, M. J .; Fish, P. V.;
Pattenden, G.; Hodgson, S. T. J . Chem. Soc., Perkin Trans. 1 1990,
2263. (f) Tsujimori, H.; Bando, M.; Mori, K. Eur. J . Org. Chem. 2000,
297. (g) Takao, K.; Sasaki, T.; Kozaki, T.; Yanagisawa, Y.; Tadano, K.;
Kawashima, A.; Shinonaga, H. Org. Lett. 2001, 3, 4291. (h) Takikawa,
H.; Hirooka, M.; Sasaki, M. Tetrahedron Lett. 2002, 43, 1713. (i)
Iwasaki, K.; Nakatani, M.; Inoue, M.; Katoh, T. Tetrahedron 2003, 59,
8763.
(4) Co-occurrence of polycyclic meroterpenoids with other metabo-
lites showing an acyclic terpenoid moiety (see ref 2a for instance)
suggests that, in the biosynthesis of meroterpenoids, the polyene
cyclization takes place after the C-C linkage between the terpenoid
and the polyketide subunits; see ref 3e.
(5) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259. (c) Fu¨rstner, A. Synlett 1999, 1523.
(d) Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 115, 320.
(6) For reviews on “sequential” (also dubbed “cascade” or “domino”)
reactions, see: (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Malacria,
M. Chem. Rev. 1996, 96, 289.
Sequential reactions generally comply with the selec-
tivity and atom- and step-economy requirements needed
in contemporary chemistry5 and are consequently re-
garded as powerful synthetic tools.6 Nevertheless, the
sequential cyclization described by Gonzalez et al.3a,b has
received scarce attention, possibly due to the limitations
imposed by the carbocationic nature of a process initiated
* Corresponding author. Fax: +34 958 248437.
(1) Simpson, T. J . Top. Curr. Chem. 1998, 195, 1-48.
10.1021/jo049253r CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/23/2004
J . Org. Chem. 2004, 69, 5803-5806
5803

SCHEME 1. Syn th etic Str a tegies to Obta in P olycyclic Mer oter p en oid s
SCHEME 2. Retr osyn th etic An a lysis to P olycyclic Mer oter p en oid s.
neighboring aromatic rings in a well-known reaction7 that
could lead to undesired byproducts.
starting material 12a with the commercially available
homologues geraniol (12b) or geranylgeraniol (12c).
To check our hypothesis, we decided to synthesize a
set of epoxypolyprenes linked to aromatic rings contain-
ing different functionalization patterns, by means of a
Stille-type coupling between allylic carbonates and aryl-
trialkylstannanes developed by Echavarren’s group (see
Scheme 3).11 To this end we prepared different stannanes
(10a -f) from commercial aryl bromides under the condi-
tions described by Morita et al.,12 obtaining yields ranging
from 66 to 99%. We then prepared allylic carbonates
14a -c by stirring sodium hydride and diethyl carbonate
with epoxypolyprenols 13a -c, easily obtained from the
corresponding precursors 12a-c as reported elsewhere.10b
Finally, the Stille coupling between different aryl stan-
nanes (10) and carbonates 14a -c under Echavarren’s
conditions provided aryl epoxypolyprenes 15-23 at yields
ranging from 66 to 92% (Scheme 3, Table 1),13 confirming
that this reaction is perfectly compatible with preformed
oxiranes.
Alkyl radicals, on the other hand, are generally com-
patible with hydroxyl groups; furthermore, homolytic
aromatic substitution is usually a slow reaction.8 There-
fore, radical cyclizations might well overcome the draw-
backs of the cationic processes mentioned above. With
this idea in mind, we planned a novel procedure for the
synthesis of polycyclic meroterpenoids from commercial
acyclic polyprenols such as farnesol (12a ) based on Stille
coupling with aryl stannanes (such as 10) followed by
the titanocene-catalyzed9 radical cyclization of the cor-
responding aryl epoxypolyprenes (such as 9) (Scheme 2).
In this way, our previous experience with titanocene
catalysis suggested that, using the combination Mn/Me3-
SiCl/collidine as titanocene-regenerating agent, the radi-
cal cyclization would give versatile intermediates with
an exocyclic double bond (such as 8),10 closely related to
zonarol (2) and also suitable to be easily transformed into
sesquiterpenoids 3-5. Moreover, this strategy could be
extended to the synthesis of other types of meroterpe-
noids, including 1, 6, and 7 by simply replacing the
(10) Some titanocene(III)-catalyzed processes can be controlled to
end in the formation of an exocyclic double bond, by working under
anhydrous conditions and using Me3SiCl/2,4,6-collidine to regenerate
Cp2TiCl2; see: (a) Barrero, A. F.; Rosales, A.; Cuerva, J . M.; Oltra, J .
E. Org. Lett. 2003, 5, 1935. (b) J usticia, J .; Rosales, A.; Bun˜uel, E.;
Oller-Lo´pez, J . L.; Valdivia, M.; Ha¨ıdour, A.; Oltra, J . E.; Barrero, A.
F.; Ca´rdenas, D. J .; Cuerva, J . M. Chem. Eur. J . 2004, 10, 1778. This
procedure has been previously used in the synthesis of other types of
natural products: (c) J usticia, J .; Oltra, J . E.; Cuerva, J . M. Tetrahe-
dron Lett 2004, 45, 4293-4296. Another titanocene-regenerating agent
has been recently reported: (d) Fuse, S.; Hanochi, M.; Doi, T.;
Takahashi, T. Tetrahedron Lett. 2004, 45, 1961.
(11) For a seminal work on coupling of allylic acetates, see: (a) Del
Valle, L.; Stille, J . K.; Hegedus, L. S. J . Org. Chem. 1990, 55, 3019.
For couplings of allylic carbonates, see: (b) Castan˜o, A. M.; Echavarren,
A. M. Tetrahedron Lett. 1996, 37, 6587. (c) Castan˜o, A. M.; Mendez,
M.; Ruano, M.; Echavarren, A. M. J . Org. Chem. 2001, 66, 589
(12) Morita, Y.; Kashiwagi, A.; Nakasuji, K. J . Org. Chem. 1997,
62, 7464.
(7) (a) Ishiara, K.; Ishibashi, H.; Yamamoto, H. J . Am. Chem. Soc.
2001, 123, 1505. (b) Rosales, V.; Zambrano, J . L.; Demuth, M. J . Org.
Chem. 2002, 67, 1167.
(8) For a recent overview on contemporary free-radical chemistry,
see: Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001; Vols. 1 and 2.
(9) For seminal works on titanocene-mediated epoxide openings,
see: (a) RajanBabu, T. V.; Nugent, W. A. J . Am. Chem. Soc. 1994,
116, 986. For seminal works on titanocene-catalyzed epoxide openings,
see: (b) Gansa¨uer, A.; Pierobon, M.; Bluhm, H. Angew. Chem., Int.
Ed. 1998, 37, 101. (c) Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J . Am.
Chem. Soc. 1998, 120, 12849. For recent reviews, see: (d) Gansa¨uer,
A.; Bluhm, H. Chem. Rev. 2000, 100, 2771. (e) Spencer, R. P.; Schwartz,
J . Tetrahedron 2000, 56, 2103. (f) Gansa¨uer, A.; Lauterbach, T.;
Narayan, S. Angew. Chem., Int. Ed. 2003, 42, 5556.
5804 J . Org. Chem., Vol. 69, No. 17, 2004

TABLE 1. P r od u cts, Yield s, a n d Rea ction Tim es in th e
Syn th esis of Com p ou n d s 15-23
SCHEME 3. Syn th esis of Ar yl Ep oxyp olyp r en es
15-23
a
b
LiCl (3 mol) was added. Performed with 10 mol % Pd(dba)2
Subsequently, epoxides 15-23 were stirred with a
substoichiometric quantity of commercial Cp2TiCl2 (20
mol %), Mn dust, and Me3SiCl/2,4,6-collidine in dry THF
at room temperature, giving cyclization products 24-32,
respectively, in moderate yields ranging from 35 to 55%
(Scheme 4). Nevertheless, even the lowest yield of 35%
obtained for 32, can be regarded as satisfactory consider-
ing that a trans/anti/trans-fused tricyclic skeleton, con-
taining six stereogenic centers and an exocyclic double
bond, was selectively formed among more than 190
potential regio- and stereoisomers.14
instead of the normal 2 mol %.
of substrates 19 and 22. This represents a significant
difference, not only with regard to carbocationic processes
but also in contrast with radical cyclizations promoted
by other transition metals.15,16 In fact, this cyclization
proceeds in a regio- and stereoselective fashion and the
intermediates involved are inert to benzene rings with
different substitution patterns, including activating and
deactivating groups with various steric demands. Thus,
our procedure has allowed us to synthesize, for example,
the zonarol-related structure 31 (which could then be
easily transformed in meroterpenoids 2-5) in only four
As we expected, the aromatic subunits remained
unchanged after radical cyclization in all the products
obtained, including the strongly activated aromatic rings
(13) Products 15-23 retained the (E)-configuration of the double
bonds unchanged after coupling reaction.
(14) It should be noted that carbocationic sequential cyclizations
towards simpler trans/anti/trans-fused tricyclic terpenoids gave yields
lower than 10%; see: vanTamelen, E. E.; Nadeau, R. C. J . Am. Chem.
Soc. 1967, 89, 176.
(15) (a) Snider, B. B.; Mohan, R. M.; Kates, S. A. J . Org. Chem. 1985,
50, 3659. (b) Snider, B. B.; Mohan, R.; Kates, S. A. Tetrahedron Lett.
1987, 28, 841.
(16) Similar results have been observed in PET-induced cycliza-
tions: Rosales, V.; Zambrano, J .; Demuth, M. Eur. J . Org. Chem. 2004,
1798.
J . Org. Chem, Vol. 69, No. 17, 2004 5805

SCHEME 4. Tita n ocen e-Ca ta lyzed Cycliza tion of 15-23.
submitted to flash chromatography (hexanes-EtOAc), affording
steps with an overall yield of 16%. The method also
proved to be useful in the synthesis of other types of
meroterpenoid-related structures, including those con-
taining a mono- (24-29) or a diterpenoid moiety (32).
In summary, we describe here a novel approach for
synthesizing polycyclic fungal and marine meroterpe-
noids based on the Stille-type coupling of aryl stannanes
and allylic carbonates followed by the titanocene-
catalyzed domino cyclization of the corresponding aryl
epoxypolyprenes. This strategy has proved useful in the
synthesis of several meroterpenoid-related structures
(24-32) containing a mono-, sesqui-, or diterpenoid
moiety and a nonfused aromatic subunit with different
substitution patterns. Moreover, as the Stille coupling
under Echavarren’s conditions proved to be compatible
with preformed epoxides, the method might presumably
be extended to the enantioselective preparation of bio-
active meroterpenoids, starting with enantiomerically
enriched epoxypolyprenols obtained from commercial
12a -c with the aid of the Noe-Lin catalyst,17 a task we
are currently engaged in.
the expected arylstannanes.
Mod el P r oced u r e for St ille Cou p lin g. A mixture of
carbonate 14a -c (1 mmol), arylstannane (1.1 mmol), Pd(dba)2
(0.02 mmol), and water (2 mmol) in DMF (3 mL) was stirred at
room temperature for several hours (see Table 1). The reaction
was then diluted with t-BuOMe, washed with saturated NaH-
CO3, and dried over anhydrous Na2SO4 and the solvent removed.
The residue was submitted to flash chromatography (hexanes-
EtOAc), giving the expected coupling products 15-22.
Mod el P r oced u r e for Ra d ica l Cycliza tion . Strictly deoxy-
genated THF (20 mL) was added to a mixture of Cp2TiCl2 (0.5
mmol) and Mn dust (20 mmol) under an Ar atmosphere, and
the suspension was stirred at room temperature until it turned
lime green (after about 15 min). Then, a solution of epoxide (2.5
mmol), 2,4,6-collidine (20 mmol), and Me3SiCl (10 mmol) in THF
(2 mL) was added, and the mixture was stirred for 16 h. The
reaction was then quenched with 2 N HCl and extracted with
t-BuOMe. The organic layer was washed with brine and dried
(anhydrous Na2SO4) and the solvent removed. The residue was
solved in THF (20 mL) and stirred with Bu4NF (10 mmol) for 2
h. The mixture was then diluted with t-BuOMe, washed with
brine, and dried (anhyd Na2SO4) and the solvent removed.
Products obtained were isolated by flash chromatography of the
residue (hexane/t-BuOMe). Besides exocyclic alkenes 24-32,
minor proportions of endocyclic regioisomers were detected.
Exp er im en ta l Section
Mod el P r oced u r e for th e Syn th esis of Allylic Ca r bon -
a tes. Diethyl carbonate (20 mmol) was added to a mixture of
epoxypolyprenols 13a -c (1 mmol) and NaH (4 mmol) in THF
(20 mL) at room temperature. The reaction was then stirred for
4 h; the solvent was removed, and the residue was submitted to
flash chromatography (hexanes-EtOAc, 20:1) obtaining the
corresponding epoxyprenyl ethyl carbonates 14a (100%), 14b
(100%), and 14c (63%).
Mod el P r oced u r e for th e Syn th esis of Ar yltr ibu tylsta n -
n a n es (10). t-BuLi (2.2 mmol) was added to a solution of the
corresponding bromoderivative (1 mmol) in THF (10 mL) at -78
°C, and the reaction was stirred for 30 min. Bu3SnCl (1.1 mmol)
was then added and the resulting mixture stirred at room
temperature for 7 h. The reaction was then diluted with
t-BuOMe, washed with saturated NaHCO3, and dried over
anhydrous Na2SO4 and the solvent removed. The residue was
Ack n ow led gm en t. The authors thank the Spanish
DGICYT (Projects PB 98-1365 and BQ2002-032M) and
the “J unta de Andaluc´ıa” (PAI group FQM339) for their
financial support. J .J . thanks the Spanish Ministry of
Science and Technology for a predoctoral grant. Thanks
are given to Dr. A. F. Barrero for his collaboration in
the early stage of this work. We thank our English
colleague Dr. J . Trout for revising our text.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
and 1H and 13C NMR spectra for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Corey, E. J .; Noe, M. C.; Lin, S. Tetrahedron Lett. 1995, 36,
8741. (b) Corey, E. J .; Luo, G.; Lin, S. J . Am. Chem. Soc. 1997, 119,
9927.
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