A convenient enantiospecific route towards bioactive merosesquiterpenes by cationic-resin-promoted Friedel-Crafts alkylation with α,β-enones

Article abstract of DOI:10.1002/ejoc.200801174

An enantiospecific route towards bioactive merosesquiterpenes, based on the cationic-resin-promoted Friedel-Crafts alkylation of alkoxyarenes with an α,β-unsaturated ketone, is reported. Reaction of ketone 11 with 3,4-methylenedioxyphenol afforded the cor

Full text of DOI:10.1002/ejoc.200801174

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200801174
A Convenient Enantiospecific Route towards Bioactive Merosesquiterpenes by
Cationic-Resin-Promoted Friedel–Crafts Alkylation with α,β-Enones
Enrique Alvarez-Manzaneda,*[a] Rachid Chahboun,[a] Eduardo Cabrera,[a] Esteban Alvarez,[a]
Ali Haidour,[a] Jose Miguel Ramos,[a] Ramón Alvarez-Manzaneda,[b] Rubén Tapia,[a]
Hakima Es-Samti,[a] Antonio Fernández,[a] and Inmaculada Barranco[a]
Keywords: Terpenoids / Arenes / Aromatic substitution / Cyclization / Biological activity
An enantiospecific route towards bioactive merosesquiter-
penes, based on the cationic-resin-promoted Friedel–Crafts
alkylation of alkoxyarenes with an α,β-unsaturated ketone,
is reported. Reaction of ketone 11 with 3,4-methylenedioxy-
a suitable intermediate in the synthesis of bioactive meroses-
quiterpenes and their 8-epi derivatives. By utilizing this
methodology, a formal synthesis of (+)-puupehenone and
other related metabolites, via triflate 25, is described.
phenol afforded the corresponding chromene. Treatment of (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
11 with protected phenol 20 gave aryl nordrimane ketone 21,
Germany, 2009)
studies have revealed that some of them inhibit lipoxygen-
ase[8a] and angiogenesis,[8b] further heightening the interest
in this class of compounds.
Introduction
Merosesquiterpenes are natural products of mixed bio-
synthetic origin (polyketide–terpenoid) containing a sesqui-
terpene unit joined to a phenolic or quinone moiety. The
most important metabolites of this family of compounds,
mainly due to their relevant, potent biological activities, are
those bearing a bicyclic terpene (drimane) moiety. Exam-
ples of drimenyl quinones are the antitumour tauranin
(1),[1] which also inhibits cholesterol biosynthesis, the anti-
HIV (+)-hyatellaquinone (2)[2] or the most recently reported
sphingosine kinase inhibitor (–)-F-12509 A (3).[3] Another
important group of compounds belonging to this family of
terpenoids is that of the marine puupehenones, which pos-
sess a tetracyclic structure, including a pyran ring. Exam-
ples of the latter are puupehenone (4),[4] 15-cyanopu-
upehenone (5),[5a] halopuupehenones 6 and 7,[5b,5c] pu-
upehedione (8a),[5a] 15-oxopuupehenol (9)[4] and 15-cyano-
puupehenol (10) (Figure 1).[6] Although a wide variety of
relevant biological properties, including antitumour, antivi-
ral, antibiotic, antituberculosis, antimalarial, antioxidant,
insecticidal and antifungal activities, have been reported for
these compounds in the last twenty years,[7] the most recent
Figure 1. Some representative merosesquiterpenes.
The important biological properties and the natural scar-
city of these metabolites have motivated chemists to study
their synthesis. In general, two main strategies have been
utilized to create the merosesquiterpene skeleton: (a) the
biomimetic cyclization of farnesylphenols, as first used by
Trammell[9a] in a racemic synthesis of 4 and more recently
by Yamamoto et al.[9b] in an asymmetric synthesis of 8b
and other related compounds; (b) a two-synthon strategy,
involving in most cases the reaction of a drimane electro-
[a] Departamento de Química Orgánica, Facultad de Ciencias, In-
stituto de Biotecnología, Universidad de Granada,
18071 Granada, Spain
Fax: +34-958-24-80-89
E-mail: eamr@ugr.es
[b] Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Almería,
04120 Almería, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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E. Alvarez-Manzaneda et al.
SHORT COMMUNICATION
phile with a nucleophilic phenol derivative,[10] usually C-8, by attack onto an oxidatively activated 1,2-dihydrox-
an aryllithium compound. An 8-oxygenated alde- yphenyl unit.[10g] Very recently, an alternative strategy was
hyde,[10a,10d,10g] an 8,9-epoxyaldehyde[10e] or an unsaturated utilized by the present authors in the synthesis of the potent
aldehyde,[10b,10c,10i] possessing the correct chirality for three angiogenesis inhibitor 8-epipuupehedione (8b), involving
of the four stereogenic centres, that is, C-5, C-9 and C-10, the Diels–Alder cycloaddition of a C19 dienol ether, derived
have been utilized as the drimane synthon. Banerjee et from sclareol oxide, with a suitable dienophile.[10j] Scheme 1
al.[10f] reported an alternative two-synthon strategy to create summarizes the most commonly utilized synthetic strategies
the carbon skeleton of compounds 8a,b, which lack the chi- towards puupehenone-related metabolites.
rality at C-9, which involves the reaction of a nordrimane
anion with a protected polyhydroxybenzaldehyde. In an-
Results and Discussion
other version of this synthetic strategy, Akita synthesized
(+)-zonarol, an exocyclic drimenyl hydroquinone, by 1,4-
addition of an arylcuprate on nordrimane α,β-enone 11.[10k]
An interesting strategy for the elaboration of a tetracyclic
skeleton, based on a [4+2] cycloaddition of 1,3,3-trimethyl-
2-vinylcyclohexene with 3-cyanochromone derivatives, has
been reported; the main drawbacks of this procedure lie
with the low yield and the unfavourable stereoselectivity of
the process.[11] Very recently, Wallace et al. described rapid
stereoselective access to the tetracyclic core of this type of
compound by utilizing metal-free radical cyclizations.[12]
The synthesis of tetracyclic merosesquiterpenes, such as
puupehenone-related metabolites 4–10, requires the con-
struction of the C pyran ring in a second phase of the syn-
thetic sequence, when the two synthon (drimane electro-
phile–nucleophile phenol) strategy is utilized. The stereose-
lectivity of this process determines the stereochemistry at
C-8, affording the natural (C8α-Me) compounds or their
epimers. Various methodologies have been utilized to elabo-
rate the pyran ring. Electrophilic acid cyclization of drimen-
ylphenols leads to, as the major diastereoisomer, the “un-
natural” (C8β-Me) compounds.[9a,10b,10d] The obtention of
natural 8-epimers, such as (+)-puupehenone (4) and related
compounds, starting from drimenylphenol, was first ac-
complished by the present authors through β-attack of the
phenol hydroxy group on an α-selene-[10a] or α-oxacyclopro-
pane[10d] generated from the carbon–carbon double bond;
more recently, a palladium-promoted cyclization was uti-
lized in the synthesis of the antitumour 15-oxopuupehenol
(9) by our group.[10i] Quideau et al. synthesized 4 by starting
from an 8-hydroxydrimane with a suitable configuration at
Continuing our investigation into the synthesis of bioac-
tive merosesquiterpenes, we are interested in developing
new methodologies, utilizing easily accessible synthons and
convenient reaction conditions, which at the same time en-
able control of the C-8 stereochemistry of the final com-
pound. An alternative to the usual two-synthon strategy,
which involves the addition of the inconvenient aryllithium
or arylcuprate to the drimane aldehyde or nordrimane α,β-
enone 11, could be the Friedel–Crafts alkylation of a suit-
able aromatic synthon with α,β-unsaturated ketone 11
(Scheme 2). Adduct I could be easily transformed into the
corresponding merosesquiterpene after regenerating the
exocyclic double bond or after introducing a methyl group
into the ketone carbonyl. Only a few examples of this type
of reaction have been reported. Bunce et al. reported the
Amberlyst-15 catalyzed addition of different phenols to
some acyclic α,β-unsaturated ketones;[13] in most cases, the
corresponding p-substituted phenols were obtained in mod-
erate yields. Alkylation of indole derivatives with β,γ-unsat-
urated α-keto esters[14] and cyclization of aryl derivatives of
diethyl malonate,[15] catalyzed by Lewis acids, were recently
described. The reaction of dicyclohexylammonium acrylate
with hydroxyarenes is another recent example.[16]
Scheme 2. Planned synthetic strategy via nordrimane α,β-enone 11.
α,β-Enone 11 is a common nordrimane synthon utilized
in the synthesis of diverse terpenoids, and different pro-
cedures have been reported for its preparation. These in-
clude a total synthesis after acid cyclization of methyl ger-
anyl acetoacetate;[17a] pure enantiomers of ketone 11 were
obtained through enzymatic functionalization[10k] or optical
resolution.[17b] An enantiospecific synthesis starting from a
natural drimane was also reported.[17c] We developed a very
efficient synthesis of compound 11, starting from diol 14
(Scheme 3). Enantiomerically pure drimane diol 14 was ob-
tained by lipase-catalyzed kinetic resolution after acid cycli-
zation of farnesyl acetate (12) (two steps, 8% overall
yield),[18] or after a three-step sequence starting from com-
mercial (–)-sclareol (13) (70% overall yield), previously re-
Scheme 1. The previous two-synthon strategy with subsequent py-
ran ring construction.
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Convenient Enantiospecific Route towards Bioactive Merosesquiterpenes
ported by our group.[19] Mesylation of diol 14 gave an unre- attack position of the aryl ether is sufficiently activated; in
solvable 2:1 mixture of mesylate regioisomers 15a/b, which this way, we confirmed that the anisol did not react and
after ozonolysis led to ketone 16 and ketoaldehyde 17. Fur- neither did the catechol dimethyl ether. However, treatment
ther treatment of compound 16 with DBU afforded enone of compound 20[22] with enone 11, under the above condi-
11.[20]
tions, afforded ketone 21 in high yield and with complete
diastereoselectivity, as the NOE experiments revealed; thus,
1
the H NMR CH2-C1 signals (doublet of doublets at δ =
2.67 and 2.73 ppm) increased after irradiating the angular
methyl protons (s, δ = 0.73 ppm). Exocyclic drimane alkene
22 was then obtained after Wittig condensation. Com-
pound 22 is a suitable intermediate in the synthesis of pu-
upehenone-related metabolites, through acid-mediated cy-
clization or selenium- or palladium-promoted cyclization.
Obviously, this resin-promoted Friedel–Crafts alkylation
will also allow the synthesis of merosesquiterpenes bearing
an exocyclic carbon–carbon double bond, such as com-
pounds 1–3, by utilizing a suitable aromatic synthon. Alter-
natively, treatment of ketone 21 with MeMgBr and further
deprotection of the benzyl ether gave drimane phenol 24,
which is a suitable intermediate for synthesizing pu-
upehenone-related metabolites and “unnatural” 8-epi deriv-
atives. Its cyclization under acidic conditions will provide
the corresponding (8R)-tetracyclic compound, as was une-
quivocally established.[10i]
Scheme 3. Synthesis of α,β-enone 11 from diol 14. Reagents and
conditions: (i) Ref.[16] (ii) Ref.[17] (iii) MsCl, pyridine, room temp.,
15 h, 80%. (iv) O3, CH2Cl2, –78 °C, 30 min; PPh3, 4 h, 16 (58%),
17 (34%). (v) DBU, benzene, room temp., 1 h, 95%.
Following this, we investigated the cationic-resin-pro-
moted Friedel–Crafts alkylation of hydroxyarenes with en-
one 11, as postulated in Scheme 2. An initial, exciting out-
come was obtained when compound 11 was treated with
sesamol (18) (Scheme 4) and cationic-resin Amberlyst A-15,
in benzene under reflux; namely, the formation of chromene
19 in high yield. Besides being a new, mild procedure to
synthesize xanthene derivatives, this finding could be ex-
ploited to develop a rapid synthesis of merosesquiterpenes;
unfortunately, the pyran ring opening of compound 19, un-
der the conditions reported in the literature, which involves
the treatment with methylmagnesium bromide in the pres-
ence of low-valent nickel species,[21] was unsuccessful.
Scheme 5. Synthesis of drimenyl phenol 23. Reagents and condi-
tions: (i) Amberlyst A-15, 4 Å molecular sieves, CH2Cl2, reflux,
12 h, 94%. (ii) Ph3P=CH2, THF, room temp., 4 h, 74%. (iii)
MeMgBr, OEt2, 0 °C, 30 min, 94%. (iv) H2, Pd–C, MeOH, room
temp., 1 h, 93%.
Scheme 4. Reaction of sesamol (18) with the nordrimane α,β-enone
11. Reagents and conditions: (i) Amberlyst A-15, 4 Å molecular
sieves, benzene, reflux, 1 h 50 min, 99%.
Hydroxyphenol 24, which possesses the correct stereo-
chemistry at C-8 to achieve natural metabolites, has been
transformed into puupehenol (27), whose transformation
In order to prevent the formation of the pyran ring, a into puupehenone-related metabolites, such as 4, 5, 9 and
protected phenol was utilized (Scheme 5). At this point, it 10, we had previously reported[10i] (Scheme 6). Cyclization
should be noted that the behaviour of aryl ethers is quite of triflate 25 with Pd(OAc)2 (10mol-%), 1,1Ј-bis(diphenyl-
different from that previously reported for phenols. Thus, phosphanyl)ferrocene (DPPF; 15mol-%) and sodium tert-
we have observed that the reaction on α,β-unsaturated butoxide in toluene at 100 °C gave tetracyclic compound 26,
ketone 11, mediated by cationic resin, only occurs when the which was easily converted into diphenol 27. The complete
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E. Alvarez-Manzaneda et al.
SHORT COMMUNICATION
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Scheme 6. Synthesis of puupehenol (27) from hydroxyphenol 24.
Reagents and conditions: (i) (TfO)2O, CH2Cl2, iPrNEt2, 0 °C,
5 min, 83%. (ii) cat. Pd(OAc)2, cat. DPPF, NaOtBu, toluene,
100 °C, 14 h, 76%. (iii) BBr3, CH2Cl2, 0 °C, 1 h 20 min, 82%.
Conclusions
In summary, a cationic-resin-promoted Friedel–Crafts al-
kylation of polyphenol ethers with an α,β-unsaturated
ketone is utilized for the first time to synthesize bioactive
merosesquiterpenes. The reaction of sesamol (18) with en-
one 11 afforded compound 19 in high yield; this process
constitutes a new, convenient procedure for synthesizing
xanthene derivatives. The reaction of protected phenol 20
with ketone 11 gave aryl nordrimane ketone 21, which was
easily transformed into merosesquiterpene 22. Alternatively,
hydroxyphenol 24, also obtained from ketone 21, was con-
verted into puupehenol (27), the precursor of puupehenone-
related metabolites, utilizing a new method involving C–O
coupling catalyzed by palladium. Compound 24 is also a
suitable intermediate in the synthesis of the 8-epi deriva-
tives, such as the angiogenesis inhibitor 8-epipuupehedione
(8b), through acid-mediated cyclization.
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spectra for all the new compounds.
Acknowledgments
The authors thank the Spanish Ministry of Science and Technology
(Project CTQ2006-12697) and Junta de Andalucia (PAI FQM-348)
for financial support. R. T. thanks the Spanish Ministry of Science
and Technology for a predoctoral grant.
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Received: November 26, 2008
Published Online: January 28, 2009
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