Synthesis of cordiaquinones B, C, J, and K on the basis of a bioinspired approach and the revision of the relative stereochemistry of cordiaquinone C

Article abstract of DOI:10.1021/jo800355y

(Chemical Equation Presented) Four members of the cordiaquinone family (cordiaquinones B, C, J, and K) were synthesized on the basis of a bioinspired scenario in five to six steps from trans,trans-farnesol. As key reactions we used the acid-catalyzed cyclization of a suitable epoxy terpenoid and a Diels-Alder reaction between a diene and benzoquinone. The relative stereochemistry of cordiaquinone C is opposite to that reported in the isolation paper and is in agreement with a plausible scenario for the biosynthesis of cordiaquinones from a common (E)-configurated naphthoquinone epoxide precursor. A fast and clean methodology for the synthesis of the naturally occurring (Z)-β-farnesene from cis-nerolidol is also reported.

Full text of DOI:10.1021/jo800355y

Synthesis of Cordiaquinones B, C, J, and K on the Basis of a
Bioinspired Approach and the Revision of the Relative
Stereochemistry of Cordiaquinone C†
Elias Arkoudis and Manolis Stratakis*
Department of Chemistry, UniVersity of Crete, Voutes 71003, Iraklion, Greece
stratakis@chemistry.uoc.gr
ReceiVed February 12, 2008
Four members of the cordiaquinone family (cordiaquinones B, C, J, and K) were synthesized on the
basis of a bioinspired scenario in five to six steps from trans,trans-farnesol. As key reactions we used
the acid-catalyzed cyclization of a suitable epoxy terpenoid and a Diels-Alder reaction between a diene
and benzoquinone. The relative stereochemistry of cordiaquinone C is opposite to that reported in the
isolation paper and is in agreement with a plausible scenario for the biosynthesis of cordiaquinones from
a common (E)-configurated naphthoquinone epoxide precursor. A fast and clean methodology for the
synthesis of the naturally occurring (Z)-ꢀ-farnesene from cis-nerolidol is also reported.
Introduction
There is no direct experimental evidence for the biosyn-
thetic origin of cordiaquinones. In our opinion, it is likely5
(Scheme 2) that they arise from the acid-catalyzed cyclization
of epoxide A, which in turn could derive from a Diels-Alder
reaction6 of the naturally occurring epoxy ꢀ-farnesene7 (B)
or ꢀ-farnesene with benzoquinone, followed by an oxidation
of the cyclo adduct.
In light of our recent findings that slightly acidic zeolite NaY
promotes the selective monocyclization of epoxy polyene
terpenes,8 we envisioned the NaY-catalyzed cyclization of the
(E)-configurated epoxide A as a promising route to the synthesis
of cordiaquinones C, J, and K (Scheme 3). Thus, alcohol C
and cordiaquinone J could directly derive from (E)-A. Further-
more, alcohol C is the precursor of cordiaquinone K. We would
like to point out that the initially proposed structure of
cordiaquinone J is a diastereomer of the revised one, as proved
through their syntheses by Yabuta and co-workers.9 Based on
a common biosynthetic scenario, epoxide A having an (E)
Cordiaquinones A-K constitute a family of 10 naturally
occurring merosesquiterpenoids that possess a naphthoquinone
moiety (Scheme 1). Cordiaquinones A-D1,2 were isolated from
the roots of Cordia corymbosa, E-H3 from the roots of Cordia
limnaei, while J and K4 from the roots of Cordia curassaVica.
They exhibit antifungal properties against Cladosporium cu-
cumerinum and the yeast Candida albicans as well as larvicidal
properties against the yellow fever-transmitting mosquito Aedes
aegypti.
† Dedicated to Professor M. Orfanopoulos on the occasion of his 60th birthday.
(1) Bieber, L. W.; Messana, I.; Lins, S. C. N.; da Silva Filho, A. A.;
Chiappeta, A. A.; De Mello, J. F. Phytochemistry 1990, 29, 1955–1959.
(2) Bieber, L. W.; Krebs, H. C.; Schafer, W. Phytochemistry 1994, 35, 1027–
1028.
(3) Ioset, J.-R.; Marston, A.; Gupta, M. P.; Hostettmann, K. Phytochemistry
1998, 47, 729–734.
(4) Ioset, J.-R.; Marston, A.; Gupta, M. P.; Hostettmann, K. Phytochemistry
2000, 53, 613–617.
(6) For the role of Diels-Alder reaction in biogenetic pathways, see:
Stocking, E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42, 3078–3115.
(7) Bocchi, M.; Garlaschelli, L.; Vidari, G.; Mellerio, G. J. Nat. Prod 1992,
55, 428–431.
(5) The possibility that the naphthoquinone moiety of cordiaquinones arises
from a polyketide pathway can not be excluded. For the biogenesis of quinones
through polyketides, see: Bringmann, G.; Noll, T. F.; Gulder, T. A. M.; Grune,
M.; Dreyer, M.; Wilde, C.; Pankewitz, F.; Hilker, M.; Payne, G. D.; Jones, A. L.;
Goodfellow, M.; Fiedler, H.-P. Nat. Chem. Biol. 2006, 2, 429–433.
(8) Tsangarakis, C.; Arkoudis, E.; Raptis, C.; Stratakis, M. Org. Lett. 2007,
9, 583–586.
4484 J. Org. Chem. 2008, 73, 4484–4490
10.1021/jo800355y CCC: $40.75 2008 American Chemical Society
Published on Web 05/23/2008

Synthesis of Cordiaquinones B, C, J, and K
SCHEME 1. Cordiaquinones A-K
SCHEME 3. Proposed Synthesis of Cordiaquinones C, J,
and K Based on the Zeolite NaY-Promoted Cyclization of
the (E)-Configured Epoxide A
SCHEME 4. Synthesis of Naphthoquinone Epoxide 5 from
Farnesol
SCHEME 2. Postulated Biosynthetic Scenario for
Cordiaquinones
dihydro-2H-pyran in the presence of a catalytic amount of
pyridinium p-toluenesulfonate (PPTS). The THP-protected far-
nesol 2 was treated with t-BuOK in THF,10 in the presence of
a catalytic amount of 18-crown-6, and furnished exclusively
(E)-ꢀ-farnesene (3) in 86% yield. The epoxidation of 3 by
reaction with N-chlorosuccinimide in THF/H2O followed by
treatment of the resulting chlorohydrin with K2CO3 in methanol
yielded the naturally occurring epoxy (E)-ꢀ-farnesene (4) in 77%
overall yield as the only regioisomer. Finally, Diels-Alder
reaction of diene 4 with 1.4 equiv of benzoquinone (14 h in
refluxing toluene), followed by addition of a 6-fold excess of
configuration on the C6-C7 double bond, (E)-A, will lead upon
acid catalysis to cordiaquinone J (revised structure) and to
alcohol C with cis-stereochemistry, which contradicts, however,
the trans stereochemistry appearing in the proposed structure2,3
of cordiaquinones C and H. To shed light on this discrepancy,
we started our synthetic journey by studying the cyclization of
the (E)-configured epoxide A.
Results and Discusssion
For the synthesis of a suitable precursor, the (E)-configured
epoxide A (compound 5, Scheme 4), trans,trans-farnesol (1)
was the starting material. trans,trans-Farnesol was protected as
a THP ether (2) in 98% yield by reaction with 5 equiv of 3,4-
(9) Yajima, A.; Saitou, F.; Sekimoto, M.; Maetoko, S.; Nukada, T.; Yabuta,
G. Tetrahedron 2005, 61, 9164–9172.
(10) Otera, J.; Niibo, Y.; Okuda, K. Chem. Lett. 1986, 11, 1829–1832.
J. Org. Chem. Vol. 73, No. 12, 2008 4485

Arkoudis and Stratakis
SCHEME 5. Intrazeolite Cyclization of Epoxy ꢀ-Farnesene
(4) and the Synthesis of Cordiaquinones J and K
activated MnO2 (one pot) and heating to reflux for 30 min,
yielded the desired epoxy naphthoquinone 5 in 78% yield (51%
overall yield from 1). A similar reaction sequence is known in
the literature,11 in which the naphthoquinone skeleton is
constructed in two separate steps, with the first step (Diels-Alder
reaction) being carried out in the presence of BF3 as a catalyst
at ambient temperature. In our case, the Lewis acid promoted
version was avoided due to the presence of the acid-sensitive
epoxide functionality on 4, yet we were happy to realize that
naphthoquinones can derive from dienes and benzoquinone
under thermal conditions in just one pot.
To our disappointment, all attempts to perform the direct
biomimetic synthesis of cordiaquinones skeleton using the NaY-
promoted cyclization of epoxide 5 failed. Upon adsorption of
5 within NaY, an intense brown-red color appeared immediately
with formation of an unidentified polymeric material. We
assume that the quinone moiety undergoes a strong complex-
ation to the acidic site of the zeolite, with subsequent unwanted
side reactions, thus leading to the failure of our proposed
cyclization scenario. To overcome this failure, a modified
strategy was followed, based on which, the intrazeolite cycliza-
tion occurred prior to the formation of the naphthoquinone
moiety. Thus, on treatment of the epoxy ꢀ-farnesene (4) with
NaY for 5 min, the monocyclized alcohols 6 (exo double bond)
and 7 (endo double bond) were primarily formed, along with
bicyclic ether 8 and the allylic alcohol 97 in 80% combined
yield and in a relative ratio (6+7)/8/9 ) 70/25/5 (Scheme 5).
The ratio of the exo/endo double regioisomers 6/7 was ∼6/1.
This product distribution resembles substantially the results
obtained from our previous studies8 on the cyclization of epoxy
polyene terpenoids promoted by NaY and once more exemplifies
the unique ability of NaY as a selective monocyclization catalyst
on its reaction with epoxy polyene terpenoids. It is noteworthy
that treatment of epoxide 4 with a catalytic amount of SnCl4 in
dry dichloromethane afforded in low yield a complex mixture
of products. For the zeolite-promoted reaction of epoxide 4,
we used low loading levels of 4 relative to the zeolite supercages
(∼0.2 mmol of 4 per 1 g of dry NaY). We also observed (NMR,
GC-MS) that on prolonged zeolite treatment (10-20 min) new
products appear, with a simultaneous decrease in the relative
yield of 6/7. The alcohols 6/7 (inseparable mixture) and the
bicyclic ether 8 were isolated from the crude reaction mixture
by column chromatography. The regioisomers 6 and 7 reacted
with benzoquinone/MnO2 in refluxing toluene to form naph-
thoquinones 10(exo) and 11(endo) in 77% isolated yield and in
a relative ratio 10/11 ) 6/1. Similarly, bicyclic ether 8 furnished
after an identical reaction sequence (Scheme 5) cordiaquinone
J (12) in 75% yield (13% overall yield from epoxide 4).
The separation between the exo and endo regioisomers 10
and 11 was impossible by column chromatography. The
purification of the major one (10) was crucial, as it could be
the precursor of cordiaquinones K and C (or its epimer). Thus,
the mixture of 10 and 11 reacted with 0.25 equiv of the powerful
enophile N-phenyl-1,2,4-triazoline-3,5-dione (PTAD12). The
trisubstituted double bond of the thermodynamically more stable
11 reacted instantaneously with PTAD to form a mixture of
10 bearing a less nucleophilic disubstituted double bond
remained intact.14 After column chromatography, the exo isomer
10 was isolated free of the undesired regioisomer 11 and
oxidized with PCC to produce cordiaquinone K (13, Scheme
5) in 91% yield (21% overall yield from epoxide 4).
For the completion of the synthesis of cordiaquinone C (or
its epimer), a simple esterification of 10 with 3,3-dimethylacry-
loyl chloride (DMAP/Et3N) was realized as a next step. Despite
the consumption of the reactant 10, a complex mixture of
products was formed without the expected product being among
them. To overcome this problem, we decided to esterify the
mixture of alcohols 6 and 7 and then attach the naphthoquinone
moiety. Thus, treatment of 6/7 with LiHMDS15 followed by
addition of 3,3-dimethylacryloyl chloride afforded the regioi-
someric dimethylacryloyl esters 14 (exo) and 15 (endo) in 85%
yield (14/15 ∼6/1). Surprisingly, treatment of 6/7 with 3,3-
dimethylacryloyl chloride in the presence of DMAP/Et3N
afforded apart of 14/15, their non conjugated terminal double
isomers on the ester functionality (3′-methylbut-3′-enoate) in
ene products,13 as seen in the crude H NMR spectrum, while
1
(11) Castro, M. A.; del Corral, J. M. M.; Gordaliza, M.; Garcia, P. A.; Gamito,
A. M.; Gualberto, S. A.; Batista, R.; San Feliciano, A. Synthesis 2005, 3202–
3208.
(14) For a similar isolation of one among other regioisomeric alkenes using
their reaction with m-CPBA, see: Basabe, P.; Bodero, O.; Marcos, I. S.; Diez,
D.; de Roman, M.; Blanco, A.; Urones, J. G. Tetrahedron 2007, 63, 11838–
11843.
(12) Vougioukalakis, G. C.; Orfanopoulos, M. Synlett 2005, 713–731.
(13) For the reaction of R-cyclogeranyl derivatives, such as 10, with PTAD,
see: Tsangarakis, C.; Zaravinos, I.-P.; Stratakis, M. Synlett 2005, 1857–1860.
(15) Nemoto, T.; Ohshima, T.; Shibasaki, M. Tetrahedron 2003, 59, 6889–
6897.
4486 J. Org. Chem. Vol. 73, No. 12, 2008

Synthesis of Cordiaquinones B, C, J, and K
SCHEME 6. Final Steps toward the Synthesis of
Cordiaquinone C (Revised Structure 16)
SCHEME 7. Synthesis of the Proposed Structure of
Cordiaquinone C (28)
appreciable relative yield (∼35%). The regioisomeric mixture
14/15 reacted with benzoquinone/MnO2 to form in 76% isolated
yield the non-chromatographically separable naphthoquinones
16 (exo) and 17 (endo), and in a relative ratio 6/1 (Scheme 6).
Treatment of 16/17 with PTAD, as described in the purification
the desired trans-alcohols 22 (exo) and 23 (endo), as well as
the bicyclic ether 24 and the allylic alcohol 25, analogous to 8
and 9. The relative product ratio was 22/23/24/25 ) 66/12/7/
15. The inseparable mixture of 22 and 23 underwent esterifi-
cation upon treatment with LiHMDS/3,3-dimethylacryloyl
chloride to form 26 (exo) and 27 (endo) in 81% yield and in
∼6/1 relative ratio. Finally, reaction of 26/27 with benzoquinone/
MnO2 afforded naphthoquinone 28 (the proposed structure of
cordiaquinone C), as well as its endo regioisomer 29 (70%
isolated yield; 12.5% overall yield from cis-nerolidol; relative
ratio 28/29 ∼ 7/1). Surprisingly, upon treatment of the mixture
of 28/29 with PTAD, as applied to the mixtures 10/11 or 16/
17, the undesired minor 29 was completely unreactive. We
attribute this lack of reactivity to the axial orientation of the
-OCOCHdC(CH3)2 substituent, which hinders triazolinedione
approach on the cycloalkene double bond. Nevertheless, neither
1
of 10, resulted to the isolation of pure 16 whose H and 13C
NMR spectra were in agreement with those of cordiaquinone
C (19.5% overall yield from epoxide 4). This result strongly
corroborates the proposed biosynthetic scenario presented in
Scheme 3.
Following the spectroscopic proof that compound 16 is
cordiaquinone C, we attempted the synthesis of the proposed
structure of cordiaquinone C, which is essentially the trans
diastereomer of 16. The synthetic route (Scheme 7) toward
accomplishing this goal was identical to the synthesis of 16,
with the only difference that the configuration of ꢀ-farnesene
was (Z). As starting material, we used the commercially
available natural product cis-nerolidol (18). Reaction of 18 with
5 equiv of SOCl2 at -78 °C afforded mainly farnesyl chloride
with Z geometry on the C6-C7 double bond (19), yet possessing
a mixture of E/Z isomers on the C2-C3 double bond in a ratio
∼3/1. The presence of the two geometrical isomers on the
C2-C3 double bond of 19 is not a problem, as both isomers
converge to the same desired product in the accompanying step.
Thus, the crude mixture 19 underwent dehydrochlorination in
the presence of t-BuOK to afford exclusively (Z)-ꢀ-farnesene
(20) in 64% isolated yield over the two steps. Although (Z)-ꢀ-
farnesene is a natural pheromone and a constituent of several
essential oils, a clean method for its preparation, free from other
regio- or geometrical isomers, is not available. The (Z)-ꢀ-
farnesene was epoxidized selectively on the terminal trisubsti-
tuted double bond under identical conditions applied to its (E)-
isomer 3, to form 21 in 72% isolated yield. Epoxide 21 was
treated with NaY for 5 min to afford in 79% yield primarily
1
the H nor the 13C NMR spectroscopic data of compound 28
are in agreement with those of cordiaquinone C, which again
indicates that, the relative stereochemistry of the substituents
on the two stereogenic centers of cordiaquinone C is cis instead
of the proposed trans. We also propose that the relative
stereochemistry of cordiaquinone H3 is cis instead of trans, as
reasonably, cordiaquinone H arises via an epoxidation of the
quinone ring of cordiaquinone C.
Regardless the failure to provide a direct access to cor-
diaquinones skeleton through the zeolite-promoted cyclization
of naphthoquinone epoxide 5, we examined the cyclization of
5 under Lewis acid catalysis. From the already abundant studies
on the acid-catalyzed epoxy polyene terpene cyclization, it well
J. Org. Chem. Vol. 73, No. 12, 2008 4487

Arkoudis and Stratakis
SCHEME 8. Cyclization of Epoxide 5 Catalyzed by SnCl4
and the Reasonable Pathway for the Formation of
Cordiaquinone B
Yabuta’s group accomplished the enantioselective synthesis of
cordiaquinones K20 and J,9 while revised the structure of
cordiaquinone J, as through its synthesis it was found that the
initially proposed structure was a diastereomer of the reported
on in the isolation paper. Those synthetic routes, however,
require multiple steps compared to our approach, while they
lack of a biomimetic inspiration.
Conclusions
In conclusion, we have presented a short and efficient
synthesis of cordiaquinones B, C, J, and K on the basis of a
bioinspired approach. In addition, the relative stereochemistry
of cordiaquinone C was revised from trans to cis. As a key step,
we used the acid-catalyzed cyclization of a suitable terpenoid
epoxide. The naphthoquinone moiety of cordiaquinones was
introduced via a Diels-Alder reaction either at an early or at a
later stage, depending on the specific synthetic route. The
cyclization was carried out using as catalysts either a Lewis
acid (homogeneous conditions) or zeolite NaY (heterogeneous
conditions), depending on the nature of the reacting epoxide.
The current results exemplify once more the valuable role of
zeolite NaY as a unique, efficient, and highly useful acidic
catalyst in epoxy terpene cyclization.10
Experimental Section
(E)-ꢀ-Farnesene (3). In one-necked flask containing dry CH2Cl2
(40 mL) were dissolved trans,trans-farnesol, 1 (1.5 g, 6.75 mmol),
pyridinium p-toluenesulfonate (0.15 g, 0.6 mmol), and 3,4-dihydro-
2H-pyran (3.1 mL, 34 mmol). After 1 h, dichloromethane was
added, and the organic layer was washed with water. Removal of
the solvent under vacuum afforded the THP-protected farnesol (2)
documented that Lewis acids are the superior catalysts.16 The
reaction of 5 with 0.5 equiv of SnCl4 in dichloromethane at 0
°C afforded after 40 min and in 82% yield a mixture of 12
(cordiaquinone J, 60% relative yield), 30 (cordiaquinone B, 25%
relative yield), as well as a minor content (15% relative yield)
of all three regiosomeric monocyclized products 10, 11, and
31 (Scheme 8). Similar results were obtained by using BF3 as
a catalyst, with the only difference that the relative ratio of 12
(cordiaquinone J)/30 (cordiaquinone B) was ∼4/1. Cordiaquino-
ne B exhibits pronounced activity17 against Gram-positive
bacteria and mycobacteria. The formation of 2,3,4-trimethyl-
cyclohexanones upon treatment of epoxypolyene terpenes with
Lewis acids is well documented18 and proposed to proceed
through the 1,2-rearrangement reaction of two hydrides and one
methyl, shown in the transition state of Scheme 8. To the best
of our knowledge, this is the first example of taking advantage
of this highly stereoselective pathway for the direct synthesis
of a natural product.
1
in 98% yield. H NMR of 2: 5.36 (t, J ) 6.5 Hz, 1H), 5.10 (m,
2H), 4.62 (t, J ) 3.5 Hz, 1H), 4.23 (dd, J1 ) 13.0 Hz, J2 ) 6.5 Hz,
1H), 4.02 (dd, J1 ) 13.0 Hz, J2 ) 6.5 Hz, 1H), 3.89 (m, 1H), 3.51
(m, 1H), 1.94-2.15 (m, 8H), 1.67 (s, 6H), 1.59 (s, 6H), 1.45-1.90
(m, 6H). The THP-farnesol 2 was dissolved in dry THF (40 mL).
Subsequently, 6.75 g (54 mmol, 10 equiv) of t-BuOK was added
in one portion, and the mixture was heated to 60 °C for 16 h. By
adding 10% of 18-crown-6 relative to the t-BuOK the reaction was
completed within 3 h. After extraction with hexane and removal
of the solvent under vacuum, the residue was chromatographed
using hexane/ethyl acetate ) 80/1 to afford 0.96 g of pure (E)-ꢀ-
1
farnesene, 2 (86% yield). H NMR: 6.38 (dd, J1 ) 17.5 Hz, J2 )
11.0 Hz, 1H), 5.25 (d, J ) 17.5 Hz, 1H), 5.17 (t, J ) 7.0 Hz, 1H),
5.10 (t, J ) 7.0 Hz, 1H), 5.06 (d, J ) 11.0 Hz, 1H), 5.02 (s, 1H),
5.00 (s, 1H), 2.17-2.25 (m, 4H), 2.08 (m, 2H), 1.98 (m, 2H), 1.68
(s, 3 H), 1.61 (s, 6H). 13C NMR: 146.1, 139.0, 135.4, 131.3, 124.4,
124.0, 115.7, 113.0, 39.7, 31.4, 26.7, 26.6, 25.7, 17.7, 16.0.7
(E)-2,2-Dimethyl-3-(3-methyl-7-methylenenona-3,8-dienyl)ox-
irane (4). In one-necked flask containing 35 mL of THF and 10
mL of H2O was added at 0 °C (E)-ꢀ-farnesene, 3 (0.78 g, 3.82
mmol). Immediately after, recrystallized NBS (0.80 g, 4.54 mmol)
was added in portions over a period of 10 min. After the
disappearance of 3, ether was added and the reaction mixture was
extracted to afford the crude bromohydrin. The bromohydrin was
added to a slurry containing methanol (40 mL) and K2CO3 (1.0 g,
7.2 mmol). The dehydrochlorination was complete within 30 min.
After aqueous workup and solvent removal, the residue was
chromatographed with hexane/ethyl acetate ) 40/1 to afford 0.65 g
The cyclization results of epoxide 5 in a homogeneous
medium (SnCl4) compliment those by using zeolite NaY in a
heterogeneous environment (epoxide 4), thus allowing the
synthesis of four members of the cordiaquinone family, employ-
ing the same concept; the acid-catalyzed rearrangement of an
epoxide. The enantioselective synthesis of (-)-cordiaquinone
B has been reported by Asaoka and co-workers.19 Later on,
1
of epoxide 4 as a single regioisomer (77% yield). H NMR: 6.36
(16) van Tamelen, E. E. Acc. Chem. Res. 1975, 8, 152–158.
(17) Filho; A, A.; Lima, R. M. O. C.; Nascimento, S. C.; Silva, E. C.;
Andrade, M. S. A. S.; Lins, S. C. N.; Bieber, L. W. Fitoterapia 1993, 64, 78–
80.
(19) Kuramochi, T.; Asaoka, M.; Ohkubo, T.; Tahei, H. Tetrahedron Lett.
1996, 37, 7075–7078.
(18) (a) van Tamelen, E. E.; Coates, R. M. Bioorg. Chem. 1982, 11, 171–
196. (b) Hoshino, T.; Sakai, Y. Tetrahedron Lett. 2001, 42, 7319–7323.
(20) Yajima, A.; Saitou, F.; Sekimoto, M.; Maetoko, S.; Yabuta, G.
Tetrahedron Lett. 2003, 44, 6915–6918.
4488 J. Org. Chem. Vol. 73, No. 12, 2008

Synthesis of Cordiaquinones B, C, J, and K
(dd, J1 ) 17.5 Hz, J2 ) 10.5 Hz, 1H), 5.23 (d, J ) 17.5 Hz, 1H),
5.20 (t, J ) 6.0 Hz, 1H), 5.05 (d, J ) 10.5 Hz, 1H), 5.00 (s, 1H),
4.98 (s, 1H), 2.70 (t, J ) 6.0 Hz, 1H), 2.06-2.25 (m, 6H),
1.56-1.69 (m, 2H), 1.62 (s, 3H), 1.30 (s, 3H), 1.26 (s, 3H). 13C
NMR: 146.0, 138.9, 134.5, 124.6, 115.8, 113.1, 64.1, 58.3, 36.3,
31.3, 27.4, 26.6, 24.9, 18.7, 16.0.
Cordiaquinone J (12). The bicyclic ether 8 (9 mg, 0.04 mmol)
reacted with 1.5 equiv of benzoquinone/6 equiv of activated MnO2
in refluxing toluene for 17 h under identical conditions applied to
the synthesis of 5 to afford after column chromatography (hexane/
ethyl acetate ) 8/1) 10 mg (75% yield) of racemic cordiaquinone
J (12) whose NMR spectroscopic data are in full agreement with
those reported in the isolation paper4 and in the synthesis of the
revised structure by Yabuta and co-workers.9 1H NMR: 8.01 (d, J
) 8.0 Hz, 1H), 7.89 (s, 1H), 7.56 (d, J ) 8.0 Hz, 1H), 6.95 (s,
2H), 3.76 (d, J ) 5.5 Hz, 1H), 2.67-2.88 (m, 2H), 1.91 (m, 1H),
1.65 (m, 2H), 1.50 (m, 2H), 1.36 (s, 3H), 1.29(m, 1H), 1.11 (s,
3H), 1.09 (s, 3H). 13C NMR: 185.4, 184.9, 149.7, 138.76, 138.5,
133.8, 132.0, 130.0, 126.8, 125.98, 88.6, 86.1, 55.6, 45.3, 38.9,
36.4, 29.5, 26.1, 25.7, 23.4, 18.9.
(E)-6-(6-(3,3-Dimethyloxiran-2-yl)-4-methylhex-3-enyl)naph-
thalene-1,4-dione (5). In one-necked flask containing toluene (5
mL) were dissolved the epoxide 4 (0.33 g, 1.5 mmol) and
benzoquinone (0.22 g, 2.0 mmol). The mixture was heated to 100
°C for 16 h until the epoxide was consumed. Within the same flask
was subsequently added 0.78 g (9.0 mmol) of activated MnO2, and
the slurry was heated to 100 °C for 30 min. The reaction mixture
was cooled and filtered through a short pad of Celite. After
evaporation of the solvent, the residue was chromatographed with
hexane/ethyl acetate ) 10/1 to afford 0.38 g of epoxide 5 (78%
Cordiaquinone K (13). The pure exomethylenic alcohol 10 (7
mg, 0.022 mmol), obtained after treatment of the mixture 10/11
with PTAD, reacted with PCC (10 mg, 0.04 mmol) in dichlo-
romethane (0.3 mL). The reaction was complete within 2 h. After
removal of solvent under vacuum, the residue was passed through
a short pad of silica using CH2Cl2/Et2O ) 1/1 to isolate 6.2 mg of
1
yield). H NMR: 7.98 (d, J ) 7.5 Hz, 1H), 7.89 (d, J ) 3.0 Hz,
1H), 7.55 (dd, J1 ) 7.5 Hz, J2 ) 3.0 Hz, 1H), 6.94 (s, 2H), 5.18 (t,
J ) 7.0 Hz, 1H), 2.78 (t, J ) 7.5 Hz, 2H), 2.66 (t, J ) 6.5 Hz,
1H), 2.36 (m, 2H), 2.09 (m, 2H), 1.57 (m, 2H), 1.53 (s, 3H), 1.27
(s, 3H), 1.23 (s, 3H). 13C NMR: 185.4, 184.9, 149.3, 138.7, 138.5,
136.0, 134.1, 131.8, 129.9, 126.6, 126.2, 123.1, 64.3, 58.3, 36.3,
36.1, 29.2, 27.4, 24.9, 18.7, 16.0. HRMS (EI): calcd for C21H24O3
324.17255, found 324.17250.
1
racemic cordiaquinone K (91% yield). H NMR: 7.99 (d, J ) 8.0
Hz, 1H), 7.84 (s, 1H), 7.52 (d, J ) 8.0 Hz, 1H), 6.95 (s, 2H), 5.12
(s, 1H), 4.90 (s, 1H), 2.69 (m, 2H), 2.52 (m, 3H), 2.34 (m, 1H),
2.21 (m, 1H), 1.90 (m, 1H), 1.46 (m, 1H), 1.20 (s, 3H), 1.03 (s,
3H). 13C NMR: 214.7, 185.3, 184.9, 149.1, 144.5, 138.8, 138.5,
134.0, 131.9, 130.1, 126.8, 126.1, 114.1, 56.0, 49.0, 37.6, 34.0,
30.7, 29.0, 27.2, 21.3.
Zeolite NaY-Promoted Cyclization of Epoxide 4. To a slurry
of dry NaY (2.0 g) in hexane (15 mL) was added epoxide 4 (80
mg). After 5 min, the heterogeneous mixture was filtered, and the
solid residue was washed with methanol (3 × 10 mL) for 30 min
each time. The combined solvents were evaporated under vacuum
to afford 0.64 g a mixture containing the regiosiomeric alcohols 6
and 7, bicyclic ether 8, and the noncyclized allylic alcohol 9 in a
relative ratio (6 + 7)/8/9 ) 70/25/5. The nonseparable mixture of
6 and 7 (36 mg) as well as ether 8 (14 mg) was isolated from the
reaction mixture by column chromatography using hexane/ethyl
acetate ) 10/1. 1H NMR of 6 (exo): 6.36 (dd, J1 ) 17.5 Hz, J2 )
11.0 Hz, 1H), 5.21 (d, J ) 17.5 Hz, 1H), 5.04 (d, J ) 11.0 Hz,
1H), 5.00 (s, 1H), 4.98 (s, 1H), 4.90 (br s, 1H), 4.63 (br s, 1H),
3.41 (dd, J1 ) 9.5 Hz, J2 ) 4.0 Hz, 1H), 2.32-2.37 (m, 2H),
1.98-2.04 (m, 2H), 1.82-1.86 (m, 1H), 1.64-1.78 (m, 2H),
1.47-1.54 (m, 2H), 1.02 (s, 3H), 0.72 (s, 3H). 13C NMR of 6:
147.3, 146.8, 139.0, 115.6, 113.2, 108.5, 77.2, 51.5, 40.5, 32.9,
cis-2,2-Dimethyl-4-methylene-3-(3-methylenepent-4-enyl)cy-
clohexyl 3-Methylbut-2-enoate (14). To a solution of alcohols 6/7
(58 mg, 0.26 mmol) in dry THF (2 mL) were added at -40 °C and
under an inert atmosphere DMAP (80 mg, 0.66 mmol, 2.5 equiv)
and a 1 M solution of LiHMDS in THF (330 µL, 0.33 mmol, 1.25
equiv). After 15 min, 3,3-dimethylacryloyl chloride (0.15 mL, 1.33
mmol, 5 equiv) was syringed, and the mixture was allowed to react
for an additional 2 h at room temperature. Then, it was quenched
with saturated solution of NaHCO3. After extraction, the solvent
was removed under vacuum, and the residue was chromatographed
(hexane/ethyl acetate ) 80/1) to afford 66 mg of a mixture of 14/
15 (85% yield). 1H NMR of the major 14: 6.36 (dd, J1 ) 17.5 Hz,
J2 ) 10.5 Hz, 1H), 5.66 (br s, 1H), 4.99-5.24 (m, 4H), 4.90 (s,
1H), 4.72 (dd, J1 ) 8.5 Hz, J2 ) 3.5 Hz, 1H), 4.66 (s, 1H), 2.31
(m, 2H), 2.17 (s, 3H), 2.01 (m, 2H), 1.89 (s, 3H), 1.55-1.90 (m,
5H), 0.96 (s, 3H), 0.81 (s, 3H). 13C NMR of the major 14: 166.3,
156.4, 147.0, 146.8, 139.0, 116.5, 115.6, 113.2, 109.2, 77.3, 52.0,
39.2, 31.5, 30.3, 28.8, 27.5, 27.4, 26.2, 24.4, 20.2. MS (EI): 302
(M+, <1), 202 (7), 187 (8), 159 (6), 131 (14), 83 (100).
cis-3-(2-(5,8-Dioxo-5,8-dihydronaphthalen-2-yl)ethyl)-2,2-di-
methyl-4-methylenecyclohexyl 3-methylbut-2-enoate (16, Cor-
diaquinone C). The mixture of 14/15 underwent reaction with
quinone/MnO2 as described in the synthesis of 5 to form a mixture
of 16 (exo) and 17 (endo) in 76% yield and in a relative ratio 16/
17 ∼6/1. The exomethylenic 16 was purified from its mixture with
17 by reacting 16/17 with 0.25 equiv of PTAD in CDCl3, just as
the regioisomeric mixture 10/11 did. 1H NMR of 16 (cordiaquinone
C): 8.01 (d, J ) 8.0 Hz, 1H), 7.87 (d, J ) 3.0 Hz, 1H), 7.57 (dd,
J1 ) 8.0 Hz, J2 ) 3.0 Hz, 1H), 6.95 (s, 2H), 5.64 (br s, 1H), 4.97
(s, 1H), 4.71 (s, 1H), 4.69 (dd, J1 ) 8.0 Hz, J2 ) 4.0 Hz, 1H), 2.87
(m, 1H), 2.55 (m, 1H), 2.36 (m, 1H), 2.16 (s, 3H), 2.07 (m, 1H),
1.73-1.97 (m, 4H), 1.88 (s, 3H), 1.63 (m, 1H), 0.93 (s, 3H), 0.81
(s, 3H). 13C NMR of 16 (cordiaquinone C): 185.4, 185.0, 166.2,
156.8, 150.1, 146.7, 138.8, 138.5, 134.1, 131.9, 130.0, 126.7, 126.1,
116.3, 109.8, 76.9, 51.8, 39.2, 35.0, 30.9, 28.7, 27.4, 26.4, 20.2,
18.6. HRMS (EI): calcd for C26H30O4 406.21441, found 406.21476.
(Z)-ꢀ-Farnesene (20).21 A flame-dried two-necked flash was
charged with dry dichloromethane (50 mL), and cis-nerolidol, 18
(1.73 g, 7.8 mmol), and pyridine (5 mL, 8 equiv) were added. The
32.2, 30.4, 25.9, 24.1, 15.7. MS (EI): 220 (M+, 2), 202 (M+
-
H2O, 7), 187 (31), 159 (32), 119 (51), 79 (100). HRMS (EI): calcd
1
for C15H24O 220.18272, found 220.18212. H NMR of 7 (endo),
characteristic absorptions: 3.46 (dd, J1 ) 13.5 Hz, J2 ) 6.0 Hz,
1H), 0.97 (s, 3H), 0.83 (s, 3H). 1H NMR of 8: 6.37 (dd, J1 ) 17.5
Hz, J2 ) 10.5 Hz, 1H), 5.22 (d, J ) 17.5 Hz, 1H), 5.06 (d, J )
10.5 Hz, 1H), 5.02 (s, 1H), 5.00 (s, 1H), 3.73 (d, J ) 5.0 Hz, 1H),
2.14-2.23 (m, 2H), 1.90-1.95 (m, 1H), 1.66-1.72 (m, 1H),
1.45-1.56 (m, 4H), 1.34 (s, 3H), 1.24-1.27 (m, 1H) 1.08 (s, 3H),
1.03 (s, 3H). 13C NMR of 8: 146.6, 139.0, 115.6, 113.2, 86.7, 86.1,
55.8, 45.3, 39.0, 31.5, 26.3, 26.1, 25.8, 23.4, 18.9. MS (EI): 220
(M+, 7), 205 (9), 187 (16), 153 (68), 135 (84), 93 (100), 79 (93),
67 (90), 55 (92).
cis-6-(2-(3-Hydroxy-2,2-dimethyl-6-methylenecyclohexyl)eth-
yl)naphthalene-1,4-dione (10). An analogous transformation for
the final step of the synthesis of cordiaquinone J applied to the
mixture of alcohols 6 and 7 afforded a mixture of 10 and 11 in
77% yield. 1H NMR of 10 (exo): 8.00 (d, J ) 7.5 Hz, 1H), 7.88 (s,
1H), 7.55 (d, J ) 7.5 Hz, 1H), 6.95 (s, 2H), 4.97 (s, 1H), 4.70 (s,
1H), 3.41 (dd, J1 ) 9.0 Hz, J2 ) 4.0 Hz, 1H), 2.88 (m, 1H), 2.54
(m, 1H), 2.40 (m, 1H), 2.03 (m, 1H), 1.89 (m, 2H), 1.72 (m, 1H),
1.52-1.58 (m, 1H), 1.24-1.30 (m, 1H), 1.00 (s, 3H), 0.76 (s, 3H).
13C NMR of 10 (exo): 185.5, 185.0, 150.2, 147.0, 138.8, 138.5,
134.1, 131.9, 129.9, 126.7, 126.1, 109.1, 76.8, 51.5, 40.4, 35.2,
32.0, 27.4, 26.1, 22.7, 16.5, 14.1. HRMS (EI): calcd for C21H24O3
324.17255, found 324.17288. 1H NMR of 11 (endo) characteristic
absorptions: 5.29 (s, 1H), 3.47 (dd, J1 ) 8.0 Hz, J2 ) 6.0 Hz, 1H),
0.93 (s, 3H), 0.87 (s, 3H).
(21) (a) Anet, E. F. L. J. Aust. J. Chem. 1970, 23, 2101–2108. (b) Hegedus,
L. S.; Varaprath, S. Organometallics 1982, 1, 259–263.
J. Org. Chem. Vol. 73, No. 12, 2008 4489

Arkoudis and Stratakis
flask was cooled to -78 °C, and then SOCl2 (2.85 mL, 39.0 mmol)
was added dropwise. After 30 min, the reaction mixture was
quenched with water, and the organic layer was washed with a
saturated solution of NaHCO3. The crude reaction mixture was seen
by 1H NMR to be (2E,6Z)-farnesyl chloride, (2Z,6Z)-farnesyl
chloride, and cis-nerolidyl chloride in a relative ratio of 4/1/1,
respectively. The crude mixture of the chlorides was treated with
8 equiv of t-BuOK in THF for 2 h at 60 °C. After workup and
chromatographic purification, using hexane as eluant, 1.02 g of (Z)-
ꢀ-farnesene (20) was isolated (64% overall yield from cis-nerolidol).
1H NMR: 6.38 (dd, J1 ) 17.5 Hz, J2 ) 11.0 Hz, 1H), 5.24 (d, J )
17.5 Hz, 1H), 5.14 (t, J ) 7.0 Hz, 1H) 5.12 (t, J ) 7.0 Hz, 1H),
5.06 (d, J ) 11.0 Hz, 1H), 5.02 (s, 1H), 5.00 (s, 1H), 2.19 (m,
4H), 2.04 (m, 2H), 1.70 (s, 3H), 1.70 (s, 3H), 1.69 (s, 3H), 1.61 (s,
6H). 13C NMR: 146.3, 139.1, 135.7, 131.7, 125.0, 124.5, 115.8,
113.2, 32.2, 31.9, 26.8, 26.7, 25.9, 23.6, 17.8. MS (EI): 204 (M+,
5), 189 (3), 161 (31), 133 (51), 93 (92), 69 (100).
eluant to afford 63 mg of cordiaquinone J (12), 28 mg of
cordiaquinone B (30), and 20 mg of an inseparable mixture
containing the regioisomers 10, 11, and 31 in a relative ratio of
∼0.8/1.0/0.4, respectively. 1H NMR of cordiaquinone B (30): 8.00
(d, J ) 8.0 Hz, 1H), 7.87 (d, J ) 2.0 Hz, 1H), 7.56 (dd, J1 ) 8.0
Hz, J2 ) 2.0 Hz, 1H), 6.95 (s, 2H), 2.78 (dt, J1 ) 13.0 Hz, J2 )
5.5 Hz, 1H), 2.62 (m, 2H), 2.40 (m, 2H), 2.13 (m, 1H), 1.91 (m,
1H), 1.58-1.73 (m, 3H), 1.01 (d, J ) 7.5 Hz, 3H), 0.99 (d, J )
7.5 Hz, 3H), 0.61 (s, 3H). 13C NMR: 213.1, 185.3, 184.8, 149.5,
138.8, 138.5, 133.9, 132.1, 130.1, 126.9, 125.9, 50.4, 43.7, 41.5,
38.8, 36.3, 30.8, 29.5, 22.6, 15.2, 7.8.
Acknowledgment. This work was partially supported by the
Greek Ministry of Education (B′ EPEAEK). E.A. thanks IKY
for a 3-year fellowship.
Supporting Information Available: Experimental details for
the synthesis of compounds 21-28. Copies of 1H and 13C NMR
spectra of all compounds; copies of the HRMS spectra of key
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Reaction of Epoxide 4 with SnCl4. To a solution of epoxide 5
(162 mg, 0.50 mmol) in dry dichloromethane (2 mL) were added
at 0 °C and 0.25 mL of SnCl4 (1 M in CH2Cl2). After 40 min, the
reaction was quenched with saturated solution of NaHCO3, and
the organic layer was washed with brine. The organic residue (132
mg) was chromatographed using hexane/ethyl acetate ) 10/1 as
JO800355Y
4490 J. Org. Chem. Vol. 73, No. 12, 2008