First enantiospecific synthesis of the antitumor marine sponge metabolite (-)-15-oxopuupehenol from (-)-sclareol

Article abstract of DOI:10.1021/ol047332j

(Chemical Equation Presented) A new route toward puupehenone-related bioactive metabolites from (-)-sclareol, based on the palladium(II)-mediated diastereoselective cyclization of a drimenylphenol, is described. Utilizing this, the first enantiospecific synthesis of the antitumor and antimalarial (-)-15-oxopuupehenol, together with improved syntheses of (+)-puupehenone, (+)-puupehedione, and (+)-15-cyanopuupehenone, were accomplished.

Full text of DOI:10.1021/ol047332j

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1477-1480
First Enantiospecific Synthesis of the
Antitumor Marine Sponge Metabolite
(−)-15-Oxopuupehenol from (−)-Sclareol
E. J. Alvarez-Manzaneda,* R. Chahboun, I. Barranco Pe´rez, E. Cabrera,
E. Alvarez, and R. Alvarez-Manzaneda†
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Instituto de Biotecnolog´ıa,
UniVersidad de Granada, 18071 Granada, and Departamento de Qu´ımica Orga´nica,
Facultad de Ciencias, UniVersidad de Almer´ıa, 04120 Almer´ıa, Spain
eamr@ugr.es
Received December 27, 2004
ABSTRACT
A new route toward puupehenone-related bioactive metabolites from (
of a drimenylphenol, is described. Utilizing this, the first enantiospecific synthesis of the antitumor and antimalarial (
together with improved syntheses of ( )-puupehenone, ( )-puupehedione, and ( )-15-cyanopuupehenone, were accomplished.
−)-sclareol, based on the palladium(II)-mediated diastereoselective cyclization
−)-15-oxopuupehenol,
+
+
+
An important group of biologically active natural products,
many of marine origin,1 is based on a sesquiterpene unit
joined to a phenolic moiety. The series includes puupehenone
(1a),2 puupehedione (2a),2b 15-cyanopuupehenol (3),3 15-
oxopuupehenol (4a),4 the halopuupehenones 5 and 6,2a,2c and
15-cyanopuupehenone (7).2b More recently, two puupe-
henone-related compounds, UPA0043 (8) and UPA0044 (9),
have been reported.5
All of these compounds display a wide range of important
biological properties, including antitumor,6a-c,g,j antiviral,6e
antimalarial,4 antibiotic,6f antituberculosis,6h,l antioxidant,6i
insecticidal,6d and antifungal activities.6e More recently some
of them have been shown to inhibit angiogenesis7b and
(5) Takao, K.-I.; Sasaki, T.; Kozaki, T.; Yaganisawa, Y.; Tadano, K.-I.;
Kawashima, A.; Shinonaga, H. Org. Lett. 2001, 3, 4291-4294 and
references therein.
(6) (a) Kohmoto, S.; McConnell, O. J.; Wright, A.; Koehn, F.; Thompson,
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Fedoreev, S. A. Khim. Prir. Soedin. 1990, 497-500. (c) Longley, R. E.;
McConnel, O. J.; Essich, E.; Harmody, D. J. Nat. Prod. 1993, 56, 915-
920. (d) El Sayed, K. A.; Dunbar, D. C.; Perry, T. L.; Wilkins, S. P. Hamann,
M. T.; Greenplate, J. T.; Wideman, M. A. J. Agric. Food Chem. 1997, 45,
2735-2739. (e) Faulkner, D. J. Nat. Prod. Rep. 1998, 113-158 and
references therein. (f) Bourguet-Kondracki, M. L.; Lacombe, F.; Guyot,
M. J. Nat. Prod. 1999, 62, 1304-1305. (g) Popov, A. M.; Stekhova, S. I.;
Utkina, N. K.; Rebachuk, N. M. Pharm. Chem. J. 1999, 33, 71-73. (h) El
Sayed, K. A.; Bartyzel, P.; Shen, X.; Perry, T. L. Zjawiony, J. K.; Hamann,
M. T. Tetrahedron 2000, 56, 949-953. (i) Takamatsu, S.; Hodges, T. W.;
Rajbhandari, I.; Gerwick, H.; Hamann, M. T.; Nagle, D. G. J. Nat. Prod.
2003, 66, 605-608. (j) Pina, I. C.; Sanders, M. L.; Crews, P. J. J. Nat.
Prod. 2003, 66, 2-6. (k) Hamann, M. T. Curr. Pharm. Des. 2003, 9, 879-
889. (l) Graus, G. A.; Nguyen, T.; Bae, J.; Hostetter, J. Steadham, E.
Tetrahedron 2004, 60, 4223-4225.
† Universidad de Almer´ıa.
(1) (a) Capon, R. J. In Studies in Natural Products Chemistry; Atta-ur-
Rahman, Ed; Elsevier Science: New York, 1995; Vol. 15, pp 289-326.
(b) Faulkner, D. J. Nat. Prod. Rep. 1996, 13, 75-125.
(2) (a) Navi, B. N.; Perzanovski, H. P.; Ross, R. A.; Erdman, T. R.;
Scheuer, P. J.; Finar, J.; Clardy, J. Pure Appl. Chem. 1979, 51, 1893-
1898. (b) Hamann, M. T.; Scheuer, P. J.; Kelly-Borges, M. J. Org. Chem.
1993, 58, 6565-6569. (c) Urban, S.; Capon, R. J. J. Nat. Prod. 1996, 59,
900-901. (c) Hua, D. H.; Huang, X.; Chen, Y.; Battina, S. K.; Tamura,
M.; Noh, S. K.; Koo, S. I.; Namatame, I.; Tomoda, H.; Perchellet, E. M.;
Perchellet, J. P. J. Org. Chem. 2004, 69, 6065-6078.
(3) Hamann, M. T.; Scheuer, P. J. Tetrahedron Lett. 1991, 32, 5671-
5672.
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10.1021/ol047332j CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/15/2005

to create the carbon skeleton lies in the reaction of a nor-
drimane anion with a protected polyhydroxybenzaldehyde;
this procedure was utilized by Banerjee et al. to prepare 2a,b,
which lack the chirality on C-9.9b
The construction of the C pyrane ring constitutes the
second phase in the complete synthetic sequence. The
stereoselectivity of this process determines the C-8 stereo-
chemistry, affording the natural (C8R-Me) compounds or
their epimers. Different methodologies have been utilized
to elaborate the pyrane ring. Electrophilic acid cyclization
of a drimenyl phenol, similar to compounds 20a,b, was first
utilized by Trammel.8a Our further studies of these processes
revealed a low degree of stereoselectivity, with the 8-epideriv-
ative found to be the major isomer,9a which is quite different
from the previously reported results.8a,10 Electrocyclization
of a conjugated tetraenone, similar to 19a,b, also allowed
the present authors to prepare 8-epipuupehedione (2b);9a the
same strategy was followed by Banerjee et al.9b The obtention
of natural 8-epimers, such as (+)-puupehenone (1a) and
related compounds, starting from drimenyl phenols, was
accomplished by the â-attack of the phenol hydroxyl group
on an R-seleno- or R-oxacyclopropane generated from the
carbon-carbon double bond; an R-selenocyclopropane was
utilized in our synthesis of (+)-puupehenone (1a).8b An
R-oxacyclopropane was the intermediate in our synthesis of
(+)-puupehedione (2a),9a this latter strategy also being
utilized by Tadano et al. in synthesizing 8 and 9.5 More
recently, Quideau et al. synthesized 1a, starting from an
8-hydroxydrimane with a suitable configuration on C-8, by
attack onto an oxidatively activated 1,2-dihydroxyphenyl
unit.8c
Figure 1. Examples of puupehenone (1a)-derived marine sponge
metabolites.
lipoxygenase,7a further heightening the interest in this class
of compounds.
The unique structural features and biological activities of
these compounds have prompted chemists to study their
synthesis.5,8-11 Most current approaches to this type of
compounds are based on a strategy involving the initial
formation of a suitably functionalized bicyclic terpenoid unit,
with the pyrane ring being generated late in the sequence.
Two strategies have been devised to elaborate the carbon
skeleton of these compounds. The first involves the reaction
of an aryllithium derived from a suitably protected phenolic
unit with an acyclic (farnesane derivative) or bicyclic
(drimane derivative) electrophile.5,9-11 The drimane synthon,
an 8-oxygenated aldehyde8b-c,9a or an 8,9-epoxyaldehyde5
or an unsaturated aldehyde,10,11 possesses the correct chirality
for three of the four stereogenic centers, i.e., C-5, C-9, and
C-10, presented by these compounds. The alternative strategy
Following our research into the synthesis of puupehenone-
related compounds based on homochiral synthons obtained
from natural sources, we are interested in developing a new
route to this type of compounds utilizing alternative synthons
and cyclizing reagents. We focused on 15-oxopuupehenol
(4a), an antitumor and antimalarial metabolite, which has
not been synthesized hitherto. The 15-oxopuupehenol deriva-
tive previously reported, the configuration of which on C-8
was assigned on the basis of the absence of NOE effect,
was actually the non-natural 8-epimer10 as is shown in the
present paper. Our planned synthesis of 4a is based on the
benzylic oxidation of a tetracyclic advanced intermediate,
which will result from a diastereoselective cyclization of a
drimenylphenol precursor, itself derived from a condensation
between a suitably protected trihydroxyaryllithium with
drimenal (15).12
(7) (a) Amagata, T.; Whitman, S.; Johnson, T. A.; Stessman, C. C.; Loo,
C. P.; Lobkovsky, E.; Clardy, J.; Crews, P.; Holman, T. R. J. Nat. Prod.
2003, 6, 230-235. (b) Castro, M. E.; Gonzalez-Iriarte, M.; Barrero, A. F.;
Salvador-Tormo, N.; Mun˜oz-Chapuli, R.; Medina, M. A.; Quesada, A. R.
Int. J. Cancer 2004, 110, 31-38.
(8) Synthesis of 1a,b in racemic form: (a) Trammel, G. L. Tetrahedron
Lett. 1978, 1525-1528. Synthesis of 1a in optically active form: (b)
Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R. Tetrahedron Lett.
1997, 38, 2325-2328. (c) Quideau, S.; Lebon, M.; Lamidey, A.-M. Org.
Lett. 2002, 22, 3975-3978.
(9) Synthesis of 2a,b in optically active form: (a) Barrero, A. F.; Alvarez-
Manzaneda, E. J.; Chahboun, R.; Corte´s, M.; Armstrong, V. Tetrahedron
1999, 55, 15181-15208. Synthesis of 2b in optically active form: (b) Maiti,
S.; Sengupta, S.; Giri, C.; Achari, B.; Banerjee, A. K. Tetrahedron Lett.
2001, 42, 2389-2391. (c) Armstrong, V.; Barrero, A. F.; Alvarez-
Manzaneda, E. J.; Corte´s, M.; Sepu´lveda, B. J. Nat. Prod. 2003, 66, 1382-
1383. (d) Ishibashi, H.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc.
2004, 126, 11122-11123.
The drimane synthon 15 is easily prepared by the oxidation
of (-)-drimenol (14).13,14 Scheme 1 shows a new and
efficient synthesis of 15 from (-)-sclareol (10), the key step
being regioselective dehydration of diol 13, by treatment with
DEAD and PPh3 in benzene; this finding resulted from our
investigation into the synthesis of carbonyl compounds under
the Mitsunobu conditions.15 The drimane precursor is the
(10) Synthesis in optically active form of the methylenedioxyderivative
of 4b: Arjona, O.; Garranzo, M.; Maluego, J.; Maroto, E.; Plumet, J.; Sa´ez,
B. Tetrahedron Lett. 1997, 38, 7249-7252.
(11) Synthesis in racemic form of monoterpene analogues of 1 and 2:
Barrero, A. F.; Alvarez-Manzaneda, E. J.; Herrador, M. M.; Valdivia, M.
V.; Chahboun, R. Tetrahedron Lett. 1998, 39, 2425-2428.
(12) Scher, J. M.; Speakman, J.-B.; Zapp, J.; Becker, H. Phytochemistry
2004, 65, 2583-2588.
(13) Isolated from the bark of D. winteri. See: Appel, H. H.; Brooks, J.
W.; Overton, K. H. J. Chem. Soc. 1959, 3322-3332.
1478
Org. Lett., Vol. 7, No. 8, 2005

Scheme 1
Scheme 2
oxy)phenol 16a8b,18 in a two-step sequence in 83% overall
yield (Scheme 2). Compound 16a was obtained from 3,4-
dihydroxybenzaldehyde in a three-step sequence in 84%
overall yield.8b,18 The sesamol derivative 18b was also
prepared to complete the acid cyclization study.
Finally, let us consider the coupling of 15 and 18a,b, and
further cyclization (Scheme 3). The treatment of aryllithium
derived from 18a,b with drimenal (15) in THF at -80 °C
gave the enone 19a,b, which resulted in condensation with
simultaneous carbamate elimination. Reduction of 19a,b with
Raney Ni gave phenol 20a,b.19 Cyclization of 20a,b under
different acid conditions gave 21a,b,20 with the C8â-Me
configuration being the main epimer. After trying new cycli-
zation reagents as an alternative to selenium derivatives,8b
we found that palladium(II) can induce cyclization with com-
plete diastereoselectivity, providing the desired C8R-Me
epimer; the most satisfactory results were obtained by treating
with PdCl2 and catalytic Pd(OAc)2 in MeOH-H2O (99:1).
Thus, 20a was transformed in high yield into 22, which after
catalytic hydrogenation gave puupehenol (23).8b The con-
figuration on C-8 can be unequivocally established by
analyzing the benzylic protons pattern in the 1HNMR spectra
of the corresponding 8-epimers.21 Thus, in the spectrum of
21a these protons appear as a doublet (J ) 8.2 Hz) at 2.52
ppm, whereas for 23 they give rise to a doublet (J ) 17.5
Hz) at 2.48 and a double doublet (J ) 17.5, 8.0 Hz) at 2.65
ppm.
Puupehenol (23) was the starting material for the prepara-
tion of (-)-15-oxopuupehenol (4a) and the other puupe-
henone-related metabolites. The benzylic oxidation of diac-
etate 24 led to 25, which after hydrolysis under mild
conditions produced 4a, together with a small quantity of
monoacetate 26; the remaining acetoxyl group was located
on C-20 on the basis of the nOe observed with H-21 (s, 7.40
ppm). The spectroscopic properties of 4a were identical to
those reported in the literature.4 (+)-Puupehenone (1a) and
(+)-puupehedione (2a) were obtained in good yield by
oxidation of 23 with the appropriate reagent. The treatment
of puupehenol (23) with Ag2O in aqueous THF afforded 1a;
2a resulted after refluxing the diphenol 23 with DDQ in
dioxane. The latter transformation represents a considerable
iodoester 11, which was obtained in a three-step sequence
from 10 in 75% overall yield.16 The treatment of 11 with
t-BuOK in DMSO-H2O gave alcohol 12,17 which leads to
diol 1314c by oxidative hydroboration. Subsequently, 13 was
dehydrated to 14 and then converted into 15.
The efficiency of strategies for synthesizing these types
of compounds depends strongly upon the careful choice of
protective groups bearing the aromatic synthon. Trammel
utilized sesamol (16b) to achieve the first approach to
puupehenone (1a);8a Plumet et al. also made use of the
methylene group to protect the 1,2-dihydroxy fragment in
preparing the methylenedioxyderivatives of 15-oxopuupe-
henol, which could not be deprotected.10 In view of the
difficulty in deprotecting the methylenedioxy group, which
our previous studies also revealed,9a we proposed the use of
the more easily removable benzyl groups.8b,9a With respect
to the protection of the 4-hydroxy group, the tert-butyldi-
methylsilyl group, first utilized in our synthesis of 1a,8b,9a
was found to be a very suitable protective group. However,
our recent investigations have revealed that the carbamyl
group is a more effective one. Besides being cheap, its use
does not require anhydrous conditions, most importantly, it
is removed under basic condensation conditions. Therefore,
we prepared the new synthon 18a from the 3,4-bis(benzyl-
(14) --Drimenol (14) can be obtained in optically pure form from
trans,trans-farnesol. Resolution of racemic 14 was achieved via chromato-
graphic separation of the diasteromeric camphonates. See ref 11 and (a)
Jordine, C.; Bick, S.; Mo¨ller, U.; Welzel, P.; Daucher, B.; Maas, C.
Tetrahedron 1994, 50, 139-160. (-)-Drimenol (14) can also be obtained
from (-)-sclareol through drimenyl acetate in a five-step synthesis with
42% overall yield. See: (b) Barrero, A. F.; Alvarez-Manzaneda, E. J.;
Altarejos, J.; Salido, S.; Ramos, J. M. Tetrahedron Lett. 1994, 35, 2945-
2948. (c) Barrero, A. F.; Manzaneda, E. A.; Altarejos, J.; Salido, S.; Ramos,
J. M.; Simmonds, M. J. S.; Blaney, W. M. Tetrahedron 1995, 51, 7435-
7450.
(15) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R. Tetrahedron
Lett. 2000, 41, 1959-1962.
(18) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R. Tetrahedron
1998, 54, 5635-5650.
(16) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.; Gonza´lez
D´ıaz, C. Synlett 2000, 1561-1564.
(19) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chaboun, R.; Meneses,
R. Synlett 1999, 1663-1666.
(17) (a) Wada, K.; Tanak, S.; Marumo, S. Agric. Biol. Chem. 1983, 47,
1075-1078. (b) Shishido, K.; Omodani, T.; Shibuya, M. J. Chem. Soc.,
Perkin Trans 1 1991, 2285-2287. (c) Dominguez, G.; Hueso-Rodriguez,
J. A.; De la Torre, M. C.; Rodriguez, B. Tetrahedron Lett. 1991, 32, 4765-
4768.
(20) Compound 21b was also obtained after cyclization with campho-
sulfonic acid, under the conditions reported by Plumet et al. (see refs 9a
and 10 and Supporting Information)
(21) See ref 9a for methylenedioxypuupehenol and its 8-epimer.
Org. Lett., Vol. 7, No. 8, 2005
1479

our group;9a that process, based on the dehydration of a
9-hydroxyderivative, takes place in low yield because of
rearrangement side reactions (Scheme 3).
Scheme 3
The direct transformation of puupehenol (23) into
(+)-15-cyanopuupehenone (7) was finally undertaken. The
treatment of 23 with NaCN and Ag2O in aqueous THF
surprisingly afforded in good yield a cyano derivative that
was identified as 18-cyanopuupehenone (27), in accordance
1
with the H NMR spectrum, which shows two olefinic
protons at 6.54 (d, J ) 7.1 Hz) and 5.95 (s), assignable to
H-15 and H-21, respectively, on the basis of NOE experi-
ments. The cyano group appears in the 13C NMR at 108.6
ppm. This regioisomer of the natural compound probably
results from the 1,6-conjugate addition to the corresponding
o-quinone. Compound 72b was obtained in one-pot reaction
from 23, by treating it successively with Ag2O in aqueous
THF and NaCN; this sequence involves the first enantiospe-
cific synthesis of (+)-15-cyanopuupehenone (7) from
(-)-sclareol (10).
In summary, a new route to puupehenone-related com-
pounds from (-)-sclareol (10) and 3,4-dihydroxybenzalde-
hyde has been developed. Utilizing this, the first enantiospe-
cific synthesis of (-)-15-oxopuupehenol (4a) (19 steps, 14%
overall yield) and improved syntheses of (+)-puupehenone
(1a), (+)-puupehedione (2a), and (+)-15-cyanopuupehenone
(7) were achieved.
Acknowledgment. The authors thank the Spanish Min-
istry of Science and Technology for financial support (Project
PPQ 2002-03308) and Prof. Plumet for his very useful
comments on these research results.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization ([R]D, 1H and 13
C
NMR, IR, EIMS and HRMS) of all new compounds, and
1
copies of H NMR spectra for compounds 18a, 19a, 20a,
21a, 21b, 22, 23, and 25. This material is available free of
charge via the Internet at http://pubs.acs.org.
improvement with respect to the synthesis of (+)-puupehe-
dione (2a) from (-)-sclareol (10), previously reported by
OL047332J
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Org. Lett., Vol. 7, No. 8, 2005