An Efficient Stereoselective Synthesis of Cytotoxic 8-Epipuupehedione

Article abstract of DOI:10.1021/np030029r

An efficient and highly stereoselective synthesis of cytotoxic 8-epipuupehedione (1b) was achieved starting from natural (-)-drimenol (6). The key step to obtain stereoselectivity was the simultaneous demethylation and oxidation of the dihydrobenzopyran methoxy derivatives 10a and 10b.

Full text of DOI:10.1021/np030029r

1382
J . Nat. Prod. 2003, 66, 1382-1383
An Efficien t Ster eoselective Syn th esis of Cytotoxic 8-Ep ip u u p eh ed ion e
Veronica Armstrong,*,† Alejandro F. Barrero,‡ Enrique J . Alvarez-Manzaneda,‡ Manuel Corte´s,† and
Beatriz Sepu´lveda†
Facultad de Qu´ımica, Pontificia Universidad Cato´lica de Chile, Casilla 306, Correo 22, Santiago, Chile, and
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain
Received J anuary 31, 2003
An efficient and highly stereoselective synthesis of cytotoxic 8-epipuupehedione (1b) was achieved starting
from natural (-)-drimenol (6). The key step to obtain stereoselectivity was the simultaneous demethylation
and oxidation of the dihydrobenzopyran methoxy derivatives 10a and 10b.
Marine sponges are recognized as a rich source of
structurally unique and biologically active terpenoids.1
Puupehedione (1a ) was isolated from a sponge of the order
Verongida and was characterized as a metabolite featuring
a sesquiterpene unit joined to a shikimate-derived moiety.2
The cytotoxic activity of 1a and its synthetic, non-natural,
8-epimer 1b was assayed against the cell lines P-338,
A-549, HT-29, and MEL-28,3 and the most active compound
was found to be 8-epipuupehedione (1b).
The syntheses previously reported for 1a and 1b3,4 were
based on electrophilic cyclization of suitable intermediates
to the respective dihydrobenzopyrans as methylenedioxy
derivatives (2a and 2b), followed by oxidative cleavage of
the methylenedioxy moiety. As we have previously estab-
lished,3 the oxidative process involves ring opening and
subsequent cyclization to obtain 1a and 1b in the same
1:4 relative proportion, independent of the C-8 epimeric
ratio for the starting methylenedioxy derivatives.
Our strategy here involves nucleophilic addition of the
organolithium derived from 5 to drim-7-en-11-al (7),5 easily
available from natural (-)-drimenol (6)6,7 (Figure 1). The
aromatic synthon 5 was prepared in high yield from 3,4-
dimethoxybenzaldehyde (Figure 2). Addition of aldehyde
7 to the aryllithium derived from 5, and subsequent
deprotection of the silyl ether, afforded 8/9 in a ratio of 3:1
(1H and 13C NMR). Acid-mediated cyclization of the mixture
gave 10a and 10b in a ratio of 1:3. Simultaneous demethy-
lation and oxidation of the epimeric dihydrobenzopyrans
F igu r e 1. Summary of synthetic transformations to produce 8-epi-
puupehedione (1b). Reagents: (i) PCC, CH2Cl2; (ii) BuLi, 5, Et2O, 7,
TsOH, C6H6; (iii) BuLi, 5, Et2O, 7, TBAF, THF; (iv) TsOH, C6H6; (v)
AgO-HNO3, THF.
Simultaneous demethylation-oxidation of the mixture
gave the epimeric 1a and 1b (1:8). The relative proportion
was the same as that obtained for the dihydrobenzopyran
methoxy derivatives, since the well-known reaction with
AgO in acid medium8 avoids ring opening, due to very fast
oxidation. These results suggest that, under acidic condi-
tions, the main product arises from attack on the less
hindered R side, and the epimeric ratio seems to depend
on the effective free nucleophilic group.
8
10a (C8-MeR) and 10b(C8-Meâ) with AgO-HNO3 led to
o-quinones 1a and 1b (1:3). A further straightforward route
was studied. Direct treatment of the condensation product
with acid, without previous deprotection of the tert-but-
yldimethylsilyl ether, afforded 10a and 10b in a ratio 1:8.
* To whom correspondence should be addressed. Tel: 56 2 68 64 434.
Fax: 56 2 68 64 744. E-mail: aarmstrl@puc.cl.
† Pontificia Universidad Cato´lica de Chile.
The present work represents the shortest and most
efficient synthesis for the highly bioactive 8-epipuupehe-
dione (1b).
‡ Universidad de Granada.
10.1021/np030029r CCC: $25.00
© 2003 American Chemical Society and American Society of Pharmacognosy
Published on Web 08/26/2003

Notes
J ournal of Natural Products, 2003, Vol. 66, No. 10 1383
Me-11), 0.87 (3H, s, Me-12); 10b δ 6.54 (1H, s, H-21), 6.42 (1H,
s, H-18), 6.06 (1H, s, H-15), 1.40 (3H, s, Me-13), 1.15 (3H, s,
Me-14), 0.92(3H, s, Me-11), 0.87 (3H, s, Me-12); 13CNMR
(CDCl3, 75 MHz), signals asignable to 10b, δ 149.5 (C-9), 148.7
(C-19), 145.6 (C-17), 143.1 (C-20), 114.9 (C-16), 113.9 (C-15),
109.3 (C-21), 100.5 (C-18), 77.9 (C-8), 52.1 (C-5), 41.5 (C-3),
41.4 (C-7), 38.9 (C-10), 37.9 (C-1), 33.7 (C-4), 33.5 (C-11), 26.0
(C-13), 23.5 (C-14), 21.6 (C-12), 19.2 (C-6), 18.8 (C-2); HRMS
(FAB+) found 379.2251 (calcd for C23H32O3Na, [M + Na]+
379.2249).
Silyl Eth er Dep r otection . The crude (0.8 g) previously
obtained, by aryllithium addition, was dissolved in THF, and
tetrabutylammonium fluoride (1.1 mmol) was added. After
stirring for 15 min at rt, water was added and the mixture
was extracted with Et2O. Workup3 gave 8/9 (ratio 3:1) as a
colorless oil: 1HNMR (CDCl3, 200 MHz) asignable to 8 (11-
(2-hydroxy-4,5-dimethoxyphenyl)drim-7-en-11-ol, δ 6.43 (1H,
s, H-3), 6.37 (1H, s, H-6), 5.69 (1H, bs, H-7′), 5.42 (1H, bs,
H-11′), 2.51 (1H, bs, H-9′), 1.62 (3H, s, Me-12′), 1.07 (3H, s,
Me-14′), 0.94 (3H, s, Me-13′), 0.91 (3H, s, Me-15′). Fractions
of pure 9 (6-(7-drimen-11-yliden)-3,4-dimethoxy-2,4-cyclohexa-
dienone) could be obtained: 1H NMR (CDCl3, 200 MHz) δ 7.11
(1H, d, J ) 12.7 Hz, H-11′), 6.15 (1H, s, H-5), 5.79 (1H, s, H-2),
5.59 (1H, bs, H-7′), 3.00 (1H, bd, J ) 12.7 Hz, H-9′), 1.53 (3H,
s, Me-12′), 0.99 (3H, s, Me-14′), 0.92 (3H, s, Me-13′), 0.89 (3H,
s, Me-15′); 13CNMR (CDCl3, 50 MHz) δ 184.1 (C-1), 164.7 (C-
3), 148.6 (C-11′), 147.8 (C-4), 133.7 (C-8′), 131.8 (C-6), 123.1
(C-7′), 104.2 (C-2), 100.1 (C-5), 54.4 (C-9′), 49.8 (C-5′), 42.3 (C-
3′), 41.0 (C-1′), 38.6 (C-10′), 33.3 (C-13′), 33.2 (C-4′), 23.7 (C-
6′), 22.5 (C-14′), 22.0 (C-12′), 18.6 (C-2′), 15.0 (C-15′); HRMS
(FAB+) found 379.2249 (calcd for C23H32O3Na, [M + Na]+
379.2249).
F igu r e 2. Synthesis of 2-bromo-1-tert-butyldimethylsilyloxy-4,5-
dimethoxybenzene (5). Reagents: (i) m-CPBA, CH2Cl2; (ii) NaOH-
MeOH; (iii) TBDMSCl, imidazole, DMF; (iv) Br2, CHCl3.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. NMR spectra were
recorded on a Bruker AM-200 and a Bruker Avance DRX-300
spectrometer. Carbon multiplicity was established by a DEPT
pulse sequence. HRMS were obtained on a trisector WG
AutoSpecQ spectrometer. Chromatographic separations were
carried out on Merck silica gel 60 (230-400 mesh), using
hexane-EtOAc gradients of increasing polarity. All organic
extracts were dried over magnesium sulfate and evaporated
under reduced pressure, below 65 °C.
Syn th esis of 5 (2-Br om o-1-ter t-bu tyld im eth ylsilyloxy-
4,5-d im eth oxyben zen e). TBDMSCl (18.0 mmol) and imida-
zole (15.0 mmol) were added to a solution of phenol 3 (15.0
mmol) in anhydrous DMF and stirred for 15 h. Usual workup3
and column chromatography gave 4 (92%) as a colorless oil:
HRMS (FAB+) found 291.1394 (calcd for C14H24O3NaSi, [M +
Na]+ 291.1392). Compound 4 (5.9 mmol) was treated, at 0 °C,
with bromine (6.0 mmol) in chloroform. After stirring for 1 h,
a solution of sodium thiosulfate was added, and the mixture
was further stirred 1 h. Usual workup3 and column chroma-
tography gave 5 (95%) as a colorless oil: HRMS (FAB+) found
369.0495 (calcd for C14H23O3NaSiBr, [M + Na]+ 369.0498).
Syn th esis of 10a (9-Deh yd r o-19,20-d i-O-m eth ylp u u p e-
h en ol) a n d 10b (9-Deh yd r o-8-ep i-19,20-d i-O-m eth ylp u u -
p eh en ol). Ar yllith iu m Ad d ition . A 1.6 M solution of butyl-
lithium in hexane (3.0 mL) was added, at -78 °C, to a solution
of 5 (4.5 mmol) in anhydrous Et2O, under N2. After stirring
for 45 min, 7 (1.96 mmol) was added, and the stirring
continued for 1 h, at -78 °C. Water was added and the mixture
was extracted with Et2O.
Ack n ow led gm en t. Support by DIPUC (Grant 99/12E),
TWAS (Grant 00-255 RG/CHE/LA), and CYTED (Project
IV.12) is gratefully acknowledged.
Refer en ces a n d Notes
(1) Faulkner, D. J . Nat. Prod. Rep. 1998, 113-158, and references
therein.
(2) Hamann, M. T.; Scheuer, P. J .; Kelly-Borges, M. J . Org. Chem. 1993,
58, 6565-6569.
(3) Barrero, A. F.; Alvarez-Manzaneda, E. J .; Chahboun, R.; Corte´s, M.;
Armstrong, V. Tetrahedron 1999, 55, 15181-15208.
(4) Maiti, S.; Sengupta, S.; Giri, C.; Achari, B.; Banerjee, A. Kr.
Tetrahedron Lett. 2001, 42, 2389-2391.
(5) Gonza´lez-Sierra, M.; Ru´veda, E. A.; Lo´pez, J . T.; Corte´s, M. J .
Heterocycles 1986, 26, 2801-2804.
(6) Isolated from the bark of D. winteri. See: Appel, H. H.; Brooks, J .
W.; Overton, K. H. J . Chem. Soc. 1959, 3322-3332.
(7) (-)-Drimenol can be obtained in optically pure form from t,t-farnesol.
Resolution of racemic 6 was achieved via chromatographic separation
of the diasteromeric camphanoates. See: (a) Arjona, O.; Garranzo,
M.; Mahugo, J .; Maroto, E.; Plumet, J .; Sa´ez, B. Tetrahedron Lett.
1997, 38, 7249-7252. (b) J ordine, G.; Bick, S.; Mo¨ller, U.; Welzel, P.;
Daucher, B.; Maas, G. Tetrahedron 1994, 50, 139-160. (-)-Drimenol
can be obtained also from (-)-sclareol through drimenyl acetate in a
five-step synthesis with 42% overall yield. See: (c) Barrero, A. F.;
Alvarez-Manzaneda, E. J .; Altarejos, J .; Salido, S.; Ramos, J . M.
Tetrahedron Lett. 1994, 35, 2945-2948.
Cycliza tion . The crude obtained above, by aryllithium
addition, was dissolved in benzene, p-toluenesulfonic acid (2.0
mmol) was added, and the mixture was stirred at rt for 16 h.
Usual workup3 and column chromatography gave 10a /10b
(ratio 1:8) (90% from 7) as a colorless oil: 1HNMR (CDCl3, 300
MHz) 10a δ 6.58 (1H, s, H-21), 6.45 (1H, s, H-18), 6.09 (1H, s,
H-15), 1.36 (3H, s, Me-13), 1.21 (3H, s, Me-14), 0.95 (3H, s,
(8) Snyder, C. D.; Rapoport, H. J . Am. Chem. Soc. 1972, 94, 227-231.
NP030029R