An efficient method for the synthesis of (+)-cyclozonarone, isozonarol δ,8,9 and isozonarone δ8,9

Article abstract of DOI:10.1081/SCC-120017187

An efficient method for the synthesis of (+)-cyclozonarone 5, isozonarol Δ^8,9 6 and isozonarone Δ^8,9 7 via the diene 4, obtained in two steps from manool 3, is described.

Full text of DOI:10.1081/SCC-120017187

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An Efficient Method for the Synthesis of (+)-
Cyclozonarone, Isozonarol Δ,8,9 and Isozonarone Δ8,9
José Villamizar a , Juan Fuentes a , Eleonora Tropper a , Angel L. Orcajo a & Randolph Alonso
a
a Centro de Química , Instituto Venezolano de Investigaciones Científicas (I.V.I.C.) , Caracas,
Venezuela
Published online: 21 Aug 2006.
To cite this article: José Villamizar , Juan Fuentes , Eleonora Tropper , Angel L. Orcajo & Randolph Alonso (2003) An Efficient
Method for the Synthesis of (+)-Cyclozonarone, Isozonarol Δ,8,9 and Isozonarone Δ8,9 , Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:7, 1121-1129, DOI: 10.1081/SCC-120017187
To link to this article: http://dx.doi.org/10.1081/SCC-120017187
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 7, pp. 1121–1129, 2003
An Efficient Method for the Synthesis of
(Q)-Cyclozonarone, Isozonarol Á,8,9
and Isozonarone Á8,9
*
Jose Villamizar, Juan Fuentes, Eleonora Tropper,
Angel L. Orcajo, and Randolph Alonso
Centro de Quımica, Instituto Venezolano de
Investigaciones Cientıficas (I.V.I.C.),
Caracas, Venezuela
ABSTRACT
An efficient method for the synthesis of (þ)-cyclozonarone 5,
isozonarol Á8,9 6 and isozonarone Á8,9 7 via the diene 4, obtained
in two steps from manool 3, is described.
Key Words: Sesquiterpene hydroquinone; Sesquiterpene quinone;
Sesquiterpene benzoquinone; Drimatie.
*Correspondence: Jose Villamizar, Centro de Quımica, Instituto Venezolano de
Investigaciones Cientıficas (I.V.I.C.), Apartado 21827, Caracas, 1020-A,
Venezuela; E-mail: jvillami@ivic.ve.
1121
DOI: 10.1081/SCC-120017187
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1122
Villamizar et al.
Because of their wide range of biological activities, the sesquiterpene
hydroquinones isolated from marine algae and sponges, have been a
target for organic synthesis in various laboratories in recent years.[1]
A
number of their synthesis, in which sclareol, sclareolide, b-ionone and
geranyl acetone were utilized as the starting material, have been reported
so far.[2] Recently we published a new efficient synthetic route to drimanic
sesquiterpenes (þ)-bicyclofarnesol 1 and (À)-bicyclofarnesal 2, via the
diene 4,[3] obtained in two steps from manool 3.[3,4]
1; R=CH2OH
2; R=CHO
3
4
In 1996 Kurata et al.[5] isolated from algae Dictyopteris ondulata (À)-
cyclozonarone possessing a potent feeding-deterrent activity toward
abalones and assigned the structure 5 to it. Recently, however,
Cortes et al.[6] reported the synthesis of (þ)-cyclozonarone 5 and
showed that the structure of the natural product, isolated by
Kurata et al., should have the opposite configuration in the A/B ring
juncture.
In continuation of our previous work we have synthesized sesquiter-
pene benzoquinone 5, isozonarol Á8,9 6 and isozonarone Á8,9 7.
5
6
7

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(Q)-Cyclozonarone, Isozonarol D,8,9 and Isozonarone D8,9
1123
Diels-Alder reaction of the diene 4 with p-benzoquinone in dry
p-xylene was carried out by heating the neat mixture in a sealed tube.
At 110ꢀC quinone 5 was formed together with two other compounds in
minor amounts, as evidenced by the NMR spectra. Above 180ꢀC almost
quantitative aromatization occurred and (þ)-cyclozonarone was
obtained in 90% yield (based on reacted starting material) as a sole
product. This compound displayed spectroscopic data identical to
those reported for the natural (À)-cyclozonarone, except that the optical
rotation was of the opposite sign.[5]
For the synthesis of isozonarol Á8,9 6 and isozonarone Á8,9 7, we
utilized the monoepoxide 8 as an ideal intermediate which had been
prepared in the synthesis of drimane sesquiterpenes 1 and 2.[3] In prepar-
ing the monoepoxide 8 we modified reaction conditions and obtained
it (84% yield based on reacted starting material) with only small amounts
of isomeric monoepoxide 9 and diepoxide 10. Subsequent reactions of
this epoxide reported previously afforded (À)-bicyclofarnesal 2.[3]
8
9
10
The nucleophilic addition of the organolithium compound, derived
from di-methyl-ether of hydroquinone, to the aldehyde 2 in the presence
of n-butyllithium, afforded a mixture of isomeric benzyl alcohols 11 (85%
yield), as evidenced from the 1H-NMR spectrum. Reduction of the
hydroxyl group of the benzyl alcohol 11 with ionic hydrogenation reac-
tion[7] afforded the compound 12 (90% yield).
Oxidation of compound 12 with ceric ammoniun nitrate (CAN)[8]
afforded the isozonarone Á8,9 7 (92% yield based on reacted starting
material). The 1H-NMR spectrum showed the absence of metoxy
protons, while 13C-NMR spectrum exhibited two quinone carbonyls at
186.56, and 187.01 ppm. Reduction of the quinone 7 with sodium hydro-
sulfite[8] gave the isozonarol Á8,9 6 (80% yield).
EXPERIMENTAL
Melting points were measured with a Kofler hot-stage apparatus
and are uncorrected. NMR spectra were recorded with a Bruker
Advance-300 and Advance-500 spectrometers for solutions in CDCl3.

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1124
Villamizar et al.
(i) TPPA, N-methylmorpholine N-oxide, CH2Cl2 or PCC, CH2Cl2; (ii) di-methyl-
ether of hydroquinone, n-BuLi, THF, 0ꢀC; (iii) Et3SiH–CF3COOH, CH2Cl2,
À78ꢀC; (iv) CAN, CH3CN–H2O, 0ꢀC; (v) Na2S2O4, THF–H2O.
Electron-impact mass spectra (EIMS) and high-resolution mass spectra
(HRMS) were obtained on a ZAB HS or Nermag R 10-10 mass spectro-
meter, and Kratos MS25RFA. The intensity of each peak in the mass
spectrum relative to the base peak is reported in parentheses. Rotations
were measured at 24ꢀC with a Zeiss ‘0.01ꢀ’ polarimeter. THF, ether, 1,2-
dimethoxyethane and benzene were freshly distilled from sodium benzo-
phenone before use. All other solvents and reagents were obtained from
commercial suppliers and used without further purification. Merck silica
gel (70–230 mesh ASTM) was used for column chromatography. TLC
was performed on Analtech silica gel 60 G254 and the spots were
observed either by exposure to iodine or by UV light. All organic extracts
were dried over anhydrous sodium sulphate and evaporated under
reduced pressure below 60ꢀC. Where necessary reactions were carried
out under a nitrogen or argon atmosphere.
Diels-Alder reaction of the diene 4 with p-benzoquinone. A mixture
of the diene 4 (0.3 g, 1.47 mmol) and p-benzoquinone (0.43 g, 3.98 mmol)
in p-xylene (3 mL) was heated in a sealed tube at 180ꢀC for 30 h. The
reaction mixture was chromatographed over silica gel and elution with
hexane yielded unreacted diene 4 (0.15 g). Elution with 5% diethyl ether
in hexane afforded the cyclozonarone 5 (0.204 g, 90% based on reacted
starting material) as a yellow oil. [a]D ¼ þ88 (c 3.5, CH3Cl); literature
data:[5] [a]D ¼ À89.1 (c 0.330, CH3Cl); HRMS m/z 308.2141 (Mþ,
C21H24O2 requires 308.1776); EIMS m/z 310 (8, M þ2), 309 (20,
M þ1), 308 (Mþ, 20), 294 (25), 293 (70), 237 (28), 225 (70), 223 (50),

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(Q)-Cyclozonarone, Isozonarol D,8,9 and Isozonarone D8,9
1125
212 (25), 211 (100), 197 (45), 69 (80), 55 (73), and 43 (60); ꢀH (300 MHz)
0.90, 0.93, 1.15 (3H, s, CH3), 2.39 (1H, bd), 2.97 (2H, m), 6.83 (1H, d, J¼
10.2 Hz), 6.86 (1H, d, J ¼ 10.2 Hz), 7.68 (1H, s), and 7.93 (1H, s);
ꢀC (75.45 MHz) 18.49, 18.95, 21.57, 24.42, 30.62, 33.12, 33.48, 38.44,
38.53, 41.34, 49.61, 122.99, 127.28, 128.97, 129.66, 138.48, 138.79,
142.74, 156.83, 185.17, and 185.17.
Partial epoxidation of the diene 4 with MCPBA. To a solution
of diene 4 (0.314 g, 1.53 mmol) in CH2Cl2 was added in small portions
MCPBA (0.39 g, 2.26 mmol) at À10ꢀC. After 3 h the reaction mixture was
filtered through a small amount of silica gel to remove precipitates.
Evaporation of the filtrate gave a crude product, which was chromato-
graphed over silica gel. Elution with hexane yielded unreacted diene
4 (0.137 g, 44% of recovery). Elution with 2% diethyl ether in hexane
afforded the monoepoxide 8 as an oil (0.161 g, 84%, based on reacted
starting material); ꢀH (300 MHz) 0.81 (3H, s, CH3-14), 0.87 (3H, s, CH3-
13), 0.97 (3H, s, CH3-15), 2.84 (2H, AB system, J ¼ 4.6 Hz, CH2O), 4.73
(1H, m, ¼CH2), and 4.84 (1H, m, ¼CH2); ꢀC (75.45 MHz) 18.33 (C-2),
19.20 (C-15), 21.80 (C-14), 23.05 (C-6), 30.88 (C-1), 32.92 (C-13), 33.48
(C-4), 33.95 (C-7), 37.86 (C-10), 41.58 (C-3), 48.62 (C-11), 49.68 (C-5),
68.05 (C-9), 110.33 (C-12) and 146.39 (C-8). Elution with 5% ether in
hexane yielded only small amounts of monoepoxide 9 and stereoisomeric
diepoxide 10. Prolongation of the reaction time for more than 3 h did
increase the amounts of monoepoxide 9 and stereoisomeric diepoxide 10.
Cleavage of the monoepoxide 8 with silica gel-supported zinc boro-
hydride. A solution of silica gel-supported zinc borohydride in 1,2-
dimethoxyethane was prepared according to the literature procedure.9
Zinc borohydride (0.647 g, 6.81 mmol) in 1,2-dimethoxyethane (10 mL)
was added under dry nitrogen to silica to silica gel HF254 (1 g) and
the mixture was stirred at room temperature for 30 min. The monoep-
oxide 8 (0.5 g, 2.27 mmol) was then added and stirring was continued for
48 h at room temperature. The excess reagent was decomposed by addi-
tion of water and the reaction mixture was filtered through silica gel. The
crude product (0.498 g) thus obtained was chromatographed over silica
gel. Elution with 2% diethyl ether in hexane afforded unreacted mono-
epoxide 8 (90 mg). Further elution with 4% diethyl ether in hexane
yielded (þ)-b-bicyclofarnesol 1 (0.390 g, 94%); M.p.: 93–94ꢀC; [a]D ¼
þ101 (c, 5.9, CHCl3); EIMS m/z 222 (Mþ, 11), 207 (8), 204 (16), 191 (86),
189 (72), 121 (57), 95 (88), 69 (64), 41 (100); ꢀH (300 MHz) 0.80, 0.85, 0.92
(each 3H, s, CH3), and 4.05 (2H, AB system, J¼12 Hz); m/z 222 (Mþ, 11),
207 (8), 204 (16), 191 (86), 189 (72), 121 (57), 95 (88), 69 (64), and 41 (100).
Oxidation of (þ)-bicyclofarnesol 1 with tetra-n-propylammonium
perruthenate. Alcohol
1
(0.18 g, 0.81 mmol) was dissolved in

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1126
Villamizar et al.
˚
dichloromethane (5 mL) containing both 4A molecular sieves (0.405 g)
and N-methylmorpholine N-oxide (0.113 g, 0.96 mmol). After stirring
the mixture for 10 min, tetra-n-propylammonium perruthenate (14 mg,
0.04 mmol) was added and the reaction followed by TLC until com-
plete. The reaction mixture was filtered through silica gel and elution
with hexane afforded (À)-bicyclofarnesal 2 (0.130 g, 82%) as a semi-
solid; [a]D À10 (c, 3.4, CHCl3); HRMS m/z 220.1826 (Mþ, C15H24O
requires 220.2505); ꢀH (300 MHz) 0.81, 0.86, 1.15, 1.99 (3H each, s,
CH3), and 10.02 (1H, s, H-11); ꢀC (75.45 MHz) 18.2, 18.8, 19.1, 20.1,
21.6, 33.2, 33.3, 36.2, 36.5, 37.5, 41.5, 51.5, 143.6, 153.5, and 192.6.
Elution with 4% diethyl ether in hexane afforded unreacted (þ)-bicy-
clofarnesol 1 (20 mg).
Oxidation of (þ)-bicyclofarnesol 1 with PCC. Alcohol 1 (0.08 g,
0.36 mmol) was dissolved in dichloromethane (2 mL) and oxidized with
pyridinium chlorocromate (0.116 g, 0.53 mmol) at room temperature for
30 min. The reaction mixture was filtered on silica gel and the filtrate was
evaporated. The resulting crude product was chromatographed over
silica gel. Elution with 1% diethyl ether in hexane afforded (À)-bicyclo-
farnesal 2 (61 mg, 77%) as a semisolid.
Coupling of the (À)-bicyclofarnesal 2 with di-methyl-ether of
hydroquinone. To a cooled solution of the di-methyl-ether of hydro-
quinone (0.150 g, 1.08 mmol) in dry THF (3 mL) at 0ꢀC, was added
n-butyllithium (0.8 mL, 1.28 mmol, 1.6 M in hexane). The resulting
yellow solution was stirred for 15 min at 0ꢀC and then slowly
warmed to room temperature, stirred for 5 min. Then a solution of
aldehyde 2 (0.086 g, 0.39 mmol) in THF (2 mL) was added. The mix-
ture was stirred for an additional 1 h, saturated aqueous NH4Cl solu-
tion was added and extracted with ether. The solvent was evaporated
under reduced pressure and the product was chromatographed over
silica gel. Elution with 20% diethyl ether in hexane afforded com-
pound 11 (0.119 g, 85%) as a colorless oil; HRMS m/z 358.3140
(Mþ, C23H34O3 requires 358.2508); ꢀH (300 MHz) 0.84, 0.90, 0.92,
1.56 (3H each, s, CH3), 3.71 (3H, s, OCH3), 3.85 (3H, s, OCH3),
5.68 (1H, m, 11-CHOH), and 6.77 (3H, m, aromatics H).
Reduction of compound 11 with Et3SiH–CF3COOH. To a solution
of compound 11 (0.152 g, 0.42 mmol) in CH2Cl2 (2 mL) at À78ꢀC, was
added CF3COOH (2 mL). The solution was allowed to warm to À15ꢀC
for more than 1 h and then at room temperature for 24 h. Triethylsilane
(1 mL) was then added dropwise. The reaction mixture was stirred for an
additional 1 h and then a saturated aqueous NaHCO3 solution was added
and extracted with ether. The solvent was evaporated under reduced
pressure and the product was chromatographed over silica gel. Elution

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(Q)-Cyclozonarone, Isozonarol D,8,9 and Isozonarone D8,9
1127
with 5% diethyl ether in hexane afforded compound 12 (0.131 g, 90%) as
a semisolid; HRMS m/z 342.3147 (Mþ, C23H34O2 requires 342.2559); ꢀH
(300 MHz) 0.83 (3H, s, CH3), 0.92 (3H, s, CH3), 1.24 (3H, s, CH3), 1.46
(3H, s, CH3), 2.55 (1H, m), 3.76 (2H, d, J¼7.5 Hz, H-11), 3.78 (3H, s,
OCH3), 3.81 (3H, s, OCH3), 6.32 (1H, bs, H-60), 6.55 (1H, d, J¼9 Hz,
H-40), and 6.65 (1H, d, J¼9 Hz, H-30); ꢀC (75.45 MHz) 18.50, 19.04,
20.12, 21.25, 21.70, 26.75, 28.75, 30.90, 33.49, 36.80, 39.01, 41.78,
52.49, 55.51, 55.69, 111.36, 111.38, 114.20, 127.10, 127.50, 139.45,
148.81, and 151.29.
Oxidation of compound 12 with CAN. An aqueous solution (0.5 mL)
of CAN (0.114 g, 0.208 mmol) was added to a solution of 12 (0.050 g,
0.146 mmol) in acetonitrile (1 mL) in an ice bath. After stirring for 10 min
in ice bath, the mixture was extracted with AcOEt. The combined
extracted were washed with brine and dried. The solvent was evaporated
under reduced pressure and the product was chromatographed over silica
gel. Elution with 5% ether in hexane yielded unreacted compound 12
(11 mg). Elution with 7% ether in hexane afforded quinone 7 as a
yellow oil (32.7 mg, 92%); HRMS m/z 312.2096 (Mþ, C21H28O2 requires
312.2089); EIMS m/z 312 (10, Mþ), 297 (8), 267 (20), 256 (25), 189 (22),
175 (30), 174 (75), 161 (24), 137 (10), 119 (26), 95 (20), 55 (100), and 43
(80); ꢀH (300 MHz) 0.78 (3H, s, 15-CH3), 0.81 (3H, s, 14-CH3), 0.86 (3H,
s, 13-CH3), 2.67 (2H, brd, J¼6 Hz, H-11), 4.66 (1H, s, H-12), 4.78 (1H, s,
H-12), 6.48 (1H, dd, J¼8/2.8 Hz, H-40), 6.58 (1H, d, J¼2.8 Hz, H-60) and
6.59 (1H, d, J¼8 Hz, H-30); ꢀC (75.45 MHz) 18.37, 19.72, 21.30, 21.60,
27.07, 27.51, 28.61, 31.57, 34.20, 39.53, 41.54, 48.08, 50.60, 131.08,
135.25, 135.58, 137.47, 145.90, 152.77, 186.56, and 187.01.
Reduction of quinone 7 with sodium hydrosulfite. An aqueous
solution (3 mL) of Na2S2O4 (0.115 g, 0.66 mmol) was added to a solution
of 7 (30 mg, 0.096 mmol) in THF (1 mL). The mixture was stirred vigor-
ously until the yellow color disappeared. Water was added and the
solution was extracted with ether. The solvent was evaporated under
reduced pressure and the product was chromatographed over silica gel.
Elution with 40% diethyl ether in hexane affording compound 6 (24.2 mg,
80%) as a solid; M.p.: 82–83ꢀC; HRMS m/z 314.2250 (Mþ, C21H30O2
requires 314.2246); EIMS m/z 314 (38, Mþ), 297 (6), 229 (8), 191 (75), 178
(20), 163 (16), 161 (30), 149 (20), 137 (10), 123 (72), 109 (25), 95 (30), 69
(65), 55 (100), and 43 (90); ꢀH (300 MHz) 0.82, 0.88, 0.97 (3H each, s,
CH3), 1.53 (3H, s, 12-CH3), 2.11 (2H, m), 3.29 (2H, AB System,
J¼18 Hz), 6.51 (1H, dd, J¼9 Hz, 3 Hz, H-40), 6.52 (1H, bs, H-60), and
6.60 (1H, d, J¼9 Hz, H-30); ꢀC (75.45 MHz) 18.81, 19.00, 20.16, 20.22,
21.70, 27.83, 29.67, 33.22, 33.51, 36.18, 39.01, 41.57, 51.78, 112.84,
115.77, 116.12, 128.24, 129.95, 137.27, 147.72, and 149.16.

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1128
Villamizar et al.
ACKNOWLEDGMENTS
We thank Dr. T. Nakano for his continued interest in this work and
Dr. L. Mitscher (University of Kansas) for the measurement of mass
spectra. This research was supported by grant from FONACIT
(S1 96001367).
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(Q)-Cyclozonarone, Isozonarol D,8,9 and Isozonarone D8,9
1129
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Received in the USA May 15, 2002

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