Stereoselective synthesis of (+)-avarol, (+)-avarone, and some nonracemic analogues

Article abstract of DOI:10.1021/jo961048r

Synthesis of the rearranged drimane sesquiterpenoids (+)-avarol and (+)-avarone from Wieland-Miescher ketone is described. This synthetic sequence provides convenient access to the natural enantiomers and, based on comparison of the optical rotation of synthetic avarol dimethyl ether with literature data, affords material of significantly higher optical rotation than a natural source. Similar synthetic strategies have been used to obtain several related compounds, including a decalin bearing an exocyclic olefin and a highly substituted cyclohexane, that can be viewed as hybrids of the trans-fused avarol and cis-fused arenarol skeletons.

Full text of DOI:10.1021/jo961048r

J . Org. Chem. 1996, 61, 8775-8779
8775
Ster eoselective Syn th esis of (+)-Ava r ol, (+)-Ava r on e, a n d Som e
Non r a cem ic An a logu es
J ianguo An and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294
Received J une 4, 1996X
Synthesis of the rearranged drimane sesquiterpenoids (+)-avarol and (+)-avarone from Wieland-
Miescher ketone is described. This synthetic sequence provides convenient access to the natural
enantiomers and, based on comparison of the optical rotation of synthetic avarol dimethyl ether
with literature data, affords material of significantly higher optical rotation than a natural source.
Similar synthetic strategies have been used to obtain several related compounds, including a decalin
bearing an exocyclic olefin and a highly substituted cyclohexane, that can be viewed as hybrids of
the trans-fused avarol and cis-fused arenarol skeletons.
Over the past two decades, dozens of natural products
with quinone or hydroquinone systems appended to a
sesquiterpene or diterpene skeleton have been isolated
from marine sponges.1 Among the more well-known
members of this family are the drimane derivatives
avarol (1) and avarone (2). Avarol and avarone were first
related compounds10 have shown interesting activity in
enzyme assays measuring inhibition of the various func-
tions of HIV-I reverse transcriptase.
Despite their interesting structures and the continued
biological interest, there has been little published work
on synthesis of avarol or avarone. The only total syn-
thesis appeared in 1982, when Sarma and Chatto-
padhyay reported their preparation of racemic avarol.11
Recently, there has been a surge of interest in prepara-
tion of related compounds, including our total synthesis
of the cis-fused (()-arenarone (3)12 and independent
syntheses of (-)-ilimaquinone (4)13 and (()-mamanutha-
quinone (5).14 In this report we present our synthesis of
(+)-avarol (1) and (+)-avarone (2), the first synthesis of
either as the natural enantiomer, along with prepara-
tions of several analogues.
isolated from the Mediterranean sponge Dysidea avara
and assigned structures in 1974,2 later assigned absolute
stereochemistry on the basis of CD experiments,3 and
finally confirmed in stereochemistry by diffraction analy-
sis of a simple derivative.4 While early studies indicated
modest activity for avarol and avarone as antibiotic and
antileukemic agents,5 subsequent research that reported
significant antiviral activity against HIV-I greatly stimu-
lated interest in these compounds.6 Unfortunately, in
vivo antiviral activity has not been confirmed by later
assays, and recent papers suggest that the initial reports
of significant antiviral activity were overly optimistic.7,8
While the pharmaceutical potential of avarol and avarone
is far from clear, a number of avarol derivatives9 and
To obtain the natural avarol/avarone enantiomers, it
was attractive to employ the methylated Wieland-Mei-
scher ketone derivative 8 because this compound has
been prepared in optically active form.15 However, given
that the L-phenylalanine mediated Robinson annulation
leading directly from 2-methyl-1,3-cyclohexanedione and
ethyl vinyl ketone to compound 8 is reported in modest
yield (60%) and limited ee (75-90%), we chose instead
to begin with Wieland-Miescher ketone (6) itself to take
advantage of the higher chemical yield and ee (96%)
X Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) (1) Faulkner, D. J . Nat. Prod. Rep. 1996, 13, 75-125, and
references cited therein.
(2) Minale, L.; Riccio, R.; Sodano, G. Tetrahedron Lett. 1974, 3401-
3404.
(3) deRosa, L.; Minale, L.; Riccio, R.; Sodano, G. J . Chem. Soc.,
Perkin Trans. 1 1976, 1408-1414.
(4) Giordano, F.; Puliti, R. Acta Crystallogr. 1987, C43, 985-988.
(5) Mu¨ller, W. E. G.; Maidhof, A.; Zahn, R. K.; Schro¨der, H. C.; Gasic,
M. J .; Heidemann, D.; Bernd, A.; Kurelec, B.; Eich, E.; Seibert, G.
Cancer Res. 1985, 45, 4822-4826.
(6) (a) Sarin, P. S.; Sun, D.; Thornton, A.; Mu¨ller, W. E. G. J . Natl.
Cancer Inst. 1987, 78, 663-666. (b) Schro¨der, H. C.; Sarin, P. S.;
Rottmann, M.; Wenger, R.; Maidhof, A.; Renneisen, K.; Mu¨ller, W. E.
G. Biochem. Pharmacol. 1988, 37, 3947-3952.
(7) Kushlan, D. M.; Faulkner, D. J . Tetrahedron 1989, 45, 3307-
3312.
(10) (a) Loya, S.; Tal, R.; Kashman, Y.; Hizi, A. Antimicrob. Agents
Chemother. 1990, 34, 2009-2112. (b) Loya, S.; Hizi, A. J . Biol. Chem.
1993, 268, 9323-9328. (c) Loya, S.; Tal, R.; Hizi, A.; Issacs, S.;
Kashman, Y.; Loya, Y. J . Nat. Prod. 1993, 56, 2120-2125.
(11) Sarma, A. S.; Chattopadhyay, P. J . Org. Chem. 1982, 47, 1727-
1731. (corrected 1982, 47, 5427).
(12) Watson, A. T.; Park, K.; Wiemer, D. F.; Scott, W. J . J . Org.
Chem. 1995, 60, 5102-5106.
(13) Bruner, S. D.; Radeke, H. S.; Tallarico, J . A.; Snapper, M. A. J .
Org. Chem. 1995, 60, 1114-1115.
(14) Yoon, T.; Danishefsky, S. J .; de Gala, S. Angew Chem., Int. Ed.
Engl. 1994, 33, 853-855.
(8) Rodriguez, J .; Quinoa, E.; Riguera, R.; Peters, B. M.; Abrell, L.
M.; Crews, P. Tetrahedron 1992, 48, 6667-6680.
(9) Loya, S.; Hizi, A. FEBS Lett. 1990, 269, 131-134.
(15) Uma, R.; Swaminathan, S.; Rajagopalan, K. Tetrahedron Lett.
1984, 25, 5825-5828.
S0022-3263(96)01048-1 CCC: $12.00 © 1996 American Chemical Society

8776 J . Org. Chem., Vol. 61, No. 25, 1996
An and Wiemer
known for its preparation.16 Despite a low yield in the
methylation step, this approach proved to be advanta-
geous from the standpoint of optical purity. After protec-
tion of the Wieland-Miescher ketone through reaction
with ethylene glycol, the enone ketal 7 was treated with
NaH/DMSO17 followed by addition of methyl iodide in
order to obtain compound 8 in optically pure form.
Reduction of enone 8 by treatment with Li/NH3, followed
by trapping the intermediate enolate through reaction
with 2,5-dimethoxybenzyl bromide, gave the expected
product 9 as a single isomer. The Wittig reaction of
ketone 9 and methylene triphenylphosphorane gave the
exocyclic olefin 10 in 70% yield.
in that avarone contains an endocyclic olefin while
arenarone bears an exocyclic olefin. In anticipation of
bioassays comparing the activity of avarone and aren-
arone, we prepared a new compound that can be viewed
as a hybrid of the two natural products, the “exo” avarone
15. Compound 15 was readily available by treatment of
compound 13 with CAN to accomplish deprotection of the
methyl ethers and formation of the quinone system.
The similarity between the structures of avarone (2)
and arenarone (3) also inspired interest in related
monocyclic analogues designed to simplify both the trans-
and cis-fused decalin systems to a common, highly
substituted, cyclohexane derivative. From this perspec-
tive (Scheme 1), hypothetical deletion of C-7 and C-8 of
avarone allowed identification of the cyclohexane 16 as
a prime target. In a retrosynthetic sense, compound 16
can be dissected to a methyl ketone or ketal at the C-4
position of a methylenecyclohexane (17). This exocyclic
olefin could be viewed as a derivative of an enone such
as compound 18, through a sequence involving conjugate
addition and alkylation of the resulting enolate. Finally,
it was anticipated that enone 18 would be readily
available by straightforward Horner-Wadsworth-Em-
mons condensation of the nonracemic phosphonate 19
with formaldehyde. Because the nonracemic â-keto
phosphonate 19 has recently been prepared from the
known, prochiral 4,4-disubstituted cyclohexanone 20 via
a diastereoselective vinyl phosphate rearrangement,19
phosphonate 19 represents a convenient starting mate-
rial for this sequence.
Catalytic hydrogenation of olefin 10 over Pd-C gave
a mixture of the desired product 11 (62%) and its C-2
epimer (27%, avarol numbering). After separation of the
diastereomers, the major product was treated with aque-
ous acid to remove the ketal, and the resulting ketone
12 was treated with methylene triphenylphosphorane to
provide the exocyclic olefin 13 in very good yield. Treat-
ment of olefin 13 with RhCl3 in ethanol, in a fashion
similar to that reported by Sarma,11 resulted in isomer-
ization of the exocyclic olefin to the more stable endocyclic
olefin in good yield, providing the known dimethyl avarol
14.
The synthetic sequence to compound 14 was conducted
twice, initially with a sample of ketone 6 of about 80%
ee, and subsequently with material of greater than 96%
ee. From the more optically pure ketone 6, we obtained
the methylated intermediate 8 in high enantiomeric
excess and ultimately obtained compound 14 in high
optical purity ([R]D ) +8.9° (CHCl3, c ) 1.1) vs a
literature3 value of [R]D ) +5.2° (CHCl3, c ) 1.7)).
Because the synthesis beginning with material of ap-
proximately 80% ee produced compound 14 with a
proportionally lower rotation, it is likely that the reported
preparation of compound 14 via methylation of natural
avarol did not provide optically pure material.
Completion of the (+)-avarone synthesis was accom-
plished by oxidation of the dimethyl ether 14 with ceric
ammonium nitrate (CAN),13,14 and (+)-avarol itself was
then obtained by sodium dithionite reduction of the
quinone 2. Both of the synthetic materials gave spec-
troscopic data identical to that reported for the natural
products, confirming the identity of the synthetic prod-
ucts.
To obtain the monocyclic avarol analogue best reflect-
ing the natural avarol stereochemistry, the 4S enanti-
omer of compound 19 was employed to begin the syn-
thetic sequence. Treatment of phosphonate 19 with
K2CO3 and formaldehyde in aqueous dioxane afforded the
expected R-methylene ketone 21 in good yield. When this
enone was treated with lithium metal in liquid ammonia,
and the resulting enolate was quenched by addition of
2,5-dimethoxybenzyl bromide, regiospecific alkylation
was achieved. The major product was assigned structure
22 based on the assumption that with the bulky ketal
moiety in an equatorial orientation the stereochemistry
A recent publication18 established that arenarone (3)
and avarone (2) share the same absolute configuration
at three of their four stereogenic centers. Thus these two
natural products differ only in that avarone incorporates
a trans-fused decalin while arenarone is cis-fused, and
(16) Gutzwiller, J .; Buchschacher, P.; Furst, A. Synthesis 1977, 167-
168.
(17) Hagiwara, H.; Uda, H. J . Org. Chem. 1988, 53, 2308-2311.
(18) Urban, S.; Capon, R. J . Aust. J . Chem. 1994, 47, 1023-1029.
(19) An, J .; Wilson, J . M.; An, Y. Z.; Wiemer, D. F. J . Org. Chem.
1996, 61, 4040-4045.

Stereoselective Synthesis of (+)-Avarol and (+)-Avarone
J . Org. Chem., Vol. 61, No. 25, 1996 8777
Sch em e 1
In conclusion, the natural products (+)-avarone and
(+)-avarol have been prepared via a stereocontrolled
sequence from Wieland-Miescher ketone. The observed
rotations for the synthetic compounds are significantly
higher than those reported for the natural products.
Further experiments with natural avarol and avarone
would be attractive to establish their ee, and further
bioassays may be desirable to clarify the impact of
natural avarol and avarone’s enantiomeric purity on their
biological activity. Parallel bioassays with nonracemic
analogues, such as compounds 15 and 16, may help
establish the importance of the trans- and cis-fused
decalin systems to the activity associated with avarol and
arenarol.
Exp er im en ta l Section
Tetrahydrofuran (THF) was distilled from sodium/ben-
zophenone, while triethylamine was distilled from CaH2. All
nonaqueous reactions were conducted in oven-dried glassware,
under an atmosphere of nitrogen, and with magnetic stirring.
Flash chromatography was carried out on Baker silica gel with
40 µm average particle diameter. Melting points are uncor-
rected. Optical rotations were measured with a Perkin-Elmer
141 automatic polarimeter. NMR spectra (1H at 300 MHz and
13C at 75 MHz) were recorded with CDCl3 as solvent and
(CH3)4Si (1H) or CDCl3 (13C, 77.0 ppm) as internal standards.
Both low and high resolution mass spectra were obtained at
an ionization potential of 70 eV; only selected ions are reported
here. High resolution mass spectra were obtained at the
University of Iowa Mass Spectrometry Facility. Elemental
analyses were performed by Atlantic Microlab, Inc. (Norcross,
GA).
of this alkylation would be controlled by the axial methyl
group and parallel that known for the trans-fused decalin
9. This product was isolated in modest yield primarily
because it was accompanied by a significant amount of
the corresponding diketone formed by hydrolysis of the
ketal upon workup.
(4a S)-(+)-5-(1,3-Dioxola n -2-yl)-1,4a â-d im eth yl-4,4a ,7,8-
tetr a h yd r o-2,5-(3H,6H)-n a p h th a len ed ion e (8). A disper-
sion of NaH (0.31 g, 13.0 mmol) in 20 mL of DMSO was stirred
at 65 °C under N2 until the solution became clear. After the
solution was allowed to cool to rt, a solution of ketal 7 (2.77 g,
12.5 mmol in 10 mL of DMSO), derived from optically active
Wieland-Miescher ketone prepared as previously described,20
was added dropwise to the reaction flask. After 1.5 h, a
solution of CH3I (2.13 g, 15.0 mmol in 40 mL DMSO) was
added over a period of 3 h, and the reaction was stirred at rt
for an additional 5 h. The reaction was quenched by addition
of saturated NH4Cl, and the aqueous layer was extracted three
times with ether (50 mL each). The combined organic layer
was washed five times with water (50 mL each) and three
times with brine (30 mL each) and dried over Na2SO4. After
concentration in vacuo, the residue was purified by flash
column chromatography (60% hexanes, 40% EtOAc) to give
compound 8 (0.99 g, 34%) as a white solid with 1H NMR data
identical to the reported partial spectrum:17 [R]D ) +114°
(CHCl3, c ) 1.1), lit.17 [R]D ) +110° (CH3OH, c ) 0.5); 1H NMR
δ 4.02-3.90 (m, 4), 2.77-2.70 (br, m, 1), 2.52-2.34 (m, 2),
2.29-2.10 (m, 2), 1.95-1.73 (m, 2), 1.79 (d, J ) 1.4 Hz, 3),
1.70-1.55 (br, m, 3), 1.34 (s, 3), 13C NMR δ 198.5, 160.0, 130.0,
112.7, 65.2, 64.9, 45.2, 33.6, 29.6, 26.4, 26.3, 21.3, 20.8, 11.3;
EIMS m/ z (rel intensity) 236 (M+, 7), 121 (3), 107 (4), 100 (13),
99 (100), 55 (31).
(1S,4a S)-(+)-tr a n s-1R-[(2,5-Dim eth oxyp h en yl)m eth yl]-
1â,4aâ-dim eth yl-5-(2-m eth yl-1,3-dioxolan -2-yl)-h exah ydr o-
2,5(3H,6H)-n a p h th a len ed ion e (9). To lithium (0.07 g, 10.0
mmol) in liquid ammonia (100 mL) at -78 °C in a flask fitted
with a Dewar condenser was added dropwise a solution of
compound 8 (0.90 g, 3.8 mmol in 10 mL of THF). The cooling
bath was withdrawn, and the reaction was allowed to warm
to reflux and maintained at that temperature for 1 h. 2,5-
Dimethoxybenzyl bromide (3.5 g, 15.2 mmol in 5 mL of THF)
was added as rapidly as possible, and an additional 30 mL of
THF was added. After 2 h at reflux, the Dewar condenser was
Olefination of ketone 22 through a Wittig reaction with
methylene triphenylphosphorane in refluxing THF gave
compound 23 in good yield (87%). Hydrogenation of this
exocyclic olefin over Pd-C gave two diastereomers,
compounds 24 and 25, in a ratio of ca. 2:1, respectively,
as measured by direct GC and HPLC analyses of the
reaction mixture. The two isomers were not readily
separable by flash column chromatography, but after
deprotection of the ketals the corresponding ketones (26
and 27) were separated. The major component was
expected to be compound 26 which has the desired avarol-
like stereochemistry at C-1, based on the assumption that
the two larger substituents, the ketal and benzyl groups,
take equatorial positions in compound 23, and that
catalytic hydrogenation is favored from the less sterically
congested face of compound 23. Finally, the carbonyl
group of ketone 26 was converted to an olefin via Wittig
methylenation to give the desired dimethyl avarol ana-
logue 16 in 81% yield.
(20) (a) MacMurray, J . E. J . Am. Chem. Soc. 1968, 90, 6821-6825.
(b) Park, K. Ph.D. Thesis, University of Iowa, December, 1993, and
references cited therein.

8778 J . Org. Chem., Vol. 61, No. 25, 1996
An and Wiemer
replaced by a water condenser, and the NH3 was allowed to
evaporate. The reaction was quenched by addition of satu-
rated NH4Cl, and the aqueous layer was extracted three times
with ether (50 mL each). The combined organic layer was
dried over Na2SO4 and concentrated in vacuo. Flash column
chromatography (40% hexanes, 60% ethyl acetate) gave com-
pound 9 (1.19 g, 81%) as an oil: [R]D ) +24.6° (CHCl3, c )
1.0); 1H NMR δ 6.72-6.71 (m, 2), 6.50 (s, 1), 3.94-3.75 (m, 4),
3.73 (s, 3), 3.70 (s, 3), 2.90 (d, J ) 13.3 Hz, 1), 2.80 (d, J )
13.3 Hz, 1), 2.57-2.47 (m, 1), 2.36-2.22 (m, 2), 1.95-1.85 (m,
1), 1.77-1.44 (br, m, 7), 1.04 (s, 6); 13C NMR δ 217.0, 152.9,
152.3, 127.4, 117.8, 112.7, 112.3, 110.8, 65.0, 64.6, 55.6, 55.3,
51.8, 45.0, 42.1, 39.6, 35.2, 29.9, 28.3, 22.8, 22.7, 20.9, 17.2;
EIMS m/ z (rel intensity) 388 (M+, 8), 237 (6), 210 (6), 151
(100), 121 (19), 99 (58), 85 (12), 55(14); HRMS calcd for
119.0, 111.0, 110.8, 55.5, 55.3, 49.3, 47.6, 42.3, 37.5, 37.2, 35.6,
32.3, 26.8, 25.6, 21.9, 18.9, 18.0, 17.3.
(1S,2S,4a S)-(-)-tr a n s-Deca h yd r o-1r-[(2,5-d im et h ox-
yp h en yl)m eth yl]-5-m eth ylen e-1â,2â,4a â-tr im eth yln a p h -
th a len e (13). To a suspension of methyltriphenylphospho-
nium bromide (0.66 g, 1.84 mmol) in anhydrous 1,4-dioxane
(10 mL) was added n-BuLi (1.1 mL, 1.60 mmol, 1.6 M in
hexane) over 2 min. The resulting orange suspension was
stirred at rt for 1 h. Ketone 12 (0.11 g, 0.31 mmol) in 2 mL of
1,4-dioxane was then added to the phosphorane solution, and
the reaction was heated at reflux for 3 h. The reaction was
quenched by addition of water (5 mL) and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy (80% hexanes, 20% ethyl acetate) to give compound 13
(0.10 g, 97%) as a white solid: [R]D ) -34° (CHCl3 c ) 1.4);
1
mp 80 °C; H NMR δ 6.74-6.63 (m, 3), 4.40 (s, 1), 4.37 (s, 1),
C
23H32O5 388.2250, found 338.2271. Anal. Calcd for
3.74 (s, 3), 3.70 (s, 3), 2.66 (d, J ) 14.0 Hz, 1), 2.58 (d, J )
14.0 Hz, 1), 2.39-2.28 (m, 1), 2.10 (br, 1), 2.06 (br, 1), 1.93-
1.88 (br, m, 1), 1.60-1.27 (br, m, 7), 1.05 (s, 3), 1.05-0.95 (m,
1), 1.00 (d, J ) 5.8 Hz, 3), 0.84 (s, 3); 13C NMR δ 160.2, 152.9,
152.7, 128.6, 118.7, 111.2, 110.7, 102.6, 55.6, 55.3, 48.1, 42.1,
40.2, 37.1, 36.5, 36.2, 33.1, 28.3, 27.7, 23.1, 20.6, 17.7, 17.5;
EIMS m/ z (rel intensity) 342 (M+, 12), 191 (10), 177 (7), 152
(100), 121 (29), 109 (16), 95 (68), 55 (14); HRMS calcd for
C23H34O2 342.2559, found 342.2559.
(1S,2S,4a S)-(+)-tr a n s-1r-[(2,5-Dim eth oxyp h en yl)m eth -
yl]-1,2,3,4,4a ,8a ,7,8-oct a h yd r o-1â,2â,4a â,5-t et r a m et h yl-
n a p h th a len e (14, d im eth yl eth er a va r ol). A mixture of
compound 13 (76 mg, 0.22 mmol) and Rh3Cl‚H2O (5 mg) in 5
mL of ethanol was heated at reflux for 20 h. After concentra-
tion of the solution, the residue was purified by flash column
chromatography (80% hexanes, 20% ethyl acetate) to give
compound 14 (68 mg, 89%) as a white solid: [R]D ) +8.9°
(CHCl3, c ) 1.1); mp 78 °C (lit.3 mp 80-81 °C); both 1H NMR
and 13C NMR spectra were identical to literature data for
material derived from the natural product; EIMS m/ z (rel
intensity) 342 (M+, 2), 191 (2), 190 (2), 152 (57), 151 (44), 121
(11), 120 (14), 95 (81), 94 (100), 55 (8).
Ava r on e (2). A mixture of compound 14 (26 mg, 0.08
mmol) and (NH4)2Ce(NO3)6 (83 mg, 0.15 mmol) in CH3CN (4
mL) and water (2 mL) was stirred at rt for 3 days. The
reaction was then concentrated in vacuo and purified by flash
column chromatography (90% hexanes, 10% ethyl acetate) to
give compound 2 (12 mg, 49%) as a yellow oil with 1H NMR
data identical to that reported for natural product;2 13C NMR
δ 187.4, 187.3, 147.4, 144.1, 137.2, 136.2, 136.0, 120.5, 47.0,
42.7, 38.5, 37.0, 36.1, 35.4, 27.4, 26.4, 20.0, 19.3, 18.0, 17.7,
16.7.
Ava r ol (1). To a solution of avarone (2, 5 mg, 0.016 mmol)
in THF (2 mL) and water (0.7 mL) was added solid Na2S2O3
at rt, and the reaction mixture was stirred for 10 min. After
concentration of the solution, the residue was purified by flash
column chromatography (10% hexanes, 90% ethyl acetate) to
give avarol 1 (3 mg, 60%): 1H NMR, identical to that reported
for natural product;2 EIMS m/ z (rel intensity) 314 (M+, 0.5),
189 (2), 107 (43), 95 (100), 55 (24); HRMS calcd for C21H30O2
314.2245, found 314.2265.
Exo-a va r on e (15). A mixture of compound 13 (45 mg, 0.13
mmol) and (NH4)2Ce(NO3)6 (288 mg, 0.53 mmol) in CH3CN (6
mL) and water (2 mL) was stirred at rt for 3 days. The
reaction was then concentrated in vacuo and purified by flash
column chromatography (90% hexanes, 10% ethyl acetate) to
give compound 15 (20.3 mg, 50%) as a yellow oil: 1H NMR δ
6.77-6.68 (m, 2), 6.64 (br, 1), 4.46 (s, 1), 4.44 (s, 1), 2.58 (d, J
) 13.5 Hz, 1), 2.40 (d, J ) 13.5 Hz, 1), 2.32-2.25 (m, 1), 2.12-
2.06 (m, 1), 1.92-1.82 (m, 2), 1.57-1.40 (m, 6), 1.25-1.10 (m,
2), 1.05 (s, 3), 0.94 (d, J ) 6.5 Hz, 3), 0.86 (s, 3); 13C NMR δ
187.4, 187.2, 159.6, 147.2, 137.2, 136.1, 136.0, 103.2, 49.3, 43.1,
40.3, 37.2, 36.8, 35.3, 32.9, 28.1, 27.5, 22.7, 20.6, 17.7, 16.8;
EIMS m/ z (rel intensity) 312 (M+, 0.3), 192 (4), 191 (23), 175
(4), 135 (10), 121 (16), 109 (23), 95 (100), 79 (18), 67 (12), 55
(13); HRMS calcd for C21H28O2 312.2089, found 312.2095.
(4S)-(+)-4-Me t h yl-4-(2-m e t h yl-1,3-d ioxola n -2-yl)-2-
m eth ylen ecycloh exa n on e (21). A mixture of â-keto phos-
phonate 19 (0.79 g, 2.3 mmol), K2CO3 (0.32 g, 2.3 mmol), and
paraformaldehyde (0.21 g, 7.0 mmol) in 1,4-dioxane (10 mL)
C23H32O5: C, 71.11; H, 8.30. Found: C, 71.01; H, 8.31.
(1S,4a S)-(+)-tr a n s-1r-[(2,5-Dim eth oxyp h en yl)m eth yl]-
1â,4a â-d im eth yl-5-(2-m eth yl-1,3-d ioxola n -2-yl)-2-m eth yl-
en eocta h yd r o-5(6H)-n a p h th a len on e (10). To a suspension
of methyltriphenylphosphonium bromide (4.20 g, 12.0 mmol)
in anhydrous 1,4-dioxane (50 mL) was added n-BuLi (6.9 mL,
11.0 mmol, 1.6 M in hexane) over 5 min. The resulting orange
suspension was stirred at rt for 60 min, compound 9 (0.66 g,
1.7 mmol) in 5 mL of 1,4-dioxane was added, and the reaction
was heated at reflux for 24 h. After the reaction was quenched
by addition of water (20 mL) and concentrated in vacuo, the
residue was purified by flash column chromatography (90%
hexanes, 10% ethyl acetate) to give olefin 10 (0.46 g, 70%) as
1
an oil: [R]D ) +101° (CHCl3, c ) 1.04); H NMR δ 6.70-6.60
(m, 3), 4.74 (br, 1), 4.27(br, 1), 4.00-3.84 (m, 4), 3.73 (s, 3),
3.70 (s, 3), 2.77 (d, J ) 13.1 Hz, 1), 2.59 (d, J ) 13.1 Hz, 1),
2.35-2.27 (m, 1), 2.17-1.95 (m, 3), 1.74-1.40 (br, m, 6), 1.30-
1.15 (m, 1), 1.05 (s, 3), 0.91 (s, 3); 13C NMR δ 153.9, 152.8,
152.4, 128.4, 118.7, 113.6, 111.4, 110.6, 107.3, 64.9, 64.5, 55.7,
55.6, 46.3, 43.5, 42.9, 39.9, 32.0, 29.8, 26.9, 23.0, 22.9, 20.8,
20.3; EIMS m/ z (rel intensity) 386 (M+, 3), 324 (2), 235 (13),
189 (1), 151 (16), 121 (12), 99 (100), 91 (9), 55 (14); HRMS
calcd for C24H34O4 386.2457, found 386.2457. Anal. Calcd for
C24H34O4: C, 74.56; H, 8.87. Found: C, 74.41; H, 8.84.
(1S,2S,4a S)-(-)-tr a n s-1R-[(2,5-Dim eth oxyp h en yl)m eth -
yl]-5-(2-m et h yl-1,3-d ioxola n -2-yl)-oct a h yd r o-1â,2â,4a â-
tr im eth yl-5(6H)-n a p h th a len on e (11). Olefin 10 (0.41 g,
1.05 mmol), 10% Pd-C (0.68 g) in triethylamine (10 mL), and
methanol (2 drops) was stirred at rt under 1 atm of hydrogen
for 12 h. The reaction was filtered through Celite, and the
filtrate was concentrated in vacuo. The residue was purified
by flash column chromatography (90% hexanes, 10% ethyl
acetate) to give compound 11 (0.25 g, 62%): 1H NMR δ 6.77-
6.66 (m, 3), 3.87-3.67 (m, 4), 3.78 (s, 3), 3.73 (s, 3), 2.63 (s, 2),
1.94 (d, J ) 13.6 Hz, 1), 1.71-1.59 (m, 3), 1.51-1.43 (m, 2),
1.39-1.22 (br, m, 6), 1.05 (s, 3), 0.94 (d, J ) 5.6 Hz, 3), 0.8 (s,
3); 13C NMR δ 152.9, 152.7, 128.9, 118.3, 113.4, 111.9, 110.9,
65.1, 64.8, 55.8, 55.4, 43.7, 43.2, 41.5, 37.2, 36.1, 30.7, 29.6,
27.3, 22.8, 21.8, 17.5 (2), 16.8; EIMS m/ z (rel intensity) 388
(M+, 6), 237 (43), 175 (27), 152 (90), 99 (100), 55 (28); HRMS
calcd for C24H36O4 388.2613, found 388.2585. Anal. calcd for
C24H36O4: C, 74.18; H, 9.34. Found: C, 74.24; H, 9.29.
(1S,2S,4a S)-(-)-tr a n s-1r-[(2,5-Dim eth oxyp h en yl)m eth -
y l]-o c t a h y d r o -1â,2â,4a â-t r im e t h y l-5(6H )-n a p h t h a le -
n on e (12). Ketal 11 (400 mg, 10 mmol) in THF (8 mL) and
aqueous HCl (5%, 2 mL) was stirred at rt for 2 h. The reaction
was quenched by addition of solid Na2CO3, and THF was
removed in vacuo. The remaining aqueous layer was extracted
three times with ether (20 mL each). The combined organic
layer was dried over Na2SO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (80%
hexanes, 20% ethyl acetate) to give compound 12 as a white
1
solid (350 mg, 99%) with H NMR data identical to the partial
spectrum reported for racemic material:11 [R]D ) -42.3°
(CHCl3, c ) 1.04); mp 105 °C; 1H NMR δ 6.74-6.61 (m, 3),
3.73 (s, 3), 3.70 (s, 3), 2.73 (d, J ) 14.0 Hz, 1), 2.63 (d, J )
14.0 Hz, 1), 2.63-2.51 (m, 1), 2.24-2.04 (br, m, 3), 1.81-1.67
(m, 1), 1.59-1.37 (m, 6), 1.14 (s, 3), 1.11 (m, 1), 1.05 (d, J )
5.8 Hz, 3), 0.90 (s, 3); 13C NMR δ 216.2, 152.7, 152.6, 127.9,

Stereoselective Synthesis of (+)-Avarol and (+)-Avarone
J . Org. Chem., Vol. 61, No. 25, 1996 8779
and water (3 drops) was stirred at rt for 12 h. After the
reaction mixture was filtered through Celite, the filtrate was
concentrated in vacuo and the residue was purified by flash
column chromatography (80% hexanes, 20% ethyl acetate) to
give compound 21 as an oil (0.42 g, 87%): [R]D ) +7.3° (CHCl3,
10% Pd-C (0.25 g), triethylamine (5 mL), and methanol (1
drop) was stirred at rt under 1 atm hydrogen for 12 h. The
reaction mixture was filtered through Celite, and the filtrate
was concentrated in vacuo. The residue was dissolved in a
solution of THF/5% HCl (4 mL/1 mL) and stirred at rt for 2 h,
and the reaction solution was neutralized by addition of solid
Na2CO3. After concentration of the filtrate in vacuo, the
residue was purified by flash column chromatography (80%
hexanes, 20% ethyl acetate) to give compound 26 (55 mg, 45%)
and compound 27 (40 mg, 32%), both as oils. For compound
1
c ) 2.4); H NMR δ 5.90 (s, 1), 5.15 (s, 1), 4.02-3.86 (m, 4),
2.73 (d, J ) 15.0 Hz, 1), 2.62-2.52 (m, 1), 2.49-2.33 (m, 2),
2.12-2.04 (m, 1), 1.75-1.65 (m, 1), 1.30 (s, 3), 1.08 (s, 3). 13C
NMR δ 201.6, 143.3, 121.3, 113.5, 65.0, 64.8, 41.5, 38.5, 36.2,
29.5, 20.5, 19.0; EIMS m/ z (rel intensity) 210 (M+, 0.1), 195
(4), 88 (6), 87 (100), 79 (3), 67 (4), 55 (5); HRMS calcd for
C12H18O3 210.1256, found 210.1233.
1
26: [R]D ) +26.3° (CHCl3, c ) 2.1); H NMR δ 6.77-6.65 (m,
3), 3.75 (s, 3), 3.73 (s, 3), 2.72 (d, J ) 12.9 Hz, 1), 2.40 (d, J )
12.9 Hz, 1), 2.06 (s, 3), 1.58-1.38 (br, m, 7), 1.10 (s, 3), 0.94
(d, J ) 6.8 Hz, 3), 0.93 (s, 3); 13C NMR δ 214.2, 152.7, 152.6,
128.5, 118.7, 111.2, 111.1, 55.6, 55.5, 47.7, 43.7, 41.8, 38.4, 37.2,
31.8, 27.1, 24.4, 22.9, 21.8, 15.9; EIMS m/ z (rel intensity) 318
(M+, 28), 167 (37), 152 (100), 151 (38), 123 (32), 109 (44), 91
(17), 85 (16), 59 (14); HRMS calcd for C20H30O3 318.2195, found
318.2181.
(2R,4S)-(+)-2-[(2,5-Dim et h oxyp h en yl)m et h yl]-2,4-d i-
m eth yl-4-(2-m eth yl-1,3-d ioxola n -2-yl)cycloh exa n on e (22).
To lithium (0.05 g, 6.9 mmol) in liquid ammonia (40 mL) at
-78 °C in a flask fitted with Dewar condenser was added
dropwise a solution of compound 21 (0.416 g, 1.98 mmol) in 5
mL of THF. The dry ice bath was withdrawn, and the reaction
was allowed to warm to reflux and maintained at that
temperature for 1 h. 2,5-Dimethoxybenzyl bromide (3.22 g,
14.0 mmol in 10 mL of THF) was then added as rapidly as
possible, and 10 mL of THF was also added. After refluxing
for 2 h, the Dewar condenser was replaced by a water
condenser, and the NH3 was allowed to evaporate. The
reaction was quenched by addition of saturated NH4Cl, and
the aqueous layer was extracted three times with ether (20
mL each). The combined organic layer was dried over Na2-
SO4, and concentrated in vacuo. Flash column chromatogra-
phy (80% hexanes, 20% ethyl acetate) gave compound 22 (0.28
For the minor isomer 27: [R]D ) +48.5° (CHCl3, c ) 1.6);
1H NMR δ 6.89 (d, J ) 2.8 Hz, 1), 6.74-6.66 (m, 2), 3.78 (s, 3),
3.74 (s, 3), 2.62 (d, J ) 13.4 Hz, 1), 2.30 (dd, J ) 14.3, 1.7 Hz,
1), 2.22 (s, 3), 2.20 (d, J ) 13.8 Hz, 1), 1.63-1.50 (m, 2), 1.38-
1.32 (m, 1), 1.22-1.10 (m, 3), 1.08 (s, 3), 0.92 (d, J ) 6.9 Hz,
3), 0.79 (s, 3); 13C NMR δ 214.5, 153.0, 152.4, 130.1, 118.1,
111.0, 110.9, 55.6, 55.6, 48.0, 46.6, 41.9, 37.7, 33.0, 33.0, 28.1,
27.8, 26.8, 25.3, 15.7; EIMS m/ z (rel intensity) 318 (M+, 28),
167 (74), 152 (100), 123 (52), 121 (42), 109 (59), 91 (25), 85
(20), 77 (17), 59 (21); HRMS calcd for C20H30O3 318.2195, found
318.2193.
1
g, 39%) as a colorless oil: [R]D ) +39.4° (CHCl3, c ) 1.0); H
NMR δ 6.76-6.68 (m, 3), 3.98-3.85 (m, 4), 3.73 (s, 3), 3.71 (s,
3), 3.00 (d, J ) 13.3 Hz, 1), 2.76 (d, J ) 13.3 Hz, 1), 2.48-2.42
(m, 2), 2.24 (d, J ) 14.3 Hz, 1), 2.12-2.02 (m, 1), 1.64-1.55
(m, 1), 1.38 (dd, J ) 14.3, 1.9 Hz, 1), 1.21 (s, 3), 1.18 (s, 3),
1.11 (s, 3); 13C NMR δ 217.0, 152.9, 152.3, 127.7, 118.3, 114.3,
111.9, 111.0, 64.9, 64.8, 55.6, 55.5, 47.8, 41.5, 40.9, 39.7, 35.8,
29.2, 26.3, 22.6, 18.8; EIMS m/ z (rel intensity) 362 (M+, 5),
151 (61), 121 (14), 91 (6), 87 (100), 77 (4), 55 (5); HRMS calcd
for C21H30O5 362.2093, found 362.2094.
(2R,4S)-(+)-2-[(2,5-Dim et h oxyp h en yl)m et h yl]-2,4-d i-
m eth yl-4-[2-m eth yl-1,3-d ioxola n -2-yl]-1-m eth ylen ecyclo-
h exa n e (23). To a suspension of methyltriphenylphospho-
nium bromide (0.73 g, 0.48 mmol in 5 mL of THF) was added
n-BuLi (0.28 mL, 0.45 mmol, 1.6 M in hexane) over 5 min.
The resulting orange suspension was stirred at rt for 60 min.
Ketone 22 (30 mg, 0.08 mmol) in 1 mL of THF was added to
the phosphorane solution, and the reaction was heated at
reflux for 18 h. After the reaction was quenched by addition
of water (5 mL), the THF was removed in vacuo, the aqueous
layer was extracted with ether (3 × 5 mL), and the organic
layer was concentrated in vacuo. The residue was purified
by flash column chromatography (90% hexanes, 10% ethyl
(1S,2R,4S)-(+)-2-[(2,5-Dim eth oxyph en yl)m eth yl]-4-(pr o-
p ylen -2-yl)-1,2,4-tr im eth ylcycloh exa n e (16). To a suspen-
sion of methyltriphenylphosphonium bromide (0.19 g, 0.55
mmol) in anhydrous 1,4-dioxane (5 mL) was added n-BuLi
(0.31 mL, 0.5 mmol, 1.6 M in hexane) over 1 min. The
resulting orange suspension was stirred at rt for 60 min.
Ketone 26 (29 mg, 0.09 mmol) in 1 mL of 1,4-dioxane was
added to the phosphorane solution, and the reaction was
heated at reflux for 48 h. The reaction was quenched by
addition of water (5 mL), and THF was removed in vacuo. After
the aqueous layer was extracted with ether (3 × 5 mL), the
combined organic layer was concentrated in vacuo, and the
residue was purified by flash column chromatography (90%
hexanes, 10% ethyl acetate) to give compound 16 (23 mg, 81%)
1
as an oil: [R]D ) +18.4° (CHCl3, c ) 1.0); H NMR δ 6.77-
6.68 (m, 3), 4.62 (s, 1), 4.58 (s, 1), 3.75 (s, 3), 3.73 (s, 3), 2.78
(d, J ) 12.8 Hz, 1), 2.37 (d, J ) 12.8 Hz, 1), 1.68 (s, 3), 1.51-
1.32 (br, m, 7), 0.99 (s, 3), 0.95 (d, J ) 6.2 Hz, 3), 0.93 (s, 3);
13C NMR δ 156.7, 152.7, 152.7, 129.0, 118.7, 111.1, 110.9,
106.5, 55.6, 55.5, 46.5, 42.5, 38.6, 38.5, 38.4, 35.4, 28.0, 24.8,
21.4, 19.3, 16.2; EIMS m/ z (rel intensity) 316 (M+, 4), 152
(100), 151 (30), 121 (19), 109 (79), 95 (85), 91 (19), 81 (18), 69
(29), 55(37), 41 (27); HRMS calcd for C21H32O2 316.2402, found
316.2418.
acetate) to give compound 23 (25 mg, 87%) as an oil: [R]D
)
1
+41.2° (CHCl3, c ) 2.0); H NMR δ 6.78-6.59 (m, 3), 4.79 (s,
1), 4.72 (s, 1), 3.96-3.83 (m, 4), 3.75 (s, 3), 3.73 (s, 3), 2.89 (d,
J ) 12.7 Hz, 1), 2.73 (d, J ) 12.7 Hz, 1), 2.48-2.38 (m, 1),
2.28-2.20 (m, 1), 1.90 (d, J ) 13.6 Hz, 1), 1.74-1.64 (m, 1),
1.47-1.42 (m, 1), 1.19 (br, 1), 1.17 (s, 3), 1.14 (s, 3), 1.07 (s, 3);
13C NMR δ 156.0, 152.8, 152.8, 129.0, 119.0, 114.6, 111.5,
111.2, 106.2, 65.1, 64.9, 55.7, 55.7, 42.7, 42.3, 42.2, 40.1, 32.2,
30.0, 27.3, 22.0, 19.1; EIMS m/ z (rel intensity) 360 (M+, 2),
345 (1), 298 (2), 209 (3), 195 (2), 151 (17), 121 (20), 87 (100),
43 (20); HRMS calcd for C22H32O4 360.2301, found 360.2306.
Anal. Calcd for C22H32O4: C, 73.29; H, 8.95. Found: C, 73.16;
H, 8.97.
Ack n ow led gm en t. Financial support from the Na-
tional Institutes of Health (GM-46631) is gratefully
acknowledged.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 13, 15, 16, 21, 22, 26, and 27 (14 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS. See any current
masthead page for ordering information.
(1S,2R,4S)-(+)-2-[(2,5-Dim eth oxyp h en yl)m eth yl]-4-(1-
k etoeth yl)-1,2,4-tr im eth ylcycloh exa n e (26) a n d Its (1R)
Isom er (27). A mixture of compound 23 (0.14 g, 0.39 mmol),
J O961048R