Highly efficient total synthesis of the marine natural products (+)-avarone, (+)-avarol, (-)-neoavarone, (-)-neoavarol and (+)-aureol

Article abstract of DOI:10.1002/chem.200701386

Biologically important and structurally unique marine natural products avarone (1), avarol (2), neoavarone (3), neoavarol (4) and aureol (5), were efficiently synthesized in a unified manner starting from (+)-5-methyl-Wieland- Miescher ketone 10. The synthesis involved the following crucial steps: i) Sequential BF₃·Et₂O-in-duced rearrangement/ cyclization reaction of 2 and 4 to produce 5 with complete stereoselectivity in high yield (2 → 5 and 4 → 5); ii) strategic salcomine oxidation of the phenolic compounds 6 and 8 to derive the corresponding quinones 1 and 3 (6 → 1 and 8 →3); and iii) Birch reductive alkylation of 10 with bromide 11 to construct the requisite carbon framework 12 (10 + 11 → 12). An in vitro cytotoxicity assay of compounds 1-5 against human histiocytic lymphoma cells U937 determined the order of cytotoxic potency (3 > 1 > 5 > 2 > 4) and some novel aspects of structure-activity relationships.

Full text of DOI:10.1002/chem.200701386

FULL PAPER
DOI: 10.1002/chem.200701386
Highly Efficient Total Synthesis of the Marine Natural Products
(+)-Avarone, (+)-Avarol, (ꢀ)-Neoavarone, (ꢀ)-Neoavarol and (+)-Aureol
Junji Sakurai,[a] Takamasa Oguchi,[a] Kazuhiro Watanabe,[a] Hideki Abe,[a]
Syu-ichi Kanno,[b] Masaaki Ishikawa,[b] and Tadashi Katoh*[a]
Abstract: Biologically important and
structurally unique marine natural
products avarone (1), avarol (2), neoa-
varone (3), neoavarol (4) and aureol
(5), were efficiently synthesized in a
unified manner starting from (+)-5-
methyl-Wieland–Miescher ketone 10.
The synthesis involved the following
crucial steps: i) Sequential BF3·Et2O-in-
duced rearrangement/cyclization reac-
tion of 2 and 4 to produce 5 with com-
plete stereoselectivity in high yield (2
! 5 and 4 ! 5); ii) strategic salcomine
oxidation of the phenolic compounds 6
and 8 to derive the corresponding qui-
nones 1 and 3 (6 ! 1 and 8 ! 3); and
iii) Birch reductive alkylation of 10
with bromide 11 to construct the requi-
site carbon framework 12 (10 + 11 !
12). An in vitro cytotoxicity assay of
compounds 1–5 against human histio-
cytic lymphoma cells U937 determined
the order of cytotoxic potency (3 > 1
> 5 > 2 > 4) and some novel aspects
of structure-activity relationships.
Keywords: biomimetic synthesis
natural products quinones
rearrangement · total synthesis
·
·
·
Introduction
highly desirable and worthwhile from the viewpoint of me-
dicinal chemistry and pharmaceuticals.
In recent years, a number of clerodane diterpenoids and re-
lated compounds have been isolated from marine organisms,
particularly from algae and sponges.[1] Several of these
marine natural products have been reported to exhibit at-
tractive biological activities such as cytotoxic, antimicrobial,
antiviral, and immunomodulatory activities.[1] In most cases,
however, further biological studies of these marine natural
products are severely restricted, presumably because of the
scarcity of samples from the marine organisms.[1] Conse-
quently, the development of an efficient and reliable
method for the synthesis of these marine natural products is
(+)-Avarone (1) and (+)-avarol (2) (Figure 1), the first
examples of naturally occurring sesquiterpenoidal quinones
and hydroquinones, were isolated from the Mediterranean
sponge Dysidea avara by Minale et al. in 1974.[2] These com-
pounds show a wide variety of pharmacological properties
including cytotoxic,[3] antimicrobial,[3a,4] antiinflammatory,[5]
antioxidant,[6] antiplatelet,[7] antipsoriatic[8] and anti-HIV[9]
activities. (ꢀ)-Neoavarone (3) and (ꢀ)-neoavarol (4) were
isolated from an Okinawan sponge Dysidea sp. by Iguchi
et al.[10] in 1990. The structures of 3 and 4 were assigned as
the C4 exo-olefinic isomers of 1 and 2;[10] however, their bio-
logical activity has not been reported to date. (+)-Aureol
(5) was originally isolated in 1980 by Faulkner et al.[11] from
a Caribbean sponge Smenospogia aurea, and subsequently
in 2000 by Fattorusso et al.[12] from a different species of the
Caribbean sponge, Verongula gigantea. Compound 5 consists
of a novel tetracyclic benzo[d]xanthene skeleton (ABCD
ring system) in which cis-fused AB and BC rings, and an
ether bond at the bridgehead of the AB ring junction are
the characteristic features. (+)-Aureol exhibits selective cy-
totoxicity against human tumor cells, including non-small
cell lung cancer A549 and colon adenocarcinoma HT-29
cells,[13] and has anti-influenza A virus activity.[14]
[a] J. Sakurai, T. Oguchi, Dr. K. Watanabe, Dr. H. Abe, Dr. T. Katoh
Laboratory of Synthetic Medicinal Chemistry
Department of Chemical Pharmaceutical Science
Tohoku Pharmaceutical University
4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558 (Japan)
Fax : (+81)22-727-0135
E-mail: katoh@tohoku-pharm.ac.jp
[b] Dr. S. Kanno, Prof. Dr. M. Ishikawa
Laboratory of Clinical Pharmacotherapeutics
Department of Biopharmaceutical Science
Tohoku Pharmaceutical University
4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558 (Japan)
The remarkable biological properties and unique structur-
al features of these marine natural products and their limit-
ed availability from natural resources have made them intri-
Supporting information for this article is available on the WWW
1
under http://www.chemeurj.org/ or from the author: H and 13C NMR
spectra for all new compounds.
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829

Figure 1. Structures of 1–5.
guing targets for total synthesis. One racemic[15] and three
enantioselective[16] total syntheses of avarone (1) and avarol
(2) have been reported. We have already reported our own
preliminary results concerning the first total synthesis of
(ꢀ)-neoavarone (3), (ꢀ)-neoavarol (4) and (+)-aureol (5) in
enantiomerically pure form.[17] In this paper, we describe the
full details of our unified total synthesis of (+)-avarone (1),
(+)-avarol (2), (ꢀ)-neoavarone (3), (ꢀ)-neoavarol (4) and
(+)-aureol (5) in an enantioselective manner. In addition,
the in vitro cytotoxic activity of these marine natural prod-
ucts 1–5 against a human cancer cell line U937 was evaluat-
ed to disclose novel aspects of the structure–activity rela-
tionships (SAR).
Results and Discussion
Synthetic plan for (+)-avarone (1), (+)-avarol (2), (ꢀ)-neo-
avarone (3), (ꢀ)-neoavarol (4) and (+)-aureol (5): Our syn-
thetic plan for (+)-avarone (1), (+)-avarol (2), (ꢀ)-neoavar-
one (3), (ꢀ)-neoavarol (4) and (+)-aureol (5) is outlined in
Scheme 1. The key feature of this plan is a novel biogenetic-
type acid-induced rearrangement/cyclization reaction of 2
and 4 to produce the tetracyclic 5 in one step; we envisioned
that this rearrangement/cyclization event would proceed ste-
reoselectively to install the requisite cis-fused decalin ring
junction (cf. 4 ! Ia ! IIa ! IIIa ! 5 and 2 ! Ib ! IIb
! IIIb ! 5, see Scheme 6). Compounds 2 and 4 would be
readily derived from 1 and 3, respectively, upon reduction of
the quinone moiety. Compounds 1 and 3 would be accessed
in a straightforward manner by employing strategic phenol
oxidation[18] of intermediates 6 and 8. To the best of our
knowledge, the utilization of the phenol oxidation method
for synthesizing sesquiterpenoidal quinones such as 1 and 3
is hitherto unknown, and hence this type of reaction poses a
considerable challenge at the synthetic chemistry level.
Methyl ethers 7 and 9 would in turn be prepared by stereo-
Scheme 1. Synthetic plan for 1–5.
controlled reductive alkylation of the known enone 10[19]
with the known bromide 11[20] applying previously described
protocols from the literature.[21] The endo-olefin 7 should be
accessible from the exo-olefin 9 by isomerization at the C4
olefinic double bond.
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Synthesis of the key intermediate 9: We initially pursued the
synthesis of the decalin derivative 9, a common key inter-
mediate for synthesis of 1–5, as shown in Scheme 2. The syn-
thesis commenced with the reductive alkylation of the
known enantiomerically pure enone 10[19] (>99% ee) with
2-methoxybenzyl bromide (11),[20] readily prepared from
commercially available 2-methoxybenzyl alcohol. Thus,
treatment of enone 10 with lithium metal (4 equiv) in liquid
ammonia followed by reaction of the intermediary lithium
enolate with bromide 11 (6 equiv) provided the expected
coupling product 12 as the single diastereomer in 74%
yield. Subsequent methylenation of the sterically hindered
carbonyl group in 12 was achieved by employing a combina-
tion of Ph3P+CH3Brꢀand tBuOK in refluxing benzene, fur-
nishing exo-olefin 13 in 86% yield. This reagent system was
reported to be highly effective for methylenation sterically
hindered carbonyl groups.[22] To establish the C8 stereogenic
center, the ethylene acetal moiety in 13 was first removed
by acid treatment (4m HCl, THF, RT, 3 h, 97%), and the re-
sulting ketone 14 was subjected to hydrogenation [H2
(1 atm), 10% Pd/C, Et3N/MeOH 50:1, RT], which afforded
the desired product 15 (80%) and its C8 epimer 16 (13%)
(15/16 ca. 6:1) after separation by column chromatography
on silica gel. When ethylene acetal 13 was used as a sub-
strate for this hydrogenation under the same reaction condi-
tions, the stereoselectivity at C8 decreased considerably (15/
16 ca. 2:1); this is probably due to an unfavorable conforma-
tion change of the decalin ring system.[23] Finally, compound
15 was efficiently converted to the desired key intermediate
9
in quantitative yield by Wittig methylenation
(Ph3P+CH3Brꢀ, tBuOK, benzene, reflux, 12 h).
Synthesis of (ꢀ)-neoavarone (3) and (ꢀ)-neoavarol (4):
With the key intermediate 9 synthesized, we next conducted
the synthesis of 3 and 4, as shown in Scheme 3. Thus, treat-
Scheme 3. Synthesis of (ꢀ)-neoavarone (3) and (ꢀ)-neoavarol (4). a)
nBuSLi, HMPA, 1108C, 92%; b) O2 (1 atm), salcomine, DMF, RT, 91%
c) NaBH4, THF/H2O 10:1, 08C, 86%. HMPA=hexamethylphosphora-
mide, salcomine=N,N’-bis(salicylidene)ethylenediaminocobalt(II).
ment of 9 with nBuSLi[24] in hexamethylphosphoramide
(HMPA) at 1108C for 3 h deprotected the phenolic O-
methyl group, leading to the liberated phenol 8 in 92%
yield. To construct the quinone system directly, phenol 8
was allowed to react with molecular oxygen (O2 balloon) in
the presence of salcomine [N,N’-bis(salicylidene)ethylene-
diaminocobalt(II)][18] in DMF at ambient temperature for
24 h, producing the target compound 3, m.p. 94–958C (lit.[10]
m.p. 78–798C), [a]D20 =ꢀ62.7 (c=1.02, CHCl3) {lit.[10] [a]2D0 =
ꢀ55.2 (c=0.07, CHCl3)}, in 91% yield. Subsequent conver-
sion of 3 to 4 was first examined using the conventional pro-
cedure (Na2S2O4, THF/H2O, RT) ;[25] however, the yield of
the desired product 4 was moderate (ꢁ50%). After several
experiments, we found that the requisite conversion pro-
ceeded smoothly and cleanly by treating 3 with NaBH4 in
THF/H2O 10:1 at 08C for 3 min, producing the desired 4,
m.p. 175–1778C (lit.[10] m.p. 151–1538C), [a]2D0 =ꢀ41.6 (c=
Scheme 2. Synthesis of the key intermediate 9. a) Li, liq. NH3/THF, ꢀ78
! ꢀ308C; at ꢀ308C, add 11, ꢀ308C to RT, 74%; b) Ph3P+CH3Brꢀ,
tBuOK, benzene, reflux, 86%; c) 4m HCl, THF, RT, 97%; d) H2 (1 atm),
10% Pd/C, Et3N/MeOH 50:1, 80% for 15, 13% for 16; e) Ph3P+CH3Brꢀ,
tBuOK, benzene, reflux, quant.
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T. Katoh et al.
0.10, CHCl3) {lit.[10] [a]D20 =ꢀ38.6 (c=0.14, CHCl3)}, in 86%
yield. The spectroscopic properties (1H and 13C NMR, MS)
of the synthetic samples 3 and 4 were identical with those
reported[10] for natural (ꢀ)-neoavarone and (ꢀ)-neoavarol,
respectively.
[a]D =+6.1, lit.[16d] [a]D25 =+10.2 (c=0.8, CH2Cl2)}, in 85%
yield. The spectroscopic properties (1H and 13C NMR, MS)
of the synthetic samples 1 and 2 were identical with those
reported[2a,b] for natural (+)-avarone and (+)-avarol, respec-
tively.
Synthesis of (+)-avarone (1) and (+)-avarol (2): Having es-
tablished the concise synthetic route to 3 and 4, we next per-
formed the synthesis of 1 and 2, both of which possess an
endo-olefinic double bond at C4, as shown in Scheme 4. Iso-
merization of the exo-olefin moiety in the key intermediate
9 to the desired endo-olefinic double bond was efficiently
achieved by treatment with RhCl3·3H2O[16b,c,18c] (20 mol%)
in refluxing EtOH for 24 h, produced endo-olefin 7 in quan-
titative yield. Compound 7 was then converted to 1 and 2
via phenol 6 by employing the same reaction sequence as
that described for the synthesis of 3 and 4 from the key in-
termediate 9 (cf. 9 ! 8 ! 3 ! 4, Scheme 3). Thus, depro-
tection of the phenolic O-methyl group in 7 by exposure to
nBuSLi in HMPA followed by salcomine oxidation of the li-
berated phenol 6 produced the desired 1, m.p. 61–638C,
[a]2D5 =+12.5 (c=0.94, CH2Cl2) {lit.[16d] [a]2D5 =+13.1 (c=0.5,
CH2Cl2)}, in 80% yield for the two steps. Reduction of 1
with NaBH4 provided the requisite 2, m.p. 147–1498C (lit.[2a]
m.p. 148–1508C), [a]2D0 =+10.8 (c=0.74, CH2Cl2) {lit.[2a]
Synthesis of (+)-aureol (5): Having obtained 4 and 2 in an
efficient and expeditious way, the stage was set for the most
crucial acid-induced rearrangement/cyclization event for the
synthesis of the final target compound 5. As shown in
Scheme 5, the desired acid-induced rearrangement/cycliza-
tion reaction was successfully achieved by treating 4 with
Scheme 5. Synthesis of (+)-aureol (5). a) BF3·Et2O, CH2Cl2, ꢀ50
ꢀ58C, 93% for 4 ! 5, 91% for 2 ! 5.
!
BF3·Et2O (5.0 equiv) in CH2Cl2 at ꢀ50 to ꢀ58C for 5 h,
which resulted in the formation of 5, m.p. 143–1448C (lit.[11]
m.p. 144–1458C), [a]2D0 =+64.5 (c=1.04, CCl4) {lit.[11] [a]2D0 =
+65 (c=2.0, CCl4)} in excellent yield (93%). In addition,
the same treatment of 2 also provided 5, m.p. 143–1448C
and [a]2D0 =+64.5 (c=1.04, CCl4), in 91% yield. It is note-
worthy that both of these reactions proceeded smoothly and
cleanly in a completely stereocontrolled manner. The spec-
1
troscopic properties (IR, H and 13C NMR, MS) of the syn-
thetic sample 5 were identical with those reported[11] for nat-
ural (+)-aureol.
The remarkable stereocontrolled BF3·Et2O-induced rear-
rangement/cyclization reaction of 4 and 2 can be rational-
ized by the mechanistic route shown in Scheme 6. Both of
the reaction processes would involve tertiary carbocation in-
termediates, such as Ia,b, IIa,b, and IIIa,b. Thus, the first
coordination-activation between the Lewis acid and the C4
olefinic double bond in 4 and 2 would lead to the formation
of intermediates Ia,b, which would further produce inter-
mediates IIa,b via migration of the C5 methyl group to the
C4 carbocation center. Intermediates IIa,b would undergo a
1,2-hydride shift from the C10 position to the C5 carbocat-
ion center on the a-face of the molecules to provide inter-
Scheme 4. Synthesis of (+)-avarone (1) and (+)-avarol (2). a)
RhCl3·3H2O, EtOH, reflux, quant.; b) nBuSLi, HMPA, 1108C, 90%; c)
O2 (1 atm), salcomine, DMF, RT, 89%; d) NaBH4, THF/H2O 10:1, 08C,
85%.
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Marine Natural Products
FULL PAPER
mediates IIIa,b, wherein the C10 carbocation center would
be trapped by the inner phenolic hydroxy group to yield,
ꢀ
after protonolysis of the C BF3 bond, the desired cyclized
product 5. We believe that this cascade-type rearrangement/
cyclization sequence would proceed under kinetically con-
trolled conditions.
Biological evaluation: Biological evaluation of compounds
1–5 is of great interest from the viewpoint of SAR. To this
end, the synthesized compounds 1–5 were evaluated for
their in vitro cytotoxicities against a human histiocytic lym-
phoma cell line, U937, which has been used extensively in
routine screening programs for the development of new an-
ticancer agents. The IC50 values of the tested compounds 1–
5 along with mitomycin C, a reference compound, at three
different culture times (24, 48, and 72 h) are shown in
Table 1. It was evident that 1, 3 and 5 exhibited cytotoxic ac-
Table 1. Inhibitory activity of compounds 1–5 against cell growth of
U937 human histiocytic lymphoma cells.[a]
IC50[b] [mm]
24 h
48 h
72 h
(+)-avarone (1)
(+)-avarol (2)
95.8
(59.2–154.9)
115.3
52.9
(24.0–116.4)
124.9
33.5
(16.6–67.2)
56.4
(65.1–203.8)
34.2
(22.2–52.6)
392.6
(195.1–790.2)
62.0
(61.0–255.6)
17.7
(27.8–114.7)
6.5
(ꢀ)-neoavarone (3)
(ꢀ)-neoavarol (4)
(+)-aureol (5)
A
A
938.0
(327.0–2691.0)
50.9
537.6
(282.6–22.0)
42.8
(27.7–138.4)
9.21
(22.9–113.2)
0.50
(21.3–86.1)
0.17
mitomycin C[c]
(5.76–14.75)
(0.27–0.92)
(0.14–0.20)
[a] Numbers in parentheses show the 95% confidence limits. [b]Concen-
tration required for 50% inhibition of cell growth after incubation at
378C, 5% in humidified air. [c]Positive control as a representative anti-
cancer agent.
tivity in a dose- and culture time-dependent manner; howev-
er, 2 and 4 displayed no time-dependent cytotoxicity.
Among the tested compounds, 3 was the most cytotoxic
1
(IC50 =6.5 mm at 72 h), while the potency was about = of
40
that of mitomycin C. The order of the potency at 72 h was
estimated to be 3 > 1 > 5 > 2 > 4. Quinone compounds 1
and 3 are more cytotoxic than the corresponding hydroqui-
none compounds 2 and 4. This observation is in good agree-
ment with a previous SAR study on naturally occurring 1
and 2 reported by Müller et al.[3a] The effect of endo- versus
exo-olefin function was also investigated. A comparison of
the cytotoxicity of the endo-olefinic quinone compound 1
(IC50 =33.5 mm) and the exo-olefinic quinone compound 3
(IC50 =6.5 mm) showed that the position of the olefinic
double bond has a large effect on activity. These results sug-
gest that both the quinone substructure and the C4 exo-ole-
finic double bond in the decalin ring are indispensable for
the cytotoxic activity of this class of marine natural prod-
ucts.
Scheme 6. Mechanisitic consideration for BF3·Et2O-induced rearrange-
ment/cyclization reaction of (ꢀ)-neoavarol (4) and (+)-avarol (2) leading
to (+)-aureol (5).
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T. Katoh et al.
17.3, 20.7, 22.7, 22.8, 28.4, 29.9, 35.2, 39.7, 42.0, 45.1, 51.7, 54.8, 64.7, 65.0,
110.0, 112.8, 120.0, 126.3, 127.7, 132.0, 158.0, 217.2 ppm; IR (neat): n˜ =
2945, 2883, 2835, 1699, 1601, 1585, 1493, 1462, 1440, 1381, 1336, 1288,
1244, 1182, 1128, 1099, 1074, 1047, 949, 910, 866, 754, 648, 588, 509,
474 cmꢀ1; HRMS(EI): m/z: calcd for C22H30O4: 358.2144; found: 358.2155
[M]+.
Conclusion
In conclusion, we have succeeded in developing a highly ef-
ficient synthetic route to the marine natural products 1–5
(31–41% overall yields in 7–10 steps). The method explored
features i) coupling reaction of the known enone 10 and 2-
methylbenzyl bromide (11) to construct the requisite carbon
framework 12 (10 + 11! 12), ii) strategic salcomine oxida-
tion of the phenolic compounds 6 and 8 to form 1 and 3, re-
spectively (6! 1 and 8! 3) and iii) BF3·Et2O-induced rear-
rangement/cyclization reaction of 4 and 2 to produce 5 with
complete stereoselectivity in high yield (2! 5 and 4! 5).
Preliminary biological evaluation of the synthesized com-
pounds 1–5 disclosed some novel aspects of the SAR of
these marine natural products, which would be useful in de-
signing and preparing new anticancer agents.
(4aS,5S,8aS)-5-(2-Methoxybenzyl)-5,8a-dimethyl-6-(methylene)octahy-
dronaphthalen-1(2H)-one-1-ethyleneacetal (13): A stirred suspension of
tBuOK (0.77 g, 6.9 mmol) and methyltriphenylphosphonium bromide
(2.45 g, 6.9 mmol) in dry benzene (30 mL) was heated at reflux for 3 h
under argon, and then roughly half volume of the solvent was evaporated
off. A solution of 12 (245 mg, 0.69 mmol) in dry benzene (7.5 mL) was
added to the above mixture. The resulting solution was refluxed for 24 h
under argon. After cooling, the reaction was quenched with H2O
(5.0 mL) at 08C, and the mixture was extracted with Et2O (2”30 mL).
The combined extracts were washed with brine, then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue, which was puri-
fied by column chromatography (hexane/EtOAc 100:1) to give 13
(209 mg, 86%) as
a
colourless viscous liquid. [a]2D5 =+60 (c=1.35,
CHCl3); 1H NMR (500 MHz, CDCl3): d=0.90 (s, 3H), 1.05 (s, 3H), 1.17
(ddd, J=7.4, 11.7, 12.8 Hz, 1H), 1.38–1.71 (m, 6H), 1.97 (dd, J=3.4,
12.2 Hz, 1H), 2.03–2.15 (m, 2H), 2.29–2.38 (m, 1H), 2.63 (d, J=13.2 Hz,
1H), 2.77 (d, J=13.2 Hz, 1H), 3.74 (s, 3H), 3.87–4.04 (m, 4H), 4.18 (d,
J=1.5 Hz, 1H), 4.69 (d, J=1.5 Hz, 1H), 6.77–6.83 (m, 2H), 6.95–6.99 (m,
1H), 7.12–7.17 ppm (m, 1H); 13C NMR (125 MHz, CDCl3): d=19.9, 21.0,
22.9, 23.1, 29.5, 29.7, 32.1, 39.9, 42.9, 43.5, 46.6, 54.9, 64.5, 64.9, 107.2,
109.8, 113.7, 119.2, 126.9, 127.3, 132.6, 153.8, 158.5 ppm; IR (neat): n˜ =
2934, 2878, 1722, 1639, 1601, 1493, 1462, 1383, 1340, 1246, 1180, 1124,
1099, 1080, 1049, 1028, 947, 906, 883, 752, 605, 532 cmꢀ1; HRMS(EI): m/
z: calcd for C23H32O3: 356.2351; found: 356.2356 [M]+.
Experimental Section
General techniques: All reactions involving air- and moisture-sensitive
reagents were carried out using oven dried glassware and standard sy-
ringe-septum cap techniques. Routine monitoring of reaction were car-
ried out using glass-supported Merck silica gel 60 F254 TLC plates. Flash
column chromatography was performed on Kanto Chemical Silica Gel
60N (spherical, neutral 40–50 mm) with the solvents indicated.
(4aS,5S,8aS)-5-(2-Methoxybenzyl)-5,8a-dimethyl-6-(methylene)octahy-
dronaphthalen-1(2H)-one (14): 4.0m HCl (8.80 mL, 36 mmol) was added
to a stirred solution of 13 (133 mg, 0.38 mmol) in THF (7.0 mL) at room
temperature. After 3 h, the reaction was quenched with saturated aque-
ous NaHCO3 (4.0 mL) at 08C, and the resulting mixture was extracted
with EtOAc (3”30 mL). The combined extracts were washed with brine,
then dried over Na2SO4. Concentration of the solvent in vacuo afforded a
residue, which was purified by column chromatography (hexane/EtOAc
10:1) to give 14 (113 mg, 97%) as a white solid. Recrystallization from
hexane afforded colourless prisms. M.p. 94–958C; [a]2D5 =+175.3 (c=1.04,
All solvents and reagents were used as supplied with following excep-
tions. Tetrahydrofuran (THF) was freshly distilled from Na/benzophe-
none under argon. MeOH and EtOH were distilled from Na metal under
argon. Benzene, hexamethylphosphoramide (HMPA), N,N-dimethyl-
formamide (DMF), and CH2Cl2, were distilled from CaH2 under argon.
Measurements of optical rotations were performed with a JASCO P-1020
automatic digital polarimeter. Melting points were taken on a Yanaco
MP-3 micro melting point apparatus and are uncorrected. 1H and
13C NMR spectra were measured with a JEOL JNM-LA500 (500 MHz)
spectrometer. Chemical shifts were expressed in ppm using Me4Si (d=0)
as an internal standard. The following abbreviations are used: singlet (s),
doublet (d), triplet (t), multiplet (m), and broad (br). Infrared (IR) spec-
tral measurements were carried out with a JASCO FT/IR-5300 spectrom-
eter. Low-resolution mass (MS) spectra was measured on a Shimadzu
GCMS-QP2010. High-resolution mass (HRMS) spectra was measured on
a JEOL MStation JMS-700 mass spectrometer. Elemental analyses were
performed with a Perkin Elmer 2400II apparatus.
1
CHCl3); H NMR (500 MHz, CDCl3): d=1.07 (s, 3H), 1.13 (s, 3H), 1.31–
1.50 (m, 2H), 1.71–1.87 (m, 3H), 2.03–2.08 (m, 1H), 2.18–2.27 (m, 3H),
2.32–2.39 (m, 1H), 2.47–2.56 (m, 1H), 2.72 (s, 2H), 3.74 (s, 3H), 4.43 (s,
1H), 4.80 (s, 1H), 6.79–6.83 (m, 2H), 7.02–7.04 (m, 1H), 7.14–7.18 ppm
(m, 1H); 13C NMR (125 MHz, CDCl3): d=21.4, 22.6, 23.3, 25.5, 28.8,
31.5, 38.1, 40.3, 44.1, 49.0, 49.2, 54.9, 108.3, 109.9, 119.5, 126.7, 127.3,
132.4, 152.7, 158.2, 215.4 ppm; IR (KBr): n˜ = 2951, 2870, 1693, 1495,
1458, 1248, 1132, 1053, 1034, 885, 754 cmꢀ1; elemental analysis calcd (%)
for C21H28O2: C 80.73, H 9.03; found: C 80.74, H 9.15.
(4aR,5S,8aS)-5-(2-Methoxybenzyl)-5,8a-(dimethyl)hexahydronaphthalen-
1,6
ACHTREUNG
(4aS,5R,6S,8aS)-5-(2-Methoxybenzyl)-5,6,8a-(trimethyl)octahydronaph-
thalen-1(2H)-one (15) and its (4aS,5R,6R,8aS)-isomer (16): 10% Pd/C
(89.0 mg) was added to a solution of 14 (53.0 mg, 0.17 mmol) in Et3N
(1.5 mL) containing MeOH (0.03 mL), and the mixture was stirred for
17 h under H2 (1 atm) at room temperature. The reaction mixture was di-
luted with EtOAc (30 mL), and the catalyst was filtered off through a
small pad of Celite. Concentration of the filtrate in vacuo afforded a resi-
due, which was purified by column chromatography (Et2O/EtOAc 100:1)
to give 15 (42.6 mg, 80%) (more polar) and its C8 epimer 16 (6.9 mg,
13%) (less polar).
hydronaphthalen-1,6
ACHTREUNG
1.3 mmol) in dry THF (3.0 mL) was added dropwise to a stirred solution
of lithium (36 mg, 5.2 mmol) in liquid ammonia (35 mL) at ꢀ788C under
argon. The resulting solution was allowed to warm at reflux of liquid am-
monia for 1 h. A solution of 2-methoxybenzyl bromide (11) (1.30 g,
6.5 mmol) in dry THF (12 mL) was added slowly to the above mixture.
The reaction mixture was allowed to stand for 2 h at room temperature
in order to evaporate off ammonia. After addition of saturated aqueous
NH4Cl (5.0 mL), the resulting mixture was extracted with Et2O (3”
30 mL). The combined extracts were washed with brine, then dried over
Na2SO4. Concentration of the solvent in vacuo afforded a residue, which
was purified by column chromatography (hexane/EtOAc 20:1) to give 12
(337 mg, 74%) as a colourless viscous liquid. [a]2D5 =+47.9 (c=1.48,
Compound 15: Colourless needles (recrystallization from hexane); M.p.
127–1288C; [a]2D5 =ꢀ43.6 (c=0.97, CHCl3); 1H NMR (500 MHz, CDCl3):
d=0.92 (s, 3H), 1.01 (d, J=5.9 Hz, 3H), 1.11 (dd, J=12.0, 2.0 Hz, 1H),
1.15 (s, 3H), 1.19–1.43 (m, 4H), 1.43–1.47 (m, 1H), 1.50 (dt, J=4.7,
17.9 Hz, 1H), 1.75 (dq, J=3.4, 13.2 Hz, 1H), 2.07–2.08 (m, 1H), 2.13–
2.19 (m, 1H), 2.23–2.26 (m, 1H), 2.58 (td, J=7.3, 14.1 Hz, 1H), 2.72 (s,
2H), 3.75 (s, 3H), 6.806.85 (m, 2H), 7.00–7.03 (m, 1H), 7.15–7.19 ppm
(m, 1H); 13C NMR (125 MHz, CDCl3): d=17.4, 18.0, 18.9, 22.0, 25.6,
26.8, 32.3, 35.6, 37.0, 37.5, 42.3, 47.6, 49.3, 54.8, 110.3, 119.8, 126.7, 127.4,
1
CHCl3); H NMR (500 MHz, CDCl3): d=1.03 (s, 3H), 1.04 (s, 3H), 1.36–
1.53 (m, 3H), 1.57–1.61 (m, 3H), 1.66–1.68 (m, 1H), 1.90 (dt, J=8.3,
13.7 Hz, 1H), 2.26 (dd, J=3.2, 11.9 Hz, 1H), 2.27–2.33 (m, 1H), 2.51
(ddd, J=6.3, 8.7, 15.6 Hz, 1H), 2.82 (d, J=13.2 Hz, 1H), 2.92 (d, J=
13.2 Hz, 1H), 3.75 (s, 3H), 3.82–3.94 (m, 4H), 6.8–6.85 (m, 2H), 6.98–
7.01 (m, 1H), 7.16–7.20 ppm (m, 1H); 13C NMR (125 MHz, CDCl3): d=
834
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 829 – 837

Marine Natural Products
FULL PAPER
132.3, 158.2, 216.3 ppm; IR (KBr): n˜ = 2953, 2932, 2864, 1705, 1494,
1456, 1317, 1288, 1244, 1176, 1130, 1099, 1030, 954, 752, 709, 598,
538 cmꢀ1; elemental analysis calcd (%) for C21H30O2: C 80.21, H 9.62;
found: C 80.11, H 9.64.
under oxygen atmosphere (O2 balloon) for 24 h at room temperature.
The reaction mixture was concentrated in vacuo to afford a residue,
which was purified by column chromatography (hexane/EtOAc 30:1) to
give 3 (42.2 mg, 91%) as a yellow solid. Recrystallization from hexane/
Et2O afforded pale yellow prisms. M.p. 94–958C; [a]2D5 =ꢀ62.7 (c=1.02,
CHCl3); 1H NMR (500 MHz, CDCl3): d=0.76 (d, J=10.2 Hz, 1H), 0.86
(s, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.05 (s, 3H), 1.11–1.21 (m, 2H), 1.32–
1.38 (m, 1H), 1.42–1.57 (m, 4H), 1.86–1.89 (m, 2H), 2.08–2.11 (m, 1H),
2.28–2.34 (m, 1H), 2.40 (d, J=13.7 Hz, 1H), 2.57 (d, J=13.7 Hz, 1H),
4.45 (d, J=8.3 Hz, 1H), 6.46 (s, 1H), 6.68–6.76 ppm (m, 2H); 13C NMR
(125 MHz, CDCl3): d=16.8, 17.6, 20.6, 22.6, 27.4, 28.1, 32.8, 35.3, 36.7,
37.2, 40.3, 43.0, 49.3, 103.2, 135.9, 136.0, 137.1, 147.3, 159.6 187.3,
187.4 ppm; IR (KBr): n˜ = 3418, 3084, 2928, 2858, 1658, 1596, 1449, 1385,
Compound 16: Colourless prisms (recrystallization from hexane); M.p.
122–1248C; [a]2D5 =ꢀ25.5 (c=0.68, CHCl3); 1H NMR (500 MHz, CDCl3):
d=0.94 (s, 3H), 1.12 (d, J=7.0 Hz, 3H), 1.21 (s, 3H), 1.26 (dt, J=3.9,
14.0 Hz, 1H), 1.37 (dq, J=4.0, 13.8 Hz, 1H), 1.50–1.71 (m, 4H), 1.80–
1.87 (m, 2H), 1.99–2.05 (m, 2H), 2.20–2.24 (m, 1H), 2.29 (d, J=13.7 Hz,
1H), 2.58 (dt, J=7.1, 13.9 Hz, 1H), 3.06 (d, J=13.7 Hz, 1H), 3.79 (s,
3H), 6.83–6.88 (m, 2H), 7.17 (dt, J=1.7, 8.1 Hz, 1H), 7.24 ppm (dd, J=
1.7, 7.6 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=16.0, 20.5, 20.7, 21.1,
24.8, 26.0, 26.4, 35.2, 36.0, 37.4, 41.1, 46.7, 49.7, 55.2, 110.4, 120.0, 127.0,
128.4, 131.0, 158.3, 215.9 ppm; IR (KBr): n˜ = 2940, 2870, 1701, 1493,
1460, 1385, 1242, 1127, 1028, 756 cmꢀ1; elemental analysis calcd (%) for
C21H30O2: C 80.21, H 9.62; found: C 80.53, H 9.78.
1354, 1289, 1069, 891 cmꢀ1
312.2090; found: 312.2090 [M]+.
; HRMS(EI): m/z: calcd for C21H28O2:
2-[[(1R,2S,4aS,8aS)-1,2,4a-Trimethyl-5-(methylene)decahydronaphthalen-
1-yl]methyl]benzene-1,4-diol [(ꢀ)-neoavarol (4)]: NaBH4 (9.70 mg,
0.26 mmol) was added in small portion to a stirred solution of 3 (40.0 mg,
0.13 mmol) in THF/H2O 10:1 (4 mL) at 08C. After 3 min, the reaction
was quenched with saturated NH4Cl (1.0 mL) at 08C. The resulting mix-
ture was extracted with Et2O (3”20 mL). The combined extracts were
washed with brine, then dried over Na2SO4. Concentration of the solvent
in vacuo afforded a residue, which was purified by column chromatogra-
phy (hexane/EtOAc 10:1) to give 4 (34.6 mg, 86%) as a white solid. Re-
crystallization from Et2O afforded colorless needles. M.p. 175–1778C;
[a]2D5 =ꢀ41.6 (c=0.10, CHCl3); 1H NMR (500 MHz, CDCl3): d=0.86 (s,
3H), 0.93–0.98 (m, 1H), 1.00 (d, J=5.9 Hz, 3H), 0.98–1.02 (m, 1H), 1.06
(s, 3H), 1.21–1.33 (m, 2H), 1.41–1.47 (m, 3H), 1.46–1.61 (m, 2H), 1.87–
1.92 (m, 1H), 1.99–2.06 (m, 1H), 2.07–2.12 (m, 1H), 2.33–2.36 (m, 1H),
2.51 (d, J=14.1 Hz, 1H), 2.62 (d, J=14.1 Hz, 1H), 4.35 (s, 2H), 4.40 (s,
1H), 4.43 (s, 1H), 6.52–6.60 ppm (m, 3H); 13C NMR (125 MHz, CDCl3):
d=17.6, 17.6, 20.6, 23.2, 27.7, 28.3, 33.0, 36.3, 36.5, 37.5, 40.3, 42.1, 48.2,
102.9, 113.9, 116.2, 119.4, 126.5, 148.6, 148.7 160.0 ppm; IR (KBr): n˜ =
3381, 2971, 2917, 2857, 1634, 1501, 1453, 1397, 1186, 1154, 889, 808,
750 cmꢀ1; HRMS(EI): m/z: calcd for C21H30O2: 314.2246; found: 314.2254
[M]+.
(1R,2S,4aS,8aS)-1-(2-Methoxybenzyl)-1,2,4a-trimethyl-5-(methylene)de-
cahydronaphthalene (9):
A stirred suspension of tBuOK (106 mg,
0.92 mmol) and methyltriphenylphosphonium bromide (340 mg,
0.92 mmol) in dry benzene (7.0 mL) was heated at reflux for 3 h under
argon, and then the roughly half volume of the solvent was evaporated
off. A solution of 15 (44.0 mg, 0.14 mmol) in dry benzene (7.0 mL) was
added to the above mixture, and the resulting solution was then refluxed
for 12 h under argon. After the reaction was quenched with H2O
(4.0 mL) at 08C, and the mixture was extracted with Et2O (2”40 mL).
The combined extracts were washed with brine, then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue, which was puri-
fied by column chromatography (hexane/EtOAc 100:1) to give
9
(43.2 mg, 100%) as a colourless viscous liquid. [a]2D5 =ꢀ48.1 (c=1.05,
CHCl3); 1H NMR (500 MHz, CDCl3): d=0.85 (s, 3H), 0.93 (dd, J=12.0,
Hz, 1H), 1.00 (d, J=5.9 Hz, 3H), 1.05 (s, 3H), 1.17–1.41 (m, 5H), 1.41–
1.47 (m, 1H), 1.47–1.54 (m, 1H), 1.86–1.93 (m, 1H), 2.04–2.14 (m, 2H),
2.29–2.38 (m, 1H), 2.60 (d, J=13.7 Hz, 1H), 2.69 (d, J=13.7 Hz, 1H),
3.74 (s, 3H), 4.34–4.36 (m, 1H), 4.39–4.40 (m, 1H), 6.79–6.86 (m, 2H),
7.02–7.05 (m, 1H), 7.13–7.17 ppm (m, 1H); 13C NMR (125 MHz, CDCl3):
d=17.6, 17.7, 20.6, 23.1, 27.8, 28.3, 33.1, 36.2, 36.6, 36.9, 40.2, 42.0, 48.0,
54.8, 102.5, 110.1, 119.6, 127.0, 127.5, 132.5, 158.4, 160.3 ppm; IR (neat):
n˜ = 3078, 3030, 2916, 2856, 1633, 1599, 1583, 1494, 1454, 1381, 1323,
(1R,2S,4aS,8aS)-1-(2-Methoxybenzyl)-1,2,4a,5-tetramethyl-1,2,3,4,4a,7,8,8a-
octahydronaphthalene (7): A mixture of 9 (34.0 mg, 0.11 mmol) and
RhCl3·3H2O (4.80 mg, 20 mmol) in EtOH (5 mL) was heated at reflux
for 24 h. After cooling, the reaction mixture was concentrated in vacuo.
The resulting residue was purified by column chromatography (hexane/
EtOAc 10:1) to give 7 (33.9 mg, 100%) as a colorless viscous liquid.
[a]2D5 =+1.1 (c=1.00, CHCl3); 1H NMR (500 MHz, CDCl3): d=0.85 (s,
3H), 0.87–0.95 (m, 1H), 1.00 (d, J=5.8 Hz, 3H), 1.01 (s, 3H), 1.15–1.17
(m, 1H), 1.32–1.40 (m, 3H),1.49 (d, J=1.5 Hz, 3H), 1.50–1.58 (m, 2H),
2.00–2.08 (m, 3H), 2.70 (s, 2H), 3.76 (s, 3H), 5.10–5.14 (s, 1H), 6.80–6.86
(m, 2H), 7.08–7.11 (m, 1H), 7.13–7.18 ppm (m, 1H); 13C NMR
(125 MHz, CDCl3): d=17.4, 17.8, 18.1, 19.7, 20.1, 26.5, 27.8, 35.8, 36.0,
37.0, 38.3, 41.7, 45.7,54.8, 110.2, 119.7, 120.4, 127.0, 127.6, 132.7, 144.4,
158.4 ppm; IR (neat): n˜ = 2928, 2833, 1599,1493, 1460, 1437, 1381, 1290,
1290, 1244, 1178, 1136, 1095, 1030, 991, 962, 927, 893, 752, 706, 540 cmꢀ1
;
HRMS (EI): m/z: calcd for C22H32O: 312.2453; found: 312.2443 [M]+.
2-[[(1R,2S,4aS,8aS)-1,2,4a-Trimethyl-5-(methylene)decahydronaphthalen-
1-yl]methyl]phenol (8): nBuSLi in HMPA (1.68m solution, 5.0 mL,
8.4 mmol) was added to a stirred solution of 9 (86.0 mg, 0.28 mmol) in
HMPA (6.0 mL) at room temperature, and the mixture was heated at
1108C for 3 h. After cooling, the reaction was quenched with saturated
aqueous NH4Cl (1.0 mL) at 08C, and the resulting mixture was extracted
with EtOAc (3”30 mL). The combined extracts were washed with brine,
then dried over Na2SO4. Concentration of the solvent in vacuo afforded a
residue, which was purified by column chromatography (hexane/EtOAc
100:1) to give 8 (75.5 mg, 92%) as a white solid. Recrystallization from
hexane/Et2O afforded colorless needles. M.p. 106–1088C; [a]2D5 =ꢀ5.8
(c=1.09, CHCl3); 1H NMR (500 MHz, CDCl3): d=0.87 (s, 3H), 0.98–
1.03 (m, 1H), 1.02 (d, J=5.8 Hz, 3H), 1.06 (s, 3H), 1.18–1.44 (m, 5H),
1.45–1.49 (m, 1H), 1.50–1.62 (m, 1H), 1.87–1.95 (m, 1H), 2.05–2.11 (m,
2H), 2.03–2.39 (m, 1H), 2.56 (d, J=14.6 Hz, 1H), 2.68 (d, J=14.6 Hz,
1H), 4.35–4.38 (s, 1H), 4.41–4.45 (m, 1H), 4.61–4.66 (br s, 1H), 6.69–6.71
(m, 1H), 6.80–6.86 (m, 1H), 6.99–7.06 ppm (m, 2H); 13C NMR
(125 MHz, CDCl3): d=17.6, 17.7, 20.6, 23.2, 27.7, 28.2, 33.0, 36.2, 36.5,
37.4, 40.2, 42.0, 48.0, 102.7, 115.5, 120.2, 125.1, 127.2, 133.0, 154.5,
160.1 ppm; IR (KBr): n˜ = 3547, 3439, 2957, 2858, 1720, 1631, 1587, 1452,
1383, 1332, 1255, 1170, 1122, 1086, 1049, 1022, 991, 927, 891, 864,
754 cmꢀ1; HRMS(EI):m/z: calcd for C21H30O: 298.2297; found: 298.2294
[M]+.
1244, 1176, 1134, 1099, 1032, 929, 896, 796, 750, 638, 528 cmꢀ1
;
HRMS(EI): m/z: calcd for C22H32O: 312.2453; found: 312.2432 [M]+.
2-[[(1R,2S,4aS,8aS)-1,2,4a,5-Tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaph-
thalen-1-yl]methyl]phenol (6): nBuSLi in HMPA (2.0m solution, 6.3 mL,
12.4 mmol) was added to a stirred solution of 7 (77.3 mg, 0.25 mmol) in
HMPA (6.0 mL) at room temperature, and the mixture was heated at
1108C for 2 h. After cooling, the reaction was quenched with saturated
aqueous NH4Cl (1.0 mL) at 08C, and the resulting mixture was extracted
with EtOAc (3”30 mL). The combined extracts were washed with brine,
then dried over Na2SO4. Concentration of the solvent in vacuo afforded a
residue, which was purified by column chromatography (hexane/EtOAc
100:1) to give 6 (66.4 mg, 90%) as a colorless viscous liquid. [a]2D5 =+4.6
(c=1.07, CHCl3); 1H NMR (500 MHz, CDCl3): d=0.87 (s, 3H), 0.91–
0.97 (m, 1H), 1.02 (d, J=4.9 Hz, 3H), 1.02 (s, 3H), 1.20–1.23 (m, 1H),
1.33–1.39 (m, 2H), 1.40–1.48 (m, 1H), 1.48–1.53 (m, 3H), 1.55–1.64 (m,
2H), 1.99–2.09 (m, 3H), 2.62 (d, J=14.1 Hz, 1H), 2.73 (d, J=14.1 Hz,
1H), 4.79 (s, 1H), 5.13 (s, 1H), 6.71 (d, J=8.3 Hz, 1H), 6.81–6.84 (m,
1H), 7.04–7.09 ppm (m, 2H); 13C NMR (125 MHz, CDCl3): d=17.5, 17.7,
2-[[(1R,2S,4aS,8aS)-1,2,4a-Trimethyl-5-(methylene)decahydronaphthalen-
1-yl]methyl]cyclohexa-2,5-diene-1,4-dione [(ꢀ)-neoavarone (3)]: Salco-
mine
[N,N’-bis(salicylidene)ethylenediaminocobalt(II)]
(96.4 mg,
0.30 mmol) was added to a stirred solution of 8 (44.4 mg, 0.15 mmol) in
dry DMF (6.0 mL) at room temperature. The suspension was stirred
Chem. Eur. J. 2008, 14, 829 – 837
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
835

T. Katoh et al.
18.1, 19.8, 20.1, 26.6, 27.7, 35.8, 36.0, 37.4, 38.3, 41.7, 45.7, 115.5, 120.1,
120.4, 125.1, 127.2, 133.1, 144.3, 154.6 ppm; IR (neat): n˜ = 3398, 2932,
1705, 1589, 1452, 1381, 1327, 1261, 1236, 1170, 1126, 1086, 1046, 854, 798,
754 cmꢀ1; HRMS(EI): m/z: calcd for C21H30O: 298.2297, found: 298.2299
[M]+.
143–1448C; [a]2D5 =+64.9 (c=1.08, CCl4). The 500 MHz 1H NMR spec-
trum of this sample was identical with that recorded in a).
Cell-growth inhibition assay:[26] Human histiocytic lymphoma cell line
U937 (obtained from the Cell Resource Center for Biomedical Research,
Tohoku University, Sendai) was maintained in suspension in RPMI cul-
ture medium (RPMI-1640 medium supplemented with 10% FCS, 2 mm
l-glutamine and penicillin/streptomycin solution, all from Sigma, St.
Louis, MO) at 378C, 5% in humidified air. Test compounds were dis-
solved in DMSO. The in vitro cytotoxicity was assessed by triplicate
assays for the reduction of [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tet-
razolium bromide] (MTT) following 24, 48 and 72 h incubation of cells
with compounds. The IC50 (concentration of the test compounds showing
50% cell growth inhibition) value was determined by using PRISM soft-
ware (GrapPad Software, Inc., CA, USA).
2-[[(1R,2S,4aS,8aS)-1,2,4a,5-Tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaph-
thalen-1-yl]methyl]cyclohexa-2,5-diene-1,4-dione [(+)-avarone (1)]: Sal-
comine (38.5 mg, 0.14 mmol) was added to
a stirred solution of 6
(42.0 mg, 0.14 mmol) in dry DMF (4.0 mL) at room temperature. The
suspension was stirred under oxygen atmosphere (O2 balloon) for 24 h at
room temperature. The reaction mixture was concentrated in vacuo to
afford a residue, which was purified by column chromatography (hexane/
EtOAc 30:1) to give 1 (39.1 mg, 89%) as a yellow solid. Recrystallization
from hexane/Et2O afforded pale yellow prisms. M.p. 61–638C; [a]D25
=
+12.5 (c=0.94, CH2Cl2); 1H NMR (500 MHz, CDCl3): d=0.86 (s, 3H),
0.94 (d, J=6.6 Hz, 3H), 1.00 (s, 3H), 1.01–1.08 (m, 2H), 1.15–1.26 (m,
1H), 1.34-.43 (m, 2H), 1.49–1.58 (m, 4H), 1.65 (td, J=3.3, 12.8 Hz, 1H),
1.80–1.90 (m, 2H), 2.00–2.07 (m, 1H), 2.44 (d, J=13.4 Hz, 1H), 2.65 (d,
J=13.4 Hz, 1H), 5.12–5.17 (m, 1H), 6.50–6.52 (m, 1H), 6.71 (dd, J=2.3,
10.1 Hz, 1H), 6.76 ppm (d, J=10.1 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d=16.7, 17.7, 18.0, 19.3, 20.0, 26.4, 27.4 35.4, 36.1 36.9, 38.5, 42.7,
47.0, 120.6, 136.0, 136.1, 137.1, 144.0, 147.4, 187.3, 187.4; IR (KBr): n˜ =
3449, 2930, 1657, 1597, 1454, 1383, 1290, 1070, 912 cmꢀ1; HRMS(EI):
m/z: calcd for C21H28O2: 312.2090; found: 312.2072 [M]+.
Acknowledgement
This work was supported in part by a Grant-in-Aid for Scientific Re-
search on Priority Area “Creation of Biologically Functional Molecules”
(no. 17035073),
a Grant-in-Aid for Scientific Research (C) (no.
18590013), and a Grant-in-Aid for High Technology Research Program
from the Ministry of Education, Culture, Sports, Science and Technology
of Japan (MEXT).
2-[[(1R,2S,4aS,8aS)-1,2,4a,5-Tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaph-
thalen-1-yl]methyl]benzene-1,4-diol [(+)-avarol (2)]: NaBH4 (9.70 mg,
0.24 mmol) was added in small portion to a stirred solution of 1 (40.0 mg,
0.12 mmol) in THF/H2O 10:1 (4 mL) at 08C. After 5 min, the reaction
was quenched with saturated NH4Cl (2.0 mL) at 08C. The resulting mix-
ture was extracted with Et2O (3”20 mL). The combined extracts were
washed with brine, then dried over Na2SO4. Concentration of the solvent
in vacuo afforded a residue, which was purified by column chromatogra-
phy (hexane/EtOAc 10:1) to give 2 (34.2 mg, 85%) as a white solid. Re-
crystallization from Et2O afforded colorless needles. M.p. 147–1498C;
[a]2D5 =+10.8 (c=0.74, CH2Cl2); 1H NMR (500 MHz, CDCl3): d=0.86 (s,
3H), 0.93–0.98 (m, 1H), 1.00 (d, J=6.3 Hz, 3H), 1.02 (s, 3H), 1.23 (dd,
J=1.4, 12.1 Hz, 1H), 1.34–1.39 (m, 2H), 1.41–1.49 (m, 1H), 1.51–1.53 (m,
3H), 1.55–1.61 (m, 2H), 1.96–2.01 (m, 1H), 2.04–2.06 (m, 2H), 2.57 (d,
J=14.1 Hz, 1H), 2.68 (d, J=14.1 Hz, 1H), 4.41 (brs, 1H), 5.14 (s, 1H),
6.52–6.61 ppm (m, 3H); 13C NMR (125 MHz, CDCl3): d=17.5, 17.7, 18.1,
19.8, 20.1, 26.6, 27.7 35.8, 36.0 37.6, 38.3, 41.8, 45.8, 113.8, 116.2, 119.6,
120.4, 126.5, 144.3, 148.6, 148.7 ppm; IR (KBr): n˜ = 3371, 2926, 2859,
[1] For recent excellent reviews on the clerodane diterpenoids and re-
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1 1976, 1408–1414; c) R. Puliti, S.
De Rosa, C. A. Mattia, Acta Crystallogr. Sect. C 1994, 50, 830–833.
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1705, 1651, 1601, 1502, 1450, 1381, 1309, 1195, 1124, 877, 806, 754 cmꢀ1
;
HRMS(EI): m/z: calcd for C21H30O2: 314.2246; found: 314.2252 [M]+.
(4aS,7S,7aR,13aS)-4,4,7,7a-Tetramethyl-1,2,3,4,4a,5,6,7,7a,8-decahydro-
benzo[d]xanthen-10-ol [(+)-aureol (5)]
a) (ꢀ)-Neoavarol (4): BF3·Et2O (0.1 mL, 0.75 mmol) was added to a
stirred solution of 4 (47.0 mg, 0.15 mmol) in CH2Cl2 (15 mL) at ꢀ508C,
and the resulting mixture was gradually warmed to ꢀ58C over 5 h. The
reaction was quenched with saturated aqueous NH4Cl (1.0 mL) at ꢀ58C,
and the mixture was extracted with dichloromethane (3”10 mL). The
combined extracts were washed with brine, then dried over Na2SO4. Con-
centration of the solvent in vacuo afforded a residue, which was purified
by column chromatography (hexane/EtOAc 10:1) to give 5 (43.7 mg,
93%) as a white solid. Recrystallization from Et2O afforded colorless
needles. M.p. 143–1448C; [a]2D5 =+64.5 (c=1.04, CCl4); 1H NMR
(500 MHz, CDCl3): d=0.78 (s, 3H), 0.92 (s, 3H), 1.07 (s, 3H), 1.10 (d,
J=7.8 Hz, 3H), 1.18–1.20 (m, 1H), 1.33–1.39 (m, 1H), 1.41–1.47 (m,
3H), 1.52–1.61 (m, 1H), 1.64–1.71 (m, 2H), 1.78–1.85 (m, 2H), 1.97 (d,
J=17.1 Hz, 1H), 2.01–2.08 (m, 2H), 3.37 (d, J=17.1 Hz, 1H), 4.27 (br s,
1H), 6.49 (d, J=2.4 Hz, 1H), 6.54–6.62 ppm (m, 3H); 13C NMR
(125 MHz, CDCl3): d=17.3, 18.3, 20.2, 22.2, 27.9, 29.3, 29.8, 31.9, 33.8,
33.9, 37.4, 38.1, 39.3, 44.0, 82.4, 114.0, 115.0, 117.2, 122.2, 145.8,
148.3 ppm; IR (KBr): n˜ = 3394, 2924, 2853, 1717, 1625, 1496, 1458, 1384,
1261, 1231, 1186, 1106, 955, 899, 862, 805, 754 cmꢀ1; HRMS(EI): m/z:
calcd for C21H31O2: 314.2246; found: 314.2234 [M]+.
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836
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Chem. Eur. J. 2008, 14, 829 – 837

Marine Natural Products
FULL PAPER
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Received: September 4, 2007
Published online: November 8, 2007
Chem. Eur. J. 2008, 14, 829 – 837
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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