Synthetic studies of kampanols, novel p21ras farnesyltransferase inhibitors: An efficient synthesis of the tetracyclic ABCD ring system of kampanols

Article abstract of DOI:10.1016/j.tet.2003.09.037

An enantioselective synthesis of the tetracyclic ABCD ring system (4) of kampanols, novel Ras farnesyltransferase inhibitors from a microorganism, was efficiently achieved for the first time starting from the known trans-decalone derivative 9. The synthetic method involves the following two key steps: (i) a conjugate addition reaction between the α-methylene ketone 6 and the Grignard reagent (7) of the ortho-disubstituted bromobenzene derivative 8 to deliver the coupling product 21 with stereoselectivity at the C9 position and (ii) a phenylselenium-mediated cyclization reaction of the phenol derivative 5 to stereoselectively construct the requisite tetracyclic intermediate 25 possessing the cis-fused connectivity of the B/C rings.

Full text of DOI:10.1016/j.tet.2003.09.037

Tetrahedron 59 (2003) 8763–8773
Synthetic studies of kampanols, novel p21ras farnesyltransferase
inhibitors: an efficient synthesis of the tetracyclic ABCD ring
system of kampanols
Katsuhiko Iwasaki,a Mari Nakatani,b Munenori Inoueb and Tadashi Katoha,b
,
*
aDepartment of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Yokohama 226-8502, Japan
bSagami Chemical Research Center, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
Received 19 August 2003; accepted 10 September 2003
Abstract—An enantioselective synthesis of the tetracyclic ABCD ring system (4) of kampanols, novel Ras farnesyltransferase inhibitors
from a microorganism, was efficiently achieved for the first time starting from the known trans-decalone derivative 9. The synthetic
method involves the following two key steps: (i) a conjugate addition reaction between the a-methylene ketone 6 and the Grignard
reagent (7) of the ortho-disubstituted bromobenzene derivative 8 to deliver the coupling product 21 with stereoselectivity at the C9 position
and (ii) a phenylselenium-mediated cyclization reaction of the phenol derivative 5 to stereoselectively construct the requisite tetracyclic
intermediate 25 possessing the cis-fused connectivity of the B/C rings.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
cerning an efficient construction of the tetracyclic model
compound 4 (ABCD ring system) possessing the requisite
substituents and asymmetric carbons,6 which, to our best
knowledge, represents the first and only synthetic studies
of these fascinating natural products.7 In this paper, we
wish to disclose the full details of our enantioselective
synthesis of 4.
In 1998, the Merck research group reported the isolation
and structure elucidation of three novel natural products,
kampanols A (1), B (2), C (3) (Fig. 1), from the fungal
culture broth of Stachybotrys kampalensis.1 Kampanols A
and B have been shown to be specific inhibitors of Ras
protein farnesyltransferase (PFTase), while kampanol C is
inactive against the enzyme.1,2 PFTase catalyzes the
S-farnesylation of a cystein residue in a conserved CAAX
sequence (C: cystein, A: aliphatic amino acid, X: serine or
methionine) located at the carboxy terminus of Ras p21
protein. This post-translational modification is an essential
first step for plasma membrane association that is critical for
triggering ras oncogene toward tumor formation.3 Conse-
quently, kampanols A and B are anticipated to be promising
new leads for novel anticancer agents. The gross structure
of kampanols including the relative stereochemistry was
determined by extensive and incisive spectroscopic studies
to have a novel pentacyclic (or tetracyclic) [ABCD(E)] ring
system with five asymmetric carbons.1,4,5 The attractive
biological properties and unique structural features
prompted us to undertake a project directed toward the
total synthesis of kampanols in enantiomerically pure forms.
Recently, we communicated our preliminary results con-
Keywords: kampanols; ras farnesyltransferase inhibitors; conjugate
addition; phenylselenium-mediated cyclization.
*
Corresponding author. Address: Sagami Chemical Research Center,
2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan. Tel.: þ81-427-
66-4298; fax: þ81-427-49-7631; e-mail: takatoh@alles.or.jp;
Figure 1. Structures of kampanols A (1), B (2), C (3) and the tetracyclic
model compound 4.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.037

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K. Iwasaki et al. / Tetrahedron 59 (2003) 8763–8773
Scheme 1. Synthetic plan for the model compound 4.
2. Results and discussion
2.1. Synthetic strategy
Scheme 2. Synthesis of the decalin segment 6. (a) TBSOTf, 2,6-lutidine,
CH2Cl2, rt, 99%; (b) NaN(TMS)2, THF, 2788C; 2-phenylsolfonyl-3-
phenyloxazindine, 2788C, 74%; (c) BOMCl, i-Pr2NEt, CH2Cl2, rt, 98%;
(d) Ph3PþCH3Br2, t-BuOK, benzene, reflux, 85% for 16, 91% for 17; (e) Li,
liq. NH3–THF, 80%; (f) Dess-Martin periodinane, CH2Cl2, rt, 98%.
Our synthetic plan for the target molecule 4 is outlined in
Scheme 1. The most crucial step in this scheme is
envisioned to be the stereocontrolled cyclization reaction
of the phenol derivative 5 to construct the dihydropyran C
ring with the requisite cis-fused B/C ring juncture (5!4).
This cyclization may involve an interesting possibility
for controlling the stereochemistry at the C8 position
(kampanols numbering) in 4 because the cyclization
precursor 5 possesses an unusual exo-olefinic substituted
pattern.7a–g The cyclization precursor 5 would be elabo-
rated through the conjugate addition reaction8 of the
Grignard reagent 7, derived from the ortho-disubstituted
bromobenzene derivative 8, with the a-methylene ketone 6
(6þ7!5). Since the C9 substituent in the coupling product
5 is placed in an equatorial orientation, we expected that
the requisite C9 stereocenter should be established under
thermodynamically and/or kinetically controlled reaction
conditions.9 The decalin segment 6 and the aromatic
segment 8, in turn, would be prepared from the
known trans-decalone 910 and the commercially available
resorcinol (10), respectively.
prepared from (þ)-11 (.99% ee) in four steps [(1) ethylene
glycol/p-TsOH/benzene, reflux, 95%; (2) Li/liquid NH3/
MeI/THF, reflux, 92%; (3) NaBH4/EtOH, 240!2108C,
99%; (4) 5% aqueous HCl/THF, rt, 99%] according to the
Hagiwara protocol.10 After protection of the hydroxy group
in 9 as its t-butyldimethylsilyl (TBS) ether, the resulting
ketone 12 was subjected to a-hydroxylation reaction by the
use of NaN(SiMe3)2 and Davis reagent (2-phenylsulfonyl-3-
phenyloxaziridine),11 which led to the formation of the
a-hydroxy ketone 13 as a single stereoisomer in 74% yield.
The C8 stereochemistry of 13 was assigned based on the
NOESY experiments, which show the interactions between
C8-H and the angular methyl group (C10-Me). The
stereoselectivity can be explained by the consideration
that the oxidizing reagent (Davis reagent) accesses exclu-
sively from the less hindered a-face of the enolate generated
in situ from 12 under the influence of the axial-oriented
methyl group at the ring juncture. To obtain the requisite
exo-olefin 15 in a straightforward manner from the
a-hydroxy ketone 13, we initially attempted Wittig
methylenation of 13 under standard reaction conditions.
However, the expected compound 15 could not be detected:
instead, the undesired methylenation product 16 was formed
in 85% yield, whose structure and stereochemistry at the C9
position was assigned based on the NMR spectral analyses
including NOESY experiments. The plausible mechanistic
pathways for the formation of 16 from 13 may involve the
intermediate 13A generated in situ from 13 via a carbonyl
transposition under the basic conditions. Therefore, we
decided to prepare 15 in a stepwise manner. Thus,
2.2. Synthesis of the decalin segment 6
At first, we investigated the synthesis of the decalin segment
6 as shown in Scheme 2. Compound 6 has been previously
synthesized by Seifert et al.9a starting from the
(þ)-Wieland-Miescher ketone in 21% overall yield in nine
steps; nevertheless, we sought an alternative, more efficient
and reliable method for the synthesis of 6. We have now
found that 6 can be synthesized starting from (þ)-Wieland-
Miescher ketone analogue 11 in 44% overall yield in a
10-step sequence. The improved synthesis commenced with
the known trans-decalone 9,10 readily and sufficiently

K. Iwasaki et al. / Tetrahedron 59 (2003) 8763–8773
8765
2.4. Synthesis of the key cyclization precursor 5 via the
conjugate addition reaction between 6 and 8
Having obtained both the decalin segment 6 and the
aromatic segment 8, our next efforts were directed toward
elaboration of the key cyclization precursor 5 through the
coupling reaction of these two segments. As shown in
Scheme 4, the critical conjugate addition of the Grignard
reagent 7, prepared from 8 and Mg powder in the presence
of 1,2-dibromoethane in Et2O, to the a-methylene ketone 6
proceeded smoothly and cleanly without the addition of any
copper salts,8,9 leading to the formation of the desired
coupling product 21 in excellent yield (95%) with complete
stereoselectivity at the C9 position. The C9 stereochemistry
1
was confirmed by NOESY experiments in the H NMR
Scheme 3. Synthesis of the aromatic segment 8. (a) MOMCl, i-Pr2NEt,
CH2Cl2, rt, 44% for 19, 29% for 20; (b) BOMCl, i-Pr2NEt, CH2Cl2, rt, 96%.
spectrum, in which a clear NOE interaction between C9-H
and C7-Ha was observed. In general, the conjugate addition
reaction of Grignard reagents to a,b-unsaturated ketones is
carried out in the presence of copper salts in order to prevent
the formation of 1,2-addition products.8 However, in this
case the 1,4-addition product 21 was exclusively formed:
this must be attributed to the structure nature of the substrate
6, which involves the highly reactive exo-olefin moiety
toward conjugate addition of carbon nucleophiles. Related
conjugate addition reactions without copper salts have been
previously described in the literature;9 however, to our
knowledge, the conjugate addition reaction between 6 and
the Grignard reagent prepared from sterically hindered
ortho-disubstituted bromobenzene derivative such as 8 is
unprecedented. To forward the synthesis, the conjugate
addition product 21 was further converted to the phenol
derivative 5, the key cyclization precursor, in excellent
overall yield via a two-step sequence involving Wittig
methylenation of the carbonyl function in 21 (97%) followed
by reductive removal of the BOM protecting group in the
resulting exo-olefin 22 under the Birch conditions (95%).
protection of the hydroxy group in 13 as its benzyloxy-
methyl (BOM) ether followed by Wittig methylenation of
the resulting BOM ether 14, provided the exo-olefin 17,
whose BOM protecting group was subsequently removed
under Birch conditions to give the desired 15 in 71% yield
for the three steps. Finally, Dess-Martin oxidation12 of 15
afforded the requisite decalin segment 6 in 98% yield.
2.3. Synthesis of the aromatic segment 8
The synthesis of the aromatic segment 8 was next pursued as
shown in Scheme 3. The starting material, 2-bromoresorci-
nol (18), was prepared from the commercially available
resorcinol (10) in two steps [(1) Br2/CHCl3, 08C!rt, 99%;
(2) Na2SO3/NaOH/MeOH–H2O, rt, 99%] according to the
literature.13 Since it was necessary to discriminate between
the two hydroxy groups of the aromatic moiety in the later
stage of the synthesis,14 the two hydroxy groups in 18 were
separately protected at this stage. Thus, reaction of 18 with
1.0 equiv. of chloromethyl methyl ether (MOMCl) in the
presence of 1.0 equiv. of i-Pr2NEt furnished the mono-
MOM ether 19 in 44% yield along with the bis-MOM ether
20 (29%) and the recovery of the starting material 18 (15%).
Further protection of 19 as its BOM ether provided the
requisite aromatic segment 8 in 96% yield.
2.5. The key cyclization reaction of 5 and the synthesis of
the requisite tetracyclic intermediate 26
With the key cyclization precursor 5 in hand, we focused
our attention on the crucial stereocontrolled cyclization
reaction of 5 to construct the requisite tetracyclic ABCD
ring system 26 as depicted in Scheme 5. We initially
examined the acid-mediated cyclization of 5 by treat-
ment with BF3·Et2O (10 equiv.) in dichloromethane at
260!2108C for 5 h, which led to the formation of the
undesired trans-cyclization product 23 as a single stereo-
isomer in 75% yield. Since the TBS protecting group was
cleaved concomitantly in this acid-mediated cyclization
reaction, the liberated hydroxy group in 23 was reprotected
under standard conditions to afford the corresponding TBS
ether 24 (85%). The b-disposition of the C8 methyl group
in 24 was established by NOESY experiments as illustrated
in the formula 24A. The stereochemical outcome observed
for this acid-mediated cyclization reaction can be rational-
ized by considering that the phenolic hydroxy group, as
depicted in the formula 5A, attacks the C8 tertiary
carbocation, generated in situ by acid treatment, from the
less hindered a-face of the molecule under the influence of
the b-oriented axial methyl group at the decalin junction,
leading to 23. Eventually, to our delight, the desired cis-
cyclization of 5 was successfully achieved by the use of an
Scheme 4. Synthesis of the key cyclization precursor 5. (a) 8, Mg,
1,2-dibromoethane, Et2O, reflux; add. 6, 08C!rt, 95%; (b) Ph3PþCH3Br2,
t-BuOK, benzene, reflux, 97%; (c) Li, liq. NH3–THF, 95%.

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K. Iwasaki et al. / Tetrahedron 59 (2003) 8763–8773
Scheme 6. Synthesis of the tetracyclic model compound 4. (a) 6 M HCl,
MeOH, 508C, 96%; (b) Ac2O, DMAP, pyridine, rt, 85%; (c) t-BuOK,
THF–t-BuOH (5:1), rt, 96%.
tetracyclic key intermediate 26 possessing the whole carbon
framework with the requisite functionalities and asymmetric
carbons, we next investigated the final transformation of 26
into the target molecule 4 to complete the project synthesis.
As shown in Scheme 6, the route required only manipulation
of the two hydroxy protecting groups in 26. To this end,
deprotection of both the TBS and MOM groups in 26 was
carried out by reaction with 6 M HCl in MeOH at 508C to
provide diol 27 in 96% yield. Initial attempts at direct
conversion of 27 to 4 by selective acetylation of the C3
hydroxy group were unfortunately fruitless. Therefore, we
decided to look at chemoselective removal of the phenolic
acetyl group in diacetate 28 prepared by complete
acetylation of 27 in 85% yield. After several experiments,
the requisite selective deacetylation of 28 was best achieved
by exposure to potassium t-butoxide (1.05 equiv.) in THF–
t-butyl alcohol (5:1) at room temperature, finally providing
4 in 96% yield. The stereostructure of the tetracyclic model
compound 4 was unambiguously confirmed by extensive
spectroscopic analysis including NOESY experiment in the
500 MHz 1H NMR spectrum. The selected NOESY
correlation of 4 is pictured in Figure 2, where key NOE
interactions between C11-Hb and C10-Me, C1-Hb, and
between C8-Me and C11-Ha, C7-Ha, C9-H are observed,
indicating that the dihydropyran C ring takes a half-chair
conformation in the cis-fused B/C rings.
Scheme 5. The key cyclization of 5 to deliver the requisite tetracyclic
intermediate 26. (a) BF3·Et2O, CH2Cl2, 260!2108C, 75%; (b) TBSOTf,
2,6-lutidine, CH2Cl2, 85%; (c) N-phenylselenophthalimide, SnCl4, CH2Cl2,
2788C, 98%; (d) n-Bu3SnH, AIBN, toluene, reflux, 78%.
organoselenenylating reagent.15 Thus, 5 was treated with
N-(phenylseleno)phthalimide (1.6 equiv.) in the presence of
tin(IV) chloride (1.4 equiv.) in dichloromethane at 2788C
for 2 h, resulting in the formation of the expected
cyclization product 25 as the single diastereomer in 98%
yield. The newly formed stereocenter at the C8 position in
1
25 was proven by NOESY experiments in the H NMR
spectrum of the deselenylated compound 26, prepared by
treating 25 with tri-n-butyltin hydride in the presence of
2,20-azobis(isobutyronitrile) (AIBN). As pictured in the
formula 26A, two key NOEs between C8-Me and C9-H,
C7-Ha were clearly observed, establishing the cis-fused
connectivity of the B/C rings. This phenylselenium-
mediated cyclization reaction would proceed through the
transition state such as selenonium ion intermediate 5B,
where the selenonium ion would be opened by the attack
of the inner phenolic hydroxy group from the b-face via a
6-exo cyclization mode, providing the desired product 25.
2.6. Completion of the synthesis of the target tetracyclic
model compound 4
Figure 2. Selected NOESY correlation of the tetracyclic model compound
4.
Having established the method for the construction of the

K. Iwasaki et al. / Tetrahedron 59 (2003) 8763–8773
8767
3. Conclusion
chromatography (hexane/ethyl acetate, 50:1) to give 12
(945 mg, 99%) as a white solid. Recrystallization from
hexane afforded an analytical sample of 12 as colorless
We have succeeded in developing a facile and efficient
method for the construction of the tetracyclic ABCD ring
system [(2)-4] of kampanols in an enantioselective manner
starting from the known trans-decalone derivative 9. The
method features a conjugate addition reaction of the
Grignard reagent (7) of the bromobenzene derivative 8
with the a-methylene ketone 6 to form the coupling product
21 as well as a phenylselenium-mediated cyclization
reaction of the phenol derivative 5 to stereoselectively
construct the tetracyclic key intermediate 25. Further
investigation toward the total synthesis of kampanols and
analogues is now in progress and will be reported in due
course.
1
plates, mp 93–948C; [a]2D0¼215.78 (c 0.90, CHCl3); H
NMR (500 MHz, CDCl3) d 0.03 (3H, s), 0.05 (3H, s), 0.86
(3H, s), 0.89 (9H, s), 0.93 (3H, s), 1.11 (1H, dd, J¼3.2,
12.0 Hz), 1.14 (3H, s), 1.46–1.53 (1H, m), 1.57–1.67 (4H,
m), 1.67–1.82 (2H, m), 2.03–2.11 (1H, m), 2.16–2.24 (1H,
m), 2.54 (1H, dt, J¼14.0, 7.0 Hz), 3.13–3.18 (1H, m); 13C
NMR (125 MHz, CDCl3) d 25.0, 23.8, 16.3, 18.1, 18.7,
21.0, 25.9 (three carbons), 26.4, 27.3, 28.4, 31.1, 37.5, 40.3,
48.6, 52.7, 78.7, 215.5; IR (KBr) 2949, 2857, 1703, 1472,
1391, 1366, 1318, 1250, 1204, 1100, 1076, 1007, 988, 943,
893, 835, 772, 671, 604, 475, 446 cm21; HRFABMS (m/z)
calcd for C19H37O2Si [(MþH)þ], 325.2563, found
325.2538.
4.1.2. (2R,4aS,6S,8aS)-6-tert-Butyldimethylsiloxy-2-
hydroxy-5,5,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydro-
naphthalen-1(2H)-one (13). A solution of 12 (357 mg,
1.1 mmol) in dry tetrahydrofuran (3.0 ml) was added
dropwise to a stirred solution of sodium bis(trimethylsilyl)-
amide in tetrahydrofuran (1.0 M solution, 1.76 ml,
1.8 mmol) at 2788C under argon. After 1.5 h, a solution
of 2-phenylsulfonyl-3-phenyloxaziridine11 (Davis reagent)
(517 mg, 2.0 mmol) in dry tetrahydrofuran (3.0 ml) was
added slowly to the above mixture at 2788C, and the
resulting mixture was further stirred for 2 h at the same
temperature. The reaction was quenched with saturated
aqueous ammonium chloride (10 ml), and the mixture was
extracted with diethyl ether (3£40 ml). The combined
extracts were washed with 3% aqueous hydrochloric acid,
saturated aqueous sodium hydrogencarbonate and brine,
then dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 50:1!20:1) to give
13 (275 mg, 74%) as a white solid. Recrystallization from
hexane afforded an analytical sample of 13 as colorless
plates, mp 82–848C; [a]2D0¼28.38 (c 1.14, CHCl3); 1H
NMR (500 MHz, CDCl3) d 0.03 (3H, s), 0.05 (3H, s), 0.87
(3H, s), 0.89 (9H, s), 0.94 (3H, s), 1.11 (1H, dd, J¼3.7,
11.6 Hz), 1.17 (3H, s), 1.24–1.36 (1H, m), 1.57–1.90 (6H,
m), 2.44–2.51 (1H, m), 3.14–3.20 (1H, m), 3.59 (1H, d,
J¼3.9 Hz), 4.40 (1H, ddd, J¼3.9, 7.4, 11.7 Hz); 13C NMR
(125 MHz, CDCl3) d 25.0, 23.9, 16.2, 18.0, 18.4, 19.5,
25.8 (three carbons), 26.7, 28.3, 30.8, 36.3, 40.4, 47.5, 53.4,
71.4, 78.4, 214.8; IR (KBr) 3883, 3823, 3746, 3491, 2951,
2857, 1703, 1472, 1391, 1364, 1250, 1142, 1103, 1076,
4. Experimental
4.1. General methods
All reactions involving air and moisture-sensitive reagents
were carried out using oven-dried glassware and standard
syringe-septum cap techniques. Routine monitoring of
reaction was carried 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.
All solvents and reagents were used as supplied with the
following exceptions. Tetrahydrofuran and diethyl ether
were freshly distilled from sodium/benzophenone 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
1
apparatus and are uncorrected. H and 13C NMR spectra
were measured with Brucker DRX-500 (500 MHz) spec-
trometers. Chemical shifts are expressed in ppm using
tetramethylsilane (d¼0) as an internal standard. The
following abbreviations are used: singlet (s), doublet (d),
triplet (t), multiplet (m), and broad (br). Infrared (IR)
spectral measurements were carried out with a JASCO
FT/IR-5300 spectrometer. Low-resolution mass (MS)
spectra and high-resolution mass (HRMS) spectra were
measured on a Hitachi M-80B spectrometer.
1055, 1009, 990, 949, 889, 837, 774, 673, 596, 511 cm21
;
4.1.1. (4aS,6S,8aS)-6-tert-Butyldimethylsiloxy-5,5,8a-tri-
methyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1(2H)-
one (12). tert-Butyldimethylsilyl trifluoromethanesulfonate
(1.02 ml, 4.4 mmol) was added dropwise to a stirred
solution of (4aS,6S,8aS)-6-hydroxy-5,5,8a-trimethyl-3,4,
4a,5,6,7,8,8a-octahydronaphthalen-1(2H)-one (9)10 (621 mg,
3.0 mmol) in dichloromethane (8.0 ml) containing 2,6-luti-
dine (0.55 ml, 4.7 mmol) at room temperature under argon.
After 30 min, the reaction was quenched with saturated
aqueous ammonium chloride (15 ml), and the mixture was
extracted with diethyl ether (3£40 ml). The combined
extracts were washed with 3% aqueous hydrochloric acid,
saturated aqueous sodium hydrogencarbonate and brine,
then dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column
HRFABMS (m/z) calcd for C19H37O3Si [(MþH)þ],
341.2512, found 341.2502.
4.1.3. (1S,4aS,6S,8aS)-6-tert-Butyldimethylsiloxy-2-
methylene-5,5,8a-(trimethyl)decahydronaphthalen-1-ol
(16). A suspension of potassium tert-butoxide (507 mg,
4.4 mmol) and methyltriphenylphosphonium bromide
(1.60 g, 4.4 mmol) in benzene (15 ml) was heated at reflux
for 3 h under argon, and then roughly half-volume of the
solvent was removed in vacuo. A solution of 13 (299 mg,
0.88 mmol) in benzene (15 ml) was added to the above
mixture, and the resulting mixture was then refluxed for
16 h under argon. After cooling, the reaction was quenched
with water (10 ml), and the mixture was extracted with

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K. Iwasaki et al. / Tetrahedron 59 (2003) 8763–8773
diethyl ether (3£50 ml). The combined extracts were
washed with water and brine, then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue,
which was purified by column chromatography (hexane/
ethyl acetate, 100:1) to give 16 (253 mg, 85%) as a colorless
extracts were washed with 3% aqueous hydrochloric acid,
saturated aqueous sodium hydrogencarbonate and brine,
then dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 100:1) to give 17
(365 mg, 91%) as a colorless oil. [a]2D0¼þ10.68 (c 1.03,
1
oil. [a]2D0¼þ15.48 (c 1.02, CHCl3); H NMR (500 MHz,
1
CDCl3) d 0.04 (3 H, s), 0.05 (3H, s), 0.75 (3H, s), 0.77 (3H,
s), 0.89 (9H, s), 0.93 (3H, s), 1.03 (1H, dd, J¼2.8, 12.5 Hz),
1.19–1.28 (1H, m), 1.31–1.42 (1H, m), 1.51 (1H, d, J¼
5.7 Hz), 1.57–1.63 (2H, m), 1.64–1.69 (1H, m), 1.84 (1H,
dt, J¼3.5, 13.3 Hz), 2.01 (1H, dt, J¼5.3, 13.4 Hz), 2.39–
2.45 (1H, m), 3.20–3.26 (1H, m), 3.59 (1H, d, J¼4.7 Hz),
4.81 (2H, dd, J¼1.8, 25.5 Hz); 13C NMR (125 MHz,
CDCl3) d 24.9, 23.8, 12.4, 16.1, 18.1, 22.8, 25.9 (three
carbons), 27.9, 28.6, 34.2, 35.9, 39.5, 40.6, 52.0, 79.4, 82.1,
104.9, 148.6; IR (neat) 3441, 2936, 2855, 1655, 1460, 1387,
CHCl3); H NMR (500 MHz, CDCl3) d 0.03 (3H, s), 0.06
(3H, s), 0.78 (3H, s), 0.89 (12H, s), 0.93 (1H, dd, J¼3.0,
12.6 Hz), 1.04 (3H, s), 1.20–1.32 (1H, m), 1.54–1.79 (6H,
m), 2.16–2.23 (1H, m), 3.20 (1H, dd, J¼4.4, 11.0 Hz), 4.30
(1H, dd, J¼5.3, 11.9 Hz), 4.60 (1H, d, J¼11.7 Hz), 4.68
(1H, s), 4.70 (1H, d, J¼11.7 Hz), 4.74 (1H, d, J¼6.9 Hz),
4.86 (1H, d, J¼6.9 Hz), 4.92 (1H, s), 7.26–7.38 (5H, m);
13C NMR (125 MHz, CDCl3) d 24.9, 23.8, 15.7, 18.1,
20.6, 20.8, 25.9 (three carbons), 27.9, 28.5, 35.2, 35.3, 39.8,
39.9, 52.8, 69.4, 74.5, 79.2, 93.2, 100.1, 127.7, 127.9 (two
carbons), 128.4 (two carbons), 138.0, 158.8; IR (neat) 2936,
2859, 1642, 1462, 1387, 1364, 1252, 1175, 1111, 1047, 995,
903, 889, 870, 837, 774, 735, 696, 673 cm21; HRFABMS
(m/z) calcd for C28H45O3Si [(M–H)þ], 457.3138, found
457.3121.
1252, 1101, 1007, 941, 885, 835, 774, 667 cm21
;
HRFABMS (m/z) calcd for C20H39O2Si [(MþH)þ],
339.2719, found 339.2722.
4.1.4. (2R,4aS,6S,8aS)-2-Benzyloxymethoxy-6-tert-butyl-
dimethylsiloxy-5,5,8a-trimethyl-3,4,4a,5,6,7,8,8a-octa-
hydronaphthalen-1(2H)-one (14). Benzyl chloromethyl
ether (0.90 ml, 5.9 mmol) was added dropwise to a stirred
solution of 13 (287 mg, 0.84 mmol) in dichloromethane
(5.0 ml) containing diisopropylethylamine (1.17 ml,
6.7 mmol) at room temperature under argon. After 15 h,
the reaction was quenched with saturated aqueous
ammonium chloride (5.0 ml), and the resulting mixture
was extracted with ethyl acetate (3£30 ml). The combined
extracts were washed with 3% aqueous hydrochloric acid,
saturated aqueous sodium hydrogencarbonate and brine,
then dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 20:1) to give 13
(379 mg, 98%) as a colorless oil. [a]2D0¼þ51.28 (c 1.20,
4.1.6. (2R,4aS,6S,8aS)-6-tert-Butyldimethylsiloxy-1-
methylene-5,5,8a-(trimethyl)decahydronaphthalen-2-ol
(15). A solution of 17 (618 mg, 1.3 mmol) in dry
tetrahydrofuran (20 ml) was added dropwise to a stirred
solution of lithium (281 mg, 41 mmol) in liquid ammonia
(ca. 80 ml) at 2788C under argon. The resulting solution
was allowed to warm at reflux of liquid ammonia for 1 h.
Furthermore, the mixture was allowed to stand at room
temperature for 5 h in order to remove ammonia. After
addition of saturated aqueous ammonium chloride (20 ml),
the resulting mixture was extracted with ethyl acetate
(3£30 ml). The combined extracts were washed with brine,
and dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 10:1) to give 15
(367 mg, 80%) as a white solid. Recrystallization from
hexane/diethyl ether (10:1) afforded an analytical sample of
15 as colorless needles, mp 114–1158C; [a]2D0¼234.08 (c
1
CHCl3); H NMR (500 MHz, CDCl3) d 0.03 (3H, s), 0.05
(3H, s), 0.85 (3H, s), 0.89 (9H, s), 0.93 (3H, s), 1.11 (1H, dd,
J¼3.1, 12.2 Hz), 1.13 (3H, s), 1.45–1.54 (2H, m), 1.58–
1.67 (2H, m), 1.67–1.89 (3H, m), 2.28–2.36 (1H, m), 3.16
(1H, dd, J¼5.0, 10.6 Hz), 4.54 (1H, dd, J¼7.1, 12.5 Hz),
4.61 (1H, d, J¼11.8 Hz), 4.67 (1H, d, J¼11.8 Hz), 4.77 (1H,
d, J¼7.1 Hz), 4.87 (1H, d, J¼7.1 Hz), 7.27–7.37 (5H, m);
13C NMR (125 MHz, CDCl3) d 25.0, 23.8, 16.2, 18.1,
18.4, 20.1, 25.9 (three carbons), 27.0, 28.3, 30.8, 33.7, 40.4,
48.5, 52.9, 69.9, 75.8, 78.5, 93.7, 127.7, 127.8, 127.9, 128.0,
128.5, 137.8, 211.5; IR (neat) 2951, 2857, 2363, 1723, 1460,
1385, 1364, 1254, 1182, 1107, 1057, 1022, 986, 970, 949,
887, 837, 775, 737, 698, 671 cm21; HREIMS (m/z) calcd for
C27H44O4Si (Mþ), 460.3009, found 460.3016.
1
1.06, CHCl3); H NMR (500 MHz, CDCl3) d 0.04 (3H, s),
0.06 (3H, s), 0.79 (3H, s), 0.85–0.95 (1H, m), 0.90 (12H, s),
1.05 (3H, s), 1.11–1.22 (1H, m), 1.40 (1H, d, J¼6.3 Hz),
1.55–1.82 (6H, m), 2.19–2.26 (1H, m), 3.19 (1H, dd, J¼
4.3, 11.0 Hz), 4.27–4.34 (1H, m), 4.70 (1H, s), 4.90 (1H, s);
13C NMR (125 MHz, CDCl3) d 24.9, 23.8, 15.8, 18.1,
20.7, 20.8, 25.9 (three carbons), 26.0, 27.8, 28.5, 35.4,
37.7, 39.9, 52.8, 69.7, 79.3, 99.3, 161.9; IR (KBr) 3304,
2934, 2857, 1642, 1460, 1387, 1364, 1252, 1105, 1061,
1007, 968, 953, 889, 870, 837, 772, 673 cm21; HRFABMS
(m/z) calcd for C20H39O2Si [(MþH)þ], 339.2719, found
339.2722.
4.1.5. (2R,4aS,6S,8aS)-2-Benzyloxymethoxy-6-tert-butyl-
dimethylsiloxy-1-methylene-5,5,8a-(trimethyl)decahy-
dronaphthalene (17). A suspension of potassium tert-
butoxide (507 mg, 4.4 mmol) and methyltriphenylphospho-
nium bromide (1.60 g, 4.4 mmol) in dry benzene (15 ml)
was heated at reflux for 3 h under argon, and then roughly
half-volume of the solvent was removed in vacuo. A
solution of 14 (403 mg, 0.88 mmol) in benzene (15 ml) was
added to the above mixture, and the resulting solution was
refluxed for 16 h under argon. After cooling, the reaction
was quenched with water (10 ml), and the mixture was
extracted with diethyl ether (3£50 ml). The combined
4.1.7. (4aR,6S,8aS)-6-tert-Butyldimethylsiloxy-5,5,8a-tri-
methyl-1-methylene-3,4,4a,5,6,7,8,8a-octahydronaph-
thalen-2(1H)-one (6). Dess-Martin periodinane (327 mg,
0.80 mmol) was added in small portions to a stirred solution
of 15 (135 mg, 0.40 mmol) in dry dichloromethane (5.0 ml)
at room temperature. After 1 h, the reaction was quenched
with 15% aqueous sodium thiosulfate (3.0 ml), and the
resulting mixture was extracted with diethyl ether
(3£30 ml). The combined extracts were washed with
saturated aqueous sodium hydrogencarbonate and brine,

K. Iwasaki et al. / Tetrahedron 59 (2003) 8763–8773
8769
then dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 10:1) to give 6
(132 mg, 98%) as a white powder, mp 60–628C; [a]2D0¼
239.08 (c 1.02, CHCl3); 1H NMR (500 MHz, CDCl3) d 0.06
(3H, s), 0.07 (3H, s), 0.86 (3H, s), 0.91 (9H, s), 0.99 (3H, s),
1.03 (3H, s), 1.40 (1H, dd, J¼3.0, 12.5 Hz), 1.58 (1H, dt,
J¼12.5, 4.5 Hz), 1.64–1.73 (2H, m), 1.76 (1H, dt, J¼3.3,
12.5 Hz), 1.85 (1H, dq, J¼5.5, 12.5 Hz), 1.94–2.01 (1H,
m), 2.31 (1H, ddd, J¼7.9, 12.5, 17.0 Hz), 2.66 (1H, ddd,
J¼1.8, 5.5, 17.0 Hz), 3.28 (1H, dd, J¼5.4, 10.0 Hz), 5.00
(1H, d, J¼0.9 Hz), 5.55 (1H, d, J¼0.9 Hz); 13C NMR
(125 MHz, CDCl3) d 25.0, 23.8, 15.9, 18.1, 20.4, 21.4,
25.9 (three carbons), 27.7, 28.6, 35.2, 40.0, 40.3, 40.6, 49.9,
79.1, 113.8, 158.5, 203.6; IR (KBr) 2955, 2895, 2857, 2708,
1723, 1698, 1613, 1472, 1389, 1362, 1285, 1254, 1215,
1177, 1101, 1071, 1005, 968, 941, 885, 870, 837, 774, 669,
590, 534, 486 cm21; HREIMS (m/z) calcd for C20H36O2Si
(Mþ), 336.2485, found 336.2479.
which was purified by column chromatography (hexane/
ethyl acetate, 10:1) to give 8 (629 mg, 96%) as a colorless
oil; H NMR (500 MHz, CDCl3): d 3.53 (3H, s), 4.77 (2H,
1
s), 5.26 (2H, s), 5.37 (2H, s), 6.85 (1H, dd, J¼1.2, 8.3 Hz),
6.91 (1H, dd, J¼1.2, 8.3 Hz), 7.19 (1H, t, J¼8.3 Hz), 7.33–
7.40 (5H, m); 13C NMR (125 MHz, CDCl3) d 56.4, 70.3,
92.9, 95.2, 103.9, 109.6, 109.7, 127.8, 127.9, 128.1, 128.2,
128.3, 128.4, 137.0, 155.0, 155.1; IR (neat) 2905, 1721,
1593, 1466, 1385, 1246, 1206, 1155, 1086, 1042, 891, 772,
739, 698, 606 cm21; HREIMS (m/z) calcd for C16H17BrO4
(Mþ), 352.0310, found 352.0309.
4.1.10. (1R,4aR,6S,8aS)-1-[2-Benzyloxymethoxy-6-
(methoxymethoxy)benzyl]-6-tert-butyldimethylsiloxy-
5,5,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphtalen-
2-one (21). Ethylene dibromide (79.0 ml, 0.91 mmol) was
added dropwise to a stirred suspension of magnesium
powder (132 mg, 5.4 mmol) in dry diethyl ether (1.0 ml) at
room temperature under argon. Immediately, a solution of 8
(1.28 g, 3.6 mmol) in dry diethyl ether (5.0 ml) was added
slowly to the above mixture, and the resulting mixture was
gently refluxed for 1 h to complete the formation of the
Grignard reagent. A solution of 6 (203 mg, 0.60 mmol) in
dry diethyl ether (4.0 ml) was added to the above mixture at
08C, and the mixture was further stirred for 5 h at room
temperature. The reaction was quenched with saturated
aqueous ammonium chloride (4.0 ml), and the mixture was
extracted with ethyl acetate (3£50 ml). The combined
extracts were washed with 3% aqueous hydrochloric acid,
saturated aqueous sodium hydrogencarbonate and brine,
then dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 50:1) to give 21
(349 mg, 95%) as a colorless viscous oil. [a]2D0¼226.38 (c
4.1.8. 2-Bromo-3-(methoxymethoxy)phenol (19) and
2-bromo-1,3-bis(methoxymethoxy)benzene (20). Chloro-
methyl methyl ether (0.32 ml, 4.2 mmol) was added
dropwise to a stirred solution of 2-bromoresorsinol13 (18)
(800 mg, 4.2 mmol) in dry dichloromethane (14.0 ml)
containing diisopropylethylamine (0.74 ml, 4.2 mmol) at
room temperature under argon. After 1 h, the reaction was
quenched with 3% aqueous hydrochloric acid (8.0 ml), and
the resulting mixture was extracted with ethyl acetate
(3£60 ml). The combined extracts were washed with 3%
aqueous hydrochloric acid, saturated aqueous sodium
hydrogencarbonate and brine, then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue,
which was purified by column chromatography (hexane/
ethyl acetate, 10:1) to give more polar 19 (430 mg, 44%)
(colorless oil) and less polar 20 (337 mg, 29%) (colorless
1
1.07, CHCl3); H NMR (500 MHz, CDCl3) d 0.01 (3H, s),
0.02 (3H, s), 0.79 (3H, s), 0.85–0.90 (1H, m), 0.87 (3H, s),
0.88 (9H, s), 0.96 (3H, s), 1.18–1.29 (1H, m), 1.42–1.50
(1H, m), 1.57–1.68 (1H, m), 1.74 (1H, dq, J¼4.9, 13.2 Hz),
1.92 (1H, dt, J¼13.5, 3.4 Hz), 1.97–2.08 (1H, m), 2.27 (1H,
dt, J¼6.9, 13.2 Hz), 2.35–2.42 (1H, m), 2.61–2.70 (2H, m),
2.66 (1H, s), 3.19–3.26 (1H, m), 3.23 (1H, dd, J¼4.3,
11.9 Hz), 3.49 (3H, s), 4.72 (2H, dd, J¼11.8, 16.6 Hz), 5.17
(2H, dd, J¼6.6, 8.4 Hz), 5.28 (2H, s), 6.75 (1H, d, J¼
8.3 Hz), 6.83 (1H, d, J¼8.3 Hz), 7.06 (1H, t, J¼8.3 Hz),
7.27–7.37 (5H, m); 13C NMR (125 MHz, CDCl3) d 24.9,
23.8, 14.4, 15.8, 16.6, 18.1, 23.9, 25.9 (three carbons), 27.9,
28.8, 36.1, 39.8, 42.1, 43.1, 53.9, 56.1, 63.7, 70.1, 79.1,
92.6, 94.8, 108.1, 121.2, 126.8, 127.9, 128.0, 128.1 (two
carbons), 128.5 (two carbons), 137.4, 156.0, 156.1, 211.3;
IR (neat) 2955, 2857, 1715, 1593, 1470, 1389, 1366, 1325,
1254, 1211, 1155, 1086, 1044, 885, 837, 775, 737, 698,
669 cm21; HREIMS (m/z) for C36H54O6Si (Mþ), 610.3690,
found 610.3680.
1
oil). 19: H NMR (500 MHz, CDCl3) d 3.52 (3H, s), 5.25
(2H, s), 5.62 (1H, s), 6.70–6.72 (1H, m), 6.72–6.74 (1H,
m), 7.15 (1H, t, J¼8.3 Hz); 13C NMR (125 MHz, CDCl3) d
56.4, 95.1, 101.3, 107.4, 109.5, 128.7, 153.5, 154.3; IR
(neat) 3426, 2932, 1593, 1466, 1385, 1321, 1260, 1190,
1154, 1088, 1034, 926, 772, 581 cm21; HREIMS (m/z)
calcd for C8H9BrO3 (Mþ), 231.9735, found 231.9740. 20:
1H NMR (500 MHz, CDCl3) d 3.52 (6H, s), 5.25 (4H, s),
6.84 (1H, d, J¼8.3 Hz), 7.18 (1H, t, J¼8.3 Hz); 13C NMR
(125 MHz, CDCl3) d 56.4 (two carbons), 95.2, 103.9 (two
carbons), 109.6 (two carbons), 128.2, 155.1 (two carbons);
IR (neat) 2957, 1595, 1468, 1250, 1204, 1155, 1086, 1038,
922, 772, 656 cm21; HREIMS (m/z) calcd for C10H13BrO4
(Mþ), 275.9997, found 275.9990.
4.1.9. 1-Benzyloxymethoxy-2-bromo-3-(methoxy-
methoxy)benzene (8). Benzyl chloromethyl ether
(0.43 ml, 2.8 mmol) was added dropwise to a stirred
solution of 19 (430 mg, 1.9 mmol) in dry dichloromethane
(8.0 ml) containing diisopropylethylamine (0.54 ml,
3.2 mmol) at room temperature under argon. After 1 h, the
reaction was quenched with saturated aqueous ammonium
chloride (8.0 ml), and the mixture was extracted with ethyl
acetate (3£60 ml). The combined extracts were washed with
3% aqueous hydrochloric acid, saturated aqueous sodium
hydrogencarbonate and brine, then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue,
4.1.11. (1S,4aR,6S,8aR)-1-[2-Benzyloxymethoxy-6-
(methoxymethoxy)benzyl]-6-tert-butyldimethylsiloxy-
5,5,8a-trimethyl-2-methylene-3,4,4a,5,6,7,8,8a-octa-
hydronaphtalene (22). A stirred suspension of potassium
tert-butoxide (330 mg, 2.9 mmol) and methyltriphenylphos-
phonium bromide (1.04 g, 2.9 mmol) in dry benzene
(5.0 ml) was heated at reflux for 3 h under argon, and then
roughly half-volume of the solvent was removed in vacuo.
A solution of 21 (349 mg, 0.57 mmol) in dry benzene

8770
K. Iwasaki et al. / Tetrahedron 59 (2003) 8763–8773
(5.0 ml) was added to the above mixture, and the resulting
solution was refluxed for 13 h under argon. After cooling,
the reaction was quenched with water (5.0 ml), and the
mixture was extracted with diethyl ether (2£60 ml). The
combined extracts were washed with 10% aqueous
hydrochloric acid, saturated aqueous sodium hydrogencar-
bonate and brine, then dried over Na2SO4. Concentration of
the solvent in vacuo afforded a residue, which was purified
by column chromatography (hexane/ethyl acetate, 50:1)
to give 22 (338 mg, 97%) as a colorless viscous oil.
[a]2D0¼220.68 (c 1.08, CHCl3); 1H NMR (500 MHz,
CDCl3) d 0.04 (6H, s), 0.76 (3H, s), 0.85 (3H, s), 0.89
(9H, s), 0.90 (3H, s), 1.10 (1H, dd, J¼2.6, 12.5 Hz), 1.24–
1.33 (1H, m), 1.39 (1H, dq, J¼4.2, 12.9 Hz), 1.48–1.55
(1H, m), 1.57–1.67 (1H, m), 1.68–1.76 (1H, m), 1.82–1.96
(2H, m), 2.29–2.36 (1H, m), 2.55 (1H, dd, J¼4.2, 8.9 Hz),
2.77 (1H, dd, J¼4.2, 13.9 Hz), 2.91 (1H, dd, J¼8.9,
13.9 Hz), 3.08–3.12 (1H, m), 3.50 (3H, s), 4.71 (1H, s),
4.73 (2H, s), 4.98 (1H, s), 5.19 (2H, dd, J¼6.6, 13.1 Hz),
5.29 (2H, s), 6.75 (1H, d, J¼8.2 Hz), 6.83 (1H, d, J¼
8.2 Hz), 7.05 (1H, t, J¼8.2 Hz), 7.27–7.37 (5H, m); 13C
NMR (125 MHz, CDCl3) d 24.9, 23.7, 14.2, 16.0, 18.1,
19.9, 24.5, 25.9 (three carbons), 28.5, 28.9, 36.6, 38.7, 39.8,
40.1, 55.0, 55.2, 56.2, 70.0, 79.5, 92.3, 94.7, 106.6, 107.9,
108.0, 120.8, 126.7, 127.9, 128.0 (two carbons), 128.5 (two
carbons), 137.3, 149.5, 156.2, 156.3; IR (neat) 2934, 2855,
1593, 1468, 1385, 1254, 1192, 1155, 1100, 1046, 941, 887,
837, 774, 698, 666 cm21; HREIMS (m/z) for C37H56O5Si
(Mþ), 608.3897, found 608.3902.
HREIMS (m/z) calcd for C29H48O4Si (Mþ), 488.3322,
found 488.3325.
4.1.13. (3S,4aR,6aR,12aR,12bS)-3-Hydroxy-11-methoxy-
metoxy-4,4,6a,12b-tetramethyl-1,3,4,4a,5,6,6a,12,12a,
12b-decahydro-2H-benzo[a]xanthene (23). Boron tri-
fluoride diethyl etherate (10.0 ml, 82 mmol) was added
dropwise to a stirred solution of 5 (4.0 mg, 8.2 mmol) in
dry dichloromethane (0.5 ml) at 2608C under argon. The
mixture was gradually warmed up to 2108C during 5 h. The
reaction was quenched with saturated aqueous sodium
hydrogencarbonate (2.0 ml), and the resulting mixture was
extracted with ethyl acetate (3£4 ml). The organic layer was
washed with saturated aqueous sodium hydrogencarbonate
and brine, then dried over Na2SO4. Concentration of the
solvent in vacuo afforded a residue, which was purified by
column chromatography (hexane/ethyl acetate, 2:1) to give
23 (2.3 mg, 75%) as a colorless viscous oil. [a]2D0¼þ23.28 (c
1
0.20, CHCl3); H NMR (500 MHz, CDCl3) d 0.83 (3H, s),
0.93 (3H, s), 1.03 (3H, s), 0.99–1.03 (1H, m), 1.09–1.17
(1H, m), 1.19 (3H, s), 1.39–1.50 (1H, m), 1.55–1.60 (1H,
m), 1.62–1.74 (4H, m), 1.75–1.81 (1H, m), 1.84 (1H, dt, J¼
13.1, 3.5 Hz), 2.08 (1H, dt, J¼12.5, 3.1 Hz), 2.34 (1H, dd,
J¼13.2, 17.0 Hz), 2.69 (1H, dd, J¼5.0, 17.0 Hz), 3.23–3.29
(1H, m), 3.49 (3H, s), 5.19 (2H, s), 6.46 (1H, d, J¼8.2 Hz),
6.59 (1H, dd, J¼0.8, 8.2 Hz), 7.01 (1H, t, J¼8.2 Hz); 13C
NMR (125 MHz, CDCl3) d 14.9, 15.6, 17.4, 19.5, 20.6,
27.2, 28.2, 36.7, 37.5, 38.8, 41.0, 51.5, 55.2, 56.1, 70.6,
78.7, 94.5, 104.8, 110.7, 112.0, 126.9, 154.0, 155.7; IR
(neat) 3443, 2928, 2855, 1726, 1591, 1468, 1381, 1333,
1263, 1225, 1192, 1154, 1127, 1096, 1051, 922, 777,
718 cm21; HREIMS (m/z) calcd for C23H34O4 (Mþ),
374.2457, found 374.2446.
4.1.12. (1S,4aR,6S,8aR)-1-[2-Hydroxy-6-(methoxy-
methoxy)benzyl]-6-tert-butyldimethylsiloxy-5,5,8a-tri-
methyl-2-methylene-3,4,4a,5,6,7,8,8a-octahydronaphta-
lene (5). A solution of 22 (338 mg, 0.56 mmol) in dry
tetrahydrofuran (7.0 ml) was added dropwise to a stirred
solution of lithium (116 mg, 17 mmol) in liquid ammonia
(ca. 20 ml) at 2788C under argon. The resulting solution
was allowed to warm at reflux of liquid ammonia for 1 h.
After addition of saturated aqueous ammonium chloride
(10 ml), the mixture was allowed to stand for 4 h at room
temperature in order to remove ammonia. The mixture was
extracted with ethyl acetate (3£40 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/
ethyl acetate, 20:1) to give 5 (258 mg, 95%) as a colorless
viscous oil. [a]D20¼212.68 (c 0.79, CHCl3); 1H NMR
(500 MHz, CDCl3) d 0.03 (3H, s), 0.04 (3H, s), 0.76 (3H,
s), 0.82 (3H, s), 0.88 (9H, s), 0.89 (3H, s), 1.11 (1H, dd,
J¼2.7, 12.5 Hz), 1.22–1.33 (1H, m), 1.35–1.46 (1H, m),
1.50–1.56 (1H, m), 1.58–1.68 (1H, m), 1.70–1.79 (1H, m),
1.88–2.01 (2H, m), 2.30–2.41 (2H, m), 2.76 (1H, dd,
J¼8.1, 14.6 Hz), 2.86 (1H, dd, J¼3.7, 14.6 Hz), 3.20 (1H,
dd, J¼4.5, 11.4 Hz), 3.50 (3H, s), 4.82 (1H, d, J¼1.1 Hz),
4.89 (1H, s), 5.04 (1H, d, J¼1.1 Hz), 5.17 (1H, d, J¼
6.6 Hz), 5.20 (1H, d, J¼6.6 Hz), 6.43 (1H, dd, J¼0.8,
8.2 Hz), 6.66 (1H, dd, J¼0.8, 8.2 Hz), 6.98 (1H, t, J¼
8.2 Hz); 13C NMR (125 MHz, CDCl3) d 24.9, 23.8, 14.2,
15.9, 18.1, 19.2, 24.4, 25.9 (three carbons), 28.5, 28.7, 36.5,
38.5, 39.8, 40.3, 54.9, 55.5, 56.2, 79.4, 94.7, 106.6, 106.7,
109.5, 118.2, 126.8, 150.3, 155.0, 156.2; IR (neat) 3420,
2936, 2855, 1719, 1647, 1595, 1466, 1385, 1254, 1194,
4.1.14. (3S,4aR,6aR,12aR,12bS)-3-tert-Butyldimethylsi-
loxy-11-methoxymetoxy-4,4,6a,12b-tetramethyl-1,3,
4,4a,5,6,6a,12,12a,12b-decahydro-2H-benzo[a]xanthene
(24). tert-Butyldimethylsilyl trifluoromethanesulfonate
(12 ml, 51 mmol) was added dropwise to a stirred solution
of 23 (1.9 mg, 5.1 mmol) in dry dichloromethane (0.5 ml)
containing 2,6-lutidine (9.0 ml, 61 mmol) at room tempera-
ture under argon. After 24 h, the reaction was quenched with
saturated aqueous ammonium chloride (2.0 ml), and the
mixture was extracted with ethyl acetate (2£4 ml). The
combined extracts were washed with 3% aqueous hydro-
chloric acid, saturated aqueous sodium hydrogencarbonate
and brine, then dried over Na2SO4. Concentration of the
solvent in vacuo afforded a residue, which was purified by
column chromatography (hexane/ethyl acetate, 5:1) to give
24 (2.1 mg, 85%) as colorless viscous oil. [a]2D0¼þ31.98 (c
1
0.23, CHCl3); H NMR (500 MHz, CDCl3) d 0.05 (6H, s),
0.79 (3H, s), 0.90 (9H, s), 0.92 (3H, s), 0.94 (3H, s), 0.99
(1H, dd, J¼1.9, 12.0 Hz), 1.03–1.11 (1H, m), 1.18 (3H, s),
1.43 (1H, dq, J¼3.1, 13.6 Hz), 1.51–1.55 (1H, m), 1.61–
1.71 (3H, m), 1.73–1.82 (2H, m), 2.06 (1H, dt, J¼3.1,
12.4 Hz), 2.33 (1H, dd, J¼13.2, 17.1 Hz), 2.68 (1H, dd,
J¼5.1, 17.1 Hz), 3.21 (1H, dd, J¼4.7, 11.3 Hz), 3.49 (3H,
s), 5.19 (2H, dd, J¼6.5, 9.6 Hz), 6.46 (1H, d, J¼8.2 Hz),
6.59 (1H, d, J¼8.2 Hz), 7.01 (1H, t, J¼8.2 Hz); 13C NMR
(125 MHz, CDCl3) d 24.9, 23.7, 14.9, 16.1, 17.4, 18.1,
19.7, 20.6, 25.9 (three carbons), 27.6, 28.6, 29.7, 36.6, 37.5,
41.1, 51.6, 55.3, 56.1, 76.5, 79.2, 94.5, 104.7, 110.8, 112.2,
126.9, 154.0, 155.7; IR (neat) 2928, 2855, 1738, 1607, 1591,
1154, 1094, 1044, 941, 887, 835, 774, 731, 664 cm21
;

K. Iwasaki et al. / Tetrahedron 59 (2003) 8763–8773
8771
1468, 1387, 1331, 1262, 1225, 1192, 1154, 1127, 1098,
1053, 966, 924, 883, 837, 804, 777, 720, 667, 608 cm21
1134, 1098, 1055, 941, 883, 837, 774, 708 cm21; HREIMS
(m/z) calcd for C29H48O4Si (Mþ), 488.3322, found
488.3355.
;
HRFABMS m/z calcd for C29H48O4Si (Mþ), 488.3322,
found 488.3311.
4.1.17. (3S,4aR,6aS,12aR,12bS)-4,4,6a,12b-Tetramethyl-
1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H-benzo[a]xan-
thene-3,11-diol (27). 6 M Hydrochloric acid (0.36 ml,
2.2 mmol) was added to a stirred solution of 26 (106 mg,
0.22 mmol) in methanol (4.0 ml) at room temperature, and
then the mixture was heated at 508C for 3 h. After cooling,
the reaction was diluted with ethyl acetate (60 ml). The
organic layer was washed with saturated aqueous sodium
hydrogencarbonate and brine, then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue,
which was purified by column chromatography (hexane/
ethyl acetate, 4:1) to give 27 (68.8 mg, 96%) as a white
solid. Recrystallization from hexane/diethyl ether (4:1)
afforded an analytical sample of 27 as white fine needles,
4.1.15. (3S,4aR,6aS,12aR,12bS)-3-tert-Butyldimethylsil-
oxy-11-methoxymethoxy-4,4,12b-trimethyl-6a-phenyl-
selenylmethyl-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H-
benzo[a]xanthene
(25).
N-(Phenylseleno)phtalimide
(86.0 mg, 0.28 mmol) in dry dichloromethane (10 ml) and
tin(IV) chloride in dichloromethane (1.0 M solution,
0.25 ml, 0.25 mmol) were added dropwise to a stirred
solution of 5 (114 mg, 0.23 mmol) in dry dichloromethane
(8.0 ml) at 2788C under argon. After 1 h, the reaction
mixture was concentrated in vacuo to afforded a residue,
which was purified by column chromatography (hexane/
ethyl acetate, 20:1) to give 25 (147 mg, 98%) as a pale
yellow viscous oil. [a]2D0¼þ21.58 (c 1.04, CHCl3); 1H NMR
(500 MHz, CDCl3) d 0.04 (3H, s), 0.05 (3H, s), 0.69 (3H, s),
0.74 (3H, s), 0.88 (9H, s), 0.89–0.92 (1H, m), 0.94 (3H, s),
1.01–1.12 (1H, m), 1.45–1.53 (1H, m), 1.55–1.61 (2H, m),
1.61–1.75 (2H, m), 1.75–1.88 (2H, m), 2.15–2.24 (1H, m),
2.44 (1H, dd, J¼8.4, 18.7 Hz), 2.73 (1H, d, J¼18.7 Hz),
3.09 (2H, s), 3.23 (1H, dd, J¼4.7, 11.3 Hz), 3.45 (3H, s),
5.17 (2H, d, J¼1.6 Hz), 6.43 (1H, dd, J¼0.8, 8.2 Hz), 6.56
(1H, dd, J¼0.8, 8.2 Hz), 6.98 (1H, t, J¼8.2 Hz), 7.14–7.23
(3H, m), 7.40–7.47 (2H, m); 13C NMR (125 MHz, CDCl3)
d 24.9, 23.7, 14.2, 16.0, 18.1, 19.9, 24.5, 25.9 (three
carbons), 28.5, 28.9, 36.6, 38.7, 39.8, 40.1, 55.0, 55.2, 56.2,
70.0, 79.5, 92.3, 94.7, 106.6, 107.9, 108.0, 120.8, 126.7,
127.9, 128.0, 128.5, 137.3, 149.5, 156.2, 156.3; IR (neat)
2951, 2855, 1730, 1591, 1468, 1389, 1360, 1254, 1155,
1098, 1053, 953, 924, 883, 837, 774, 737, 691, 529,
467 cm21; HREIMS (m/z) calcd for C35H52O4SeSi (Mþ),
644.2800, found 644.2794.
mp 108–1098C; [a]2D0¼240.68 (c 0.91, CHCl3); H NMR
1
(500 MHz, CDCl3) d 0.71 (3H, s), 0.79 (3H, s), 0.89–0.95
(1H, m), 1.03 (3H, s), 1.04–1.12 (1H, m), 1.17 (3H, s), 1.37
(1H, d, J¼7.8 Hz), 1.55–1.62 (3H, m), 1.62–1.75 (2H, m),
1.92 (1H, dt, J¼13.0, 3.6 Hz), 2.14–2.21 (1H, m), 2.17 (1H,
s), 2.65 (1H, dd, J¼7.7, 17.8 Hz), 2.73 (1H, d, J¼17.8 Hz),
3.21–3.27 (1H, m), 4.63 (1H, s), 6.30 (1H, dd, J¼1.0,
8.1 Hz), 6.37 (1H, dd, J¼1.0, 8.1 Hz), 6.92 (1H, t, J¼
8.1 Hz); 13C NMR (125 MHz, CDCl3) d 14.0, 14.1, 15.6,
17.4, 17.9, 26.9, 27.0, 28.5, 38.1, 38.2, 38.8, 40.6, 48.8,
54.3, 75.0, 79.1, 106.2, 109.5, 126.5, 153.5, 155.8; IR (KBr)
3439, 2928, 1616, 1593, 1466, 1370, 1273, 1169, 1134,
1026, 903, 775 cm21; HRFABMS (m/z) calcd for C21H30O3
(Mþ), 330.2195, found 330.2226.
4.1.18. (3S,4aR,6aS,12aR,12bS)-3,11-Diacetoxy-4,4,6a,
12b-tetramethyl-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-
2H-benzo[a]xanthene (28). Acetic anhydride (0.172 ml,
1.8 mmol) was added dropwise to a stirred solution of 27
(60.4 mg, 0.18 mmol) in pyridine (1.0 ml) containing
4-(dimethylamino)pyridine (11.0 mg, 92 mmol) at room
temperature. After 18 h, the reaction mixture was diluted
with ethyl acetate (10 ml). The organic layer was washed
with 3% aqueous hydrochloric acid, saturated aqueous
sodium hydrogencarbonate and brine, then dried over
Na2SO4. Concentration of the solvent in vacuo afforded a
residue, which was purified by column chromatography
(hexane/ethyl acetate, 10:1) to give 28 (64.4 mg, 85%) as a
amorphous white powder, mp 144–1468C; [a]2D0¼28.38 (c
4.1.16. (3S,4aR,6aS,12aR,12bS)-3-tert-Butyldimethylsil-
oxy-11-methoxymethoxy-4,4,6a,12b-tetramethyl-1,3,4,
4a,5,6,6a,12,12a,12b-decahydro-2H-benzo[a]xanthene
(26). Tributyltin hydride (102 ml, 0.37 mmol) and 2,20-azo-
bisisobutyronitrile (2.0 mg, 12 mmol) were added success-
ively to a stirred solution of 25 (79.1 mg, 0.12 mmol) in dry
toluene (3.0 ml) at room temperature. The mixture was
frozen using liquid nitrogen, and then the reaction bottle was
evacuated in vacuo followed by filled with dry argon. After
warming to room temperature, the mixture was heated at
reflux for 7 h under argon. After cooling, the reaction
mixture was concentrated in vacuo to afford a residue,
which was purified by column chromatography (hexane/
ethyl acetate, 50:1!20:1) to give 26 (47.0 mg, 78%) as a
colorless oil. [a]D20¼213.88 (c 0.74, CHCl3); 1H NMR
(500 MHz, CDCl3) d 0.04 (6H, s), 0.69 (3H, s), 0.74 (3H, s),
0.84–0.91 (1H, m), 0.88 (9H, s), 0.93 (3H, s), 0.97–1.10
(1H, m), 1.16 (3H, s), 1.32 (1H, d, J¼8.2 Hz), 1.45–1.63
(4H, m), 1.64–1.74 (1H, m), 1.80–1.89 (1H, m), 2.11–2.21
(1H, m), 2.63 (1H, dd, J¼8.2, 18.5 Hz), 2.80 (1H, d, J¼
18.5 Hz), 3.20 (1H, dd, J¼4.6, 11.4 Hz), 3.49 (3H, s), 5.20
(2H, s), 6.44 (1H, d, J¼8.2 Hz), 6.56 (1H, d, J¼8.2 Hz),
6.99 (1H, t, J¼8.2 Hz); 13C NMR (125 MHz, CDCl3) d
24.9, 23.7, 14.2, 16.2, 17.7, 18.1, 18.2, 25.9 (three
carbons), 27.0, 27.6, 29.0, 38.0, 38.3, 39.4, 40.8, 49.0,
54.5, 56.0, 75.0, 79.5, 94.4, 104.9, 110.9, 112.4, 126.4,
154.8, 155.6; IR (neat) 2930, 1591, 1470, 1389, 1256, 1155,
1
1.02, CHCl3); H NMR (500 MHz, CDCl3) d 0.72 (3H, s),
0.85 (3H, s), 0.90 (3H, s), 0.96–1.01 (1H, m), 1.07–1.15
(1H, m), 1.17 (3H, s), 1.33 (1H, d, J¼7.8 Hz), 1.54–1.63
(2H, m), 1.63–1.77 (3H, m), 1.83 (1H, dt, J¼13.1, 3.6 Hz),
2.05 (3H, s), 2.14–2.21 (1H, m), 2.32 (3H, s), 2.56 (1H, d,
J¼18.1 Hz), 2.63 (1H, dd, J¼7.8, 18.1 Hz), 4.49 (1H, dd,
J¼4.8, 11.6 Hz), 6.56 (1H, dd, J¼1.0, 8.1 Hz), 6.65 (1H,
dd, J¼1.0, 8.1 Hz), 7.07 (1H, t, J¼8.1 Hz); 13C NMR
(125 MHz, CDCl3) d 14.1, 16.8, 17.7, 17.8, 20.8, 21.3, 23.4,
26.8, 28.4, 37.7, 37.8, 37.9, 40.4, 48.6, 54.4, 75.3, 80.7,
113.1, 114.8, 115.7, 126.7, 148.9, 155.7, 169.1, 171.0; IR
(KBr) 2971, 2932, 2886, 1753, 1723, 1615, 1584, 1466,
1372, 1318, 1252, 1209, 1165, 1136, 1086, 1030, 1009, 974,
916, 893, 876, 849, 804, 785, 725, 706, 658, 598, 557,
527 cm21; HRFABMS (m/z) calcd for C25H34O5 (Mþ),
414.2406, found 414.2420.

8772
K. Iwasaki et al. / Tetrahedron 59 (2003) 8763–8773
Ohtani, M. Curr. Pharm. Des. 1997, 3, 323–334. (h) Leonard,
D. M. J. Med. Chem. 1997, 40, 2971–2990.
4.1.19. (3S,4aR,6aS,12aR,12bS)-3-Acetoxy-11-hydroxy-
4,4,6a,12b-tetramethyl-1,3,4,4a,5,6,6a,12,12a,12b-deca-
hydro-2H-benzo[a]xanthene (4). Potassium tert-butoxide
(51.7 mg, 0.48 mmol) was added in small portions to a
stirred solution of 28 (61.9 mg, 0.15 mmol) in THF-tert-
butyl alcohol (5:1) (3.0 ml) at room temperature under
argon. After 20 min, the reaction was quenched with
saturated aqueous ammonium chloride (5.0 ml), and the
mixture was extracted with ethyl acetate (3£20 ml). The
organic layer was washed with 3% aqueous hydrochloric
acid, saturated aqueous sodium hydrogencarbonate and
brine, then dried over Na2SO4. Concentration of the solvent
in vacuo afforded a residue, which was purified by column
chromatography (hexane/ethyl acetate, 10:1!2:1) to give 4
(53.4 mg, 96%) as a white solid. Recrystallization from
hexane/diethyl ether (20:1) afforded an analytical sample of
4 as white fine needles, mp 233–2348C; [a]2D0¼210.48 (c
4. The absolute configurations of kampanols had not been
discussed in the literature (Ref. 1).
5. Recently, Jarvis and co-workers reported the isolation of
structurally closely related antibiotic, memnobotrin A, from
Memnoniella echinata organism, wherein the g-lactone ring
(E ring) of kampanol A is only replaced by a g-lactam ring,
see: Hinkley, S. F.; Fettinger, J. C.; Dudley, K.; Jarvis, B. B.
J. Antibiot. 1999, 52, 988–997.
6. Iwasaki, K.; Nakatani, M.; Inoue, M.; Katoh, T. Tetrahedron
Lett. 2002, 43, 7937–7940.
7. Synthetic studies including total synthesis of structurally
analogous polyphenol-fused drimane-type terpenoids, such as
hongoquercins A and B, puupephenone and its analogues,
UPA0043 and UPA0044, and spirodihydrobenzofuranlactam
have been reported. See for hongoquercins A and B:
(a) Tsujimori, H.; Bando, M.; Mori, K. Eur. J. Org. Chem.
2000, 297–302. (b) Tsujimori, H.; Mori, K. Biosci. Biotech-
nol. Biochem. 2000, 64, 1410–1415. See for puupephenone
and its analogues: (c) Maiti, S.; Sengupta, S.; Giri, C.; Achari,
B.; Banerjee, A. K. Tetrahedron Lett. 2001, 42, 2389–2391.
(d) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.;
1
0.98, CHCl3); H NMR (500 MHz, CDCl3) d 0.74 (3H, s),
0.86 (3H, s), 0.90 (3H, s), 0.97–1.03 (1H, m), 1.09–1.21
(1H, m), 1.18 (3H, s), 1.38 (1H, d, J¼7.5 Hz), 1.49–1.77
(5H, m), 1.91 (1H, dt, J¼13.2, 3.5 Hz), 2.05 (3H, s), 2.12–
2.21 (1H, m), 2.66 (1H, dd, J¼7.5, 17.9 Hz), 2.72 (1H, d,
J¼17.9 Hz), 4.50 (1H, dd, J¼4.7, 11.7 Hz), 4.77 (1H, s),
6.30 (1H, dd, J¼0.8, 8.0 Hz), 6.37 (1H, d, J¼8.0 Hz), 6.92
(1H, t, J¼8.0 Hz); 13C NMR (125 MHz, CDCl3) d 14.2,
16.8, 17.4, 17.8, 21.3, 23.4, 26.8, 28.4, 37.7, 37.8, 38.0,
40.5, 48.7, 54.4, 75.0, 81.1, 106.2, 109.5, 109.8, 126.6,
153.5, 155.8, 171.4; IR (KBr) 3447, 2946, 2361, 1699,
1616, 1595, 1468, 1377, 1277, 1169, 1136, 1084, 1030, 972,
905, 777, 561 cm21; HREIMS (m/z) calcd for C23H32O4
(Mþ), 372.2301, found 372.2298: Anal. calcd for C23H32O4:
C, 74.16; H, 8.66, found C, 74.25; H, 8.53.
´
Cortes, M.; Armstrong, V. Tetrahedron 1999, 55,
15181–15208. (e) Barrero, A. F.; Alvarez-Manzaneda, E. J.;
Herrador, M. M.; Chahboun, R.; Galera, P. Bioorg. Med.
Chem. Lett. 1999, 9, 2325–2328. (f) Arjona, O.; Garranzo, M.;
´
Mahugo, J.; Maroto, E.; Plumet, J.; Saez, B. Tetrahedron Lett.
1997, 38, 7249–7252. (g) Barrero, A. F.; Alvarez-Manzaneda,
E. J.; Chahboun, R. Tetrahedron Lett. 1997, 38, 2325–2328.
See for UPA0043 and UPA0044: (h) Takao, K.; Sasaki, T.;
Kozaki, T.; Yanagisawa, Y.; Tadano, K.; Kawashima, A.;
Shinonaga, H. Org. Lett. 2001, 3, 4291–4294. See for
spirodihydrobenzofuranlactam: (i) Kende, A. S.; Deng,
W.-P.; Zhong, M.; Guo, X.-C. Org. Lett. 2003, 5, 1785–1788.
8. For a review, see: Lee, V. J. Conjugate Additions of Reactive
Carbanions to Activated Alkenes and Alkynes. Compre-
hensive Organic Synthesis, Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; 4, pp 69–138.
Acknowledgements
We thank Dr Naoki Sugimoto, National Institute of Health
Sciences, for assistance with HRMS measurements. This
work was supported in part by the Pfizer Award in Synthetic
Organic Chemistry, Japan.
9. (a) Pemp, A.; Seifert, K. Tetrahedron Lett. 1997, 38,
2081–2084. (b) Mori, K.; Komatsu, M. Bull. Soc. Chim.
Belg. 1986, 95, 771–781. (c) Welch, S. C.; Prakasa Rao, A. S.
C. J. Org. Chem. 1978, 43, 1957–1961. (d) Welch, S. C.;
Prakasa Rao, A. S. C. Tetrahedron Lett. 1977, 505–508.
(e) Ireland, R. E.; Baldwin, S. W.; Welch, S. C. J. Am. Chem.
Soc. 1973, 94, 2056–2066.
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K. Iwasaki et al. / Tetrahedron 59 (2003) 8763–8773
8773
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