Enantioselective total synthesis of (+)-ottelione A, (-)-ottelione B, (+)-3-epi-ottelione A and preliminary evaluation of their antitumor activity

Article abstract of DOI:10.1002/chem.200700789

Enantioselective total synthesis of (+)-ottelione A (1) and (-)ottelione B (2), novel and potent antitumor agents from a freshwater plant, and (+)-3-epi-ottelione A (3), the earlier proposed stereostructure of 1, was efficiently achieved starting from the

Full text of DOI:10.1002/chem.200700789

DOI: 10.1002/chem.200700789
Enantioselective Total Synthesis of (+)-Ottelione A, (ꢀ)-Ottelione B,
(+)-3-epi-Ottelione A and Preliminary Evaluation of Their Antitumor
Activity
Hiroshi Araki,[f] Munenori Inoue,[e] Takeyuki Suzuki,[d] Takao Yamori,[c]
Michiaki Kohno,[b] Kazuhiro Watanabe,[a] Hideki Abe,[a] and Tadashi Katoh*[a]
Abstract: Enantioselective total syn-
thesis of (+)-ottelione A (1) and (ꢀ)-
ottelione B (2), novel and potent anti-
tumor agents from a freshwater plant,
and (+)-3-epi-ottelione A (3), the earli-
er proposed stereostructure of 1, was
efficiently achieved startingfrom the
known tricyclic compound 10. The syn-
thesis involved the followingkey steps:
hemiacetal-opening/epimerization reac-
tions of the cyclic hemiacetals 6 and 27
(6!17 and 27a!26a), and iii) Corey–
Winterꢀs reductive olefination of the
cyclic thiocarbonates 21 and 36 (21!22
and 36!37). The present total synthe-
sis fully established the absolute config-
uration of these natural products. The
cell growth inhibition profile, COM-
PARE analysis, and tubulin inhibitory
assay of (+)-3-epi-ottelione A (3) and
its O-acetyl derivative 24 demonstrated
that these unnatural substances could
be prominent lead compounds for the
development of anticancer agents with
a novel mode of action.
Keywords:
natural products
antitumor agents
otteliones
·
·
·
i) couplingreactions of aldehydes
8
total synthesis · tubulin polymeri-
zation inhibitors
and 9 with the aromatic portion 7 (8+
7!15 and 9+7!27), ii) base-induced
Introduction
[a] Dr. K. Watanabe, Dr. H. Abe, Prof. 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)
In 1998, Ayyad and Hoye et al. reported the isolation and
structural elucidation of two novel diastereomeric natural
products, otteliones A (1) and B (2) (Figure 1), from the
freshwater plant Ottelia alismoides collected from the Nile
Delta, Egypt.[1,2] These substances were found to exhibit
prominent biological properties such as antitubercular[3] and
antitumor activities.[1,2] Remarkably, these small-molecule
Fax : (+81)22-727-0135
E-mail: katoh@tohoku-pharm.ac.jp
[b] Prof. Dr. M. Kohno
Laboratory of Cell Regulation
Department of Pharmaceutical Sciences
Graduate School of Biomedical Sciences
Nagasaki University, 1-14 Bunkyo-machi
Nagasaki 852-8521 (Japan)
[c] Prof. Dr. T. Yamori
Division of Molecular Pharmacology, Cancer Chemotherapy Center
Japanese Foundation for Cancer Research, 3-10-6 Ariake
Koto-ku, Tokyo 135-8550 (Japan)
[d] Prof. Dr. T. Suzuki
The Institute of Scientific and Industrial Research (ISIR)
Osaka University, Mihogaoka
Ibaraki, Osaka 567-0047 (Japan)
[e] Dr. M. Inoue
Sagami Chemical Research Center, 2743-1 Hayakawa
Ayase, Kanagawa 252-1193 (Japan)
[f] Dr. H. Araki
Department of Electronic Chemistry
Tokyo Institute of Technology, Nagatsuta
Yokohama 226-8502 (Japan)
Supportinginformation 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.
Figure 1. Structures of ottelione A (1), ottelione B (2), 3-epi-ottelione A
(3), and 1-epi-ottelione A (4).
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natural products were reported to display quite potent cyto-
toxicity at nanomolar to picomolar levels of IC50 values
against a panel of 60 human tumor cell lines at the National
Cancer Institute in the United States.[1] It has also been re-
ported that ottelione A inhibits tubulin polymerization into
microtubules similarly to the well-known alkaloids colchi-
cine, vincristine, and vinbrastine.[4] In addition, ottelione A
has been shown to inhibit doxorubicin-resistant leukemia
cells (P388/DOX) with an IC50 value of 1.0 ngmLꢀ1
(3.0 nm).[1] Otteliones, therefore, are expected to be promis-
ingnew leads for the development of cancer chemothera-
peutic agents. However, detailed study of the biological
properties of these natural products is severely limited by
their scarcity. It has been reported that each 9.0 mgof otte-
lione A (1) and B (2) was isolated from 1.0 kg(dry weight)
of the plant O. alismoides (each 0.0009% isolated yield).[1]
Structurally, otteliones A and B possess a novel bicyclic
hydrindane skeleton with four contiguous asymmetric
carbon centers, in which the rare and sensitive 4-methylene-
2-cyclohexenone substructure is a special characteristic fea-
ture.[5] When these natural products were isolated, the rela-
tive configuration of ottelione B was elucidated as shown in
formulation 2 (Figure 1) by the combination of molecular
modelingand 1H NMR studies; however, ottelione A could
not be assigned unambiguously and both formulations 3 and
4 were proposed as possible stereostructures with more pref-
erence for 3.[1] In 2000, scientists from Rhône-Poulenc Rorer
(now Sanofi-Aventis) proposed an alternative stereostruc-
ture 1 for ottelione A, which was assigned based on the
analysis of 2D-NMR spectra includingCOSY, HMQC, and
NOESY experiments,[6] while its absolute configuration was
not determined.
Results and Discussion
Synthesis of 3-epi-ottelione A (3), an earlier proposed ste-
reostructure of ottelione A (1)
AHCTREUNG
Synthetic plan: At the beginning of this project (April
2000), formulation 3 was considered as the most likely ste-
reostructure for ottelione A (1); therefore, our initial syn-
thetic efforts were targeted toward structure 3. Our synthet-
ic plan for 3-epi-ottelione A (3) is outlined in Scheme 1. The
A
The remarkable biological properties, unique structural
features, and limited availability from natural resources, as
well as the necessity of confirmingthe absolute configura-
tion, have made the otteliones exceptionally intriguing and
timely targets for total synthesis. A number of synthetic ap-
proaches for otteliones A and B has been reported to
date.[7] The first total synthesis of racemic (ꢁ)-otteliones A
(1) and B (2) was reported by Mehta and Islam in 2002,[8]
which verified their relative stereostructures. In the follow-
Scheme 1. Synthetic plan for 3-epi-ottelione A (3). TBS=tert-butyldime-
thylsilyl, MOM=methoxymethyl.
key feature of this plan is the utilization of the highly and
appropriately functionalized intermediate 8, which contains
the requisite bicyclic hydrindane core framework possessing
the correct stereochemistries at the C3, C3a, and C7a posi-
tions as well as the desirable functionalities for elaboration
of the target molecule 3. Intermediate 8 should be accessible
from intermediate 9 by epimerization at the C3 position.
The 4-methylene-2-cyclohexenone substructure present in
molecule 3 was expected to be highly sensitive; therefore,
we decided to elaborate this substructure at the final stage
of the synthesis. Since the C1 formyl group of 8 is masked
as an internal hemiacetal moiety, intermediate 6 would be
constructed through the coupling reaction of 8 with the aryl-
lithium generated from bromobenzene derivative 7. Inter-
mediate 6 would be converted into the target molecule 3
through the advanced key intermediate 5 by sequential func-
tional group manipulation and deprotection or vice versa;
the sequence involves base-induced hemiacetal-opening/epi-
merization at the masked C1 formyl group and subsequent
construction of the 4-methylene-2-cyclohexenone substruc-
[9]
ingyear, Mehta and Islam and our groups[10] independent-
ly accomplished the first enantioselective total synthesis of
naturally occurring( +)-ottelione A (1) and (ꢀ)-ottelione B
(2), leadingto the establishment of their absolute configura-
tions as depicted in Figure 1. In addition, we also achieved
an enantioselective total synthesis of 3-epi-ottelione A
(3),[7f] which represents the earlier proposed formulation of
ottelione A. Recently, Clive and Liu reported the elegant
total synthesis of (+)-1 and (ꢀ)-2 in an enantioselective
manner.[11] In this paper, we describe the enantioselective
total synthesis of ottelione A (1), ottelione B (2), and 3-epi-
ottelione A (3). In addition, the cell growth inhibition analy-
sis and tubulin polymerization assay of unnatural 3-epi-otte-
lione A (3) and its O-acetyl derivative 24 alongwith otte-
lione A (1) are also described.
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T. Katoh et al.
ture as the crucial steps. Intermediate 9 should in turn be ac-
cessed from the known tricyclic compound 10, which was
previously prepared in our laboratories by Diels–Alder cy-
cloaddition between optically active cyclohexenone 11 and
cyclopentadiene (12).[12]
Synthesis of intermediate 9: First, as shown in Scheme 2, we
pursued the synthesis of intermediate 9 startingfrom the
known enantiomerically pure tricyclic compound 10.[12]
Thus, stereoselective reduction of the carbonyl group in 10
with NaBH4 provided the expected alcohol 13 in 87% yield
as a single stereoisomer. Subsequent Lemieux–Johnson oxi-
dation (OsO4/NaIO4)[13] of 13 furnished the cyclic hemiace-
tal 9 in 75% yield through the intermediary dialdehyde 14.
The stereochemistry at the C8 position in 9 was assigned
based on NOESY experiments in the 500 MHz 1H NMR
spectrum, in which a clear NOE interaction between C8-H
and C2-Ha was observed.
Scheme 3. Synthesis of intermediate 5. a) DBU, THF, RT, quant.; b) 4-
bromo-1-methoxy-2-(methoxymethoxy)benzene
(7),
nBuLi,
THF,
ꢀ788C; at ꢀ788C, add. 8, quant.; c) Ac2O, DMAP, pyridine, RT, quant.;
d) Li, liq. NH3, THF, ꢀ788C, 87%; e) DBU, toluene, reflux, 52% (see
entry 3 in Table 1); f) Dess–Martin periodinane, CH2Cl2, RT, 90%;
g
)
PhP+CH3Brꢀ, tBuOK, benzene, RT!reflux, 88%. DBU=1,8-
3
diazabicyclo[5.4.0]undec-7-ene, DMAP=4-dimethylaminopyridine.
A
NH3) were unsuccessful. This was attributed to the presence
of reactive hemiacetal function in substrate 15; therefore,
we decided to protect the hydroxy group in the hemiacetal
moiety. Thus, acetylation of the hydroxy groups in 15 fol-
lowed by treatment of the resultingdiacetates 16 with a
large excess of Li metal (50 equiv) in liquid NH3/THF at
ꢀ788C for 5 min resulted in the formation of the desired de-
oxygenated lactol 6 in 87% yield in two steps. In Birch re-
ductive deacetoxylation, the best results were obtained with
a large excess of Li metal at low temperature (ꢀ788C) in a
short time (5 min).
Scheme 2. Synthesis of intermediate 9. a) NaBH4, THF/H2O 10:1, 08C,
87%; b) OsO4, NaIO4, tBuOH/THF/H2O 8:6:3, 08C!RT, 75 %.
Synthesis of intermediate 5: Havingobtained intermediate
9, we next performed the synthesis of intermediate 5 pos-
sessingthe requisite carbon skeleton and correct stereoche-
mistries at the C1, C3, C3a and C7a positions as shown in
Scheme 3. Epimerization at the C3 position of 9 occurred
smoothly and cleanly by treatment with 1,8-diazabicyclo-
A
for 2 h to give the desired b-formyl compound 8 in quantita-
tive yield. The b-disposition of the C3 formyl group in 8 was
confirmed by NOESY experiments, which showed clear
NOE interactions between C3-H and C5-H, C2-Ha.
The crucial couplingreaction of 8 with the aromatic por-
tion 7 was efficiently achieved by halogen/metal exchange
of 4-bromo-1-methoxy-2-(methoxymethoxy)benzene (7)[14]
with nBuLi in THF at ꢀ788C followed by the addition of 8
at the same temperature; the desired couplingproduct 15
was obtained in quantitative yield as an inseparable mixture
of epimeric alcohols (9:1 by 500 MHz 1H NMR). All at-
tempts to directly remove the benzylic hydroxy group from
15 under conventional conditions such as Barton–McCom-
We next examined the base-induced hemiacetal-opening/
epimerization reaction of 6 to obtain 17 possessingthe
requisite stereochemistry at the C1 position. The result sum-
marized in Table 1 deserves some comments. This one-pot
two-step reaction via the intermediary 6 A was best ach-
ieved by treatment of 6 with DBU (20 equiv) in refluxing
toluene for 1.5 h (entry 3), which provided the desired prod-
uct 17 in 52% yield alongwith 40% recovery of the starting
material 6. The choice of the appropriate reaction condi-
tions such as equivalent of DBU and temperature is very
crucial in this reaction. By employinglower amounts of
DBU (2–10 equiv) (entries 1, 2), a lower yield of 17 (14–
25%) was produced and a large amount of the starting ma-
terial 6 (86–70% yield) was recovered unchanged. When a
large excess of DBU (50 equiv) was used (entry 4), only un-
bie deoxygenation [NaN
A
AIBN] or Birch reductive deoxygenation (Li metal, liq.
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Enantioselective Total Synthesis
FULL PAPER
Table 1. Base-induced hemiacetal-opening/epimerization reaction of intermediate 6 leadingto intermediate 17.
Entry
DBU [equiv]
Solvent
T[a] [8C]
t [h]
Yield [%][b]
17
6
1
2
3
4
5
6
2
10
20
50
20
20
toluene
toluene
toluene
toluene
benzene
xylene
110
110
110
110
80
10
5
1.5
1.5
1.5
1.5
14
25
52
86
70
40
decomposition
no reaction
decomposition
140
[a] Reflux temperature. [b] Isolated yield.
identified decomposition products were generated in the re-
action mixture. In addition, when the reaction was carried
out at a lower temperature (808C) (entry 5), it did not pro-
ceed and substrate 6 was recovered quantitatively. At a
higher temperature (1408C) (entry 6), the complete decom-
position of the materials was observed. To continue the syn-
thesis (cf. Scheme 3), compound 17 was further converted to
the key intermediate 5 in 79% overall yield via a two-step
sequence involvingDess–Martin oxidation followed by two-
fold Wittigmethylenation of the resultingketo-aldehyde 18.
Completion of synthesis of (+)-3-epi-ottelione
A (3):
Havingobtained the key intermediate 5 in an efficient way,
we next investigated the synthesis of 3-epi-ottelione A (3),
as shown in Scheme 4, which involves the crucial elabora-
tion of the highly sensitive 4-methylene-2-cyclohexenone
substructure. To this end, treatment of 5 with CF3CO2H in
THF containingH O at 08C effected simultaneous depro-
2
tection of both the acetonide moiety and the MOM group
to provide the correspondingtriol 19 in 76% yield. Subse-
quent chemoselective acetylation of the phenolic hydroxy
group in 19 afforded the acetate 20 in 90% yield. Installa-
ꢀ
tion of the C5 C6 double bond was successfully achieved by
Scheme 4. Synthesis of 3-epi-ottelione A (3). a) CF3CO2H, THF/H2O
10:1, 08C, 76%; b) Ac2O, 2 m NaOH, iPrOH, RT, 90%; c) CSCl2, DMAP,
CH2Cl2, RT, 96%; d) (EtO)3P, reflux, 68%; e) TBAF, THF, RT; Ac2O,
92%; f) Dess–Martin periodinane, CH2Cl2, RT, 97%; g) K2CO3, MeOH,
08C, 98%. TBAF=tetra-n-butylammonium fluoride.
[15]
employingCorey-Winterꢀs protocol
with some modifica-
tions to the reaction conditions. Thus, treatment of 20 with
thiophosgene (2.0 equiv) in the presence of DMAP
(5.0 equiv) followed by exposure of the resultingcyclic thio-
carbonate 21 to refluxingtriethyl phosphite, resulted in the
formation of the requisite diene 22 in 73% yield in two
steps. Subsequent selective removal of the TBS group in 22
was successfully attained via a one-pot two-step operation
involvingtreatment with tetra- n-butylammonium fluoride
(TBAF) followed by chemoselective acetylation of the liber-
ated phenolic hydroxy group; the desired alcohol 23 was
produced in 92% yield. Dess–Martin oxidation of 23 fur-
nished dienone 24 possessingthe sensitive 4-methylene-2-cy-
clohexenone substructure in 97% yield. Finally, the targeted
3-epi-ottelione A (3) was obtained in 98% yield upon de-
acetylation (K2CO3, MeOH, 08C) of 24.
The structure and stereochemistry of 3, the earlier pro-
posed stereostructure of ottelione A (1), was unambiguously
confirmed by extensive spectroscopic analysis including
1
NOESY experiments in the 500 MHz H NMR spectra. The
selected NOESY correlation of 3 is depicted in Figure 2,
wherein clear NOE interactions between H3a and H2b, H7a,
H10a, H10b, between H7a and H2b, H8, and between H2a and
H3, H1 are observed, revealingthat both the C1 and C3 sub-
stituents are syn to the bridgehead protons H3a and H7a in
the cis-fused hydrindane skeleton. To our disappointment,
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T. Katoh et al.
via the intermediates 26 and 25 by a methodology similar to
the synthesis of 3-epi-ottelione (3) from intermediate 9 (cf.
Scheme 1 and two previous sections). Epimerization at the
C3a position in ottelione A (1) would result in ottelione B
(2). Intermediate 27 would, in turn, be produced through
the couplingreaction of the common intermediate 9 and the
aromatic portion 7.
Synthesis of intermediate 26: As shown in Scheme 6, we ini-
tially investigated the synthesis of the advanced key inter-
mediate 26a possessingall four correct stereogenic centers
(C1, C3, C3a, and C7a) and the proper functionalities for
elaboration of the target molecules 1 and 2. The couplingre-
action of the aldehyde 9 with the aryllithium generated in
Figure 2. Selected NOESY correlation of 3-epi-ottelione A (3).
1
the H NMR spectral data of the synthesized compound 3
did not match that of the natural product ottelione A; how-
ever, we achieved the first total synthesis of 3 (3-epi-otte-
lione A), the earlier proposed formulation of ottelione A
(1), in an enantiomerically pure form.[7f] Coincidentally, at
the time we completed the projected synthesis of 3, the first
total synthesis of (ꢁ)-ottelione A (1) and B (2) was report-
ed by Mehta and Islam,[8] which verified their relative ste-
reostructures as shown in Figure 1. Consequently, our syn-
thetic efforts were directed toward formulations 1 and 2
(i.e., otteliones A and B). This is the subject of the following
section.
Synthesis of ottelione A (1) and ottelione B (2)
Synthetic plan: Our redesigned synthetic plan for ottelione
A (1) and B (2) is outlined in Scheme 5, based on the syn-
thesis of 3-epi-ottelione A (3) described above. We envis-
aged that the highly and appropriately elaborated intermedi-
ate 27 would be converted to the target molecules 1 and 2
Scheme 6. Synthesis of intermediate 26a. a) 4-bromo-1-methoxy-2-(me-
thoxymethoxy)benzene (7), nBuLi, THF,ꢀ788C; at ꢀ788C, add. 9, 80%
for 27a, 20% for 27b; b) Li, liq. NH3, THF, ꢀ788C, 73% for 27a!28,
75% for 27b!28; c) DBU, toluene, reflux, no reaction (recovery of 28)
for 28!29; 30% (65% based on recyclingfour times) for 27a!26a ; no
reaction (recovery of 27b) for 27b!26b.
Scheme 5. Synthetic plan for ottelione A (1) and ottelione B (2).
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Enantioselective Total Synthesis
FULL PAPER
situ from 7 proceeded cleanly and smoothly to furnish the
desired products 27a (80% yield) and 27b (20% yield) as a
mixture of epimeric alcohols separated by column chroma-
tography on silica gel. The stereochemistry at the benzylic
C10 position in the couplingproducts 27a,b was tentatively
assigned based on the well-known Felkin-Anh model, while
the stereogenic center disappeared at a later stage of the
synthesis. The C10 hydroxy group in both 27a and 27b was
removed under Birch reduction conditions (Li metal, liquid
NH3/THF, ꢀ788C) to obtain the deoxygenated hemiacetal
28 in 73 and 75% yield, respectively. The crucial base-in-
duced hemiacetal-opening/epimerization reaction of 28 lead-
ingto the hydroxy aldehyde 29 was attempted next under
similar conditions (DBU, toluene, reflux) to those employed
in the Section on intermediate 5 (cf. 6!17, Scheme 3 and
Table 1); however, the reaction did not proceed and the
startingmaterial 28 was recovered unchanged. We reasoned
that substrate 28 might be thermodynamically much more
stable than the hemiacetal-opened hydroxy aldehyde 28a.
Therefore, we next examined the hemiacetal-opening/epi-
merization reaction employinghemiacetals 27a,b as the al-
ternative substrates. Thus, in the case of 27a, the expected
hemiacetal-opening/epimerization reaction proceeded under
the same conditions (DBU, toluene, reflux, 1.5 h) described
above, which resulted in the formation of the desired prod-
uct 26a (30% yield) alongwith the startingmaterial 27a
(60% yield). Since prolonged reaction time caused decom-
position of 26a and/or 27a, the reaction was terminated
when an approximately 1:2 mixture of 26a/27a was generat-
ed. After recyclingthe recovered startingmaterial 27a four
times, we could obtain 65% yield of the desired compound
26a. On the contrary, the same treatment of the minor prod-
uct 27b turned out to be unsuccessful and the startingmate-
rial was recovered unchanged. Therefore, the projected syn-
thesis was conducted forward usingonly the major coupling
product 27a.
From these results, it is evident that the stereochemistry
of the C10 hydroxy group in substrates 27a,b plays an im-
portant role in the hemiacetal-opening/epimerization reac-
tion. The difference in reactivity between 27a and 27b is
not clear, but can be rationalized by the tentative mechanis-
tic route depicted in Scheme 7. Thus, in the case of 27a, the
formation of six-membered hemiacetal 27a-II would partici-
pate in the equilibrium event between 27a and 27a-I;[16] this
may bringabout an equilibrium shift to 27a-I, facilitating
the production of the desired 26a upon epimerization at C1
in 27a-I. On the other hand, in the case of 27b, the forma-
tion of the six-membered hemiacetal 27b-II would be pre-
cluded due to a severe steric interaction between the aro-
matic ringand the C4-OTBS group in the intermediary 27b-
I; this phenomenon would prohibit the desired production
of 26b.
Scheme 7. Tentative mechanistic route in the hemiacetal-opening/epime-
rization reaction of 27a,b.
Synthesis of intermediate 25: In the next stage, we pursued
the synthesis of the key intermediate 25 as shown in
Scheme 8. Thus, reduction of the formyl group in compound
26a with LiAlH4 followed by complete acetylation of the
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T. Katoh et al.
Scheme 8. Synthesis of intermediate 25. a) LiAlH4, THF, 08C, 96%;
b) Ac2O, DMAP, pyridine, RT, 95%; c) Li, liq. NH3, THF, ꢀ788C, 98%;
d) Dess–Martin periodinane, CH2Cl2, RT, 90%; e) Ph3P+CH3Brꢀ,
tBuOK, benzene, RT!reflux, 95%.
three hydroxy groups in the resulting alcohol 30 furnished
triacetate 31 in 91% overall yield in two steps. Subsequent
reaction of 31 with a large excess of Li metal (100 equiv) in
liquid NH3/THF at ꢀ788C resulted in the desired deoxygen-
ated diol 32 in 98% yield. Simultaneous oxidation of the
primary and secondary hydroxy groups in 32 with Dess–
Martin periodinane provided the correspondingketo-alde-
hyde 33 in 90% yield, which was then subjected to twofold
Wittigmethylenation to give the requisite key intermediate
25 in 95% yield.
Scheme 9. Synthesis of ottelione A (1) and ottelione B (2). a) CF3CO2H,
THF/H2O 10:1, 08C, 86%; b) Ac2O, 2 m NaOH, iPrOH, RT, 91%;
c) CSCl2, DMAP, CH2Cl2, RT, 93%; d) (EtO)3P, reflux, 78%; e) TBAF,
THF, RT, 83%; f) (CHCl2CO)2O, pyridine, CH2Cl2, RT, 79%; g) Dess–
Martin periodinane, CH2Cl2, RT, 95%; h) 50% aqueous NaHCO3/MeCN
1:1, RT, 90%; i) tBuOK, tBuOH, RT, 79% (1/2 23:77 by 500 MHz
1H NMR); isolation of 2 by HPLC, 23%.
Completion of the total synthesis of (+)-ottelione A (1) and
(ꢀ)-ottelione B (2): The final route that led to the comple-
tion of the total synthesis of the targeted ottelione A (1)
and ottelione B (2) is summarized in Scheme 9. The key in-
termediate 25 was initially converted to the triene 37 in four
steps in 57% overall yield by the same reaction sequence
described for the synthesis of 3-epi-ottelione A (3) from
diene 5 (cf. 5!19!20!21!22, Scheme 4). Thus, deprotec-
tion of both the acetonide moiety and the MOM group in
25 by exposure to CF3CO2H/H2O at 08C followed by che-
moselective acetylation of the phenolic hydroxy group in
the resultingtriol 34 afforded acetate 35 in 78% yield in
two steps. Subsequent treatment of the diol 35 with thio-
phosgene in the presence of DMAP furnished the cyclic thi-
ocarbonate 36 in 93% yield, which was then heated in
triethyl phosphite, resulted in the desired diene 37 in 78%
yield. Treatment of 37 with TBAF effected simultaneous de-
protection of the TBS and acetyl groups to give the diol 38
in 83% yield. Chemoselective dichloroacetylation of the
phenolic hydroxy group in 38 furnished the dichloroacetate
39 in 79% yield. It is noteworthy that selection of this di-
chloroacetyl group proved useful at a later deprotection
stage (cf. 40!1) (vide infra). Finally, compound 39 was effi-
ciently converted to ottelione A (1) in 86% overall yield via
a two-step sequence of reactions involvingDess–Martin oxi-
dation of the C4 hydroxy group and removal of the dichlor-
oacetyl group in the resulting dienone 40 by brief exposure
to 50% aqueous NaHCO3 in MeCN at ambient tempera-
ture. In the last deprotection step (40!1), selection of the
dichloroacetyl group proved important because this protect-
ingrgoup could be smoothly and cleanly removed under
mild conditions without appreciable epimerization at the
C3a position. In our preliminary experiment, we had pre-
pared an O-acetyl variant of 40 (R=Ac); unfortunately, all
attempts to remove the O-acetyl group from this compound
under standard conditions (e.g., aq. NaOH, aq. KOH in
MeOH or THF; K2CO3, NaOMe in MeOH) resulted in par-
tial epimerization at the C3a position. We emphasize here
that a only small amount of contamination of the C3a-epi-
merized product [ottelione B (2)] should be precluded for
accurately measuringthe optical rotation of ottelione A ( 1),
because the absolute value of [a]D for ottelione B (vide
infra) is much greater than that for ottelione A.
1
The spectroscopic properties (IR, H and 13C NMR, MS)
of the synthetic sample 1 were identical to those of the natu-
ral product 1. Comparison of the optical rotation [synthetic
1, [a]2D5 =+17.3(c=0.55 in CHCl3); natural 1, [a]2D5 =
+14.0 (c=0.87 in CHCl3)[17,18] established the absolute con-
figuration of (+)-ottelione A (1) to be (1S,3S,3aR,7aS) as
shown in Scheme 9.
9872
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Chem. Eur. J. 2007, 13, 9866 – 9881

Enantioselective Total Synthesis
FULL PAPER
Table 2. Growth inhibition of compounds 1, 3, and 24 against a panel of
39 human cancer cell lines.
Conversion of ottelione A (1) to ottelione B (2) was suc-
cessfully achieved via epimerization at the C3a position by
exposure to tBuOK in tBuOH at room temperature for 2 h,
which resulted in a 23:77 mixture of 1 and 2. Isolation of 2
from this mixture by column chromatography on silica gel
was not effective; therefore, we performed the isolation
usingHPLC (DAICEL CHIRALPAK AD-H) to yield an
entirely pure sample of 2, whose spectroscopic properties
logGI [a] [m]
50
Origin of cancer
breast
Cell line
1
3
24
HBC-4
BSY-1
HBC-5
MCF-7
MDA-MB-
231
ꢀ8.46
ꢀ8.39
ꢀ8.32
ꢀ9.40
ꢀ6.51
ꢀ8.13
ꢀ8.47
ꢀ10.0[c] ꢀ9.51
ꢀ9.74
ꢀ8.47
ꢀ9.13
ꢀ8.11
ꢀ8.16
ꢀ8.49
1
(IR, H and 13C NMR, MS) were identical to those of natu-
central nervous system
(brain)
U-251
ꢀ8.40
ꢀ8.42
ꢀ8.35
ral 2. The optical rotation of a pure synthetic sample of 2
{[a]2D5 =ꢀ333.0(c=0.18 in CHCl3)} was essentially identical
to that of natural 2 (contaminated with a small amount of 1,
2/1 85:15) {[a]D25 =ꢀ276 (c=0.20 in CHCl3)},[17,18] indicating
that natural 2 possesses (1S,3S,3aS,7aS) absolute configura-
tion as depicted in Scheme 9.
SF-268
SF-295
SF-539
SNB-75
SNB-78
HCC2998
KM-12
HT-29
ꢀ8.42
ꢀ8.34
ꢀ9.48
ꢀ8.55
ꢀ9.36
8.66
ꢀ8.43
ꢀ8.66
ꢀ8.95
ꢀ7.47
ꢀ8.71
ꢀ8.55
ꢀ9.30
ꢀ6.22
ꢀ8.45
ꢀ8.30
ꢀ8.34
ꢀ7.49
ꢀ8.60
ꢀ8.40
ꢀ9.46
ꢀ6.62
ꢀ8.62
ꢀ8.66
ꢀ9.33
ꢀ6.42
ꢀ8.61
ꢀ8.38
ꢀ8.28
ꢀ6.77
colon
ꢀ9.41
ꢀ6.40
ꢀ8.46
ꢀ9.14
ꢀ8.49
ꢀ8.84
ꢀ9.67
ꢀ8.48
ꢀ7.55
ꢀ9.56
ꢀ9.40
ꢀ9.03
ꢀ9.80
ꢀ8.44
ꢀ8.09
ꢀ8.50
ꢀ8.45
ꢀ7.02
Preliminary biological evaluation of (+)-ottelione A (1),
(+)-3-epi-ottelione A (3), and (+)-O-acetyl-3-epi-ottelione
A (24)
HCT-15
HCT-116
lungNCI-H23
NCI-H226
NCI-H522
NCI-H460
A549
ꢀ9.56[c] ꢀ9.55[c]
Biological evaluation of unnatural 3-epi-ottelione A (3) and
O-acetyl-3-epi-ottelione A (24) alongwith ( ꢀ)-ottelione A
(1) is of great interest from the viewpoint of structure–activ-
ity relationships. To this end, we used a panel of 39 human
cancer cell lines (termed JFCR39) coupled to a drugactivity
database[19] comparable to the panel developed by the Na-
tional Cancer Institute.[20] The cell growth inhibition profiles
against the JFCR39 (herein termed fingerprints) of more
than 60 standard anticancer drugs were compared using
COMPARE analysis,[19a,c] which showed that this is an infor-
mation-rich approach for identifyingthe molecular target of
a new compound, as described by Paull et al.[20a] This system
can be used to predict the molecular target or the mode of
action of test compounds by assessingthe correlation coeffi-
cient between the fingerprints mediated by such test com-
pounds and various reference compounds with known
modes of action.[21]
The growth inhibitory activity of 1, 3, and 24 was evaluat-
ed by JFCR39 in the Japanese Foundation for Cancer Re-
search.[19] The number of cell lines and their origin (organ)
are as follows: five breast, six central nervous system
(brain), one melanoma, five ovary, two kidney, six stomach,
and two prostate cancers. Dose-response curves were mea-
sured at five different concentrations (10ꢀ10–10ꢀ6 m, one log
interval) for each compound, and the concentration causing
50% cell growth inhibition (GI50) was compared with the
ꢀ8.19
ꢀ7.94
ꢀ8.53
ꢀ8.50
ꢀ8.44
ꢀ8.53
ꢀ7.09
ꢀ7.08
ꢀ8.31
ꢀ8.41
ꢀ8.13
ꢀ8.23
ꢀ8.65
ꢀ8.65
ꢀ8.75
ꢀ8.53
ꢀ7.17
ꢀ7.25
ꢀ8.42
ꢀ8.45
DMS273
DMS114
LOX-IMVI
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
RXF-631 L
ACHN
St-4
MKN1
MKN7
MKN28
MKN45
MKN74
DU-145
PC-3
melanoma
ovary
kidney
ꢀ6.00[b] ꢀ6.71
ꢀ6.00[b] ꢀ8.55
ꢀ8.35
stomach
ꢀ6.29
ꢀ9.12
ꢀ8.58
ꢀ9.14
ꢀ8.26
ꢀ9.41
ꢀ6.00[b] ꢀ6.00[b]
ꢀ8.71
8.90
ꢀ8.91
ꢀ9.11
ꢀ9.24
ꢀ7.20
ꢀ8.43
ꢀ8.50
ꢀ9.15
ꢀ8.22
1.32
ꢀ9.27
ꢀ7.12
ꢀ9.21
prostate
ꢀ6.00[b] ꢀ8.52
ꢀ6.00[b] ꢀ9.18
MG-MID[d]
delta[e]
ꢀ8.44
1.52
ꢀ8.26
1.31
range[f]
4.00
3.56
3.55
[a] Logconcentration that induces 50% inhibition of cell growth com-
pared to control. [b] The least sensitive cell. [c] The most sensitive cell.
[d] Mean value of logGI over all cell lines tested. [e] The difference in
50
logGI value of the most sensitive cell and MG-MID value. [f] The dif-
50
ference in logGI value of the most sensitive cell and the least sensitive
50
cell.
control. The results are presented in Table 2 as logGI
50
values. It was evident that the test compounds exhibited ex-
tremely potent cytotoxic activity against almost all of the 39
cell lines [logGI 50 =ꢀ10.0 (1.0”10ꢀ10 m)–ꢀ6.0 (1.0”
10ꢀ6 m)]. The order of the potency was estimated by MG-
1.32 and 3.55 for 24 (effective value: delta ꢂ 0.5 as well as
range ꢂ 1.0), respectively, indicatingthat all of these com-
pounds showed pronounced selective cytotoxic activity.
Next, the pattern of differential cytotoxicity was analyzed
[19a,c,21]
MID value (mean value of logGI over all cell lines tested)
usingCOMPARE analysis,
which indicated that (+)-
50
to be 1 (ꢀ8.44) > 3 (ꢀ8.26)=24 (ꢀ8.22). The delta values
ottelione A (1) was actingvia a mechanism similar to vin-
cristine (r=0.816) that is widely used in cancer chemothera-
py as a prominent tubulin polymerization inhibitor. Interest-
ingly, the modes of action for 3-epi analogues 3 and 24 did
not correlate with that shown by any other anticancer drugs
(the difference in logGI
value of the most sensitive cell
50
and MG-MID value) and the range values (the difference in
logGI values of the most sensitive cell and the least sensi-
50
tive cell) were 1.52 and 4.00 for 1, 1.31 and 4.00 for 3, and
Chem. Eur. J. 2007, 13, 9866 – 9881
ꢁ 2007 Wiley-VCH VerlagGmbH & Co. KGaA, Weinheim
www.chemeurj.org
9873

T. Katoh et al.
developed to date (3/r=0.481, 24/r=0.422), suggesting that
these compounds may represent new leads for anticancer
agents with a novel action mechanism.
In order to confirm that compounds 1, 3, and 24 actually
inhibit the polymerization of tubulin, we employed the two-
step bioassay for tubulin inhibitors established by the
ScreeningCommittee of New Anticancer Aegnts in
Japan.[22] The results summarized in Table 3 clearly show
Experimental Section
General techniques: All reactions involvingair- and moisture-sensitive
reagents were carried out using oven dried glassware and standard sy-
ringe-septum cap techniques. Routine monitorings 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.
All solvents and reagents were used as supplied with following excep-
tions. THF was freshly distilled from Na metal/benzophenone under
argon. Toluene was distilled from Na metal under argon. CH2Cl2, ben-
zene, and pyridine were distilled from CaH2 under argon.
Table 3. Inhibitory activity of compounds 1, 3, and 24 against tubulin
polymerization.
Measurements of optical rotations were performed with a JASCO P-1020
automatic digital polarimeter. Melting points were taken on a Yanaco
MP-3 micro meltingpoint apparatus and are uncorrected. 1H and
13C NMR spectra were measured with a Bruker DRX-500 (500 MHz)
spectrometer. Chemical shifts were expressed in ppm usingMe 4Si (d=0)
as an internal standard. The followingabbreviations are used: singlet (s),
doublet (d), triplet (t), multiplet (m), and broad (br). Copies of 1H and
13C NMR spectra for all new compounds are shown in the SupportingIn-
formation. Infrared (IR) spectral measurements were carried out with a
JASCO FT/IR-5300 spectrometer. 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 appara-
tus.
1
3
24
510ꢀ9
Vincristine[b]
510ꢀ9
EC[a] [m]
510ꢀ10
>10ꢀ10
[a] Effective concentration that induces inhibition of tubulin polymeri-
zation. [b] Positive control as a representative tubulin polymerization in-
hibitor.
that all of these compounds exhibit potent inhibitory activity
against tubulin polymerization. Compound 1 was found to
exhibit ꢃ10 times more potent activity compared to vincris-
tine, a reference compound. Furthermore, the potency of 3-
epi analogues 3 and 24 was similar or superior to that of vin-
cristine. Consideringthe results obtained by both the COM-
PARE analysis and tubulin inhibitory assay, 3-epi analogues
3 and 24 could be promisingcandidates or potential lead
compounds for the development of novel anticancer agents
targeting tubulin, albeit the binding sites are unknown at
present.
(1R,4S,4aR,5R,6R,7R,8S,8aS)-5-tert-Butyldimethylsiloxy-6,7-O-isopropy-
lidenedioxy-1,4,4a,5,6,7,8,8a-octahydro-endo-methanonaphthalen-8-ol
(13): NaBH4 (153 mg, 4.0 mmol) was added to a stirred solution of
(1R,4S,4aS,5R,6S,7S,8aS)-5-tert-butyldimethylsiloxy-6,7-O-isopropylidene-
dioxy-1,4,4a,5,6,7,8,8a-octahydro-endo-methanonaphthalen-8-one (10)[12]
(737 mg, 2.0 mmol) in THF/H2O 10:1 (22 mL) at 08C. After 30 min, the
reaction was quenched with saturated aqueous NH4Cl (5 mL) at 08C.
The reaction mixture was extracted with Et2O (2”100 mL). The organic
layer was washed successively with saturated aqueous NaHCO3 (2”
50 mL) and brine (2”50 mL), then dried over Na2SO4. Concentration of
the solvent in vacuo afforded a residue, which was purified by column
chromatography (hexane/EtOAc 10:1!4:1) to give 13 (644 mg, 87%) as
a white solid. Recrystallization from hexane/Et2O afforded colorless nee-
dles. M.p. 147.0–147.78C; [a]2D0 =ꢀ25.1 (c=0.98 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=0.10 (s, 6H), 0.90 (s, 9H), 1.23–1.34 (m, 4H),
1.38–1.49 (m, 4H), 2.58–2.79 (m, 2H), 2.80–3.05 (m, 2H), 3.80–4.30 (m,
4H), 6.03 (s, 1H), 6.09 ppm (s, 1H); 13C NMR (125 MHz, CDCl3): d=
ꢀ4.95, ꢀ4.71, 18.0, 23.8, 25.8, 25.9, 26.6, 44.9, 51.7, 78.1, 107.7, 134.5 ppm;
IR (KBr): n˜ =3426, 2934, 2858, 2363, 1630, 1381, 1251, 1207, 1167, 1111,
1064, 898, 862, 837, 777 cmꢀ1; MS (CI): m/z: 367 [M+H]+; elemental
analysis calcd (%) for C20H34O4Si: C 65.53, H 9.35; found: C 65.57, H
9.35.
Conclusion
We initially achieved the total synthesis of (+)-3-epi-otte-
lione A (3), the earlier proposed stereostructure of (+)-otte-
lione A (1) startingfrom the known, readily available tricy-
clic compound 10. Subsequently, by applyingthis approach,
we accomplished the total synthesis of (+)-ottelione A (1)
and (ꢀ)-ottelione B (2); this synthesis resulted in the estab-
lishment of their absolute configurations. Importantly, the
routes explored have potential for preparingvarious types
of ottelione analogues in enantiomerically pure forms due
to their generality and flexibility. Preliminary biological
evaluation of the synthetic (+)-ottelione A (1), (+)-3-epi-ot-
telione A (3), and (+)-O-acetyl-3-epi-ottelione A (24) re-
vealed that all of the test compounds exhibited significant
tumor growth inhibitory activity as well as extremely potent
tubulin inhibitory potency. It was evident that unnatural 3-
epi analogues 3 and 24 displayed a unique tumor growth in-
hibitory profile. On the basis of the present study, further in-
vestigations concerning structure–activity relationships and
in vivo antitumor activity are currently under way and will
be reported in due course.
(2S,2aS,4R,4aS,5R,6R,7R,7aS,7bR)-5-tert-Butyldimethylsiloxy-2-hydroxy-
6,7-(O-isopropylidenedioxy)decahydroindeno[7,1-bc]furan-4-carbalde-
G
hyde (9): OsO4 in tBuOH (0.04m solution, 1.35 mL, 55 mmol) and NaIO4
(467 mg, 2.2 mmol) were added successively to a stirred solution of 13
(200 mg, 0.55 mmol) in tBuOH/THF/H2O 8:6:3 (10 mL) at 08C, and the
mixture was allowed to warm up to room temperature. After 12 h, the re-
action was quenched with 20% aqueous NaS2O3 (10 mL), and the result-
ingmixture was extracted with Et 2O (2”50 mL). The combined extracts
were washed with saturated aqueous NaHCO3 (2”25 mL) and brine (2”
25 mL), then dried over Na2SO4. Concentration of the solvent in vacuo
afforded
a residue, which was purified by column chromatography
(hexane/EtOAc 5:1) to give 9 (163 mg, 75%) as a white solid. Recrystal-
lization from hexane/Et2O afforded colorless needles. M.p. 120.7–
121.58C; [a]2D0 =+19.0 (c=0.99 in CHCl3); 1H NMR (500 MHz, CDCl3):
d=0.06 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 1.34 (s, 3H), 1.44 (s, 3H),
2.07–2.15 (m, 1H), 2.18–2.25 (m, 1H), 2.26 (d, 1H, J=2.3 Hz), 2.74–2.91
(m, 3H), 2.91–2.97 (m, 1H), 4.17 (dd, 1H, J=6.7, 4.5 Hz), 4.23 (s, 1H),
4.46 (dd, 1H, J=12.2, 6.7 Hz), 4.47 (dd, 1H, J=12.2, 6.7 Hz), 5.27 (d,
1H, J=2.3 Hz), 9.93 ppm (s, 1H); 13C NMR (125 MHz, CDCl3): d=
ꢀ4.43, ꢀ4.37, 18.2, 24.3, 25.9, 27.0, 30.2, 40.6, 41.9, 52.0, 55.8, 69.4, 73.6,
9874
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Enantioselective Total Synthesis
FULL PAPER
75.7, 76.0, 103.1, 107.7, 202.9 ppm; IR (KBr): n˜ =3433, 2955, 2928, 2854,
1714, 1469, 1371, 1246, 1221, 1151, 1103, 1057, 1012, 956, 898, 860, 831,
775, 511 cmꢀ1; HRMS (EI): m/z: calcd for C20H34O6Si: 398.2125, found
398.2124 [M]+.
1H), 2.10–2.16 (m, 1H), 2.43–2.50 (m, 1H), 2.83–2.92 (m, 2H), 3.50 (s,
3H), 3.83 (t, 1H, J=4.4 Hz), 3.86 (s, 3H), 4.17 (dd, 1H, J=6.9, 4.4 Hz),
4.36 (dd, 1H, J=6.9, 1.9 Hz), 4.44 (dd, 1H, J=6.9, 2.0 Hz), 5.20 (s, 2H),
5.67 (d, 1H, J=6.9 Hz), 5.92 (s, 1H), 6.83 (d, 1H, J=8.3 Hz), 6.88 (dd,
1H, J=8.3, 1.9 Hz), 7.06 ppm (d, 1H, J=1.9 Hz); 13C NMR (125 MHz,
CDCl3): d=ꢀ4.82, ꢀ4.45, 18.3, 21.3, 21.3, 24.4, 25.9, 26.9, 31.0, 41.7, 49.0,
51.1, 55.9, 56.1. 71.0, 73.9, 75.7, 76.8, 77.2, 79.0, 95.6, 103.7, 107.7, 111.5,
114.5, 120.6, 132.8, 140.6, 149.3, 170.2, 170.3 ppm; IR (neat): n˜ =2934,
(2S,2aS,4S,4aS,5R,6R,7R,7aS,7bR)-5-tert-Butyldimethylsiloxy-2-hydroxy-
6,7-(O-isopropylidenedioxy)decahydroindeno[7,1-bc]furan-4-carbalde-
A
hyde (8): DBU (0.50 mL, 3.3 mmol) was added to a stirred solution of 9
(657 mg, 1.6 mmol) in dry THF (20 mL) at room temperature under
argon. After 2 h, the mixture was diluted with Et2O (100 mL) and the or-
ganic layer was washed successively with 3% aqueous HCl (2”50 mL),
saturated aqueous NaHCO3 (2”50 mL), and brine (50 mL), then dried
over Na2SO4. Concentration of the solvent in vacuo afforded a residue,
which was purified by column chromatography (hexane/EtOAc 2:1) to
give 8 (657 mg, quant.) as a white solid. Recrystallization from hexane/
CH2Cl2 afforded colorless needles. M.p. 108.7–110.08C; [a]2D0 =ꢀ25.0 (c=
0.93 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.06 (s, 3H), 0.11 (s,
3H), 0.87 (s, 9H), 1.36 (s, 3H), 1.48 (s, 3H), 1.72–1.79 (m, 1H), 1.95–2.05
(m, 1H), 2.31 (d, 1H, J=2.2 Hz), 2.46 (ddd, 1H, J=12.5, 7.8, 4.6 Hz),
2.59–2.67 (m, 1H), 2.83–2.88 (m, 1H), 3.00–3.02 (m, 1H), 3.89 (dd, 1H,
J=7.8, 4.6 Hz), 4.13 (dd, 1H, J=7.8, 6.2 Hz), 4.49 (d, 1H, J=6.2 Hz),
4.56 (d, 1H, J=7.3 Hz), 5.22 (d, 1H, J=2.2 Hz), 9.50 ppm (d, 1H, J=
3.7 Hz); 13C NMR (125 MHz, CDCl3): d=ꢀ4.51, ꢀ4.31, 18.1, 25.5, 25.8,
28.1, 31.4, 42.7, 49.5, 50.3, 51.7, 71.9, 76.4, 76.6, 76.8, 103.3, 107.5,
202.0 ppm; IR (KBr): n˜ =3391, 2937, 2891, 1707, 1471, 1386, 1246, 1219,
1089, 1014, 904, 829, 779, 667 cmꢀ1; MS (CI): m/z: 399 [M+H]+; elemen-
tal analysis cald (%) for C20H34O6Si: C 60.27, H 8.64; found: C 60.25, H
8.32.
1741, 1514, 1464, 1373, 1234, 1155, 1134, 1080, 1005, 837, 777, 733 cmꢀ1
;
HRMS (FAB): m/z: calcd for C33H50NaO11Si: 673.3020, found 673.3022
[M+Na]+.
(2S,2aS,4R,4aR,5R,6R,7R,7aS,7bR)-5-tert-Butyldimethylsiloxy-4-[4-me-
thoxy-3-(methyoxymethoxy)benzyl]-6,7-(O-isopropylidenedioxy)decahy-
A
N
dry THF (20 mL) was added dropwise to a stirred solution of Li metal
(215 mg, 31 mmol) in liquid NH3 (40 mL) at ꢀ788C under argon. After
5 min, the reaction was quenched with saturated aqueous NH4Cl (10 mL)
at the same temperature. The mixture was then allowed to stand at room
temperature for 4 h in order to evaporate off excess NH3. The mixture
was extracted with EtOAc (3”100 mL) and the extracts were washed
with saturated aqueous NaHCO3 (2”60 mL) and brine (60 mL), then
dried over Na2SO4. Concentration of the solvent in vacuo afforded a resi-
due, which was purified by column chromatography (hexane/EtOAc 2:1)
to give 6 (299 mg, 87%) as a white solid. Recrystallization from hexane/
Et2O afforded colorless needles. M.p. 112.8–113.58C; [a]2D0 =ꢀ36.6 (c=
0.77 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.10 (s, 3H), 0.13 (s,
3H), 0.91 (s, 9H), 1.36 (s, 3H), 1.47 (s, 3H), 1.43–1.49 (m, 1H), 1.62
(ddd, 1H, J=13.5, 6.3, 3.0 Hz), 1.90–1.95 (m, 1H), 1.96–2.03 (m, 1H),
2.07 (dd, 1H, J=13.1, 10.4 Hz), 2.15 (d, 1H, J=2.1 Hz), 2.65–2.70 (m,
1H), 2.93–2.99 (m, 1H), 3.34 (dd, 1H, J=13.1, 3.7 Hz), 3.52 (s, 3H), 3.85
(s, 3H), 3.93 (dd, 1H, J=7.7, 4.23–4.27 Hz), 4.25 (m, 1H), 4.46–4.49 (m,
2H), 5.07 (d, 1H, J=2.1 Hz), 5.20 (s, 2H), 6.79 (dd, 1H, J=8.2, 1.9 Hz),
6.80 (d, 1H, J=8.2 Hz), 6.91 ppm (d, 1H, J=1.9 Hz); 13C NMR
(125 MHz, CDCl3): d=ꢀ4.50, ꢀ4.42, 18.2, 25.2, 25.9, 27.8, 36.8, 41.1,
42.4, 43.8, 49.0, 49.5, 55.9, 56.2, 72.8, 76.3, 76.9, 77.8, 95.7, 103.4, 107.3,
111.7, 117.4, 122.5, 134.6, 146.1, 148.0 ppm; IR (KBr): n˜ =3449, 2955,
1516, 1257, 1132, 1082, 1006, 837, 779 cmꢀ1; MS (EI): m/z: 550 [M]+; ele-
mental analysis calcd (%) for C29H46O8Si: C 63.24, H 8.42; found: C
63.39, H 8.55.
(2S,2aS,4S,4aR,5R,6R,7R,7aS,7bR)-5-tert-Butyldimethylsiloxy-4-[1-hy-
droxy[4-methoxy-3-(methoxymethoxy)phenyl]methyl]-6,7-(O-isopropyl-
A
N
(1.55m solution, 3.10 mL, 4.8 mmol) was added dropwise to a stirred solu-
tion of 4-bromo-1-methoxy-2-(methoxymethoxy)benzene (7) (1.50 g,
5.2 mmol) in dry THF (50 mL) at ꢀ788C under argon. After 30 min, a so-
lution of 8 (510 mg, 1.3 mmol) in dry THF (25 mL) was added dropwise
to the above mixture at ꢀ788C. After 1 h, the reaction was quenched
with saturated aqueous NH4Cl (10 mL), and the reaction mixture was ex-
tracted with Et2O (2”100 mL). The organic layer was washed with satu-
rated aqueous NaHCO3 (2”30 mL) and brine (2”30 mL), then dried
over Na2SO4. Concentration of the solvent in vacuo afforded a residue,
which was purified by column chromatography (hexane/EtOAc 2:1!1:1)
to give 15 (724 mg, quant.) as an inseparable mixture of two diastereo-
mers (9:1) as a colorless viscous liquid. 1H NMR (500 MHz, CDCl3): d=
0.16 (s, 3H), 0.18 (s, 3H), 0.94 (s, 9H), 1.34 (s, 3H), 1.46 (s, 3H), 1.31–
1.39 (m, 1H), 1.90–1.94 (m, 1H), 2.12–2.20 (m, 1H), 2.17 (s, 1H), 2.31–
2.36 (m, 1H), 2.47 (d, 1H, J=4.4 Hz), 2.54–2.57 (m, 1H), 2.93–2.99 (m,
1H), 3.51 (s, 3H), 3.86 (s, 3H), 3.94 (dd, 1H, J=7.4, 4.1 Hz), 4.25–4.30
(m, 1H), 4.40 (dd, 1H, J=8.4, 2.3 Hz), 4.42 (dd, 1H, J=7.4, 2.3 Hz),
5.01–5.05 (m, 1H), 5.09 (s, 1H), 5.19–5.24 (m, 2H), 6.85 (d, 1H, J=
8.4 Hz), 6.92 (dd, 1H, J=8.4, 1.9 Hz), 7.08 ppm (d, 1H, J=1.9 Hz);
13C NMR (125 MHz, CDCl3): d=ꢀ4.07, ꢀ3.82, 18.5, 23.7, 26.1, 26.4, 32.7,
36.6, 42.1, 52.1, 52.4, 53.4, 55.9, 56.1, 68.6, 74.9, 76.0, 95.6, 103.6, 107.4,
111.7, 114.9, 120.5, 136.6, 146.7, 149.4 ppm; IR (neat): n˜ =3420, 2934,
2858, 1720, 1608, 1512, 1464, 1381, 1257, 1155, 1078, 1005, 912, 837,
779 cmꢀ1; HRMS (FAB): m/z: calcd for C29H45O9Si: 565.2833, found
565.2831 [MꢀH]+.
(1R,3R,3aR,4R,5R,6R,7S,7aR)-4-tert-Butyldimethylsiloxy-7-hydroxy-5,6-
O-isopropylidenedioxy-3-[4-methoxy-3-(methoxymethoxy)benzyl]octahy-
droinden-1-carbaldehyde (17): DBU (2.6 mL, 17 mmol) was added to a
stirred solution of 6 (480 mg, 0.87 mmol) in dry toluene (10 mL) at room
temperature under argon. The mixture was heated at reflux for 1.5 h.
After cooling, the mixture was directly subjected to column chromatogra-
phy on silica gel eluting with EtOAc in order to remove excess DBU.
The fractions containing 17 and startingmaterial 6 were collected and
then concentrated in vacuo. The residue was purified by column chroma-
tography (hexane/EtOAc 4:1) to give less polar 17 (250 mg, 52%, color-
less viscous liquid) and more polar startingmaterial 6 (192 mg, 40%). 17:
[a]2D0 =+7.09 (c=0.92 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.18
(s, 6H), 0.93 (s, 9H), 1.35 (s, 3H), 1.46 (s, 3H), 1.32–1.40 (m, 1H), 1.96–
2.03 (m, 1H), 2.13–2.19 (m, 1H), 2.26–2.35 (m, 1H), 2.40 (dd, 1H, J=
13.4, 9.5 Hz), 2.66–2.73 (m, 1H), 2.85 (dd, 1H, J=13.4, 9.5 Hz), 3.04–3.12
(m, 1H), 3.50 (s, 3H), 3.86 (s, 3H), 3.89 (ddd, 1H, J=12.5, 5.0, 2.9 Hz),
4.01–4.04 (m, 1H), 4.20 (d, 1H, J=12.5 Hz), 4.33 (dd, 1H, J=7.1,
2.8 Hz), 4.53 (dd, 1H, J=7.1, 2.9 Hz), 5.20 (s, 2H), 6.76 (dd, 1H, J=8.2,
1.9 Hz), 6.81 (d, 1H, J=8.2 Hz), 6.97 (d, 1H, J=1.9 Hz), 9.73 ppm (d,
1H, J=1.9 Hz); 13C NMR (125 MHz, CDCl3): d=ꢀ4.33, ꢀ3.85, 18.0,
23.6, 25.7, 26.2, 32.9, 38.5, 40.0, 41.4, 41.7, 52.3, 55.9, 56.1, 67.0, 69.8, 75.5,
76.3, 95.6, 108.3, 111.7, 117.1, 122.5, 132.9, 146.5, 148.2, 203.1 ppm; IR
(neat): n˜ =3418, 2932, 1722, 1514, 1263, 1157, 1026, 839 cmꢀ1; HRMS
(EI): m/z: calcd for C29H46O8Si: 550.2962, found 550.2939 [M]+.
(2R,2aS,4S,4aR,5R,6R,7R,7aS,7bR)-2-Acetoxy-5-tert-butyldimethylsil-
oxy-4-[1-acetoxy-[4-methoxy-3-(methoxymethoxy)phenyl]methyl]-6,7-(O-
isopropylidenedioxy)decahydroindeno[7,1-bc]furan (16): (CH3CO)2O
R
(1.17 mL, 12 mmol) and 4-dimethylaminopyridine (DMAP) (15.0 mg,
0.12 mmol) were added to a stirred solution of 15 (700 mg, 1.2 mmol) in
pyridine (12 mL) at room temperature. After 3 h, the mixture was diluted
with Et2O (120 mL). The organic layer was washed with 3% aqueous
HCl (4”30 mL), saturated aqueous NaHCO3 (2”30 mL), and brine
(30 mL), then dried over Na2SO4. Concentration of the solvent in vacuo
gave a residue, which was purified by column chromatography (hexane/
EtOAc 2:1) to give 16 (804 mg, quant.) as a colorless viscous liquid.
1H NMR (500 MHz, CDCl3): d=0.10 (s, 6H), 0.91 (s, 9H), 1.29 (s, 3H),
1.34 (s, 3H), 1.78–1.85 (m, 1H), 2.02 (s, 3H), 2.08 (s, 3H), 2.03–2.07 (m,
(1R,3R,3aR,4R,5R,6S,7aR)-4-tert-Butyldimethylsiloxy-5,6-O-isopropyli-
denedioxy-3-[4-methoxy-3-(methoxymethoxy)benzyl]-7-oxooctahydroin-
den-1-carbaldehyde (18): Dess–Martin periodinane (865 mg, 2.0 mmol)
was added to a stirred solution of 17 (375 mg, 0.68 mmol) in dry CH2Cl2
(7 mL) at room temperature. After 1 h, the reaction was quenched with
Chem. Eur. J. 2007, 13, 9866 – 9881
ꢁ 2007 Wiley-VCH VerlagGmbH & Co. KGaA, Weinheim
www.chemeurj.org
9875

T. Katoh et al.
10% aqueous Na2S2O3 (3 mL), and the resultingmixture was extracted
with EtO2 (2”50 mL). The organic layer was washed with saturated
aqueous NaHCO3 (2”20 mL) and brine (20 mL), then dried over
Na2SO4. Concentration of the solvent in vacuo afforded a residue, which
was purified by column chromatography (hexane/EtOAc 3:1) to give 18
(336 mg, 90%) as a colorless viscous liquid. [a]2D0 =+17.8 (c=1.19 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=0.03 (s, 3H), 0.04 (s, 3H), 0.82
(s, 9H), 1.34 (s, 3H), 1.30–1.39 (m, 1H), 1.57 (s, 3H), 1.95–2.02 (m, 1H),
2.24–2.33 (m, 1H), 2.58 (dd, 1H, J=13.5, 8.2 Hz), 2.70 (dd, 1H, J=13.5,
6.7 Hz), 2.85 (ddd, 1H, J=11.8, 7.9, 1.7 Hz), 2.99–3.07 (m, 1H), 3.42 (dd,
1H, J=11.8, 10.4 Hz), 3.51 (s, 3H), 3.65 (dd, 1H, J=3.5, 1.7 Hz), 3.86 (s,
3H), 4.26 (d, 1H, J=7.4 Hz), 4.41 (dd, 1H, J=7.4, 3.5 Hz), 5.21 (s, 2H),
6.75 (dd, 1H, J=8.2, 1.9 Hz), 6.82 (d, 1H, J=8.2 Hz), 6.96 (d, 1H, J=
1.9 Hz), 9.82 ppm (d, 1H, J=1.2 Hz); 13C NMR (125 MHz, CDCl3): d=
ꢀ4.67, ꢀ4.48, 17.8, 23.9, 25.5, 26.1, 33.0, 40.5, 42.7, 46.4, 46.5, 53.2, 56.0,
56.1, 69.3, 76.77, 77.3, 80.5, 95.6, 111.8, 112.0, 117.0, 122.5, 132.9, 146.6,
148.2, 202.5, 206.0 ppm; IR (neat): n˜ =2932, 1728, 1512, 1466, 1383, 1261,
(d, 1H, J=8.0 Hz); 13C NMR (125 MHz, CDCl3): d=ꢀ4.78, ꢀ4.43, 17.8,
25.8, 39.5, 39.8, 43.1, 45.7, 48.9, 52.6, 55.9, 68.1, 74.1, 75.7, 110.5, 111.4,
114.2, 114.9, 120.1, 134.6, 141.7, 144.7, 145.3, 145.4 ppm; IR (neat): n˜ =
3429, 2930, 2856, 1591, 1512, 1442, 1273, 1076, 875, 835, 775, 505, 430,
407 cmꢀ1; HRMS (FAB): m/z: calcd for C26H40NaO5Si: 483.2543, found,
483.2546 [M+Na]+.
(1S,3R,3aR,4R,5R,6R,7aS)-3-(3-Acetoxy-4-methoxybenzyl)-4-tert-butyl-
dimethylsiloxy-7-methylene-1-(vinyl)octahydroinden-5,6-diol (20): 2m
NaOH (0.42 mL, 0.84 mmol) and (CH3CO)2O (79 mL, 0.84 mmol) were
added dropwise to a stirred solution of 19 (140 mg, 0.30 mmol) in 2-prop-
anol (3.5 mL) at room temperature. After 30 min, the mixture was dilut-
ed with EtOAc (50 mL). The organic layer was washed with H2O (2”
15 mL) and brine (15 mL), then dried over Na2SO4. Concentration of the
solvent in vacuo gave a residue, which was purified by column chroma-
tography (hexane/EtOAc 2:1) to give 20 (138 mg, 90%) as a colorless vis-
cous liquid. [a]2D0 =+6.16 (c=0.97 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.04 (s, 3H), 0.05 (s, 3H), 0.89 (s, 9H), 1.14 (ddd, 1H, J=
12.9, 10.3, 7.3 Hz), 1.94–1.99 (m, 2H), 2.08–2.14 (m, 1H), 2.14–2.18 (m,
1H), 2.29 (s, 3H), 2.31–2.39 (m, 1H), 2.46–2.54 (m, 2H), 2.67 (dd, 1H,
J=13.5, 6.7 Hz), 2.72–2.81 (m, 1H), 3.58–3.62 (m, 1H), 3.79–3.84 (s, 3H),
3.82 (m, 1H), 4.56–4.60 (m, 1H), 4.87 (d, 1H, J=17.1 Hz), 4.93 (d, 1H,
J=10.2 Hz), 4.96 (s, 1H), 5.18–5.22 (m, 1H), 5.56 (ddd, 1H, J=17.1,
10.2, 7.9 Hz), 6.84 (d, 1H, J=2.1 Hz), 6.87 (d, 1H, J=8.3 Hz), 6.98 ppm
(dd, 1H, J=2.1, 8.3 Hz); 13C NMR (125 MHz, CDCl3): d=ꢀ4.90, ꢀ4.40,
17.8, 20.7, 25.7, 39.7, 39.9, 42.5, 45.2, 48.9, 52.5, 55.9, 68.9, 74.1, 75.5,
111.3, 112.3, 114.3, 123.3, 126.9, 134.1, 139.3, 141.5, 145.5, 149.1,
169.3 ppm; IR (neat): n˜ =3452, 2930, 2856, 1768, 1639, 1512, 1460, 1369,
1263, 1205, 1122, 1066, 1018, 902, 835, 775, 408 cmꢀ1; HRMS (FAB): m/z:
calcd for C28H42NaO6Si: 525.2648, found, 525.2634 [M+Na]+.
1209, 1157, 1076, 1006, 839, 777 cmꢀ1
C29H44O8Si: 548.2805, found 548.2806 [M]+.
; HRMS (EI): m/z: calcd for
(1S,3R,3aR,4R,5R,6R,7aS)-4-tert-Butyldimethylsiloxy-5,6-O-isopropyli-
denedioxy-3-[4-methoxy-3-(methoxymethoxy)benzyl]-7-mehtylene-1-(vi-
nyl)octahydroindene (5): Wittigreagent (Ph 3P=CH2) in benzene solu-
tion was first prepared as follows: a suspension of Ph3P+CH3Brꢀ (1.0 g,
2.8 mmol) and tBuOK (314 mg, 2.8 mmol) in dry benzene (6 mL) were
heated at reflux for 4 h under argon, and the solution was cooled to
room temperature. A solution of the Wittigreagent in benzene (1.0 mL,
0.47 mmol) was added very slowly to a stirred solution of 18 (257 mg,
0.47 mmol) in dry benzene (20 mL) at room temperature under argon.
After the first methylenation of the C1-formyl group was completed
(monitored by TLC), a solution of the Wittigreagent in benzene (4 mL,
1.9 mmol) was added once again and the resulting mixture was heated
under reflux for 30 min to pursue the second methylenation of the C7-
carbonyl group. After cooling, the reaction was quenched with saturated
aqueous NH4Cl (5 mL), and the mixture was extracted with Et2O (2”
50 mL). The organic layer was washed with brine (2”20 mL), 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 5 (224 mg, 88%) as a colorless viscous liquid. [a]2D0 =+9.75 (c=0.77
in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.03 (s, 3H), 0.04 (s, 3H),
0.83 (s, 9H), 1.08–1.19 (m, 1H), 1.35 (s, 3H), 1.49 (s, 3H), 1.78–1.84 (m,
1H), 2.18–2.26 (m, 1H), 2.26–2.32 (m, 1H), 2.45 (dd, 1H, J=13.4,
8.9 Hz), 2.46–2.54 (m, 1H), 2.61–2.68 (m, 1H), 2.78 (dd, 1H, J=13.4,
5.5 Hz), 3.50 (s, 3H), 3.64–3.67 (m, 1H), 3.85 (s, 3H), 4.18 (dd, 1H, J=
7.4, 3.0 Hz), 4.61 (d, 1H, J=7.4 Hz), 4.94 (dd, 1H, J=10.3, 1.0 Hz), 5.00–
5.08 (m, 3H), 5.18–5.23 (m, 2H), 5.81 (ddd, 1H, J=17.4, 10.3, 7.3 Hz),
6.77 (dd, 1H, J=8.2, 1.9 Hz), 6.80 (d, 1H, J=8.2 Hz), 6.97 ppm (d, 1H,
J=1.9 Hz); 13C NMR (125 MHz, CDCl3): d=ꢀ4.73, ꢀ4.37, 17.9, 24.0,
25.6, 26.3, 40.5, 41.0, 41.1, 42.8, 45.0, 48.3, 55.9, 56.1, 70.2, 78.3, 79.1, 95.6,
108.7, 111.6, 112.2, 113.6, 117.2, 122.5, 134.1, 143.0, 145.6, 146.3,
147.8 ppm; IR (neat): n˜ =2928, 2856, 1512, 1462, 1379, 1261, 1209, 1155,
(3aR,4R,4aR,5R,7S,7aS)-5-(3-Acetoxy-4-methoxybenzyl)-4-tert-butyldi-
methylsiloxy-8-methylene-7-(vinyl)octahydroindeno[5,6-d,1,3]dioxol-2-
thione (21): A solution of CSCl2 (50 mL, 0.66 mmol) in dry CH2Cl2
(1.5 mL) was added dropwise to
a stirred solution of 20 (165 mg,
0.33 mmol) in dry CH2Cl2 (6 mL) containingDMAP (200 mg, 1.7 mmol)
at room temperature. After 1 h, silica gel (2.0 g) was added to the reac-
tion mixture, and the solvent was carefully evaporated off in vacuo. The
resulting solid was charged on the top of a silica gel column chromatogra-
phy, and elution with hexane/EtOAc 10:1 gave 21 (172 mg96%) as a col-
orless viscous liquid. [a]2D0 =+5.04 (c=0.91 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=0.01 (s, 3H), 0.02 (s, 3H), 0.81 (s, 9H), 1.15–2.24
(m, 1H), 1.87–1.94 (m, 1H), 2.11–2.16 (m, 1H), 2.16–2.24 (m, 1H), 2.31
(s, 3H), 2.48–2.55 (m, 1H), 2.57 (d, 1H, J=18.3, 8.0 Hz), 2.61–2.72 (m,
2H), 3.66–3.70 (m, 1H), 3.81 (s, 3H), 4.81 (dd, 1H, J=8.6, 3.2 Hz), 5.00
(d, 1H, J=10.2 Hz), 5.07 (d, 1H, J=17.2 Hz), 5.19 (d, 1H, J=2.5 Hz),
5.28 (d, 1H, J=8.6 Hz), 5.32 (d, 1H, J=2.5 Hz), 5.78 (ddd, 1H, J=17.2,
7.6, 10.2 Hz), 6.82 (d, 1H, J=2.1 Hz), 6.90 (d, 1H, J=8.3 Hz), 6.97 ppm
(dd, 1H, J=8.3, 2.1 Hz); 13C NMR (125 MHz, CDCl3): d=ꢀ4.78, ꢀ4.69,
17.8, 20.7, 25.5, 40.4, 40.5, 41.1, 44.4, 48.8, 56.0, 68.0, 77.2, 81.9, 85.5,
112.5, 114.6, 116.7, 123.2, 126.9, 133.2, 139.6, 140.6, 141.7, 149.5, 168.9,
191.0 ppm; IR (neat): n˜ =2930, 2856, 1768, 1512, 1460, 1367, 1329, 1269,
1080, 1030, 902, 837, 810, 775 cmꢀ1
C31H48O6Si: 544.3220, found 544.3224 [M]+.
; HRMS (EI): m/z: calcd for
1203, 1093, 995, 916, 833, 777 cmꢀ1
; HRMS (EI): m/z: calcd for
C29H40O6SSi: 544.2315, found 544.2303 [M]+.
(1S,3R,3aR,4R,5R,6R,7aS)-4-tert-Butyldimethylsiloxy-3-(3-hydroxy-4-me-
thoxybenzyl)-7-methylene-1-(vinyl)octahydroinden-5,6-diol (19): A solu-
tion of CF3CO2H/H2O 10:1 (11 mL) was added to a stirred solution of 5
(230 mg, 0.42 mmol) in THF (1 mL) at 08C. After 10 min, the mixture
was neutralized with 6m NaOH and then extracted with EtOAc (3”
40 mL). The organic layer was washed with saturated aqueous NaHCO3
(2”20 mL) and brine (2”20 mL), then dried over Na2SO4. Concentration
of the solvent in vacuo afforded a residue, which was purified by column
chromatography (hexane/EtOAc 3:1) to give 19 (148 mg, 76%) as a col-
orless viscous liquid. [a]2D0 =+15.1 (c=0.93 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=0.08 (s, 3H), 0.11 (s, 3H), 0.91 (s, 9H), 1.14 (ddd,
1H, J=13.1, 10.1, 6.9 Hz), 1.70 (d, 1H, J=5.9 Hz), 1.91 (d, 1H, J=
7.4 Hz), 2.06–2.15 (m, 2H), 2.35–2.43 (m, 1H), 2.47–2.60 (m, 3H), 2.73–
2.82 (m, 1H), 3.72–3.75 (m, 1H), 3.81–3.85 (m, 1H), 3.86 (s, 3H), 4.61–
4.65 (m, 1H), 4.87 (d, 1H, J=17.0 Hz), 4.93 (d, 1H, J=10.2 Hz), 4.99 (s,
1H), 5.18–5.20 (m, 1H), 5.52 (s, 1H), 5.57 (ddd, 1H, J=17.0, 10.2,
7.9 Hz), 6.62 (dd, 1H, J=8.0, 1.8 Hz), 6.73 (d, 1H, J=1.8 Hz), 6.74 ppm
(1S,3R,3aR,4S,7aS)-3-(3-Acetoxy-4-methoxybenzyl)-4-tert-butyldimethyl-
siloxy-7-methylene-1-vinyl-1,2,3,3a,7,7a-hexahydroindene (22): A solution
of 21 (153 mg, 0.28 mmol) in (EtO)3P (20 mL) was heated at reflux for
2 h under argon. After cooling, excess (EtO)3P was removed through
short column chromatography eluting with hexane. The combined frac-
tions were concentrated in vacuo to afford a residue, which was purified
by column chromatography (hexane/EtOAc 100:1) to give 21 (89.0 mg,
68%) as a colorless viscous liquid. [a]2D0 =+103.3 (c=1.06 in CHCl3);
1H NMR (500 MHz, CDCl3): d=0.04 (s, 3H), 0.07 (s, 3H), 0.88 (s, 9H),
1.15 (ddd, 1H, J=13.1, 8.9, 5.7 Hz), 1.98–2.02 (m, 1H), 2.09 (dt, 1H, J=
13.1, 8.2 Hz), 2.26 (dd, 1H, J=13.5, 7.6 Hz), 2.30 (s, 3H), 2.46–2.54 (m,
2H), 2.66–2.75 (m, 1H), 2.71 (dd, 1H, J=13.5, 8.3 Hz), 3.80 (s, 3H), 4.06
(t, 1H, J=5.0 Hz), 4.81 (s, 1H), 4.88 (d, 1H, J=17.0 Hz), 4.94 (d, 1H,
J=10.2 Hz), 4.99 (s, 1H), 5.65–5.73 (m, 2H), 6.09 (d, 1H, J=9.8 Hz),
6.85 (d, 1H, J=2.1 Hz), 6.86 (d, 1H, J=8.3 Hz), 6.99 ppm (dd, 1H, J=
8.3, 2.1 Hz); 13C NMR (125 MHz, CDCl3): d=ꢀ4.80, ꢀ4.05, 18.0, 20.6,
9876
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ꢁ 2007 Wiley-VCH VerlagGmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9866 – 9881

Enantioselective Total Synthesis
FULL PAPER
25.8, 38.8, 40.4, 42.4, 47.1, 47.1, 50.0, 55.9, 66.6, 112.2, 114.1, 114.7, 123.1,
126.9, 129.8, 130.1, 134.7, 139.4, 142.1, 143.1, 149.0, 169.0 ppm; IR (neat):
n˜ =2928, 2854, 1770, 1512, 1460, 1367, 1265, 1201, 1124, 1028, 885, 835,
773, 432, 414 cmꢀ1; HRMS (FAB): m/z: calcd for C28H41O4Si: 469.2774,
found 469.2771 [M+H]+.
d=37.5, 41.3, 41.9, 48.7, 50.2, 53.7, 56.0, 110.6, 115.4, 115.9, 120.3, 121.5,
126.5, 133.9, 140.5, 140.7, 144.9, 145.3, 145.6, 199.8 ppm; IR (neat): n˜ =
3423, 2920, 1655, 1589, 1510, 1440, 1273, 1234, 1130, 1028, 912, 804,
760 cmꢀ1; HRMS (EI): m/z: calcd for C20H22O3: 310.1569, found 310.1565
[M]+.
(2S,2aS,4R,4aR,5R,6R,7R,7aS,7bR)-5-tert-Butyldimethylsiloxy-4-[1-hy-
droxy-[4-methoxy-3-(methoxymethoxy)phenyl]methyl]-6,7-(O-isopropyl-
(1S,3R,3aR,4S,7aS)-3-(Acetoxy-4-methoxybenzyl)-7-methylene-1-vinyl-
1,2,3,3a,7,7a-hexahydroinden-4-ol (23): Tetra-n-butylammonium fluoride
(TBAF) in THF (1m solution, 0.90 mL, 0.90 mmol) was added to a stirred
solution of 22 (105 mg, 0.22 mmol) in THF (5 mL) at room temperature.
After 16 h, (CH3CO)2O (62 mL, 0.66 mmol) was added very slowly to the
reaction mixture. After 10 min, the reaction was quenched with saturated
aqueous NH4Cl (1 mL), and the resultingmixture was extracted with
EtOAc (2”50 mL). The combined extracts were washed with saturated
aqueous NaHCO3 (2”20 mL) and brine (20 mL), then dried over
Na2SO4. Concentration of solvent in vacuo afforded a residue, which was
purified by column chromatography (hexane/EtOAc 4:1) to give 23
(73 mg, 92%) as a colorless viscous liquid. [a]2D0 =+61.8 (c=0.78 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=1.18–1.35 (m, 2H), 2.02–2.06
(m, 1H), 2.15–2.22 (m, 1H), 2.30 (s, 3H), 2.50–2.59 (m, 2H), 2.60–2.69
(m, 3H), 3.80 (s, 3H), 4.03 (t, 1H, J=5.1 Hz), 4.89 (s, 1H), 4.91 (d, 1H,
J=17.1 Hz), 4.96 (d, 1H, J=10.2 Hz), 5.04 (s, 1H), 5.68 (ddd, 1H, J=
17.1, 10.2, 7.8 Hz), 5.84 (dd, 1H, J=9.8, 5.1 Hz), 6.18 (d, 1H, J=9.8 Hz),
6.87 (d, 1H, J=8.3 Hz), 6.90 (d, 1H, J=2.1 Hz), 7.02 ppm (dd, 1H, J=
8.3, 2.1 Hz); 13C NMR (125 MHz, CDCl3): d=20.7, 38.9, 40.3, 42.4, 46.7,
46.7, 50.7, 55.9, 65.7, 112.2, 114.6, 116.0, 123.1, 127.0, 128.5, 131.4, 134.2,
139.5, 141.4, 142.8, 149.2, 169.1 ppm; IR (neat): n˜ =3516, 1766, 1639,
1512, 1442, 1369, 1267, 1205, 1122, 1014, 904, 810 cmꢀ1; HRMS (EI): m/z:
calcd for C22H26O4: 354.1831, found 354.1843 [M]+.
A
N
ane (1.55m solution, 4.50 mL, 7.0 mmol) was added dropwise to a stirred
solution of 4-bromo-1-methoxy-2-(methoxymethoxy)benzene (7) (2.30 g,
7.7 mmol) in dry THF (40 mL) at ꢀ788C under argon. After 1 h, a solu-
tion of 9 (930 mg, 2.3 mmol) in dry THF (30 mL) was added to the above
mixture at ꢀ788C. After 1 h, the reaction was quenched with saturated
aqueous NH4Cl (10 mL), and the resultingmixture was extracted with
Et2O (2”100 mL). The organic layer was washed with saturated aqueous
NaHCO3 (2”30 mL) and brine (30 mL), then dried over Na2SO4. Con-
centration of the solvent in vacuo afforded a residue, which was purified
by column chromatography (hexane/EtOAc 2:1!1:1) to give 27a (1.06 g,
80%, more polar) and 27b (263 mg, 20%, less polar).
27a: colorless oil; [a]2D0 =+20.1 (c=0.74 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.17 (s, 3H), 0.24 (s, 3H), 0.95 (s, 9H), 1.26 (s, 6H), 1.81
(brs, 1H), 1.88 (brs, 1H), 1.98–2.08 (m, 1H), 2.27 (brs, 1H), 2.29 (d, 1H,
J=2.4 Hz), 2.47–2.56 (m, 1H), 2.76–2.87 (m, 2H), 3.51 (s, 3H), 3.88 (s,
3H), 3.99 (t, 1H, J=3.4 Hz), 4.20–4.25 (m, 1H), 4.42–4.49 (m, 1H), 4.47
(dd, 1H, J=7.1, 1.6 Hz), 4.82–4.89 (m, 1H), 5.23 (s, 2H), 5.27 (d, 1H, J=
2.5 Hz), 6.88 (d, 1H, J=8.3 Hz), 7.03 (dd, 1H, J=8.3, 1.9 Hz), 7.22 ppm
(d, 1H, J=1.9 Hz); 13C NMR (125 MHz, CDCl3): d=ꢀ4.07, ꢀ3.82, 18.5,
23.7, 26.1, 26.4, 32.7, 36.6, 42.1, 52.1, 52.4, 53.4, 55.9, 56.1, 68.6, 73.9, 74.9,
76.0, 95.6, 103.6, 107.4, 111.7, 114.9, 120.5, 136.6, 146.7, 149.4 ppm; IR
(neat): n˜ =3423, 2932, 2856, 1606, 1510, 1464, 1385, 1259, 1211, 1155,
(1S,3R,3aR,7aS)-3-(3-Acetoxy-4-methoxybenzyl)-7-methylene-1-vinyl-
1,2,3,3a,7,7a-hexahydroinden-4-one (24): Dess–Martin periodinane
(81.0 mg, 0.51 mmol) was added in small portions to a stirred solution of
23 (90.0 mg, 0.25 mmol) in dry CH2Cl2 (6 mL) at room temperature.
After 30 min, the reaction was quenched with 20% aqueous Na2S2O3
(1.5 mL), and the mixture was extracted with EtOAc (2”25 mL). The
combined extracts were washed with brine (2”15 mL), then dried over
Na2SO4. Concentration of the solvent in vacuo afforded a residue, which
was purified by column chromatography (hexane/EtOAc 5:1) to give 24
(74.9 mg, 84%) as a white cloudy oil. [a]2D0 =+18.0 (c=0.67 in CHCl3);
1H NMR (500 MHz, CDCl3): d=1.20 (ddd, 1H, J=13.0, 10.6, 7.5 Hz),
1.99 (dt, 1H, J=13.0, 7.7 Hz), 2.24 (m, 1H), 2.30 (s, 3H), 2.57 (dd, 1H,
J=8.2, 3.6 Hz), 2.61 (dd, 1H, J=13.9, 8.6 Hz), 2.72 (dd, 1H, J=10.6,
8.2 Hz), 2.84 (dd, 1H, J=13.0, 7.0 Hz), 2.90–2.99 (m, 1H), 3.80 (s, 3H),
4.87 (d, 1H, J=17.0 Hz), 5.00 (d, 1H, J=10.2 Hz), 5.21 (s, 1H), 5.36 (s,
1H), 5.62 (ddd, 1H, J=17.0, 10.2, 8.1 Hz), 5.90 (d, 1H, J=9.4 Hz), 6.88
(d, 1H, J=8.3 Hz), 6.92 (d, 1H, J=2.1 Hz), 6.95 (d, 1H, J=9.4 Hz),
7.08 ppm (dd, 1H, J=8.3, 2.1 Hz); 13C NMR (125 MHz, CDCl3): d=20.7,
37.6, 41.2, 41.7, 48.7, 50.2, 53.7, 55.9, 112.3, 116.0, 121.6, 123.4, 126.5,
133.2, 139.5, 140.3, 140.5, 145.7, 149.4, 169.1, 199.7, 127.1 ppm; IR (neat):
n˜ =2934, 1766, 1664, 1581, 1512, 1442, 1369, 1267, 1203, 1124, 1028, 906,
812, 779 cmꢀ1; HRMS (EI): m/z: calcd for C22H24O4: 352.1675, found
352.1674 [M]+.
1132, 1080, 1012, 868, 835, 775 cmꢀ1
; HRMS (EI): m/z: calcd for
C29H46O9Si: 566.2911, found 566.2904 [M]+.
27b: colorless oil; [a]2D0 =+12.5 (c=0.74 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.20 (s, 3H), 0.24 (s, 3H), 0.97 (s, 9H), 1.26 (s, 3H), 1.36–1.44
(m, 1H), 1.44 (s, 3H), 1.67–1.78 (m, 1H), 1.77 (m, 1H), 2.15–2.18 (m,
1H), 2.36–2.40 (m, 1H), 2.51–2.58 (m, 1H), 2.63–2.72 (m, 1H), 2.84–2.93
(m, 1H), 3.51 (s, 3H), 3.84–3.90 (m, 3H), 4.36 (m, 1H), 4.48 (d, 1H, J=
7.0 Hz), 4.54 (d, 1H, J=6.4 Hz), 4.55–4.60 (m, 1H), 4.86 (d, 1H, J=
10.7 Hz), 5.18 (s, 1H), 5.21 (s, 2H), 6.87 (d, 1H, J=8.3 Hz), 6.97 (d, 1H,
J=7.7 Hz), 7.19 ppm (s, 1H); 13C NMR (125 MHz, CDCl3): d=ꢀ3.81,
ꢀ3.66, 18.5, 23.7, 25.8, 26.2, 26.5, 32.6, 36.4, 42.0, 52.6, 53.1, 68.3, 72.4,
73.8, 74.5, 75.1, 95.6, 103.8, 107.5, 111.6, 114.8, 120.0, 137.6, 146.4,
149.3 ppm; IR (neat): n˜ =3435, 2934, 1510, 1464, 1383, 1261, 1157, 1078,
1049, 1006, 868, 835, 775 cmꢀ1; HRMS (FAB): m/z: calcd for C29H46O9Si:
566.2911, found 566.2914 [M]+.
(1R,3R,3aR,4R,5R,6R,7S,7aS)-4-tert-Butyldimethylsiloxy-7-hydroxy-3-
[(1S)-hydroxy[4-methoxy-3-(methoxymethoxy)phenyl]methyl]-5,6-(O-iso-
propylidenedioxy)octahydroinden-1-carbaldehyde (26a): DBU (4.70 mL,
32 mmol) was added to a stirred solution of 27a (900 mg, 1.6 mmol) in
dry toluene (30 mL) at room temperature under argon. The mixture was
heated at reflux for 1.5 h. After cooling, the mixture was directly subject-
ed to column chromatography eluting with EtOAc in order to remove
excess DBU. The fractions containing 26a and startingmaterial 27a were
collected and then concentrated in vacuo. The residue was purified by
column chromatography (hexane/EtOAc 2:1!1:1) to give less polar 26a
(270 mg, 30%) as a colorless viscous liquid and more polar starting mate-
rial 27a (540 mg, 60%).
26a: [a]2D0 =ꢀ34.3 (c=0.98 in CHCl3); 1H NMR (500 MHz, CDCl3): d=
0.23 (s, 6H), 0.31 (s, 3H), 0.97 (s, 9H), 1.24 (d, 6H, J=2.0 Hz), 2.01–2.12
(m, 1H), 2.22–2.43 (m, 3H), 3.02–3.09 (m, 1H), 3.37–3.43 (m, 1H), 3.50
(s, 3H), 3.82–3.89 (m, 2H), 3.87 (s, 3H), 4.02 (ddd, 1H, J=10.8, 6.6,
4.1 Hz), 4.14–4.21 (m, 1H), 4.45 (br, 1H), 4.73 (br, 1H), 6.87 (d, 1H, J=
8.3 Hz), 6.99 (dd, 1H, J=8.3, 2.0 Hz), 7.18 (d, 1H, J=2.0 Hz), 9.73 ppm
(s, 1H); 13C NMR (125 MHz, CDCl3): d=ꢀ4.33, ꢀ3.84, 14.2, 18.1, 21.0,
23.8, 25.9, 26.1, 50.7, 55.9, 56.2, 60.3, 75.7, 75.9, 77.2, 95.6, 108.5, 111.8,
114.9, 120.1, 135.9, 146.7, 203.0 ppm; IR (neat): n˜ =3422, 2934, 2860,
1718, 1512, 1383, 1261, 1211, 1155, 1078, 1022, 864, 839, 781 cmꢀ1; HRMS
(EI): m/z: calcd for C29H46O9Si: 566.2911, found 566.2916 [M]+.
(1S,3R,3aR,7aS)-3-(3-Hydroxy-4-methoxybenzyl)-7-methylene-1-vinyl-
1,2,3,3a,7,7a-hexahydroinden-4-one (3) (3-epi-ottelione A): K2CO3
(29.0 mg, 0.21 mmol) was added in small portions to a stirred solution of
24 (74.0 mg, 0.21 mmol) in MeOH (4 mL) at 08C. After 30 min, the mix-
ture was diluted with EtOAc (30 mL). The organic layer was washed suc-
cessively with 3% aqueous HCl (2”6 mL), saturated aqueous NaHCO3
(2”6 mL) and brine (3 mL), then dried over Na2SO4. Concentration of
the solvent in vacuo gave a residue, which was purified by column chro-
matography (hexane/EtOAc 4:1) to give 3 (63.8 mg, 98%) as a white
cloudy oil. [a]2D0 =+15.6 (c=0.32 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=1.20 (ddd, 1H, J=17.7, 10.3, 7.4 Hz), 1.98 (dt, 1H, J=13.1,
7.8 Hz), 2.19–2.28 (m, 1H), 2.54–2.60 (m, 2H), 2.73 (dd, 1H, J=10.6,
8.4 Hz), 2.79 (dd, 1H, J=13.7, 7.1 Hz), 2.90–2.98 (m, 1H), 3.85 (s, 3H),
4.87 (d, 1H, J=17.0 Hz), 4.99 (d, 1H, J=10.2 Hz), 5.21 (s, 1H), 5.36 (s,
1H), 5.53 (s, 1H), 5.64 (ddd, 1H, J=17.0, 10.2, 8.1 Hz), 5.88–5.92 (m,
1H), 6.73 (dd, 1H, J=8.1, 1.9 Hz), 6.77 (d, 1H, J=8.1 Hz), 6.81 (d, 1H,
J=1.9 Hz), 6.94 ppm (d, 1H, J=9.9 Hz); 13C NMR (125 MHz, CDCl3):
Chem. Eur. J. 2007, 13, 9866 – 9881
ꢁ 2007 Wiley-VCH VerlagGmbH & Co. KGaA, Weinheim
www.chemeurj.org
9877

T. Katoh et al.
(1R,3R,3aS,4S,5R,6R,7R,7aR)-7-tert-Butyldimethylsiloxy-1-[(1S)-hy-
droxy[4-methoxy-3-(methoxymethoxy)phenyl]methyl]-3-hydroxymethyl-
5,6-(O-isopropylidenedioxy)octahydroinden-4-ol (30): A solution of 26a
(306 mg, 0.54 mmol) in dry THF (6 mL) was added dropwise to a stirred
suspension of LiAlH4 (41.0 mg, 1.1 mmol) in dry THF (4 mL) at 08C
under argon. After 1 min, H2O (40 mL), 15% aqueous NaOH (40 mL),
H2O (0.12 mL), and Na2SO4 (500 mg) were added successively to the re-
action mixture at 08C, and the resultingmixture was further stirred for
30 min at room temperature. The mixture was filtrated through a pad of
Celite, and the filtrate was concentrated in vacuo to afford a residue,
which was purified by column chromatography (hexane/EtOAc 1:1!
6.99 ppm (d, 1H, J=1.9 Hz); 13C NMR (125 MHz, CDCl3): d=ꢀ4.46,
ꢀ3.56, 18.1, 24.0, 25.9, 26.4, 33.8, 35.4, 40.1, 40.6, 42.4, 42.8, 55.9, 56.1,
67.1, 67.3, 71.6, 76.1, 76.3, 95.5, 108.4, 111.6, 116.9, 122.1, 134.3, 146.3,
147.8 ppm; IR (neat): n˜ =3433, 2932, 2858, 1512, 1466, 1383, 1261, 1211,
1155, 1134, 1078, 1016, 923, 868, 837, 808, 779 cmꢀ1; HRMS (EI): m/z:
calcd for C29H48O8Si: 552.3118, found 552.3129 [M]+.
(1R,3S,3aR,4R,5R,6S,7aR)-4-tert-Butyldimethylsiloxy-5,6-O-isopropyli-
dene-3-[4-methoxy-3-(methoxymethoxy)benzyl]-7-oxooctahydroinden-1-
carbaldehyde (33): Dess–Martin periodinane (609 mg, 1.4 mmol) was
added in small portions to a stirred solution of 32 (265 mg, 0.48 mmol) in
dry CH2Cl2 (10 mL) at room temperature. After 30 min, the reaction was
quenched with 10% aqueous Na2S2O3 (3 mL), and the resultingmixture
was extracted with Et2O (2”50 mL). The organic layer was washed suc-
cessively with saturated aqueous NaHCO3 (2”20 mL) and brine (20 mL),
then dried over Na2SO4. Concentration of the solvent in vacuo afforded a
residue, which was purified by column chromatography (hexane/EtOAc
6:1) to give 33 (237 mg, 90%) as a colorless viscous oil. [a]2D0 =+24.5 (c=
2.50 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.16 (s, 3H), 0.22 (s,
3H), 0.86 (s, 9H), 1.34 (s, 3H), 1.57 (s, 3H), 1.82–1.92 (m, 2H), 2.13–2.23
(m, 1H), 2.57 (dd, 1H, J=13.5, 10.0 Hz), 2.81 (dd, 1H, J=13.5, 5.3 Hz),
3.13–3.18 (m, 1H), 3.47–3.54 (m, 1H), 3.51 (s, 3H), 3.68 (dd, 1H, J=9.6,
5.1 Hz), 3.86 (s, 3H), 4.09–4.12 (m, 1H), 4.33 (d, 1H, J=7.4 Hz), 4.40
(dd, 1H, J=7.4, 3.1 Hz), 5.21 (s, 2H), 6.75 (dd, 1H, J=8.2, 1.9 Hz), 6.82
(d, 1H, J=8.2 Hz), 6.97 (d, 1H, J=1.9 Hz), 9.63 ppm (s, 1H); 13C NMR
(125 MHz, CDCl3): d=ꢀ4.07, ꢀ3.56, 17.9, 24.0, 25.6, 25.9, 30.5, 35.2,
43.3, 44.1, 44.8, 52.1, 55.9, 56.1, 68.8, 77.2, 80.4, 95.5, 111.7, 112.0, 116.7,
121.9, 133.2, 146.4, 148.0, 201.9, 206.2 ppm; IR (neat): n˜ =2932, 2858,
1728, 1514, 1466, 1383, 1263, 1209, 1157, 1134, 1060, 1006, 925, 858, 837,
808, 777, 538, 468, 405 cmꢀ1; HRMS (EI): m/z: calcd for C29H44O8Si:
548.2805, found 548.2801 [M]+.
EtOAc) to give 30 (294 mg, 96%) as a colorless viscous liquid. [a]D20
=
ꢀ36.6 (c=0.83 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.22 (s, 3H),
0.27 (s, 3H), 0.96 (s, 9H), 1.26 (s, 6H), 1.63 (br, 1H), 1.74 (br, 1H), 1.91–
1.99 (m, 1H), 2.31–2.39 (m, 2H), 2.46–2.54 (m, 1H), 2.68 (br, 1H), 3.43
(m, 1H), 3.51 (s, 3H), 3.48–3.56 (m, 1H), 3.55–3.62 (m, 1H), 3.83–3.90
(m, 1H), 3.87 (s, 3H), 4.04 (br, 1H), 4.17–4.22 (m, 1H), 4.42 (dd, 1H, J=
7.3, 5.2 Hz), 4.80–4.84 (m, 1H), 5.23 (s, 2H), 6.87 (d, 1H, J=8.3 Hz), 7.01
(dd, 1H, J=8.3, 2.0 Hz), 7.19 ppm (d, 1H, J=2.0 Hz); 13C NMR
(125 MHz, CDCl3): d=ꢀ4.31, ꢀ3.99, 18.1, 24.0, 25.9, 26.1, 26.2, 30.2,
40.0, 43.7, 49.0, 55.9, 56.2, 67.3, 67.4, 72.0, 73.0, 76.4, 76.5, 95.5, 108.5,
111.5, 114.5, 120.0, 136.4, 146.5, 149.1 ppm; IR (neat): n˜ =3435, 2932,
1512, 1383, 1259, 1155, 1078, 1018, 864, 837, 779 cmꢀ1; HRMS (EI): m/z:
calcd for C29H48O9Si: 568.3068, found 568.3085 [M]+.
(1R,3R,3aS,4S,5R,6R,7R,7aR)-4-Acetoxy-3-acetoxymethyl-7-tert-butyldi-
methylsiloxy-1-[(1S)-acetoxy[4-methoxy-3-(methoxymethoxy)phenyl]-
methyl]-5,6-(O-isopropylidenedioxy)octahydroindene (31): (CH3CO)2O
(1.50 mL, 16 mmol) and DMAP (19.0 mg, 0.16 mmol) were added to a
stirred solution of 30 (294 mg, 0.52 mmol) in pyridine (5 mL) at room
temperature. After 1 h, the mixture was diluted with Et2O (50 mL). The
organic layer was washed successively with 3% aqueous HCl (2”10 mL),
saturated aqueous NaHCO3 (2”10 mL) and brine (10 mL), then dried
over Na2SO4. Concentration of the solvent in vacuo gave a residue, which
was purified by column chromatography (hexane/EtOAc 1:1) to give 31
(341 mg, 95%) as a colorless viscous liquid. [a]2D0 =ꢀ38.8 (c=1.16 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=0.20 (s, 3H), 0.33 (s, 3H), 0.96
(s, 9H), 1.13 (s, 3H), 1.21 (s, 3H), 1.62 (ddd, 1H, J=12.6, 8.6, 3.8 Hz),
1.99 (s, 3H), 2.03 (s, 3H), 2.09 (s, 3H), 1.96–2.13 (m, 2H), 2.31–2.37 (m,
1H), 2.65–2.76 (m, 1H), 2.76–2.84 (m, 1H), 3.51 (s, 3H), 3.86 (s, 3H),
3.84–3.89 (m, 1H), 3.94–4.03 (m, 2H), 4.06 (dd, 1H, J=6.3, 2.4 Hz), 4.21
(dd, 1H, J=6.3, 4.9 Hz), 5.20–5.26 (m, 2H), 5.43 (dd, 1H, J=8.4,
4.7 Hz), 5.82 (d, 1H, J=10.6 Hz), 6.86 (d, 1H, J=8.3 Hz), 7.05 (dd, 1H,
J=8.3, 1.9 Hz), 7.23 ppm (d, 1H, J=1.9 Hz); 13C NMR (125 MHz,
CDCl3): d=ꢀ3.96, ꢀ3.89, 18.1, 20.9, 21.2, 24.7, 26.0, 26.4, 31.9, 37.3, 39.7,
41.8, 46.0, 55.9, 56.2, 68.2, 68.8, 69.3, 73.5, 76.6, 77.1, 95.6, 108.1, 111.3,
115.4, 121.7, 132.5, 146.5, 149.6, 169.9, 170.4, 171.3 ppm; IR (neat): n˜ =
2935, 2856, 1738, 1608, 1516, 1466, 1371, 1238, 1157, 1371, 1238, 1157,
1132, 1078, 1024, 869, 837, 775, 607, 518, 412 cmꢀ1; HRMS (EI): m/z:
calcd for C35H54O12Si: 694.3385, found 694.3380 [M]+.
(1S,3S,3aR,4R,5R,6R,7aS)-4-tert-Butyldimethylsiloxy-5,6-O-isopropylide-
nedioxy-3-[4-methoxy-3-(methoxymethoxy)benzyl]-7-methylene-1-(vi-
nyl)octahydroindene (25): Wittigreagent (Ph 3P=CH2) in benzene solu-
tion was first prepared as follows: a suspension of Ph3P+CH3Brꢀ(1.22 g,
3.4 mmol) and tBuOK (380 mg, 3.4 mmol) in dry benzene (10 mL) were
heated at reflux for 4 h under argon, and the solution was cooled to
room temperature. A solution of the Wittigreagent in benzene (1.0 mL,
0.34 mmol) was added very slowly to a stirred solution of 33 (187 mg,
0.34 mmol) in dry benzene (8 mL) at room temperature under argon.
After the first methylenation of the C1-formyl group was completed
(monitored by TLC),
a solution of the Wittigreaegnt in benzene
(4.0 mL, 1.36 mmol) was added once again and the resulting mixture was
heated under reflux for 30 min to pursue the second methylenation of
the C7-carbonyl group. The reaction was quenched with saturated aque-
ous NH4Cl (5 mL), and the mixture was extracted with Et2O (2”50 mL).
The organic layer was washed with brine (2”30 mL), then dried over
Na2SO4. Concentration of the solvent in vacuo afforded a residue, which
was purified by column chromatography (hexane/EtOAc 20:1!10:1) to
give 25 (176 mg, 95%) as a colorless viscous liquid. [a]2D0 =ꢀ21.9 (c=0.93
in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.14 (s, 3H), 0.18 (s, 3H),
0.88 (s, 9H), 1.35 (s, 3H), 1.41 (ddd, 1H, J=12.2, 8.4, 3.6 Hz), 1.45 (s,
3H), 1.91–2.00 (m, 1H), 2.36–2.45 (m, 1H), 2.53 (dd, 1H, J=13.3,
10.3 Hz), 2.58–2.63 (m, 1H), 2.72–2.78 (m, 1H), 2.83 (dd, 1H, J=13.3,
5.2 Hz), 2.85–2.93 (m, 1H), 3.51 (s, 3H), 3.84 (s, 3H), 3.95–3.98 (m, 1H),
4.15 (dd, 1H, J=7.3, 2.4 Hz), 4.62 (d, 1H, J=7.3 Hz), 4.84–4.88 (m, 1H),
4.93–4.99 (m, 1H), 5.14–5.17 (m, 1H), 5.21–5.24 (s, 2H), 5.22 (m, 1H),
5.88 (ddd, 1H, J=17.8, 10.2, 7.8 Hz), 6.78–6.81 (m, 2H), 7.00 ppm (d,
1H, J=1.3 Hz); 13C NMR (125 MHz, CDCl3): d=ꢀ4.15, ꢀ3.57, 18.0,
24.2, 25.8, 26.4, 36.2, 38.2, 42.0, 43.0, 44.8, 49.2, 55.9, 56.1, 70.0, 78.5, 78.8,
95.6, 108.6, 111.6, 111.7, 114.1, 117.0, 122.2, 134.6, 145.8, 146.1, 146.3,
147.8 ppm; IR (neat): n˜ =2932, 2858, 1637, 1512, 1464, 1381, 1259, 1209,
1157, 1134, 1078, 1059, 1030, 1005, 908, 864, 835, 810, 775 cmꢀ1; HRMS
(EI): m/z: calcd for C31H48O6Si: 544.3220, found 544.3224 [M]+.
(1S,3R,3aS,4S,5R,6R,7R,7aR)-7-tert-Butyldimethylsiloxy-3-hydroxymeth-
yl-5,6-O-isopropylidenedioxy-1-[4-methyoxy-3-(methoxymethoxy)benzyl]-
octahydroinden-4-ol (32): A solution of 31 (340 mg, 0.49 mmol) in dry
THF (15 mL) was added dropwise to a stirred solution of Li metal
(100 mg, 9.0 mmol) in liquid NH3 (30 mL) at ꢀ788C under argon. After
5 min, the reaction was quenched with saturated aqueous NH4Cl (5 mL)
at the same temperature. The mixture was then allowed to stand at room
temperature for 4 h in order to evaporate off excess NH3. The mixture
was extracted with EtOAc (2”100 mL) and the extracts were washed
with saturated aqueous NaHCO3 (2”50 mL) and brine (50 mL), then
dried over Na2SO4. Concentration of the solvent in vacuo afforded a resi-
due, which was purified by column chromatography (hexane/EtOAc 1:1)
to give 32 (265 mg, 98%) as
a =
colorless viscous liquid. [a]D20
ꢀ27.7(c=0.91 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.23 (s, 3H),
0.26 (s, 3H), 0.97 (s, 9H), 1.34 (s, 3H), 1.44 (s, 3H), 1.42–1.49 (m, 1H),
1.64–1.71 (m, 1H), 1.81 (br, 1H), 2.26–2.38 (m, 2H), 2.50–2.57 (m, 2H),
2.61–2.69 (m, 1H), 2.88 (dd, 1H, J=13.3, 4.6 Hz), 3.43 (dd, 1H, J=10.3,
7.3 Hz), 3.51 (m, 1H), 3.52 (s, 3H), 3.86 (s, 3H), 3.90–4.04 (m, 2H), 4.06
(t, 1H, J=3.0 Hz), 4.28 (dd, 1H, J=7.2, 2.9 Hz), 4.50–4.55 (m, 1H),
5.19–5.23 (m, 2H), 6.77 (dd, 1H, J=8.2, 1.9 Hz), 6.82 (d, 1H, J=8.2 Hz),
(1S,3S,3aR,4R,5R,6R,7aS)-4-tert-Butyldimethylsiloxy-3-(3-hydroxy-4-
methoxybenzyl)-7-methylene-1-vinyloctahydroinden-5,6-diol (34): A solu-
tion of TFA/H2O 10:1 (11 mL) was added dropwise to a stirred solution
of 25 (177 mg, 0.33 mmol) in THF (1 mL) at 08C. After 10 min, the reac-
tion mixture was neutralized with 6m NaOH and extracted with EtOAc
9878
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ꢁ 2007 Wiley-VCH VerlagGmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9866 – 9881

Enantioselective Total Synthesis
FULL PAPER
(3”40 mL). The organic layer was washed with saturated aqueous
NaHCO3 (2”20 mL) and brine (30 mL), then dried over Na2SO4. Con-
centration of the solvent in vacuo afforded a residue, which was purified
by column chromatography (hexane/EtOAc 3:1) to give 34 (129 mg,
86%) as a colorless viscous liquid. [a]2D0 =+19.2 (c=1.97 in CHCl3);
1H NMR (500 MHz, CDCl3): d=0.22 (s, 3H), 0.26 (s, 3H), 0.98 (s, 9H),
1.59 (ddd, 1H, J=15.8, 10.0, 5.7 Hz), 1.74 (d, 1H, J=6.1 Hz), 1.93 (d,
1H, J=7.5 Hz), 1.96–2.00 (m, 1H), 2.27–2.33 (m, 1H), 2.41–2.51 (m,
2H), 2.69 (dd, 1H, J=13.6, 8.9 Hz), 2.77–2.86 (m, 2H), 3.86 (s, 3H),
3.95–3.99 (m, 1H), 4.26 (t, 1H, J=4.0 Hz), 4.70–4.74 (m, 1H), 4.80–4.85
(m, 1H), 4.86–4.90 (m, 1H), 4.95 (s, 1H), 5.15 (t, 1H, J=1.8 Hz), 5.54 (s,
1H), 5.62 (ddd, 1H, J=18.3, 10.1, 8.3 Hz), 6.66 (dd, 1H, J=8.2, 2.1 Hz),
6.76 (d, 1H, J=8.2 Hz), 6.78 ppm (d, 1H, J=2.1 Hz); 13C NMR
(125 MHz, CDCl3): d = ꢀ4.05, ꢀ3.37, 18.1, 26.1, 35.5, 37.1, 43.2, 44.2,
47.5, 54.3, 56.0, 68.2, 72.7, 75.4, 110.6, 110.8, 113.4, 114.6, 119.6, 135.3,
142.8, 144.7, 145.4, 145.8 ppm; IR (neat): n˜ =3422, 2932, 2858, 1639, 1591,
1512, 1442, 1259, 1130, 1062, 1037, 904, 873, 835, 775, 706 cmꢀ1; HRMS
(FAB): m/z: calcd for C26H41O5Si: 461.2723, found 461.2697 [M+H]+.
under argon. After cooling, excess (EtO)3P was removed usingshort
column chromatography eluting with hexane. The combined fractions
were concentrated in vacuo to afford a residue, which was purified by
column chromatography (benzene/EtOAc 100:1) to give 37 (32.2 mg,
78%) as a colorless viscous liquid. [a]2D0 =+98.4 (c=1.07 in CHCl3);
1H NMR (500 MHz, CDCl3): d=0.11 (s, 3H), 0.16 (s, 3H), 0.92 (s, 9H),
1.50–1.57 (m, 1H), 1.93 (ddd, 1H, J=12.7, 10.1, 8.3 Hz), 2.13 (m, 1H),
2.30 (s, 3H), 2.38–2.50 (m, 2H), 2.70 (dd, 1H, J=13.7, 9.3 Hz), 2.78–2.87
(m, 1H), 2.96 (dd, 1H, J=13.7, 6.0 Hz), 3.80 (s, 3H), 4.45 (t, 1H, J=
4.9 Hz), 4.84–4.92 (m, 3H), 4.95 (s, 1H), 5.73 (ddd, 1H, J=16.9, 10.0,
8.8 Hz), 5.83 (dd, 1H, J=9.7, 4.9 Hz), 6.13 (d, 1H, J=9.8 Hz), 6.85–6.89
(m, 2H), 7.01 ppm (dd, 1H, J=8.3, 2.0 Hz); 13C NMR (125 MHz,
CDCl3): d=ꢀ4.08, ꢀ3.29, 18.1, 20.7, 26.0, 35.7, 43.9, 45.9, 47.9, 49.6, 55.9,
65.5, 112.2, 113.5, 114.3, 122.8, 126.6, 129.9, 131.1, 135.4, 139.5, 143.3,
144.0, 148.9, 169.0 ppm; IR (neat): n˜ =2928, 2857, 1771, 1512, 1464, 1368,
1262, 1204, 1125, 1030, 882, 835, 773 cmꢀ1; HRMS (EI): m/z: calcd for
C28H40O4Si: 468.2696, found 468.2700 [M]+.
(1S,3S,3aR,4S,7aS)-3-(3-Hydroxy-4-methoxybenzyl)-7-methylene-1-vinyl-
1,2,3,3a,7,7a-hexahydroinden-4-ol (38): Tetra-n-butylammonium fluoride
(TBAF) in THF (1m solution, 0.86 mL. 0.86 mmol) was added to a stirred
solution of 37 (40.0 mg, 85 mmol) in THF (2 mL) at room temperature.
After 48 h, the reaction was quenched with saturated aqueous NH4Cl
(1 mL), and extracted with EtOAc (2”30 mL). The combined extracts
were washed successively with saturated aqueous NaHCO3 (2”10 mL)
and brine (10 mL), then dried over Na2SO4. Concentration of the solvent
in vacuo afforded a residue, which was purified by column chromatogra-
phy (benzene/EtOAc 4:1) to give 38 (22.1 mg, 83%) as a colorless vis-
cous liquid. [a]2D0 =+74.6 (c=0.35 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=1.05 (br, 1H), 1.65 (ddd, 1H, J=16.1, 10.1, 6.0 Hz), 1.99–2.03
(m, 1H), 2.04–2.09 (m, 1H), 2.44 (dd, 1H, J=10.8, 6.3 Hz), 2.47–2.54 (m,
1H), 2.55–2.61 (m, 1H), 2.87 (dd, 1H, J=13.7, 8.3 Hz), 2.98 (dd, 1H, J=
13.7, 7.2 Hz), 3.86 (s, 3H), 4.36 (br, 1H), 4.83–4.88 (m, 2H), 4.90 (dd,
1H, J=10.0, 1.9 Hz), 4.99–5.03 (m, 1H), 5.54 (br, 1H), 5.70 (ddd, 1H,
J=18.7, 10.0, 8.8 Hz), 5.93 (dd, 1H, J=9.7, 5.6 Hz), 6.19 (d, 1H, J=
9.7 Hz), 6.73 (dd, 1H, J=8.2, 1.9 Hz), 6.76 (d, 1H, J=8.2 Hz), 6.84 ppm
(d, 1H, J=1.9 Hz); 13C NMR (125 MHz, CDCl3): d=36.7, 37.9, 44.4,
44.9, 48.6, 49.9, 55.9, 64.3, 110.4, 113.9, 114.7, 115.8, 119.9, 128.1, 131.5,
135.8, 142.0, 143.7, 144.5, 145.3 ppm; IR (neat): n˜ =3510, 2924, 1591,
1512, 1442, 1273, 1130, 1008, 904, 802, 761 cmꢀ1; HRMS (EI): m/z: calcd
for C20H24O3: 312.1725, found 312.1729 [M]+.
(1S,3S,3aR,4R,5R,6R,7aS)-3-(3-Acetoxy-4-methoxybenzyl)-4-tert-butyldi-
methylsiloxy-7-methylene-1-(vinyl)octahydroinden-5,6-diol
(35):
2m
NaOH (0.40 mL, 0.80 mmol) and (CH3CO)2O (76 mL, 0.80 mmol) were
added dropwise to a stirred solution of 34 (128 mg, 0.28 mmol) in 2-prop-
anol (2 mL) at room temperature. After 30 min, the reaction mixture was
diluted with EtOAc (70 mL). The organic layer was washed with H2O
(2”20 mL) and brine (2”20 mL), then dried over Na2SO4. Concentration
of the solvent in vacuo gave a residue, which was purified by column
chromatography (benzene/EtOAc 10:1) to give 35 (127 mg, 91%) as a
colorless viscous liquid. [a]2D0 =+20.9 (c=0.80 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=0.21 (s, 3H), 0.24 (s, 3H), 0.97 (s, 9H), 1.56–1.63
(m, 1H), 1.78 (d, 1H, J=5.8 Hz), 1.92 (d, 1H, J=7.6 Hz), 1.95–2.00 (m,
1H), 2.27–2.33 (m, 1H), 2.31 (s, 3H), 2.39–2.49 (m, 2H), 2.72 (dd, 1H,
J=13.7, 8.8 Hz), 2.82 (dd, 1H, J=13.7, 6.3 Hz), 2.77–2.87 (m, 1H), 3.80
(s, 3H), 3.95–3.99 (m, 1H), 4.22–4.26 (m, 1H), 4.68–4.73 (m, 1H), 4.80–
4.85 (m, 1H), 4.88 (dd, 1H, J=10.0, 1.3 Hz), 4.94 (s, 1H), 5.14–5.17 (m,
1H), 5.62 (ddd, 1H, J=17.1, 10.0, 8.3 Hz), 6.85 (d, 1H, J=2.1 Hz), 6.87
(d, 1H, J=8.3 Hz), 7.00 ppm (dd, 1H, J=8.3, 2.1 Hz); 13C NMR
(125 MHz, CDCl3): d=ꢀ4.06, ꢀ3.36, 18.1, 20.7, 26.1, 35.3, 37.1, 43.1,
44.2, 47.5, 54.3, 55.9, 68.2, 72.7, 75.4, 110.9, 112.4, 113.5, 122.6, 126.4,
134.6, 139.5, 142.7, 145.7, 149.1, 168.3 ppm; IR (neat): n˜ =3449, 2955,
2932, 2858, 1768, 1639, 1512, 1464, 1442, 1369, 1263, 1205, 1122, 1062,
1035, 902, 873, 835, 775, 706 cmꢀ1
; HRMS (FAB): m/z: calcd for
(1S,3S,3aR,4S,7aS)-3-(3-Dichloroacetoxy-4-methoxybenzyl)-7-methylene-
C28H43O6Si: 503.2829, found 503.2832 [M+H]+.
1-vinyl-1,2,3,3a,7,7a-hexahydroinden-4-ol
(39):
A
solution
of
(3aR,4R,4aR,5S,7S,7aS)-5-(3-Acetoxy-4-methoxybenzyl)-4-tert-butyldi-
methylsiloxy-8-methylene-7-(vinyl)octahydroindeno[5,6-d,1,3]dioxol-2-
thione (36): A solution of CSCl2 (18 mL, 0.24 mmol) in dry CH2Cl2
(CHCl2CO)2O (10 mL, 65 mmol) in dry CH2Cl2 (0.2 mL) was added very
slowly to a stirred solution of 38 (17.0 mg, 54 mmol) in dry CH2Cl2
(0.8 mL) containingpyridine (9.0 mL, 0.1 mmol) at room temperature.
The reaction mixture was diluted with EtOAc (10 mL), and the organic
layer was washed with brine (3 mL), and dried over Na2SO4. Concentra-
tion of the solvent in vacuo afforded a residue, which was purified by
column chromatography (benzene/EtOAc 20:1) to give 39 (18.2 mg,
79%) as a white cloudy oil. [a]2D0 =+71.5 (c=0.37 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=1.02 (d, 1H, J=6.3 Hz), 1.64 (ddd, 1H, J=19.0,
10.1, 6.0 Hz), 1.99–2.03 (m, 1H), 2.05–2.10 (m, 1H), 2.43–2.62 (m, 3H),
2.93 (dd, 1H, J=13.9, 8.6 Hz), 3.03 (dd, 1H, J=13.9, 6.9 Hz), 3.82 (s,
3H), 4.30–4.36 (m, 1H), 4.83–4.85 (m, 1H), 4.86–4.89 (m, 1H), 4.92 (dd,
1H, J=9.9, 1.8 Hz), 5.01–5.04 (m, 1H), 5.70 (ddd, 1H, J=18.7, 9.9,
8.8 Hz), 5.91–5.96 (m, 1H), 6.18 (s, 1H), 6.20 (d, 1H, J=9.6 Hz), 6.91 (d,
1H, J=8.4 Hz), 7.01 (d, 1H, J=2.0 Hz), 7.14 ppm (dd, 1H, J=8.4,
2.0 Hz); 13C NMR (125 MHz, CDCl3): d=35.9, 37.8, 44.3, 44.9, 48.6, 49.9,
56.1, 64.0, 64.3, 112.6, 114.0, 116.0, 121.9, 127.6, 128.0, 131.6, 135.4, 138.8,
141.9, 143.5, 148.6, 162.5 ppm; IR (neat): n˜ =3568, 2926, 2345, 1782, 1512,
1269, 1141, 1028, 815, 407 cmꢀ1; HRMS (EI): m/z: calcd for C22H24Cl2O4:
422.1052, found 422.1050 [M]+.
(0.5 mL) was added dropwise to
a stirred mixture of 35 (60.0 mg,
0.12 mmol) in dry CH2Cl2 containingDMAP (72.0 m,g 0.60 mmol) at
room temperature. After 30 min, silica gel (1.0 g) was added to the reac-
tion mixture, and the solvent was carefully evaporated off in vacuo. The
resulting solid was charged on the top of a silica gel column chromatogra-
phy, and elution usinghexane/EtOAc 10:1 gave 36 (60.3 mg, 93%) as a
colorless viscous liquid. [a]2D0 =+25.3 (c=0.60 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=0.16 (s, 3H), 0.22 (s, 3H), 0.87 (s, 9H), 1.44–1.50
(m, 1H), 1.88–1.96 (m, 1H), 2.31 (s, 3H), 2.30–2.34 (m, 1H), 2.40–2.52
(m, 2H), 2.79–2.85 (m, 1H), 2.86–2.93 (m, 2H), 3.80 (s, 3H), 4.15–4.18
(m, 1H), 4.85 (dd, 1H, J=8.5, 2.4 Hz), 4.91 (d, 1H, J=10.1 Hz), 4.94–
4.99 (m, 1H), 5.28–5.33 (m, 2H), 5.47 (d, 1H, J=2.5 Hz), 5.85 (ddd, 1H,
J=17.2, 10.1, 7.8 Hz), 6.82 (d, 1H, J=2.1 Hz), 6.89 (d, 1H, J=8.3 Hz),
6.97 ppm (dd, 1H, J=8.3, 2.1 Hz); 13C NMR (125 MHz, CDCl3): d=
ꢀ4.41, ꢀ3.49, 17.9, 20.7, 25.6, 35.7, 38.0, 42.5, 43.0, 43.9, 49.6, 55.9, 67.6,
82.1, 85.3, 112.5, 112.6, 118.8, 122.7, 126.5, 133.5, 139.6, 141.1, 144.6,
149.4, 169.0, 190.8 ppm; IR (neat): n˜ =3076, 2955, 2932, 2858, 1768, 1639,
1583, 1512, 1464, 1442, 1369, 1331, 1267, 1205, 1163, 1124, 1089, 1064,
1032, 995, 958, 904, 866, 837, 777, 758 cmꢀ1; HRMS (EI): m/z: calcd for
C29H40O6SSi: 544.2315, found 544.2316 [M]+.
(1S,3S,3aS,7aS)-3-(3-Dichloroacetyl-4-methoxybenzyl)-1,2,3,3a,7,7a-hexa-
hydro-7-methylene-1-(vinyl)inden-4-one (40): Dess–Martin periodinane
(34.0 mg, 81 mmol) was added to
a stirred solution of 39 (17.0 mg,
(1S,3S,3aR,4S,7aS)-3-(3-Acetoxy-4-methoxybenzyl)-4-tert-butyldimethyl-
siloxy-7-methylene-1-vinyl-1,2,3,3a,7,7a-hexahydroindene (37): A solution
of 36 (48.0 mg, 88 mmol) in (EtO)3P (8.8 mL) was heated at reflux for 2 h
40 mmol) in dry CH2Cl2 (1.2 mL) at room temperature. After 15 min, the
reaction was quenched with 20% aqueous Na2S2O3 (0.5 mL), and the
mixture was extracted with EtOAc (2”15 mL). The combined extracts
Chem. Eur. J. 2007, 13, 9866 – 9881
ꢁ 2007 Wiley-VCH VerlagGmbH & Co. KGaA, Weinheim
www.chemeurj.org
9879

T. Katoh et al.
were washed with brine (10 mL), then dried over Na2SO4. Concentration
of the solvent in vacuo afforded a residue, which was purified by column
chromatography (hexane/EtOAc 4:1) to give 40 (16.0 mg, 95%) as a
white cloudy oil. [a]2D0 =+22.4 (c=0.83 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=1.58–1.63 (m, 1H), 1.69–1.77 (m, 1H), 2.47 (m, 1H), 2.54–
2.63 (m, 2H), 2.73–2.78 (m, 1H), 2.78–2.83 (m, 1H), 3.16 (dd, 1H, J=
13.6, 6.9 Hz), 3.80 (s, 3H), 4.90–4.95 (m, 1H), 4.96–5.00 (m, 1H), 5.29 (d,
1H, J=1.1 Hz), 5.32 (s, 1H), 5.75 (ddd, 1H, J=18.3, 10.1, 8.2 Hz), 5.92
(dd, 1H, J=9.9, 0.6 Hz), 6.18 (s, 1H), 6.89 (d, 1H, J=8.4 Hz), 6.97 (d,
1H, J=8.4 Hz), 6.98 (d, 1H, J=2.1 Hz), 7.11 ppm (dd, 1H, J=8.4,
2.1 Hz); 13C NMR (125 MHz, CDCl3): d=35.5, 35.6, 46.3, 48.7, 49.1, 51.0,
56.1, 64.0, 112.6, 114.5, 120.1, 122.2, 128.0, 128.3, 134.8, 138.7, 141.6,
142.5, 145.8, 148.8, 162.5, 200.2 ppm; IR (neat): n˜ =2932, 1784, 1660,
1512, 1442, 1267, 1217, 1141, 1028, 912, 814 cmꢀ1; HRMS (EI): m/z: calcd
for C22H22Cl2O4: 420.0895, found 420.0888 [M]+.
cell lines (HCC panel): breast cancer HBC-4, BSY-1, HBC-5, MCF-7,
and MDA-MB-231; brain cancer U-251, SF-268, SF-295, SF-539, SNB-75,
and SNB-78; colon cancer HCC2998, KM-12, HT-29, HCT-15, and HCT-
116; lungcancer NCI-H23, NCI-H226, NCI-H522, NCI-H460, A549,
DMS273, and DMS114; melanoma LOX-IMVI; ovarian cancer
OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV-3; renal
cancer RXF-631 L and ACHN; stomach cancer St-4, MKN1, MKN7,
MKN28, MKN45, and MKN74; prostate cancer DU-145 and PC-3. The
GI50 (50% cell growth inhibition) value for these cell lines was deter-
mined by usingthe sulforhodamine B colorimetric method.
Tubulin polymerization assay:[22] Ability of the test compounds to inter-
fere with the polymerization dynamics of tubulin was examined by the
two-step bioassay. In brief, the nerve growth factor (NGF)/rat pheochro-
mocytoma (PC12) cell system was utilized in the first step to examine
whether the test compounds had the ability to affect the polymerization
dynamics of tubulin. In the second step, effect of the test compounds on
the microtuble structures was examined in HT1080 human fibrosarcoma
cells to distinguish whether they inhibited the polymerization of tubulin
(to destabilize microtubule structures) or the depolymerization of tubulin
(to stabilize microtubule structures).
(1S,3S,3aR,7aS)-1,2,3,3a,7,7a-Hexahydro-3-(3-hydroxy-4-methoxybenzyl)-
7-methylene-1-(vinyl)inden-4-one (1) [(+)-ottelione A]: Compound 40
(13.0 mg, 31 mmol) was dissolved in a solution of 50% aqueous NaHCO3/
CH3CN 1:1 (2.0 mL), and the mixture was stirred for 1 h at room temper-
ature. The reaction mixture was diluted with EtOAc (20 mL), and the or-
ganic layer was washed with brine (2”5 mL), then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue, which was puri-
fied by column chromatography (benzene/EtOAc 20:1) to give 1 (8.6 mg,
90%) as white cloudy oil. [a]2D5 =+17.3 (c=0.55 in CHCl3). The
1H NMR, 13C NMR, IR, and MS spectra (see below) are compatible with
those of natural (+)-ottelione A. 1H NMR (500 MHz, CDCl3): d=1.52–
1.61 (m, 1H), 1.69–1.76 (m, 1H), 2.48–2.54 (m, 2H), 2.58–2.66 (m, 1H),
2.78 (t, 1H, J=8.2 Hz), 2.86 (dd, 1H, J=8.2, 5.9 Hz), 3.01–3.09 (m, 1H),
3.85 (s, 3H), 4.91–4.99 (m, 2H), 5.30–5.33 (m, 2H), 5.53 (br, 1H), 5.76
(ddd, 1H, J=18.2, 10.1, 8.2 Hz), 5.93 (d, 1H, J=10.0 Hz), 6.68 (dd, 1H,
J=8.2, 2.0 Hz), 6.75 (d, 1H, J=8.2 Hz), 6.79 (d, 1H, J=2.0 Hz),
6.99 ppm (d, 1H, J=9.9 Hz); 13C NMR (125 MHz, CDCl3): d=35.6, 35.8,
46.3, 48.5, 49.0, 51.4, 55.9, 110.4, 114.4, 114.9, 119.9, 120.2, 128.3, 135.1,
141.8, 142.9, 144.6, 145.2, 145.9, 200.4 ppm; IR (neat): n˜ =3439, 2926,
1658, 1589, 1510, 1440, 1275, 1236, 1130, 1030, 958, 800, 760 cmꢀ1; HRMS
(EI): m/z: calcd for C20H22O3: 310.1569, found 310.1571 [M]+.
Acknowledgements
We are especially grateful to Professor Thomas R. Hoye, University of
Minnesota, for providingus with copies of the IR, 1H and 13C NMR, and
MS spectra of natural otteliones A (1) and B (2) and for kindly informing
us the optical rotation of 1 and 2. We also thank the ScreeningCommit-
tee of New Anticancer Agents supported by Grant-in-Aid for Scientific
Research on Priority Area “Cancer” from the Ministry of Education,
Culture, Sports, Science and Technology of Japan (MEXT), for biological
evaluation of compounds 1, 3, and 24. We also thank Dr. Naoki Sugimoto
and Dr. Nobuo Kawahara, National Institute of Health Sciences, for
measurements of HRMS and assistance with NMR experiments. This
work was supported in part by a Grant-in-Aid for Scientific Research on
Priority Area “Creation of Biologically Functional Molecules” (No.
17035073), a Grant-in-Aid for Scientific Research (C) (No. 18590013),
(1S,3S,3aS,7aS)-1,2,3,3a,7,7a-Hexahydro-3-(3-hydroxy-4-methoxybenzyl)-
7-methylene-1-(vinyl)inden-4-one (2) [(+)-ottelione B]: tBuOK (8.0 mg,
0.13 mmol) was added in small portions to a stirred solution of ottelione
A (1) (8.0 mg, 26 mmol) in tBuOH (1 mL) at room temperature. After
5 h, the reaction mixture was diluted with EtOAc (20 mL). The organic
layer was washed with saturated aqueous NH4Cl (2”4 mL), saturated
aqueous NaHCO3 (2”4 mL) and brine (4 mL), then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue, which was puri-
fied by column chromatography (hexane/EtOAc 4:1) to give a mixture of
2 and 1 (6.3 mg, 79%, 2/1 77:23 determined by 500 MHz 1H NMR) as a
colorless viscous liquid. Isolation of 2 from this mixture was performed
by means of HPLC (DAICEL CHIRALPAK AD-H, i.d. 4.6”250 mm,
hexane/2-propanol 4:1, 0.5 mLminꢀ1; measurement of UV 254 nm ab-
sorbance, tR-2: 34.7 min, tR-1: 29.6 min) to give 2 (1.8 mg, 23%) as a
white crystal, m.p. 142.2–143.08C; [a]2D5 =ꢀ330.0 (c=0.18 in CHCl3). The
1H NMR, 13C NMR, IR, and MS (FAB) spectra (see below) are compati-
ble with those of natural (ꢀ)-ottelione B. 1H NMR (500 MHz, CDCl3):
d=1.59 (ddd, 1H, J=13.8, 10.2, 8.2 Hz), 1.78 (ddd, 1H, J=13.8, 9.8,
6.7 Hz), 2.27 (dd, 1H, J=13.9, 9.8 Hz), 2.34 (dd, 1H, J=13.9, 10.2 Hz),
2.46–2.56 (m, 2H), 2.69–2.77 (m, 1H), 3.14 (dd, 1H, J=13.4, 3.6 Hz),
3.86 (s, 3H), 4.98–5.01 (m, 1H), 5.06–5.11 (m, 1H), 5.29–5.32 (m, 1H),
5.43–5.45 (m, 1H), 5.52 (br, 1H), 5.74 (ddd, 1H, J=18.2, 10.2, 8.0, Hz),
5.94 (d, 1H, J=9.7 Hz), 6.69 (dd, 1H, J=8.1, 2.0 Hz), 6.76 (d, 1H, J=
8.1 Hz), 6.80 (d, 1H, J=2.0 Hz), 6.98–7.02 ppm (m, 1H); 13C NMR
(125 MHz, CDCl3): d=36.9, 37.9, 40.6, 44.5, 50.5, 55.9, 58.3, 110.5, 114.6,
115.3, 117.1, 120.5, 128.7, 134.1, 141.5, 144.8, 144.9, 145.2, 147.6,
200.6 ppm; IR (KBr): n˜ =3395, 2930, 1664, 1589, 1512, 1440, 1275, 1176,
1126, 1035, 916, 808, 761 cmꢀ1; HRMS (FAB): m/z: calcd for C20H23O3:
311.1647, found 311.1633 [M+H]+.
and
MEXT.
a Grant-in-Aid for High Technology Research Program from
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9880
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Chem. Eur. J. 2007, 13, 9866 – 9881

Enantioselective Total Synthesis
FULL PAPER
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Received: May 24, 2007
Published online: September 18, 2007
Chem. Eur. J. 2007, 13, 9866 – 9881
ꢁ 2007 Wiley-VCH VerlagGmbH & Co. KGaA, Weinheim
www.chemeurj.org
9881