Total synthesis of actinobolin from d-glucose by way of the stereoselective three-component coupling reaction

Article abstract of DOI:10.1016/j.tet.2006.04.079

The total synthesis of (-)-actinobolin 3, an antipode of the natural product, starting from d-glucose is described. A three-component coupling reaction of functionalized cyclohexenone (+)-6 derived from d-glucose by way of Ferrier's carbocyclization react

Full text of DOI:10.1016/j.tet.2006.04.079

Tetrahedron 62 (2006) 6926–6944
Total synthesis of actinobolin from D-glucose by way of the
stereoselective three-component coupling reaction
*
Satoshi Imuta, Hiroki Tanimoto, Miho K. Momose and Noritaka Chida
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
Received 3 April 2006; revised 25 April 2006; accepted 26 April 2006
Available online 18 May 2006
Abstract—The total synthesis of (ꢀ)-actinobolin 3, an antipode of the natural product, starting from D-glucose is described. A three-com-
ponent coupling reaction of functionalized cyclohexenone (+)-6 derived from D-glucose by way of Ferrier’s carbocyclization reaction,
with vinyl cuprate and 2-alkoxypropanal 7 effectively constructed the carbon framework of 3 in a highly stereoselective manner. In an aldol
process of the three-component coupling reaction, stereochemical control (chelation and Felkin–Anh conditions) was achieved by the choice
of the protecting groups of a hydroxy function in 2-hydroxypropanal and the reaction solvents. The formal synthesis of the natural enantiomer,
(+)-actinobolin 1, starting from D-glucose was also accomplished.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
product, (ꢀ)-bactobolin 2 was discovered in Pseudomonas
BMG13-A7 and found to show more potent activities than
actinobolin.5 Such interesting and challenging structures
with potent biological properties have naturally received
considerable attention from the synthetic community, and
several reports on total syntheses,6 synthetic approach,7
and chemical modification8 of actinobolin and bactobolin
have been described. In 1984, Ohno and co-workers reported
the first and elegant total synthesis of (+)-actinobolin 1 start-
ing from L-threonine using an intramolecular Diels–Alder
reaction as the key reaction.6a Second synthesis was accom-
plished in 1985 by Weinreb and co-workers.6b The features
of Weinreb’s work were shorter synthetic route than Ohno’s
synthesis and the preparation of common bicyclic olefinic
g-lactone, which could be utilized for the synthesis of both
actinobolin and bactobolin. In 1986, Kozikowski and co-
workers also completed the synthesis of actinobolin from
L-threonine.6c,d Most recently, Ward and co-workers carried
out the total synthesis in 19936e,f in which they used the
novel diastereoselective 6-endo-trig radical cyclization of
a thiocarbamate derived from D-glucose. On the other
hand, N-acetylactinobolin was prepared by two groups.7
Rahman and Fraser-Raid synthesized it in an optically active
form via a [4+2] cycloaddition.7a Danishefsky and co-
workers achieved a synthesis of racemic N-acetylactinobolin
utilizing a key siloxy Cope rearrangement.7b
(+)-Actinobolin 1, isolated from the culture broth of
Streptomyces griceoviridus by Haskell and Bartz in 1959,
has a broad antibacterial spectrum as well as moderate anti-
tumor activity.1 The substance is a hydrophilic, amphoteric,
water soluble base, and it chelates with iron, aluminum, and
other metal ions. It has also been reported that actinobolin,
which suppresses antibody production, has a therapeutic
effect on autoimmune encephalomyelitis2 and serves to
increase the hardness of human enamel.3 The structure elu-
cidation study revealed that actinobolin has a highly oxygen-
ated bicyclic g-lactone (tetrahydroisochromane) framework
with five contiguous chiral centers including an L-alanine
residue (Fig. 1).4 Later, in 1979, a structurally related natural
O
OH
O
OH
8
1
4
O
O
6
5
3
R1
OH
OH
R2
H
H
OH
OH
NH
NH
O
O
1'
2'
NH2
NH2
R1 = Me, R2 = H: (+)-actinobolin 1
1 = Cl2CH, R2 = Me: (–)-bactobolin 2
(–)-actinobolin 3
R
Figure 1. Structures of actinobolin and bactobolin.
We report here the new synthesis of (ꢀ)-actinobolin 3, the
antipode of the natural product expected to show some
biological activity, starting from D-glucose using stereo-
selective three-component coupling reactions as the key
Keywords: Actinobolin; Ferrier’s carbocyclization; Three-component cou-
pling reaction.
* Corresponding author. Tel./fax: +81 455661573; e-mail: chida@applc.
keio.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.079

S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
6927
transformation.9 The formal synthesis of natural enantiomer
1 from D-glucose is also presented.
Ph
O
Ph
O
6
1) TsCl
pyridine
O
O
DIBAL-H
toluene
(73%)
5
2
O
O
4
3
1
2) LiAlH4
THF
(75%)
OMe
HO
OMe
2. Results and discussion
2.1. Retrosynthesis
OH
9
OH
8
1) I2, Ph3P
HO
I
imidazole
(99%)
Our retrosynthetic analysis for (ꢀ)-actinobolin 3 suggested
that bicyclic g-lactone possessing an azide function 4 would
be a promising intermediate for the total synthesis (Fig. 2).
Lactone 4 was expected to arise from cyclohexanone deriv-
ative 5, which we planned to prepare by way of a one-pot
three-component coupling reaction10 of cyclohexenone
(+)-6, a vinyl metal species, and 2-hydroxypropanal deriva-
tive 7. The aldol process in the three-component coupling re-
action of an enolate generated from (+)-6 with (R)- or (S)-7
was expected to show stereoselectivities, since both partners
in the reaction are chiral, therefore, the reaction would pro-
ceed under ‘double diastereoselection conditions’.11 The cy-
clohexenone (+)-6, in turn, was envisioned to be synthesized
in optically pure form starting from D-glucose utilizing
Ferrier’s carbocyclization12 as the key transformation.
BnO
BnO
t-BuOK
O
O
THF
2) TBSCl
(81%)
imidazole
DMF
OMe
OMe
OMe
OH
OTBS
(quant.)
11
10
O
30 mol%
BnO
BnO
Hg(OCOCF3)2
acetone /
1
4
O
2
5
OH
acetate buffer (pH = 4.8)
rt
OTBS
13
OTBS
12
α-OH : β-OH
= ca. 1 : 10
O
BnO
1
6
MsCl, Et3N
CH2Cl2, 0°C
4
3
O
OTBS
OTBS
(86% from 12)
OTBS
(+)-6
H
O
PO
3
Scheme 1. Bn¼–CH2Ph, TBS¼–SiMe2(t-Bu).
OBn
N3 OMOM
OBn
H
H
HO
O
reduction with DIBAL-H afforded (R)-7a in 86% overall
yield. Similar treatment of methyl (S)-lactate gave enantio-
meric aldehyde (S)-7a.
5
4
OTBS
OH
M
1) MPMOC(=NH)CCl3
CSA, CH2Cl2
OMPM
CHO
OH
HO
OH
OH
OMe
PO
O
2) DIBAL-H, CH2Cl2/ toluene
OBn
O
–78 °C
(86%)
O
(+)-6
(R)-7a
(S)-7a
CH2OH
methyl (R)- lactate
O
7
D-glucose
methyl (S)- lactate
Figure 2. Retrosynthetic analysis of (ꢀ)-actinobolin.
Scheme 2. MPM¼–CH2C6H4(p-OMe).
2.3. Three-component coupling reaction
2.2. Preparation of subunits
With chiral cyclohexenone (+)-6 and aldehydes (R)-, (S)-,
and (ꢁ)-7a in hand, the crucial three-component coupling
reaction was investigated using vinyl metal species as the
nucleophile (Scheme 3). At first, 1,4-addition of a vinyl
group to (+)-6 was attempted. Treatment of (+)-6 with higher
order vinyl cuprate16 in Et2O at ꢀ78 ꢂC followed by quench-
ing the reaction with aqueous NH4Cl, afforded 14 as a single
isomer in a quantitative yield. The observed large coupling
constants (J3ax,4¼10.8 Hz, J4,5¼9.6 Hz) in 1H NMR spectra
of 14 clearly revealed that the vinyl group was introduced
from the less crowded b-face.
Synthesis of cyclohexenone (+)-6 commenced from the
known 3-deoxy-D-glucose derivative13 9 prepared from
the commercially available methyl 4,6-O-benzylidene-a-D-
glucopyranoside 8 in two steps (Scheme 1). Cleavage of
a benzylidene acetal in 9 with diisobutylaluminum hydride
(DIBAL-H) gave 10, whose primary hydroxy group was
selectively iodinated and the remaining hydroxy function
was protected as a TBS ether to afford 11. Treatment of
11 with t-BuOK provided 5-enopyranoside 12. Catalytic
Ferrier’s carbocyclization reaction14 of 12 in acetone–
acetate buffer (pH 4.8) gave 13 as a mixture of diastereomer
(a-OH/b-OH¼ca. 1:10). Use of acetate buffer was effective
to suppress the partial hydrolysis of the O-TBS group due to
the acidity of the catalyst, and greatly improved the cycliza-
tion yields. b-Elimination of the hydroxy function cleanly
generated cyclohexenone (+)-6.
OTBS
H
1) CuCN, CH2=CHLi,
H 3
4
TBSO
OBn
O
Et2O, –78 °C
5
1
H
2) aqueous NH4Cl
(quant.)
H
OBn
14
O
(+)-6
J
J
J
3ax,4 = 10.8 Hz
3eq,4 = 4.3 Hz
4,5 = 9.6 Hz
The other requisite subunit, aldehyde 7a, was synthesized
in optically active forms and as a racemate from methyl
lactate (Scheme 2). Acid catalyzed p-methoxybenzylation
of the hydroxy group in methyl (R)-lactate,15 followed by
Scheme 3.

6928
S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
OTBS
Then, the intermediate enolate was trapped with excess
amount (6 equiv to (+)-6) of racemic aldehyde (ꢁ)-7a in
Et2O to give 15 as the major isomer in 68% isolated yield
after chromatographic separation (Scheme 4). The coupling
constant (J2,3¼10.6 Hz) in 1H NMR spectrum of 15 showed
the stereochemical relationship between C-2 and C-3 sub-
stituents to be trans. The similar reaction employing vinyl-
magnesium bromide as a nucleophile in the presence of
N,N,N0,N0-tetramethylethylenediamine (TMEDA) and CuI
in THF gave less satisfactory results to afford 15 in 48%
yield. When chiral aldehyde (R)-7a was employed as an
electrophile, the same diastereomer 15 was obtained in
85% yield. Interestingly with another chiral aldehyde (S)-
7a, the aldol process was found to proceed much slower
than the reaction with (R)-7a, and a different diastereomer
16, in which the stereochemistry of substituents at C-2 and
C-3 were cis (J2,3¼6.8 Hz), was formed in 72% yield.
BuLi
TsCl
5
MPMO
Me4NBH(OAc)3
THF / AcOH
(70%)
3
15
1
2
1'
THF
0 °C
2'
OBn
H
HO
OH
(quant.)
17
OTBS
OTBS
MOMCl
i-Pr2NEt
(CH2Cl)2
(98%)
MPMO
MPMO
OBn
OBn
OMOM
H
H
TsO
OH
TsO
18
19
OTBS
HO
DDQ
CH2Cl2
/ H2O
DBU
toluene
(94%)
OBn
OMOM
H
TsO
(97%)
20
OTBS
J
J
J
J
1,2 = 9.0 Hz
2,3 = 9.9 Hz
3,4 = 9.3 Hz
4,5 = 9.3 Hz
5
4
3
OTBS
O
1
2'
1) CuCN, CH2=CHLi
2
H
OBn
MPMO
–78 °C, Et2O, 30 min
1'
H
3
2
H
6
OMOM
1
1'
OMPM
2'
OBn
2)
NOE
H
–78 °C
21
HO
O
20 min
CHO
( )-7a
15 (68%)
OTBS
J
2,3 = 10.6 Hz
1) NaBH4, MeOH
2) Ac2O, pyridine
3) DDQ, CH2Cl2/H2O
(46% for 3 steps)
HO
1) CuCN, CH2=CHLi
16
–78 °C, Et2O, 30 min
(+)-6
OBn
15 (85%)
H
OMPM
2)
AcO
OAc
22
–78 °C
CHO
20 min
(R)-7a
OTBS
1) MsCl, DMAP
pyridine
OTBS
5
4
3
1) CuCN, CH2=CHLi
O
1
2
2'
MPMO
–78 °C, Et2O, 30 min
3
2) NaOMe, MeOH
3) Ac2O, DMAP
pyridine
H
OBn
2
6
1'
H
1
1'
H
OMPM
2)
2'
OBn
OAc
23
H
–78 °C
HO
O
CHO
(74% for 3 steps)
1.5 h
(S)-7a
16 (72%)
NOE
2' H
J
2,3 = 6.8 Hz
J
J
J
J
J
1,2 = 8.3 Hz
2,3 = 4.4 Hz
4,5 = 9.3 Hz
1,6ax = 9.5 Hz
5,6ax = 9.3 Hz
H
1'
H
Scheme 4.
O
H
H
5
6 OTBS
AcO3
1
2
The stereochemistry at C-10 of 15 and 16 was determined by
NOE experiments of epoxides 21 and 23 derived from 15
and 16, respectively (Scheme 5). Treatment of 15 with
Me4NBH(OAc)317 at room temperature stereoselectively re-
duced the carbonyl group to give syn diol 17 in 70% yield.
The hydroxy group at C-2 in 17 was anticipated to show
less reactivity than that at C-10 due to the steric congestion.
Indeed, reaction of 17 with BuLi (3 equiv) at 0 ꢂC, followed
by treatment with TsCl (2.8 equiv) generated 10-OTs deriva-
tive 18, quantitatively. The remaining hydroxy function was
then masked as a MOM ether to afford 19 in 92% yield.
The MPM group in 19 was deprotected by DDQ to afford
20, which was then converted into epoxide 21 by treatment
with DBU. The observed NOE between H-10 and H-20 in 21
revealed the relationship of these protons to be cis, showing
that thestereochemistry atC-10 in15shouldbeR. Ontheother
hand, reduction of 16 with NaBH4 gave b-alcohol, which was
converted into diacetate 22 possessing (10S,2R) configuration
by O-acetylation and deprotection of the O-MPM group.
Methanesulfonylation of the hydroxy group in 22 followed
by treatment with NaOMe provided an epoxide, whose O-
acetylation gave 23. The observed coupling constants and
NOE experiments unambiguously supported the whole struc-
ture of 23, indicating the stereochemistry at C-10 in 16 to be S.
H
BnO
H
H
Scheme 5. Ts¼–SO2C6H4(p-Me).
The predominant formation of 10,20-syn isomers (15 and 16)
in the three-component coupling reactions suggested that
the chelation control (chelation between the alkoxy and
aldehyde oxygens in (R)-7a and (S)-7a) should be an impor-
tant factor in the aldol process.11 Reaction of the inter-
mediate enolate with chelated (R)-7a would proceed in
a ‘matched pair’ manner (route a in Fig. 3) to give 15
smoothly, whereas combination of (S)-7a and the enolate
Me
O
TBSO
kS
O
MPM
H
M
16
OBn
a
c
H
O
kR
TBSO
O
15
OBn
Me
MPM
O
M
b
H
O
Me
H
MPM
O
O
(R)-7a
M
kR > kS
(S)-7a
Figure 3.

S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
6929
would be ‘mismatched’. The steric repulsion between che-
lated (S)-7a and the enolate (routes b and c) rendered the
aldol reaction much sluggish, but gave 2,3-cis-adduct 16
stereoselectively via less crowded pathway (route c) when
(S)-7a was employed as the electrophile. Apparently, a ki-
netic resolution had taken place in the aldol process with
racemic aldehyde (ꢁ)-7a, providing 15 as the major product,
since the aldol reaction of the intermediate enolate with (R)-
7a was much faster than that with (S)-7a.
oxidation of 20 provided methyl ketone 27 (Scheme 6).
Reduction of 27 with various reducing reagents was carried
out, however, the desired inverted alcohol could not be
obtained as the major isomer. After several attempts, it
was found that the stereoselective reduction successfully
proceeded when carboxylic acid 28 was employed as the
substrate (Scheme 7). Thus, ozonolysis of 27, followed by
further oxidation gave 28. Treatment of 28 with NaBH4
provided desired product 29 as the major isomer, and bicy-
clic compound 30 was obtained in 72% yield from 27 after
lactonization followed by separation with silica gel chroma-
tography. Azidolysis of 30 with NaN3 cleanly provided
advanced intermediate 4 in 86% yield, whose structure
was confirmed by NOE experiments.
The stereoselective formation of three-component adduct 15
led us to use this compound as the precursor for the synthesis
of (ꢀ)-actinobolin. Successful conversion of 15 into 19
(Scheme 5) revealed that the required transformations into
the desired lactone would be (1) introduction of a nitrogen
function at C-10 via SN2 fashion and (2) formation of g-lac-
tone with inversion of the configuration at the C-20 hydroxy
group.
OTBS
1) O3, MeOH, –78 °C
then Me2S
HO2C
O
NaBH4
MeOH
27
2) NaClO2, HOSO2NH2,
NaH2PO4, t-BuOH / H2O
OBn
OMOM
H
TsO
2.4. Total synthesis of (L)-actinobolin
28
OTBS
O
OTBS
Ozonolysis of a vinyl group in 19 and further oxidation with
NaClO2 afforded 24 in 75% yield (Scheme 6). The MPM pro-
tecting group in 24 was removed to give hydroxycarboxylic
acid 25. To obtain a g-lactone with inversion of the hydroxy
group, compound 25 was subjected to the intramolecular
Mitsunobu reaction18 (DEAD, PPh3). However, it was found
that the product obtained in 80% yield was g-lactone 26 with
retention of the C-20 stereochemistry. The structure of 26
was confirmed by the fact that DCC-mediated lactonization
of 25 afforded the same lactone 26. These results revealed
that Mitsunobu reagent did not activate the alcohol moiety
in 25 probably due to the steric congestion, but activated
the carboxylic acid moiety. A similar phenomenon has been
documentated,18b and mechanistic study on Mitsunobu lac-
tonization of hydroxycarboxylic acid with hindered alcohol
system has been reported in detail by DeShong.19
H
HO2C
HO
DCC, DMAP
CH2Cl2
(72% from 27)
O
OBn
OMOM
OBn
OMOM
H
H
TsO
TsO
29
30
8%
O
OTBS
9%
H
H
H
7%
OMOM
8
1
O
H
8a
NaN3
O
OBn
4a
3
5
4
TBSO
DMF
110°C
(86%)
OBn
H
H
O
N3 OMOM
H
N3
H
: NOE
4
6% enhancement
Scheme 7.
With the desired lactone 4 possessing proper functionalities
and stereochemistry in hand, the final transformation to 3
was then explored. Deprotection of the O-TBS moiety in 4
gave 31, whose Swern oxidation afforded b-ketoester 32
in 89% yield from 4 (Scheme 8). Interestingly, the methoxy-
methyl group was unexpectedly removed during the purifica-
tion process with silica gel chromatography. Hydrogenation
of 32 in the presence of Pd catalyst in aqueous HCl reduced
the azide function as well as induced removal of the O-benzyl
group to provide an amine hydrochloride, which, without
isolation, was condensed with N-benzyloxycarbonyl-D-
alanine (Z-D-alanine) by the action of DCC to give protected
actinobolin 33 in 57% yield. Finally, removal of the benzyl-
oxycarbonyl group by hydrogenolysis in MeOH–AcOH–
aqueous HCl, followed by purification with Sephadex
LH-20 (MeOH) furnished (ꢀ)-actinobolin hydrochloride
(3$HCl) in 76% yield. The spectral (1H and 13C NMR)
data of synthetic 3$HCl were fully identical with those of
natural (+)-actinobolin hydrochloride, kindly provided by
Dr. Y. Nishimura, and the [a]D value of the synthetic com-
pound {[a]D24 ꢀ51 (c 0.24, H2O): lit.6c,d [a]2D1 +53 (c 0.65,
H2O)} confirmed its unnatural absolute configuration.
OTBS
1) O3, MeOH, –78 °C
HO2C
MPMO
then Me2S
DDQ
CH2Cl2
/ H2O
19
2) NaClO2, HOSO2NH2,
NaH2PO4, t-BuOH / H2O
OBn
OMOM
H
TsO
(75% for 2 steps)
(76%)
24
O
OTBS
OTBS
H
DEAD
Ph3P
HO2C
HO
8
5
1
4
O
2
5
1
6
3
6
benzene
4
1'
OBn
OMOM
80 °C
2'
OBn
H
(84%)
H
TsO
TsO
OMOM
25
26
DCC, DMAP
(CH2Cl2)2
OTBS
Dess-Martin
periodinane
5
O
4
3
20
1
1'
CH2Cl2
(quant.)
2'
OBn
OMOM
27
H
TsO
Scheme 6. MOM¼–CH2OMe.
Attempted inversion of a hydroxy function in 20 by intermo-
lecular Mitsunobu reaction proved also fruitless, so we next
adopted an oxidation–reduction procedure. Dess–Martin
Thus, total synthesis of (ꢀ)-actinobolin (3) starting from
D-glucose was accomplished. The high stereoselectivities
observed in the three-component coupling reaction under

6930
S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
1)
(COCl)2, DMSO
hydroxy group with TESCl, followed by reduction
(Scheme 9).21
O
OH
H
CH2Cl2, –78 °C
then i-Pr2NEt
1
8
O
HF-pyridine
MeCN
3
4
4a
6
5
2) silica gel
OBn
4
H
OH
1) TESCl, imidazole
CH2Cl2
OTES
CHO
N3 OMOM
(100%)
(89%)
OH
OMe
31
2) DIBAL, toluene, –78 °C
O
(70%)
O
O
O
OH
(S)-7b
methyl (S)- lactate
1) H2, Pd/C
aq. HCl/MeOH
O
Scheme 9. TES¼–SiEt3.
2) DCC, Et3N
Cbz-D-alanine
DMF
OH
OBn
H
H
OH
N3 OH
H
N
Three-component coupling reaction of (+)-6, vinyl cuprate,
and aldehyde (S)-7b at ꢀ78 ꢂC resulted in the formation of
34 (chelation product, 51%) and 35 (Felkin–Anh product,
40%) (Scheme10). Contrary toourexpectation, thealdolpro-
cess provided a 5:4 mixture of chelation and Felkin–Anh
products, in spite of using an O-TES protecting group. To
reduce the degree of the chelation in (S)-7b, hexamethylphos-
phoramide (HMPA) was added22 to the reaction mixture. To
our delight, in the presence of HMPA, the three-component
coupling reaction with (S)-7b proceeded stereoselectively
to provide Felkin–Anh products 35 and 36 in 47% and 20%
isolated yields, respectively, and chelation product 34 could
not be isolated in this case. The ketal product 36, presumably
formed by the further reaction of 35 with excess (S)-7b, was
converted into 35 in 76% yield by treatment with acetic acid.
Thus, desired compound 35 was obtained in 62% overall
yield from (+)-6 after acetolysis of 36.
O
(57% for 2 steps)
32
NHCbz
33
O
OH
OH
O
H2, Pd/C
OH
H
MeOH/
AcOH/
synthetic:
HN
[α]D24 – 51 (c 0.24, H2O)
O
1M aq. HCl
lit.: [α]D21 + 53 (c 0.65, H2O)
NH2·HCl
(76%)
(–)-actinobolin hydrochloride
(3•HCl)
Scheme 8. Cbz¼–C(O)OCH2Ph.
the chelation control led us to explore the possibility of the
coupling reaction under non-chelation conditions. If a three-
component coupling reaction with (S)-hydroxypropanal
derivative proceeded via Felkin–Anh conditions, the product
possessing the proper stereochemistries for the synthesis
of actinobolin was anticipated to be obtained as the major
isomer, which would bring about the shorter step synthesis
of actinobolin.
The structure of compound 34 was assigned by comparison
of its NMR spectra with those of the structurally related
compound 16, and finally confirmed by its conversion into
the known compound 22, by the similar procedures as
described for the preparation of 22 from 16. On the other
hand, the structure of 35 was verified by its transformation
into the known synthetic intermediate 30 of actinobolin as
shown in Scheme 11. Thus, treatment of 35 with LiBH4, in
THF/AcOH at room temperature reduced the carbonyl group
stereoselectively to give syn diol 37 in 87% yield. Reduction
of 35 with NaBH(OAc)323 and Me4NBH(OAc)317 also gave
37 as a major isomer, but the yields (76% and 25%, respec-
tively) were less satisfactory. Reaction of 37 with BuLi in
Et2O at 0 ꢂC, followed by treatment with TsCl generated
the 10-OTs derivative 38, quantitatively. The remaining
2.5. Three-component coupling with a TES-aldehyde:
a shorter route to (L)-actinobolin
For the aldol reaction under Felkin–Anh conditions, alde-
hyde 7b possessing O-TES protecting group was employed
for three-component coupling reaction. It has been reported
that O-silyl protecting group does not form chelation
between alkoxy and carbonyl oxygens.20 Aldehyde (S)-7b
was prepared from methyl lactate by protection of the
OTBS
OTBS
OTES
2)
4
TESO
TESO
3
2
CHO
(S)-7b
6
+
1'
1
2'
OBn
OBn
H
H
HO
O
HO
O
–78 °C
34 (51%)
35 (40%)
1) CuCN, CH2=CHLi
(+)-6
Et2O, –78 °C, 30 min
OTBS
TESO
2) HMPA, –78 °C
OBn
OH
O
35 (47%)
+
H
OTES
CHO
(S)-7b
3)
O
–78 °C
TESO
AcOH-THF
(76%)
36 (20%)
(35: overall 62%)
Scheme 10.

S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
6931
hydroxy function was then masked as a MOM ether to afford
39 in 92% yield. The TES protecting group was removed by
the action of DDQ24 to give 40 in 86% yield. Ozonolysis of
40 followed by reductive workup afforded lactol 41 as a sin-
gle anomer. Oxidation of 41 by PDC provided lactone 30,
which was fully identical with the compound prepared in
previous route as shown in Scheme 7. This new synthetic
sequence to actinobolin from 35, which has no necessity to
invert the configuration at C-20 hydroxy group, is three steps
shorter than the previous route using O-MPM aldehyde
(R)-7a.
Protection of a hydroxy group in 45 as a THP ether and
subsequent reduction of the ketone carbonyl gave 46.
Methanesulfonylation of the hydroxy function in 46 fol-
lowed by acidic workup afforded 47 as the major product
in 66% isolated yield. The observed large coupling constants
in 47 (J1,2¼8.8, J4,5¼9.0 Hz) clearly showed that both OMs
and OH groups were in the equatorial positions. Swern oxi-
dation of 47 was accompanied by the b-elimination of the
OMs group to furnish (ꢀ)-6 in 93% yield. The spectral
data and the absolute value of [a]D of (ꢀ)-6 {[a]1D9 ꢀ22
(c 0.80, CHCl3)} were fully identical with those of (+)-6
{[a]2D3 +22 (c 0.94, CHCl3)}, representing a formal synthesis
of (+)-actinobolin.
1) NaBH4, MeOH
2) Ac2O, pyridine
22
34
3) DDQ, CHCl2/H2O
(46% overall)
Ph
O
HO
HO
6
1) BnBr, NaH
DMF
2) AcOH-H2O
(4 : 1)
O
5
2
O
O
4
(95%)
(92%)
1
OTBS
OMe
OMe
5
TESO
BuLi, TsCl
Et2O, 0 °C
(quant.)
LiBH4
OH
OBn
42
35
3
1
1'
9
2
THF / AcOH
(87%)
2'
OBn
H
HO
OH
37
1) I2, Ph3P, imidazole
toluene (quant.)
HO
O
TBSCl, imidazole
DMF
OTBS
2) t-BuOK, THF
OTBS
MOMCl
i-Pr2NEt
NaI
OMe
(85%)
(70%)
OBn
43
TESO
TESO
1'
(CH2Cl)2
50 °C
2'
OBn
OMOM
39
OBn
H
H
O
TsO
TsO
OH
10 mol%
Hg(OCOCF3)2
38
TBSO
TBSO
(92%)
1
2
O
5
acetone / acetate buffer
(pH 4.8)
4
OMe
OH
OTBS
OBn
44
OBn
45
(83%)
O3, MeOH
DDQ
HO
α-OH : β-OH
= ca. 1 : 6
CH3CN / H2O
(86%)
then Me2S
(80%)
OBn
OMOM
H
TsO
1) dihydro-2H-pyran
CAN, CH3CN
0 °C
2) NaBH4, CeCl3·7H2O
MeOH, 0 °C
OH
40
TBSO
MsCl, pyridine
then aq. HCl
(66% for 3 steps)
HO
H
OTBS
OTHP
8
1
O
8a
OBn
46
PDC, MS4A
CH2Cl2
(83%)
30
4a
3
5
4
OBn
OMOM
41
H
OMs
TsO
TBSO
TBSO
(COCl)2, DMSO
–78 °C, CH2Cl2
1
4
2
5
Scheme 11.
O
OH
then Et3N
OBn
(–)-6
OBn
47
(93%)
2.6. Formal synthesis of (+)-actinobolin
[ ] 19 –22 (c 0.80, CHCl3) for (–)-6
α
D
[α]D23 +22 (c 0.94, CHCl3) for (+)-6
Having established the new synthetic pathways to (ꢀ)-acti-
nobolin from D-glucose, we turned our attention to the
synthesis of the natural enantiomer 1, also starting from
D-glucose. It is interesting and important issue for synthetic
chemistry to prepare both enantiomers from the same start-
ing material. For this purpose, 3-deoxy-D-glucose derivative
9 was again chosen as a building block, and its transforma-
tion into the enantiomer of (+)-6 was investigated.
Scheme 12.
3. Conclusion
In this work, a new synthesis route to both (ꢀ)- and (+)-acti-
nobolin starting from D-glucose has been established. This
synthesis demonstrated that the methodology involving the
three-component coupling reaction on chiral cyclohexe-
nones, derived from D-glucose by way of catalytic Ferrier’s
carbocyclization, is effective for the chiral and stereoselec-
tive synthesis of natural products possessing highly func-
tionalized cyclohexane units. The stereochemical control
in three-component coupling reaction by way of the choice
of the protecting groups on aldehydes and the reaction
Benzylation of a hydroxy group in 9, followed by acetal
hydrolysis afforded 42 in 87% overall yield (Scheme 12).
Selective iodination of primary alcohol of 42 and subsequent
treatment with base gave 5-enopyranoside 43 in 70% yield.
Protection of the remaining hydroxy function as a TBS ether
afforded 44 in 85% yield. Catalytic Ferrier’s carbocycliza-
tion of 44 in acetone–acetate buffer generated 45 as a
diastereomeric mixture (a:b¼ca. 1:6) in 83% yield.

6932
S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
solvents would be an important finding and could be
applicable to the stereoselective synthesis of other natural
products.
4.2.2. Methyl 4-O-benzyl-2-O-(tert-butyldimethylsilyl)-
3,6-dideoxy-6-iodo-a-D-ribo-hexopyranoside (11). To a
solution of 10 (1.04 g, 3.88 mmol) in toluene (25 mL) were
added PPh3 (1.63 g, 6.22 mmol), imidazole (0.840 g,
12.3 mmol), and iodine (1.97 g, 7.76 mmol), and the reaction
mixture was stirred at room temperature for 28 h. The
reaction mixture was diluted with EtOAc, and washed suc-
cessively with 10% aqueous Na2S2O3 solution, saturated
aqueous NaHCO3 solution and brine, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (silica gel: 60 g, EtOAc/tol-
uene¼1:5) to give methyl 4-O-benzyl-3,6-dideoxy-6-iodo-
a-D-ribo-hexopyranoside (1.16 g, 99%) as a colorless syrup:
Rf 0.55 (EtOAc/toluene¼1:1); [a]2D2 +124 (c 0.85, CHCl3); IR
4. Experimental
4.1. General
Melting points were determined on a Mitamura–Riken micro
hot stage and were not corrected. Optical rotations were re-
corded using a sodium lamp (589 nm) with a JASCO DIP-
370 instrument with 1 dm tube. Infrared (IR) spectra were
measured with a JASCO FT/IR-200 spectrometer. 1H NMR
spectra were recorded at 300 MHz on a JEOL Lambda 300
or on a Varian MVX-300 spectrometer. Chemical shifts are
reported as d values in parts per million relative to tetra-
methylsilane (d¼0) or chloroform (d¼7.26). Coupling con-
stants (J) are reported in Hertz. Abbreviations used are br
(broad peak), s (singlet), d (doublet), t (triplet), q (quartet),
and m (complex multiplet). 13C NMR spectra were recorded
at 75 MHz on the JEOL Lambda 300 spectrometer. Chemical
shifts are reported as d values in parts per million relative to
chloroform-d (d¼77.00) or methanol-d4 (d¼49.00) as inter-
nal references. Mass spectra are measured by a JEOL GC
Mate spectrometer with EI (70 eV) or FAB mode. Organic
extracts were dried over solid anhydrous Na2SO4 and con-
centrated below 40 ꢂC under reduced pressure. Column chro-
matography was carried out with silica gel (Merck Kieselgel
60 F254; 230–400 mesh) or alumina powder (WAKO alumina,
activated; 300 mesh) for purification. Preparative TLC (PLC)
(neat) 3440, 2940, 1600, 1455, 1030 cmꢀ1 1H NMR
;
(300 MHz) d 7.40–7.27 (5H, m), 4.67 (1H, s), 4.65 and
4.47 (each 1H, 2d, J¼11.2 Hz), 3.68 (1H, ddd, J¼4.9, 10.5,
11.5 Hz), 3.56 (1H, dd, J¼2.0, 10.5 Hz), 3.49 (3H, s), 3.41
(1H, ddd, J¼2.0, 6.8, 9.4 Hz), 3.30 (1H, dd, J¼6.8,
10.5 Hz), 3.29 (1H, ddd, J¼4.4, 9.4, 11.2 Hz), 2.38 (1H,
ddd, J¼4.4, 4.9, 11.5 Hz), 1.95 (1H, br d, J¼10.5 Hz), 1.68
(1H, ddd, J¼11.2, 11.5, 11.5 Hz); 13C NMR (75 MHz)
d 137.7, 128.5, 127.94, 127.88, 98.6, 75.5, 70.8, 70.1, 67.3,
55.3, 33.1, 7.6; LRMS (EI) m/z 378 (M+, 0.8%), 346 (1.4),
219 (37.6), 201 (41.9) 175 (84.6), 117 (100); HRMS (EI)
m/z calcd for C14H19O4I, (M+) 378.0328, found 378.0328.
Anal. Calcd for C14H19IO4: C, 44.46; H, 5.06. Found: C,
44.65; H, 5.05.
To a solution of the 6-iodide derivative (10.3 g, 27.2 mmol)
in DMF (200 mL) were added imidazole (11.1 g, 163 mmol)
and TBSCl (6.20 g, 41.1 mmol), and the reaction mixture
was stirred at room temperature for 8.5 h. The reaction mix-
ture was diluted with EtOAc, washed with H2O, and then
dried. Removal of the solvent gave a residue, which was pu-
rified by column chromatography (silica gel: 300 g, EtOAc/
toluene¼1:20) to give 2-O-silyl ether 11 (13.4 g, 100%) as
a colorless syrup: Rf 0.81 (EtOAc/toluene¼1:8); [a]D25
+89.4 (c 0.93, CHCl3); IR (neat) 2960, 2930, 2860, 1100,
was performed with Merck PLC plate (Kieselgel 60 F254
0.5 mm thickness).
,
4.2. Total synthesis of (L)-actinobolin
4.2.1. Methyl 4-O-benzyl-3-deoxy-a-D-ribo-hexopyrano-
side (10). To a solution of methyl 4,6-O-benzylidene-3-
deoxy-a-D-ribo-hexopyranoside13 9 (1.57 g, 5.90 mmol) in
toluene (10 mL) under Ar at 0 ꢂC was slowly added
1.01 mol/L solution of DIBAL-H in toluene (23.4 mL,
23.6 mmol). After being stirred at room temperature for
6 h, the reaction mixture was quenched with water, and the
products were extracted with EtOAc. The organic layer
was washed successively with 1 mol/L aqueous HCl solu-
tion, saturated aqueous NaHCO3 solution and brine, and
then dried. Removal of the solvent gave a residue, which
was recrystallized from EtOAc/hexane (2:5, 28 mL), to af-
ford 10 (1.15 g, 73%) as colorless crystals: Rf 0.12 (EtOAc/
toluene¼1:1); mp 130.0–130.5 ꢂC; [a]D20 +184 (c 0.95,
CHCl3); IR (KBr disk) 3240, 2900, 1120, 1095, 1075, 1055,
1
1030, 840 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.40–7.27
(5H, m), 4.66 (1H, d, J¼11.3 Hz), 4.55 (1H, d, J¼3.4 Hz),
4.47 (1H, d, J¼11.3 Hz), 3.73 (1H, ddd, J¼3.4, 4.1,
11.6 Hz), 3.55 (1H, dd, J¼2.1, 10.2 Hz), 3.47 (3H, s), 3.43
(1H, ddd, J¼2.1, 6.6, 9.1 Hz), 3.31 (1H, dd, J¼6.6,
10.2 Hz), 3.29 (1H, ddd, J¼4.6, 9.1, 11.6 Hz), 2.15 (1H,
ddd, J¼4.1, 4.6, 11.5 Hz), 1.88 (1H, ddd, J¼11.5, 11.6,
11.6 Hz), 0.89 (9H, s), 0.08 (6H, s); 13C NMR (75 MHz,
CDCl3) d 137.8, 128.5, 128.2, 127.9, 127.8, 127.7, 99.4,
75.9, 70.7, 69.6, 68.5, 55.3, 32.6, 25.8, 18.2, 8.1, ꢀ4.6;
LRMS (EI) m/z 461 (M+ꢀOMe, 2.7%), 435 (34.3), 329
(22.8), 313 (33.6), 201 (96.9), 91 (100); HRMS (EI) m/z calcd
for C19H30IO3Si, (M+ꢀOMe) 461.1009, found 461.1007.
1
1030, 1000, 715 cmꢀ1; H NMR (300 MHz) d 7.40–7.24
(5H, m), 4.65 (1H, d, J¼11.6 Hz), 4.64 (1H, d, J¼3.5 Hz),
4.47 (1H, d, J¼11.6 Hz), 3.83 (1H, dd, J¼3.3, 11.5 Hz),
3.73 (1H, dd, J¼4.4, 11.5 Hz), 3.63 (1H, ddd, J¼3.5, 4.3,
11.7 Hz), 3.59 (1H, ddd, J¼3.3, 4.4, 9.8 Hz), 3.45 (1H, ddd,
J¼4.6, 9.8, 11.3 Hz), 3.44 (3H, s), 2.38 (1H, ddd, J¼4.3,
4.6, 11.5 Hz), 1.68 (1H, ddd, J¼11.3, 11.5, 11.7 Hz); 13C
NMR (75 MHz) d 137.8, 128.5, 127.8, 127.7, 98.4, 71.9,
70.9, 70.7, 67.3, 62.2, 55.0, 33.3; LRMS (EI) m/z 268 (M+,
14.5%), 236 (53), 146 (100); HRMS (EI) m/z calcd for
C14H20O5 (M+) 268.1311, found 268.1310. Anal. Calcd for
C14H20O5: C, 62.67; H, 7.51. Found: C, 62.47; H, 7.21.
4.2.3. Methyl 4-O-benzyl-2-O-(tert-butyldimethylsilyl)-
3,6-dideoxy-a-D-erythro-hex-5-enopyranoside (12). To
a solution of 11 (13.4 g, 27.2 mmol) in THF (260 mL) was
added t-BuOK (12.3 g, 81.6 mmol) at 0 ꢂC, and the reaction
mixture was stirred at 0 ꢂC for 2 h. The reaction mixture was
diluted with EtOAc, washed successively with H2O and
brine, and then dried over Na2CO3. Removal of the solvent
gave a residue, which was purified by column chromato-
graphy (silica gel: 200 g, EtOAc/hexane¼1:30 contain-
ing 1 vol % Et3N) to give 12 (8.0 g, 81%) as a colorless

S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
6933
syrup: Rf 0.68 (EtOAc/hexane¼1:5); [a]2D4 +42.0 (c 0.61,
CHCl3); IR (neat) 2960, 2930, 2855, 1660, 1260, 1100,
1030, 840 cmꢀ1; 1H NMR (300 MHz) d 7.42–7.24 (5H, m),
4.83 (1H, br s), 4.69 and 4.64 (each 1H, 2d, J¼12.3 Hz),
4.60 and 4.59 (each 1H, 2br s), 3.94–3.82 (2H, m), 3.47
(3H, s), 2.15–2.05 (1H, m), 2.01 (1H, m), 0.89 (9H, s), 0.08
(6H, s); 13C NMR (75 MHz) d 154.9, 138.2, 128.4, 127.7,
127.4, 100.8, 95.1, 72.4, 71.2, 68.4, 55.4, 34.2, 25.8, 18.2,
ꢀ4.6; HRMS (FAB+, NBA matrix) m/z calcd for
C20H32O4Si, (M+H)+ 365.2152, found 365.2148.
Calcd for C19H28O3Si: C, 68.63; H, 8.49. Found: C, 68.46;
H, 8.52.
4.2.6. (2R)-2-(4-Methoxybenzyloxy)propanal [(R)-7a]
and its enantiomer [(S)-7a]. To a solution of methyl (R)-lac-
tate (1.14 g, 11.0 mmol) in CH2Cl2 (20 mL) were added (4-
methoxybenzyl)trichloroacetimidate (6.17 g, 21.8 mmol)
and CSA (0.50 g, 2.15 mmol) at room temperature, and the
reaction mixture was stirred for 15 h. The reaction mixture
was quenched with MeOH and the products were extracted
with EtOAc. The organic layer was washed successively
with saturated aqueous NaHCO3 solution and brine, and
then dried. Removal of the solvent gave a residue, which
was purified by column chromatography (EtOAc/hexane¼
1:20) to give methyl (R)-lactate p-methoxybenzyl ether
4.2.4. A mixture of (2S,4R,5R)-2-benzyloxy-4-(tert-butyl-
dimethylsilyloxy)-5-hydroxy-cyclohexen-1-one and its
(5S)-isomer (13). To a solution of 12 (4.46 g, 12.2 mmol)
in acetone (300 mL) and acetate buffer (0.1 mol/L solution,
prepared from 0.2 mol/L aqueous sodium acetate and acetic
acid, pH 4.8, 150 mL) was added Hg(OCOCF3)2 (1.56 g,
3.66 mmol), and the mixture was stirred at room temperature
for 14 h. The reaction mixture was partially concentrated and
then extracted with EtOAc. The organic layer was washed
successivelywith 10% aqueous KI solution and 20% aqueous
Na2S2O3 solution and brine, and then dried. Removal of the
solvent gave a residue, which was purified by column chro-
matography (silica gel: 90 g, EtOAc/hexane¼1:5) to give
13 as a diastereomeric mixture (5S:5R¼ca. 1:10, 3.97 g,
93%) as a colorless syrup: Rf 0.51 (EtOAc/hexane¼1:5);
1H NMR (300 MHz, for the major isomer) d 7.40–7.28
(5H, m), 4.87 and 4.49 (each 1H, 2d, J¼11.6 Hz), 3.98
(1H, dd, J¼6.1, 12.7 Hz), 3.75 (1H, ddd, J¼4.1, 8.3,
10.6 Hz), 3.60 (1H, ddd, J¼5.1, 8.3, 12.1 Hz), 2.76 (1H,
dd, J¼5.1, 13.8 Hz), 2.51 (1H, br s), 2.39 (1H, dd, J¼12.1,
13.8 Hz), 2.35 (1H, ddd, J¼4.1, 6.1, 12.1 Hz), 1.69 (1H,
ddd, J¼10.6, 12.1, 12.7 Hz), 0.90 (9H, s), 0.13 and 0.11
(each 3H, 2s); 13C NMR (75 MHz, for the major isomer)
d 204.9, 137.5, 128.5, 128.0, 127.9, 78.6, 73.8, 73.4, 72.2,
43.8, 36.5, 25.7, 17.9, ꢀ4.3, ꢀ4.6; HRMS (FAB+, NBA
matrix) m/z calcd for C19H30O4Si, (M+H)+ 351.1992, found
351.2002.
1
(2.40 g) as a colorless syrup: H NMR (300 MHz) d 7.29
and 6.88 (each 2H, 2d, J¼8.6 Hz), 4.62 and 4.39 (each 1H,
2d, J¼11.4 Hz), 4.05 (1H, q, J¼6.9 Hz), 3.80 and 3.75
(each 3H, 2s), 1.42 (3H, d, J¼6.9 Hz); 13C NMR (75 MHz)
d 173.7, 159.3, 129.58, 129.48, 113.7, 73.5, 71.6, 55.2,
51.8, 18.7.
To a solution of methyl (R)-lactate p-methoxybenzyl ether
(2.40 g, 10.7 mmol) in CH2Cl2 (50 mL) was added
1.01 mol/L solution of DIBAL-H in toluene (13.7 mL,
13.9 mmol) at ꢀ78 ꢂC, and the reaction mixture was stirred
for 20 min at ꢀ78 ꢂC. The reaction mixture was quenched
with water, and the products were extracted with EtOAc.
The organic layer was washed successively with 1 mol/L
aqueous HCl solution, saturated aqueous NaHCO3 solution
and brine, and then dried. Removal of the solvent gave a
residue, which was purified by column chromatography
(EtOAc/hexane¼1:15) to give (R)-7a (1.82 g, 86% for two
steps) as a colorless liquid: [a]2D0 +26.0 (c 0.93, CHCl3);
IR (neat) 2940, 2840, 2480, 1730, 1615, 1515, 1250,
1035 cmꢀ1
;
1H NMR (300 MHz) d 9.63 (1H, d, J¼
1.7 Hz), 7.29 and 6.89 (each 2H, 2d, J¼8.6 Hz), 4.58 and
4.53 (each 1H, 2d, J¼11.5 Hz), 3.87 (1H, qd, J¼6.8,
1.7 Hz), 3.81 (3H, s), 1.31 (3H, d, J¼6.8 Hz); 13C NMR
(75 MHz,) d 203.5, 159.5, 129.6, 129.3, 113.9, 79.1, 71.7,
55.2, 15.3; HRMS (FAB+, NBA matrix) m/z calcd for
C11H14O3, (M+H)+ 195.1040, found 195.1021.
4.2.5. (4R,6S)-6-Benzyloxy-4-(tert-butyldimethyl-
silyloxy)-2-cyclohexenone [(+)-6]. To a solution of 13
(3.97 g, 11.3 mmol) in CH2Cl2 (80 mL) were added MsCl
(3.50 mL, 25.2 mmol) and Et3N (12.6 mL, 90.4 mmol) at
0 ꢂC, and the reaction mixture was stirred at 0 ꢂC for
2.5 h. The reaction mixture was diluted with EtOAc, and
washed successively with 1 mol/L aqueous HCl solution,
saturated aqueous NaHCO3 solution and brine, and then
dried. Removal of the solvent gave a residue, which was pu-
rified by column chromatography (silica gel: 70 g, EtOAc/
hexane¼1:6) to give (+)-6 (3.50 g, 86% from 12) as a white
solid: Rf 0.57 (EtOAc/hexane¼1:4); mp 46.5–47.5 ꢂC; [a]D23
+22.0 (c 0.94, CHCl3); IR (KBr disk) 2955, 2930, 2860,
The similar treatment of methyl (S)-lactate (1.14 g,
11.0 mmol) as described for the preparation of (R)-7a
afforded (2S)-2-(4-methoxybenzyloxy)propanal [(S)-7a]
(1.26 g, 60% for two steps) as a colorless liquid: [a]D20
ꢀ25.0 (c 0.95, CHCl3).
4.2.7. (3R,4R,6S)-6-Benzyloxy-4-(tert-butyldimethyl-
silyloxy)-3-vinylcyclohexan-1-one (14). To a suspension
of copper(I) cyanide (CuCN, 18.0 mg, 0.20 mmol) in ether
(0.6 mL) at ꢀ78 ꢂC was added dropwise vinyllithium
(freshly prepared from tetravinyltin and PhLi, according to
the procedure reported by Seyferth and Weiner,16 1.0 mol/L
solution in ether, 0.45 mL, 0.45 mmol) under Ar. After being
stirred at ꢀ78 ꢂC for 3 min, the mixture was allowed to warm
to 0 ꢂC and further stirred at 0 ꢂC for 1 min. The resulting
clear solution was cooled to ꢀ78 ꢂC, and to this solution
was added slowly a solution of enone (+)-6 (50.0 mg,
0.15 mmol) in ether (0.6 mL) via a cannula. After being
stirred at ꢀ78 ꢂC for 15 min, the reaction mixture was
quenched with saturated aqueous NH4Cl solution, and the
1700, 1255, 1100, 1070, 965, 940 cmꢀ1
;
1H NMR
(300 MHz) d 7.45–7.28 (5H, m), 6.77 (1H, ddd, J¼1.9,
2.1, 10.2 Hz), 5.96 (1H, dd, J¼2.4, 10.2 Hz), 4.99 and
4.66 (each 1H, 2d, J¼11.7 Hz), 4.58 (1H, dddd, J¼2.1,
2.4, 5.1, 10.0 Hz), 3.91 (1H, dd, J¼4.9, 13.7 Hz), 2.51
(1H, dddd, J¼1.9, 4.9, 5.1, 11.9 Hz), 2.09 (1H, ddd,
J¼10.0, 11.9, 13.7 Hz), 0.90 (9H, s), 0.12 and 0.11 (each
3H, 2s); 13C NMR (75 MHz) d 198.2, 153.8, 137.8, 128.4,
127.9, 127.8, 127.3, 76.6, 72.4, 67.7, 40.8, 25.7, 18.0,
ꢀ4.6, ꢀ4.8; HRMS (FAB+, NBA matrix) m/z calcd for
C19H28O3Si, (M+H)+ 333.1886, found 333.1883. Anal.

6934
S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
products were extracted with EtOAc. The organic layer was
washed successively with saturated aqueous NaHCO3, brine,
and then dried. Removal of the solvent gave a residue, which
was purified by column chromatography (silica gel: 1 g,
EtOAc/hexane¼1:10) to give 14 (54.1 mg, 100%) as a color-
less syrup: [a]2D3 ꢀ93.1 (c 1.00, CHCl3); IR (KBr disk) 2960,
2930, 2860, 1730, 1260, 1100, 860, 840, 780, 700 cmꢀ1; 1H
NMR (300 MHz) d 7.42–7.28 (5H, m), 5.77 (1H, ddd,
J¼6.9, 10.5, 17.4 Hz), 5.08 (1H, dd, J¼0.9, 10.5 Hz), 5.20
(1H, dd, J¼0.9, 17.4 Hz), 4.87 and 4.49 (each 1H, 2d,
J¼11.9 Hz), 3.98 (1H, dd, J¼6.3, 12.9 Hz), 3.74 (1H, ddd,
J¼4.3, 9.6, 10.8 Hz), 2.50–2.36 (3H, m), 2.25 (1H, m),
1.85 (1H, ddd, J¼10.8, 12.3, 12.9 Hz), 0.87 (9H, s), 0.06
and 0.05 (each 3H, 2s); 13C NMR (75 MHz) d 207.5,
138.8, 137.8, 128.6, 116.1, 78.3, 72.1, 71.7, 50.0, 41.9,
41.6, 25.9, 18.2, ꢀ4.2, ꢀ4.4; HRMS (FAB+, NBA matrix)
m/z calcd for C21H33O3Si, (M+H)+ 361.2199, found
361.2197.
copper(I) cyanide (CuCN, 259 mg, 2.89 mmol), vinyllithium
(5.80 mmol), and aldehyde (R)-7a (1.09 g, 5.61 mmol)
afforded 15 (855.1 mg, 85%).
4.2.10. Three-component coupling reaction with (S)-7a.
The similar treatment of (+)-6 (78.7 mg, 0.237 mmol) with
copper(I) cyanide (CuCN, 42.4 mg, 0.474 mmol) and vinyl-
lithium (1.0 mol/L solution in ether, 0.95 mL, 0.95 mmol) as
described for the preparation of 15 afforded 1,4-addition in-
termediate. To an ethereal solution of the enolate (5 mL) at
ꢀ78 ꢂC was added a solution of aldehyde (S)-7a (184 mg,
0.948 mmol) in ether (1.0 mL) dropwise via a cannula.
After being stirred at ꢀ78 ꢂC for 1.5 h, the reaction mixture
was quenched and processed similarly as described for
the preparation of 15. Purification by column chromato-
graphy (silica gel: 18 g, EtOAc/hexane¼1:10) gave
(2R,3R,4R,6S)-6-benzyloxy-4-(tert-butyldimethylsilyloxy)-
2-[(10S,20S)-10-hydroxy-20-(4-methoxybenzyloxy)propyl]-
3-vinylcyclohexan-1-one (16) (91.9 mg, 72%) as a white
solid: Rf 0.69 (EtOAc/hexane¼1:2); mp 118–119 ꢂC;
[a]1D9 ꢀ15.0 (c 0.66, CHCl3); IR (neat) 3420, 2930, 2860,
4.2.8. Three-component coupling reaction with ( )-7a. To
a suspension of copper(I) cyanide (CuCN, 112 mg,
1.25 mmol) in ether (3.0 mL) at ꢀ78 ꢂC was added dropwise
vinyllithium (freshly prepared from tetravinyltin and PhLi,
1.0 mol/L solution in ether, 2.51 mL, 2.51 mmol) under
Ar. After being stirred at ꢀ78 ꢂC for 10 min, the mixture
was allowed to warm to 0 ꢂC and further stirred at 0 ꢂC for
2 min. The resulting clear solution was cooled to ꢀ78 ꢂC,
and to this solution was added slowly a solution of enone
(+)-6 (209 mg, 0.627 mmol) in ether (1.0 mL) via a cannula.
After being stirred at ꢀ78 ꢂC for 30 min, a solution of alde-
hyde (ꢁ)-7a (740 mg, 3.76 mmol) in ether (1.0 mL) was
added to the mixture dropwise via a cannula, and the mixture
was stirred for 20 min at ꢀ78 ꢂC. The reaction mixture was
quenched with saturated aqueous NH4Cl solution, and the
products were extracted with EtOAc. The organic layer
was washed successively with saturated aqueous NaHCO3,
brine, and then dried. Removal of the solvent gave a residue,
which was purified by column chromatography (silica gel:
35 g, EtOAc/hexane¼1:8) to give (2S,3R,4R,6S)-6-benzyl-
oxy-4-(tert-butyldimethylsilyloxy)-2-[(10R,20R)-10-hydroxy-
20-(4-methoxybenzyloxy)propyl]-3-vinylcyclohexan-1-one
(15) (228.9 mg, 68%) as a colorless syrup: Rf 0.59 (EtOAc/
hexane¼1:3); [a]2D3 ꢀ69.0 (c 0.56, CHCl3); IR (neat) 3420,
1700, 1255, 1140, 1090, 860, 840 cmꢀ1
;
1H NMR
(300 MHz) d 7.40–7.24 (5H, m), 7.21 and 6.84 (each 2H,
2d, J¼8.8 Hz), 5.80 (1H, ddd, J¼9.3, 10.0, 16.7 Hz), 5.13
(1H, dd, J¼1.7, 10.0 Hz), 5.09 (1H, dd, J¼1.7, 16.7 Hz),
4.62 and 4.56 (each 1H, 2d, J¼11.3 Hz), 4.41 (1H, ddd,
J¼4.6, 9.3, 10.1 Hz), 4.29 (1H, dd, J¼6.1, 12.3 Hz), 4.24
and 4.23 (each 1H, 2d, J¼11.4 Hz), 3.72–3.68 (1H, m),
3.71 (3H, s), 3.19 (1H, qd, J¼6.1, 7.6 Hz), 3.00 (1H, br s),
2.69 (1H, dd, J¼3.2, 6.8 Hz), 2.57 (1H, ddd, J¼6.8, 9.3,
9.3 Hz), 2.33 (1H, ddd, J¼4.6, 6.1, 12.4 Hz), 1.74 (1H,
ddd, J¼10.1, 12.3, 12.4 Hz), 1.20 (3H, d, J¼6.1 Hz), 0.83
(9H, s), 0.04 and 0.02 (each 3H, 2s); 13C NMR (75 MHz)
d 210.0, 159.4, 138.1, 136.9, 129.8, 129.6, 128.3, 127.9,
127.7, 118.6, 113.9, 80.3, 75.8, 72.1, 72.1, 70.3, 68.8,
55.2, 54.6, 53.9, 42.9, 25.8, 18.1, 15.1, ꢀ4.2, ꢀ4.4; HRMS
(FAB+, NBA matrix) m/z calcd for C32H47O6Si, (M+H)+
555.3142, found 555.3139.
4.2.11. (1S,2S,3S,4R,5R)-1-Benzyloxy-5-(tert-butyldi-
methylsilyloxy)-3-[(10R,20R)-10-hydroxy-20-(4-methoxy-
benzyloxy)propyl]-4-vinylcyclohexan-2-ol (17). To
a
solution of 15 (164 mg, 0.296 mmol) in AcOH/THF (2:1,
3.3 mL) was added Me4NBH(OAc)3 (479 mg, 1.82 mmol)
at 0 ꢂC, and the reaction mixture was stirred at room temper-
ature for 24 h. The reaction mixture was quenched with
saturated aqueous Rochelle salt solution, and the products
were extracted with EtOAc. The organic layer was washed
successively with saturated aqueous NaHCO3 solution and
brine, and then dried. Removal of the solvent gave a residue,
which was purified by column chromatography (silica gel:
6 g, EtOAc/hexane¼1:8) to give 17 (114 mg, 70%) as a white
solid: Rf 0.59 (EtOAc/hexane¼1:2); [a]2D1 ꢀ15.0 (c 0.91,
CHCl3); mp 81–84 ꢂC; IR (neat) 3500, 2960, 2930, 2860,
2960, 2930, 2860, 2360, 1715, 1615 cmꢀ1 1H NMR
;
(300 MHz) d 7.36–7.26 (7H, m), 6.84 (2H, d, J¼8.8 Hz),
5.40 (1H, ddd, J¼11.7, 15.0, 17.2 Hz), 5.21 (1H, dd,
J¼1.6, 11.7 Hz), 5.20 (1H, dd, J¼1.6, 17.2 Hz), 4.67 (1H,
d, J¼11.5 Hz), 4.57 (1H, d, J¼11.2 Hz), 4.43 (1H, d,
J¼11.5 Hz), 4.31 (1H, d, J¼11.2 Hz), 3.95 (1H, dd, J¼6.3,
12.7 Hz), 3.90–3.75 (1H, m), 3.85–3.70 (2H, m), 3.81 (3H,
s), 2.68 (1H, ddd, J¼10.6, 12.4, 15.0 Hz), 2.44 (1H, ddd,
J¼4.6, 6.1, 10.8 Hz), 2.28 (1H, d, J¼10.6 Hz), 1.85 (1H,
ddd, J¼10.8, 12.6, 12.7 Hz), 1.18 (3H, d, J¼6.1 Hz), 0.84
(9H, s), 0.03 (6H, s); 13C NMR (75 MHz) d 210.9, 159.1,
137.5, 130.6, 129.4, 128.5, 127.8, 119.9, 113.7, 113.6,
78.2, 77.3, 73.9, 71.7, 71.1, 70.3, 55.1, 54.6, 48.3, 42.0,
25.7, 17.9, 16.1, ꢀ4.4; HRMS (FAB+, NBA matrix) m/z calcd
for C32H47O6Si, (M+H)+ 555.3142, found 555.3151. Anal.
Calcd for C32H46O6Si: C, 69.28; H, 8.36. Found: C, 69.36;
H, 8.42.
1
2360, 1615 cmꢀ1; H NMR (300 MHz) d 7.36–7.32 (5H,
m), 7.26 and 6.86 (each 2H, 2d, J¼8.7 Hz), 5.28 (1H,
ddd, J¼9.9, 10.3, 16.6 Hz), 5.11 (1H, dd, J¼2.2, 9.9 Hz),
5.08 (1H, dd, J¼2.2, 16.6 Hz), 4.68 and 4.53 (each 1H, 2d,
J ¼11.7 Hz), 4.58 and 4.35 (each 1H, 2d, J¼11.0 Hz),
4.00 (1H, qd, J¼6.1, 8.2 Hz), 3.82–3.76 (1H, m), 3.79
(3H, s), 3.63 (1H, dd, J¼2.1, 8.2 Hz), 3.32 (1H, ddd,
J¼3.9, 9.8, 10.7 Hz), 3.24 (1H, ddd, J¼3.9, 9.0, 12.9 Hz),
2.83 (1H, d, J¼2.0 Hz), 2.73 (1H, d, J¼2.1 Hz), 2.25 (1H,
4.2.9. Three-component coupling reaction with (R)-7a.
The similar treatment of (+)-6 (600 mg, 1.81 mmol) with

S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
6935
ddd, J¼9.8, 10.3, 10.7 Hz), 2.19 (1H, ddd, J¼3.9, 3.9,
11.8 Hz), 1.39 (1H, ddd, J¼10.7, 11.8, 12.9 Hz), 1.32 (1H,
m), 1.13 (3H, d, J¼6.1 Hz), 0.83 (9H, s), ꢀ0.04 (6H, s);
13C NMR (75 MHz) d 159.2, 139.0, 138.4, 130.6, 129.6,
128.4, 127.7, 119.2, 113.8, 80.0, 78.4, 74.6, 71.6, 71.1,
71.0, 70.7, 55.2, 51.9, 43.0, 37.5, 25.8, 18.0, 15.3, ꢀ4.3,
ꢀ4.4; HRMS (FAB+, NBA matrix) m/z calcd for
C32H49O6Si, (M+H)+ 557.3298, found 557.3304. Anal.
Calcd for C32H48O6Si: C, 69.03; H, 8.69. Found: C, 69.20;
H, 8.63.
3.37–3.28 (1H, m), 3.32 (3H, s), 3.22 (1H, ddd, J¼3.9,
10.4, 11.6 Hz), 2.36 (3H, s), 2.20–2.10 (1H, m), 2.11 (1H,
ddd, J¼3.9, 3.9, 12.4 Hz), 1.62 (1H, dd, J¼10.5, 10.5 Hz),
1.29 (1H, ddd, J¼11.6, 11.6, 12.4 Hz), 1.05 (3H, d,
J¼6.3 Hz), 0.81 (9H, s), ꢀ0.04 and ꢀ0.05 (each 3H, 2s);
13C NMR (75 MHz) d 158.2, 143.8, 138.3, 138.2, 135.1,
130.7, 129.2, 129.1, 128.3, 127.7, 127.6, 113.4, 98.9, 86.2,
80.0, 78.5, 75.2, 71.5, 70.8, 70.7, 57.0, 55.1, 51.3, 43.0,
38.3, 25.7, 21.5, 17.9, 16.8, ꢀ4.3, ꢀ4.5; HRMS (FAB+,
NBA matrix) m/z calcd for C41H58O9SSiK, (M+K)+
793.3208, found 793.3197.
4.2.12. (1S,2S,3S,4R,5R)-1-Benzyloxy-5-(tert-butyldi-
methylsilyloxy)-3-[(10R,20R)-20-(4-methoxybenzyloxy)-
10-(p-toluenesulfonyloxy)propyl]-4-vinylcyclohexan-2-ol
(18). To a solution of 17 (413 mg, 0.742 mmol) in THF
(8.3 mL) were added 1.59 mol/L solution of BuLi in hexane
(1.40 mL, 2.23 mmol) and TsCl (293 mg, 2.08 mmol) at
0 ꢂC, and the reaction mixture was stirred at 0 ꢂC for
20 min. The mixture was diluted with EtOAc, and washed
successively with saturated aqueous NH4Cl solution and
brine, and then dried. Removal of the solvent gave a residue,
which was purified by column chromatography (silica gel:
11 g, EtOAc/hexane¼1:7) to give 18 (534 mg, 100%) as
a colorless oil: Rf 0.59 (EtOAc/hexane¼1:2); [a]2D2 +3.0 (c
1.05, CHCl3); IR (neat) 3560, 2960, 2930, 2860,
1615 cmꢀ1; 1H NMR (300 MHz) d 7.78 (2H, d, J¼8.4 Hz),
7.39–7.27 (5H, m), 7.19 and 7.12 (each 2H, 2d, J¼8.6 Hz),
6.79 (2H, d, J¼8.4 Hz), 5.30–5.20 (3H, m), 4.86 (1H, d,
J¼7.5 Hz), 4.67 and 4.52 (each 1H, 2d, J¼11.6 Hz), 4.30
and 4.16 (each 1H, 2d, J¼11.8 Hz), 3.90 (1H, qd, J¼6.1,
7.5 Hz), 3.78 (3H, s), 3.67 (1H, ddd, J¼1.5, 8.5, 10.2 Hz),
3.29 (1H, ddd, J¼4.4, 12.0, 12.2, Hz), 3.19 (1H, ddd,
J¼4.4, 8.5, 12.2 Hz), 2.95 (1H, d, J¼1.5 Hz), 2.37 (3H, s),
2.12 (1H, m), 2.08–2.00 (1H, m), 1.46 (1H, dd, J¼10.2,
11.9 Hz), 1.26 (1H, m), 1.06 (3H, d, J¼6.1 Hz), 0.83 (9H,
s), ꢀ0.03 and ꢀ0.05 (each 3H, 2s); 13C NMR (75 MHz)
d 159.0, 143.9, 138.3, 135.1, 130.5, 129.4, 128.5, 127.8,
120.6, 113.5, 86.1, 79.5, 75.6, 72.1, 71.3, 71.1, 70.9, 55.2,
51.1, 43.5, 37.4, 25.7, 21.6, 18.0, 16.7, ꢀ4.3, ꢀ4.4; HRMS
(FAB+, NBA matrix) m/z calcd for C39H54NaO8SSi,
(M+Na)+ 733.3207, found 733.3207.
4.2.14. (1S,2S,3S,4R,5R)-1-Benzyloxy-5-(tert-butyldi-
methylsilyloxy)-3-[(10R,20R)-20-hydroxy-10-(p-toluene-
sulfonyloxy)propyl]-2-methoxymethyloxy-4-vinylcyclo-
hexane (20). To a solution of 19 (674 mg, 0.89 mmol) in
CH2Cl2/H2O (10:1, 11 mL) was added DDQ (405 mg,
1.78 mmol) at 0 ꢂC, and the reaction mixture was stirred at
room temperature for 1 h. The reaction mixture was diluted
with EtOAc and washed successively with 10% aqueous
Na2S2O3 solution, saturated aqueous NaHCO3 solution and
brine, and then dried. Removal of the solvent gave a residue,
which was purified by column chromatography (silica gel:
18 g, EtOAc/hexane¼1:4) to give 20 (549 mg, 97%) as a col-
orless oil: Rf 0.34 (EtOAc/hexane¼1:2); [a]2D2 ꢀ9.0 (c 1.1,
1
CHCl3); IR (neat) 3500, 2960, 2930, 2860, 2360 cmꢀ1; H
NMR (300 MHz) d 7.83 (2H, d, J¼8.0 Hz), 7.36–7.27
(7H, m), 5.32–5.25 (3H, m), 4.89 and 4.78 (each 1H, 2d,
J¼5.1 Hz), 4.83 (1H, d, J¼4.6 Hz), 4.59 and 4.54 (each
1H, 2d, J¼11.6 Hz), 3.93 (1H, qd, J¼4.6, 5.8 Hz), 3.64
(1H, br s), 3.51 (1H, dd, J¼10.3, 10.9 Hz), 3.37 (1H, ddd,
J¼4.0, 11.9, 11.9 Hz), 3.32 (3H, s), 3.25 (1H, ddd, J¼4.0,
10.9, 12.8 Hz), 2.44 (3H, s), 2.22 (1H, ddd, J¼11.5,
11.9 Hz), 2.14 (1H, ddd, J¼4.0, 4.1, 12.2 Hz), 1.72 (1H,
dd, J¼10.3, 11.5 Hz), 1.33 (1H, ddd, J¼11.9, 12.2,
12.8 Hz), 1.04 (3H, d, J¼4.6 Hz), 0.81 (9H, s), ꢀ0.04
and ꢀ0.05 (each 3H, 2s); 13C NMR (75 MHz) d 144.9,
138.3, 138.1, 133.7, 129.7, 128.4, 127.8, 127.7, 120.6,
99.0, 85.9, 79.9, 78.0, 71.6, 70.5, 69.1, 57.3, 52.2, 44.2,
38.3, 25.7, 21.6, 19.7, 17.9, ꢀ4.4, ꢀ4.5; HRMS (FAB+,
NBA matrix) m/z calcd for C33H51O8SSi, (M+H)+
635.3074, found 635.3084.
4.2.13. (1S,2S,3S,4R,5R)-1-Benzyloxy-5-(tert-butyldi-
methylsilyloxy)-3-[(10R,20R)-20-(4-methoxybenzyloxy)-
10-(p-toluenesulfonyloxy)propyl]-2-methoxymethyloxy-
4-vinylcyclohexane (19). To a solution of 18 (536 mg,
0.754 mmol) in (CH2Cl)2 (11 mL) were added i-Pr2NEt
(1.30 mL, 7.54 mmol) and MOMCl (0.570 mL, 7.54 mmol)
at 0 ꢂC, and the reaction mixture was stirred at 50 ꢂC for
3.5 h. The reaction mixture was diluted with EtOAc and
washed successively with saturated aqueous NaHCO3 solu-
tion and brine, and then dried. Removal of the solvent gave
a residue, which was purified by column chromatography
(silica gel: 20 g, EtOAc/hexane¼1:10) to give 19 (557 mg,
98%) as a colorless oil: Rf 0.67 (EtOAc/hexane¼1:2);
[a]2D3 +16.0 (c 1.0, CHCl3); IR (neat) 2980, 2930, 2860,
4.2.15. (1S,2S,3S,4R,5R)-1-Benzyloxy-5-(tert-butyldi-
methylsilyloxy)-2-methoxymethyloxy-3-[(10S,20R)-20-
methyloxiranyl]-4-vinylcyclohexane (21). To a solution of
20 (78.5 mg, 0.124 mmol) in toluene (1.6 mL) was added
DBU (0.15 mL, 0.99 mmol) at 0 ꢂC, and the reaction mix-
ture was stirred at 50 ꢂC for 20 h. The reaction mixture
was diluted with EtOAc, and washed successively with sat-
urated aqueous NaHCO3 solution and brine, and then dried.
Removal of the solvent gave a residue, which was purified by
column chromatography (silica gel: 1 g, EtOAc/hexane¼
1:6) to give 21 (49.7 mg, 94%) as a colorless syrup; [a]D24
ꢀ14.0 (c 0.53, CHCl3); IR (neat) 2960, 2920, 2860, 1260,
1
1080, 1020 cmꢀ1; H NMR (300 MHz) d 7.36–7.27 (5H,
1615 1515 cmꢀ1
;
1H NMR (300 MHz) d 7.76 (2H, d,
m), 5.80 (1H, ddd, J¼9.3, 10.5, 15.9 Hz), 5.26 (1H, dd,
J¼1.8, 10.5 Hz), 5.10 (1H, dd, J¼1.8, 15.9 Hz), 4.97 and
4.69 (each 1H, 2d, J¼6.3 Hz), 4.61 and 4.59 (each 1H, 2d,
J¼11.4 Hz), 3.48 (1H, dd, J¼9.0, 9.9 Hz), 3.29–3.45 (2H,
m), 3.36 (3H, s), 3.01 (1H, qd, J¼4.2, 5.7 Hz), 2.78 (1H,
dd, J¼4.2, 9.3 Hz), 2.26 (1H, ddd, J¼4.2, 4.2, 11.1 Hz),
2.14 (1H, ddd, J¼9.3, 9.3, 9.3 Hz), 1.47 (1H, ddd, J¼11.1,
J¼8.0 Hz), 7.36–7.27 (5H, m), 7.16 (2H, d, J¼8.0 Hz),
7.08 and 6.79 (each 2H, 2d, J¼8.7 Hz), 5.30–5.26 (3H, m),
4.90 (1H, d, J¼8.7 Hz), 4.87 and 4.75 (each 1H, 2d,
J¼5.3 Hz), 4.59 and 4.53 (each 1H, 2d, J¼11.6 Hz), 4.25
and 4.13 (each 1H, 2d, J¼11.6 Hz), 4.00 (1H, qd, J¼6.3,
8.7 Hz), 3.77 (3H, s), 3.58 (1H, dd, J¼10.4, 10.5 Hz),

6936
S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
11.1, 11.1 Hz), 1.28–1.40 (1H, m), 1.30 (3H, d, J¼5.7 Hz),
0.84 (9H, s), ꢀ0.01 and ꢀ0.02 (each 3H, 2s); 13C NMR
(75 MHz) d 138.72, 138.40, 128.38, 127.65, 117.01, 98.24,
79.87, 79.58, 71.78, 70.24, 59.39, 56.48, 55.10, 52.62,
42.21, 39.35, 25.83, 18.09, 14.75, ꢀ4.37; HRMS (FAB+,
NBA matrix) m/z calcd for C26H43O5Si, (M+H)+
463.2880, found 463.2875.
dried. Removal of the solvent gave a residue, which was
roughly purified by column chromatography (silica gel:
1 g, EtOAc/hexane¼1:5) to give mesylate (17.9 mg, 93%)
as a colorless syrup.
To a solution of the mesylate (17.9 mg, 0.0300 mmol) in
MeOH (1 mL) was added NaOMe (5.1 mg, 0.15 mmol) at
0 ꢂC, and the reaction mixture was stirred at room tempera-
ture for 18 h. The reaction mixture was neutralized with
acidic resin (Amberlite 120B, H+ form) and filtered.
Removal of the solvent gave a residue, which was dissolved
in pyridine (1 mL). To this solution were added Ac2O
(0.5 mL) and DMAP (1.0 mg) at room temperature, and
the reaction mixture was stirred at room temperature for
18 h. The reaction mixture was diluted with EtOAc, and
washed successively with 1 mol/L aqueous HCl solution,
saturated aqueous NaHCO3 solution and brine, and then
dried. Removal of the solvent gave a residue, which was pu-
rified by column chromatography (silica gel: 0.5 g, EtOAc/
hexane¼1:15) to give 23 (11.0 mg, 74% from 22) as a color-
less syrup: [a]2D4 ꢀ2.5 (c 0.22, CHCl3); IR (neat) 2960, 2940,
2860, 1820 cmꢀ1; 1H NMR (300 MHz) d 7.39–7.24 (5H, m),
5.69 (1H, ddd, J¼9.8, 9.8, 16.8 Hz), 5.10 (1H, dd, J¼1.5,
16.8 Hz), 5.07 (1H, dd, J¼1.5, 9.8 Hz), 4.95 (1H, dd,
J¼4.4, 8.3 Hz), 4.72 and 4.64 (each 1H, 2d, J ¼11.9 Hz),
3.85 (1H, ddd, J¼4.6, 8.3, 9.5 Hz), 3.74 (1H, ddd, J¼4.1,
9.3, 9.3 Hz), 2.96 (1H, qd, J¼3.9, 5.6 Hz), 2.86 (1H, dd,
J¼3.9, 5.6 Hz), 2.41–2.26 (2H, m), 2.20 (1H, ddd, J¼4.1,
4.6, 13.1 Hz), 2.08 (3H, s), 1.62 (1H, ddd, J¼9.3, 9.5,
13.1 Hz), 1.18 (3H, d, J¼5.6 Hz), 0.83 (9H, s), 0.02 and
0.00 (each 3H, 2s); 13C NMR (75 MHz) d 170.76, 138.67,
137.50, 128.30, 127.50, 127.45, 118.09, 76.31, 73.74,
72.23, 68.39, 53.86, 51.20, 50.93, 37.68, 36.70, 25.71,
21.28, 18.00, 13.76, ꢀ4.29, ꢀ4.61; HRMS (FAB+, NBA
matrix) m/z calcd for C26H40O5SiNa, (M+Na)+ 483.2543,
found 483.2543.
4.2.16. (1S,2S,3R,4R,5R)-2-Acetoxy-1-benzyloxy-5-(tert-
butyldimethylsilyloxy)-3-[(10S,20S)-10-acetoxy-20-hydroxy-
propyl]-4-vinylcyclohexane (22). To a solution of 16
(32.8 mg, 0.0591 mmol) in MeOH (1.2 mL) was added
NaBH4 (22.4 mg, 0.592 mmol) at 0 ꢂC, and the reaction
mixture was stirred at room temperature for 35 min. The re-
action mixture was diluted with EtOAc, and washed succes-
sively with 1 mol/L aqueous HCl solution, saturated aqueous
NaHCO3 solution and brine, and then dried. Removal of the
solvent gave a residue, which was purified by column chro-
matography (silica gel: 1 g, EtOAc/hexane¼1:5) to give an
alcohol (21.7 mg, 66%) as a colorless syrup.
To a solution of the alcohol (21.7 mg, 0.0390 mmol) in
pyridine (1 mL) were added Ac2O (0.5 mL) and DMAP
(1.0 mg) at 0 ꢂC, and the reaction mixture was stirred at
50 ꢂC for 4 h. The reaction mixture was diluted with
EtOAc, and washed successively with 1 mol/L aqueous
HCl solution, saturated aqueous NaHCO3 solution and brine,
and then dried. Removal of the solvent gave a residue, which
was dissolved in CH2Cl2/H2O (10:1, 1.0 mL). To this solu-
tion was added DDQ (42.0 mg, 0.185 mmol) at 0 ꢂC, and
the reaction mixture was stirred at room temperature for
2 h. The reaction mixture was diluted with EtOAc and
washed successively with 20% aqueous Na2S2O3 solution,
saturated aqueous NaHCO3 solution and brine, and then
dried. Removal of the solvent gave a residue, which was pu-
rified by column chromatography (silica gel: 0.5 g, EtOAc/
hexane¼1:5) to give 22 (14.3 mg, 46% from 16) as a color-
less syrup: [a]2D6 +3.7 (c 0.57, CHCl3); IR (neat) 3500, 2970,
4.2.18. (4S,5S,6S,1R,2R)-4-Benzyloxy-2-(tert-butyldi-
methylsilyloxy)-6-[(10R,20R)-20-hydroxy-10-(p-toluene-
sulfonyloxy)propyl]-5-methoxymethyloxy-cyclohexan-
carboxylic acid (25). Ozone was introduced to a solution
of 19 (7.9 mg, 0.010 mmol) in MeOH (1 mL) at ꢀ78 ꢂC
for 5 min. To the reaction mixture was added Me2S
(0.070 mL, 0.95 mmol) at ꢀ78 ꢂC. After being stirred at
room temperature for 12 h, the reaction mixture was diluted
with Et2O. The organic layer was washed with brine, and
then dried. Removal of the solvent gave a crude aldehyde,
which was used for the next reaction without purification.
1
2860, 1740, 1250 cmꢀ1; H NMR (300 MHz) d 7.24–7.38
(5H, m), 6.10 (1H, ddd, J¼10.2, 10.5, 16.5 Hz), 5.13–5.07
(2H, m), 5.08 (1H, dd, J¼1.5, 9.0 Hz), 4.93 (1H, dd,
J¼1.5, 11.1 Hz), 4.66 and 4.59 (each 1H, 2d, J¼12.6 Hz),
3.99 (1H, qd, J¼1.5, 6.6 Hz), 3.81 (1H, ddd, J¼3.0, 3.0,
4.2 Hz), 3.55 (1H, ddd, J¼3.0, 3.0, 9.0 Hz), 2.98 (1H, ddd,
J¼3.3, 3.9, 11.1 Hz), 2.56 (1H, ddd, J¼3.0, 3.9, 10.2 Hz),
2.06 and 2.01 (each 3H, 2s), 1.90 (1H, ddd, J¼2.7, 2.7,
15.3 Hz), 1.72 (1H, ddd, J¼3.0, 4.2, 15.3 Hz), 1.10 (3H, d,
J¼6.6 Hz), 0.87 (9H, s), 0.07 and 0.06 (each 3H, 2s); 13C
NMR (75 MHz) d 170.74, 170.40, 138.89, 137.87, 128.10,
127.38, 127.18, 118.24, 74.35, 73.74, 71.29, 70.75, 69.14,
65.15, 48.43, 32.17, 28.52, 25.72, 21.28, 20.80, 20.32,
17.99, ꢀ4.73, ꢀ4.99; HRMS (FAB+, NBA matrix) m/z calcd
for C28H44O7SiNa, (M+Na)+ 543.2754, found 543.2757.
To a solution of the crude aldehyde in t-BuOH/H2O (1:1,
0.2 mL) were added NaH2PO4$H2O (16 mg, 0.10 mmol),
HOSO2NH2 (9.7 mg, 0.10 mmol), and NaClO2 (9.1 mg,
0.10 mmol) at room temperature, and the reaction mixture
was stirred at room temperature for 12 h. The reaction mix-
ture was diluted with EtOAc, and washed successively with
1 mol/L aqueous HCl solution and brine, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (silica gel: 1 g, EtOAc/
hexane¼1:1) to give carboxylic acid 24 (6.1 mg, 75% for
two steps) as a colorless syrup.
4.2.17. (1S,2S,3R,4R,5R)-2-Acetoxy-1-benzyloxy-5-(tert-
butyldimethylsilyloxy)-3-[(10S,20R)-20-methyloxiranyl]-
4-vinylcyclohexane (23). To a solution of 22 (16.8 mg,
0.0323 mmol) in pyridine (1 mL) at 0 ꢂC were added
MsCl (0.025 mL, 0.32 mmol) and DMAP (1.0 mg), and
the reaction mixture was stirred at room temperature for
1.5 h. The reaction mixture was diluted with EtOAc, and
washed successively with 1 mol/L aqueous HCl solution,
saturated aqueous NaHCO3 solution and brine, and then
To a solution of carboxylic acid 24 (6.1 mg, 0.0081 mmol) in
CH2Cl2/H2O (10:1, 0.5 mL) was added DDQ (3.7 mg,

S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
6937
0.016 mmol) at 0 ꢂC, and the reaction mixture was stirred at
room temperature for 20 min. The reaction mixture was di-
luted with EtOAc and washed successively with 10% aque-
ous Na2S2O3 solution, saturated aqueous NaHCO3 solution
and brine, and then dried. Removal of the solvent gave a
residue, which was purified by column chromatography
(silica gel: 0.5 g, EtOAc/hexane¼1:2) to give 25 (3.9 mg,
76% from 19) as a colorless syrup: Rf 0.34 (EtOAc/
hexane¼1:1); IR (neat) 3480, 2955, 2930, 1730, 1715,
was added Dess–Martin periodinane (874 mg, 2.06 mmol)
at 0 ꢂC, and the reaction mixture was stirred at room temper-
ature for 23 h. The reaction mixture was diluted with EtOAc
and washed successively with 10% aqueous Na2S2O3 solu-
tion, saturated aqueous NaHCO3 solution and brine, and
then dried. Removal of the solvent gave a residue, which
was purified by column chromatography (silica gel: 2 g,
EtOAc/hexane¼1:9) to give 27 (130 mg, 100%) as a color-
less oil: Rf 0.65 (EtOAc/hexane¼1:2); [a]1D9 ꢀ6.0 (c 0.56,
1
1255, 1180, 1100, 850 cmꢀ1; H NMR (300 MHz) d 7.86
CHCl3); IR (neat) 2960, 2930, 2860, 1720, 1600 cmꢀ1
;
(2H, d, J¼8.3 Hz), 7.39–7.25 (7H, m), 4.91 and 4.76 (each
1H, 2d, J¼6.1 Hz), 4.72 (1H, br), 4.56 (2H, s), 4.17 (1H,
qd, J¼6.4, 3.4 Hz), 3.71 (1H, ddd, J¼4.0, 10.0, 11.7 Hz),
3.47–3.27 (2H, m), 3.36 (3H, s), 2.85 (1H, dd, J¼10.0,
10.5 Hz), 2.42 (3H, s), 2.23 (1H, ddd, J¼2.2, 10.5,
10.5, Hz), 2.11 (1H, ddd, J¼4.0, 4.0, 12.7 Hz), 1.34 (1H,
ddd, J¼11.7, 11.7, 12.7 Hz), 1.26 (1H, s), 1.06 (3H, d, J¼
6.4 Hz), 0.82 (9H, s), ꢀ0.02 (6H, s); HRMS (FAB+,
NBA matrix) m/z calcd for C32H48O10SSiNa, (M+Na)+
675.2636, found 675.2627.
1H NMR (300 MHz) d 7.85 (2H, d, J¼8.0 Hz), 7.36–7.30
(7H, m), 5.41 (1H, ddd, J¼8.8, 10.3, 17.1 Hz), 5.26 (1H,
dd, J¼2.0, 10.3 Hz), 5.15 (1H, dd, J¼2.0, 17.1 Hz), 4.69
and 4.57 (each 1H, 2d, J¼5.1 Hz), 4.56 and 4.20 (each 1H,
2d, J¼11.5 Hz), 3.47 (1H, dd, J¼9.0, 10.8 Hz), 3.36 (1H,
ddd, J¼4.1, 9.0, 11.6 Hz), 3.30 (1H, ddd, J¼4.4, 8.8,
11.6 Hz), 3.23 and 2.45 (each 3H, 2s), 2.23 (1H, dd,
J¼10.8, 11.2 Hz), 2.18 (3H, s), 2.15 (1H, ddd, J¼4.1, 4.4,
12.4 Hz), 2.01 (1H, ddd, J¼8.8, 8.8, 11.2 Hz), 1.32 (1H,
ddd, J¼8.8, 11.6, 12.4 Hz), 0.82 (9H, s), ꢀ0.04 and ꢀ0.05
(each 3H, 2s); 13C NMR (75 MHz) d 204.4, 145.0, 138.1,
137.7, 133.9, 129.7, 128.4, 127.9, 127.8, 127.7, 120.8,
98.1, 82.8, 79.4, 76.9, 71.5, 71.0, 56.8, 50.3, 45.8, 38.5,
26.5, 25.7, 21.6, 17.9, ꢀ4.3, ꢀ4.5; HRMS (FAB+, NBA
matrix) m/z calcd for C33H48O8SSiNa, (M+Na)+ 655.2737,
found 655.2740.
4.2.19. (3R,4R,4aS,5S,6S,8R,8aR)-6-Benzyloxy-8-(tert-
butyldimethylsilyloxy)-5-methoxymethyloxy-3-methyl-
4-(p-toluenesulfonyloxy)-perhydroisochroman-1-one
(26). By Mitsunobu reaction: To a solution of 25 (3.2 mg,
0.0049 mmol) in benzene (1 mL) were added Ph3P (3.2 mg,
0.012 mmol) and DEAD (0.0022 mL, 0.012 mmol) at 0 ꢂC,
and the reaction mixture was stirred at 80 ꢂC for 30 h. The
reaction mixture was diluted with Et2O and washed succes-
sively with brine, and then dried. Removal of the solvent
gave a residue, which was purified by column chromato-
graphy (silica gel: 0.5 g, EtOAc/hexane¼1:4) to give 26
(2.6 mg, 84%) as a colorless oil: Rf 0.16 (EtOAc/hexane¼
1:5); [a]2D3 +22.6 (c 0.69, CHCl3); IR (neat) 2960, 2930,
4.2.21. (3S,4R,4aS,5S,6S,8R,8aR)-6-Benzyloxy-8-(tert-
butyldimethylsilyloxy)-5-methoxymethyloxy-3-methyl-
4-(p-toluenesulfonyloxy)-perhydroisochroman-1-one
(30). Ozone was introduced to a solution of 27 (300 mg,
0.473 mmol) in MeOH (30 mL) at ꢀ78 ꢂC for 10 min.
To the reaction mixture was added Me2S (3.00 mL,
40.8 mmol) at ꢀ78 ꢂC, and the reaction mixture was stirred
at room temperature for 3 h. The products were extracted
with Et2O, and the organic layer was washed with brine,
and then dried. Removal of the solvent gave a crude alde-
hyde (311 mg), which was used for the next reaction without
purification.
1
2860, 1760, 1360, 1180, 1015, 940, 850 cmꢀ1; H NMR
(300 MHz) d 7.81 (2H, d, J¼8.4 Hz), 7.40–7.22 (7H, m),
5.29 (1H, s), 5.12 and 4.71 (each 1H, 2d, J¼6.3 Hz), 4.59
and 4.54 (each 1H, 2d, J¼11.4 Hz), 4.53 (1H, q, J¼6.3 Hz),
3.84 (1H, ddd, J¼4.7, 9.3, 9.3 Hz), 3.54 (3H, s), 3.48 (1H,
dd, J¼8.4, 11.4 Hz), 3.31 (1H, ddd, J¼4.2, 8.4, 11.4 Hz),
2.44 (3H, s), 2.32–2.18 (2H, m), 1.78 (1H, dd, J¼11.4,
12.9 Hz), 1.44 (3H, d, J¼6.3 Hz), 1.50–1.33 (1H, m), 0.82
(9H, s), 0.09 and 0.08 (each 3H, 2s); 13C NMR (75 MHz)
d 169.7, 144.6, 138.1, 134.8, 129.5, 128.5, 127.8, 127.7,
127.6, 98.3, 80.0, 79.3, 78.9, 73.9, 72.0, 66.1, 57.1, 47.3,
44.6, 39.2, 29.7, 25.8, 21.7, 18.0, 16.4, ꢀ4.7, ꢀ4.8; HRMS
(FAB+, NBA matrix) m/z calcd for C32H46O9SSiNa,
(M+Na)+ 657.2529, found 657.2521.
To a solution of the crude aldehyde (311 mg) in t-BuOH/
H2O (1:1, 6 mL) were added NaH2PO4$H2O (382 mg,
2.45 mmol), HOSO2NH2 (238 mg, 2.45 mmol), and NaClO2
(222 mg, 2.45 mmol) at room temperature, and the reaction
mixture was stirred at room temperature for 10 h. The reac-
tion mixture was diluted with EtOAc, and washed succes-
sively with 1 mol/L aqueous HCl solution and brine, and
then dried. Removal of the solvent gave a residue, which
was roughly purified by column chromatography (silica
gel: 7 g, EtOAc/hexane¼1:4, containing 1 vol % AcOH) to
give carboxylic acid 28 (308 mg) as a colorless syrup. This
was used for the next reaction without further purification.
By DCC-mediated lactonization: To a solution of 25
(1.9 mg, 0.0029 mmol) in (CH2Cl)2 (0.3 mL) were added
DCC (2.0 mg, 0.0096 mmol) and DMAP (1 mg) at 0 ꢂC,
and the reaction mixture was stirred at room temperature
for 4 h. The reaction mixture was diluted with EtOAc, and
successively washed with 1 mol/L aqueous HCl solution
and brine, and then dried. Removal of the solvent gave a resi-
due, which was purified by column chromatography (silica
gel: 0.5 g, EtOAc/hexane¼1:4) to give 26 (1.1 mg, 60%).
To a solution of 28 (308 mg, 0.473 mmol) in MeOH
(6.5 mL) was added NaBH4 (35.8 mg, 0.946 mmol) at
0 ꢂC, and the reaction mixture was stirred at 0 ꢂC for
30 min. The reaction mixture was diluted with EtOAc, and
successively washed with 1 mol/L aqueous HCl solution
and brine, and then dried. Removal of the solvent gave a
residue, which was roughly purified by column chromato-
graphy (silica gel: 7 g, EtOAc/hexane¼1:4, containing
1 vol % AcOH) to give a colorless syrup, which was dis-
solved in CH2Cl2 (6 mL).
4.2.20. (1S,2S,3S,4R,5R)-1-Benzyloxy-5-(tert-butyldi-
methylsilyloxy)-2-methoxymethyloxy-3-[(R)-10-(p-toluene-
sulfonyloxy)-20-oxopropyl]-4-vinylcyclohexane (27). To a
solution of 20 (131 mg, 0.206 mmol) in CH2Cl2 (2.6 mL)

6938
S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
To this solution were added DCC (231 mg, 1.12 mmol) and
DMAP (9.1 mg, 0.074 mmol) at 0 ꢂC, and the mixture was
stirred at room temperature for 2 h. The reaction mixture
was diluted with EtOAc, and washed successively with
1 mol/L aqueous HCl solution and brine, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (silica gel: 6 g, EtOAc/hexane¼
1:5) to give lactone 30 (216 mg, 72% from 27) as a colorless
syrup: Rf 0.54 (EtOAc/toluene¼1:6); [a]1D9 +3.0 (c 0.91,
1H NMR (300 MHz) d 7.78 (2H, d, J¼8.3 Hz), 7.36–7.28
(7H, m), 5.15 (1H, d, J¼3.2 Hz), 4.99 (1H, d, J¼6.4 Hz),
4.82 (1H, q, J¼6.9 Hz), 4.62–4.52 (3H, m), 3.85 (1H, ddd,
J¼4.9, 9.5, 10.4 Hz), 3.53 (1H, dd, J¼8.4, 10.5 Hz), 3.46
(3H, s), 3.35 (1H, ddd, J¼4.7, 8.4, 10.7 Hz), 2.44 (3H, s),
2.39 (1H, dd, J¼9.5, 13.7 Hz), 2.26 (1H, ddd, J¼4.7, 4.9,
13.4 Hz), 1.90 (1H, ddd, J¼3.2, 10.5, 13.7 Hz), 1.53 (3H,
d, J¼6.9 Hz), 1.44 (1H, ddd, J¼10.4, 10.7, 13.4 Hz), 0.84
(9H, s), 0.11 and 0.09 (each 3H, 2s); 13C NMR (75 MHz)
d 169.1, 144.8, 138.0, 134.4, 129.7, 128.4, 127.7, 127.6,
127.5, 97.8, 80.0, 79.5, 79.2, 77.7, 71.9, 66.5, 56.6, 45.6,
43.2, 38.9, 25.9, 21.6, 18.7, 18.0, ꢀ4.7, ꢀ5.0; HRMS
(FAB+, NBA matrix) m/z calcd for C32H46NaO9SSi,
(M+Na)+ 657.2529, found 657.2522. Anal. Calcd for
C32H46O9SSi: C, 60.54; H, 7.30. Found: C, 60.61; H, 7.39.
31 (33.4 mg) as a white solid. A solution of (COCl)2
(2.0 mol/L solution in CH2Cl2, 1.28 mL, 2.56 mmol) and
DMSO (0.400 mL, 5.17 mmol) in CH2Cl2 (1 mL) was stirred
at ꢀ78 ꢂC for 10 min under Ar. To this mixture was added
a solution of the crude alcohol 31 (33.4 mg) in CH2Cl2
(1 mL) at ꢀ78 ꢂC. After stirring at ꢀ78 ꢂC for 2 h, to the re-
action mixture was added i-Pr2NEt (1.32 mL, 7.66 mmol) at
ꢀ78 ꢂC. The resulting mixture was further stirred at room
temperature for 2 h and then diluted with Et2O. The mixture
was washed with brine, and then dried. Removal of the
solvent gave a residue, which was purified by column chro-
matography (silica gel: 1 g, EtOAc/hexane¼1:4) to give 32
(25.2 mg, 89% from 4) as a colorless syrup: Rf 0.47
(EtOAc/hexane¼1:1); [a]2D3 ꢀ16.0 (c 0.92, CHCl3); IR
CHCl3); IR (neat) 2960, 2930, 2860, 1760, 1600 cmꢀ1
;
(neat) 3460, 3030, 2900, 2120, 1650 cmꢀ1 1H NMR
;
(300 MHz) d 13.04 (1H, s), 7.44–7.30 (5H, m), 4.73 and
4.54 (each 1H, 2d, J¼11.4 Hz), 4.49 (1H, qd, J¼1.5,
6.6 Hz), 4.04 (1H, dd, J¼1.5, 2.9 Hz), 3.74 (1H, dd, J¼9.3,
9.5 Hz), 3.62 (1H, ddd, J¼6.4, 9.5, 9.5 Hz), 2.93 (1H, ddd,
J¼1.1, 6.4, 18.3 Hz), 2.88 (1H, s), 2.72 (1H, dddd, J¼1.1,
2.5, 2.9, 9.3 Hz), 2.45 (1H, ddd, J¼2.5, 9.5, 18.3 Hz), 1.52
(3H, d, J¼6.6 Hz); 13C NMR (75 MHz) d 172.6, 169.7,
137.2, 128.7, 128.3, 128.0, 90.0, 77.3, 76.3, 71.7, 70.1,
58.3, 42.2, 34.6, 18.4; LRMS (EI) m/z 345 (M+, 1.3%), 239
(9.0), 191 (5.6), 91 (100); HRMS (EI) m/z calcd for
C17H19N3O5, (M+) 345.1325, found 345.1326.
4.2.22. (3S,4S,5S,6S,8R,9R,10S)-4-Azido-6-benzyloxy-8-
(tert-butyldimethylsilyloxy)-5-methoxymethyloxy-3-
methyl-perhydroisochroman-1-one (4). To a solution of
lactone 30 (25.0 mg, 0.0394 mmol) in DMF (1 mL) was
added NaN3 (25.0 mg, 0.385 mmol) at room temperature,
and the reaction mixture was stirred at 110 ꢂC for 4 h. The
reaction mixture was diluted with EtOAc and washed with
brine, and then dried. Removal of the solvent gave a residue,
which was purified by column chromatography (silica gel:
0.5 g, EtOAc/toluene¼1:7) to give 4 (17.2 mg, 86%) as a
colorless oil: Rf 0.33 (EtOAc/toluene¼1:6); [a]2D1 ꢀ96.0
(c 0.70, CHCl3); IR (neat) 2960, 2930, 2860, 2110,
4.2.24. N-Benzyloxycarbonyl-(L)-actinobolin (33). To
a solution of 32 (6.5 mg, 0.019 mmol) in MeOH (1 mL)
were added 10% Pd/C (2.0 mg) and 4 mol/L HCl in dioxane
(0.0095 mL, 0.038 mmol). The reaction mixture was stirred
under an atmospheric pressure of H2 at room temperature for
18 h. The catalyst was removed by filtration through a pad of
Celite and the filtrate was concentrated to give a residue,
which was dissolved in DMF (0.5 mL). To this solution
were added DCC (19.4 mg, 0.0940 mmol), N-benzyloxy-
carbonyl-D-alanine (12.6 mg, 0.0564 mmol), and Et3N
(0.100 mL, 0.717 mmol). The mixture was stirred at room
temperature for 14 h, and then concentrated to give a residue,
which was purified by preparative TLC (acetone/toluene¼
1:2) to give 33 (4.7 mg, 57% from 32) as a colorless oil: Rf
0.34 (acetone/toluene¼1:1); [a]2D4 +34.0 (c 0.17, CHCl3);
1H NMR (300 MHz) d 13.05 (1H, s), 7.40–7.30 (5H, m),
6.78 (1H, br d, J¼8.9 Hz), 5.19 (1H, br d, J¼6.9 Hz), 5.11
and 5.04 (each 1H, 2d, J¼11.7 Hz), 4.70–4.60 (1H, br s),
4.61 (1H, qd, J¼1.5, 6.6 Hz), 4.33 (1H, ddd, J¼1.5, 1.8,
8.9 Hz), 4.27 (1H, qd, J¼6.9, 7.2 Hz), 3.89 (1H, ddd,
J¼6.9, 9.6, 9.9 Hz), 3.14 (1H, dd, J¼9.6, 9.6 Hz), 3.05
(1H, br s), 2.93 (1H, dd, J¼6.9, 18.9 Hz), 2.65 (1H, dd,
J¼1.8, 9.6 Hz), 2.47 (1H, dd, J¼9.9, 18.9 Hz), 1.41 (3H,
d, J¼7.2 Hz), 1.34 (3H, d, J¼6.6 Hz); 13C NMR (75 MHz)
d 175.9, 175.6, 170.4, 156.0, 135.6, 128.6, 128.4, 128.3,
89.8, 76.8, 71.6, 68.0, 67.5, 50.9, 46.3, 43.4, 36.4, 17.9,
17.6; LRMS (EI) m/z 434 (M+, 9.1%), 416 (6.8), 325 (3.8),
223 (100); HRMS (EI) m/z calcd for C21H26N2O8, (M+)
434.1689, found 434.1696.
1745 cmꢀ1 1H NMR (300 MHz) d 7.40–7.19 (5H, m),
;
4.97 and 4.76 (each 1H, 2d, J¼5.9 Hz), 4.63 and 4.56
(each 1H, 2d, J¼11.7 Hz), 4.47 (1H, qd, J¼2.4, 6.6 Hz),
4.11 (1H, dd, J¼1.9, 2.4 Hz), 3.80 (1H, ddd, J¼4.6, 9.6,
11.2 Hz), 3.59 (1H, dd, J¼8.9, 10.2 Hz), 3.41 (3H, s), 3.30
(1H, ddd, J¼3.9, 8.9, 12.9 Hz), 2.50 (1H, dd, J¼9.6,
13.5 Hz), 2.25 (1H, ddd, J¼3.9, 4.6, 12.5 Hz), 1.79 (1H,
ddd, J¼1.9, 10.2, 13.5 Hz), 1.50 (3H, d, J¼6.6 Hz), 1.40
(1H, ddd, J¼11.2, 12.5, 12.5 Hz), 0.85 (9H, s), 0.12
and 0.06 (each 3H, 2s); 13C NMR (75 MHz) d 168.8,
138.2, 128.4, 127.8, 127.5, 98.7, 79.3, 78.8, 78.6, 71.8,
67.0, 59.4, 56.0, 43.8, 42.7, 39.0, 25.9, 18.2, 18.1, ꢀ4.6,
ꢀ4.8; HRMS (FAB+, NBA matrix) m/z calcd for
C25H39N3O6SiCs, (M+Cs)+ 638.1659, found 638.1633.
IR (neat) 3330, 2980, 2930, 1650, 1540, 1230, 1050 cmꢀ1
;
4.2.23. (3S,4S,5S,6S,10S)-4-Azido-6-benzyloxy-5,8-di-
hydroxy-3-methyl-5,6,7,4a-tetrahydroisochroman-1-one
(32). To a solution of azide 4 (41.3 mg, 0.0817 mmol) in
CH3CN (3 mL) in a polyethylene vial was added HF/pyri-
dine (ca. 0.1 mL) at 0 ꢂC, and the reaction mixture was
stirred at 0 ꢂC for 10 min. The reaction mixture was diluted
with EtOAc and neutralized with saturated aqueous
NaHCO3 solution. The organic layer was washed succes-
sively with saturated aqueous NaHCO3 solution and brine,
and then dried. Removal of the solvent gave crude alcohol
4.2.25. (L)-Actinobolin hydrochloride (3$HCl). To a solu-
tion of 33 (3.4 mg, 0.0078 mmol) in MeOH (0.6 mL) and
AcOH (0.5 mL) were added 10% Pd/C (3 mg) and 1 mol/L
aqueous HCl solution (0.023 mL, 0.023 mmol). The reac-
tion mixture was stirred under an atmospheric pressure of

S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
6939
H2 at room temperature for 30 min. The catalyst was re-
moved by filtration through a pad of Celite, and the filtrate
was concentrated. The residue was purified by column chro-
matography (Sephadex LH-20, MeOH as an eluent) to give
3$HCl (2.0 mg, 76%) as an amorphous solid: [a]2D4 ꢀ51.2
(c 0.24, H2O), {lit.6c,d for (+)-actinobolin hydrochloride:
10 min, the mixture was allowed to warm to 0 ꢂC and further
stirred at 0 ꢂC for 1 min. The resulting clear solution was
cooled to ꢀ78 ꢂC, and to this solution was added slowly a
solution of enone (+)-6 (100 mg, 0.302 mmol) in ether
(1.0 mL) via a cannula. After being stirred at ꢀ78 ꢂC
for 30 min, a solution of aldehyde (S)-7b (265 mg,
1.40 mmol) in ether (1.5 mL) was added to the mixture drop-
wise via a cannula, and the mixture was stirred for 2 h at
ꢀ78 ꢂC. The reaction mixture was quenched with saturated
aqueous NH4Cl solution, and the products were extracted
with EtOAc. The organic layer was washed successively
with saturated aqueous NaHCO3, brine, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (silica gel: 7 g, EtOAc/hexane¼
1:40) to give (2R,3R,4R,6S)-6-benzyloxy-4-(tert-butyl-
dimethylsilyloxy)-2-[(10S,20S)-10-hydroxy-20-(triethylsilyl-
oxy)propyl]-3-vinylcyclohexan-1-one (34) (84.8 mg, 51%)
and its (10R)-isomer (35) (66.7 mg, 40%) as a colorless
syrup. Data for 34: Rf 0.62 (EtOAc/hexane¼1:6); mp
82.5–83.0 ꢂC; [a]D23 ꢀ35.5 (c 1.02, CHCl3); IR (KBr disk)
3500, 2960, 2880, 1710, 1260, 1090, 1020 cmꢀ1; 1H NMR
(300 MHz) d 7.44–7.25 (5H, m), 5.83 (1H, ddd, J¼9.0,
9.0, 16.8 Hz), 5.15 (1H, dd, J¼1.4, 9.0 Hz), 5.11 (1H, dd,
J¼1.4, 16.8 Hz), 4.82 (1H, d, J¼11.4 Hz), 4.49–4.36 (2H,
m), 4.40 (1H, d, J¼11.4 Hz), 3.60 (1H, dd, J¼1.5, 6.4 Hz),
3.52 (1H, qd, J¼5.9, 6.4 Hz), 3.00 (1H, s), 2.68 (1H, dd,
J¼1.5, 9.0 Hz), 2.58 (1H, ddd, J¼9.0, 9.0, 9.2 Hz), 2.39
(1H, ddd, J¼4.6, 6.4, 12.4 Hz), 1.76 (1H, ddd, J¼10.5,
10.5, 12.4 Hz), 1.16 (3H, d, J¼5.9 Hz), 0.95 (9H, t,
J¼7.8 Hz), 0.85 (9H, s), 0.60 (6H, q, J¼7.8 Hz), 0.06 and
0.05 (each 3H, 2s); 13C NMR (75 MHz) d 210.0, 138.1,
137.0, 128.3, 127.8, 127.7, 118.4, 80.5, 73.0, 72.2, 70.5,
68.7, 54.2, 53.8, 41.0, 25.8, 19.7, 18.0, 6.8, 5.0, ꢀ4.3,
ꢀ4.4; HRMS (FAB+, NBA matrix) m/z calcd for
C30H53O5Si2, (M+H)+ 549.3432, found 549.3435. Anal.
Calcd for C30H52O5Si2: C, 65.64; H, 9.55. Found: C,
65.36; H, 9.36. Data for 35: Rf 0.52 (EtOAc/hexane¼1:6);
[a]2D3 ꢀ64.3 (c 0.71, CHCl3); IR (neat) 3540, 2960, 2930,
1
[a]2D1 +53 (c 0.65, H2O)}; H NMR (300 MHz, MeOH-d4)
d 4.70 (1H, qd, J¼1.8, 6.6 Hz), 4.56 (1H, dd, J¼1.8,
3.5 Hz), 4.01 (1H, q, J¼6.9 Hz), 3.78 (1H, ddd, J¼6.6,
9.6, 9.8 Hz), 3.13 (1H, dd, J¼9.6, 9.6 Hz), 2.82–2.74 (1H,
m), 2.81 (1H, dd, J¼6.6, 18.9 Hz), 2.35 (1H, ddd, J¼2.7,
9.6, 18.9 Hz), 1.50 (3H, d, J¼6.9 Hz), 1.33 (3H, d,
J¼6.6 Hz); 13C NMR (75 MHz, MeOH-d4) d 175.1, 172.7,
172.1, 91.8, 79.3, 72.8, 70.1, 50.2, 47.0, 43.3, 38.0, 18.5,
18.1; HRMS (FAB+, NBA matrix) m/z calcd for
C13H21N2O6, (M+H)+ 301.1400, found 301.1400. The
1H and 13C NMR spectra of the synthetic compound were
fully identical with those of natural (+)-actinobolin hydro-
chloride.
4.3. An improved route to (L)-actinobolin
4.3.1. (2S)-2-(Triethylsilyloxy)propanal [(S)-7b]. To a so-
lution of methyl (S)-lactate (335 mg, 3.22 mmol) in CH2Cl2
(7 mL) were added TESCl (0.620 mL, 3.69 mmol) and imi-
dazole (285 mg, 4.19 mmol) at 0 ꢂC, and the mixture was
stirred at room temperature for 10 min. The reaction mixture
was diluted with EtOAc, and washed successively with
1 mol/L aqueous HCl solution and brine, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (EtOAc/hexane¼1:20) to give
methyl (S)-lactate triethylsilyl ether (702 mg, 100%) as
a colorless syrup: Rf 0.77 (EtOAc/hexane¼1:3); [a]2D2 ꢀ26.9
(c 1.06, CHCl3); IR (neat) 2955, 2880, 1760, 1740, 1145,
1005, 745 cmꢀ1 1H NMR (300 MHz) d 4.34 (1H, q,
;
J¼6.6 Hz), 3.73 (3H, s), 1.41 (3H, d, J¼6.6 Hz), 0.96 (9H,
t, J¼7.8 Hz), 0.62 (6H, q, J¼7.8 Hz); 13C NMR (75 MHz)
d 174.5, 68.0, 51.8, 21.5, 6.6, 4.5.
1
1715, 1090, 835, 775 cmꢀ1; H NMR (300 MHz) d 7.42–
To a solution of methyl (S)-lactate triethylsilyl ether
(702 mg, 3.21 mmol) in toluene (10 mL) was added
1.01 mol/L solution of DIBAL-H in toluene (3.76 mL,
3.80 mmol) at ꢀ78 ꢂC, and the mixture was stirred at
ꢀ78 ꢂC for 2 h. The reaction mixture was quenched with
water, and the products were extracted with EtOAc. The or-
ganic layer was washed successively with 1 mol/L aqueous
HCl solution, saturated aqueous NaHCO3 solution and brine,
and then dried. Removal of the solvent gave a residue, which
was purified by column chromatography (EtOAc/hexane¼
1:50) to give (S)-7b (426 mg, 70%) as a colorless syrup: Rf
0.77 (EtOAc/hexane¼1:3); [a]2D3 ꢀ6.5 (c 1.1, CHCl3); IR
7.25 (5H, m), 5.44 (1H, ddd, J¼8.0, 10.7, 16.0 Hz), 5.22
(1H, dd, J¼1.7, 8.0 Hz), 5.21 (1H, dd, J¼1.7, 16.0 Hz),
4.81 and 4.39 (each 1H, 2d, J¼11.4 Hz), 4.05–3.96 (2H,
m), 3.82 (1H, ddd, J¼4.4, 8.4, 11.2 Hz), 3.28 (1H, dd,
J¼8.8, 12.2 Hz), 3.10 (1H, d, J¼12.2 Hz), 2.76–2.60 (2H,
m), 2.47 (1H, ddd, J¼4.4, 6.1, 12.7 Hz), 1.85 (1H, ddd,
J¼11.2, 12.7, 12.7 Hz), 1.27 (3H, d, J¼6.1 Hz), 0.93 (9H,
t, J¼7.9 Hz), 0.85 (9H, s), 0.63–0.47 (6H, m), 0.06 and
0.03 (each 3H, 2s); 13C NMR (75 MHz) d 212.5, 138.6,
137.6, 128.5, 127.9, 127.8, 119.7, 78.6, 75.7, 72.0, 70.6,
69.9, 54.2, 47.0, 42.3, 25.7, 21.6, 18.0, 7.0, 5.1, ꢀ4.3,
ꢀ4.4; HRMS (FAB+, NBA matrix) m/z calcd for
C30H53O5Si2, (M+H)+ 549.3432, found 549.3423. Anal.
Calcd for C30H52O5Si2: C, 65.64; H, 9.55. Found: C,
65.42; H, 9.56.
(neat) 2960, 2880, 1740, 1140, 1010 cmꢀ1 1H NMR
;
(300 MHz) d 9.62 (1H, s), 4.08 (1H, q, J¼6.8 Hz), 1.29
(3H, d, J¼6.8 Hz), 0.97 (9H, t, J¼7.8 Hz), 0.64 (6H, q,
J¼7.8 Hz); 13C NMR (75 MHz,) d 204.2, 73.5, 18.6, 6.6,
4.7; HRMS (FAB+, NBA matrix) m/z calcd for C11H14O3,
(M+H)+ 189.1325, found 189.1311.
4.3.3. Three-component coupling reaction with (S)-7b in
the presence of HMPA. The similar treatment of (+)-6
(96.8 mg, 0.291 mmol) with copper(I) cyanide (CuCN,
36.5 mg, 0.408 mmol) and vinyllithium (1.0 mol/L solution
in ether, 0.65 mL, 0.65 mmol) as described for the prepara-
tion of 34 afforded 1,4-addition intermediate. To an ethereal
solution of the enolate (4 mL) at ꢀ78 ꢂC was added HMPA
(0.345 mL, 1.98 mmol) and, after 5 min, a solution of
4.3.2. Three-component coupling reaction with (S)-7b. To
a suspension of copper(I) cyanide (CuCN, 43.3 mg,
0.483 mmol) in ether (1.0 mL) at ꢀ78 ꢂC was added drop-
wise vinyllithium (1.0 mol/L solution in ether, 0.75 mL,
0.75 mmol) under Ar. After being stirred at ꢀ78 ꢂC for

6940
S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
aldehyde (S)-7b (232 mg, 1.23 mmol) in ether (1.2 mL) was
added to the mixture dropwise over 60 min via a cannula.
After being stirred at ꢀ78 ꢂC for 2 h, the reaction mixture
was quenched and processed similarly as described for the
preparation of 34. Purification by column chromatography
(silica gel: 3 g, EtOAc/hexane¼1:40) gave 35 (75.2 mg,
47%) and bicyclic ketal (36) (42.2 mg, 20%) as a colorless
syrup. Data for 36: Rf 0.65 (EtOAc/hexane¼1:6); [a]D24
ꢀ49.1 (c 1.21, CHCl3); IR (neat) 3440, 2955, 2880, 1100,
The mixture was diluted with EtOAc and washed succes-
sively with saturated aqueous NaHCO3 solution and brine,
and then dried over Na2CO3. Removal of the solvent gave
a residue, which was purified by column chromatography
(silica gel: 1 g, EtOAc/hexane¼1:7) to give 37 (19.2 mg,
87%) as a colorless syrup: Rf 0.40 (EtOAc/toluene¼1:6);
[a]2D1 +6.5 (c 0.895, CHCl3); IR (neat) 3420, 2955, 2930,
1
2880, 1255, 1090, 1070, 840 cmꢀ1; H NMR (300 MHz)
d 7.44–7.20 (5H, m), 5.30 (1H, ddd, J¼9.3, 10.2, 16.8 Hz),
5.14 (1H, dd, J¼2.4, 10.2 Hz), 5.10 (1H, dd, J¼2.4,
16.8 Hz), 4.78 and 4.68 (each 1H, 2d, J ¼12.3 Hz), 4.28
(1H, d, J¼1.8 Hz), 4.03 (1H, qd, J¼5.1, 6.3 Hz), 3.74–
3.61 (2H, m), 3.40–3.26 (2H, m), 2.32 (1H, d, J¼9.0 Hz),
2.18 (1H, ddd, J¼4.2, 4.2, 12.0 Hz), 2.10 (1H, ddd, J¼9.3,
9.6, 11.4 Hz), 1.56 (1H, dd, J¼9.6, 9.9 Hz), 1.46 (1H, ddd,
J¼11.4, 11.4, 12.0 Hz), 1.15 (3H, d, J¼6.3 Hz), 0.97 (9H,
t, J¼7.8 Hz), 0.83 (9H, s), 0.63 (6H, q, J¼7.8 Hz), ꢀ0.01
and ꢀ0.04 (each 3H, 2s); 13C NMR (75 MHz) d 139.4,
139.0, 128.3, 127.7, 127.5, 119.1, 79.3, 75.2, 72.5, 72.0,
71.5, 71.1, 53.2, 42.9, 38.8, 25.8, 19.3, 18.0, 6.7, 4.8,
ꢀ4.3, ꢀ4.4; HRMS (FAB+, NBA matrix) m/z calcd for
C30H55O5Si2, (M+H)+ 551.3588, found 551.3590. Anal.
Calcd for C30H54O5Si2: C, 65.40; H, 9.88. Found: C,
65.48; H, 10.02.
1
1075, 1000 cmꢀ1; H NMR (300 MHz) d 7.38–7.25 (5H,
m), 5.34 (1H, ddd, J¼9.6, 9.6, 17.4 Hz), 5.13–5.00 (3H,
m), 4.95 and 4.65 (each 1H, 2d, J¼11.6 Hz), 4.52 (1H, q,
J¼6.0 Hz), 4.03 (1H, d, J¼10.2 Hz), 3.86 (1H, qd, J¼3.9,
6.0 Hz), 3.39 (1H, dd, J¼4.8, 11.7 Hz), 3.24 (1H, s), 3.22
(1H, ddd, J¼4.8, 9.9, 11.4 Hz), 2.19 (1H, ddd, J¼9.6, 9.9,
11.4 Hz), 2.02 (1H, ddd, J¼4.8, 4.8, 12.6 Hz), 1.72 (1H,
ddd, J¼11.4, 11.7, 12.6 Hz), 1.39 (1H, dd, J¼10.2,
11.4 Hz), 1.16 and 1.06 (each 3H, 2d, J¼6.0 Hz), 0.94 and
0.89 (each 9H, 2t, J¼7.8 Hz), 0.81 (9H, s), 0.60 and 0.53
(each 6H, 2q, J¼7.8 Hz), ꢀ0.02 and ꢀ0.07 (each 3H, 2s);
HRMS (FAB+, NBA matrix) m/z calcd for C39H72O7Si3Na,
(M+Na)+ 759.4484, found 759.4493.
4.3.4. Conversion of 36 to 35. A solution of 36 (20.8 mg,
0.0282 mmol) in THF (1.5 mL) and AcOH (1.5 mL) was
stirred at room temperature for 3 days. The reaction mixture
was diluted with EtOAc, and washed successively with sat-
urated aqueous NaHCO3 solution and brine, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (silica gel: 0.5 g, EtOAc/
hexane¼1:6) to give 35 (11.8 mg, 76%).
4.3.7. (1S,2S,3S,4R,5R)-1-Benzyloxy-5-(tert-butyldi-
methylsilyloxy)-3-[(10R,20S)-10-(p-toluenesulfonyloxy)-20-
(triethylsilyloxy)propyl]-4-vinylcyclohexan-2-ol (38). To
a solution of 37 (39.0 mg, 0.0708 mmol) in THF (2 mL)
were added 1.59 mol/L solution of BuLi in hexane
(0.140 mL, 0.223 mmol) and TsCl (81 mg, 0.42 mmol) at
0 ꢂC, and the reaction mixture was stirred at 0 ꢂC for
10 min. The mixture was diluted with EtOAc, and washed
successively with saturated aqueous NaHCO3 solution and
brine, and then dried. Removal of the solvent gave a residue,
which was purified by column chromatography (silica gel:
10 g, EtOAc/hexane¼1:10) to give 38 (50.0 mg, 100%) as
a white solid: Rf 0.71 (EtOAc/toluene¼1:6); [a]2D6 +7.7 (c
0.79, CHCl3); IR (KBr disk) 3410, 2960, 1360, 1175,
1090, 1070, 925 cmꢀ1; 1H NMR (300 MHz) d 7.81 (2H, d,
J¼8.4 Hz), 7.39–7.27 (7H, m), 5.32–5.15 (2H, m), 5.06
(1H, dd, J¼3.6, 15.6 Hz), 4.74 (1H, d, J¼12.0 Hz), 4.68
(1H, d, J¼5.7 Hz), 4.66 (1H, d, J¼12.0 Hz), 4.30 (1H, qd,
J¼5.7, 6.3 Hz), 4.15 (1H, s), 3.62 (1H, dd, J¼8.7, 8.7 Hz),
3.29–3.16 (2H, m), 2.43 (3H, s), 2.06 (1H, ddd, J¼3.9,
3.9, 12.0 Hz), 1.81–1.74 (2H, m), 1.22 (1H, ddd, J¼11.4,
11.4, 12.0 Hz), 1.05 (3H, d, J¼6.3 Hz), 0.94 (9H, t,
J¼7.8 Hz), 0.81 (9H, s), 0.61 (6H, q, J¼7.8 Hz), ꢀ0.05
and ꢀ0.08 (each 3H, 2s); 13C NMR (75 MHz) d 144.7,
138.9, 134.2, 129.7, 128.3, 127.9, 127.8, 127.5, 120.1,
84.4, 79.4, 71.9, 71.6, 71.0, 69.9, 51.6, 42.4, 38.3, 25.7,
21.6, 20.5, 17.9, 6.7, 4.7, ꢀ4.3, ꢀ4.5; HRMS (FAB+, NBA
matrix) m/z calcd for C37H61O7SSi2, (M+H)+ 705.3677,
found 705.3684.
4.3.5. Conversion of 34 to 22. To a solution of 34 (52.1 mg,
0.0949 mmol) in MeOH (1 mL) was added NaBH4 (16.0 mg,
0.423 mmol) at 0 ꢂC, and the reaction mixture was stirred at
0 ꢂC for 10 min. The mixture was diluted with EtOAc, and
washed successively with saturated aqueous NaHCO3 solu-
tion and brine, and then dried over Na2SO4. Removal of
the solvent gave a residue, which was roughly purified
by column chromatography (EtOAc/hexane¼1:15) to give
diol (34.5 mg, 66%). To a solution of the diol (34.5 mg,
0.0626 mmol) in pyridine (1 mL) were added Ac2O (0.5 mL)
and DMAP (1.0 mg) at 0 ꢂC, and the reaction mixture was
stirred at room temperature for 12 h. The reaction mixture
was diluted with EtOAc, and washed successively with
1 mol/L aqueous HCl solution, saturated aqueous NaHCO3
solution and brine, and then dried. Removal of the solvent
gave a residue, which was dissolved in CH2Cl2/H2O (10:1,
1.0 mL). To this solution was added DDQ (15.3 mg,
0.0673 mmol) at 0 ꢂC, and the mixture was stirred at room
temperature for 1 h. The reaction mixture was diluted
with EtOAc and washed successively with 10% aqueous
Na2S2O3 solution, saturated aqueous NaHCO3 solution and
brine, and then dried. Removal of the solvent gave a residue,
which was purified by column chromatography (silica gel:
1 g, EtOAc/hexane¼1:7) to give 22 (22.7 mg, 46% from 34).
4.3.8. (1S,2S,3S,4R,5R)-1-Benzyloxy-5-(tert-butyldi-
methylsilyloxy)-3-[(10R,20S)-10-(p-toluenesulfonyloxy)-20-
(triethylsilyloxy)propyl]-2-methoxymethyloxy-4-vinyl-
cyclohexane (39). To a solution of 38 (33.6 mg, 0.0477
mmol) in (CH2Cl)2 (1 mL) were added i-Pr2NEt (0.088 mL,
0.51 mmol) and MOMCl (0.039 mL, 0.52 mmol) at 0 ꢂC,
and the reaction mixture was stirred at 50 ꢂC for 3.5 h. The
mixture was diluted with EtOAc and washed successively
4.3.6. (1S,2S,3S,4R,5R)-1-Benzyloxy-5-(tert-butyldime-
thylsilyloxy)-3-[(10R,20S)-10-hydroxy-20-(triethylsilyl-
oxy)propyl]-4-vinylcyclohexan-2-ol (37). To a solution of
35 (22.0 mg, 0.0401 mmol) in AcOH/THF [1:5 (v/v),
1 mL] was added LiBH4 (12.0 mg, 0.551 mmol) at 0 ꢂC,
and the reaction mixture was stirred at 0 ꢂC for 10 min.

S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
6941
with saturated aqueous NaHCO3 solution and brine, and then
dried. Removal of the solvent gave a residue, which was pu-
rified by column chromatography (silica gel: 1 g, EtOAc/
hexane¼1:10) to give 39 (35.8 mg, 92%) as a pale yellow
syrup: Rf 0.71 (EtOAc/toluene¼1:6); [a]2D2 ꢀ10.5 (c 0.92,
CHCl3); IR (neat) 2955, 2930, 1360, 1180, 1100, 1075,
syrup: Rf 0.56 (EtOAc/hexane¼1:2); IR (neat) 3420, 2960,
1
2930, 2860, 1720, 1600 cmꢀ1; H NMR (300 MHz) d 7.81
(2H, d, J¼8.3 Hz), 7.50–7.20 (7H, m), 5.23 (1H, d,
J¼2.5 Hz), 4.75 (1H, d, J¼6.7 Hz), 4.67–4.53 (3H, m),
4.33 (1H, dd, J¼9.5, 10.0 Hz), 4.08 (1H, qd, J¼6.7,
9.5 Hz), 3.83 (1H, dd, J¼7.4, 7.6 Hz), 3.72 (1H, ddd,
J¼5.4, 9.3, 9.8 Hz), 3.59 (1H, ddd, J¼4.6, 7.6, 8.4 Hz),
3.28 (3H, s), 2.43 (3H, s), 2.42–2.33 (1H, m), 2.20 (1H,
ddd, J¼4.6, 5.4, 13.4 Hz), 1.85 (1H, ddd, J¼2.5, 9.8,
10.2 Hz), 1.47 (1H, ddd, J¼8.4, 9.3, 13.4 Hz), 0.87 (3H, d,
J¼6.7 Hz), 0.82 (9H, s), 0.02 (6H, s); 13C NMR (75 MHz)
d 144.4, 138.8, 135.3, 129.5, 128.3, 127.8, 127.7, 127.4,
96.2, 90.1, 86.0, 79.1, 77.9, 71.2, 67.1, 66.7, 55.9, 48.1,
38.7, 37.4, 25.7, 21.6, 18.3, 17.6, ꢀ4.2, ꢀ5.0.
1
1000, 925, 840 cmꢀ1; H NMR (300 MHz) d 7.80 (2H, d,
J¼7.8 Hz), 7.40–7.22 (7H, m), 5.38–5.10 (3H, m), 4.85
and 4.74 (each 1H, 2d, J¼5.0 Hz), 4.66–4.52 (1H, m),
4.58 (2H, s), 4.26 (1H, qd, J¼6.0, 9.0 Hz), 3.52 (1H, dd,
J¼9.3, 9.3 Hz), 3.30 (3H, s), 3.36–3.20 (1H, m), 3.15 (1H,
ddd, J¼3.9, 11.7, 12.0 Hz), 2.43 (3H, s), 2.11 (1H, ddd,
J¼3.9, 4.3, 12.3 Hz), 2.16–1.92 (2H, m), 1.27 (1H, ddd,
J¼12.0, 12.0, 12.3 Hz), 1.02 (3H, d, J¼6.0 Hz), 0.95 (9H,
t, J¼7.8 Hz), 0.83 (9H, s), 0.60 (6H, q, J¼7.8 Hz), ꢀ0.05
and ꢀ0.06 (each 3H, 2s); 13C NMR (75 MHz) d 144.5,
138.7, 138.5, 134.5, 129.6, 128.3, 127.8, 127.7, 127.5,
119.7, 98.7, 85.0, 80.3, 78.9, 71.6, 70.8, 69.0, 57.0, 52.0,
38.8, 25.8, 21.6, 21.2, 18.0, 6.8, 5.1, ꢀ4.3, ꢀ4.4; HRMS
(FAB+, NBA matrix) m/z calcd for C39H64O8SSi2Na,
(M+Na)+ 771.3758, found 771.3767.
To a solution of lactol 41 (15.1 mg, 0.0237 mmol) in CH2Cl2
(1 mL) were added PDC (178 mg, 0.473 mmol) and MS4A
(300 mg) at 0 ꢂC, and the reaction mixture was stirred at
room temperature for 12 h. The insoluble material was re-
moved by filtration through a pad of Celite, and the filtrate
was diluted with EtOAc. The organic layer was washed
with 10% aqueous Na2S2O3 solution, saturated aqueous
NaHCO3 solution and brine, and then dried. Removal of
the solvent gave a residue, which was purified by column
chromatography (silica gel: 1 g, EtOAc/toluene¼1:19) to
give 30 (12.5 mg, 83%).
4.3.9. (1S,2S,3S,4R,5R)-1-Benzyloxy-5-(tert-butyl-
dimethylsilyloxy)-3-[(10R,20S)-20-hydroxy-10-(p-toluene-
sulfonyloxy)propyl]-2-methoxymethyloxy-4-vinylcyclo-
hexane (40). To a solution of 39 (31.7 mg, 0.0423 mmol) in
CH3CN/H2O (10:1, 3 mL) was added DDQ (10.6 mg,
0.0467 mmol) at 0 ꢂC, and the reaction mixture was stirred
at room temperature for 1 h. The reaction mixture was di-
luted with EtOAc and washed successively with 20% aque-
ous Na2S2O3 solution, saturated aqueous NaHCO3 solution
and brine, and then dried. Removal of the solvent gave a resi-
due, which was purified by column chromatography (silica
gel: 1 g, EtOAc/hexane¼1:4) to give 40 (23.1 mg, 86%) as
a white solid: Rf 0.40 (EtOAc/hexane¼1:2); mp 107.8–
108.5 ꢂC; [a]D26 ꢀ31.7 (c 0.89, CHCl3); IR (neat) 3420,
4.4. Formal synthesis of (+)-actinobolin
4.4.1. Methyl 2-O-benzyl-3-deoxy-a-D-glucopyranoside
(42). To a suspension of NaH (18.0 mg, 0.450 mmol) in
DMF (0.5 mL) at 0 ꢂC was added a solution of 9 (20.0 mg,
0.0751 mmol) in DMF (0.5 mL). After being stirred for
10 min, to the mixture was added BnBr (0.0180 mL,
0.151 mmol) at 0 ꢂC, and the mixture was stirred at room
temperature for 10 min. The reaction mixture was diluted
with EtOAc, and washed successively with saturated aque-
ous NaHCO3 solution and brine, and then dried. Removal
of the solvent gave a residue, which was purified by column
chromatography (silica gel: 0.5 g, EtOAc/hexane¼1:6) to
give methyl 4,6-O-benzylidene-2-O-benzyl-3-deoxy-a-
D-ribo-hexopyranoside (25.4 mg, 95%) as a white solid:
Rf 0.55 (EtOAc/hexane ¼1:2); mp 102.0–102.5 ꢂC; [a]D20
+21.4 (c 0.99, CHCl3); IR (KBr disk) 2940, 2900, 2860,
1
2930, 2860, 1360, 1180, 1100, 1075, 840 cmꢀ1; H NMR
(300 MHz) d 7.79 (2H, d, J¼8.0 Hz), 7.37–7.28 (7H, m),
5.30 (1H, ddd, J¼9.6, 10.2, 16.6 Hz), 5.17 (1H, dd, J¼2.3,
10.2 Hz), 5.13 (1H, dd, J¼2.3, 16.6 Hz), 4.88 (2H, s), 4.85
(1H, d, J¼5.4 Hz), 4.60 and 4.55 (each 1H, 2d,
J¼11.8 Hz), 3.94 (1H, qd, J¼6.3, 5.4 Hz), 3.63 (1H, dd,
J¼9.8, 10.4 Hz), 3.41 (3H, s), 3.31 (1H, ddd, J¼4.0, 9.8,
11.7 Hz), 3.21 (1H, ddd, J¼4.0, 11.2, 11.7 Hz), 2.44 (3H,
s), 2.16 (1H, ddd, J¼9.6, 11.2, 11.4 Hz), 2.16 (1H, ddd,
J¼4.0, 4.0, 11.9 Hz), 1.89 (1H, dd, J¼10.4, 11.7 Hz), 1.36
(1H, ddd, J¼11.7, 11.7, 11.9 Hz), 1.03 (3H, d, J¼6.3 Hz),
0.82 (9H, s), ꢀ0.04 and ꢀ0.06 (each 3H, 2s); 13C NMR
(75 MHz) d 144.7, 138.6, 138.2, 134.3, 129.7, 128.4, 127.8,
127.7, 119.6, 99.5, 84.3, 79.7, 77.2, 71.7, 70.4, 68.2, 57.1,
51.6, 38.7, 25.7, 21.6, 21.4, 18.0, ꢀ4.3, ꢀ4.4; HRMS
(FAB+, NBA matrix) m/z calcd for C33H50O8SSiNa,
(M+Na)+ 657.2894, found 657.2893.
1
1500, 1100, 1050, 990 cmꢀ1; H NMR (300 MHz, CDCl3)
d 7.50–7.27 (5H, m), 5.49 (1H, s), 4.68 (1H, d, J¼3.3 Hz),
4.67 and 4.58 (each 1H, 2d, J¼12.6 Hz), 4.25 (1H, dd,
J¼4.5, 10.2 Hz), 3.77 (1H, ddd, J¼4.5, 9.6, 10.2 Hz), 3.66
(1H, dd, J¼10.2, 10.6 Hz), 3.60 (1H, ddd, J¼3.3, 4.2,
11.7 Hz), 3.49 (1H, ddd, J¼4.5, 9.6, 11.7 Hz), 3.45
(3H, s), 2.27 (1H, ddd, J¼4.2, 4.5, 11.4 Hz), 2.05 (ddd,
J¼11.4, 11.7, 11.7 Hz); 13C NMR (75 MHz, CDCl3)
d 137.9, 137.4, 129.1, 128.5, 128.3, 127.91, 127.86, 126.2,
101.8, 98.0, 76.7, 73.8, 71.0, 69.4, 63.9, 55.1, 30.1;
LRMS (EI) m/z 356 (M+, 1.7%), 265 (4.5), 233 (3.4), 218
(81.6), 162 (61.9), 105 (100), 91 (100); HRMS (EI) m/z
calcd for C19H30IO3Si 356.1624, found 356.1629. Anal.
Calcd for C21H24O5: C, 70.77; H, 6.79. Found: C, 70.56;
H, 6.93.
4.3.10. Lactone (30) from 40. Ozone was introduced to a
solution of 40 (45.2 mg, 0.0712 mmol) in MeOH (4.5 mL)
at ꢀ78 ꢂC for 6 min. To the reaction mixture was added
Me2S (0.5 mL) at ꢀ78 ꢂC, and the reaction mixture was
stirred at room temperature for 3 h and then diluted with
Et2O. The organic layer was washed with brine, and then
dried. Removal of the solvent gave a residue, which was pu-
rified by column chromatography (silica gel: 1 g, EtOAc/
hexane¼1:6) to give lactol 41 (36.2 mg, 80%) as a colorless
A solution of methyl 4,6-O-benzylidene-2-O-benzyl-3-de-
oxy-a-D-ribo-hexopyranoside (25.4 mg, 0.0713 mmol) in
80% AcOH (1 mL) was stirred at 80 ꢂC for 1 h. The reaction

6942
S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
mixture was concentrated to give a residue, which was puri-
fied by column chromatography (silica gel: 0.6 g, EtOAc/
toluene¼1:1) to afford 42 (17.5 mg, 92%) as a white solid:
Rf 0.1 (EtOAc/toluene¼1:1); mp 101.0–102.0 ꢂC; [a]D20
+65.1 (c 0.71, CHCl3); IR (KBr disk) 3320, 2900, 2880,
4.4.3. Methyl 2-O-benzyl-4-O-(tert-butyldimethylsilyl)-
3,6-dideoxy-a-D-xylo-hex-5-enopyranoside(44). Toasolu-
tion of enopyranoside 43 (26.7 mg, 0.107 mmol) in DMF
(1 mL) were added imidazole (21.8 mg, 0.320 mmol) and
TBSCl (24.1 mg, 0.160 mmol), and the mixture was stirred
at room temperature for 20 h. The reaction mixture was
diluted with EtOAc, washed with H2O, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (silica gel; 4 g, EtOAc/hexane¼
1:50 containing 1 vol % Et3N) to give 44 (33.1 mg, 85%) as
a white solid: Rf 0.70 (EtOAc/hexane ¼1:20); mp 78–79 ꢂC;
[a]2D3 +41.0 (c 1.1, CHCl3); IR (KBr disk) 2955, 2860, 1665,
1105, 1050, 1030, 1000 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 7.38–7.28 (5H, m), 4.64 (1H, d, J¼4.2 Hz), 4.64
and 4.56 (each 1H, 2d, J¼12.3 Hz), 3.85 (1H, dd, J¼3.7,
11.5 Hz), 3.75 (1H, dd, J¼3.6, 11.5 Hz), 3.62 (1H, ddd,
J¼4.8, 10.0, 11.2 Hz), 3.56–3.45 (2H, m), 3.42 (3H, s),
2.11 (1H, ddd, J¼4.7, 4.8, 11.4 Hz), 1.87 (1H, ddd,
J¼11.2, 11.4, 11.8 Hz); 13C NMR (75 MHz, CDCl3)
d 137.9, 128.5, 127.90, 127.85, 97.1, 73.5, 71.9, 71.9,
66.1, 62.6, 55.0, 33.1; HRMS (FAB+, NBA matrix) m/z
(M+H)+ calcd for C14H21O5 269.1389, found 269.1384.
Anal. Calcd for C14H20O5: C, 62.67; H, 7.51. Found: C,
62.79; H, 7.50.
1115, 1060, 1000, 855, 840 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 7.38–7.24 (5H, m), 4.77 (1H, d, J¼2.4 Hz), 4.74
and 4.72 (each 1H, 2br s), 4.65 and 4.58 (each 1H, 2d, J¼
12.6 Hz), 3.68 (1H, ddd, J¼2.4, 6.9, 9.6 Hz), 3.56–3.30
(1H, m), 3.42 (3H, s), 2.23–1.90 (2H, m), 0.92 (9H, s), 0.10
and 0.08 (each 3H, 2s); HRMS (FAB+, NBA matrix) m/z
calcd for C20H33O4Si, (M+H)+ 365.2148, found 365.2149.
4.4.2. Methyl 2-O-benzyl-3,6-dideoxy-a-D-xylo-hex-5-
enopyranoside (43). To a solution of 42 (997 mg,
3.72 mmol) in toluene (20 mL) were added PPh3 (1.56 g,
5.95 mmol), imidazole (1.01 g, 14.8 mmol), and iodine
(1.51 g, 5.95 mmol), and the reaction mixture was stirred
at room temperature for 18 h. The reaction mixture was
diluted with EtOAc, and washed successively with 10%
aqueous Na2S2O3 solution, saturated aqueous NaHCO3 and
brine, and then dried. Removal of the solvent gave a residue,
which was purified by column chromatography (silica
gel: 30 g, EtOAc/hexane¼1:2) to give methyl 2-O-benzyl-
3,6-dideoxy-6-iodo-a-D-glucopyranoside (1.40 g, 100%) as
a colorless syrup: Rf 0.55 (EtOAc/hexane¼1:1); [a]D22
+64.2 (c 1.3, CHCl3); IR (neat) 3430, 2940, 2900, 1090,
4.4.4. A mixture of (2S,4R,5R)-4-benzyloxy-2-(tert-butyl-
dimethylsilyloxy)-5-hydroxy-cyclohexan-1-one and its
(5S)-isomer (45). To a solution of 44 (2.30 g, 6.31 mmol)
in acetone (120 mL) and acetate buffer (0.1 mol/L solution,
pH 4.8, 120 mL) was added Hg(OCOCF3)2 (0.81 g,
1.9 mmol), and the mixture was stirred at room temperature
for 48 h. The reaction mixture was partially concentrated
and the products were extracted with EtOAc. The organic
layer was washed successively with 10% aqueous KI solu-
tion, 20% Na2S2O3 solution and brine, and then dried.
Removal of the solvent gave a residue, which was purified
bycolumnchromatography (silicagel: 45 g, EtOAc/hexane¼
1:5) to give 45 (1.84 g, 83%) as a diastereomeric mixture
(5S:5R¼ca. 1:6): Rf 0.41 (EtOAc/hexane¼1:2); IR (neat)
1
1060, 980 cmꢀ1; H NMR (300 MHz) d 7.38–7.27 (5H,
m), 4.69 (1H, d, J¼3.4 Hz), 4.63 and 4.56 (each 1H, 2d,
J¼12.4 Hz), 3.62–3.23 (6H, m), 3.48 (3H, s), 2.19 (1H,
ddd, J¼4.6, 4.6, 11.5 Hz), 1.89 (1H, ddd, J¼11.5, 11.5,
11.5 Hz); 13C NMR (75 MHz) d 137.9, 128.5, 127.9,
127.8, 97.3, 73.7, 71.5, 71.2, 69.5, 55.3, 33.4, 7.3; LRMS
(EI) m/z 378 (M+, 0.9%), 347 (1.1), 272 (13.9), 240 (100),
135 (89.5), 91 (100); HRMS (EI) m/z calcd for C14H19IO4,
(M+) 378.0328, found 378.0335.
3450, 2930, 2860, 1740, 1250, 1150, 1075, 840 cmꢀ1
;
1H NMR (300 MHz, for the major isomer) d 7.42–7.28
(5H, m), 4.77 and 4.58 (each 1H, 2d, J¼11.5 Hz), 4.15
(1H, dd, J¼6.6, 12.5 Hz), 3.76 (1H, ddd, J¼5.4, 8.8,
12.2 Hz), 3.62 (1H, ddd, J¼4.0, 8.8, 11.6 Hz), 2.76 (1H,
dd, J¼5.4, 13.9 Hz), 2.46 (1H, ddd, J¼4.0, 6.6, 12.5 Hz),
2.37 (1H, dd, J¼12.2, 13.9 Hz), 1.62 (1H, ddd, J¼11.6,
12.5, 12.5 Hz), 0.90 (9H, s), 0.13 and 0.02 (each 3H, 2s);
13C NMR (75 MHz, for the major isomer) d 204.6, 137.6,
128.6, 128.1, 127.9, 79.4, 74.1, 72.1, 71.8, 43.5, 35.2, 25.7,
18.4, ꢀ4.6, ꢀ5.5; HRMS (FAB+, NBA matrix) m/z calcd
for C19H31O4Si, (M+H)+ 351.1992, found 351.1992.
To a solution of the iodide (2.40 g, 9.59 mmol) in THF
(45 mL) was added t-BuOK (2.14 g, 28.8 mmol) at 0 ꢂC,
and the reaction mixture was stirred at room temperature
for 3 h. The reaction mixture was diluted with EtOAc, and
successively washed with H2O and brine, and then dried
over Na2CO3. Removal of the solvent gave a residue, which
was purified by column chromatography (silica gel: 40 g,
EtOAc/hexane¼1:10 contain 1 vol % Et3N) to give eno-
pyranoside 43 (1.10 g, 70%) as a colorless syrup: Rf 0.54
(EtOAc/hexane¼1:1); [a]2D0 +62.3 (c 0.23, CHCl3); IR
(neat) 3440, 2940, 1680, 1085, 1055, 1020 cmꢀ1; 1H NMR
(300 MHz, CDCl3) d 7.40–7.22 (5H, m), 4.72 (1H, d,
J¼3.3 Hz), 4.70 (1H, br s), 4.67 (1H, d, J¼12.6 Hz), 4.65
(1H, br s), 4.61 (1H, d, J¼12.6 Hz), 4.09 (1H, m), 3.67
(1H, ddd, J¼3.3, 4.7, 11.1 Hz), 3.49 (3H, s), 2.25
(1H, ddd, J¼4.7, 5.7, 11.3 Hz), 2.04 (1H, d, J¼8.7 Hz),
1.94 (1H, ddd, J¼11.3, 11.1, 10.8 Hz); 13C NMR
(75 MHz, CDCl3) d 157.8, 137.8, 128.5, 128.0, 127.9,
99.3, 94.6, 73.1, 71.5, 66.0, 55.5, 34.0; HRMS (FAB+,
glycerol matrix) m/z (M+H)+ calcd for C14H19O4:
251.1283, found 251.1289.
4.4.5. (1S,2S,4R,5R)-4-benzyloxy-2-(tert-butyldimethylsilyl-
oxy)-5-hydroxy-1-methanesulfonyloxy-cyclohexane (47).
To a solution of 45 (207 mg, 0.591 mmol) in acetonitrile
(4 mL) were added CAN (64.8 mg, 0.118 mmol) and di-
hydro-2H-pyran (0.11 mL, 1.2 mmol), and the reaction
mixture was stirred at 0 ꢂC for 50 min. The reaction mixture
was diluted with EtOAc, and washed successively with satu-
rated aqueous NaHCO3 solution and brine, and then dried.
Removal of the solvent gave a residue, which was purified
by column chromatography (silica gel: 6 g, EtOAc/hexane¼
1:15) to give O-THP ether (227 mg, 89%) as a diastereomer
mixture. To a solution of the THP ether (227 mg,
0.522 mmol) in MeOH (5 mL) in the presence of
CeCl3$7H2O (389 mg, 1.04 mmol) was added NaBH4
(29.6 mg, 0.782 mmol) at 0 ꢂC, and the mixture was stirred
at 0 ꢂC for 30 min. The reaction mixture was diluted with

S. Imuta et al. / Tetrahedron 62 (2006) 6926–6944
6943
McAlpine, R. J.; Thompson, P. E.; Ehrlich, J. Antibiot.
Ann. 1958–1959, 497–504; (d) Merker, P. C.; Woolley,
G. W. Antibiot. Ann. 1958–1959, 515–517; (e) Teller,
M. N.; Merker, P. C.; Palm, J. E.; Woolley, G. W. Antibiot.
Ann. 1958–1959, 518–521; (f) Sugiura, K.; Reilly, H. C.
Antibiot. Ann. 1958–1959, 522–527.
EtOAc, and washed successively with saturated aqueous
NaHCO3 solution and brine, and then dried. Removal of
the solvent gave a crude 46, which was dissolved in pyridine
(4 mL). To this solution were added MsCl (0.067 mL,
0.86 mmol) and DMAP (15 mg, 0.12 mmol) at 0 ꢂC, and
the reaction mixture was stirred at 80 ꢂC for 13 h. The reac-
tion mixture was diluted with 1 mol/L aqueous HCl solution
and stirred at room temperature for 1 h. The products were
extracted with EtOAc, and the organic layer was washed
successively with saturated aqueous NaHCO3 solution and
brine, and then dried. Removal of the solvent gave a residue,
which was purified by column chromatography (silica gel:
4 g, EtOAc/hexane¼1:3) to give 47 (167 mg, 66% from
45) as a colorless syrup: Rf 0.50 (EtOAc/hexane¼1:1);
[a]2D2 w0 (c 0.92, CHCl3); IR (neat) 3450, 2960, 2930,
2. (a) Ishizuka, M.; Fakasawa, S.; Masuda, T.; Sato, J.;
Kanbayashi, N.; Takeuchi, T.; Umezawa, H. J. Antibiot.
1980, 33, 1054–1062; (b) Tabira, T.; Da-Lin, Y.; Yamamura,
T.; Aoyagi, T. Proc. Jpn. Acad. Ser. B 1987, 63, 127–130.
3. (a) Hunt, D. E.; Sandham, H. J.; Caldwell, R. C. J. Dent. Res.
1970, 49, 137–139; (b) Hunt, D. E.; Navia, J. M.; Lopez, H.
J. Dent. Res. 1971, 50, 371–373.
4. (a) Struck, R. F.; Thorpe, W. C.; Coburn, W. C., Jr.; Shealy, Y. F.
Tetrahedron Lett. 1967, 1589–1595; (b) Antosz, F. J.; Nelson,
D. B.; Herald, D. L., Jr.; Munk, M. E. J. Am. Chem. Soc.
1970, 92, 4933–4942; (c) Wetherington, J. B.; Moncrief,
J. W. Acta Crystallogr. 1975, B31, 501–511.
2890, 2860, 1255, 1180, 1080, 955, 920, 840 cmꢀ1
;
1H NMR (300 MHz) d 7.42–7.27 (5H, m), 4.65 and 4.55
(each 1H, 2d, J¼11.5 Hz), 4.31 (1H, ddd, J¼4.4, 8.8,
11.7 Hz), 3.68–3.52 (2H, m), 3.22 (1H, ddd, J¼4.4, 9.0,
11.7 Hz), 3.00 (3H, s), 2.63 (1H, s), 2.52 (1H, ddd, J¼4.7,
4.9, 12.6 Hz), 2.20 (1H, ddd, J¼4.4, 4.7, 12.9 Hz), 1.60
(1H, ddd, J¼11.7, 12.0, 12.6 Hz), 1.35 (1H, ddd, J¼11.7,
11.7, 12.9 Hz), 0.88 (9H, s), 0.08 and 0.06 (each 3H, 2s);
13C NMR (75 MHz) d 137.8, 128.6, 128.1, 127.9, 82.2,
71.9, 70.7, 70.6, 38.4, 35.4, 35.0, 25.7, 17.9, ꢀ4.4, ꢀ4.9;
HRMS (FAB+, NBA matrix) m/z calcd for C20H35O6SSi,
(M+H)+ 431.1924, found 431.1919.
5. (a) Kondo, S.; Horiuchi, Y.; Hamada, M.; Takeuchi, T.;
Umezawa, H. J. Antibiot. 1979, 32, 1069–1071; (b) Hori, M.;
Suzukake, K.; Ishikawa, C.; Asakura, H.; Umezawa, H.
J. Antibiot. 1981, 34, 465–468.
6. (a) Yoshioka, M.; Nakai, H.; Ohno, M. J. Am. Chem. Soc. 1984,
106, 1133–1135; Heterocycles 1984, 21, 151–165; (b)
Garigipati, R. S.; Tschaen, D. M.; Weinreb, S. M. J. Am.
Chem. Soc. 1985, 107, 7790–7792; J. Am. Chem. Soc. 1990,
112, 3475–3482; (c) Kozikowski, A. P.; Konoike, T.;
Nieduzak, T. R. J. Chem. Soc., Chem. Commun. 1986, 1350–
1352; (d) Kozikowski, A. P.; Nieduzak, T. R.; Konoike, T.;
Springer, J. P. J. Am. Chem. Soc. 1987, 109, 5167–5175; (e)
Ward, D. E.; Kaller, B. F. Tetrahedron Lett. 1993, 34, 407–
410; J. Org. Chem. 1994, 59, 4230–4238; (f) Ward, D. E.;
Yuanzhu, G.; Kaller, B. F. J. Org. Chem. 1996, 61, 5498–5505.
7. (a) Rahman, M. A.; Fraser-Reid, B. J. Am. Chem. Soc. 1985,
107, 5576–5578; (b) Askin, D.; Angst, C.; Danishefsky, S.
J. Org. Chem. 1985, 50, 5005–5007; J. Org. Chem. 1987, 52,
622–635.
8. (a) Munakata, T. Yakugaku Zasshi 1981, 101, 138–147;
(b) Munakata, T.; Okumoto, T. Chem. Pharm. Bull. 1981, 29,
891–894; (c) Nishimura, Y.; Kondo, S.; Takeuchi, T. J. Antibiot.
1992, 45, 735–741; (d) Adachi, M.; Nishimura, Y.; Kondo, S.;
Takeuchi, T. J. Antibiot. 1998, 51, 202–209; (e) Adachi, H.;
Nishimura, Y.; Takeuchi, T. J. Antibiot. 2002, 55, 92–98.
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5047–5051.
4.4.6. Preparation of enantiomeric cyclohexenone [(L)-6].
A solution of (COCl)2 (2.0 mol/L solution in CH2Cl2,
0.11 mL, 0.22 mmol) and DMSO (0.030 mL, 0.423 mmol)
in CH2Cl2 (0.5 mL) was stirred at ꢀ78 ꢂC for 10 min under
Ar. To this mixture was added a solution of 47 (15.4 mg,
0.0358 mmol) in CH2Cl2 (0.5 mL) at ꢀ78 ꢂC. After being
stirred at ꢀ78 ꢂC for 2 h, the reaction mixture was quenched
by addition of Et3N (0.040 mL, 0.29 mmol) at ꢀ78 ꢂC. The
resulting suspension was further stirred at 0 ꢂC for 1 h, and
then diluted with Et2O. The organic layer was washed with
brine and then dried. Removal of the solvent gave a residue,
whichwaspurifiedbycolumnchromatography(silicagel:1 g,
EtOAc/hexane¼1:7) to give (ꢀ)-6 (11.1 mg, 93%) as a white
solid: mp 46–47 ꢂC; [a]D19 ꢀ22.0 (c 0.80, CHCl3); HRMS
(FAB+, NBA matrix) m/z calcd for C19H29O3Si, (M+H)+
333.1886, found 333.1889. Anal. Calcd for C21H24O5: C,
68.63; H, 8.49. Found: C, 68.49; H, 8.39. The 1H and
13C NMR spectra were fully identical with those of (+)-6.
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Acknowledgements
We thank Dr. Y. Nishimura (Institute of Microbial Chemistry,
Tokyo, Japan) for a generous gift of natural actinobolin. We
also thank the Ministry of Education, Culture, Sports,
Science, and Technology, Japan (Grant-in-Aid for Scientific
Research, B15350027 and Grant-in-Aid for the 21st
Century COE program ‘KEIO LCC’) for financial assistance.
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