Preparation of seven-membered carbocycles using ring-closing metathesis reaction and application to syntheses of tormesol and cyathane skeleton

Article abstract of DOI:10.1246/bcsj.79.1955

Various precursors were synthesized and were reacted with the Grubbs reagent as well as the second generation Grubbs reagent to cyclize them into seven-membered carbocycles with di- or tri-substituted double bonds. These reactions were used to synthesize

Full text of DOI:10.1246/bcsj.79.1955

Ó 2006 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 79, No. 12, 1955–1962 (2006) 1955
Preparation of Seven-Membered Carbocycles Using
Ring-Closing Metathesis Reaction and Application
to Syntheses of Tormesol and Cyathane Skeleton
Katsuyuki Nakashima, Norihiro Fujisaki, Kosuke Inoue, Atsushi Minami,
ꢀ
Chisako Nagaya, Masakazu Sono, and Motoo Tori
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514
Received June 8, 2006; E-mail: tori@ph.bunri-u.ac.jp
Various precursors were synthesized and were reacted with the Grubbs reagent as well as the second generation
Grubbs reagent to cyclize them into seven-membered carbocycles with di- or tri-substituted double bonds. These reac-
tions were used to synthesize (ꢁ)-tormesol, which is an enantiomer of sphenolobane-type diterpene that was isolated
from Halimium viscosum, and a basic skeleton of cyathane-type diterpene.
Seven-membered carbocycles are frequently found in natu-
ral products.1 Syntheses of seven-membered rings are usually
carried out by aldol condensations,2 ene-reactions,3 and so
on. We recently communicated4 the total synthesis of spheno-
lobane-type diterpene isolated from the liverwort Anastrophyl-
lum aurium5b and reported an effective way to prepare cyclo-
heptenones with a tri-substituted double bond using ring-clos-
ing metathesis (RCM) reaction catalyzed by the first genera-
tion Grubbs reagent.6 As Grubbs himself reported,7 the
syntheses of seven-membered carbocycles are highly depend-
ent on the substrate structure. For example, diene 1 cyclized
to afford a seven-membered ring compound 2 in 96% yield.
In contrast, diene 3 gave compound 4 only in 25% yield
(Scheme 1).7 This is probably due to the conformation of the
diene substrate, because the RCM reaction mechanism is not
dependent on the ionic species. Although, two olefinic moie-
ties do not have any affinity for reaction, under the reaction
conditions, the second generation Grubbs catalyst8 works very
effectively for most of the substrates. In the previous report,4
the second generation Grubbs catalyst8 could not be used.
Therefore, it is worth studying how the second generation
Grubbs catalyst8 works for the construction of seven-mem-
bered carbocycles, and we have applied this methodology to
the synthesis of tormesol (5) (Chart 1).9
(+)-Tormesol (5)9 is a diterpene, which was isolated from
Halimium viscosum by Urones et al., and it belongs to a sphe-
nolobane family.5,9,10 We have, recently, reported the synthesis
of two sphenolobane-type diterpenoids4 isolated from the
liverwort Anastrophyllum aurium5b using the RCM reaction
applied to the formation of seven-membered carbocycles.
There have been several reports towards the synthesis of
tormesol (5),9 but, to the best of our knowledge, no successful
example has appeared. Since we had a synthetic intermediate
for the above-mentioned diterpenes,4 it was used for the
synthesis of (ꢁ)-tormesol (5), which is the enantiomer of the
natural product, in this study.
Cyathanes were first isolated from the bird’s nest fungi
Cyathus earlei by Ayer,11 then, from the fungi Hericium erina-
ceum12 and Sarcodon scabrosus,13 and the liverwort Jameso-
niella tasmanica.14 We have synthesized allocyathine B2 (6),15
which is a seven-membered carbocycle, via aldol cyclization.
[Ru]
EtO2C
CO2Et
EtO2C
CO2Et
(5 mol%)
OH
CH2Cl2
H
O
(10 mM)
H
rt
1
2
4 days
96%
CHO
5
6
[Ru]
EtO2C
CO2Et
EtO2C
CO2Et
PCy3
(5 mol%)
Ph
Cl
Cl
Mes
N
N
Mes
Ph
Ru
Cl
Cl
CH2Cl2
Ru
PCy3
PCy3
(10 mM)
rt
4 days
3
4
Grubbs reagent [Ru]
Chart 1.
25%
[DHImRu]
Scheme 1. Reported examples.
Published on the web December 13, 2006; doi:10.1246/bcsj.79.1955

1956 Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006)
Table 1. RCM Reactions Producing Seven-Membered Carbocycles
Preparation of Seven-Membered Carbocycles
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
MeO2C
CO2Me
CO2Me
7
8
9
10
MeO2C
MeO2C
MeO2C
CO2Me
CO2Me
CO2Me
MeO2C
CO2Me
11
12
13
14
Entry
Substrate
Reagent/mol %
SolventaÞ
Temp (time/h)
Products (yield/%)
1
2
3
4
5
6
7
8
9
10
7
7
7
8
8
8
9
9
10
10
[Ru] (3)
CH2Cl2
CH2Cl2
PhH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
reflux (2)
reflux (18)
reflux (18)
rt (39)
11 (96)
[DHImRu] (3)
[DHImRu] (3)
[Ru] (5)
[DHImRu] (5)
[DHImRu] (3)
[Ru] (3)
[DHImRu] (3)
[Ru] (3)
[DHImRu] (3)
11 (68), 12 (23)
11 (60), 12 (33)
13 (96)
13 (98)
13 (86)
12 (95)
11 (13), 12 (79)
14 (23)
14 (100)
rt (39)
reflux (2)
reflux (2)
reflux (2)
reflux (2)
reflux (2)
a) The concentration was 10 mM.
RCM reactions have not been applied to the synthesis of cya-
thanes. Therefore, the construction of the seven-membered
ring in the cyathane-type diterpene using RCM reactions was
also investigated. Here, we report the details of these results.
Grubbs reagent (Table 1).
Chiral cycloheptenone derivative 1718 was prepared from a
keto ester derivative 15 which was described in our previous
report (Scheme 2).4 Since the second generation Grubbs re-
agent8 worked very well as demonstrated, we have reinvesti-
gated the conversion of 15 into 16 using this catalyst. The
results are listed in the Table 2.
Results and Discussion
At first, we checked the formation of seven-membered car-
bocycles with di-substituted double bond using both [Ru] and
[DHImRu] as shown in Table 1. When diene 716 was treated
with [Ru] in CH2Cl2 under reflux for 2 h, cycloheptene
1116,17 was formed in 96% yield (Entry 1). However, when
[DHImRu] was used, isomer 1217 was formed in 23% yield
along with 1116,17 (68%) (Entry 2). This was presumably
formed by isomerization of 11.16,17 The total yield of 1116,17
and 1217 in PhH was slightly better than that in CH2Cl2 (Entry
3). Diene 9 was treated with [Ru] in CH2Cl2 to produce 1217 in
95% yield (Entry 7). However, when [DHImRu] was used,
1217 was formed in 79% yield along with a small amount of
1116,17 (13%) (Entry 8). Thus, isomerization tends to occur
when the second generation reagent was used. Compounds 8
and 10 were treated with [Ru] and [DHImRu], although the
cyclization of the corresponding ethyl ester with [Ru] was
already reported by Grubbs.7 The reported yield of compound
13 was very high, although normally the formation of a ring
with the tri-substituted double bond using [Ru] is not easy.
The yields for compounds 13 and 14 with [Ru] were 96 and
23%, respectively (Entries 4 and 9). When [DHImRu] was
used, yields for 13 and 14 were 86 and 100%, respectively
(Entries 6 and 10). When the reaction was carried out at rt
for 39 h, the yield of 13 improved to 98% (Entry 5). These
results were better than the results with Grubbs reagent, which
was quite reasonable in view of higher reactivity of a second
generation Grubbs reagent. Thus, seven-membered carbocy-
cles can be prepared effectively by using the second generation
Compound 15 did not afford carbocycle 16 in good yield
using Grubbs reagent [Ru] (Entry 1) as described in our previ-
ous report.4 One mol % of the new reagent [DHImRu] at rt suc-
cessfully gave 16 in 82% yield (Entry 2). Moreover, at reflux
temperature the yield of 16 improved to 95% (Entry 5). The
yield only slightly changed depending on work-up19 (Entries
4 and 5). Thus, the effectiveness of the reagent [DHImRu] in
this cyclization is obvious.
The synthesis of bicyclic compound 22 was carried out ac-
cording to the procedure in the previous paper4 as summarized
in Scheme 2. After methylation of 19, without isomerization as
before, direct separation of the crude mixture yielded 22 and
23, in 15 and 13% yields, respectively, which were lower than
expected. Finally, methyl ketone 22 was alkylated using 5-bro-
mo-2-methyl-2-pentene under lithium exchange conditions in
ether at ꢁ78 ꢂC to furnish in 24% yield a single isomer, which
was ent-tormesol (5). The spectral data for 5 were completely
identical with those provided by Prof. Urones, except that the
sign of the specific rotation was opposite (see the Experimen-
tal). Preferential formation of 13R stereocenter is presumably
explained by a Felkin–Anh model as shown in Fig. 1. In the
most stable conformation calculated by CONFLEX,20 the car-
bonyl group was located on the same side as that of the methyl
group at the C-6 position. Thus, the reagent must approach
from the less hindered right-hand side in Fig. 1 to afford the
desired configuration needed for tormesol (5) synthesis.21
Therefore, we have succeeded in the total synthesis of (ꢁ)-

K. Nakashima et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006) 1957
O
O
O
O
CN
[RCM]
O
OEt
CN
OEt
H
COOMe
15
16
17
18
CN
CN
CN
H
H
1) Mg, MeOH
+
+
2) HPLC
21
18
19 (21%)
20 (56%)
13% (GC 2 peaks)
CN
1) MeLi
Et2O, rt, 21 h
H
O
O
H
H
+
2) HPLC
19
22 (15%)
23 (13%)
Scheme 2. Preparation of ketone 22.
Table 2. RCM of 15 into 16 in CH2Cl2
O
O
O
O
[RCM]
OEt
OEt
15
16
Entry
Reagent/mol %
Conc./mM
Temp/ꢂC
Results/%
Work up16
1aÞ
2
3
4
[Ru] (30)
10
100
100
100
100
40
rt
reflux
reflux
reflux
15:16 = 1:1 (GC-MS)
[DHImRu] (1.0)
[DHImRu] (1.0)
[DHImRu] (1.0)
[DHImRu] (1.0)
82
88
90
95
Ph3PO
DMSO
5
a) Ti(OiPr)4 (1.0 equiv) was added.
OH
14
t-BuLi
Br
15
17
H
18
19
13
16
9
11
10
3
6
22
20
4
Et2O
–78 °C, overnight
12
(–)-5
24% (recover 46%)
13
O
H
H
O
13
13
22
22
R
Fig. 1. The Felkin–Anh model of 22.
tormesol (5) starting from keto ester 15 using the RCM reaction
as the key steps for the construction of the seven-membered
carbocycle. These syntheses support the absolute stereochemis-
try of tormesol (5) as well as configuration at C-13 position (S
in the natural product), which was deduced by NOE experiment
by Urones et al.9 Compounds 24 and 25, isolated from the liver-
wort,5b have the absolute configuration shown in Fig. 2 as dem-
onstrated by our synthesis.4 Compounds 26 and 27 were isolat-
ed from the liverwort5a and should have the same absolute con-
figuration as 24 and 25. However, (+)-tormesol (5), isolated

1958 Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006)
Preparation of Seven-Membered Carbocycles
OH
liverwort
H
H
OH
H
H
OH
O
O
O
O
OAc
OAc
(–)-245a
(–)-255a
275b
265b
marine source
OH
OH
H
H
H
O
O
HO
O
polasol A (28)10b
polasol B (29)10b
reiswigin B (30)10a
HO
H
higher plant
(+)-tormesol (5)9
Fig. 2. Absolute configuration of sphenolobane-type diterpenes.
bon takes place as reported.23 The position of cyclization of
OTMS
compound 3522 is the same as that of 31, and the yield of prod-
uct 36 was 100% in this case.
[DHImRu] (20 mol%)
OTMS
H
CH2Cl2 (1 mM)
reflux, overnight
Compound 3722 was prepared by modifying the method
used to prepare allocyathine B2 (6)15 (Scheme 4). Similarly
20 mol % of [DHImRu] worked well to cyclize 37, and tricy-
clic cycloheptene 38 was obtained in 91% yield. The position
of the bond to be formed in the reaction of 3922 is shifted to the
next one compared with that of 37. Compound 3922 afforded
40 in 88% yield. This change had little effect on the yield. Sub-
strate 4122 was taken from the total synthesis of allocyathine
B2 (6).15 Compound 4122 cyclized into 42 in 67% yield. Since
the stereochemistry of 42 was single, it was established by
NOESY experiment at the stage of 43. Finally, compound
4422 was treated with 20 mol % of [DHImRu] to provide com-
pound 45 in 87% yield, the stereochemistry of which was also
established by NOESY experiment of deprotected compound
46. Compound 46 has all the carbon atoms required for the cy-
athane skeleton, although the configuration of the C-5 position
is opposite. Thus, a cyathane skeleton has been synthesized
using the RCM reaction.
H
96%
31
32 (10:1 by GC-MS)
OTMS
OTMS
[DHImRu] (20 mol%)
H
CH2Cl2 (1 mM)
reflux, overnight
H
86%
33
OH
34 (10:3 by GC-MS)
OH
[DHImRu] (20 mol%)
H
CH2Cl2 (1 mM)
reflux, overnight
H
quant.
35
36
Scheme 3. Preparation of seven-membered rings.
from the terrestrial higher plant, has the opposite absolute con-
figuration9 to those of the sphenolobane diterpenes isolated
from the liverwort5 or marine sources10 as shown in Fig. 2.
Fused bicyclic systems of six- and seven-membered carbo-
cycles included in cyathane-type diterpenes11–14 were next at-
tempted to prepare by RCM reactions. Compound 3122 derived
from cyclohexanone was treated with 20 mol % of [DHImRu]
in CH2Cl2 to give 32 in 96% yield as a 10:1 diastereomeric
mixture detected by GC-MS based on the configuration of
the oxymethine (Scheme 3). Compound 3322 was converted
to a tri-substituted cycloheptene 34 in 86% yield (10:3 mixture
by GC-MS). For 33, it was necessary to protect the hydroxy
group with TMS, otherwise isomerization or loss of one car-
Conclusion
We have developed the synthesis of cycloheptenes by RCM
reactions and described its application to the synthesis of tor-
mesol and a cyathane skeleton. This study shows that the use
of the first and second generation Grubbs catalyst depends on
the substrate structure. The synthesis of (ꢁ)-tormesol support-
ed the assignment of the absolute configuration of the natural
product reported by Urones, and its absolute configuration was
clearly different from those originated from marine sources,
liverworts, and higher plants.

K. Nakashima et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006) 1959
[DHImRu] (20 mol%)
H
OTES
OTES
CH2Cl2 (1 mM)
reflux
H
overnight
91%
37
38 (10:3 by GC-MS)
[DHImRu] (20 mol%)
OTES
OTES
CH2Cl2 (1 mM)
reflux, overnight
H
39
(single isomer)
40
88%
NOE
[DHImRu] (20 mol%)
TBAF
OTES
OTES
OH
H
CH2Cl2 (1 mM)
reflux, overnight
H
THF, rt
overnight
H
41
67%
94%
42
43
(single isomer)
[DHImRu] (20 mol%)
TBAF
OTES
OTES
OH
H
H
CH2Cl2 (1 mM)
reflux, overnight
THF, rt
overnight
H
87%
68%
44
45
46
Scheme 4. Preparation of seven-membered carbocycles in a cyathane-skeleton.
The ether-layer was washed with sat. NaCl aq, and dried (MgSO4),
and the solvent was evaporated to afford a residue (38.8 mg). The
residue was separated by silica-gel column chromatography (hex-
ane:EtOAc = 100:0–85:15) followed by HPLC (Nucleosil 50–5,
Experimental
General. All reactions were carried out under an argon atmo-
sphere. Yields refer to chromatographically and spectroscopically
homogeneous materials. Anhydrous solvents were purchased from
Kanto Chemical Co., Inc. Reagents were purchased at the highest
commercial quality and used without further purification. The IR
spectra were measured on a JASCO FT/IR 500 spectrophotome-
ter. 1H and 13C NMR spectra were recorded on a Varian Unity
600, a JEOL ECP-400, a Varian Mercury 300, a Varian Unity 200,
or a Varian Gemini 200 spectrometer. The solvent used for NMR
spectra was CDCl3 unless otherwise stated. MS spectra were mea-
sured on a JEOL JMS-700 MStation spectrometer. Silica-gel BW-
300 (200–400 mesh, Fuji Silycia) was used for column chroma-
tography, and silica gel 60F254 plate (0.25 mm, Merck) was used
for TLC.
4:6ꢀ ꢃ 250 mm, hexane:EtOAc = 95:5, flow rate: 1.5 mL minꢁ1
)
20
to give 22 (8.1 mg, 15%) and 23 (7.0 mg, 13%). 22: ½ꢁꢄD ꢁ108:2
(c 0.8, CHCl3); FTIR 2920, 1710, 1450, 1350, 1170 cmꢁ1
;
1H NMR (300 MHz, CDCl3) ꢂ 0.77 (3H, s), 1.30–1.57 (2H, m),
1.60–1.69 (1H, m), 1.71–1.91 (2H, m), 1.74 (3H, t, J ¼ 1:5 Hz),
1.96–2.11 (4H, m), 2.12 (3H, s), 3.24 (1H, td, J ¼ 9:9, 6.9 Hz),
5.34–5.42 (1H, m); 13C NMR (75 MHz, CDCl3) ꢂ 17.8 (CH3),
23.8 (CH2), 25.1 (CH3), 27.0 (CH3), 32.3 (CH3), 34.7 (CH3),
41.1 (CH3), 41.8 (CH3), 42.5 (C), 55.0 (CH), 57.1 (CH), 122.8
(CH), 138.9 (C), 211.6 (C); MS (EI) m=z 206 (Mþ), 188, 163,
121, 107, 95 (base); HRMS (EI) Found m=z 206.1693 (Mþ),
19
C14H22O requires 206.1670. 23: ½ꢁꢄD þ35:5 (c 0.7, CHCl3); FTIR
General Procedure for RCM Reactions.
RCM reac-
1710, 1450, 1360 cmꢁ1 1H NMR (300 MHz, CDCl3) ꢂ 0.74
;
tions were carried out by slow addition of a solution of [Ru] or
[DHImRu] (3 to 20 mol %) in CH2Cl2 or PhH into a stirred solu-
tion of a substrate in the same solvent (10 mM) under Ar atmo-
sphere. The mixture was stirred at rt or refluxed for certain period
of time, and then, the seal was removed to expose the open air for
30 min. The solvent was evaporated, and the residue was purified
by silica-gel column chromatography to afford the product, which
sometimes needs further purification.
Synthesis of 22 and 23. To a stirred solution of 194 (52.3 mg,
0.28 mmol) in ether (4 mL) was added MeLi (1.14 M ether soln.,
1.15 mL, 1.3 mmol) at 0 ꢂC, and the mixture was stirred for 19 h
at rt. More MeLi (1.14 M ether soln., 0.23 mL, 0.26 mmol) was
added, and the mixture was further stirred for 2 h. Hydrochloric
acid (1 M) was added, and the mixture was extracted with ether.
(3H, s), 1.10–1.27 (1H, m), 1.43 (1H, q, J ¼ 3:0 Hz), 1.41–1.51
(1H, m), 1.47 (1H, dd, J ¼ 8:7, 5.7 Hz), 1.57–1.71 (2H, m), 1.74
(3H, s), 1.78 (1H, td, J ¼ 11:4, 3.0 Hz), 1.89–2.15 (4H, m), 2.15
(3H, s), 2.67 (1H, td, J ¼ 11:1, 6.3 Hz), 5.38 (1H, m); 13C NMR
(75 MHz, CDCl3) ꢂ 18.1 (CH3), 24.7 (CH2), 25.2 (CH2), 27.1
(CH3), 29.7 (CH3), 33.8 (CH2), 40.2 (CH2), 40.5 (CH2), 42.2
(C), 56.3 (CH), 56.7 (CH), 122.3 (CH), 139.4 (C), 212.2 (C);
MS (EI) m=z 206 (Mþ), 188, 163, 121, 107, 95 (base); HRMS
(EI) Found m=z 206.1684 (Mþ), C14H22O requires 206.1670.
Synthesis of (À)-5. A solution of 5-bromo-2-methylpentene
(128 mg, 0.78 mmol) in ether (1.7 mL) was treated with t-BuLi
(1.51 M ether soln., 0.48 mL, 0.72 mmol) at ꢁ78 ꢂC under Ar.
The mixture was stirred for 8.6 h. This solution (1.1 mL) was add-
ed into a solution of 22 (8.1 mg, 0.039 mmol) in ether (1 mL) at

1960 Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006)
Preparation of Seven-Membered Carbocycles
ꢁ78 ꢂC, and the mixture was stirred for 3.3 h. More lithiated solu-
tion (1.1 mL) was added, and the mixture was stirred for 4 h more.
A sat. NH4Cl aq was added and the mixture was extracted with
ether. The organic layer was washed with sat. NaCl aq, and dried
(MgSO4), and the solvent was evaporated to give a residue
(39.4 mg). The residue was washed with silica-gel column chro-
matography (hexane:EtOAc = 100:0–1:1) followed by HPLC
(Nucleosil 50–5, 4:6ꢀ ꢃ 250 mm, hexane:EtOAc = 95:5, flow
mmol) in degassed CH2Cl2 (20 mL) was added a solution of
[DHImRu] (5.2 mg, 0.006 mmol) in degassed CH2Cl2 (7 mL),
and the mixture was refluxed overnight. The solvent was evaporat-
ed, and the residue was purified by silica-gel column chromatog-
raphy (hexane:EtOAc = 100:0–93:7) to afford 38 (9.2 mg, 91%);
FTIR 1680, 1630 cmꢁ1 1H NMR (300 MHz, CDCl3) isomer 1;
;
ꢂ 0.59 (6H, q, J ¼ 7:8 Hz), 0.93 (6H, d, J ¼ 7:5 Hz), 0.96 (9H,
t, J ¼ 7:8 Hz), 1.01 (3H, s), 1.36–1.44 (4H, m), 1.55–1.69 (4H,
m), 1.98–2.16 (4H, m), 2.58 (1H, sep, J ¼ 6:6 Hz), 2.99 (1H, dd,
J ¼ 10:2, 5.4 Hz), 3.84 (1H, d, J ¼ 9:6 Hz), 4.26 (1H, d, J ¼ 7:5
Hz), 5.54 (1H, dd, J ¼ 3:3, 1.5 Hz), 5.62 (1H, d, J ¼ 2:4 Hz); iso-
mer 2; ꢂ 0.62 (6H, q, J ¼ 7:8 Hz), 0.95 (6H, d, J ¼ 7:5 Hz), 0.96
(9H, t, J ¼ 7:8 Hz), 0.99 (3H, s), 1.45–1.54 (4H, m), 1.62–1.89
(4H, m), 2.13–2.36 (4H, m), 2.67 (1H, sep, J ¼ 6:6 Hz), 2.99
(1H, dd, J ¼ 10:2, 5.4 Hz), 3.83 (1H, d, J ¼ 9:6 Hz), 4.25 (1H, d,
J ¼ 7:5 Hz), 5.54 (1H, dd, J ¼ 3:3, 1.5 Hz), 5.62 (1H, d, J ¼ 2:4
Hz); 13C NMR (75 MHz, CDCl3) ꢂ 4.9 (CH2 ꢃ 6), 7.0 (CH3 ꢃ 6),
21.3 (CH3), 21.4 (CH3 ꢃ 2), 21.5 (CH3), 23.9 (CH2), 24.6 (CH3),
26.1 (CH2), 26.1 (CH2), 26.3 (CH), 26.8 (CH), 27.4 (CH2), 27.5
(CH2), 27.6 (CH2), 27.7 (CH2), 28.8 (CH2), 29.5 (CH3), 34.9
(CH), 35.1 (CH2), 39.7 (CH2, CH), 41.0 (CH2), 41.2 (CH2),
42.7 (CH2), 46.1 (C), 46.4 (C), 46.6 (CH), 46.7 (CH), 74.0 (CH),
77.3 (CH), 127.6 (CH), 128.4 (CH), 133.6 (CH), 136.8 (C), 138.1
(CH), 140.0 (C), 141.9 (C), 143.0 (C); MS (EI) m=z 374 (Mþ),
359, 331, 227, 184, 117, 103 (base), 75; HRMS (EI) Found m=z
374.2999 (Mþ), C24H42OSi requires 374.3005.
17
rate: 1.5 mL minꢁ1) to yield (ꢁ)-5 (2.7 mg, 24%); ½ꢁꢄD ꢁ30:0
(c 1.34, CHCl3); FTIR 3470, 1450, 1380, 1110 cmꢁ1 1H NMR
;
(400 MHz, CDCl3) ꢂ 0.79 (3H, s), 1.19 (3H, s), 1.63 (3H, s),
1.69 (3H, d, J ¼ 0:8 Hz), 1.74 (3H, s), 1.79–1.89 (1H, m), 1.93–
2.14 (6H, m), 2.41 (1H, dt, J ¼ 10:6, 9.9 Hz), 5.09–5.16 (1H, m),
5.39 (1H, br s); 13C NMR (75 MHz, CDCl3) ꢂ 17.8 (CH3), 19.2
(CH3), 22.8 (CH2), 24.0 (CH2), 25.8 (CH3), 26.3 (CH2), 27.0
(CH3), 27.8 (CH3), 36.0 (CH2), 40.1 (CH2), 41.4 (CH2), 42.4
(C), 42.4 (CH2), 52.6 (CH), 56.7 (CH), 75.8 (C), 122.8 (CH),
124.7 (CH), 131.7 (C), 139.1 (C).
Synthesis of 32. A solution of [DHImRu] (3.4 mg, 0.004
mmol) in degassed CH2Cl2 (5 mL) was added into refluxing
CH2Cl2 (15 mL) solution of compound 31 (6.6 mg, 0.02 mmol).
The solution was heated overnight under reflux. The mixture
was cooled to rt and stirred in the air before evaporation of the sol-
vent. The residue was subjected to silica-gel column chromatogra-
phy (hexane:AcOEt = 95:5–4:1) to afford compound 32 (6.0 mg,
96%); FTIR 1650 cmꢁ1; 1H NMR (200 MHz, CDCl3); ꢂ 0.09 (9H,
s), 0.99 (3H, s), 0.99–1.51 (12H, m), 1.57 (3H, m), 1.67–2.64 (9H,
m), 3.68 (1H, br d, J ¼ 10:8 Hz), 3.70 (1H, s), 5.61–5.68 (2H, m);
MS (CI) m=z 252 (Mþ), 237, 205, 163 (base), 162, 117, 89;
HRMS (CI) Found m=z 252.1911 (Mþ). Calcd for C15H28OSi
252.1909.
Synthesis of 40. To a stirred solution of 3922 (4.2 mg, 0.01
mmol) in degassed CH2Cl2 (5 mL) was added a solution of
[DHImRu] (1.9 mg, 0.0022 mmol) in degassed CH2Cl2 (5 mL)
and the mixture was refluxed overnight. The solvent was evaporat-
ed and the residue was purified by silica-gel column chromatogra-
phy (hexane:EtOAc = 100:0–95:5) to afford 40 (3.4 mg, 88%);
Synthesis of 34. A solution of [DHImRu] (25.6 mg, 0.03
mmol) in degassed CH2Cl2 (30 mL) was added into refluxing
CH2Cl2 (150 mL) solution of compound 33 (50.9 mg, 0.151
mmol). The solution was heated overnight under reflux. The mix-
ture was cooled to rt and stirred in the air before evaporation of the
solvent. The residue was subjected to silica-gel column chroma-
tography (hexane:CHCl3 = 9:1–0:100) to afford compound 34
FTIR 1460 cmꢁ1 1H NMR (300 MHz, CDCl3) ꢂ 0.59 (6H, q,
;
J ¼ 7:9 Hz), 0.78 (3H, s), 0.91 (3H, d, J ¼ 6:8 Hz), 0.95 (3H, d,
J ¼ 6:8 Hz), 0.96 (9H, t, J ¼ 7:9 Hz), 0.98 (3H, s), 1.38–1.71
(7H, m), 1.91 (1H, dd, J ¼ 13:4, 7.5 Hz), 2.13 (1H, dd, J ¼ 15:0,
8.4 Hz), 2.25 (1H, ddd, J ¼ 15:8, 9.0, 7.1 Hz), 2.41 (1H, d,
J ¼ 11:5 Hz), 2.46–2.54 (1H, m), 2.59 (1H, t, J ¼ 6:9 Hz), 2.64–
2.72 (1H, m), 3.75 (1H, dd, J ¼ 10:5, 1.3 Hz), 5.62 (1H, quint,
J ¼ 11:0 Hz); 13C NMR (75 MHz, CDCl3) ꢂ 5.2 (CH2 ꢃ 3), 7.1
(CH3 ꢃ 3), 17.6 (CH3), 21.1 (CH3), 21.5 (CH3), 24.9 (CH3), 26.2
(CH), 27.8 (CH2), 29.4 (CH2), 33.1 (CH2), 33.9 (CH2), 36.7
(CH2), 40.8 (C), 41.7 (CH2), 42.0 (CH), 46.2 (C), 79.1 (CH),
126.5 (CH), 127.4 (CH), 128.7 (CH), 131.4 (CH), 140.1 (C),
141.4 (C); MS (EI) m=z 388 (Mþ), 359, 256, 241, 214, 169 (base),
133, 103; HRMS (EI) Found m=z 388.3148 (Mþ), C25H44OSi
requires 388.3161.
(38.5 mg, 86%); FTIR 1680 cmꢁ1 1H NMR (200 MHz, CDCl3)
;
ꢂ 0.30 (9H, s), 0.98 (1H, s), 1.10 (3H, s), 1.25 (3H, s), 1.95 (4H,
s), 1.49–1.94 (15H, m), 1.99–2.50 (6H, m), 4.27–4.28 (1H, m),
5.36–5.39 (1H, m); 13C NMR (50 MHz, CDCl3) ꢂ 0.20 (CH3),
21.5 (CH2), 21.6 (CH2), 23.8 (CH3), 24.6 (CH3), 26.0 (CH2),
28.3 (CH2), 30.7 (CH2), 32.5 (CH2), 44.7 (CH), 39.7 (C), 78.8
(CH), 131.0 (CH2), 137.4 (C); MS (CI) m=z 266 (Mþ), 265,
177, 156, 89 (base), 61; HRMS (CI) Found m=z 266.2044 (Mþ).
Calcd for C16H30OSi 266.2066.
Synthesis of 36. A solution of [DHImRu] (40.82 mg, 0.048
mmol) in degassed CH2Cl2 (25 mL) was added into refluxing
CH2Cl2 (240 mL) solution of compound 35 (50 mg, 0.24 mmol).
The solution was heated overnight under reflux. The mixture
was cooled to rt and stirred in the air before evaporation of the sol-
vent. The residue was subjected to silica-gel column chromatogra-
phy (CH2Cl2) to afford compound 36 (56.3 mg, 100%); FTIR
3485, 1672 cmꢁ1; 1H NMR (200 MHz, CDCl3); ꢂ 1.17–1.76 (15H,
m), 2.28–2.34 (1H, m), 2.55 (1H, dd, J ¼ 9:4, 8.6 Hz), 5.50–5.55
(1H, m); 13C NMR (50 MHz, CDCl3) ꢂ 21.4 (CH2), 25.6 (CH3),
26.2 (CH2), 27.6 (CH2), 30.0 (CH2), 30.3 (CH2), 40.7 (CH2), 41.0
(CH2), 44.7 (CH), 73.1 (C), 125.1 (CH), 140.8 (C); MS (CI) m=z
180 (Mþ), 162 (base), 134, 133, 105, 93, 43; HRMS (CI) Found
m=z 180.1499 (Mþ). Calcd for C12H20O 180.1514.
Synthesis of 42. To a stirred solution of 4122 (7.4 mg, 0.018
mmol) in degassed CH2Cl2 (10 mL) was added a solution of
[DHImRu] (3.4 mg, 0.0036 mmol) in degassed CH2Cl2 (8 mL),
and the mixture was refluxed overnight. The solvent was evaporat-
ed, and the residue was purified by silica-gel column chromatog-
raphy (hexane:EtOAc = 100:0–97:3) to afford 42 (4.7 mg, 67%);
FTIR 1460 cmꢁ1 1H NMR (200 MHz, CDCl3) ꢂ 0.58 (6H, q,
;
J ¼ 7:9 Hz), 0.83 (3H, s), 0.92 (3H, d, J ¼ 7:0 Hz), 0.96 (9H, t,
J ¼ 7:9 Hz), 0.96 (3H, d, J ¼ 7:0 Hz), 1.01 (3H, s), 1.17–1.38
(3H, m), 1.43–1.58 (2H, m), 1.60–1.75 (2H, m), 1.81 (1H, dd,
J ¼ 12:2, 4.0 Hz), 2.02–2.10 (3H, m), 2.17–2.32 (2H, m), 2.63
(1H, quint, J ¼ 6:8 Hz), 4.18 (1H, dd, J ¼ 4:6, 1.6 Hz), 5.60
(1H, ddd, J ¼ 10:5, 4.7, 1.5 Hz), 5.79 (1H, tdd, J ¼ 10:0, 6.0,
1.8 Hz); 13C NMR (50 MHz, CDCl3) ꢂ 5.0 (CH2 ꢃ 3), 6.9
(CH3 ꢃ 3), 21.2 (CH3), 23.6 (CH3), 25.2 (CH3), 26.0 (CH3),
Synthesis of 38. To a stirred solution of 3722 (10.8 mg, 0.027

K. Nakashima et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006) 1961
26.1 (CH), 27.4 (CH2), 27.7 (CH2), 29.7 (CH2), 36.2 (CH2), 40.4
(C), 42.6 (CH2), 46.1 (C), 46.4 (CH), 78.2 (CH), 130.0 (CH),
136.9 (CH), 139.0 (C), 142.4 (C); MS (CI) m=z 389 ½M þ Hꢄþ,
388 (base), 359, 257, 255, 197, 184; HRMS Found m=z
388.3153 (Mþ), C25H44OSi requires 388.3162.
78.2 (C), 156.5 (C); MS (CI) m=z 289 ½M þ Hꢄþ, 288, 287 (base),
271, 243, 189; HRMS Found m=z 288.2460 (Mþ), C20H32O re-
quires 288.2453.
We thank Professor Julio G. Urones, Universidad de
Salamanca, Salamanca, Spain, for sending us the spectral
data for tormesol and Dr. Masami Tanaka and Miss Yasuko
Okamoto, of this University, for measurement of 600 MHz
NMR and MS spectra, respectively.
Synthesis of 43. A solution of 42 (4.7 mg, 0.012 mmol) in
THF (2 mL) was added TBAF (1.0 M in THF, 0.02 mL, 0.02
mmol), and the mixture was stirred overnight. Water was added,
and the solvent was evaporated. The residue was extracted with
ether, and the organic layer was washed with sat. NaCl aq, and
dried (MgSO4). The solvent was evaporated to give a residue.
The residue was purified by silica-gel column chromatography
(hexane:EtOAc = 100:0–9:1) to afford 43 (3.1 mg, 94%); FTIR
Supporting Information
Experimental procedures for the preparation of compounds 8–
1
14, 31, 33, 35, 37, 39, 41, and 44, H NMR spectra of new com-
3400, 1460 cmꢁ1 1H NMR (600 MHz, CDCl3) ꢂ 0.91 (3H, s),
;
pounds and some important compounds on the way to the sub-
strates described in the manuscript. This material is available free
of charge on the Web at http://www.csj.jp/journals/bscj/.
0.93 (3H, d, J ¼ 6:9 Hz), 0.97 (3H, d, J ¼ 6:9 Hz), 1.03 (3H, s),
1.25–1.32 (2H, m), 1.40 (1H, td, J ¼ 13:8, 4.2 Hz), 1.48 (1H, td,
J ¼ 15:9, 9.1 Hz), 1.57 (1H, dt, J ¼ 13:2, 3.4 Hz), 1.67 (1H, dd,
J ¼ 12:0, 6.9 Hz), 1.76 (1H, dddd, J ¼ 14:5, 12.0, 11.9, 2.8 Hz),
1.86 (1H, td, J ¼ 13:9, 4.0 Hz), 2.04–2.14 (2H, m), 2.11 (1H, dd,
J ¼ 15:3, 8.5 Hz), 2.23 (1H, ddd, J ¼ 16:4, 9.5, 7.1 Hz), 2.32 (1H,
dd, J ¼ 12:0, 2.9 Hz), 2.63 (1H, sep, J ¼ 6:9 Hz), 4.25 (1H, d,
J ¼ 3:8 Hz), 5.65 (1H, ddd, J ¼ 10:8, 4.8, 2.2 Hz), 5.88 (1H,
dddd, J ¼ 11:3, 5.9, 5.9, 2.0 Hz); 13C NMR (150 MHz, CDCl3)
ꢂ 21.1 (CH3), 21.3 (CH3), 23.1 (CH2), 24.6 (CH3), 26.1 (CH),
27.5 (CH2), 27.7 (CH2), 29.6 (CH2), 36.1 (CH2), 39.9 (C), 42.7
(CH2), 46.1 (C), 46.4 (CH), 78.1 (CH), 131.2 (CH), 134.8 (CH),
139.6 (C), 141.7 (C); MS (EI) m=z 274 (Mþ), 259 (base), 241,
204, 191, 189, 175, 135, 105, 91; HRMS (EI) Found m=z
274.2293 (Mþ), C19H30O requires 274.2296.
References
1
a) Y. Asakawa, Chemical Constituents of Hepaticae, in
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B. B. Snider, G. B. Philiips, J. Org. Chem. 1983, 48, 3685.
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Synthesis of 45.
To a stirred solution of 4422 (14.3 mg,
0.033 mmol) in degassed CH2Cl2 (25 mL) was added a solution
of [DHImRu] (6.2 mg, 0.0073 mmol) in degassed CH2Cl2 (8 mL),
and the mixture was refluxed overnight. The solvent was evaporat-
ed, and the residue was purified by silica-gel column chromatog-
raphy (hexane:EtOAc = 100:0–95:5) to afford 45 (11.6 mg,
87%); 1H NMR (300 MHz, CDCl3) ꢂ 0.58 (6H, q, J ¼ 7:9 Hz),
0.83 (3H, s), 0.92 (3H, d, J ¼ 6:9 Hz), 0.95 (3H, d, J ¼ 6:9 Hz),
0.96 (9H, t, J ¼ 7:9 Hz), 1.01 (3H, s), 1.16–1.57 (9H, m), 1.71
(3H, s), 1.76–1.88 (1H, m), 2.05–2.27 (3H, m), 2.59 (1H, sep,
J ¼ 6:8 Hz), 4.12 (1H, d, J ¼ 3:9 Hz), 5.28 (1H, br s); MS (EI)
m=z 402 (Mþ), 211 (base), 190, 175, 115, 103.
5
a) From Anastrophyllum minutum: J. Beyer, H. Becker, M.
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6
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7
7310.
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P. Schwab, R. H. Grubbs, J. W. Ziller, J. Am. Chem. Soc.
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Synthesis of 46. A solution of 45 (11.6 mg, 0.029 mmol) in
THF (2 mL) was added TBAF (1.0 M in THF, 0.043 mL, 0.043
mmol), and the mixture was stirred overnight. Water was added,
and the solvent was evaporated. The residue was extracted with
ether, and the organic layer was washed with sat. NaCl aq, and
dried (MgSO4). The solvent was evaporated to give a residue.
The residue was purified by silica-gel column chromatography
(hexane:EtOAc = 100:0–94:6) to afford 46 (5.6 mg, 68%); FTIR
Tetrahedron Lett. 1999, 40, 2247.
a) J. G. Urones, I. S. Marcos, N. M. Garrido, J. De Pascal
9
Teresa, A. S. F. Martın, Phytochemistry 1989, 28, 183. b) I. S.
´
Marcos, I. M. Oliva, D. Dıez, P. Basabe, A. M. Lithgow, R. F.
´
Moro, N. M. Garrido, J. G. Urones, Tetrahedron 1995, 51,
´
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3440, 1450 cmꢁ1 1H NMR (600 MHz, CDCl3) ꢂ 0.90 (3H, s),
;
0.93 (3H, d, J ¼ 6:9 Hz), 0.96 (3H, d, J ¼ 6:9 Hz), 1.02 (3H, s),
1.25–1.30 (2H, m), 1.38 (1H, td, J ¼ 13:7, 4.1 Hz), 1.47 (1H, td,
J ¼ 15:6, 9.1 Hz), 1.53–1.56 (2H, m), 1.67 (1H, dd, J ¼ 11:7,
6.9 Hz), 1.67 (1H, ddd, J ¼ 12:4, 2.4, 1.8 Hz), 1.76 (3H, t, J ¼
1:5 Hz), 1.81 (1H, td, J ¼ 13:8, 4.1 Hz), 1.88 (1H, ddt, J ¼
14:4, 6.0, 1.6 Hz), 2.11 (1H, dd, J ¼ 15:6, 9.1 Hz), 2.17 (1H, dd,
J ¼ 14:1, 12.2 Hz), 2.22 (1H, ddd, J ¼ 15:3, 10.8, 6.9 Hz), 2.29
(1H, dd, J ¼ 12:9, 3.3 Hz), 2.63 (1H, sep, J ¼ 6:8 Hz), 4.19
(1H, d, J ¼ 3:8 Hz), 5.31 (1H, sep, J ¼ 1:6 Hz); 13C NMR (150
MHz, CDCl3) ꢂ 21.2 (CH3), 21.3 (CH3), 23.0 (CH2), 24.5
(CH3), 24.7 (CH3), 26.1 (CH), 26.3 (CH3), 27.5 (CH2), 29.2
(CH2), 33.2 (CH2), 36.0 (CH2), 40.0 (C), 42.7 (CH2), 46.1 (C),
14 M. Toyota, E. Nakaishi, Y. Asakawa, Phytochemistry

1962 Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006)
Preparation of Seven-Membered Carbocycles
1996, 43, 1057.
15 M. Tori, N. Toyoda, M. Sono, J. Org. Chem. 1998, 63,
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16 A. Furstner, A. F. Hill, M. Liebl, J. D. E. T. Wilton-Ely,
Chem. Commun. 1999, 601.
17 Both compounds 11 and 12 afforded the same dimethyl
1,1-cycloheptanedicarboxylate on hydrogenation.22 cf. G. L.
Buchanan, A. C. W. Curran, J. M. McCrae, G. W. McLay, Tetra-
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21 Similar to hydrindane systems, the S-stereoisomer is
always predominated. cf. a) R. Tavares, T. Randoux, J. C.
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S. Lin, J. Am. Chem. Soc. 1996, 118, 8765. c) W. S. Johnson,
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18 The absolute configuration of ketone 17 was determined by
the CD spectrum (see Ref. 4 and references cited therein).
19 Y. M. Ahn, K. L. Yang, G. I. George, Org. Lett. 2001, 3,
1411.
22 See the Supporting Information.
23 K. Nakashima, S. Okamoto, M. Sono, M. Tori, Molecule
2004, 9, 541.