Synthesis of bicyclo[4.2.0]octan-2-ol, a substructure of solanoeclepin A

Article abstract of DOI:10.1016/j.tetlet.2011.01.152

A sesterterpenoid solanoeclepin A (1) has a unique structure including a bicyclo[4.2.0]octane substructure, for which a new synthetic methodology is explored particularly to cyclize functionalized cyclobutane rings. An optically active (R)-carvone and a racemic cyclohexenone were each converted into the respective epoxyvinylsulfones, and then subjected to the heteroatom-directed conjugate addition (HADCA) by a lithium acetylide nucleophile. The intermediate carbanions from HADCA were used for the following epoxide opening reaction yielding the four-membered carbocyclic products.

Full text of DOI:10.1016/j.tetlet.2011.01.152

Tetrahedron Letters 52 (2011) 1847–1850
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Tetrahedron Letters
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Synthesis of bicyclo[4.2.0]octan-2-ol, a substructure of solanoeclepin A
⇑
Minoru Isobe , Supaporn Niyomchon, Chia-Yi Cheng, Anuch Hasakunpaisarn
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A sesterterpenoid solanoeclepin A (1) has a unique structure including a bicyclo[4.2.0]octane substruc-
ture, for which a new synthetic methodology is explored particularly to cyclize functionalized cyclobu-
tane rings. An optically active (R)-carvone and a racemic cyclohexenone were each converted into the
respective epoxyvinylsulfones, and then subjected to the heteroatom-directed conjugate addition (HAD-
CA) by a lithium acetylide nucleophile. The intermediate carbanions from HADCA were used for the fol-
lowing epoxide opening reaction yielding the four-membered carbocyclic products.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 5 January 2011
Revised 31 January 2011
Accepted 31 January 2011
Available online 13 February 2011
Synthesis of natural products allows us to confirm the stereo
structure and the biological activity of these compounds particu-
larly when they are only available in a trace amount from nature.
In the case that a target compound would contain such a substruc-
ture as a functionalized cyclobutane ring, the methodologies are
limited, so that a new methodology be explored. We became inter-
ested in the synthesis of solanoeclepin A (1), which was isolated in
a small quantity (0.245 mg) from a large amount (ca. 1000) of po-
tato plants cultivation, showing a hatching-stimulant activity to-
ward the potato cyst nematodes, Globodera rostochiensis and G.
pallida. Its structure contains 3, 4, 5, 6, and 7 membered rings with
two bicyclic substructures as demonstrated by Shenk in 1999 from
X-ray crystallographic analysis.1 At the time, the absolute configu-
ration of structure 1 was not determined and was only assumed to
be the same as glycinoeclepin A 2, having similar hatching-stimu-
lant activity to soybean cyst nematodes.2 Since then, it has been
receiving the attention of the synthetic organic chemistry commu-
nity.3–12 Very recently Tanino and his colleagues have achieved the
first total synthesis of 1, confirming its absolute stereochemistry
(Fig. 1).13
When we selected solanoeclepin A 1 as the synthetic target
molecule, we first focused on developing a new methodology
applicable for the synthesis of cyclobutane substructure having
multiple functional groups. The retrosynthetic analysis can bisect
1 by disconnecting the seven-membered carbocyclic B-ring into
two segments; 3 oxabicyclo[2.2.1]-heptanone12 and 4 having a
cyclobutane moiety (Scheme 1). In this retrosynthesis, segment 4
was further simplified into the tricyclic compound 5, in which
the bicyclo[2.1.1]hexane substructure could be constructed
through a ring cyclization to form a cyclopentane starting from 6
having a bicyclo[4.2.0]octane substructure (Scheme 1). We have
reported the synthesis of 3,12 and some results for the formation
of cyclobutane by exploiting the heteroatom-directed conjugate
H
CO2H
OH
Me
Me
Me
HO
Me
E
CO2H
O
C
AO
O
D
H
B
O
O
CO2H
HO
O
Me Me
Me Me
OMe
2
1
Figure 1. Solanoeclepin A and Glycinoeclepin A, nematode hatching-stimulant.
H
CO2H
H
OR
RO
Me
AO
X
+
1
C
D
OH
O
Y
X
4
3
HO
OR"
COOH
R'
R'
R"
SO2Ph
C
D
SO2Ph
R
OH
R
HO
6
5
Scheme 1. Retrosynthesis of Solanoeclepin A 1 and simplified design of cyclobu-
tane ring formation model study.
addition (HADCA).14,15 In this paper, we report the synthesis with
a high stereochemical control of more advanced intermediates 6
having the bicyclo[4.2.0]octane moiety.
Our construction of the bicyclo[4.2.0]octane from heteroatom-
directed conjugate addition (HADCA) showcases the synthesis of
compounds having multifunctionalized cyclobutyl group using this
strategy (Scheme 2). The plan is to add lithium acetylide nucleo-
phile to epoxyvinylsulfone 7 by HADCA as shown in Scheme 2.
The first step is chelation of the lithium acetylide nucleophile with
a
- and/or b-oxygen atom(s) which accelerates nucleophilic addi-
⇑
Corresponding author.
E-mail address: minoru@mx.nthu.edu.tw (M. Isobe).
tion via
a
- or b-chelation effects.16 The resulting intermediate
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.152

1848
M. Isobe et al. / Tetrahedron Letters 52 (2011) 1847–1850
SiMe3
R4
H
R1O
H
R1O
O
H
PhMe2Si
SiR3
Nucleophile
Li
R4
3
8
3 eq. TBAF
O
HO
X
X
12
SO2Ph
R2 SiR3
9
SO2Ph
2
5
7
Me
H
1
3
4
R2
Me
H
-78 °C ~ -20 °C
8 h, 79%
9
6C 11 SO2Ph
3
α-chelation
7
SO2Ph
OH
Nu
R1O
O
MeH
MeH
SiR3
SiMe3
HO
10
16
3
HO
PhMe2Si
epoxide
opening
17
HMBC between H11 and C6
X
SO2Ph
R2
O
HADCA
Me
H
8
p-NO2C6H4COOH
DCC, DMAP, CH 2Cl2
β-chelation
SO2Ph
16
Me
H
O
Scheme 2. HADCA leading to cyclobutane ring formation.
81%
NO2
O
18 mp 162 °C
PhS
H
Scheme 4. Conversion of 16 to crystalline compound 18.
(1.3 eq.)
H2O2, NaOH
MeOH, 0 °C
Me 1 h, 96%
O
O
Me
Me
nBuLi (1.5 eq.)
-78° C (3 h) ~ 0 °C
(12 h) THF
of 12 was achieved in hot dichloroethane in the presence of dim-
ethylphenylsilane and 10 mol % biscobalthexacarbonyl catalyst 13
to afford vinylsulfide in 69% yield. It was subsequently oxidized
with 75% mCPBA at 0 °C to afford epoxyvinylsulfone 14 in 28%
yield, together with a minor isomer 14a (for details see in SI S5–
7) in 13% yield in two steps, respectively (Scheme 3).
Next, the addition of lithium trimethylsilylacetylide to 14 was
examined under various conditions, and the results are summa-
rized in Table 1. The lithium acetylide was first generated with Me-
LiÁLiBr complex at À40 °C. A THF solution of 14 was cooled down to
À78 °C, and then acetylide was added and stirred for 1 h at this
temperature. The temperature was then gradually raised to 0 °C
over a few hours to give acetylene adduct 15 in 65% yield (entry
1). When the similarly prepared reaction mixture using 2 equiv
of MeLiÁLiBr at À78 °C and then at 25 °C was further heated to
60 °C, the cyclobutane compound was obtained in 20% yield (entry
2). Epoxide opening was found to take place slowly only at higher
temperatures and not at room temperature.
Me
O
10
HO
11
(1)
OH
Co2(CO)6
13 (10 mol%)
SPh
H
HO
SiMe2Ph
Me
Me
PhMe2SiH (5.0 eq.)
dichloroethane, 50 °C, 3 h
(2) mCPBA (2.5 eq.)
DCM, 0 °C, 1 h
SO2Ph
Me
Me
O
O
12 (78%)
14 (28%)
Scheme 3. Epoxyvinylsulfone 14 synthesis from (R)-Carvone 10.
anion 8 is a second nucleophile for opening the epoxide ring to
yield the cyclobutane compound as 9. For this synthetic plan, we
describe two examples in chiral and racemic cases.
A commercially available monoterpene (R)-carvone 10 was em-
ployed as a starting material for epoxyvinylsulfone 14. Enone 10
was first treated with 35% hydrogen peroxide and 2 M sodium
hydroxide as a basic catalyst in methanol to give the a-epoxy-ke-
To facilitate the epoxide opening, we tried adding 0.5 equiv
BF3ÁOEt2 as a Lewis acid to the lithium acetylide, but this resulted
in many products (entry 3). However, a similar treatment with
0.7 equiv BF3ÁTHF yielded cyclobutane product 16 in 12% yield, to-
gether with the simple addition product 15 in 41% yield (entry 4).
tone 11 selectively in 96% yield. Subsequently, lithium phenylthio-
acetylide was added to 11 at À78 °C then the temperature was
raised to 0 °C to provide b-acetylenyl adduct 12 in 78% yield, two
isomers (12a and 12b, for details see in SI S4–5) in 6% and 5%
yields, respectively. The hydrosilylation17 of the acetylene moiety
Table 1
Lithium acetylide addition to 14 and/or epoxide opening
SiMe3
H
SiMe3
PhMe2Si
O
H
SiMe3
HO
O
.
MeLi LiBr
SiMe2Ph
Me
H
Me
14
+
SO2Ph
Lewis acid
THF
SO2Ph
Me
MeH
HO
16
15
Entry
Nucleophile
SiMe3
Lewis acidd (equiv)
Temp. (°C)
Time (h)
Products yield (%)
H
MeLiÁLiBr
5 equiv
2 equiv
1a
2c
5 equiv
5 equiv
—
—
À78 °C to 0 °C
7
1
5
32
30
15b:65% (>95:5)
16:20%
À78 °C to À20 °C
Then to 60 °C
À78 °C to 60 °C
À78 °C to rt
3a
4a
5 equiv
5 equiv
5 equiv
5 equiv
BF3ÁOEt2 (0.5)
BF3ÁTHF (0.7)
Messy
15:41%
16:12%
15:30%
16:10%
15:86%
15:50%
16:8%
5a
5 equiv
5 equiv
BF3ÁTHF (0.7)
À78 °C to 60 °C
30
6a
7a
5 equiv
5 equiv
10 equiv
ZnCl2 (0.5)
BF3ÁTHF (1.4)
À78 °C to 60 °C
À78 °C to rt
30
24
10 equiv
a
b
c
The trimethylsilylacetylene was deprotonated with MeLiÁLiBr at À40 °C for 1 h.
Isolated yields after column chromatography; the ratios were determined by 1H NMR.
The trimethylsilylacetylene was deprotonated with MeLiÁLiBr at À78 °C for 1 h.
The Lewis acid was added to the mixture solution at 0 °C.
d

M. Isobe et al. / Tetrahedron Letters 52 (2011) 1847–1850
1849
BF3ÁTHF (entry 7). When we utilized ZnCl2 as a Lewis acid, this gave
only the major addition product 15 in 86% yield without any for-
mation of the cyclobutane product 16 (entry 6).
The cyclobutane compound 16 showed HMBC-correlation be-
tween H-11 and C-6 to indicate the cyclobutane ring formation
(Scheme 4). The structure was further proven though desilylation
to 17 and p-nitrobenzoylation, yielding a crystalline material 18
(mp 162 °C), which was analyzed by X-ray crystallography to the
structure as shown in Figure 2.
Judging from the structure 16 having the phenyldimethylsilyl
group at the tert-hydroxy group, the intermediate after HADCA
must be a dianion which underwent the Brook rearrangement.18
This anion may be too reactive to undergo cyclobutane formation,
causing side reactions such as deprotonation of the epoxide proton.
To prevent the formation of the dianion, it was decided that we
would examine a substrate that had C1 alcohol protected as methyl
ether. The desired epoxyvinylsulfone 23 was synthesized from
cyclohexenone as shown in Scheme 5. The addition of the lithium
phenylthioacetylide to 19 was followed by O-methylation with MeI
to give 20. Cobalt-catalyzed hydrosilylation with 13 and subse-
quent oxidation afforded the vinylsulfone 21. Epoxidation of this
vinylsulfone with mCPBA gave us a single epoxide, which was anti
to OMe.19 The alternative syn epoxide 23 was indirectly prepared
via bromohydrin 22. Thus, the treatment of 21 with N-bromosuc-
cinimide (NBS) in dimethylsulfoxide (DMSO) containing 10%
water20 provided largely 22 in 58% yield together with its stereo-
isomer (see SI). Further the treatment of 22 with sodium hydride
yielded epoxyvinylsulfone 23 possessing the epoxide syn to the
OMe group.
HADCA by lithium trimethylsilylacetylide to 23 was first stud-
ied to determine the diastereoisomer ratio of the primary addition
products (24 and 25) by quenching the reaction mixture at À78 °C.
However, these products were not separable even after desilyltion
by TBAF. So we further continued with cyclobutane formation un-
der the conditions as summarized in Table 2. Acetylide was gener-
ated from ethynyltrimethylsilane by the treatment with MeLiÁLiBr
at À78 °C in THF. The addition of this nucleophile to 23 was imple-
mented in THF at À78 °C for 1 h and then the reaction mixture was
raised to 0 °C and further raised to room temperature to provide
cyclobutane compound 26. This cyclobutane product was obtained
in 54% yield as a crystalline material (entry 1).
Figure 2. ORTEP of the crystal structure of cyclobutane 18.
SPh
(1)
PhS
nBuLi, THF,
-78 °C, 87%
H
MeO
(1)
OH
Co2(CO)6
O
13
(2) MeI, NaH, THF,
0 °C ~ rt, 80%
Et3SiH, 60 °C;
(2) mCPBA, CH2Cl2,
0 °C, 71% (2 steps)
20
19
H
NBS,
MeO
OH
H
MeO
SiEt3
DMSO, H2O
NaH, THF
SiEt3
SO2Ph
0 °C ~ rt, 89%
0 °C ~ rt,
bromohydrin 58%
(isomer 14%)
SO2Ph
Br
22
21
H
MeO
MeO
MeO
H
SiMe3
SiEt3
SO2Ph
or
SO2Ph
SO2Ph
1) MeLi•LiBr,
THF, -78 °C
2) TBAF
O
O
O
24
25
23
Scheme 5. Synthesis of racemic epoxyvinylsulfone 23.
In order to facilitate the epoxide opening from the intermediate
carbanion after the HADCA, BF3ÁOEt2 was further added to this
reaction mixture at À40 °C and the temperature was gradually
raised to room temperature (entry 2). It afforded two cyclobutane
products, which were separated by silica gel column chromatogra-
phy to give crystalline 26 in 71% and 27 in 14%. When the acetylide
After the reaction temperature was raised to 60 °C, the yields of 15
and 16 slightly decreased to 30% and 10%, respectively (entry 5).
There was no clear enhancement of the cyclobutane yield by the
use of Lewis acid, even when we employed double the amount of
Table 2
Acetylide addition to 23 to afford cyclobutane compounds
SiMe3
SiMe3
+
MeO
MeO
H
H
Li
SiMe3
23
SiEt3
SO2Ph
H
SO2Ph
H
SiEt3
OH
OH
27
26
Entry
Nucleophile
SiMe3 Base
Additive
Temp. (°C)
Time (h)
Products yield (%)
H
1a
2a
1.5 equiv
10 equiv
MeLiÁLiBr (1.35 equiv)
MeLiÁLiBr (9.5 equiv)
—
À78 to 30
À78 to 30
6
7
26:54%
26:71%
27:14%
26:75%
b
BF3ÁOEt2
3c
5.5 equiv
MeLi (5.0 equiv)
NaBr:LiBr (1:5)
À40 to 22
7
a
b
c
Solvent in THF and ether (from MeLiÁLiBr).
The BF3ÁOEt2 was added to the mixture solution at À40 °C.
Solvent in n-hexane and ether (from MeLi). (see SI S16–S18).

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M. Isobe et al. / Tetrahedron Letters 52 (2011) 1847–1850
carbanion intermediates, which further reacted intramolecularly to
open the epoxide ring to produce cyclobutane products 16, 26, and
27. Further synthetic studies toward solanoeclepin A are now un-
der way along this line in our laboratory.
Acknowledgments
We acknowledge the National Science Council, and National
Tsing Hua University, Taiwan for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.152.
References and notes
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Figure 3. ORTEP of the crystal structure of cyclobutane 26.
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was generated in a mixed solvent of n-hexane–Et2O at À20 °C, and
reacted with 23 at À40 °C, the product was 26 (entry 3). The X-ray
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