A method for synthesis of bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones with one-carbon ring expansion and its application to a formal synthesis of racemic 1-desoxyhypnophilin

Article abstract of DOI:10.1016/j.tet.2007.03.019

A method for synthesis of 2-cyanobicyclo[3.3.0]oct-1-en-3-ones and 2-substituted bicyclo[3.3.0]oct-1-en-3-ones was developed by assembly of three components, cyclobutanones, chloromethyl p-tolyl sulfoxide, and nitriles, with one-carbon ring expansion of t

Full text of DOI:10.1016/j.tet.2007.03.019

Tetrahedron 63 (2007) 3953–3963
A method for synthesis of bicyclo[3.3.0]oct-1-en-3-ones from
cyclobutanones with one-carbon ring expansion and its application
to a formal synthesis of racemic 1-desoxyhypnophilin
*
Hiroaki Kashima, Tadashi Kawashima, Daisuke Wakasugi and Tsuyoshi Satoh
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-funagawara-machi 12,
Shinjuku-ku, Tokyo 162-0826, Japan
Received 7 February 2007; revised 5 March 2007; accepted 5 March 2007
Available online 7 March 2007
Abstract—A method for synthesis of 2-cyanobicyclo[3.3.0]oct-1-en-3-ones and 2-substituted bicyclo[3.3.0]oct-1-en-3-ones was developed
by assembly of three components, cyclobutanones, chloromethyl p-tolyl sulfoxide, and nitriles, with one-carbon ring expansion of the
cyclobutane ring. As an application of this method, a formal synthesis of 1-desoxyhypnophilin in racemic form was performed starting
from 3,3-di(phenylthiomethyl)cyclobutanone.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
chlorovinyl p-tolyl sulfoxides with nitriles.9 In continuation
of our investigation of this chemistry we found that when
cyclobutanones were used as the cyclic ketones in this proce-
dure, bicyclo[3.3.0]oct-1-en-3-ones could be synthesized.10
In this paper we describe, in detail, this chemistry and an
application of this methodology to a formal synthesis of
racemic 1-desoxyhypnophilin.
To date, numerous natural products containing fused five-
membered rings have been isolated and they are called
polyquinane natural products. The natural products contain-
ing three five-membered rings are triquinanes and they are
classified into two categories, linear triquinanes and angular
triquinanes.1 Both triquinanes contain a bicyclo[3.3.0]octane
ring as the basic skeletal structure. The unique structure and
promising biological activities of triquinanes have stimu-
lated biochemists and organic chemists for a long time,
and enormous efforts were made for the chemical synthesis
of these compounds.2
The essence of the chemistry described hereafter is as
follows (Scheme 1). Thus, 1-chlorovinyl p-tolyl sulfoxides
1 are synthesized starting from cyclobutanones and chloro-
methyl p-tolyl sulfoxide in three steps in high overall yields.
Reaction of vinyl sulfoxides 1 with excess cyanomethyl-
lithium results in spiro-type enaminonitrile 2. Treatment of
2 with acid under heating gives 2-cyanobicyclo[3.3.0]oct-
1-en-3-one 3. On the other hand, treatment of the vinyl sulf-
oxides 1 with cyanomethyllithium followed by lithium
a-carbanion of nitriles affords enaminonitriles 4. Heating
of 4 with acid gives 2-substituted bicyclo[3.3.0]oct-1-en-
3-ones 5 in good yields. By using this method, linear
triquinane 7, an intermediate for the total synthesis of 1-
desoxyhypnophilin, is synthesized starting from 3,3-di-
(phenylthiomethyl)cyclobutanone 6 in good yield.
As for the synthesis of the bicyclo[3.3.0]octane ring system,
various kinds of methods have appeared including aldol-type
annulation,3 Nazarov cyclization,4 and Pauson–Khand reac-
tion.5 Especially, asymmetric Pauson–Khand reaction is rec-
ognized to be quite promising for the synthesis of optically
active natural products.6 On the other hand, a few methods
for the construction of a fused five-membered ring by ring
expansion of cyclobutane derivatives have been reported.7
Wehavealso beeninterestedin thering-expansion reactions.8
Recently, we reported a new method for synthesis of spiro-
type 2-cyclopentenones from cyclic ketones through 1-
2. Results and discussion
2.1. Synthesis of 2-cyanobicyclo[3.3.0]oct-1-en-3-one
from cyclobutanone and its reactions
Keywords: 2-Cyanobicyclo[3.3.0]oct-1-en-3-one; 2-Substituted bi-
cyclo[3.3.0]oct-1-en-3-one; Cyclobutanone; One-carbon ring expansion;
1-Desoxyhypnophilin.
First, [chloro(p-tolylsulfinyl)methylidene]cyclobutane
was synthesized starting from cyclobutanone and
8
* Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261 4631;
e-mail: tsatoh@rs.kagu.tus.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.019

3954
H. Kashima et al. / Tetrahedron 63 (2007) 3953–3963
CN
CN
NH2
H+
R
R
TolS(O)CH2Cl
R
R
R
R
S(O)Tol
Cl
R
R
LiCH2CN
O
O
heating
2
3
1
CN
R'
NH2
R'
H+
heating
1) LiCH2CN
R
R
R
R
O
2) R'(Li)CH2CN
5
4
H
PhSCH2
PhSCH2
O
H
O
6
7
Scheme 1.
chloromethyl p-tolyl sulfoxide in three steps in 93% overall
yield.9 Vinyl sulfoxide 8 was treated with 5 equiv of cyano-
methyllithium in THF to give the expected enaminonitrile 9
in 91% yield.9 Finally, enaminonitrile 9 was heated with
H3PO4 in acetic acid containing water for 1 h to give a clean
reaction mixture from which a cyclopentenone derivative
was obtained in quantitative yield (Scheme 2).
give bicyclo[3.3.0]octenol 15. Tautomerization of the enol
portion of 15 finally gives 10. The simple acid treatment of
9 created bicyclo[3.3.0]octane derivative 10 and it is thought
that the strained four-membered ring eventually provides the
driving force for the skeletal rearrangement.
CN
CN
H+
H
NH2
O
H3PO4
TolS(O)CH2Cl
3 steps, 93%
LiCH2CN (5 eq)
91%
S(O)Tol
Cl
AcOH-H2O
O
9
14
8
CN
CN
CN
CN
NH2
H3PO4
O
O
OH
O
O
AcOH-H2O
reflux, 1 h, 99%
15
10
9
11
10
Scheme 3. A plausible mechanism for the formation of 10 from enamino-
nitrile 9 by the acid treatment.
CN
H
H
H3PO4
H2 / Pd-C
10
O
The product, 2-cyanobicyclo[3.3.0]oct-1-en-3-one, 10 is
a quite interesting compound as starting material for the
synthesis of polyquinane natural products. We tried some
reactions on carbons 1–3 of 10 and the results are summa-
rized in Scheme 4. Thus, TBDMSO-Tf-promoted conjugate
addition of 10 and organocuprate prepared from PhMgBr
and copper(I) iodide gave quantitative yield of the corre-
sponding silyl enol ether having a phenyl group at the angu-
lar position in 16.12 This intermediate was treated with
methyllithium followed by allyl iodide to give 17 in 65%
overall yield from 10.
AcOH-H2O
reflux, 20 h
H
H
13
12
Scheme 2.
Initially, we anticipated that the product would be spiro-
[3.4]alkenone 11 on the basis of our experience.9 However,
the product has a cyano group and the structure of the prod-
uct 10 was presumed to be 2-cyanobicyclo[3.3.0]oct-1-en-3-
one judging from 1H and 13C NMR. In order to confirm the
skeletal structure of 10, the product was hydrogenated to
ketone 12 followed by hydrolysis and decarboxylation to
give a known cyclopentanone derivative 13. Spectral data
for the product 13 were found to be in agreement with those
reported for bicyclo[3.3.0]octan-3-one 13.11
On the other hand, treatment of 12 with bromoacetone in the
presence of sodium hydride in THF resulted in the formation
of a cyanocyclopentanone derivative bearing a 2-oxopropyl
group at the 2-position of 18, which is a good precursor for
synthesis of linear triquinane, in good yield. Treatment of 10
with PhMgBr without a copper catalyst resulted in the
formation of 1,2-adduct 19 in good yield.
A plausible mechanism for the formation of 10 from enami-
nonitrile 9 by the acid treatment is shown in Scheme 3. Thus,
acidic hydrolysis of the enamine function of 9 gives enone
14. Protonation of the carbonyl oxygen of enone 14 followed
by rearrangement of a bond of the cyclobutane ring would
In order to investigate the generality of this reaction, two
cyclobutanone derivatives 21a and 21b were synthesized

H. Kashima et al. / Tetrahedron 63 (2007) 3953–3963
3955
applied to 1-chlorovinyl p-tolyl sulfoxide 8 and very inter-
esting results were obtained as shown in Table 1.
CN
CN
Ph
Ph
b
OTBDMS
O
Thus, 1-chlorovinyl p-tolyl sulfoxide 8 was treated with
3 equiv of cyanomethyllithium in THF at ꢀ78 ꢁC for
10 min to afford adduct 25 in 95% yield. Adduct 25 was
then treated with LDA in THF (lithium a-sulfinyl carbanion
of 25 was generated) at ꢀ78 ꢁC and to this reaction mixture
was added slowly a THF solution of 7 equiv of lithium
a-carbanion of phenylacetonitrile (entry 1 in Table 1). The
reaction mixture was slowly allowed to warm to ꢀ40 ꢁC to
give the desired enaminonitrile 26a in 78% yield. Finally,
enaminonitrile 26a was heated under the conditions de-
scribed above to afford the product in 99% yield.
H
H
17
16
a
O
CN
2
CN
H
1
c
12
3 O
O
H
H
18
10
d
CN
Quite surprisingly, the obtained compound was not the
expected 2-cyano-4-phenylbicyclo[3.3.0]oct-1-en-3-one but
2-phenylbicyclo[3.3.0]oct-1-en-3-one 27a. Spectral data
for the product 27a were in good agreement with those
reported for 2-phenylbicyclo[3.3.0]oct-1-en-3-one.15
OH
Ph
H
19
Scheme 4. Some reactions at carbons 1–3 of 10. Reagents and yields:
(a) PhMgBr, CuI, TBDMSO-Tf; (b) CH3Li, allyl iodide, THF, 65% from
10; (c) BrCH2COCH3, NaH, THF, 79%; (d) PhMgBr, THF, 88%.
A plausible mechanism for the formation of 27a from enami-
nonitrile 26a by heating with acid is as follows (Scheme 6).
First, the acidic hydrolysis of the enamine portion of 26a
gives enone 28. The ring expansion of the cyclobutane
ring would take place as described above (see Scheme 3)
to give 2-cyano-4-phenylbicyclo[3.3.0]oct-1-en-3-one 29.
Migration of the double bond in 29 occurs under the
acidic conditions to afford 30. Finally, the cyano group
is hydrolyzed followed by decarboxylation to afford the
product 27a.
from reported cyclobutanol derivative 20, which was derived
starting from benzyl bromide and epichlorohydrin.13 The
results are summarized in Scheme 5. 1-Chlorovinyl p-tolyl
sulfoxides 22a and 22b were obtained from the ketones
21a and 21b, respectively, in high overall yields by the
same procedure as described above without any problem.
Treatment of 22a and 22b with 5 equiv of cyanomethyl-
lithium afforded the desired enaminonitriles 23a and 23b
both in 84% yield. The acidic treatment of the enaminoni-
triles gave the 7,7-disubstituted 2-cyanobicyclo[3.3.0]oct-1-
en-3-ones 24a and 24b in 66% and 62% yields, respectively.
In the case of the reaction with 23b, the acetal was hydro-
lyzed and the produced alcohol was acetylated to give
acetate 24b.
CN
CN
CN
H+
H
NH2
Ph
O
H3PO4
O
AcOH-H2O
Ph
Ph
26a
28
29
CN
hydrolysis and
decarboxylation
migration of
double bond
2.2. Synthesis of 2-substituted bicyclo[3.3.0]oct-1-en-3-
ones from cyclobutanone
O
O
Ph
Ph
Previously, we reported a novel method for synthesis of
2,4,4-trisubstituted 2-cyclopentenones from 1-chlorovinyl
p-tolyl sulfoxides by consecutive reaction with cyano-
methyllithium and its homologues.14 This methodology was
30
27a
Scheme 6. A plausible mechanism for the formation of 27a from enamino-
nitrile 26a by the acid treatment.
PhCH2Br
HOCH2
OCH2Ph
O
HOCH2
Lit. 13
ClH2C
20
CN
CN
EtOCH2
EtOCH2
NH2
NH2
EtOCH2
EtOCH2
EtOCH2
EtOCH2
EtOCH2
S(O)Tol
Cl
O
O
66%
62%
84%
84%
EtOCH2
24a
21a
23a
CN
22a
CN
AcO
AcO
O
O
O
O
O
O
S(O)Tol
Cl
O
O
22b
21b
23b
24b
Scheme 5. Synthesis of 2-cyanobicyclo[3.3.0]oct-1-en-3-ones 24a and 24b from cyclobutanones 21a and 21b.

3956
H. Kashima et al. / Tetrahedron 63 (2007) 3953–3963
Table 1. Synthesis of 2-substituted bicyclo[3.3.0]oct-1-en-3-one 27 from vinyl sulfoxide 8 with cyanomethyllithium and its homologues through enamino-
nitrile 26
3 eq. LiCH2CN
CN
Cl
1) LDA
S(O)Tol
2) 7 eq. R1C(Li)HCN
-78 ~ 0 °C
THF, -78 °C,
10 min, 95%
S(O)Tol
Cl
8
25
CN
NH2
R1
H3PO4, H2O
AcOH, reflux
O
R1
26
27
Entry
R1CH2CN
Enaminonitrile 26
Conditions for hydrolysis (h)
2-Substituted bicyclo[3.3.0]oct-1-en-3-one 27
R1
Yield %
Yield %
1
2
26a
78a
99
12
14
27a
27b
99
CH2CN
CH2CN
CH3CH2CN
26b
75
H3CO
H3CO
3
4
5
26c
26d
26e
97
95
64
65
85
50
27c
27d
27e
CH3
CH3(CH2)3
Ph3C
78
83
53
CH3(CH2)3CH2CN
Ph3CCH2CN
a
Conditions: ꢀ78 to ꢀ40 ꢁC and ꢀ40 ꢁC for 1.5 h.
Because the product 27a and its congeners are thought to be
very important compounds for synthesis of polyquinanes, we
investigated the generality of this reaction using a variety of
nitriles and the results are summarized in Table 1. The reac-
tion using 4-methoxyphenylacetonitrile also gave the enone
having an aryl group at 2-position of 27b in good overall
yield from 25 (entry 2). Entries 3 and 4 show that both the
methyl group and the long alkyl group can be introduced
at the 2-position of the enone in good overall yields. Interest-
ingly, it was found that the enaminonitriles having alkyl
groups need much longer time for the hydrolysis compared
with those having aryl groups. Avery bulky triphenylmethyl
group can be placed at the 2-position by this method though
the overall yield was not satisfactory (entry 5).
mentioned above, gave rather complex mixture and the
desired enaminonitrile 35 was obtained in only 45% yield.
This problem was overcome by direct treatment of 34 with
excess lithium a-carbanion of propionitrile to give the
desired 35 in 91% yield.
The acidic treatment of 35 was found to be sluggish; how-
ever, the desired 2-methylbicyclo[3.3.0]oct-1-en-3-one 36
was obtained in 73% yield after 132 h heating. Both the
double bond and the sulfide groups were reduced with
Raney-Ni in ethanol to give 2,7,7-trimethylbicyclo[3.3.0]-
octan-2-one 37 in 77% yield. Allylation of 37 was performed
with allyl iodide in THF using NaH as a base17 to afford 38
as a single isomer in 67% yield.
2.3. A formal synthesis of desoxyhypnophilin
The terminal olefin in 38 was oxidized to a methyl ketone 39
employing Tsuji’s procedure.18 Aldol reaction of the dike-
tone 39 with potassium tert-butoxide19 afforded the desired
triquinane 7 in 77% overall yield. All spectral data for the
product 7 were highly consistent with those reported for tri-
quinane 7.20 Harrowven et al. reported the first total synthe-
sis of racemic 1-desoxyhypnophilin from 7 in two steps.20
Finally, we applied our above-mentioned method for synthe-
sis of 2-substituted bicyclo[3.3.0]oct-1-en-3-one to a formal
total synthesis of desoxyhypnophilin and the results are sum-
marized in Scheme 7. We selected the reported cyclobutanol
derivative 20 as the starting material.
At first, both hydroxyl groups of 20 were converted to bissul-
fide 31 in quantitative yield by the conventional method. The
deprotection of the benzyl group of 31 by catalytic hydroge-
nation using Pd as catalyst did not work at all because of the
presence of the sulfur. Fortunately, removal of the benzyl
group was effective with TMSI as reported by Jung16 to af-
ford alcohol 32; however, the yield was not satisfactory. The
hydroxyl group of 32 was oxidized under Swern’s conditions
to give cyclobutanone 6 in quantitative yield.
In conclusion, a new method for synthesis of 2-cyanobicy-
clo[3.3.0]oct-1-en-3-ones and 2-substituted bicyclo[3.3.0]-
oct-1-en-3-ones was established from cyclobutanones with
one-carbon ring expansion. The developed method was
successfully applied to a formal total synthesis of 1-desoxy-
hypnophilin.
3. Experimental
3.1. General
Cyclobutanone 6 was converted to 1-chlorovinyl p-tolyl sulf-
oxide 33 in 93% overall yield without any problem in the
procedure described above. The addition reaction of cyano-
methyllithium to the vinyl sulfoxide 33 proceeded smoothly
to give adduct 34 in 94% yield. We encountered some prob-
lems in the next step. Treatment of 34 with LDA followed
by lithium a-carbanion of propionitrile, the procedure
All melting points were measured on Yanaco MP-S3
1
heated stage apparatus and were uncorrected. H and 13C
NMR spectra were taken with JEOL JNM A-500 or Bruker
DPX 400 and AV 600 spectrometer using CDCl3 solutions
with tetramethylsilane as an internal standard. Mass spectra

H. Kashima et al. / Tetrahedron 63 (2007) 3953–3963
3957
HOCH2
HOCH2
PhSCH2
PhSCH2
PhSCH2
PhSCH2
PhSSPh, n-Bu3P
TMSCl, NaI
Swern oxid.
99%
OCH2Ph
OCH2Ph
OH
THF, 99%
CH3CN, r.t., 56%
20
31
32
LiCH2CN
94%
10 eq CH3(Li)CHCN
PhSCH2
PhSCH2
PhSCH2
S(O)Tol
PhSCH2
PhSCH2
CH2CN
S(O)Tol
O
THF, -78 ~ -40 °C
1.5 h, 91%
3 steps
93%
PhSCH2
Cl
Cl
33
34
6
CN
H
NH2
CH3
PhSCH2
PhSCH2
H3PO4
PhSCH2
PhSCH2
Raney Ni
EtOH, 77%
NaH, allyl iodide
O
O
AcOH-H2O
reflux, 132 h, 73%
THF, 67%
H
36
35
37
H
H
H
H
H
O
PdCl2, CuCl
t-BuOK
O
O
O
t-BuOH
78%
DMF-H2O
99%
Lit. 19
O
O
H
H
H
38
39
7
Desoxyhypnophilin
Scheme 7. A formal synthesis of racemic desoxyhypnophilin from 3,3-di(phenylthiomethyl)cyclobutanone 6 via triquinane 7.
were measured on a Hitachi M-80 spectrometer. IR spectra
were recorded on Spectrum One series Fourier trans-
form infrared spectrometer using either NaCl plates or KBr
pellets. Column chromatography was performed with
silica gel (Kanto Chemical). In experiments requiring dry
reagents and solvents, THF was distilled from sodium-
benzophenone ketyl. Diisopropylamine and CH2Cl2 were
distilled from CaH2. Acetone was dried over CaSO4 and
distilled before use. All reactions involving air- or water-
sensitive compounds were routinely conducted in glass-
ware, which was flame-dried under a positive pressure of
argon.
n-BuLi in 94 mL of dry THF at 0 ꢁC. After 10 min, the reac-
tion was quenched by adding satd aq NH4Cl. The whole was
extracted with CHCl3 and the organic layer was washed once
with water. The organic layer was dried over MgSO4 and the
product was purified by silica gel flash column chromato-
graphy to give 8 (3.17 g; 99%) as colorless crystals; mp
82–83 ꢁC (AcOEt–hexane); IR (KBr) 2966, 2912, 1646,
1493, 1453, 1404, 1086, 1055 (SO), 1016, 882, 810,
1
529 cmꢀ1; H NMR d 2.10–2.24 (2H, m), 2.42 (3H, s),
2.80–2.93 (2H, m), 3.09–3.16 (1H, m), 3.21–3.28 (1H, m),
7.32 (2H, d, J¼8.0 Hz), 7.50 (2H, d, J¼8.0 Hz). MS m/z
(%) 240 (M+, 70), 225 (35), 223 (97), 187 (20), 139 (56),
123 (37), 105 (40), 91 (47), 65 (100). Calcd for C12H13ClOS:
M, 240.0375. Found: m/z 240.0383. Anal. Calcd for
C12H13ClOS: C, 59.87; H, 5.44; Cl, 14.73; S, 13.32%.
Found: C, 59.92; H, 5.51; Cl, 14.34; S, 13.27%.
3.1.1. [Chloro(p-tolylsulfinyl)methylidene]cyclobutane
(8). A solution of chloromethyl p-tolyl sulfoxide (3.19 g;
16.9 mmol) in dry THF (3 mL) was added dropwise to a so-
lution of LDA (16.9 mmol) in 25 mL of THF at ꢀ78 ꢁC. The
solution was stirred at ꢀ78 ꢁC for 10 min and then cyclo-
butanone (1.05 mL; 14.1 mmol) was added. The reaction
mixture was stirred for 20 min and the reaction was
quenched by satd aq NH4Cl. The whole was extracted with
CHCl3. The organic layer was washed once with water and
dried over MgSO4. The solvent was evaporated to leave
the adduct as colorless crystals. The crystals were filtered
and used without further purification.
3.1.2. 6-Aminospiro[3.4]octa-5,7-diene-5-carbonitrile
(9). Acetonitrile (0.166 mL; 3.18 mmol) was added to a solu-
tion of n-BuLi (3.12 mmol) in 7.5 mL of dry THF at ꢀ78 ꢁC
with stirring. The solution was stirred for 10 min and then
a solution of 8 (150 mg; 0.623 mmol) in 1.5 mL of dry
THF was added dropwise to this solution. The temperature
of the reaction mixture was gradually allowed to warm to
room temperature over 2 h and the reaction mixture was fur-
ther stirred at room temperature for 30 min. The reaction
was quenched by adding satd aq NH4Cl. The whole was ex-
tracted with CHCl3 and the organic layer was washed once
with water. The organic layer was dried over MgSO4 and
the product was isolated by silica gel flash column chroma-
tography to give 82.5 mg (91%) of 9 as colorless crystals;
mp 63–64 ꢁC (AcOEt–hexane); IR (KBr) 3441, 3349,
3233 (NH), 2930, 2175 (CN), 1642, 1606, 1539, 1428,
The adduct was dissolved in a mixture of acetic anhydride
(27 mL) and pyridine (57 mL). 4-Dimethylaminopyridine
(288 mg; 2.35 mmol) was added to the solution and the
reaction mixture was stirred at room temperature for 3 h.
The acetic anhydride and pyridine were evaporated under
vacuum and the residue was purified by silica gel column
chromatography to give an acetate (4.0 g; 94%).
1
767 cmꢀ1; H NMR d 1.96–2.05 (1H, m), 2.07–2.19 (3H,
To a solution of the acetate (4.0 g; 13.3 mmol) in 8 mL of dry
THF was added dropwise with stirring a solution of N-lithio-
2-piperidone (41.2 mmol), prepared from 2-piperidone and
m), 2.49–2.56 (2H, m), 4.53 (2H, br s, NH2), 5.97 (1H,
d, J¼5.5 Hz), 6.87 (1H, d, J¼5.5 Hz). MS m/z (%) 146
(M+, 40), 118 (100), 91 (18). Calcd for C9H10N2: M,

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H. Kashima et al. / Tetrahedron 63 (2007) 3953–3963
146.0844. Found: m/z 146.0849. Anal. Calcd for C9H10N2:
C, 73.94; H, 6.89; N, 19.16%. Found: C, 73.62; H, 6.89;
N, 18.74%.
iodide (64.7 mg; 0.340 mmol) in dry THF (0.7 mL) was
added phenylmagnesium bromide (0.23 mL of 3 M solution
in diethyl ether; 0.68 mmol) at 0 ꢁC. The suspension was
stirred for 1 h and 10 (20 mg; 0.136 mmol) in 0.8 mL of
dry THF followed by tert-butyldimethylsilyl trifluorometh-
anesulfonate (0.156 mL; 0.680 mmol) were added slowly to
the organocuprate suspension. The reaction mixture was
stirred for 2.5 h at 0 ꢁC and allowed to warm to room temper-
ature over 30 min. To the reaction mixture was added methyl-
lithium (0.15 mmol) at 0 ꢁC and the reaction mixture was
stirred for 30 min. Allyl iodide (0.062 mL; 0.680 mmol) and
hexamethylphosphoramide (0.243 mL; 0.136 mmol) were
added to the reaction mixture and the reaction mixture was
allowed to warm to room temperature and stirred overnight.
The reaction was quenched by adding satd aq NH4Cl and the
whole was extracted with CHCl3 and the organic layer was
washed with satd aq NH4Cl. The solvent was evaporated
under vacuum and the residue was purified by silica gel col-
umn chromatography to give 17 (23.5 mg; 65%) as a color-
less oil; IR (neat) 2926, 2856, 2205 (CN), 1627, 1494, 1447,
3.1.3. 2-Cyanobicyclo[3.3.0]oct-1-en-3-one (10). To a solu-
tion of 9 (300 mg; 2.05 mmol) in acetic acid (117 mL) were
added phosphoric acid (85%; 52 mL) and water (14 mL).
The reaction mixture was stirred and heated under reflux
for 1 h. The reaction mixture was neutralized with 10% aq
NaOH and the whole was extracted with CHCl3 and the or-
ganic layer was washed with brine. The organic layer was
dried over MgSO4 and the product was purified by silica
gel flash column chromatography to give 300 mg (99%) of
10 as a colorless oil; IR (neat) 2971, 2229 (CN), 1724
1
(CO), 1642, 1270, 1257 cmꢀ1; H NMR d 1.24–1.33 (1H,
m), 2.08–2.26 (3H, m), 2.29–2.34 (1H, m), 2.79–2.92 (3H,
m), 3.06–3.12 (1H, m); 13C NMR d 202.89 (C), 202.35
(C), 112.01 (C), 111.75 (C), 47.05 (CH), 41.69 (CH2),
30.68 (CH2), 27.39 (CH2), 25.15 (CH2). MS m/z (%) 147
(M+, 100), 119 (71), 104 (47), 91 (33), 81 (25), 79 (15).
1
1378, 1339, 1259, 1035, 977 cmꢀ1; H NMR d 1.51–1.57
3.1.4. 2-Cyanobicyclo[3.3.0]octan-3-one (12). To a solution
of 10 (450 mg; 3.06 mmol) in methanol (38 mL) was added
10% Pd on carbon (540 mg). The reaction mixture was
stirred at room temperature under H2 atmosphere (1 atm)
for 1 h. The suspension was filtered through a pad of Celite.
The filtrate was evaporated under reduced pressure to dry-
ness to afford 12 (446 mg, 99%) as a colorless oil (about
1:1 diastereomeric mixture); IR (neat) 2955, 2872, 2246
(CN), 2201 (CN), 1752 (CO), 1670, 1634, 1451, 1381,
(1H, m), 1.71–1.79 (1H, m), 1.80–1.88 (1H, m), 1.98–2.12
(2H, m), 2.24–2.27 (1H, m), 2.30 (1H, dd, J¼18.0,
2.0 Hz), 2.68 (1H, ddt, J¼9.0, 3.6, 2.0 Hz), 3.03 (1H, dd,
J¼18.0, 8.9 Hz), 4.79–4.87 (2H, m), 5.32 (1H, dq, J¼10.5,
1.3 Hz), 5.40 (1H, dq, J¼17.5, 1.5 Hz), 5.97 (1H, dq,
J¼17.3, 5.3 Hz), 7.21–7.24 (1H, m), 7.33, 7.34 (each 2H,
s); 13C NMR d 169.78 (C), 146.57 (C), 131.91 (CH),
128.50 (CH), 126.50 (CH), 125.98 (CH), 121.75 (C),
118.56 (CH2), 89.26 (C), 71.47 (CH2), 64.00 (C), 46.51
(CH), 40.78 (CH2), 38.06 (CH2), 36.20 (CH2), 25.65
(CH2). MS m/z (%) 265 (M+, 85), 236 (100), 224 (46), 196
(32), 182 (31), 167 (12), 154 (23), 141 (18), 127 (21), 115
(27). Calcd for C18H19NO: M, 265.1466. Found: m/z
265.1472.
1134 cmꢀ1
;
1H NMR d 1.40 (0.5H, sextet, J¼7.0 Hz),
1.51–1.60 (1H, m), 1.64–1.87 (1.5H, m), 1.99–2.07 (3H,
m), 2.30 (0.5H, dd, J¼19.3, 4.3 Hz), 2.65–2.84 (2.5H, m),
2.94–3.00 (1H, m), 3.05 (0.5H, d, J¼9.2 Hz), 3.63 (0.5H,
d, J¼8.9 Hz); 13C NMR d 207.20 (C), 207.15 (C), 116.71
(C), 115.89 (C), 45.40 (CH), 44.84 (CH), 44.76 (CH),
42.91 (CH2), 42.44 (CH2), 42.27 (CH), 38.16 (CH), 37.68
(CH), 33.36 (CH2), 32.83 (CH2), 31.78 (CH2), 29.81
(CH2), 24.90 (CH2), 24.84 (CH2). MS m/z (%) 149 (M+,
95), 120 (93), 106 (33), 81 (88), 67 (100), 55 (71), 39 (63).
Calcd for C9H11NO: M, 149.0840. Found: m/z 149.0844.
3.1.7. 2-Oxo-1-(2-oxopropyl)octahydropentalene-1-
carbonitrile (18). To a suspension of sodium hydride
(10 mg; 0.24 mmol) in dry THF (4 mL) was added a solution
of 12 (30 mg; 0.2 mmol) in dry THF (0.5 mL) at ꢀ78 ꢁC and
the reaction mixture was stirred for 30 min. Bromoacetone
(0.09 mL; 0.96 mmol) was added to the reaction mixture
and the solution was stirred for 3 h. Temperature of the
reaction mixture was gradually allowed to warm to room
temperature over 2 h and the reaction mixture was further
stirred at room temperature for 30 min. The reaction was
quenched by satd aq NH4Cl. The whole was extracted with
CHCl3 and the organic layer was washed once with water.
The solvent was evaporated under vacuum and the residue
was purified by silica gel column chromatography to give
18 (32.8 mg; 79%) as a colorless oil; IR (neat) 2958, 2873,
2238 (CN), 1751, 1721 (CO), 1403, 1364, 1173, 1149,
3.1.5. Bicyclo[3.3.0]octan-3-one (13). To a solution of 12
(280 mg; 1.88 mmol) in acetic acid (100 mL) were added
phosphoric acid (85%; 40 mL) and water (13 mL). The reac-
tion mixture was stirred and heated under reflux for 23 h.
The reaction mixture was neutralized with 10% aq NaOH.
The whole was extracted with CHCl3 and the combined or-
ganic extracts were washed with brine, dried over MgSO4,
and concentrated in vacuo to give a yellow oil. The product
was purified by silica gel flash column chromatography to
give 91.7 mg (39%) of 13 as a colorless oil; IR (neat)
1
1
2950, 2868, 1740 (CO), 1450, 1405, 1375, 1233 cmꢀ1; H
1042 cmꢀ1; H NMR d 1.51 (1H, sextet, J¼7.0 Hz), 1.65–
NMR d 1.37–1.44 (2H, m), 1.59–1.68 (1H, m), 1.72–1.80
(1H, m), 1.94 (2H, m), 2.01, 2.05 (each 1H, d, J¼4.3 Hz),
2.46, 2.51 (each 1H, br d, J¼9.8 Hz), 2.67–2.74 (2H, m);
13C NMR d 221.41 (C), 44.74 (CH2), 39.66 (CH), 33.46
(CH2), 25.53 (CH2). MS m/z (%) 124 (M+, 58), 95 (18), 81
(100), 67 (56), 54 (73), 39 (40). Calcd for C8H12O: M,
124.0888. Found: m/z 124.0892.
1.73 (1H, m), 1.87–1.95 (2H, m), 1.97–2.11 (2H, m), 2.18
(3H, s), 2.30 (1H, dd, J¼19.2, 6.4 Hz), 2.63–2.68 (1H, m),
2.78 (1H, sextet, J¼8.0 Hz), 2.88 (1H, dd, J¼19.2,
9.3 Hz), 3.15, 3.21 (each 1H, d, J¼18.0 Hz); 13C NMR
d 209.90 (C), 202.98 (C), 117.70 (C), 50.07 (C), 49.02
(CH2), 48.13 (CH), 43.19 (CH2), 37.69 (CH), 33.31 (CH2),
30.54 (CH2), 29.61 (CH2), 25.71 (CH3). MS m/z (%) 205
(M+, 11), 162 (22), 148 (100), 134 (27), 120 (10), 92 (10),
43 (74). Calcd for C12H15NO2: M, 205.1102. Found: m/z
205.1112.
3.1.6. 2-Allyloxy-6a-phenyl-3,3a,4,5,6,6a-hexahydropen-
talene-1-carbonitrile (17). To a suspension of cuprous

H. Kashima et al. / Tetrahedron 63 (2007) 3953–3963
3959
3.1.8. 2-Hydroxy-2-phenyl-2,3,3a,4,5,6-hexahydropenta-
lene-1-carbonitrile (19). Phenylmagnesium bromide
(0.048 mL of 3 M solution in diethyl ether; 0.143 mmol)
was added to a solution of 10 (10 mg; 0.068 mmol) in dry
THF (0.36 mL) at 0 ꢁC. The reaction mixture was stirred
for 5 h and the reaction was quenched by adding satd aq
NH4Cl. The whole was extracted with CHCl3. The organic
layer was washed once with water and dried over MgSO4.
The product was purified by silica gel column chromato-
graphy to give 13.4 mg (88%) of 19 as a colorless oil; IR
(neat) 3436 (OH), 2962, 2928, 2857, 2216 (CN), 1665,
was neutralized by satd aq NaHCO3. The whole was ex-
tracted with CHCl3. The organic layer was evaporated under
vacuum and the residue was purified by silica gel column
chromatography to give 2-benzyloxy-7,7-dimethyl-6,8-
dioxaspiro[3.5]nonane (49.8 mg; 84%) as a colorless oil.
To a solution of the acetal (30 mg; 0.114 mmol) in methanol
(3 mL) was added 10% Pd on carbon (40 mg). The reaction
mixture was stirred at room temperature under H2 atmo-
sphere (1 atm) for 2 h. The suspension was filtered through
a pad of Celite. The filtrate was evaporated under reduced
pressure to dryness to afford 7,7-dimethyl-6,8-dioxaspiro-
[3.5]nonan-2-ol (17.7 mg; 90%) as a colorless oil.
1
1449, 1069 cmꢀ1; H NMR d 1.25–1.33 (2H, m), 1.99–
2.07 (3H, m), 2.12–2.19 (1H, m), 2.51–2.65 (2H, m), 2.71
(1H, dd, J¼12.5, 7.1 Hz), 2.88–2.94 (1H, m), 7.31–7.34
(1H, m), 7.37–7.40 (2H, m), 7.45–7.47 (2H, m); 13C NMR
d 175.63 (C), 143.33 (C), 128.81 (CH), 128.18 (CH),
124.84 (CH), 115.26 (C), 110.00 (C), 76.60 (C), 50.23
(CH), 49.60 (CH2), 31.47 (CH2), 27.16 (CH2), 25.29
(CH2). MS m/z (%) 225 (M+, 100), 207 (23), 196 (49), 182
(72), 105 (87), 77 (81), 51 (31). Calcd for C15H15NO: M,
225.1153. Found: m/z 225.1157.
To a solution of oxalyl chloride (3.7 mL; 43.5 mmol) in
CH2Cl2 (75 mL) was added dropwise DMSO (4.6 mL;
65 mmol) at ꢀ78 ꢁC. The solution was stirred at ꢀ78 ꢁC
for 10 min. The alcohol (1.5 g; 8.7 mmol) in 5 mL of
CH2Cl2 was added slowly to the reaction mixture. After stir-
ring for 15 min at ꢀ78 ꢁC, the temperature was warmed to
ꢀ45 ꢁC and then the reaction mixture was stirred for 1 h.
Et3N (10 mL; 74 mmol) was added to the reaction mixture,
and warmed to 0 ꢁC and then stirred for 20 min. The reaction
was quenched by satd aq NH4Cl and the whole was extracted
with CHCl3. The organic layer was washed with water and
dried, and the solvent was evaporated under vacuum. The
residue was purified by silica gel column chromatography
to give 21b (1.3 g; 88%) as colorless crystals; mp 58–
59 ꢁC (AcOEt–hexane); IR (KBr) 2995, 2945, 2868, 1780
3.1.9. 3,3-Di(ethoxymethyl)cyclobutanone (21a). A solu-
tion of 20 (1.41 g; 6.35 mmol) in dry THF (2 mL) was added
to a suspension of sodium hydride (0.76 g; 19.1 mmol) in
dry THF (40 mL) at room temperature. After the reaction
mixture was stirred for 5 min, iodoethane (2.54 mL;
31.8 mmol) was added. The whole was stirred overnight
and the reaction was quenched by satd aq NH4Cl. The reac-
tion mixture was extracted with CHCl3. The organic layer
was washed with water and the solvent was evaporated under
vacuum. The residue was purified by silica gel column chro-
matography to give (3,3-bisethoxymethyl)cyclobutyl benzyl
ether (1.52 g; 86%) as a colorless oil.
1
(CO), 1377, 1271, 1194, 1074, 1032, 823 cmꢀ1; H NMR
d 1.46 (6H, s), 2.88 (4H, s), 3.88 (4H, s). MS m/z (%) 157
(M+, 98), 113 (30), 97 (46), 59 (100), 43 (85). Anal. Calcd
for C9H14O3: C, 63.51; H, 8.29%. Found: C, 63.49; H,
8.34%.
To a solution of this product (1.52 g; 5.45 mmol) in metha-
nol (30 mL) was added 10% Pd on carbon (1.82 g). The
reaction mixture was stirred at room temperature under H2
atmosphere (1 atm) for 3 h. The suspension was filtered
thought a pad of Celite. The filtrate was evaporated under re-
duced pressure to dryness to afford (3,3-bisethoxymethyl)-
cyclobutanol (1.00 g; 97%) as a colorless oil.
3.1.11. 3,3-Diethoxymethyl-1-[chloro(p-tolylsulfinyl)-
methylidene]cyclobutane (22a). Colorless oil; IR (neat)
2975, 2930, 2867, 1399, 1378, 1356, 1113, 1089, 1062
1
(SO) cmꢀ1; H NMR d 1.20, 1.22 (each 3H, t, J¼7.0 Hz),
2.42 (3H, s), 2.64–2.73 (2H, m), 2.97–3.04 (2H, m), 3.44–
3.47 (4H, m), 3.52, 3.53 (each 2H, q, J¼7.0 Hz), 7.32 (2H,
d, J¼8.0 Hz), 7.50 (2H, d, J¼8.0 Hz). MS m/z (%) 356
(M+, 35), 339 (97), 311 (46), 297 (60), 235 (67), 203 (54),
181 (38), 171 (35), 139 (92), 123 (78), 91 (75), 77 (62), 59
(100). Calcd for C18H25ClO3S: M, 356.1213. Found: m/z
356.1213.
A solution of IBX (3.01 g; 10.7 mmol) in 22 mL of DMSO
was stirred for 20 min. Cyclobutanol (1.01 g; 5.37 mmol)
was added to the solution and the reaction mixture was
stirred for 1.5 h. The reaction mixture was diluted with ether
and the solution was washed twice with water and dried over
MgSO4. The organic layer was evaporated under vacuum
and the residue was purified by silica gel column chromato-
graphy to give 21a (847 mg; 85%) as a colorless oil; IR
(neat) 2977, 2932, 2867, 1789 (CO), 1379, 1356,
3.1.12. 6-Amino-3,3-bisethoxymethylspiro[3.4]octa-5,7-
diene-5-carbonitrile (23a). Colorless oil; IR (neat) 3350
(NH), 3232, 2975, 2930, 2868, 2178 (CN), 1646, 1608,
1
1422, 1110, 757 cmꢀ1; H NMR d 1.20, 1.24 (each 3H, t,
J¼7.0 Hz), 2.28 (2H, d, J¼13.5 Hz), 2.37 (2H, d,
J¼13.8 Hz), 3.47–3.58 (8H, m), 4.53 (2H, br s, NH2),
5.90, 6.89 (each 1H, d, J¼5.4 Hz). MS m/z (%) 262 (M+,
28), 203 (100), 157 (97), 118 (35), 85 (16). Calcd for
C15H22N2O2: M, 262.1679. Found: m/z 262.1673.
1
1112 cmꢀ1; H NMR d 1.20 (6H, t, J¼7.0 Hz), 2.90 (4H,
s), 3.53 (4H, s), 3.53 (4H, q, J¼7.0 Hz). MS m/z (%) 186
(M+, 5), 158 (67), 111 (27), 99 (38), 85 (100), 71 (38), 57
(61), 55 (100). Calcd for C10H18O3: M, 186.1255. Found:
m/z 186.1250.
3.1.13. 5,5-Bisethoxymethyl-2-oxo-2,3,3a,4,5,6-hexahy-
dropentalene-1-carbonitrile (24a). Colorless crystals; mp
56–57 ꢁC (AcOEt–hexane); IR (KBr) 2976, 2933, 2869,
2230 (CN), 1727 (CO), 1645, 1110 cmꢀ1; 1H NMR d 1.16,
1.19 (each 3H, t, J¼6.9 Hz), 2.17–2.23 (2H, m), 2.77 (1H,
dd, J¼18.3, 6.7 Hz), 2.80, 2.86 (each 1H, d, J¼19.0 Hz),
3.1.10. 7,7-Dimethyl-6,8-dioxaspiro[3.5]nonan-2-one
(21b). To a solution of 20 (50 mg; 0.225 mmol) in dry ace-
tone (2.3 mL) were added pyridinium p-toluenesulfonate
(16.8 mg; 0.068 mmol) and magnesium sulfate at room
temperature. The whole was stirred for 3 h and the reaction

3960
H. Kashima et al. / Tetrahedron 63 (2007) 3953–3963
1
3.24, 3.30 (each 1H, d, J¼9.0 Hz), 3.36–3.56 (8H, m); 13C
NMR d 202.21 (C), 201.75 (C), 112.03 (C), 111.29 (C),
75.06 (CH2), 74.89 (CH2), 66.88 (CH2), 66.78 (CH2),
49.94 (C), 45.01 (CH), 42.24 (CH2), 37.23 (CH2), 35.02
(CH2), 15.02 (CH3), 14.90 (CH3). MS m/z (%) 263 (M+,
35), 217 (35), 171 (28), 160 (38), 146 (21), 85 (57), 59
(100). Calcd for C15H21NO3: M, 263.1520. Found: m/z
263.1511. Anal. Calcd for C15H21NO3: C, 68.43; H, 8.04;
N, 5.22%. Found: C, 68.42; H, 8.04; N, 5.32%.
1046 (SO), 1015, 810, 511 cmꢀ1; H NMR d 1.98–2.07
(1H, m), 2.14–2.20 (1H, m), 2.21–2.33 (2H, m), 2.40–2.47
(1H, m), 2.45 (3H, s), 2.66–2.72 (1H, m), 2.99, 3.21 (each
1H, d, J¼16.8 Hz), 4.62 (1H, s), 7.37, 7.71 (each 2H, d,
J¼7.9 Hz). MS m/z (%) 281 (M+, 2), 140 (100), 92 (41),
79 (13), 65 (9). Calcd for C14H16ClNOS: M, 281.0641.
Found: m/z 281.0642. Anal. Calcd for C14H16ClNOS: C,
59.67; H, 5.72; Cl, 12.58; N, 4.97; S, 11.38%. Found: C,
59.68; H, 5.51; Cl, 12.58; N, 4.93; S, 11.31%. 25-P. Mp
127–129 ꢁC (AcOEt–hexane); IR (KBr) 2990, 2942, 2911,
1
3.1.14. 2-[Chloro(p-tolylsulfinyl)methylene]-7,7-di-
methyl-6,8-dioxaspiro[3.5]nonane (22b). Colorless crys-
tals; mp 174–175 ꢁC (AcOEt–hexane); IR (KBr) 2992,
2861, 1388, 1367, 1231, 1200, 1085, 1059 (SO), 886, 828,
2240 (CN), 1596, 1491, 1081, 1055 (SO), 817 cmꢀ1; H
NMR d 2.02–2.11 (1H, m), 2.15–2.22 (1H, m), 2.26–2.31
(1H, m), 2.35–2.41 (2H, m), 2.44 (3H, s), 2.50–2.57 (1H,
m), 2.91, 3.05 (each 1H, d, J¼17.4 Hz), 4.49 (1H, s), 7.37,
7.50 (each 2H, d, J¼8.3 Hz). MS m/z (%) 281 (M+, 3),
140 (100), 92 (37), 79 (14), 65 (10). Calcd for
C14H16ClNOS: M, 281.0642. Found: m/z 281.0634. Anal.
Calcd for C14H16ClNOS: C, 59.67; H, 5.72; Cl, 12.58; N,
4.97; S, 11.38%. Found: C, 59.66; H, 5.54; Cl, 12.54; N,
4.95; S, 11.33%.
1
807 cmꢀ1; H NMR d 1.43, 1.44 (each 3H, s), 2.42 (3H,
s), 2.59 (1H, dd, J¼17.4, 3.0 Hz), 2.67 (1H, ddd, J¼17.4,
3.6, 1.2 Hz), 2.94 (1H, dd, J¼17.4, 3.0 Hz), 3.07 (1H, ddd,
J¼17.4, 3.6, 0.6 Hz), 3.78, 3.80 (each 1H, d, J¼12.0 Hz),
3.82 (2H, s), 7.33, 7.50 (each 2H, d, J¼7.8 Hz). MS m/z
(%) 340 (M+, 100), 325 (70), 235 (89), 123 (87), 91 (78),
77 (83), 43 (91). Calcd for C17H21ClO3S: M, 340.0899.
Found: m/z 340.0901. Anal. Calcd for C17H21ClO3S: C,
59.90; H, 6.21; Cl, 10.40; S, 9.41%. Found: C, 59.82; H,
6.20; Cl, 10.38; S, 9.39%.
3.1.18. 6-Amino-7-phenylspiro[3.4]octa-5,7-diene-5-car-
bonitrile (26a). To a solution of LDA (0.442 mmol) in
1.5 mL of dry THF was added a solution of 25-L (40 mg;
0.143 mmol) in 1.3 mL of dry THF at ꢀ78 ꢁC and the reac-
tion mixture was stirred for 30 min. To the reaction mixture
was added lithium a-carbanion of phenylacetonitrile
(1 mmol), which was generated from phenylacetonitrile
and n-BuLi at ꢀ78 ꢁC, through a cannula and the tempera-
ture of the reaction mixture was slowly allowed to warm to
ꢀ40 ꢁC over 1.5 h. The reaction was quenched by MeOH.
The whole was extracted with CHCl3. The product was iso-
lated by silica gel column chromatography to give 24.7 mg
(78%) of 26a as colorless crystals; mp 93–95 ꢁC (AcOEt–
hexane); IR (KBr) 3377, 3226 (NH), 2929, 2853, 2177
3.1.15. 2-Amino-10,10-dimethyl-9,11-dioxadispiro-
[4.1.5.1]trideca-1,3-dienecarbonitrile (23b). Colorless
amorphous; IR (KBr) 3413, 3360, 3246 (NH), 2991, 2937,
2856, 2178 (CN), 1667, 1622, 1542, 1426, 1195, 1065,
834 cmꢀ1; 1H NMR d 1.41 (6H, s), 2.25, 2.33 (each 2H, br d,
J¼13.7 Hz), 3.86, 3.91 (each 2H, s), 4.58 (2H, br s, NH2),
5.98, 6.65 (each 1H, d, J¼5.5 Hz). MS m/z (%) 246 (M+, 60),
231 (50), 171 (62), 157 (100), 132 (26), 118 (74), 43 (45).
Calcd for C14H18N2O2: M, 246.1366. Found: m/z 246.1359.
1
3.1.16. Diacetate (24b). Colorless oil; IR (neat) 2955, 2231
(CN), 1638, 1548, 1414, 764, 703 cmꢀ1; H NMR d 2.01–
1
(CN), 1739 (CO), 1651, 1384, 1367, 1232, 1040 cmꢀ1; H
2.08 (1H, m), 2.13–2.20 (1H, m), 2.22–2.27 (2H, m),
2.55–2.62 (2H, m), 4.67 (2H, br s, NH2), 6.82 (1H, s),
7.35–7.45 (5H, m). MS m/z (%) 222 (M+, 98), 194 (100),
166 (9). Calcd for C15H14N2: M, 222.1157. Found: m/z
222.1159. Anal. Calcd for C15H14N2: C, 81.05; H, 6.35; N,
12.60%. Found: C, 80.88; H, 6.20; N, 12.60%.
NMR d 2.09 (3H, s), 2.12 (3H, s), 2.24–2.29 (2H, m), 2.79
(1H, d, J¼19.5 Hz), 2.84 (1H, dd, J¼18.6, 7.0 Hz), 2.91
(1H, d, J¼19.5 Hz), 3.35–3.41 (1H, m), 3.98, 4.10 (each
1H, d, J¼11.0 Hz), 4.14, 4.19 (each 1H, d, J¼11.0 Hz);
13C NMR d 200.97 (C), 197.54 (C), 170.67 (C), 170.56
(C), 112.41 (C), 111.47 (C), 67.27 (CH2), 66.57 (CH2),
47.78 (C), 44.17 (CH), 41.87 (CH2), 36.30 (CH2), 34.53
(CH2), 20.73 (CH3), 20.65 (CH3). MS m/z (%) 291 (M+,
1), 218 (27), 171 (58), 159 (23), 143 (21), 43 (100). Calcd
for C15H17NO5: M, 291.1107. Found: m/z 291.1108.
3.1.19. 6-Amino-7-(4-methoxyphenyl)spiro[3.4]octa-5,7-
diene-5-carbonitrile (26b). Colorless crystals; mp 144–
145 ꢁC (AcOEt–hexane); IR (KBr) 3426, 3339 (NH),
2969, 2932, 2176 (CN), 1650, 1605, 1555, 1507, 1461,
1445, 1248, 1177, 1028, 830, 602 cmꢀ1; H NMR d 2.00–
1
3.1.17. {1-[Chloro(p-tolylsulfinyl)methyl]cyclobutyl}aceto-
nitrile (25). Acetonitrile (0.139 mL; 2.66 mmol) was added
to a solution of n-BuLi (2.58 mmol) in 9 mL of dry THF at
ꢀ78 ꢁC with stirring. The solution was stirred for 10 min
and a solution of 8 (200 mg; 0.831 mmol) in 3 mL of dry
THF was added to the above reaction mixture. The reaction
mixture was stirred for 10 min and the reaction was
quenched by adding satd aq NH4Cl. The whole was ex-
tracted with CHCl3. The products (less polar product 25-L
and more polar product 25-P) were isolated by silica gel
column chromatography to give 25-L (167 mg; 71%) and
25-P (56 mg; 24%) as colorless crystals.
2.08 (1H, m), 2.10–2.19 (1H, m), 2.21–2.26 (2H, m),
2.54–2.61 (2H, m), 3.84 (3H, s), 4.62 (2H, br s, NH2), 6.75
(1H, s), 6.95, 7.29 (each 2H, d, J¼10.6 Hz). MS m/z (%)
252 (M+, 100), 224 (91), 209 (17), 193 (10). Calcd for
C16H16N2O: M, 252.1261. Found: m/z 252.1257. Anal.
Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10%. Found:
C, 76.15; H, 6.15; N, 11.15%.
3.1.20. 6-Amino-7-methylspiro[3.4]octa-5,7-diene-5-
carbonitrile (26c). Colorless crystals; mp 114–115 ꢁC
(AcOEt–hexane); IR (KBr) 3446, 3353 (NH), 3252, 2971,
2931, 2171 (CN), 1660, 1647, 1560, 1454, 1420,
1
1243 cmꢀ1; H NMR d 1.87 (3H, d, J¼1.5 Hz), 1.94–2.01
Compound 25-L: Mp 117–118 ꢁC (AcOEt–hexane); IR
(KBr) 2991, 2937, 2243 (CN), 1493, 1409, 1087, 1059,
(1H, m), 2.08–2.15 (3H, m), 2.44–2.50 (2H, m), 4.55 (2H,
br s, NH2), 6.51 (1H, q, J¼1.5 Hz). MS m/z (%) 160 (M+,

H. Kashima et al. / Tetrahedron 63 (2007) 3953–3963
3961
33), 145 (12), 132 (100), 104 (8). Calcd for C10H12N2: M,
160.0999. Found: m/z 160.1007.
2.75–2.76 (1H, m); 13C NMR d 211.08 (C), 184.01 (C),
131.88 (C), 44.32 (CH), 41.60 (CH2), 31.32 (CH2), 25.58
(CH2), 24.95 (CH2), 8.57 (CH3). MS m/z (%) 136 (M+,
100), 108 (78), 93 (88), 79 (60), 53 (13), 39 (30). Calcd
for C9H12O: M, 136.0888. Found: m/z 136.0897.
3.1.21. 6-Amino-7-butylspiro[3.4]octa-5,7-diene-5-car-
bonitrile (26d). Colorless oil; IR (neat) 3428, 3354, 3250
(NH), 2956, 2930, 2856, 2169 (CN), 1679, 1649, 1559,
1
1432 cmꢀ1; H NMR d 0.94 (3H, t, J¼7.3 Hz), 1.39 (2H,
3.1.26. 2-Butylbicyclo[3.3.0]oct-1-en-3-one (27d). Color-
less oil; IR (neat) 2957, 2861, 1702 (CO), 1664,
sextet, J¼7.3 Hz), 1.54 (2H, quintet, J¼7.7 Hz), 1.94–2.04
(1H, m), 2.06–2.17 (5H, m), 2.43–2.51 (2H, m), 4.60 (2H,
br s, NH2), 6.49 (1H, s). MS m/z (%) 202 (M+, 48), 195
(20), 181 (23), 174 (24), 159 (100), 145 (20), 132 (50),
118 (12). Calcd for C13H18N2: M, 202.1469. Found: m/z
202.1465.
1
1466 cmꢀ1; H NMR d 0.90 (3H, t, J¼7.2 Hz), 1.02–1.09
(1H, m), 1.26–1.32 (2H, m), 1.37–1.45 (2H, m), 2.00–2.11
(4H, m), 2.13–2.17 (1H, m), 2.21–2.26 (1H, m), 2.47–2.56
(2H, m), 2.62 (1H, dd, J¼12.0, 6.0 Hz), 2.73–2.76 (1H,
m); 13C NMR d 210.91 (C), 183.93 (C), 136.30 (C), 44.43
(CH), 41.80 (CH2), 31.35 (CH2), 30.21 (CH2), 25.75
(CH2), 25.15 (CH2), 23.61 (CH2), 22.66 (CH2), 13.89
(CH3). MS m/z (%) 178 (M+, 63), 149 (100), 136 (62), 107
(26), 91 (23), 79 (31). Calcd for C12H18O: M, 178.1357.
Found: m/z 178.1364.
3.1.22. 6-Amino-7-trityl-spiro[3.4]octa-5,7-diene-5-carbo-
nitrile (26e). Colorless crystals; mp 235–236 ꢁC (AcOEt–
hexane); IR (KBr) 3455, 3368 (NH), 2931, 2185 (CN),
1
1633, 1596, 1548, 1490, 1442, 1399, 704 cmꢀ1; H NMR
d 1.93–2.05 (2H, m), 2.14–2.18 (2H, m), 2.51–2.57 (2H,
m), 3.91 (2H, br s, NH2), 6.50 (1H, s), 7.14–7.16 (6H, m),
7.27–7.33 (9H, m). MS m/z (%) 388 (M+, 97), 311 (38),
243 (100), 165 (55), 144 (11). Calcd for C28H24N2: M,
388.1938. Found: m/z 388.1940.
3.1.27. 3-Triphenylmethylbicyclo[3.3.0]oct-1-en-3-one
(27e). Colorless crystals; mp >300 ꢁC (AcOEt–hexane);
IR (KBr) 2926, 2859, 1706 (CO), 1624, 1492, 1444, 1253,
1
701 cmꢀ1; H NMR d 0.97–1.04 (1H, m), 1.59–1.67 (1H,
m), 1.75–1.87 (2H, m), 1.93 (1H, dd, J¼15.3, 3.6 Hz),
2.05–2.14 (2H, m), 2.66 (1H, dd, J¼18.0, 6.6 Hz), 2.89–
2.94 (1H, m), 7.14–7.17 (3H, m), 7.20–7.24 (12H, m); 13C
NMR d 208.05 (C), 184.58 (C), 144.84 (C), 142.05 (C),
130.22 (CH), 127.41 (CH), 125.92 (CH), 59.56 (C), 45.45
(CH), 42.12 (CH2), 31.47 (CH2), 28.40 (CH2), 25.83
(CH2). MS m/z (%) 364 (M+, 100), 287 (22), 165 (24). Calcd
for C27H24O: M, 364.1828. Found: m/z 364.1825. Anal.
Calcd for C27H24O: C, 88.97; H, 6.64%. Found: C, 88.66;
H, 6.66%.
3.1.23. 2-Phenylbicyclo[3.3.0]oct-1-en-3-one (27a). To
a solution of 26a (25 mg; 0.11 mmol) in 8 mL acetic acid
were added phosphoric acid (85%; 3.3 mL) and water
(0.75 mL). The reaction mixture was stirred and heated un-
der reflux for 12 h. The reaction mixture was neutralized
with 10% aq NaOH and the whole was extracted with
CHCl3. The product was purified by silica gel column chro-
matography to give 22.1 mg (99%) of 27a as a colorless oil;
IR (neat) 2962, 2930, 1692 (CO), 1627, 1595, 1133, 927,
1
765, 699 cmꢀ1; H NMR d 1.09–1.17 (1H, m), 2.07–2.13
(2H, m), 2.20–2.24 (1H, m), 2.26 (1H, dd, J¼17.7,
3.6 Hz), 2.62–2.68 (1H, m), 2.81 (1H, dd, J¼17.4, 7.2 Hz),
2.86–2.94 (2H, m), 7.28–7.31 (1H, m), 7.38–7.40 (2H, m),
7.59 (2H, d, J¼7.8 Hz); 13C NMR d 208.75 (C), 185.38
(C), 134.56 (C), 131.79 (C), 128.30 (CH), 128.25 (CH),
127.73 (CH), 44.67 (CH), 42.95 (CH2), 31.02 (CH2), 27.31
(CH2), 25.94 (CH2). MS m/z (%) 198 (M+, 100), 170 (57),
155 (24), 142 (65), 128 (23), 115 (31), 91 (10). Calcd for
C14H14O: M, 198.1043. Found: m/z 198.1036.
3.1.28. 3,3-Di(phenylsulfanyl)methylcyclobutyl benzyl
ether (31). To a solution of 20 (1.0 g; 4.5 mmol) in 30 mL
of dry THF at 0 ꢁC was added diphenyl disulfide (4.72 g;
21.6 mmol) in 20 mL of dry THF followed by tri-n-butyl-
phosphine (6.73 mL; 27 mmol). The reaction mixture was
stirred for 10 min at 0 ꢁC and the temperature of the reaction
mixture was allowed to warm to room temperature and then
stirred overnight. The reaction was quenched by 5% aq
NaOH and the whole was extracted with CHCl3. The organic
layer was washed with water and the solvent was evaporated
under vacuum to give a residue, which was purified by silica
gel column chromatography to give 31 (1.81 g; 99%) as
a colorless oil; colorless oil; IR (neat) 3059, 3030, 2968,
2928, 1583, 1480, 1454, 1438, 1350, 1251, 1111, 1090,
3.1.24. 2-(4-Methoxyphenyl)bicyclo[3.3.0]oct-1-en-3-one
(27b). Colorless oil; IR (neat) 2958, 2867, 1695 (CO),
1640, 1608, 1513, 1298, 1288, 1250, 1176, 1134, 1033,
1
831 cmꢀ1; H NMR d 1.09–1.16 (1H, m), 2.07–2.13 (2H,
1
m), 2.20–2.27 (2H, m), 2.62–2.68 (1H, m), 2.81 (1H, dd,
J¼17.7, 6.0 Hz), 2.86–2.91 (2H, m), 3.84 (3H, s), 6.94,
7.58 (each 2H, d, J¼9.0 Hz); 13C NMR d 209.11 (C),
183.62 (C), 159.07 (C), 133.96 (C), 129.48 (CH), 124.39
(C), 113.74 (CH), 55.26 (CH3), 44.52 (CH3), 42.91 (CH2),
31.04 (CH2), 27.32 (CH2), 26.09 (CH2). MS m/z (%) 228
(M+, 100), 200 (45), 185 (12), 172 (33), 157 (13), 145
(11), 128 (14), 115 (13). Calcd for C15H16O2: M,
228.1150. Found: m/z 228.1152.
1060, 1026 cmꢀ1; H NMR d 1.95–1.99 (2H, m), 2.28–
2.32 (2H, m), 3.23 (2H, s), 3.29 (2H, s), 4.06 (1H, quintet,
J¼6.8 Hz), 4.35 (2H, s), 7.13–7.18 (2H, m), 7.21–7.36
(13H, m). MS m/z (%) 406 (M+, 51), 163 (27), 129 (17),
123 (41), 91 (100). Calcd for C25H26OS2: M, 406.1425.
Found: m/z 406.1424.
3.1.29. 3,3-Di(phenylsulfanyl)methylcyclobutanol (32).
To a suspension of sodium iodide (1.11 g; 7.38 mmol) in
dry CH3CN (3 mL) was added dropwise a solution of
TMSCl (0.58 mL; 7.38 mmol) at room temperature. The
solution was stirred for 10 min. A solution of 31 (2.0 g;
4.92 mmol) in 2 mL of dry THF was added to the solution.
The reaction mixture was stirred for 20 min and the reaction
was quenched by adding MeOH. The whole was extracted
3.1.25. 2-Methylbicyclo[3.3.0]oct-1-en-3-one (27c). Color-
less oil; IR (neat) 2959, 2867, 1705 (CO), 1668, 1448, 1379,
1339, 1315, 1292, 1072, 1049 cmꢀ1; 1H NMR d 1.02–1.10
(1H, m), 1.70 (3H, s), 1.96–2.09 (3H, m), 2.13–2.17 (1H,
m), 2.44–2.56 (2H, m), 2.63 (1H, dd, J¼18.0, 6.0 Hz),

3962
H. Kashima et al. / Tetrahedron 63 (2007) 3953–3963
with CHCl3. The organic layer was washed once with water
and dried over MgSO4. The product was purified by silica
gel column chromatography to give 873 mg (76%; calcu-
lated from consumed starting material) of 32 as a colorless
oil; IR (neat) 3368 (OH), 3057, 2927, 1945, 1871, 1583,
(3H, d, J¼1.6 Hz), 2.35 (2H, d, J¼13.1 Hz), 2.40 (2H, d,
J¼13.1 Hz), 3.42, 3.44 (each 2H, s), 4.52 (2H, br s, NH2),
6.38 (1H, t, J¼1.6 Hz), 7.13–7.19 (2H, m), 7.23–7.28 (4H,
m), 7.37–7.42 (4H, m). MS m/z (%) 404 (M+, 67), 295
(19), 281 (92), 185 (99), 172 (41), 123 (53), 110 (18). Calcd
for C24H24N2S2: M, 404.1378. Found: m/z 404.1371.
1
1480, 1438, 1249, 1090, 1042, 738, 689 cmꢀ1; H NMR
d 1.72 (1H, br s, OH), 1.87–1.93 (2H, m), 2.35–2.41 (2H,
m), 3.18–3.26 (4H, m), 4.28–4.32 (1H, m), 7.15–7.28 (8H,
m), 7.32–7.37 (2H, m). MS m/z (%) 316 (M+, 100), 163
(30), 147 (12), 123 (49), 109 (28), 97 (18), 79 (23). Calcd
for C18H20OS2: M, 316.0953. Found: m/z 316.0952.
3.1.34. 2-Methyl-7,7-di(phenylsulfanyl)methylbicyclo-
[3.3.0]oct-1-en-3-one (36). Colorless oil; IR (neat) 3057,
2952, 2916, 1945, 1871, 1705 (CO), 1667, 1583, 1480,
1438, 1411, 1378, 1318, 1267, 1089, 1070, 1025, 740,
1
690 cmꢀ1; H NMR d 1.27 (1H, t, J¼12.5 Hz), 1.66 (3H,
3.1.30. 3,3-Di(phenylsulfanyl)methylcyclobutanone (6).
To a solution of oxalyl chloride (1.08 mL; 12.1 mmol) in
CH2Cl2 (25 mL) was added DMSO (1.28 mL; 24.2 mmol)
at ꢀ78 ꢁC dropwise with stirring. The solution was stirred
t, J¼1.3 Hz), 2.01 (1H, dd, J¼18.0, 2.8 Hz), 2.27 (1H, dd,
J¼12.9, 8.2 Hz), 2.62 (1H, dd, J¼18.0, 6.5 Hz), 2.65 (2H,
s), 3.01 (1H, m), 3.17, 3.20 (each 1H, d, J¼12.5 Hz), 3.31,
3.36 (each 1H, d, J¼12.2 Hz), 7.16–7.21 (2H, m), 7.24–
7.28 (4H, m), 7.29–7.33 (2H, m), 7.36–7.39 (2H, m); 13C
NMR d 209.88 (C), 179.80 (C), 136.57 (C), 132.58 (C),
129.82 (CH), 129.80 (CH), 129.04 (CH), 128.99 (CH),
126.44 (CH), 126.38 (CH), 50.27 (C), 45.43 (CH2), 44.73
(CH2), 42.21 (CH), 41.93 (CH2), 41.85 (CH2), 37.22
(CH2), 8.48 (CH3). MS m/z (%) 380 (M+, 73), 161 (17),
147 (12), 123 (99), 91 (13). Calcd for C23H24OS2: M,
380.1268. Found: m/z 380.1270.
at ꢀ78 ꢁC for 10 min.
A solution of 32 (1.53 g;
4.84 mmol) in 13 mL of CH2Cl2 was added slowly to the
above reaction mixture. After being stirred for 15 min at
ꢀ78 ꢁC, the temperature of the reaction mixture was allowed
to warm to ꢀ45 ꢁC and the reaction mixture was stirred for
1 h. Triethylamine (2.9 mL; 40.2 mmol) was added to the re-
action mixture at the temperature, and it was warmed to 0 ꢁC
and then stirred for 20 min. The reaction was quenched by
satd aq NH4Cl and the whole was extracted with CHCl3.
The organic layer was washed with water and dried, and
the solvent was evaporated under vacuum to give a residue,
which was purified by silica gel column chromatography to
give 6 (1.51 g; 99%) as a colorless oil; IR (neat) 3056, 2915,
3.1.35. 2,7,7-Trimethylbicyclo[3.3.0]octan-3-one (37). To
a solution of 36 (21 mg; 0.055 mmol) in EtOH (1.5 mL)
was added Raney-Ni at room temperature. The suspension
was stirred and heated under reflux for 4 h. The nickel was
filtered off and the filtrate was diluted with hexane. The
solution was washed three times with water and dried over
MgSO4. The product was purified by silica gel column chro-
matography to give 7.1 mg (77%) of 37 as a colorless oil; IR
(neat) 2953, 2935, 2866, 1739 (CO), 1458, 1365, 1157,
1
1785 (CO), 1582, 1480, 1438, 1376, 1091, 1025 cmꢀ1; H
NMR d 2.95 (4H, s), 3.39 (4H, s), 7.18–7.22 (2H, m),
7.25–7.29 (4H, m), 7.36–7.38 (4H, m). MS m/z (%) 314
(M+, 100), 205 (13), 191 (43), 177 (11), 161 (68), 147
(16), 129 (56), 109 (43), 95 (20), 91 (18). Calcd for
C18H18OS2: M, 314.0798. Found: m/z 314.0798.
1063 cmꢀ1
;
1H NMR d 0.99 (3H, s), 1.01 (3H, d,
J¼7.1 Hz), 1.06 (3H, s), 1.21 (2H, t, J¼7.0 Hz), 1.43–1.47
(1H, m), 1.86 (1H, dd, J¼18.8, 5.9 Hz), 1.92 (1H, ddd,
J¼13.4, 8.4, 1.7 Hz), 2.45–2.51 (1H, m), 2.63 (1H, ddd,
J¼18.7, 10.8, 1.8 Hz), 2.69–2.76 (1H, m), 2.88–2.96 (1H,
m). MS m/z (%) 166 (M+, 66), 149 (61), 123 (28), 109
(100), 95 (43), 83 (34), 69 (76), 55 (80). Calcd for
C11H18O: M, 166.1355. Found: m/z 166.1354.
3.1.31. 3,3-Di(phenylsulfanyl)methyl-1-[chloro(p-tolyl-
sulfinyl)methylidene]cyclobutane (33). Colorless oil; IR
(neat) 3056, 2915, 1945, 1909, 1733, 1652, 1584, 1481,
1
1440, 1303, 1256, 1178, 1087, 1056 (SO) cmꢀ1; H NMR
d 2.41 (3H, s), 2.71 (1H, dd, J¼17.6, 2.8 Hz), 2.77 (1H, dd,
J¼17.6, 2.8 Hz), 3.03 (1H, dd, J¼16.9, 2.8 Hz), 3.12 (1H,
dd, J¼16.9, 2.8 Hz), 3.27 (1H, d, J¼12.5 Hz), 3.31 (1H, d,
J¼12.5 Hz), 3.32 (2H, s), 7.20–7.23 (2H, m), 7.26–7.31
(6H, m), 7.34–7.40 (4H, m), 7.47 (2H, d, J¼8.3 Hz). MS
m/z (%) 484 (M+, 17), 467 (13), 361 (28), 235 (13), 199
(17), 161 (13), 139 (14), 123 (100), 109 (20), 91 (32). Calcd
for C26H25ClOS3: M, 484.0756. Found: m/z 484.0744.
3.1.36. 1-Allyl-1,5,5-trimethylhexahydropentalen-2-one
(38). To a suspension of sodium hydride (3.3 mg;
0.138 mmol) in dry THF (0.3 mL) was added a solution of
37 (15.3 mg; 0.092 mmol) in dry THF (0.9 mL) at room tem-
perature. After the reaction mixture was stirred for 30 min,
allyl iodide (0.026 mL; 0.276 mmol) was added. The reac-
tion mixture was stirred for 2 h and the reaction was
quenched by satd aq NH4Cl. The whole was extracted with
CHCl3. The organic layer was washed and dried, and the
solvent was evaporated under vacuum to give a residue,
which was purified by silica gel column chromatography
to give 38 (12.8 mg; 67%) as a colorless oil; IR (neat)
2933, 2866, 1738 (CO), 1731, 1641, 1465, 1457, 1410,
3.1.32. {1-[Chloro(p-tolylsulfinyl)methyl]-3,3-bis(phenyl-
sulfanylmethyl)cyclobutyl}acetonitrile (34). Colorless oil
(about 2:1 diastereomeric mixture); IR (neat) 2931, 2245
(CN), 1732, 1584, 1481, 1440, 1256, 1090, 1062, 1026
(SO), 810, 741, 691 cmꢀ1 1H NMR (selected data are
;
reported) d 2.44 (2H, s, CH3), 2.45 (1H, s, CH3), 4.87
(0.66H, s), 4.90 (0.33H, s). MS m/z (%) 525 (M+, 16), 386
(7), 140 (14), 123 (99), 110 (12), 91 (17). Calcd for
C28H28ClNOS3: M, 525.1022. Found: m/z 525.1024.
1
1374 cmꢀ1; H NMR d 0.95 (3H, s), 0.97 (3H, s), 1.06
(3H, s), 1.12 (1H, t, J¼12.5 Hz), 1.20 (1H, dd, J¼13.3,
5.1 Hz), 1.44 (1H, ddd, J¼12.5, 6.9, 1.5 Hz), 1.89–1.93
(2H, m), 2.07–2.16 (2H, m), 2.59–2.77 (3H, m), 5.03 (1H,
dq, J¼16.9, 1.4 Hz), 5.08 (1H, dq, J¼13.1, 0.9 Hz), 5.70
(1H, ddt, J¼17.2, 9.8, 7.3 Hz); 13C NMR d 222.71 (C),
133.48 (CH), 118.19 (CH2), 52.51 (C), 50.01 (CH), 48.98
3.1.33. 6-Amino-7-methyl-2,2-di(phenylsulfanyl)methyl-
spiro[3.4]octa-5,7-diene-5-carbonitrile (35). Colorless
oil; IR (neat) 3352, 3233 (NH), 2927, 2174 (CN), 1652,
1
1563, 1480, 1438, 1416, 739, 690 cmꢀ1; H NMR d 1.83

H. Kashima et al. / Tetrahedron 63 (2007) 3953–3963
3963
(CH2), 44.53 (CH2), 43.53 (CH2), 40.21 (C), 34.18 (CH),
References and notes
30.07 (CH3), 28.55 (CH3), 17.32 (CH3). MS m/z (%) 206
(M+, 53), 191 (12), 149 (29), 137 (21), 123 (100), 109
(25), 95 (35), 81 (34), 67 (24). Calcd for C14H22O: M,
206.1668. Found: m/z 206.1665.
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Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier:
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2002, 4, 4547.
8. Our recent work concerning ring-expansion reactions: (a) Satoh,
T.; Hayashi, Y.; Mizu, Y.; Yamakawa, K. Tetrahedron Lett.
1992, 33, 7181; (b) Satoh, T.; Itoh, N.; Gengyo, K.;
Yamakawa, K. Tetrahedron Lett. 1992, 33, 7543; (c) Satoh, T.;
Hayashi, Y.; Mizu, Y.; Yamakawa, K. Bull. Chem. Soc. Jpn.
1994, 67, 1412; (d) Satoh, T.; Itoh, N.; Gengyo, K.; Takada,
S.; Asakawa, N.; Yamani, Y.; Yamakawa, K. Tetrahedron
1994, 50, 11839; (e) Satoh, T.; Mizu, Y.; Kawashima, T.;
Yamakawa, K. Tetrahedron 1995, 51, 703; (f) Satoh, T.;
Miyashita, K. Tetrahedron Lett. 2004, 45, 4859; (g) Miyashita,
K.; Satoh, T. Tetrahedron 2005, 61, 5067; (h) Satoh, T.;
Tanaka, S.; Asakawa, N. Tetrahedron Lett. 2006, 47, 6769.
9. Satoh, T.; Kawashima, T.; Takahashi, S.; Sakai, K. Tetrahedron
2003, 59, 9599.
10. Preliminary results of this study were reported as a communica-
tion: Kawashima, T.; Kashima, H.; Wakasugi, D.; Satoh, T.
Tetrahedron Lett. 2005, 46, 3767.
11. Whitesell, J. K.; Matthews, R. S. J. Org. Chem. 1977, 42, 3878.
12. Cadieux, J. A.; Buller, D. J.; Wilson, P. D. Org. Lett. 2003,
5, 3983.
3.1.37. 1,5,5-Trimethyl-1-(2-oxopropyl)hexahydropenta-
len-2-one (39). Oxygen was bubbled through a mixture
of PdCl2 (10.4 mg; 0.059 mmol) and CuCl (46.1 mg;
0.465 mmol) and water (0.3 mL). To this reaction mixture
a solution of 38 (32 mg; 0.155 mmol) in DMF (1.7 mL)
was added, and the reaction mixture was stirred at room tem-
perature for 24 h with O2 being bubbled through the mixture.
The suspension was filtered through a pad of Celite. The or-
ganic layer was evaporated under vacuum and the residue
was purified by silica gel column chromatography to give
39 (34.3 mg; 99%) as a colorless oil; IR (neat) 2953, 2866,
1735 (CO), 1717 (CO), 1459, 1397, 1365, 1196, 1158,
1
1076 cmꢀ1; H NMR d 0.96 (3H, s), 0.99 (3H, s), 1.08
(3H, s), 1.15 (1H, dd, J¼12.8, 7.5 Hz), 1.30 (1H, t,
J¼11.8 Hz), 1.51 (1H, ddd, J¼12.7, 7.7, 1.7 Hz), 1.88
(1H, ddd, J¼12.9, 8.1, 1.8 Hz), 2.05 (1H, dd, J¼18.7,
7.0 Hz), 2.10 (3H, s), 2.65–2.87 (5H, m); 13C NMR
d 223.46 (C), 206.41 (C), 53.18 (CH2), 49.19 (CH2), 48.88
(CH), 48.81 (C), 43.93 (CH2), 42.40 (CH2), 40.72 (C),
35.46 (CH), 30.59 (CH3), 29.59 (CH3), 27.90 (CH3), 20.58
(CH3). MS m/z (%) 222 (M+, 2), 165 (100), 109 (17), 95
(10), 55 (13). Calcd for C14H22O2: M, 222.1618. Found:
m/z 222.1615.
3.1.38. Linear triquinane (7). To a solution of 39 (20 mg;
0.09 mmol) in dry t-BuOH (0.45 mL) was added t-BuOK
(8.4 mg; 0.135 mmol) in one portion. After being stirred
for 10 min at room temperature, satd aq NH4Cl was added
to the reaction mixture and the whole was extracted with
CHCl3. The organic layer was washed and dried, and the sol-
vent was evaporated under vacuum to give a residue, which
was purified by silica gel column chromatography to give 7
(14.3 mg; 78%) as a colorless oil; IR (neat) 2953, 2867, 1713
(CO), 1635, 1465, 1414, 1366, 1224, 1189, 1151 cmꢀ1; 1H
NMR d 0.96 (3H, s), 1.09 (3H, s), 1.11 (3H, s), 1.19–1.26
(1H, m), 1.43–1.54 (2H, m), 1.80 (1H, dd, J¼12.1,
6.0 Hz), 2.23–2.31 (3H, m), 2.36–2.42 (1H, m), 2.77–2.82
(2H, m), 5.68 (1H, d, J¼1.7 Hz); 13C NMR d 210.90 (C),
195.82 (C), 122.07 (CH), 52.78 (CH2), 50.60 (CH), 49.53
(CH2), 49.29 (C), 44.45 (CH), 43.83 (C), 40.32 (CH2),
32.91 (CH2), 29.00 (CH3), 27.42 (CH3), 24.62 (CH3). MS
m/z (%) 204 (M+, 32), 189 (20), 176 (6), 161 (7), 147 (6),
133 (7), 119 (9), 108 (23), 95 (19), 80 (19), 79 (13). Calcd
for C14H20O: M, 204.1512. Found: m/z 204.1512.
13. Michejda, C. J.; Comnick, R. W. J. Org. Chem. 1975, 40, 1046.
14. (a) Satoh, T.; Wakasugi, D. Tetrahedron Lett. 2003, 44, 7517;
(b) Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61, 1245.
15. Kobayashi, T.; Koga, Y.; Narasaka, K. J. Organomet. Chem.
2001, 624, 73.
16. Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977, 42, 3761.
17. Rao, Y. K.; Nagarajan, M. Tetrahedron Lett. 1988, 29, 107.
18. (a) Takahashi, T.; Kasuga, K.; Takahashi, M.; Tsuji, J. J. Am.
Chem. Soc. 1979, 101, 5072; (b) Rao, Y. K.; Nagarajan, M.
J. Org. Chem. 1989, 54, 5678.
Acknowledgements
19. Paquette, L. A.; Meister, P. G.; Friedrich, D.; Sauer, D. R.
J. Am. Chem. Soc. 1993, 115, 49.
20. Harrowven, D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron
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This work was supported by Tokyo University of Science,
Joint Study Program in Graduate Course, which is gratefully
acknowledged.