Enatio- and diastereoselective construction of 4,9-dimethylspiro[4.4]nonane-2,7-dione using Rh-catalyzed asymmetric cyclization

Article abstract of DOI:10.1016/S0040-4020(00)01106-6

Asymmetric cyclization using Rh-complexes was applied to the synthesis of 4,9-dimethylspiro[4.4]nonane-2,7-diones. The spiro[4.4]nonane skeleton bearing a chiral quaternary carbon could be stepwisely constructed by using Rh-catalyzed cyclization twice. All diastereomers of the spirodiketone could be stereoselectively prepared from the identical starting material by the combination of a neutral Rh(PPh₃)₃Cl and a cationic Rh[BINAP]ClO₄. The cyclization by the neutral Rh(PPh₃)₃Cl proceeded to give cis-3,4-disubstituted cyclopentanones, while that by the cationic Rh[BINAP]ClO₄ proceeded to afford trans-3,4-disubstituted cyclopentanones. Four spirodiketones of six stereoisomers could be prepared in optically active form, and the relationship between the stereochemistry of the spirodiketones and the Rh-complex was discussed based on the plausible acyl-hydride Rh-complexes.

Full text of DOI:10.1016/S0040-4020(00)01106-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1197±1204
Enantio- and diastereoselective construction of
4,9-dimethylspiro[4.4]nonane-2,7-dione using Rh-catalyzed
asymmetric cyclization
Masakazu Tanaka,p Miyuki Takahashi, Eishi Sakamoto, Masanori Imai, Akiko Matsui,
Masakazu Fujio, Kazuhisa Funakoshi, Kiyoshi Sakai and Hiroshi Suemunep
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Received 23 October 2000; accepted 20 November 2000
AbstractÐAsymmetric cyclization using Rh-complexes was applied to the synthesis of 4,9-dimethylspiro[4.4]nonane-2,7-diones. The
spiro[4.4]nonane skeleton bearing a chiral quaternary carbon could be stepwisely constructed by using Rh-catalyzed cyclization twice.
All diastereomers of the spirodiketone could be stereoselectively prepared from the identical starting material by the combination of a neutral
Rh(PPh3)3Cl and a cationic Rh[BINAP]ClO4. The cyclization by the neutral Rh(PPh3)3Cl proceeded to give cis-3,4-disubstituted cyclo-
pentanones, while that by the cationic Rh[BINAP]ClO4 proceeded to afford trans-3,4-disubstituted cyclopentanones. Four spirodiketones of
six stereoisomers could be prepared in optically active form, and the relationship between the stereochemistry of the spirodiketones and the
Rh-complex was discussed based on the plausible acyl-hydride Rh-complexes. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction1
nonane-2,7-dione, as shown in Fig. 1. One is a one-step
construction, in which the spiro[4.4]nonane skeleton may
be directly formed from symmetrical diene-1,5-dial (i)
using Rh-catalyzed cyclization. The other is a stepwise
method, in which the Rh-catalyzed cyclization would be
used twice to construct spiro[4.4]nonane, and the rings
would be formed step-by-step. It was expected that the
selection between a neutral or a cationic Rh-complex, and
the choice of proper phosphin ligands would afford the
desired optically active spiro compounds stereoselectively.
Some spiro compounds, found as biologically active
products from natural sources,2 have been designed as chiral
ligands for asymmetric reactions,3 and prepared as new
materials. Considerable efforts have been already taken to
synthesize the chiral spiro compounds because construction
of the chiral quaternary carbon in spirane skeletons
continues to be fascinating challenge to organic chemists.4
The chiral quaternary carbon could not yet be easily
constructed by a catalytic asymmetric reaction.5 We have
previously reported the construction of spiro compounds
using enzymatic methods6 and diastereoselective and
enantioselective methods using cycloalkane-1,2-diols as a
chiral auxiliary.7 We have also reported the Rh-catalyzed
cyclization of 4-pentenals,8 and recently, the cyclization
could be applied to the construction of a chiral quaternary
carbon.9 Here, we wish to describe the enantio- and dia-
stereoselective synthesis of 4,9-dimethylspiro[4.4]nonane-
2,7-dione using the Rh-catalyzed cyclization.
2.2. Approach to the construction of spiro[4.4]nonane in
one-step
First, we undertook to construct the spirane skeleton from
diene-dial 5 in one-step using a Rh-complex. The prepa-
ration of 5 was attempted by several routes. Acetylacetone
1 was converted into diester 2 by dialkylation with methyl
bromoacetate in 84% yield. Ole®nation of the 1,3-dicarbo-
nyl function in 2 with Nysted reagent {cyclodibromodi-m-
methylene[m-(tetrahydrofuran)]trizinc}10 afforded diene 3
in 30% yield. The conversion of 3 into the diene-dial 5 by
reduction with DIBAL-H or LiAlH4/DEA11 did not proceed
at all. Next, the ester function in 3 was once reduced to
alcohol, that is to say, the diester 3 was converted to diol
4 in 99% yield. Oxidation of the diol into dialdehyde was
attempted by several reagents and conditions such as PCC,
PDC, and tetrapropylammonium perruthenate (TPAP).12
Unfortunately, the diene-dial 5 was not isolated, but only
d-lactone 6 was obtained as a major product in these
reactions. This result could be attributable to the fact that
2. Results and discussion
2.1. Synthetic strategy
We planned two routes to construct 4,9-dimethylspiro[4.4]-
Keywords: cyclization; spiro compounds; rhodium; asymmetric reactions.
Corresponding authors. Tel.: 181-92-642-6604; fax: 181-92-642-6545;
e-mail: mtanaka@phar.kyushu-u.ac.jp; suemune@phar.kyushu-u.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01106-6

1198
M. Tanaka et al. / Tetrahedron 57 (2001) 1197±1204
Figure 1.
the oxidation of an alcohol afforded not an aldehyde but a
lactol due to the cyclization with another alcohol function
and subsequent oxidation (Scheme 1).
The relative stereochemistry of product 9a was unambigu-
1
ously determined by the NOESY H±1H NMR spectrum.
Correlation between the methyl proton signals d 1.06 (d,
Jˆ7.3 Hz, 3H) and the methylene signals d 2.41±2.50 (m,
2H) was observed. The enantiomeric excess of 9a was deter-
mined to be 95% ee by the 1H NMR and 13C NMR spectra,
after conversion of 9a into the (R,R)-butane-2,3-diol acetal.
Furthermore, the relative and absolute stereochemistries of
(1)-9a were correlated with those of (3R,4R)-3,4-dimethyl-
3-isopropenylcyclopentanone (2)-13 which was obtained
by the Rh[(S)-BINAP]ClO4-catalyzed cyclization.9 There-
fore, the absolute stereochemistry of (2)-9a should be
3S,4S, and that of (1)-9a should be 3R,4R. Cyclization by
the neutral Rh[BINAP]Cl did not proceed at all, due to the
low catalytic activity of the neutral Rh-complex and the
bulkiness of the BINAP ligand. The cyclization of 8 by an
achiral Rh(PPh3)3Cl afforded racemic (^)-9b in the ratio of
2.3. Stepwise construction of spiro[4.4]nonane
Next, we examined the construction of spiro[4.4]nonane by
a stepwise method. It was considered there were several
advantages to the stepwise method as follows: (i) stereo-
chemistry of the cyclized product would be easily expected
from the previous results;8,9 (ii) different diastereomers
could be prepared by changing the kind of Rh-complex in
the ®rst and second cyclization steps; (iii) a minor diastereo-
mer, which was contaminated as a by-product, may be
removed by silica-gel chromatography before the second
Rh-cyclization.
1
92 (cis) and 8 (trans) in 87% yield. In the NOESY H±1H
The 4-pentenal 8 for the ®rst Rh-cyclization was prepared
from the diol 4 by monoacetylation and subsequent oxi-
dation with PCC in 62% overall yields, as depicted in
Scheme 2.
NMR spectra of (^)-9b, correlation between the methyl
proton signals d 0.90 (d, Jˆ7.1 Hz, 3H) at C(4)-position
and the methyl signals d 1.78 (br s, 3H) of isopropenyl
function was observed, and thus, the stereochemistry of
cis-3,4 was determined. The obtained cyclopentanones
9a,b were converted into 4-pentenals 11a,b by solvolysis
of the acetyl function and subsequent oxidation of primary
2.3.1. The ®rst Rh-cyclization. The results of cyclization of
8 by Rh-complexes are summarized in Table 1 (entry 1-3).
The cyclization by the cationic Rh[(R)-BINAP]ClO4
(0.05 equiv.) afforded cyclopentanone (2)-9a in 88%
yield and by the Rh[(S)-BINAP]ClO4 gave (1)-9a in 94%
yield. The ratio of cis and trans in product cyclized by the
cationic Rh[BINAP]ClO4 was 1 (9b, cis) to 99 (9a, trans).
Scheme 1. Reagents and conditions: (i) BrCH2COOCH3, NaH;
(ii) BrCH2COOCH3, t-BuOK; (iii) Nysted reagent, TiCl4; (iv) LiAlH4.
Scheme 2. Reagents and conditions: (i) Ac2O, 4-DMAP, pyridine; (ii) PCC;
(iii) Rh-complex; (iv) K2CO3, MeOH.

Table 1. The ®rst cyclization of 8 and the second cyclization of 11 by the Rh-complexes
Entry
Rh-complex
Product
Entry
Substrate
Rh-complex
Product
Yield (%)
[9b (cis)/9a (trans)]
ee %
Yield (%)
Ratio of
12a:12b:12c
1
Rh[(R)-BINAP]ClO4
88
95
1-1
1-2
1-3
1-4
1-5
(2)-11a
(2)-11a
(2)-11a
(2)-11a
(2)-11a
Rh[(R)-BINAP]ClO4
Rh[(S)-BINAP]ClO4
Rh[(R)-BINAP]Cl
Rh[(S)-BINAP]Cl
Rh(PPh3)3Cl
83
0
97:3:0
(1/99)
±
0
±
±
0
81
4:96:0
2
Rh[(S)-BINAP]ClO4
94
95
2-1
2-2
2-3
2-4
2-5
(1)-11a
(1)-11a
(1)-11a
(1)-11a
(1)-11a
Rh[(R)-BINAP]ClO4
Rh[(S)-BINAP]ClO4
Rh[(R)-BINAP]Cla
Rh[(S)-BINAP]Clb
Rh(PPh3)3Cl
0
94
0
-
(1/99)
97:3:0
-
-
0
90
5:94:1
3
Rh(PPh3)3Cl
87
3-1
(^)-11b
Rh(PPh3)3Cl
85
1:17:82
(92/8)
Cyclizations were carried out in CH2Cl2 using 0.05 equiv. of the cationic Rh-complex or 0.50 equiv. of the neutral Rh-complex at room temperature.
Spirodiketone was not isolated, but decarbonylated product (2)-13 was obtained.
The reaction in re¯uxing benzene afforded the cyclized product (2)-12b in 30% yield.
a
b

1200
M. Tanaka et al. / Tetrahedron 57 (2001) 1197±1204
alcohol, as shown in Scheme 2. The 4-pentenal (2)-11a was
obtained from (2)-9a, (1)-11a from (1)-9a, and (^)-11b
from (^)-9b in 95±98% yields.
2.3.2. The second Rh-cyclization. The results of the second
cyclization by the Rh-complexes are summarized in Table 1
(entry 1-1-5, 2-1-5, and 3-1). The cyclization of (2)-11a by
the neutral Rh[(R)- or (S)-BINAP]Cl did not proceed at all
because of the bulky quaternary carbon at the C(3)-position
and the low reactivity of the neutral Rh[(R)- or (S)-
BINAP]Cl complex. The cyclization of (2)-11a by the
cationic Rh[(S)-BINAP]ClO4 did not proceed, but the cycli-
zation by the cationic Rh[(R)-BINAP]ClO4 proceeded to
afford spirodiketone (1)-12a in 83% yield. The cyclization
of (2)-11a by the achiral Rh(PPh3)3Cl afforded (1)-12b in
81%. The spectroscopic data of (1)-12a and (1)-12b were
apparently different. The cyclization of (1)-11a, the enan-
tiomer of (2)-11a, by the neutral Rh[(R)- or (S)-BINAP]Cl
or the cationic Rh[(R)-BINAP]ClO4 did not proceed at room
temperature, but the cyclization by the cationic Rh[(S)-
BINAP]ClO4 afforded (2)-12a in 94% yield. The cycli-
zation of (1)-11a by the Rh(PPh3)3Cl afforded (2)-12b in
90% yield. In the case that (1)-11a and Rh[(S)-BINAP]Cl
were re¯uxed in benzene, the cyclized product (2)-12b was
also obtained in 30% yield. The cyclization of (^)-11b by
the Rh(PPh3)3Cl afforded (^)-12c in 85% yield. The
spectroscopic data of (^)-12c were different from those of
12a and/or 12b.
Figure 2. ORTEP drawing of spirodiketone (2)-12a.
6H), the signal of 12b at d 1.14, 1.03 (each d, total 6H), and
12c at d 1.12 (d, 6H) in the H NMR spectrum. The dia-
1
stereomeric ratio in entry (1-5 and 2-5) was 4 (12a), 96
(12b), and 0 (12c), and that in entry 3-1 was 1 (12a), 17
(12b), and 82 (12c).
2.4. Stereoselection in the Rh-catalyzed cyclization
The stereoselectivity for the ®rst cyclization was consistent
with the previous experiments.8,9 That is to say, the cycli-
zation by the neutral Rh(PPh3)3Cl gave cis-3,4-cyclopenta-
none (^)-9b by way of the favorable intermediate, whereas
the cyclization by the cationic Rh[(R)-BINAP]ClO4
afforded trans-3,4-product (2)-9a and its absolute stereo-
chemistry would be 3S,4S by way of the most unfavorable
intermediate.
The spirodiketones 12 contain three chiral carbons, and the
C2-axis at the quaternary carbon C(5) exists in some spiro-
diketones; therefore, six stereoisomers, that is to say, three
pairs of enantiomers exist. Thus, the compounds 12a, 12b,
and 12c would be diastereomers. The 13C NMR spectra of
12a and (^)-12c showed six peaks, while those of 12b
showed eleven peaks. These results indicate that the
C2-symmetry exists in the structures 12a and 12c, but not
in 12b. In the NOESY-1H±1H NMR spectrum of 12a, corre-
lation between the methyl proton signals d 1.08 (d,
Jˆ6.9 Hz, 6H) at C(4 and 9)-position and the methylene
signals d 2.31 (d, Jˆ17.6 Hz, 2H) at the C(1 and 6)-position
was observed. In the spectrum of 12b, the correlation
between the methyl proton signals d 1.14 (d, Jˆ6.9 Hz,
3H) at the C(9)-positon and the methine signals d 2.34
(m, 1H) at the C(4)-position and also the methyl signals d
1.03 (d, Jˆ6.9 Hz, 3H) at the C(4)-position and the
methylene signals d 2.50 (d, Jˆ18.0 Hz, 1H) at the C(6)-
position were observed. Moreover, it is already reported that
the stereochemistry of 3,4-substituted cyclopentanones
cyclized from 4-pentenal by the Rh(PPh3)3Cl is cis-3,4.
Furthermore, the relative stereochemistry of (2)-12a
constructed by using the Rh[(S)-BINAP]ClO4 twice was
unambiguously determined to be 4Rp,5Sp,9Rp by the X-ray
crystallographic analysis. The X-ray analysis revealed that
only a half of the spirodiketone (2)-12a existed in the asym-
metric unit, due to the C2-symmetry of the molecule (Fig.
2). Based on these results, we concluded that the stereo-
chemistry of (1)-12a as 4S,5R,9S, (1)-12b as 4S,5R,9R,
and (^)-12c as 4RS,5RS,9RS.
The outcome in the stereochemistry of spirodiketones 12
could be explained as follows: ®rst, the stereochemistry of
C(4)- and C(5)-carbons in the spirodiketones was derived
from the C(4)- and C(3)-carbons of cyclopentanone 9 with
the retention of its chirality, respectively. Thus, the stereo-
chemistry of the C(9)-carbon in spirodiketones 12 was
newly constructed by the second Rh-catalyzed cyclization.
The second cyclization by the neutral Rh(PPh3)3Cl would be
explained by considering the plausible acyl-rhodium inter-
mediates (a±d). The intermediate (a) would be less stable
than the intermediate (b) because the repulsion between the
methyl function at the C(4)-position and the rhodium metal
exists in the intermediate (a). Similarly, the intermediate (c)
would be less stable than the intermediate (d). Conse-
quently, the spirodiketones 12b (entry 1-5, 2-5) and (^)-
12c (entry 3-1) were formed as a major product by way of
the stable intermediates (b and d), as shown in Fig. 3. The
relative stereochemistry of 12b and 12c was cis between the
methyl function at the C(9)-position and the C(4)-carbon of
the spirane skeleton. The second cyclization by the cationic
Rh-complex gave the opposite stereochemistry of the
methyl function at the C(9)-position to that by the neutral
Rh-complex. These phenomena have been already observed
in the Rh-cyclization of 4-pentenals,8,9 and could be
explained by the assumption that the cyclization by the
The diasteromeric ratio of spirodiketones 12 in entry (1-1
and 2-2) was determined to be 97 (12a), 3 (12b), and 0 (12c)
by the ratio of methyl proton signals of 12a at d 1.08 (d,

M. Tanaka et al. / Tetrahedron 57 (2001) 1197±1204
1201
Figure 3. Plausible mechanism for the stereoselection of the second cyclization by the Rh(PPh3)3Cl.
cationic Rh-complex proceeded by way of an unstable inter-
mediate. The cyclization of (2)-11a by the Rh[(R)-BINAP]-
ClO4 proceeded to afford (1)-12a, but not by the Rh[(S)-
BINAP]ClO4. This result would be attributed to the fact that
the absolute stereochemistry of (3S,4S)-(2)-11a was
matched with (R)-BINAP, but mismatched with (S)-BINAP.
4.1.1. Dimethyl 3,3-diacetylglutarate (2). A solution of
acetylacetone (6.00 g, 60 mmol) in THF (20 mL) was
added to a stirred suspension of NaH (2.40 g, 60%) in
THF (60 mL) at 08C, and the whole was stirred at room
temperature for 10 min. Methyl bromoacetate (9.18 g,
60 mmol) in THF (20 mL) was added to the solution at
08C, and stirred overnight at room temperature. The solution
was diluted with brine, extracted with ether, washed with
brine, and dried over MgSO4. After removal of the solvent,
the residue was puri®ed by column chromatography on
silica gel (30% EtOAc in hexane) to give an alkylated
product (9.50 g, 92%) as a colorless oil: 1H NMR
(60 MHz, CDCl3) d 4.13 (t, Jˆ7 Hz, 1H), 3.72 (s, 3H),
2.89 (d, Jˆ7 Hz, 2H), 2.22 (s, 6H). A solution of the alkyl-
ated product (3.44 g, 20 mmol) in t-BuOH (5 mL) was
added dropwise to a stirred solution of t-BuOK (2.70 g,
24 mmol) in t-BuOH (40 mL), and stirred at room tempera-
ture for 30 min. Then, a solution of methyl bromoacetate
(3.68 g, 24 mmol) in t-BuOH (5 mL) was added dropwise,
and stirred at room temperature for 18 h. The reaction was
quenched with saturated aqueous NH4Cl, extracted with
EtOAc, washed with 5% aqueous Na2S2O3, brine, and
dried over MgSO4. Removal of the solvent afforded an
oily residue, which was puri®ed by column chromatography
on silica gel. The fraction eluted with 30% EtOAc in
hexane gave 2 (4.37 g, 91%) as a colorless oil: IR
3. Conclusions
The Rh-catalyzed cyclization was applied to construct the
optically active spiro[4.4]nonane-2,7-dione skeleton. All
diastereomers 12a±c, bearing a chiral quaternary carbon,
could be stereoselectively constructed from the identical
4-pentenal 8 by using the Rh-complex twice. The spiro-
diketones 12a and 12b could be prepared in diastereoselec-
tive and enantioselective manner. The strategy described here
would be useful for the construction of spirane skeletons.
4. Experimental
4.1. General methods
THF was purchased from Kanto Chemical Co., and used
without distillation. Et2O was distilled from Na/benzo-
phenone before use. Benzene and CH2Cl2 were distilled
from P2O5. (R)- and (S)-BINAP were purchased from
1
(neat) 1740, 1710 cm21; H NMR (270 MHz, CDCl3) d
3.67 (s, 6H), 3.28 (s, 4H), 2.18 (s, 6H); EIMS m/z 244
(M1); HRMS calcd for C11H16O6 (M1) 244.0947, found
244.0940.
1
Kanto Chemical Co. Inc. H NMR spectra were deter-
mined at 60, 270 or 500 MHz. Infrared spectra were
recorded on a JASCO A-100 spectrometer (Nujol or
neat). EIMS, FABMS, and HRMS spectra were taken
on a JEOL JMS 610H, D300, or SX102 spectrometer.
General procedures used for syntheses followed those of the
previous reports.8,9
4.1.2. Dimethyl 3,3-diisopropenylglutarate (3). A solution
of 2 (6.10 g, 25 mmol) in THF (100 mL) was added drop-
wise to a vigorously stirred suspension of Nysted reagent
(20% suspension in THF, 148 g) in THF (100 mL) at

1202
M. Tanaka et al. / Tetrahedron 57 (2001) 1197±1204
2788C, and stirred for 15 min. Then, TiCl4 (5.6 mL) was
added dropwise to the stirred mixture at 2788C, and then
the whole was warmed to room temperature, and stirred for
30 min. The mixture was diluted with water, and extracted
with EtOAc. The extract was washed with 5% aqueous
NaHCO3, brine, and dried over MgSO4. After removal of
the solvent, the oily residue was puri®ed by column chroma-
tography on silica gel (2% EtOAc in hexane) to give 3
(1.74 g, 29%) as a colorless oil: IR (neat) 1740,
206 (9), 181 (69), 43 (100); HRMS calcd for C13H20O3 (M1)
224.1412, found 224.1410.
4.1.7. (3S,4S)-3-(2-Acetoxyethyl)-3-isopropenyl-4-methyl-
cyclopentanone (2)-(9a). A solution of [Rh(NBD)(R)-
BINAP]ClO4 (23 mg, 0.025 mmol) in CH2Cl2 (4 mL) was
stirred under an H2 atmosphere at room temperature for
2 h. Then, an Ar gas was bubbled into the solution for
15 min. This bright red solution of [Rh(R)-BINAP]ClO4
was used for the cyclization without isolation. A solution of
4-pentenal 8 (112 mg, 0.50 mmol) in CH2Cl2 (3 mL) was
added dropwise to the stirred solution of [Rh(R)-BINAP]-
ClO4 under an Ar atmosphere. After being stirred for 3 h,
the solution was concentrated in vacuo to leave a residue.
The residue was dissolved in ether (20 mL), and the precipi-
tated Rh-complex was ®ltered off. The concentration of
®ltrate gave an oily residue, which was puri®ed by column
chromatography on silica gel to afford (2)-9a (92 mg, 88%)
1640 cm21 1H NMR (270 MHz, CDCl3) d 4.97 (br s,
;
2H), 4.77 (br s, 2H), 3.62 (s, 6H), 3.02 (s, 4H), 1.65 (br s,
6H); EIMS m/z 240 (M1, 8), 209 (100); HRMS calcd for
C13H20O4 (M1) 240.1361, found 240.1368.
4.1.3. 3,3-Diisopropenyl-1,5-pentanediol (4). A solution of
3 (1.20 g, 5.0 mmol) in ether (30 mL) was added dropwise
to a stirred suspension of LiAlH4 (760 mg, 20 mmol) in
ether (70 mL) at room temperature, and stirred for 5 h.
The reaction was quenched with EtOAc and H2O, then
®ltered through celite, and the ®ltrate was dried over
MgSO4. Removal of the solvent afforded an oily residue,
which was puri®ed by column chromatography on silica gel
(2% EtOAc in hexane) to give 4 (718 mg, 78%) as a color-
as a colorless oil: [a]30 ˆ286.90 (c 2.01, CHCl3); IR (neat)
D
1745, 1635 cm21; 1H NMR (500 MHz, CDCl3) d 4.97 (br s,
1H), 4.75 (br s, 1H), 4.06 (ddd, Jˆ5.3, 8.8, 11.1 Hz, 1H), 3.85
(ddd, Jˆ6.8, 8.6, 11.1 Hz, 1H), 2.57 (dd, Jˆ0.9, 18.3 Hz,
1H), 2.41±2.50 (m, 2H), 2.25 (dd, Jˆ1.4, 18.3 Hz, 1H),
2.03 (s, 3H), 2.02 (ddd, Jˆ5.2, 8.8, 13.9 Hz, 1H), 1.85 (m,
1H), 1.80 (s, 3H), 1.75 (ddd, Jˆ6.6, 8.7, 13.9 Hz, 1H), 1.06
(d, Jˆ7.3 Hz, 3H); 13C NMR (125.7 MHz, CDCl3) d 217.6,
170.9, 146.2, 113.6, 61.9, 48.9, 46.4, 44.4, 36.2, 32.0, 20.9,
19.7, 16.2; EIMS m/z 224 (M1, 2), 181 (4), 164 (13), 140
(20), 122 (41), 94 (71), 79 (100); HRMS calcd for C13H20O3
(M1) 224.1412, found 224.1408.
;
less oil: IR (neat) 3220 (br), 1620 cm21 1H NMR
(270 MHz, CDCl3) d 4.99 (m, 2H), 4.89 (br s, 2H), 3.60
(t, Jˆ6.8 Hz, 4H), 2.22 (br s, 2H), 1.93 (t, Jˆ6.8 Hz, 4H),
1.57 (br s, 6H); FDMS m/z 185 (M111).
4.1.4. 3,3-Diisopropenyl-d-valerolactone (6). IR (neat)
1
1745, 1650 cm21; H NMR (270 MHz, CDCl3) d 5.05 (br
s, 2H), 4.89 (br s, 2H), 4.28 (t, Jˆ5.9 Hz, 2H), 2.66 (br s,
2H), 2.04 (t, Jˆ5.9 Hz, 2H), 1.61 (br s, 3H), 1.59 (br s, 3H);
EIMS m/z 180 (M1, 2), 165 (15), 152 (9), 121 (33), 108 (51),
93 (100); HRMS calcd for C11H16O2 (M1) 180.1150, found
180.1155.
4.1.8. (3R,4R)-3-(2-Acetoxyethyl)-3-isopropenyl-4-methyl-
cyclopentanone (1)-(9a). The cyclization of 8 by the
[Rh(S)-BINAP]ClO4 afforded (1)-9a in 94% yield.
[a]26 ˆ186.0 (c 1.21, CHCl3).
D
4.1.5. 5-Acetoxy-3,3-diisopropenylpentanol (7). A mix-
ture of 4 (9.2 g, 50 mmol), Ac2O (5.1 g, 50 mmol), 4-
DMAP (733 mg, 6.0 mmol) and pyridine (4.7 g, 60 mmol)
in CH2Cl2 (200 mL) was stirred at 08C for 45 min. After
removal of the solvent, the residue was puri®ed by column
chromatography on silica gel (20% EtOAc in hexane) to
afford 7 (7.9 g, 70%) as a colorless oil: IR (neat) 3435
4.1.9. Determination of enantiomeric excess of 9a. The
enantiomeric excesses of 9a were determined by H NMR
1
spectra of acetals derived from (R,R)-2,3-butandiol. A
mixture of cyclopentanone 9a (67 mg, 0.30 mmol), (R,R)-
butanediol (81 mg, 0.90 mmol), and p-TsOH-H2O (10 mg)
in benzene (20 mL) was re¯uxed for 3 h, ®xed with Dean±
Stark apparatus. After being cooled to room temperature,
the solution was washed with 5% aqueous NaHCO3, brine,
and dried over MgSO4. After removal of the solvent, the
residue was brie¯y puri®ed by column chromatography on
silica gel to give the crude acetal. The 1H NMR spectrum of
the butanediol acetal of (2)-9a cyclized by Rh[(R)-
BINAP]ClO4 showed the ole®n proton signals at d 4.846
(br s) and 4.819 (br s) in the ratio of 2 to 98, and the methyl
proton signals at d 0.974 (d, Jˆ6.8 Hz) and 0.958 (d,
Jˆ6.6 Hz) in the same ratio, while that from (1)-9a
cyclized by Rh[(S)-BINAP]ClO4 showed ole®nic signals
at d 4.846 (br s) and 4.819 (br s), and the methyl signals
at d 0.974 (d, Jˆ6.8 Hz) and 0.958 (d, Jˆ6.6 Hz) in the ratio
of 98 to 2. The enantiomeric excesses were also supported
by 13C NMR spectra. (R,R)-2,3-Butanediol acetal of (2)-9a:
13C NMR (125.7 MHz, CDCl3) d 171.1, 147.5, 115.0, 111.7,
78.4, 78.0, 62.6, 49.9, 47.3, 45.7, 39.7, 29.7, 21.0, 20.6,
17.07, 17.06, 14.8; (R,R)-2,3-Butanediol acetal of (1)-9a:
13C NMR (125.7 MHz, CDCl3) d 171.1, 147.4, 115.3, 112.0,
78.3, 78.0, 62.6, 50.0, 46.9, 45.4, 39.4, 31.0, 21.0, 20.4,
17.27, 17.14, 15.2.
(br), 1745, 1635 cm21 1H NMR (270 MHz, CDCl3) d
;
4.99 (br s, 2H), 4.86 (br s, 2H), 3.99 (t, Jˆ7.5 Hz, 2H),
3.60 (t, Jˆ7.8 Hz, 2H), 2.04 (s, 3H), 1.82±1.99 (m, 4H),
1.75 (br, 1H), 1.59 (br s, 6H); FABMS m/z 227 (M11H);
HRFAB(1)MS calcd for C13H23O3 (M11H) 227.1647,
found 227.1650.
4.1.6. 5-Acetoxy-3,3-diisopropenylvaleraldehyde (8). A
mixture of 7 (4.52 g, 20 mmol), PCC (5.2 g, 24 mmol),
and NaOAc (0.40 g, 4.8 mmol) in CH2Cl2 (60 mL) was
stirred at room temperature for 3 h. The mixture was diluted
with ether, and ®ltered through ¯orisil to remove chromate.
The ®ltrate was concentrated in vacuo to leave an oily
residue, which was puri®ed by column chromatography on
silica gel. The fraction eluted with 12% ether in pentane
afforded 8 (3.94 g, 88%) as a colorless oil: IR (neat) 1745,
;
1725 cm21 1H NMR (270 MHz, CDCl3) d 9.62 (t,
Jˆ3.0 Hz, 1H), 5.07 (br s, 2H), 4.87 (br s, 2H), 4.03 (t,
Jˆ7.2 Hz, 2H), 2.60 (d, Jˆ3.0 Hz, 2H), 2.07 (t, Jˆ7.2 Hz,
2H), 2.03 (s, 3H), 1.64 (br s, 6H); EIMS m/z 224 (M1, 1),

M. Tanaka et al. / Tetrahedron 57 (2001) 1197±1204
1203
4.1.10. (3RS,4SR)-3-(2-Acetoxyethyl)-3-isopropenyl-4-
methylcyclopentanone (^)-(9b). solution of
13C NMR (125.7 MHz, CDCl3) d 216.1, 201.4, 145.7, 113.8,
48.3, 47.4, 46.0, 44.1, 36.7, 20.2, 15.6; EIMS m/z 180 (M1,
1), 138 (52), 82 (100); HRMS calcd for C11H16O2 (M1)
180.1150, found 180.1156.
A
8
(112 mg, 0.5 mmol) in CH2Cl2 (2 mL) was added dropwise
to a stirred solution of Rh(PPh3)3Cl (231 mg, 0.25 mmol) in
CH2Cl2 (3 mL), and the solution was stirred overnight at
room temperature. Removal of the solvent afforded a
residue, which was dissolved in ether (30 mL), and the
precipitated Rh-complex was ®ltered off. After removal of
ether, the oily residue was puri®ed by column chroma-
tography on silica gel to afford (^)-9b (97 mg, 87%) as a
4.1.15. (3R,4R)-3-Formylmethyl-3-isopropenyl-4-methyl-
cyclopentanone (1)-(11a). Compound (1)-11a was
prepared from (1)-10a in a similar manner to that described
for the preparation of 8: [a]27 ˆ157.0 (c 1.01, CHCl3).
D
colorless oil: IR (neat) 1745, 1645 cm21
;
1H NMR
4.1.16.
(3RS,4SR)-3-Formylmethyl-3-isopropenyl-4-
(500 MHz, CDCl3) d 4.98 (br s, 1H), 4.68 (s, 1H), 4.02
(ddd, Jˆ5.6, 8.6, 11.2 Hz, 1H), 3.82 (ddd, Jˆ5.9, 8.9,
11.2 Hz, 1H), 2.56 (dd, Jˆ7.9, 19.2 Hz, 1H), 2.50 (d, Jˆ
17.3 Hz, 1H), 2.28 (m, 1H), 2.23 (d, Jˆ17.3 Hz, 1H), 2.04
(m, 1H), 2.03 (m, 1H), 2.01 (s, 3H), 1.78 (br s, 3H), 1.66 (m,
1H), 0.90 (d, Jˆ7.1 Hz, 3H); 13C NMR (125.7 MHz,
CDCl3) d 217.7, 170.9, 145.0, 113.7, 61.5, 50.4, 44.9,
44.7, 38.6, 35.0, 20.9, 19.4, 16.9; EIMS m/z 224 (M1, 2),
182 (4), 164 (17), 140 (16), 122 (46), 94 (68), 79 (100).
methylcyclopentanone (11b). Compound 11b was
prepared from 10b in a similar manner to that described
for the preparation of 8: a colorless oil; IR (neat) 1745,
1
1725, 1640 cm21; H NMR (500 MHz, CDCl3) d 9.58 (t,
Jˆ2.8 Hz, 1H), 5.05 (br s, 1H), 4.78 (br s, 1H), 2.78 (dm,
Jˆ15.6 Hz, 1H), 2.70 (d, Jˆ18.1 Hz, 1H), 2.50 (dd, Jˆ8.24,
19.2 Hz, 1H), 2.38±2.38 (m, 3H), 2.09 (dd, Jˆ3.6, 19.2 Hz,
1H), 1.82 (br s, 3H), 0.94 (d, Jˆ7.1 Hz, 3H); EIMS m/z 180
(M1, 2), 138 (51), 110 (21), 82 (100).
4.1.11. (3S,4S)-3-Isopropenyl-3-(2-hydroxyethyl)-4-methyl-
cyclopentanone (2)-(10a). A mixture of (2)-9a (200 mg,
0.89 mmol) and K2CO3 (123 mg, 0.89 mmol) in MeOH
(20 mL) was stirred overnight at room temperature. After
removal of the solvent, the residue was puri®ed by column
chromatography on silica gel (50% EtOAc in hexane) to
4.1.17.
(4S,5R,9S)-4,9-Dimethylspiro[4.4]nonane-2,7-
dione (1)-12a. A solution of [Rh(NBD)(R)-BINAP]ClO4
(46 mg, 0.050 mmol) in CH2Cl2 (8 mL) was stirred under
an H2 atmosphere at room temperature for 2 h. Then, an Ar
gas was bubbled into the red solution for 30 min. This bright
red solution of [Rh(R)-BINAP]ClO4 was used for the cycli-
zation without isolation. A solution of 4-pentenal (2)-11a
(180 mg, 1.00 mmol) in CH2Cl2 (3 mL) was added dropwise
to the stirred solution of [Rh(R)-BINAP]ClO4 under an Ar
atmosphere. After being stirred at room temperature for 2 h,
the solution was concentrated in vacuo to leave a residue.
The residue was dissolved in ether (20 mL), and the pre-
cipitated Rh-complex was ®ltered off. The concentration of
®ltrate gave an oily residue, which was puri®ed by column
chromatography on silica gel (30% ether in pentane) to
afford (1)-12a (149 mg, 83%) as a colorless solid. Recrys-
tallization from hexane afforded pure (1)-12a as colorless
give (2)-10a (163 mg, quant.) as a colorless oil:
[a]29 ˆ2109.23 (c 1.36, CHCl3); IR (neat) 3450 (br),
D
1
1740, 1640 cm21; H NMR (270 MHz, CDCl3) d 4.95 (br
s, 1H), 4.75 (br s, 1H), 3.64±3.46 (m, 2H), 2.57 (d, Jˆ
18.1 Hz, 1H), 2.35±2.55 (m, 2H), 2.26 (d, Jˆ18.1 Hz,
1H), 1.99 (m, 1H), 1.81 (br s, 3H), 1.69 (m, 1H), 1.55 (br,
1H), 1.07 (d, Jˆ7.0 Hz, 3H); 13C NMR (125.7 MHz,
CDCl3) d 218.0, 147.3, 113.0, 60.3, 49.0, 46.6, 44.4, 36.3,
36.0, 19.9, 16.3; EIMS m/z 182 (M1, 0.6), 167 (2), 138 (39),
83 (100); HRMS calcd for C11H18O2 (M1) 182.1307, found
182.1306.
crystals: mp 143±1448C; [a]26 ˆ1301.8 (c 0.46, CHCl3);
D
4.1.12. (3R,4R)-3-Isopropenyl-3-(2-hydroxyethyl)-4-methyl-
cyclopentanone (1)-(10a). [a]28 ˆ1116.2 (c 1.04,
IR (Nujol) 1745 cm21; 1H NMR (500 MHz, CDCl3) d 2.51
(dd, Jˆ8.0, 18.5 Hz, 2H), 2.38 (m, 2H), 2.31 (d, Jˆ17.6 Hz,
2H), 2.01 (d, Jˆ17.6 Hz, 2H), 1.87 (ddd, Jˆ1.2, 11.6,
18.5 Hz, 2H), 1.08 (d, Jˆ6.9 Hz, 6H); 13C NMR
(125.7 MHz, CDCl3) d 215.7, 50.7, 45.7, 45.1, 35.1, 14.0;
EIMS m/z 180 (M1, 52), 137 (15), 110 (66), 68 (95), 42
(100); HRMS calcd for C11H16O2 (M1) 180.1150, found
180.1153.
D
CHCl3).
4.1.13. (3RS,4SR)-3-Isopropenyl-3-(2-hydroxyethyl)-4-
methylcyclopentanone (^)-(10b). 99% yield from (^)-
9b: IR (neat) 3450 (br), 1740, 1640 cm21 1H NMR
;
(500 MHz, CDCl3) d 4.95 (br s, 1H), 4.69 (br s, 1H),
3.51±3.58 (m, 2H), 2.57 (dd, Jˆ7.5, 18.1 Hz, 1H), 2.49
(d, Jˆ17.9 Hz, 1H), 2.28 (m, 1H), 2.26 (d, Jˆ17.9 Hz,
1H), 2.03 (m, 1H), 1.99 (m, 1H), 1.79 (br s, 3H), 1.61
(ddd, Jˆ6.0, 7.3, 13.0 Hz, 1H), 1.48 (br, 1H), 0.89 (d,
Jˆ7.1 Hz, 3H); EIMS m/z 182 (M1, 16), 138 (36), 83 (100).
4.1.18.
(4R,5S,9R)-4,9-Dimethylspiro[4.4]nonane-2,7-
dione (2)-12a. Cyclization of (1)-11a by the Rh[(S)-
BINAP]ClO4 afforded (2)-12a in 94% yield: colorless crys-
tals; mp 143±1448C (recryst. from hexane); [a]22 ˆ2309.8
D
(c 0.47, CHCl3).
4.1.14. (3S,4S)-3-Formylmethyl-3-isopropenyl-4-methyl-
cyclopentanone (2)-(11a). Compound (2)-11a was
prepared from (2)-10a in a similar manner to that described
for the preparation of 8: 98% yield; a colorless oil;
4.1.19. X-Ray crystallographic analysis of (2)-12a. Data
collection was performed on a Rigaku AFC5R diffract-
ometer, Ni foil ®ltered CuKa radiation. The crystal
remained stable at room temperature during the X-ray
data collection. The structure was solved by direct methods
using shelx 8613 and expanded using Fourier techniques14.
All non-hydrogen atoms were given anisotropic thermal
parameters and hydrogen atoms included in calculated
positions given isotropic thermal parameters. All calculations
[a]28 ˆ248.21 (c 1.57, CHCl3); IR (neat) 1745, 1725,
D
1640 cm21
;
1H NMR (270 MHz, CDCl3) d 9.64 (t,
Jˆ2.6 Hz, 1H), 5.04 (br s, 1H), 4.84 (br s, 1H), 2.78 (dd,
Jˆ2.9, 15.9 Hz, 1H), 2.69 (d, Jˆ18.1 Hz, 1H), 2.45±2.58
(m, 2H), 2.43 (d, Jˆ18.1 Hz, 1H), 2.33 (dd, Jˆ2.1, 15.9 Hz,
1H), 1.92 (m, 1H), 1.85 (br s, 3H), 1.06 (d, Jˆ6.8 Hz, 3H);

1204
M. Tanaka et al. / Tetrahedron 57 (2001) 1197±1204
were performed using the teXsan15 crystallographic pack-
age of Molecular Structure Corporation: solvent of
recryst.ˆhexane, C11H16O2, Mrˆ180.25, tetragonal, space
F.; White, C. T. In The Total Synthesis of Sesquiterpines,
ApSimon, J., Ed.; Wiley: New York, 1983; Vol. 5, pp 264±
313. (b) Crimmins, M. T.; Wang, Z.; McKerlie, L. A. J. Am.
Chem. Soc. 1998, 120, 1747±1756. (c) Stocking, E. M.; Sanz-
Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 2000, 122,
1675±1683.
Ê
group P41212 (No. 92), aˆ7.666, cˆ17.064 A, Vˆ
Ê 3
1002.9 A , Zˆ4, Dcalcdˆ1.194 g cm23
,
m
(CuKa)ˆ
6.43 cm21, no. of observationˆ340 (I.3.0s(I)), Rˆ0.043,
3. (a) Srivastava, N.; Mital, A.; Kumar, A. J. Chem. Soc., Chem.
Commun. 1992, 493±494. (b) Jiang, Y. Z.; Xue, S.; Li, Z.;
Deng, J.; Mi, A.; Chan, A. S. C. Tetrahedron: Asymmetry
1998, 9, 3185±3189. (c) Falck-Pedersen, M. L.; Romming,
C.; Undheim, K. Tetrahedron 1999, 55, 8525±8538.
4. Sannigrahi, M. Tetrahedron 1999, 55, 9007±9071 (and refer-
ences therein).
Rwˆ0.042.
4.1.20. (4S,5R,9R)-4,9-Dimethylspiro[4.4]nonane-2,7-dione
(1)-12b. Cyclization of (2)-11a by the Rh(PPh3)3Cl
afforded (1)-12b in 81% yield:
a colorless oil;
1
[a]21 ˆ133.08 (c 1.23, CHCl3); IR (neat) 1740 cm21; H
D
NMR (500 MHz, CDCl3) d 2.42±2.58 (m, 3H), 2.50 (d,
Jˆ18.0 Hz, 1H), 2.40 (d, Jˆ18.0 Hz, 1H), 2.34 (m, 1H),
2.21 (d, Jˆ18.0 Hz, 1H), 2.06 (d, Jˆ18.0 Hz, 1H), 1.96±
2.10 (m, 2H), 1.14 (d, Jˆ6.9 Hz, 3H), 1.03 (d, Jˆ6.9 Hz,
3H); 13C NMR (125.7 MHz, CDCl3) d 216.5, 216.2, 50.8,
49.3, 46.0, 45.73, 45.72, 38.2, 34.1, 16.4, 14.9; EIMS m/z
180 (M1, 48), 137 (7), 110 (61), 82 (50), 68 (92), 42 (100);
HRMS calcd for C11H16O2 (M1) 180.1150, found 180.1160.
5. Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. Engl.
1998, 37, 388±401.
6. Fujita, T.; Tanaka, M.; Norimine, Y.; Suemune, H.; Sakai, K.
J. Org. Chem. 1997, 62, 3824±3830.
7. (a) Suemune, H.; Maeda, K.; Kato, K.; Sakai, K. J. Chem.
Soc., Perkin Trans. 1 1994, 3441±3447. (b) Yamada, S.;
Karasawa, S.; Takahashi, Y.; Aso, M.; Sakai, K. Tetrahedron
1998, 54, 15555±15566. (c) Sakai, K.; Suemune, H.
Tetrahedron: Asymmetry 1993, 4, 2109±2118.
4.1.21. (4R,5S,9S)-4,9-Dimethylspiro[4.4]nonane-2,7-dione
(2)-12b. Cyclization of (1)-11a by the Rh(PPh3)3Cl
8. (a) Sakai, K.; Ide, J.; Oda, O.; Nakamura, N. Tetrahedron Lett.
1972, 13, 1287±1290. (b) Taura, Y.; Tanaka, M.; Wu, X.-M.;
Funakoshi, K.; Sakai, K. Tetrahedron 1991, 47, 4879±4888.
(c) Sakai, K. J. Synth. Org. Chem. Jpn 1993, 51, 733±743.
(d) Fujio, M.; Tanaka, M.; Wu, X. M.; Funakoshi, K.; Sakai,
K.; Suemune, H. Chem. Lett. 1998, 881±882.
afforded (2)-12b in 90% yield: a colorless oil; [a]21
228.29 (c 1.29, CHCl3).
ˆ
D
4.1.22. (4RS,5RS,9RS)-4,9-Dimethylspiro[4.4]nonane-2,7-
dione (^)-12c. Cyclization of (^)-11b by the Rh(PPh3)3Cl
afforded (^)-12c in 85% yield: a colorless oil; IR (neat)
9. (a) Tanaka, M.; Imai, M.; Fujio, M.; Sakamoto, E.; Takahashi,
M.; Eto-Kato, Y.; Wu, X.-M.; Funakoshi, K.; Sakai, K.;
Suemune, H. J. Org. Chem. 2000, 65, 5806±5816.
(b) Takahashi, M.; Tanaka, M.; Sakamoto, E.; Imai, M.;
Funakoshi, K.; Sakai, K.; Suemune, H. Chem. Pharm. Bull.
2000, 48, 1822±1825.
1
1740 cm21; H NMR (500 MHz, CDCl3) d 2.26±2.57 (m,
4H), 2.27 (d, Jˆ17.6 Hz, 2H), 2.13 (d, Jˆ18.0 Hz, 2H),
2.08 (d, Jˆ18.0 Hz, 2H), 1.12 (d, Jˆ6.6 Hz, 6H); 13C NMR
(125.7 MHz, CDCl3) d 216.8, 50.0, 47.7, 47.0, 37.1, 16.1;
EIMS m/z 180 (M1, 63), 165 (6), 137 (11), 110 (66), 82 (54),
68 (99), 42 (100); HRMS calcd for C11H16O2 (M1) 180.1150,
found 180.1162.
10. Nysted reagent is commercially available from Aldrich Co.:
Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313±
315.
4.1.23. (3R,4R)-3,4-Dimethyl-3-isopropenylcyclopenta-
11. Cha, J. S.; Kwon, S. S. J. Org. Chem. 1987, 52, 5486±5487.
12. Grif®th, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625±1627 (TPAP
oxidation: tetrapropylammonium perruthenate).
25
none (13)9. [a]D ˆ2110.08 (c 1.10, CHCl3); IR (neat)
1
1740, 1630 cm21; H NMR (500 MHz, CDCl3) d 4.89 (m,
1H), 4.84 (br s, 1H), 2.45±2.52 (m, 2H), 2.43 (d, Jˆ18.8 Hz,
1H), 2.12 (d, Jˆ18.8 Hz, 1H), 1.98 (m, 1H), 1.79 (br s, 3H),
1.05 (s, 3H), 0.99 (d, Jˆ6.6 Hz, 3H).
13. Sheldrick, G. M. Crystallographic Computing 3, Oxford
University Press, 1985 (pp 175±189).
14. Beursken, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.;
Garcia-Granda, S.; Gould, R. O.; Smits, J. M. M.; Smykalla,
C. The DIRDIF program system, Technical Report of the
Crystallography Laboratory, University of Nijmegen, The
Netherlands, 1992.
References
1. A part of work has been reported as preliminary communi-
cation. Takahashi, M.; Tanaka, M.; Sakamoto, E.; Imai, M.;
Matsui, A.; Funakoshi, K.; Sakai, K.; Suemune, H.
Tetrahedron Lett. 2000, 41, 7879±7883.
15. Molecular Structure Corporation, 3200 Research Forest Drive,
The Woodlands, TX 77381, USA. teXsan: Crystal Structure
Analysis Package, 1985 and 1992.
2. (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac,