Tandem conjugate addition-aldol cyclization of 2-formylbenzylidenemalonate with ether radicals by the mediation of dimethylzinc

Article abstract of DOI:10.1016/j.tet.2008.11.009

The chemoselective radical conjugate addition reaction of THF or 4,4,5,5-tetramethyl-1,3-dioxolane with 2-formylbenzylidenemalonate gave tandem conjugate addition-aldol cyclization product in one pot. The radical tandem reaction was extended to the asymme

Full text of DOI:10.1016/j.tet.2008.11.009

Tetrahedron 65 (2009) 903–908
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Tetrahedron
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Tandem conjugate addition–aldol cyclization of 2-formylbenzylidenemalonate
with ether radicals by the mediation of dimethylzinc
Ken-ichi Yamada, Masaru Maekawa, Tito Akindele, Yasutomo Yamamoto, Mayu Nakano,
*
Kiyoshi Tomioka
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The chemoselective radical conjugate addition reaction of THF or 4,4,5,5-tetramethyl-1,3-dioxolane with
2-formylbenzylidenemalonate gave tandem conjugate addition–aldol cyclization product in one pot. The
radical tandem reaction was extended to the asymmetric reaction using bis(8-phenylmenthyl) 2-for-
mylbenzylidenemalonate as a chiral Michael acceptor to provide an enantioenriched indane derivative.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 26 September 2008
Received in revised form 28 October 2008
Accepted 4 November 2008
Available online 8 November 2008
1. Introduction
that may attack the internal formyl carbon to give cyclized indanol
skeleton 5 via 7 or 9 in a one pot sequence (Scheme 2).
Our recent report1 indicates that carbon-centered radicals,
generated directly from ethers such as THF (1) or acetals by the
action of dimethylzinc and air,2–4 undergo a chemoselective con-
jugate addition reaction5 with 4-formyl- or 4-iminobenzylidene-
malonate 2 to give the corresponding conjugate addition products
3a with the formyl6 or imino7 group intact (Scheme 1).8 We have
also reported diastereoface-selective addition of acetal radicals to
chiral N-sulfinyl imines providing a reasonably efficient method-
ology for the asymmetric synthesis of oxygenated chiral amine
derivatives.9 With a view of widening the applicability of the rad-
ical reaction, we investigated the conjugate addition of carbon-
centered ether radicals to Michael acceptors having a pendant
formyl group. Sequential conjugate addition and intramolecular
aldol trapping of the resulting carbon-centered radical with the
formyl group produced a cyclic indane skeleton in a single opera-
tion.10,11 We describe herein the tandem conjugate addition of
ether radicals to 2-formylbenzylidenemalonate and aldol cycliza-
tion12,13 giving an indane skeleton, and also application to an
asymmetric reaction.
Requisite benzylidenemalonate 4 was prepared in 59% yield in
one step by heating a mixture of phthalaldehyde (10) and dimethyl
malonate (11) in benzene under Knoevenagel conditions (Scheme 3).
The reaction of 4 with THF (1) proceeded smoothly at room tem-
perature for 17 h to give a mixture of four diastereomers 5 in 79%
yield. The diastereomers of 5 were separated by silica gel column
chromatography (ethyl acetate/toluene 1/5).
Similarly, the reaction of 4,4,5,5-tetramethyl-1,3-dioxolane (12)
with 4 gave a 3/1 mixture of diastereomers 13 in 53% yield (Scheme 4).
The diastereomers of 13 were separated by silica gel column
chromatography (ethyl acetate/hexane 1/4). Recrystallization of the
major diastereomer from ethyl acetate/hexane gave colorless cubes,
whose X-ray diffraction undoubtedly determined the relative
configuration as shown.14 Triethylsilane reduction of the acetal and
benzylic moieties of 13 gave tricyclic lactone 14 as a single di-
astereomer in 61% yield. The stereochemistry was tentatively
O
O
1
Me2Zn
CO2Me
CO2Me
3a 76%
+
CO2Me
CO2Me
THF
rt
O
O
2a
2. Results and discussions
Me2Zn
3a 53%
+
1
Al2O3
BF3•OEt2
2.1. Sequential conjugate addition–aldol cyclization
+
THF
rt
CO2Me
CO2Me
CO2Me
CO2Me
Chemoselective conjugate addition of 1 to 2-formylbenzy-
lidenemalonate 4 would produce radical 6 or anion intermediate 8
H
N
N
Ts
Ts
3b 12%
2b
O
* Corresponding author.
E-mail address: tomioka@pharm.kyoto-u.ac.jp (K. Tomioka).
Scheme 1. Chemoselective conjugate addition of THF radical.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.009

904
K.-i. Yamada et al. / Tetrahedron 65 (2009) 903–908
1
dimethylzinc at room temperature for 18 h to give a 55/33/11/1
mixture of four diastereomers 17 in 50% yield.
+
O
CO2Me
CO2Me
CO2Me
CO2Me
piperidine
CO2 Men
CO2 Men
16
CO2 Men
4
AcOH
O
+
+
10
5
OH
PhMe
reflux, 2 d
59%
CO2 Men
15
O
O
O
CO2Me
CO2Me
CO2Me
CO2Me
O
O
Me2Zn
air
rt, 18 h
50%
55:33:11:1 dr
O
7
O
6
CO2 Men
CO2 Men
Me2Zn
16
12
17
OH
O
O
OMe
O
Me
=
Men Ph
Me
CO2Me
CO2Me
ZnMe
Me
O
Scheme 5. Synthesis and tandem reaction of chiral bis(8-phenylmenthyl) 2-
formylbenzylidenemalonate.
OMe
O
8
9
OZnMe
Scheme 2. Possible tandem radical conjugate addition–aldol cyclization.
Manipulation of 17 was not as easy as that of 13 because of
the bulkiness of the 8-phenylmenthyl ester moieties. The hydroxy
group of 17 was first reduced to give 19 in reasonably high yield
by the tributyltin hydride reduction of chloride 18 (Scheme 6).
The facial selectivity of the radical addition reaction was de-
termined at this stage to be 83/17 by the integration area of 1H
NMR signals at 3.64 and 3.84 ppm, respectively, where one of the
benzylic methylene protons of each isomer appears. Hydrolysis of
phenylmenthyl ester with potassium hydroxide and subsequent
methylation with trimethylsilyldiazomethane gave 20 in 80%
yield. Triethylsilane reduction in trifluoroacetic acid gave chiral
indane derivative 21 quantitatively. Lactonization failed to pro-
ceed because of the trans-configuration of the hydroxymethyl
and ester groups in 21. The absolute configuration was tentatively
assigned as shown based on the analogy to the diastereoface
differentiating radical conjugate addition of simple 8-phenyl-
menthyl benzylidenemalonate.1
piperidine
CO2Me
CO2Me
CHO
CHO
CO2Me
AcOH
+
PhH
reflux, 2 d
59%
CO2Me
11
O
10
4
O
Me2Zn
air
4
+
1
CO2Me
CO2Me
rt, 17 h
79%
39:35:14:11 dr
OH
5
Scheme 3. Synthesis and tandem reaction of 2-formylbenzylidenemalonate.
assigned based on the preferred cis-bicyclo[3.3.0] skeleton. Thus,
two-step conversion of 4 to tricyclic lactone 14 evidently indicated
the usefulness of the chemoselective radical conjugate addition of
ether radicals and tandem radical conjugate addition–aldol cycli-
zation. It is also interesting to find that 4,4,5,5-tetramethyl-1,
3-dioxolane (12) works as a hydroxymethyl equivalent in this two-
step conversion.
O
O
O
O
Bu3SnH
AIBN
SOCl2
NEt3
CO2 Men
CO2 Men
CO2 Men
CO2 Men
17
PhMe
reflux, 1 h
86%
CH2Cl2
reflux, 2 h
71%
18
19
Cl
83:17 dr
O
O
O
1.KOH
Me2Zn
air
O
OH
H
O
aq. DMSO
Et3SiH
CO2Me
CO2Me
+
140 °C, 1 h
Et3SiH
4
O
O
TFA
reflux, 2 h
61%
rt, 5 h
53%
3:1 dr
CO2Me
CO2Me
O
TFA
reflux, 1 h
quant
2.TMSCHN2
PhH/MeOH
rt, 0.5 h
CO2Me
12
OH
20
21
14
13
80%
Scheme 4. Tandem conjugate addition–aldol cyclization.
Scheme 6. Conversion of tandem cyclization product 17 to 21.
2.2. Asymmetric reaction of bis(8-phenylmenthyl)
benzylidenemalonate
3. Summary
In summary, we have developed tandem radical conjugate ad-
dition–aldol cyclization reaction of benzylidenemalonate. In this
reaction, two carbon–carbon bonds could be made in one pot, and
the addition and cyclization product was transformed into tricyclic
lactone. Furthermore, using 8-phenylmenthyl ester, radical tandem
reaction was extended to an asymmetric reaction, which enables
the formation of an enantioenriched indane skeleton.
Extension to an asymmetric reaction was the next challenge.
Bis( -8-phenylmenthyl) 2-formylbenzylidenemalonate (16) was
L
prepared in 59% yield by the condensation of 10 with bis(L-8-
phenylmenthyl) malonate (15)1 under Knoevenagel conditions in
refluxing toluene for 2 days (Scheme 5). Tandem conjugate addi-
tion–aldol cyclization of acetal 12 was mediated by 6 equiv of

K.-i. Yamada et al. / Tetrahedron 65 (2009) 903–908
905
4. Experimental section
4.1. General
by silica gel column chromatography (ethyl acetate/toluene 1/5) of
the mixture obtained above.
The major isomer was isolated as colorless solid of mp 142–
143 ꢁC. Rf¼0.36 (ethyl acetate/toluene 1/5). 1H NMR: 1.58 (m, 1H),
1.72 (m, 1H), 1.96–2.03 (m, 2H), 2.64 (d, J¼5.8, 1H), 3.36 (m, 1H),
3.55 (m, 1H), 3.69 (s, 3H), 3.82 (s, 3H), 3.95 (d, J¼4.0, 1H), 4.25 (ddd,
J¼4.0, 7.0, 7.0, 1H), 6.05 (d, J¼5.8, 1H), 7.24–7.38 (m, 4H). 13C NMR:
25.6 (CH2), 28.9 (CH2), 52.5 (CH), 52.6 (CH3), 52.7 (CH3), 68.2 (CH2),
70.6 (C), 78.3 (CH), 78.9 (CH), 123.8 (CH), 125.7 (CH), 127.7 (CH),
128.0 (CH), 139.9 (C), 142.3 (C), 170.1 (C), 170.3 (C). IR (KBr): 3418,
2962, 1736, 1265, 1203, 1018, 771. FABMS m/z: 321 (MþH).
FABHRMS m/z: 321.1335 (calcd for C17H21O6: 321.1338).
Although a 1.0 M solution of dimethylzinc in hexane is easily
handled and we have not experienced the spontaneous combustion,
dimethylzinc is pyrophoric and there is potential danger of ignition.
All melting points were uncorrected. IR spectra were expressed
in cmꢀ1. All 1H NMR (500 MHz) and 13C NMR (125 MHz) spectra
were measured in CDCl3, except for 17, whose 13C NMR spectrum
was measured in C6D6. 13C NMR peak multiplicity assignments
were made based on DEPT. Chemical shifts and coupling constants
were presented in part per million (
d
) and hertz, respectively. Ab-
The second major isomer was isolated as colorless solid of mp
109–111 ꢁC Rf¼0.25 (ethyl acetate/toluene 1/5). 1H NMR: 1.45 (m,
1H), 1.71–1.83 (m, 3H), 3.06 (d, J¼6.7, 1H), 3.70 (m, 1H), 3.72 (s, 3H),
3.78 (s, 3H), 3.80 (m, 1H), 4.06 (ddd, J¼6.3, 6.3, 8.6, 1H), 4.22 (d,
J¼6.3, 1H), 5.92 (d, J¼6.7, 1H), 7.23–7.32 (m, 3H), 7.38 (m, 1H). 13C
NMR: 25.9 (CH2), 28.3 (CH2), 52.6 (CH3), 52.8 (CH3), 52.9 (CH), 67.9
(CH2), 68.7 (C), 78.2 (CH), 78.5 (CH), 123.8 (CH), 125.4 (CH), 128.0
(CH), 128.6 (CH), 139.7 (C), 141.6 (C), 170.0 (C), 170.2 (C). IR (KBr):
3370, 2953, 2928, 1732, 1435, 1229, 1063, 758. FABMS m/z: 321
(MþH). FABHRMS m/z: 321.1338 (calcd for C17H21O6: 321.1338).
The third major isomer was isolated as colorless oil. Rf¼0.42
(ethyl acetate/toluene 1/5). 1H NMR: 1.74 (m, 1H), 1.81 (m, 1H), 2.05
(m, 1H), 2.12 (m, 1H), 3.31 (m, 1H), 3.67 (m, 1H), 3.67 (s, 3H), 3.79 (s,
3H), 3.88 (d, J¼2.7, 1H), 4.89 (d, J¼12, 1H), 4.91 (m, 1H), 5.40 (d,
J¼12, 1H), 7.23–7.35 (m, 3H), 7.47 (d, J¼7.3, 1H). 13C NMR: 25.7
(CH2), 28.9 (CH2), 52.4 (CH3), 52.9 (CH), 53.0 (CH3), 68.3 (C), 68.4
(CH2), 76.6 (CH), 77.9 (CH), 124.9 (CH), 126.0 (CH), 128.3 (CH), 128.4
(CH), 139.1 (C), 143.7 (C), 168.6 (C), 170.6 (C). IR (neat): 3379, 2955,
1735, 1435, 1273, 1227, 1057, 756. FABMS m/z: 321 (MþH).
FABHRMS m/z: 321.1350 (calcd for C17H21O6: 321.1338).
breviations are as follows: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broad. Column chromatography was carried out
with silica gel. A hexane solution of dimethylzinc was purchased
from Kanto chemical Co., Inc. 4,4,5,5-Tetramethyl-1,3-dioxolane
(12) was prepared according to the reported procedure.15 Before
introduction to a reaction mixture, air was passed through a drying
tube filled with NaOH.
4.2. Procedure for the dimethylzinc-mediated tandem radical
conjugate addition–aldol cyclization of ethers to
alkylidenemalonates
4.2.1. Dimethyl 2-(2-formylbenzylidene)malonate (4)
A mixture of dimethyl malonate (11) (211 mg, 1.6 mmol),
phthaldialdehyde (10) (430 mg, 3.2 mmol), piperidine (0.01 mL),
and acetic acid (0.02 mL) in toluene (5 mL) was stirred at reflux for
48 h under Dean–Stark conditions. The reaction mixture was
cooled to room temperature, diluted with benzene (20 mL), and
then washed successively with 1 N hydrochloric acid, saturated
aqueous sodium bicarbonate, and water. The organic layer was
dried over sodium sulfate and concentrated under reduced pres-
sure to give pale yellow amorphous oil, which was purified by
column chromatography (ethyl acetate/hexane 1/4) to give amor-
phous white solid (234 mg, 59%). Recrystallization from ethyl ace-
tate gave 4 as colorless needles of mp 70–71 ꢁC. Rf¼0.40 (ethyl
acetate/hexane 1/3). 1H NMR: 3.64 (s, 3H), 3.89 (s, 3H), 7.41 (m, 1H),
7.57–7.62 (m, 2H), 7.90 (m, 1H), 8.43 (s, 1H), 10.2 (s, 1H). 13C NMR:
52.3 (CH3), 52.7 (CH3), 129.0 (CH), 129.9 (CH), 131.1 (C), 132.9 (CH),
133.8 (CH), 134.0 (C), 135.3 (C), 142.8 (CH), 164.0 (C), 166.0 (C) 191.7
(CH). MS m/z: 249 (Mþ1), 248 (Mþ), 189 (MꢀCO2Me). IR (KBr):
2955, 1732, 1634, 1259, 1199, 1022, 762. Anal. Calcd for C13H12O5: C,
62.90; H, 4.87. Found: C, 62.82; H, 4.77.
The minor isomer was isolated as colorless oil. Rf¼0.36 (ethyl
acetate/toluene 1/5). 1H NMR: 1.54–2.04 (m, 4H), 3.35 (m, 1H), 3.53
(m, 1H), 3.69 (s, 3H), 3.82 (s, 3H), 3.94 (d, J¼3.7, 1H), 4.24 (m, 1H),
4.91 (d, J¼3.7, 1H), 5.47 (d, J¼3.1, 1H), 7.27–7.47 (m, 4H). 13C NMR:
28.9, 30.1, 52.6, 53.1, 54.4, 66.0, 68.3, 79.4, 79.7, 122.7, 125.0, 125.1,
129.0, 142.0, 142.3, 167.4, 170.4. IR (neat): 3369, 2952, 2926, 1738,
1462, 1435, 1242, 1207, 1055, 756. FABMS m/z: 321 (MþH).
FABHRMS m/z: 321.1335 (calcd for C17H21O6: 321.1338).
4.2.3. Dimethyl 1-hydroxy-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-
yl)indane-2,2-dicarboxylate (13)
To a solution of 4 (248 mg, 1 mmol) in 4,4,5,5-tetramethyl-1,3-
dioxolane (12) (36 mL, 250 mmol) was added a 1.0 M hexane so-
lution of dimethylzinc (6.0 mL, 6.0 mmol), and the whole was
stirred for 5 h at room temperature. The same work-up as for 5 gave
colorless oil, which was purified by column chromatography (ethyl
acetate/hexane 1/5) to give a 3/1 diastereoisomeric mixture of 13
(200 mg, 53%) as colorless oil. The diastereomeric ratio of 13 was
determined by the integration area of 1H NMR signals at 5.31 and
5.46 ppm. The two diastereomers were separated in at most 10 mg
scale by column chromatography (ethyl acetate/hexane 1/4) of the
mixture obtained above.
The major isomer was isolated as colorless solid, which was
recrystallized from ethyl acetate/hexane to give colorless cubes of
mp 140–141 ꢁC, suitable for X-ray diffraction analysis. The relative
configuration was confirmed to be (1RS, 3RS) by X-ray diffraction
(Fig. 1). Rf¼0.27 (ethyl acetate/hexane 1/3). 1H NMR: 0.65 (s, 3H),
0.91 (s, 3H), 1.05 (s, 3H), 1.14 (s, 3H), 2.89 (d, J¼6.1, 1H), 3.68 (s, 3H),
3.82 (s, 3H), 3.97 (d, J¼4.6, 1H), 5.31 (d, J¼4.6, 1H), 6.08 (d, J¼6.1,
1H), 7.23–7.29 (m, 2H), 7.33–7.39 (m, 2H). 13C NMR: 22.2 (CH3), 22.3
(CH3), 23.6 (CH3), 23.7 (CH3), 52.5 (CH3), 52.8 (CH3), 53.1 (CH), 69.0
(C), 79.2 (CH), 82.0 (C), 82.7 (C), 98.6 (CH), 123.1 (CH), 127.5 (CH),
127.8 (CH), 127.9 (CH), 138.3 (C), 141.8 (C), 169.9 (C), 170.0 (C).
FABMS m/z: 379 (MþH). IR (KBr): 3549, 2955, 1736, 1265, 1218,
4.2.2. Dimethyl 1-hydroxy-3-(tetrahydrofuran-2-yl)indane-2,2-
dicarboxylate (5)
A dry three-neck round bottom flask was equipped with a stir
bar and dimethyl 2-(2-formylbenzylidene)malonate (4) (248 mg,
1.0 mmol). The flask was filled with argon by evacuation and
refilled three times. THF (20 mL, 250 mmol) was added at room
temperature. To the stirred solution was added a 1.0 M hexane
solution of dimethylzinc (6.0 mL, 6.0 mmol). The argon source was
replaced with a NaOH drying tube and air was injected into the
reaction mixture via an air bubbler at a rate of 0.5 mL/h. The re-
action mixture was stirred for 17 h followed by quenching with
saturated ammonium chloride (20 mL). The aqueous layer was
extracted with ethyl acetate (3ꢂ20 mL). The combined organic
layers were washed with brine (20 mL), dried over sodium sulfate,
filtered, and concentrated under reduced pressure to give colorless
oil. Column chromatography (ethyl acetate/toluene 1/8) gave a 39/
35/14/11 diastereoisomeric mixture of 5 (252 mg, 79%) as colorless
oil. The diastereomeric ratio of 5 was determined by the integration
area of 1H NMR signals at 6.05, 5.92, 5.40, and 4.91 ppm. The four
diastereomers of 5 were carefully separated at most on 10 mg scale

906
K.-i. Yamada et al. / Tetrahedron 65 (2009) 903–908
bicarbonate, and water. The organic layer was dried over sodium
sulfate and concentrated under reduced pressure to give pale yel-
low amorphous oil, which was purified by column chromatography
(ethyl acetate/hexane 1/16) to give 16 (609 mg, 59%) as white solid
25
of mp 73–75 ꢁC and [
a
]
ꢀ18.2 (c 1.00, CHCl3). Rf¼0.40 (ethyl ac-
D
etate/hexane 1/16). 1H NMR: 0.35 (m, 1H), 0.62 (m, 1H), 0.73–1.73
(m, 13H), 0.76 (d, J¼6.8, 3H), 0.93 (d, J¼6.8, 3H), 1.07 (s, 3H), 1.09 (s,
3H), 1.25 (s, 3H), 1.38 (s, 3H), 2.08 (m, 1H), 4.73 (ddd, J¼4.0, 11, 11,
1H), 5.00 (ddd, J¼4.0, 11, 11, 1H), 6.89 (m, 1H), 7.08–7.33 (m, 10H),
7.42 (s, 1H), 7.47–7.57 (m, 2H), 7.87 (d, J¼7.3, 1H), 9.97 (s, 1H). 13C
NMR: 21.6 (CH3), 21.7 (CH3), 23.9 (CH3), 25.4 (CH3), 26.6 (CH2), 27.0
(CH2), 27.7 (CH3), 28.6 (CH3), 31.0 (CH), 31.3 (CH), 34.2 (CH2), 34.5
(CH2), 39.7 (C), 39.9 (C), 40.5 (CH2), 41.6 (CH2), 50.3 (CH), 50.5 (CH),
76.0 (CH), 76.6 (CH), 124.9 (CH), 125.1 (CH), 125.5 (CH), 125.6 (CH),
127.8 (CH), 128.0 (CH), 129.4 (CH), 129.9 (CH), 130.6 (CH), 130.7 (C),
133.5 (CH), 133.6 (C), 136.3 (C), 140.2 (CH), 150.7 (C), 151.5 (C), 162.3
(C), 164.4 (C), 191.1 (CH). IR (KBr): 2955, 2924, 1728, 1705, 1258,
1219, 1057, 764, 702. FABMS m/z: 649 (MþH). FABHRMS m/z:
649.3890 (calcd for C43H53O5: 649.3893).
4.3.2. Bis((1R,2S,5R)-5-methyl-2-(2-phenylpropan-2-yl)cyclohexyl)
1-hydroxy-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)indane-2,2-
dicarboxylate (17)
Figure 1. ORTEP (50% probability) of the major isomer of 13.
To a solution of 16 (648 mg, 1.0 mmol) in 4,4,5,5-tetramethyl-
1,3-dioxolane (12) (36 mL, 250 mmol) was added a 1.0 M hexane
solution of dimethylzinc (6.0 mL, 6.0 mmol), and the whole was
stirred for 18 h at room temperature. The same work-up as for 5
gave colorless oil, which was purified by column chromatography
(ethyl acetate/hexane 1/5) to give a 55/33/11/1 diastereoisomeric
1134. Anal. Calcd for C20H26O7: C, 63.48; H, 6.93. Found: C, 63.27; H,
6.74.
The minor isomer was isolated as colorless oil. Rf¼0.23 (ethyl
acetate/hexane 1/3). 1H NMR: 0.62 (s, 3H), 1.09 (s, 3H), 1.12 (s, 3H),
1.21 (s, 3H), 3.66 (s, 3H), 3.80 (s, 3H), 3.95 (d, J¼4.6, 1H), 4.72 (d,
J¼9.2, 1H), 5.46 (d, J¼9.2, 1H), 5.87 (d, J¼4.6, 1H), 7.27–7.29 (m, 2H),
7.43–7.45 (m, 2H). 13C NMR: 22.1 (CH3), 22.7 (CH3), 23.3 (CH3), 23.8
(CH3), 52.4 (CH3), 53.1 (CH3), 53.6 (CH), 66.8 (C), 78.4 (CH), 82.4 (C),
82.7 (C), 98.5 (CH), 124.7 (CH), 127.7 (CH), 127.8 (CH), 128.4 (CH),
139.2 (C), 142.9 (C), 168.9 (C), 170.0 (C). IR (neat): 3549, 2955, 1736,
1265, 1218, 1134. FABMS m/z: 379 (MþH). FABHRMS m/z: 379.1755
(calcd for C20H27O7: 379.1757).
mixture of 17 (388 mg, 50%) as colorless solid of mp 73–79 ꢁC and
25
[a
]
ꢀ16.0 (c 1.00, CHCl3). The diastereomeric ratio of 17 was de-
D
termined by the integration area of 1H NMR signals at 2.74, 3.79,
3.36, and 2.85 ppm.
The 55/33/11/1 diastereomeric mixture of 17: Rf¼0.38 (ethyl
acetate/hexane 1/16). 1H NMR: 0.07 (s, 0.03H), 0.23 (s, 0.99H), 0.27
(s, 0.33H), 0.32 (s, 1.65H), 0.23–2.47 (m, 43H), 2.61 (d, J¼8.3, 0.01H),
2.74 (d, J¼5.8, 0.55H), 2.78 (d, J¼5.5, 0.11H), 2.85 (d, J¼1.9, 0.01H),
3.36 (d, J¼3.1, 0.11H), 3.79 (d, J¼2.7, 0.33H), 3.91 (d, J¼3.1, 0.55H),
4.76–5.12 (m, 2H), 4.92 (d, J¼12, 0.33H), 5.40 (d, J¼3.1, 0.11H), 5.42
(d, J¼12, 0.33H), 5.59 (d, J¼1.9, 0.01H), 5.69 (d, J¼8.3, 0.01H), 5.74–
5.76 (m, 1.1H), 6.01 (d, J¼5.5, 0.11H), 6.14 (d, J¼2.7, 0.33H), 6.92–7.47
(m,14H). 13C NMR (C6D6), major: 21.8 (CH3), 22.04 (CH3), 22.3 (CH3),
22.6 (CH3), 23.1 (CH3), 24.1 (CH3), 24.5 (CH3), 27.6 (CH2), 27.77
(CH2), 30.3 (CH3), 31.21 (CH), 31.3 (CH3), 31.5 (CH), 34.3 (CH2), 34.67
(CH2), 40.5 (C), 40.6 (C), 41.85 (CH2), 42.4 (CH2), 50.59 (CH), 50.77
(CH), 52.4 (CH), 70.3 (C), 76.9 (CH), 77.5 (CH), 79.9 (CH), 82.29 (C),
82.6 (C), 99.1 (CH), 124.0 (CH), 125.6 (CH), 125.8 (CH), 126.2 (CH),
126.3 (CH), 127.2 (CH), 127.9 (CH), 128.22 (CH), 128.36 (CH), 128.44
(CH), 139.1 (C), 144.0 (C), 150.3 (C), 150.9 (C), 169.06 (C), 169.9 (C);
second major: 21.9 (CH3), 22.00 (CH3), 22.14 (CH3), 22.97 (CH3),
22.99 (CH3), 24.00 (CH3), 26.7 (CH3), 27.4 (CH2), 27.5 (CH3), 28.0
(CH2), 30.3 (CH3), 31.15 (CH), 31.3 (CH3), 31.7 (CH), 34.9 (CH2), 35.1
(CH2), 40.3 (C), 40.9 (C), 41.77 (CH2), 42.1 (CH2), 50.2 (CH), 51.3 (CH),
53.1 (CH), 69.4 (C), 76.8 (CH), 77.6 (CH), 78.1 (CH), 83.0 (C), 98.3
(CH), 125.2 (CH), 125.7 (CH), 125.88 (CH), 126.02 (CH), 126.4 (CH),
127.8 (CH), 128.2 (CH), 128.30 (CH), 128.40 (CH), 128.5 (CH), 139.17
(C), 145.7 (C), 150.2 (C), 150.8 (C), 167.2 (C), 169.5 (C); third major:
21.7 (CH3), 21.95 (CH3), 22.11 (CH3), 22.9 (CH3), 23.0 (CH3), 24.01
(CH3), 24.3 (CH3), 26.5 (CH3), 26.9 (CH2), 27.1 (CH3), 27.81 (CH2),
30.4 (CH3), 31.1 (CH), 31.5 (CH), 34.2 (CH2), 34.69 (CH2), 39.9 (C),
40.7 (C), 41.5 (CH2), 41.77 (CH2), 50.2 (CH), 50.6 (CH), 51.0 (CH), 70.9
(C), 76.8 (CH), 77.2 (CH), 79.2 (CH), 82.0 (C), 82.32 (C), 99.3 (CH),
123.2 (CH), 125.8 (CH), 125.93 (CH), 126.3 (CH), 127.0 (CH), 127.5
(CH), 127.7 (CH), 128.30 (CH), 128.43 (CH), 128.6 (CH), 139.9 (C),
144.1 (C), 150.9 (C), 151.6 (C), 169.1 (C), 169.5 (C). IR (KBr): 3410,
2955, 1728, 1450, 1373, 1250, 1211, 1157, 1134, 1087, 972, 764, 702.
4.2.4. Methyl 1-oxo-3,3a,8,8a-tetrahydro-1H-indeno[2,1-c]furan-
8a-carboxylate (14)
A mixture of 13 (71 mg, 0.18 mmol) and triethylsilane (0.31 mL,
2.0 mmol) in TFA (3 mL) was stirred under reflux for 2 h. The
mixture was cooled to room temperature and then concentrated to
give colorless oil (67 mg). Silica gel column chromatography (ethyl
acetate/hexane 1/5) gave 14 (25.6 mg, 61%) as colorless solid, which
was recrystallized from CHCl3 to give colorless needles of mp 103–
104 ꢁC. Rf¼0.45 (ethyl acetate/hexane 1/3). 1H NMR: 3.61 (d, J¼17,
1H), 3.77 (d, J¼17,1H), 3.85 (s, 3H), 4.26 (d, J¼6.4,1H), 4.54 (d, J¼8.9,
1H), 4.83 (dd, J¼6.4, 8.9, 1H), 7.22–7.30 (m, 4H). 13C NMR: 39.2
(CH2), 51.4 (CH), 53.3 (CH3), 60.2 (C), 72.7 (CH2), 123.7 (CH), 124.9
(CH), 128.0 (CH), 128.8 (CH), 140.1 (C), 140.3 (C), 169.3 (C), 175.8 (C).
IR (KBr): 1774, 1736, 1257, 1150. MS m/z: 233 (Mþ1), 232 (Mþ), 128
(MꢀCO2H). Anal. Calcd for C13H12O4: C, 67.23; H, 5.21. Found: C
67.04; H, 5.14.
4.3. Asymmetric reaction of bis(8-phenylmenthyl) 2-
formylbenzylidenemalonate
4.3.1. Bis((1R,2R,5S)-5-methyl-2-(2-phenylpropan-2-yl)cyclohexyl)
2-(2-formylbenzylidene)malonate (16)
A
mixture of bis((1R,2S,5R)-5-methyl-2-[2-phenylpropan-2-
yl]cyclohexyl) malonate (15)1 (870 mg, 1.6 mmol), phthaldialde-
hyde (10) (430 mg, 3.2 mmol), piperidine (0.01 mL), and acetic acid
(0.02 mL) in toluene (5 mL) was stirred at reflux for 48 h under
Dean–Stark conditions. The reaction mixture was cooled to room
temperature, diluted with toluene (20 mL), and then washed suc-
cessively with 1 N hydrochloric acid, saturated aqueous sodium

K.-i. Yamada et al. / Tetrahedron 65 (2009) 903–908
907
FABMS m/z: 801 (MþNa). FABHRMS m/z: 801.4721 (calcd for
(CH2), 39.2 (CH2), 40.29 (C), 40.5 (C), 41.3 (CH2), 41.4 (CH2), 50.1
(CH), 50.3 (CH), 53.3 (CH), 64.78 (C), 76.69 (CH), 76.8 (CH), 81.9 (C),
82.15 (C), 99.1 (CH), 123.5 (CH), 125.3 (CH), 125.38 (CH), 125.6 (CH),
125.8 (CH), 125.9 (CH), 127.3 (CH), 127.89 (CH), 127.92 (CH), 128.01
(CH), 139.3 (C), 142.3 (C), 149.9 (C), 150.6 (C), 168.6 (C), 170.8 (C). 13C
NMR minor: 21.75 (CH3), 22.1 (CH3), 22.5 (CH3), 22.6 (CH3), 23.24
(CH3), 23.66 (CH3), 23.8 (CH3), 27.7 (CH2), 27.84 (CH2), 30.5 (CH3),
31.09 (CH3), 31.1 (CH), 31.27 (CH), 31.6 (CH3), 34.3 (CH2), 38.6 (CH2),
39.6 (CH2), 40.26 (C), 40.7 (C), 41.0 (CH2), 41.5 (CH2), 50.2 (CH), 50.6
(CH), 54.6 (CH), 64.76 (C), 76.73 (CH), 76.9 (CH), 81.8 (C), 82.20 (C),
98.8 (CH), 123.4 (CH), 125.1 (CH), 125.44 (CH), 125.7 (CH), 126.0
(CH), 127.6 (CH), 128.00 (CH), 128.1 (CH), 140.0 (C), 141.1 (C), 150.0
(C), 150.8 (C), 169.0 (C), 170.7 (C). IR (KBr): 2924, 1720, 1458, 1373,
1250, 1157, 1065, 972, 764, 702. FABMS m/z: 763 (MþH). FABHRMS
m/z: 763.4930 (calcd for C50H67O6: 763.4938).
C50H66O7Na: 801.4706).
4.3.3. Bis((1S,2R,5S)-5-methyl-2-(2-phenylpropan-2-yl)cyclohexyl)
1-chloro-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)indane-2,2-
dicarboxylate (18)
To a solution of 17 (222 mg, 0.28 mmol) and triethylamine
(0.12 mL) in dry dichloromethane (1 mL) was added thionyl chlo-
ride (0.04 mL, 0.6 mmol) dropwise at 0 ꢁC. After stirring for 0.5 h at
0 ꢁC, the mixture was heated under reflux for 2 h. The mixture was
cooled to 0 ꢁC and poured into ice water. The aqueous layer was
extracted with chloroform, and the combined organic layers were
washed with brine, dried over Na2SO4, and concentrated to give
dark brown oil (276 mg), which was purified by column chroma-
tography (ethyl acetate/hexane 1/20) to give a 71/15/8/6 di-
25
astereoisomeric mixture of 18 (167 mg, 71%) as yellow solid of [a]
D
ꢀ25.2 (c 1.00, CHCl3). Rf¼0.50 (ethyl acetate/hexane 1/16). The di-
astereomeric ratio of 18 was determined by the integration area of
1H NMR signals at 6.08, 5.65, 6.10, and 5.72 ppm.
4.3.5. Methyl 1-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)indane-2-
carboxylate (20)
A mixture of 19 (84 mg, 0.11 mmol) and 4 M aq KOH (0.4 mL,
2 mmol) in DMSO (2 mL) was stirred at 140 ꢁC for 2 h, and then
diluted with 2 mL of ice water and 2 mL of diethyl ether. The
aqueous layer was extracted with diethyl ether, and the combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated to give pale yellow oil. Silica gel column chromato-
1H NMR: 0.07 (s, 0.5H), 0.16 (s, 0.2H), 0.21 (s, 0.2H), 0.22 (s, 2.1H),
0.50–2.55 (m, 43H), 2.97 (d, J¼7.0, 0.15H), 3.24 (d, J¼2.8, 0.06H),
3.51 (d, J¼7.1, 0.08H), 3.95 (d, J¼2.8, 0.71H), 4.75–5.26 (m, 2H), 5.28
(d, J¼7.0, 0.15H), 5.35 (d, J¼2.8, 0.06H), 5.37 (d, J¼7.1, 0.08H), 5.65 (s,
0.15H), 5.72 (s, 0.06H), 5.78 (d, J¼2.8, 0.71H), 6.08 (s, 0.71H), 6.10 (s,
0.08H), 6.49–7.52 (m, 14H). 13C NMR, major isomer: 21.67 (CH3),
21.70 (CH3), 21.92 (CH3), 22.24 (CH3), 22.9 (CH3), 23.0 (CH3), 23.6
(CH3), 27.3 (CH2), 27.48 (CH2), 31.0 (CH3), 31.1 (CH3), 31.2 (CH), 31.4
(CH), 34.2 (CH2), 34.3 (CH2), 40.35 (C), 40.43 (C), 41.4 (CH2), 42.2
(CH2), 50.46 (CH), 50.50 (CH), 53.1 (CH), 64.5 (CH), 69.2 (C), 77.3
(CH), 77.5 (CH), 82.4 (C), 82.6 (C), 98.4 (CH), 124.0 (CH), 125.2 (CH),
125.3 (CH), 125.4 (CH), 125.71 (CH), 125.73 (CH), 125.8 (CH), 127.58
(CH), 127.87 (CH), 128.0 (CH), 138.7 (C), 141.4 (C), 150.3 (C), 150.53
(C), 167.5 (C), 168.7 (C); other isomers: 21.2 (CH3), 21.3 (CH3), 21.51
(CH3), 21.54 (CH3), 21.61 (CH3), 21.63 (CH3), 21.87 (CH3), 22.02
(CH3), 22.04 (CH3), 22.11 (CH3), 22.13 (CH3), 22.21 (CH3), 22.3 (CH3),
22.4 (CH3), 22.5 (CH3), 22.7 (CH3), 23.5 (CH3), 23.8 (CH3), 24.0 (CH3),
27.51 (CH2), 27.4 (CH2), 29.5 (CH2), 31.21 (CH), 31.30 (CH), 34.1
(CH2), 34.4 (CH2), 34.5 (CH2), 34.6 (CH2), 40.5 (C), 40.6 (C), 41.0
(CH2), 41.3 (CH2), 41.6 (CH2), 42.0 (CH2), 50.0 (CH), 50.1 (CH), 50.5
(CH), 50.9 (CH), 53.7 (CH), 66.0 (CH), 68.4 (C), 68.9 (C), 70.3 (C), 76.1
(CH), 77.2 (CH), 77.9 (CH), 81.7 (C), 82.2 (C), 100.8 (CH), 123.7 (CH),
125.0 (CH), 125.2 (CH), 125.5 (CH), 125.71 (CH), 127.64 (CH), 127.92
(CH), 137.7 (C), 139.9 (C), 140.0 (C), 150.50 (C), 150.6 (C), 151.1 (C),
165.5 (C),169.2 (C). IR (KBr): 2924,1737,1732,1258,1199,1163,1134,
1078, 759, 700. FABMS m/z: 797 (MþH). FABHRMS m/z: 797.4527
(calcd for C50H66O6Cl: 797.4548).
graphy (ethyl acetate/hexane 1/12) recovered L-8-phenylmenthol
(51 mg, quant) as colorless oil. In turn, the combined aqueous layers
were acidified with 10% HCl (2 mL) at 0 ꢁC and extracted with
diethyl ether. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated. The resulting crude oil
in benzene (3.5 mL) and MeOH (0.5 mL) was treated with 1 M
hexane solution of TMSCHN2 at room temperature. The mixture
was stirred until gas evolution ceased, and subsequently concen-
trated to give colorless oil (98.3 mg). Silica gel column chroma-
tography (ethyl acetate/hexane 1/10) gave 20 (26.7 mg, 80%) as
25
colorless oil of [
a
]
D
ꢀ46.1 (c 1.33, CHCl3). Rf¼0.31 (ethyl acetate/
hexane 1/15). 1H NMR: 1.18 (s, 3H), 1.19 (s, 3H), 1.20 (s, 3H), 1.21 (s,
3H), 3.15 (m,1H), 3.23–3.29 (m, 2H), 3.72 (s, 3H), 3.77 (dd, J¼6.1, 6.4,
1H), 5.11 (d, J¼6.4, 1H), 7.16–7.19 (m, 3H), 7.44 (m, 1H). 13C NMR:
22.2 (CH3), 22.3 (CH3), 23.9 (CH3), 24.1 (CH3), 36.0 (CH2), 45.4 (CH),
51.8 (CH3), 54.3 (CH), 81.9 (C), 82.4 (C), 102.2 (CH), 124.2 (CH), 125.7
(CH), 126.6 (CH), 127.4 (CH), 141.0 (C), 142.2 (C), 175.9 (C). IR (neat):
2982, 2951, 1738, 1442, 1369, 1221, 1163, 1134, 750. FABMS m/z: 305
(MþH). FABHRMS m/z: 305.1721 (calcd for C18H25O4: 305.1753).
4.3.6. Methyl 1-(hydroxymethyl)indane-2-carboxylate (21)
A mixture of 20 (26 mg, 0.08 mmol) and triethylsilane (0.08 mL,
0.8 mmol) in TFA (0.5 mL) was stirred under reflux for 1 h. The
mixture was cooled to room temperature and then concentrated to
give colorless oil (27.8 mg). Silica gel column chromatography
4.3.4. Bis((1S,2R,5S)-5-methyl-2-(2-phenylpropan-2-yl)cyclohexyl)
1-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)indane-2,2-
dicarboxylate (19)
(ethyl acetate/hexane 1/12) gave 21 (20.6 mg, quant) as colorless oil
25
A
mixture of 18 (166 mg, 0.21 mmol), Bu3SnH (0.14 mL,
of [
a
]
D ꢀ39.2 (c 0.95, CHCl3). Rf¼0.33 (ethyl acetate/hexane 1/15).
0.5 mmol), and AIBN (7 mg, 0.03 mmol) in toluene (2 mL) was
stirred under reflux for 1 h. Concentration gave colorless oil, which
was purified by silica gel column chromatography to give an 83/17
1H NMR: 3.15 (ddd, J¼7.6, 8.0, 9.5, 1H), 3.26 (dd, J¼7.6, 16, 1H), 3.30
(dd, J¼9.5, 16, 1H), 3.75 (s, 3H), 3.98 (ddd, J¼5.5, 7.1, 7.6, 1H), 4.62
(dd, J¼7.1, 11, 1H), 4.69 (dd, J¼5.5, 11, 1H), 7.19–7.28 (m, 4H). 13C
NMR: 35.2 (CH2), 47.0 (CH), 47.1 (CH), 52.2 (CH3), 69.5 (CH2), 123.7
(CH), 124.8 (CH), 127.2 (CH), 128.1 (CH), 139.8 (C), 141.5 (C), 174.5 (C).
IR (neat): 3395, 2955, 1790, 1736, 1218, 1165, 756. FABMS m/z: 207
(MþH). FABHRMS m/z: 207.1062 (calcd for C12H15O3: 207.1021).
diastereoisomeric mixture of 19 (77.3 mg, 86%) as colorless solid of
25
mp 50–55 ꢁC and [
a
]
ꢀ19.4 (c 1.17, CHCl3). Rf¼0.55 (ethyl acetate/
D
hexane 1/16). The diastereomeric ratio of 19 was determined by the
integration area of 1H NMR signals at 3.64 and 3.84 ppm.
1H NMR, major: 0.47 (s, 3H), 0.65–2.17 (m, 43H), 3.37 (d, J¼16,
1H), 3.64 (d, J¼16,1H), 4.05 (d, J¼4.0,1H), 4.82 (m,1H), 4.98 (m,1H),
5.72 (d, J¼4.0, 1H), 7.07–7.38 (m, 14H); minor: 0.63 (s, 3H), 0.65–
2.23 (m, 43H), 3.32 (d, J¼16, 1H), 3.84 (d, J¼16, 1H), 4.07 (d, J¼4.6,
1H), 4.82 (m, 1H), 4.98 (m, 1H), 5.28 (d, J¼4.6, 1H), 7.07–7.38 (m,
14H). 13C NMR major: 21.7 (CH3), 21.79 (CH3), 22.3 (CH3), 22.7 (CH3),
23.18 (CH3), 23.35 (CH3), 23.38 (CH3), 23.69 (CH3), 27.4 (CH2), 27.75
(CH2), 30.8 (CH3), 30.9 (CH3), 31.13 (CH), 31.30 (CH), 34.2 (CH2), 34.4
Acknowledgements
This research was partially supported by the 21st Century Center
of Excellence Program ‘Knowledge Information Infrastructure for
Genome Science’ and a Grant-in-Aid for Young Scientist (B) from
JSPS, a Grant-in-Aid for Scientific Research on Priority Areas ‘Ad-
vanced Molecular Transformations’ from the Ministry of Education,

908
K.-i. Yamada et al. / Tetrahedron 65 (2009) 903–908
9. Akindele, T.; Yamamoto, Y.; Maekawa, M.; Umeki, H.; Yamada, K.; Tomioka, K.
Org. Lett. 2006, 8, 5729–5732.
10. Reviews for radical conjugate addition: (a) Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vols. 1 and 2; (b)
Srikanth, G. S. C.; Castle, S. L. Tetrahedron 2005, 61, 10377–10441.
Culture, Sports, Science and Technology, Japan, and Targeted Pro-
teins Research Program from Japan Science and Technology Agency.
M.M. and T.A. thank JSPS for a fellowship.
11. Recent examples for conjugate addition of
a-hydroxy or a-alkoxyalkyl radi-
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