Pd-catalyzed asymmetric allylic alkylation of 2-substituted cycloalkenyl carbonates using a chiral diaminophosphine oxide: (S,RP)-Ph-DIAPHOX

Article abstract of DOI:10.1016/j.tetasy.2008.03.027

A Pd-catalyzed asymmetric allylic alkylation of 2-substituted cycloalkenyl carbonates using a chiral diaminophosphine oxide is described. Asymmetric allylic substitution of various cyclic substrates proceeded using 5 mol % of Pd catalyst, 10 mol % of (S,R

Full text of DOI:10.1016/j.tetasy.2008.03.027

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1106–1113
Pd-catalyzed asymmetric allylic alkylation of 2-substituted
cycloalkenyl carbonates using a chiral diaminophosphine oxide:
(S,RP)-Ph-DIAPHOX
Long Jin, Tetsuhiro Nemoto, Hiroshi Nakamura and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 14 March 2008; accepted 26 March 2008
Abstract—A Pd-catalyzed asymmetric allylic alkylation of 2-substituted cycloalkenyl carbonates using a chiral diaminophosphine oxide
is described. Asymmetric allylic substitution of various cyclic substrates proceeded using 5 mol % of Pd catalyst, 10 mol % of (S,RP)-Ph-
DIAPHOX 1, 10 mol % of LiOAc, and N,O-bis(trimethylsilyl)acetamide (BSA), to afford the corresponding products in excellent yields
with up to 92% ee.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Pd-catalyzed asymmetric allylic substitution of cycloalken-
yl alcohol derivatives is one of the most powerful methods
for introducing chirality on the allylic carbon in a cyclic
framework. The cyclic products obtained from this type
of reaction can be utilized as versatile chiral building blocks
for organic synthesis. Therefore, various reaction systems
using carbon nucleophiles, nitrogen nucleophiles, and oxy-
gen nucleophiles, have been developed.1 There are many
reports of asymmetric allylic substitution using simple
cycloalkenyl alcohol derivatives as substrates. However,
only limited success in the asymmetric allylic substitution
of 2-substituted cycloalkenyl alcohol derivatives has been
reported so far.2–4 We recently reported the Pd-catalyzed
asymmetric allylic amination of various 2-substituted
cycloalkenyl alcohol derivatives using chiral diaminophos-
phine oxide preligands: DIAPHOXs (Fig. 1). Primary
amines, secondary amines, and aromatic amines are appli-
cable to this reaction system, and cycloalkenyl amines with
a substituent at the 2-position were obtained in excellent
yield and enantioselectivity.5 In contrast, the asymmetric
allylic alkylation with dimethyl malonate proceeded slowly
under the same reaction conditions, affording the corre-
sponding product with only moderate yield and enantio-
selectivity (e.g., Table 1, entry 1). We anticipated that we
HN
N
H
O
(
S,R )-Ph-DIAPHOX 1
P
P
N
H
Figure 1.
could overcome this drawback by tuning the reaction con-
ditions. Herein, we report an asymmetric allylic alkylation
of 2-substituted cycloalkenyl carbonates with malonate
nucleophiles6 using the Pd-DIAPHOX catalyst system.7,8
Further transformations of the reaction adducts into chiral
heterocyclic compounds with a quaternary stereocenter are
also described.
2. Results and discussion
2.1. Asymmetric allylic alkylation of 2-substituted cyclo-
alkenyl carbonates using the Pd-DIAPHOX catalyst system
We first optimized the reaction conditions using asymmet-
ric allylic alkylation of 2-phenylcyclohexenyl carbonate 2a
with malonate nucleophiles (Table 1). Using 2.5 mol % of
*
Corresponding author. Tel./fax: +81 43 290 2987; e-mail: hamada@
p.chiba-u.ac.jp
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.027

L. Jin et al. / Tetrahedron: Asymmetry 19 (2008) 1106–1113
Table 1. Optimization of the reaction conditions
1107
3
(
η -C H PdCl) (2.5 mol %)
3 5 2
(
S,R )-1 (10 mol %)
P
COOR
COOR
Malonate Nucleophile (3 eq)
Additive (10 mol %)
OCOOMe
BSA (3 eq)
CH CN (0.25 M), rt
3
a
2a
(R)-4aa-4ad
Entry
Nucleophile
Additive
Product
Time
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
CH2(COOMe)2 3a
CH2(COOMe)2 3a
CH2(COOMe)2 3a
CH2(COOMe)2 3a
CH2(COOMe)2 3a
CH2(COOMe)2 3a
CH2(COOEt)2 3b
CH2(COOt-Bu)2 3c
CH2(COOBn)2 3d
CH2(COOBn)2 3d
CH2(COOBn)2 3d
—
4aa
4aa
4aa
4aa
4aa
4aa
4ab
4ac
4ad
4ad
4ad
48
4
4
43
94
95
93
55
40
94
91
94
92
54
68
80
67
66
80
81
85
81
86
83
91
LiOAc
NaOAc
KOAc
Mg(OAc)2
Zn(OAc)2
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
4
96
96
4
4
4
10d
11e
4
48
a Absolute configuration of 4ad was determined to be (R). See Scheme 1.
b Isolated yield.
c Determined by HPLC analysis.
d Reaction was preformed in the presence of 20 mol % of LiOAc.
e Reaction was preformed at 4 °C.
[g3-C3H5PdCl]2 (5 mol % of Pd catalyst) and 10 mol % of
(S,RP)-Ph-DIAPHOX 1, the reaction proceeded slowly at
room temperature to afford product 3a in 43% yield and
68% ee.9 The addition of an acetate salt often affects both
the reactivity and enantioselectivity in the asymmetric
allylic alkylation using transition metal-DIAPHOX cata-
lyst systems. Thus, we investigated the effect of the additive
in detail. Both reactivity and enantioselectivity were
remarkably affected by the addition of acetate salts; LiOAc
was the best additive for both reactivity and enantioselec-
tivity (entry 2).10 Further optimization of the ester substit-
uents of a malonate nucleophile indicated that dibenzyl
malonate resulted in the best enantioselectivity (entry 9).
The increase in the amount of LiOAc did not affect reactiv-
ity (entry 10); although enantioselectivity was improved
when the reaction was performed at 4 °C, the reactivity
decreased remarkably (entry 11).
substrate. This reaction was sluggish even at 50 °C, afford-
ing the corresponding product in only 50% yield with 71%
ee. 2-Phenyl-substituted cyclopentenyl carbonate was also
applicable to this reaction, and the product was obtained
in 92% yield with 89% ee (entry 10). In addition, substrates
with an ester group or an amide group were examined
using the same reaction conditions, providing the corre-
sponding products in good yield with 71% ee and 79% ee,
respectively (entries 11 and 12). Asymmetric allylic alkyl-
ation of simple cyclohexenyl carbonate gave a less satisfac-
tory result using the present catalyst system (entry 13).
2.2. Determination of the absolute configuration of 4ad and
4id, and their synthetic applications
The absolute configuration of 4ad and 4id was determined
by transforming them into known chiral alcohols (Scheme
1). Hydrolysis of the dibenzyl ester in 4ad, followed by
treatment with acetic acid, gave carboxylic acid 5 in 92%
yield (2 steps). Reduction of the carboxylic acid moiety
using LiAlH4 afforded the known chiral alcohol 6 in 93%
yield. Comparison of the measured specific rotation of 6
with the literature data revealed that the absolute stereo-
chemistry of the allylic position was (R). {6 from 4ad:
We next examined the scope and limitations of other
2-substituted cycloalkenyl carbonates using dibenzyl
malonate as a nucleophile (Table 2). Using 5 mol % of Pd
catalyst, 10 mol % of 1, and 10 mol % of LiOAc, the asym-
metric allylic alkylation of cyclohexenyl carbonates with a
2-naphthyl group proceeded at room temperature to pro-
vide the corresponding product in 86% yield and 92% ee
(entry 2). Substrates bearing an aryl group with an elec-
tron-withdrawing functionality as well as an electron-
donating functionality at the para- or meta-position were
applicable to this reaction system, giving the products in
excellent yield (93–99% yield) and with high enantioselec-
tivity (85–91% ee) (entries 3–6). There was a remarkable
decrease in reactivity when substrates with an ortho-substi-
tuted aromatic ring were used (entries 7–9). In particular,
no reaction occurred at room temperature using 2-
methoxyphenyl-substituted cyclohexenyl carbonate as the
23
25
½aꢀD ¼ ꢁ118:6 (c 0.84, CH2Cl2) 86% ee. Lit.11 ½aꢀD
¼
þ107:2 (c 0.05, CH2Cl2) 97% ee, (S)-isomer}. Similarly,
4id was transformed into the corresponding chiral alcohol
8 in 86% yield (3 steps), and the absolute configuration
21
of 8 was determined to be (R). {8 from 4id: ½aꢀD ¼ ꢁ49:9
24
(c 0.58, CH2Cl2) 89% ee. Lit.11 ½aꢀD ¼ þ62:3 (c 0.27,
CH2Cl2) 98% ee, (S)-isomer}. Carboxylic acid 5 and alco-
hol 8 could be transformed into chiral heterocyclic com-
pounds with a quaternary stereocenter (Scheme 2). The
treatment of 5 with KI and I2 in aqueous NaHCO3 at room
temperature induced iodolactonization and provided iodo-

1108
L. Jin et al. / Tetrahedron: Asymmetry 19 (2008) 1106–1113
Table 2. Scope and limitations
3
[
(
η
-C H PdCl] (2.5 mol %)
P
3
5
2
R
R
COOBn
COOBn
S,R )-1 (10 mol %)
OCOOMe
CH (COOBn) 3d (3 eq)
2
2
LiOAc (10 mol %)
n
n
BSA (3 eq), CH CN (0.25 M), rt
3
2a—2l
4ad—4ld
Entry
Substrate
Product
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9c
10
11
12
13e
2a
2b
2c
2d
2e
2f
n = 2, R = C6H5
4ad
4
24
4
6
3
94
86
93
94
99
99
77
86 (R)
92
87
85
87
91
85
—
71
89 (R)d
71
79
53 (S)
n = 2, R = 2-Naphthyl
n = 2, R = 4-F–C6H4
n = 2, R = 4-MeO–C6H4
n = 2, R = 3-F–C6H4
n = 2, R = 3-MeO–C6H4
n = 2, R = 2-F–C6H4
n = 2, R = 2-MeO–C6H4
n = 2, R = 2-MeO–C6H4
n = 1, R = C6H5
4bd
4cd
4dd
4ed
4fd
4gd
4hd
4hd
4id
6
2g
2h
2h
2i
24
24
72
4
4
4
No reaction
50
92
89
86
97
2j
n = 2, R = COOMe
n = 2, R = CONHBn
n = 2, R = H
4jd
2k
2l
4kd
4ld
24
a Isolated yield.
b Determined by HPLC analysis.
c Reaction was preformed at 50 °C.
d Absolute configuration of 4id was determined to be R. See Scheme 1.
e Reaction was performed in CH2Cl2 in the absence of LiOAc.
Ph
Ph
Ph
c
a,b
92%
OH
COOH
4ad
93%
5
(
R
)-6
)-8
Ph
c
a,b
91%
OH
4id
COOH
94%
7
(R
Scheme 1. Determination of the absolute configuration of 4ad and 4id. Reagents and conditions: (a) NaOH, H2O–MeOH, reflux, 8 h; (b) AcOH, reflux,
12 h; (c) LiAlH4, THF, reflux, 16 h.
O
H
3. Conclusion
O
O
O
a
b
Ph
Ph
In conclusion, we have achieved the Pd-catalyzed asym-
metric allylic alkylation of 2-substituted cycloalkenyl car-
bonates using a chiral diaminophosphine oxide. Using
the Pd-DIAPHOX catalyst system, the corresponding
products were obtained in excellent yield with a high
enantioselectivity. In addition, the reaction adducts were
transformed into chiral heterocycles with a quaternary
stereocenter.
5
I
93%
86%
H
9
10
O
Ph
c
8
11
88%
H
Scheme 2. Transformation of 5 and 8. Reagents and conditions: (a) I2, KI,
NaHCO3, H2O, rt, 24 h; (b) DBU, toluene, reflux, 12 h; (c) Pd(OAc)2
(5 mol %), O2 (1 atm), DMSO, rt, 24 h.
4. Experimental
4.1. General
lactone 9 (93% yield), which was converted into a bicyclic
lactone 10 in 86% yield. In addition, oxidative cyclization
of 8 proceeded in the presence of 5 mol % of Pd(OAc)2
under an oxygen atmosphere, affording bicyclic furan 11
in 88% yield.12
Infrared (IR) spectra were recorded on a JASCO FT/IR
230 Fourier transform infrared spectrophotometer,
equipped with ATR (Smiths Detection, DuraSample IR

L. Jin et al. / Tetrahedron: Asymmetry 19 (2008) 1106–1113
1109
II). NMR spectra were recorded on a JEOL ecp 400 spec-
trometer, operating at 400 MHz for H NMR, 100 MHz
4.2.2. 2-Phenyl-2-cyclohexen-1-yl malonic acid dimethyl
ester 4aa. Colorless oil. IR (ATR): m 2950, 1739, 1730,
1492, 1434, 1274, 1159, 1029, 696 cmꢁ1; 1H NMR (CDCl3):
d 1.62–1.68 (m, 2H), 1.86–1.92 (m, 2H), 2.18–2.22 (m, 2H),
3.21 (s, 3H), 3.54 (d, J = 8.0 Hz, 1H), 3.52–3.60 (m, 1H),
3.64 (s, 3H), 3.74 (s, 3H), 5.90–5.93 (m, 1H), 7.18–7.30
(m, 5H); 13C NMR (CDCl3): d 18.5, 25.6, 25.9, 36.0,
51.8, 52.0, 54.6, 126.7, 126.8 (ꢂ2), 128.0 (ꢂ2), 129.9,
138.4, 141.9, 168.8, 168.9; FAB-LRMS m/z 289 (MH+);
1
for 13C NMR. Chemical shifts in CDCl3 were reported
downfield from TMS (=0 ppm) for 1H NMR. For 13C
NMR, chemical shifts were reported downfield from
TMS (=0 ppm) or on a scale relative to the solvent signal
[CHCl3 (77.0 ppm)] as an internal reference. Optical rota-
tions were measured on a JASCO P-1020 polarimeter. EI
mass spectra were measured on JEOL GC-mate. FAB mass
spectra were measured on JMX-AX500. The enantiomeric
excess (ee) was determined by HPLC analysis. HPLC was
performed on JASCO HPLC systems consisting of the
following: pump, PU-980; detector, UV-970, measured at
254 nm; column, DAICEL CHIRALPAK AD, DAICEL
CHIRALPAK AD-H, DAICEL CHIRALPAK AS-H,
DAICEL CHIRALCEL OD–H; mobile phase, 2-propa-
nol/hexane. Reactions were carried out in dry solvent
under an argon atmosphere. Other reagents were purified
by the usual methods.
FAB-HRMS. Calcd for C17H21O4 (MH+): 289.1440.
17
Found: 289.1434; ½aꢀD ¼ ꢁ114:2 (c 1.37, CHCl3, 80% ee).
The enantiomeric excess of 4aa was determined by HPLC
analysis (DAICEL CHIRALCEL OD-H, 2-propanol/hex-
ane 5/95, flow rate 0.4 mL/min, tR 14.6 min (major isomer)
and 20.2 min (minor isomer), detection at 254 nm).
4.2.3. 2-Phenyl-2-cyclohexen-1-yl malonic acid diethyl ester
4ab. Colorless oil. IR (ATR): m 2983, 2937, 1750, 1732,
1
1444, 1369, 1331, 1265, 1151, 1033, 700 cmꢁ1; H NMR
(CDCl3): d 1.06–1.10 (m, 3H), 1.17–1.21 (m, 3H), 1.64–
1.69 (m, 2H), 1.87–1.95 (m, 2H), 2.17–2.22 (m, 2H), 3.50
(d, J = 7.2 Hz, 1H), 3.52–3.60 (m, 1H), 4.08–4.13 (m,
2H), 4.17–4.24 (m, 2H), 5.90–5.92 (m, 1H), 7.18–7.28 (m,
5H); 13C NMR (CDCl3): d 13.7, 13.9, 18.9, 25.6, 25.7,
36.0, 54.6, 60.9, 61.4, 126.6, 126.8 (ꢂ2), 128.0 (ꢂ2),
129.9, 138.6, 142.0, 168.3, 168.7; FAB-LRMS m/z 317
4.2. Experimental procedure for the Pd-catalyzed asymmet-
ric allylic alkylation and compound characterization
Reaction products 4aa–4ld were prepared according to the
general procedure. Cycloalkenyl carbonates 2a–2l were
prepared from the corresponding allylic alcohols using a
usual procedure (methyl chloroformate, pyridine, CHCl3,
rt). For the spectral data of these cycloalkenyl carbonates,
see Ref. 5.
(MH+); FAB-HRMS. Calcd for C19H25O4 (MH+):
20
317.1753. Found: 317.1739; ½aꢀD ¼ ꢁ86:9 (c 0.48, CHCl3,
85% ee). The enantiomeric excess of 4ab was determined
by HPLC analysis (DAICEL CHIRALCEL OD-H, 2-
propanol/hexane 5/95, flow rate 0.4 mL/min, tR 11.7 min
(major isomer) and 13.7 min (minor isomer), detection at
254 nm).
4.2.1. General procedure for asymmetric allylic alkylation
using the Pd-DIAPHOX catalyst system. (1R)-2-Phenyl-2-
cyclohexen-1-yl malonic acid dibenzyl ester (R)-4ad. To a
stirred mixture of [g3-C3H5PdCl]2 (2.0 mg, 0.0055 mmol),
(S,RP)-1 (8.6 mg, 0.022 mmol), LiOAc (1.5 mg, 0.022
mmol), and 2a (51.1 mg, 0.22 mmol) in CH3CN (0.9 mL)
at room temperature was added BSA (163 lL, 0.66 mmol),
and the solution stirred for 5 min at the same temperature.
Dibenzyl malonate (165 lL, 0.66 mmol) was added and the
resulting mixture was stirred for 4 h. The reaction mixture
was concentrated under reduced pressure, and the residue
obtained was purified by flash column chromatography
(SiO2, hexane/ethyl acetate: 40/1 to 20/1) to give (R)-4ad
as a colorless oil (91.2 mg, 94%, 86% ee). IR (ATR): m
3032, 2937, 1747, 1732, 1454, 1334, 1271, 1215, 1149,
4.2.4. 2-Phenyl-2-cyclohexen-1-yl malonic acid di-tert-butyl
ester 4ac. Colorless oil. IR (ATR): m 2978, 2931, 1722,
1366, 1254, 1133, 849, 758, 698 cmꢁ1; 1H NMR (CDCl3): d
1.33 (s, 9H), 1.38 (s, 9H), 1.56–1.66 (m, 1H), 1.72–1.82 (m,
1H), 1.88–2.21 (m, 4H), 3.37 (d, J = 5.6 Hz, 1H), 3.39–
3.44 (m, 1H), 5.88–5.91 (m, 1H), 7.19–7.30 (m, 5H); 13C
NMR (CDCl3): d 20.3, 25.1, 25.7, 27.8 (ꢂ3), 27.9 (ꢂ3),
36.3, 55.6, 80.8, 81.3, 126.6, 126.9 (ꢂ2), 128.1 (ꢂ2), 129.4,
139.3, 142.3, 167.7, 168.6; FAB-LRMS m/z 373 (MH+);
FAB-HRMS. Calcd for C23H33O4 (MH+): 373.2379.
22
Found: 373.2358; ½aꢀD ¼ ꢁ41:5 (c 1.15, CHCl3, 82% ee).
The enantiomeric excess of 4ac was determined by HPLC
analysis (DAICEL CHIRALPAK AD, 2-propanol/hexane
1/100, flow rate 0.5 mL/min, tR 9.4 min (minor isomer)
and 10.0 min (major-isomer), detection at 254 nm).
1
746, 698 cmꢁ1; H NMR (CDCl3): d 1.50–1.65 (m, 2H),
1.80–1.96 (m, 2H), 2.06–2.11 (m, 2H), 3.65 (d, J =
6.8 Hz, 1H), 3.55–3.65 (m, 1H), 4.60 (dd, J = 2.0 Hz,
12.8 Hz, 1H), 4.70 (dd, J = 2.0 Hz, 12.8 Hz, 1H), 4.99
(dd, J= 2.0 Hz, 12.4 Hz, 1H), 5.06 (dd, J = 2.0 Hz,
12.4 Hz, 1H), 5.84–5.88 (m, 1H), 7.14–7.30 (m, 15H); 13C
NMR (CDCl3): d 19.0, 25.5, 25.6, 36.2, 54.4, 66.5, 66.6,
126.6, 126.8 (ꢂ2), 127.8 (ꢂ2), 127.9, 128.0 (ꢂ2), 128.1,
128.1 (ꢂ2), 128.3 (ꢂ2), 128.3 (ꢂ2), 128.4, 129.8, 135.2,
138.3, 141.8, 167.9, 168.3; FAB-LRMS m/z 441 (MH+);
4.2.5. 2-(2-Naphthyl)-2-cyclohexen-1-yl malonic acid dibenz-
yl ester 4bd. Colorless oil. IR (ATR): m 3032, 2947, 1748,
1732, 1331, 1269, 1215, 1147, 1003, 746, 698 cmꢁ1 1H
;
NMR (CDCl3): d 1.62–1.72 (m, 2H), 1.89–2.03 (m, 2H),
2.16–2.23 (m, 2H), 3.68 (d, J = 7.2 Hz, 1H), 3.68–3.75
(m, 1H), 4.48 (d, J = 12.4 Hz, 1H), 4.62 (d, J = 12.4 Hz,
1H), 4.98 (d, J = 12.4 Hz, 1H), 5.05 (d, J = 12.4 Hz, 1H),
5.99–6.02 (m, 1H), 7.01–7.03 (m, 2H), 7.14–7.43 (m,
11H), 7.62 (s, 1H), 7.69–7.78 (m, 3H); 13C NMR (CDCl3):
d 19.2, 25.8, 25.8, 36.4, 54.5, 66.7, 66.8, 125.3, 125.5, 125.6,
126.0, 127.5, 127.6, 127.8, 128.0 (ꢂ2), 128.0, 128.2, 128.3
(ꢂ2), 128.3 (ꢂ2), 128.4 (ꢂ2), 130.6, 132.4, 133.3, 135.2,
FAB-HRMS. Calcd for C29H29O4 (MH+): 441.2066.
22
Found: 441.2049; ½aꢀD ¼ ꢁ35:4 (c 0.32, CHCl3, 86% ee).
The enantiomeric excess of 4ad was determined by HPLC
analysis (DAICEL CHIRALCEL OD-H, 2-propanol/
hexane 5/95, flow rate 0.5 mL/min, tR 19.7 min [(S)-isomer]
and 21.7 min [(R)-isomer], detection at 254 nm).

1110
L. Jin et al. / Tetrahedron: Asymmetry 19 (2008) 1106–1113
135.2, 138.4, 139.3, 168.1, 168.5; FAB-LRMS m/z 491
130.9, 135.2 (d, J = 4.6 Hz), 137.5 (d, J = 1.9 Hz), 144.3
(d, J = 7.3 Hz), 162.6 (d, J = 244.3 Hz), 167.9, 168.3;
(MH+); FAB-HRMS. Calcd for C33H31O4 (MH+):
21
491.2222. Found: 491.2237; ½aꢀD ¼ ꢁ35:2 (c 0.47, CHCl3,
FAB-LRMS m/z 459 (MH+); FAB-HRMS. Calcd for
24
92% ee). The enantiomeric excess of 4ad was determined
by HPLC analysis (DAICEL CHIRALPAK AS-H, 2-
propanol/hexane 1/9, flow rate 0.5 mL/min, tR 14.6 min
(major-isomer) and 17.0 min (minor isomer), detection at
254 nm).
C29H28FO4 (MH+): 459.1972. Found: 459.1954; ½aꢀD
¼
ꢁ47:4 (c 0.65, CHCl3, 87% ee). The enantiomeric excess
of 4ed was determined by HPLC analysis (DAICEL CHI-
RALCEL OD-H, 2-propanol/hexane 1/200, flow rate
0.5 mL/min, tR 74.8 min (minor isomer) and 84.6 min
(major isomer), detection at 254 nm).
4.2.6. 2-(4-Fluorophenyl)-2-cyclohexen-1-yl malonic acid
dibenzyl ester 4cd. Colorless oil. IR (ATR): m 3033,
2935, 1746, 1731, 1601, 1510, 1454, 1234, 1161, 1005,
4.2.9. 2-(3-Methoxyphenyl)-2-cyclohexen-1-yl malonic acid
dibenzyl ester 4fd. Colorless oil. IR (ATR): m 3032, 2935,
1
1
698 cmꢁ1; H NMR (CDCl3): d 1.57–1.64 (m, 2H), 1.85–
1750, 1732, 1599, 1577, 1456, 1217, 1165, 698 cmꢁ1; H
1.96 (m, 2H), 2.10–2.16 (m, 2H), 3.52–3.55 (m, 1H), 3.60
(d, J = 7.2 Hz, 1H), 4.67 (d, J = 12.4 Hz, 1H), 4.76 (d,
J = 12.4 Hz, 1H), 5.01 (d, J = 12.4 Hz, 1H), 5.09 (d,
J = 12.4 Hz, 1H), 5.81–5.83 (m, 1H), 6.87–6.91 (m, 2H),
7.11–7.30 (m, 12H); 13C NMR (CDCl3): d 19.0, 25.6,
25.7, 36.5, 54.5, 66.8, 66.9, 114.9 (d, J = 21.4 Hz) (ꢂ2),
127.9 (ꢂ2), 128.2 (ꢂ2), 128.3, 128.3 (ꢂ2), 128.4, 128.4
(ꢂ2), 128.4, 128.5, 130.1, 135.2 (d, J = 4.9 Hz) (ꢂ2),
137.5, 138.0, 161.7 (d, J = 244.3 Hz), 168.0, 168.4; FAB-
NMR (CDCl3): d 1.57–1.64 (m, 2H), 1.83–1.99 (m, 2H),
2.10–2.16 (m, 2H), 3.52–3.58 (m, 1H), 3.66 (d, J =
6.8 Hz, 1H), 3.70 (s, 3H), 4.70 (d, J = 12.4 Hz, 1H), 4.78
(d, J = 12.4 Hz, 1H), 5.02 (d, J = 12.4 Hz, 1H), 5.09 (d,
J = 12.4 Hz, 1H), 5.91 (dd, J = 2.8 Hz, 4.0 Hz, 1H), 6.72–
6.81 (m, 3H), 7.14–7.33 (m, 11H); 13C NMR (CDCl3): d
19.2, 25.6, 25.6, 36.4, 54.3, 55.0, 66.7, 66.8, 112.4, 112.4,
119.3, 127.9 (ꢂ2), 128.1, 128.2, 128.2 (ꢂ2), 128.3, 128.4
(ꢂ2), 128.4 (ꢂ2), 129.1, 130.0, 135.3, 138.4, 143.4, 159.4,
168.1, 168.5; FAB-LRMS m/z 471 (MH+); FAB-HRMS.
LRMS m/z 459 (MH+); FAB-HRMS. Calcd for
17
C29H28FO4 (MH+): 459.1972. Found: 459.1997; ½aꢀD
¼
Calcd for C30H31O5 (MH+): 471.2171. Found: 471.2155;
24
ꢁ46:2 (c 1.25, CHCl3, 87% ee). The enantiomeric excess
of 4cd was determined by HPLC analysis (DAICEL CHI-
RALCEL OD-H, 2-propanol/hexane 1/200, flow rate
0.5 mL/min, tR 47.7 min (minor isomer) and 52.2 min
(major isomer), detection at 254 nm).
½aꢀD ¼ ꢁ37:4 (c 0.45, CHCl3, 91% ee). The enantiomeric
excess of 4fd was determined by HPLC analysis (DAICEL
CHIRALCEL OD-H, 2-propanol/hexane 1/99, flow rate
0.15 mL/min, tR 176.5 min (major isomer) and 192.3 min
(minor isomer), detection at 254 nm).
4.2.7. 2-(4-Methoxyphenyl)-2-cyclohexen-1-yl malonic acid
dibenzyl ester 4dd. Colorless oil. IR (ATR): m 3033, 2949,
1747, 1732, 1456, 1331, 1265, 1215, 1149, 1003, 750,
4.2.10. 2-(2-Fluorophenyl)-2-cyclohexen-1-yl malonic acid
dibenzyl ester 4gd. Colorless oil. IR (ATR): m 3033, 2935,
1754, 1732, 1487, 1450, 1257, 1219, 1140, 758, 698 cmꢁ1
;
698 cmꢁ1; H NMR (CDCl3): d 1.54–1.65 (m, 2H), 1.84–
1H NMR (CDCl3): d 1.55–1.74 (m, 2H), 1.83–1.93 (m,
2H), 2.12–2.18 (m, 2H), 3.53–3.58 (m, 2H), 4.78 (d,
J = 12.4 Hz, 1H), 4.88 (d, J = 12.4 Hz, 1H), 4.99 (d, J =
12.4 Hz, 1H), 5.03 (d, J = 12.4 Hz, 1H), 5.83–5.85 (m,
1H), 6.92–7.32 (m, 14H); 13C NMR (CDCl3): d 19.9,
25.4, 25.6, 37.3, 54.3, 66.7, 66.7, 115.3 (d, J = 22.6 Hz),
123.9 (d, J = 3.4 Hz), 127.9 (ꢂ2), 128.2, 128.3, 128.3
(ꢂ2), 128.4 (ꢂ2), 128.4 (ꢂ2), 128.4, 128.5, 129.4 (d, J =
14.5 Hz), 130.8 (d, J = 4.6 Hz), 132.1, 134.5, 135.3, 158.8
(d, J = 419.9 Hz), 167.8, 168.4; FAB-LRMS m/z 459
1
1.99 (m, 2H), 2.11–2.15 (m, 2H), 3.52–3.55 (m, 1H), 3.67
(d, J = 6.8 Hz, 1H), 3.74 (s, 3H), 4.68 (d, J = 12.4 Hz,
1H), 4.76 (d, J = 12.4 Hz, 1H), 5.02 (d, J = 12.4 Hz, 1H),
5.10 (d, J = 12.4 Hz, 1H), 5.80–5.84 (m, 1H), 6.74–6.78
(m, 2H), 7.11–7.36 (m, 12H); 13C NMR (CDCl3): d 19.0,
25.6, 25.8, 36.4, 54.5, 66.7, 66.8, 113.5, 127.8, 127.9,
128.0, 128.2, 128.3 (ꢂ2), 128.3 (ꢂ2), 128.4 (ꢂ2), 128.6
(ꢂ2), 128.8, 134.7, 135.2, 135.4, 137.8, 161.7, 168.1,
168.5; FAB-LRMS m/z 471 (MH+); FAB-HRMS. Calcd
20
D
for C30H31O5 (MH+): 471.2171. Found: 471.2147; ½aꢀ
¼
(MH+); FAB-HRMS. Calcd for C29H28FO4 (MH+):
24
ꢁ18:1 (c 1.29, CHCl3, 85% ee). The enantiomeric excess
of 4dd was determined by HPLC analysis (DAICEL CHI-
RALCEL OD-H, 2-propanol/hexane 1/99, flow rate
0.5 mL/min, tR 50.9 min (minor isomer) and 58.6 min
(major isomer), detection at 254 nm).
459.1972. Found: 459.1954; ½aꢀD ¼ ꢁ28:0 (c 0.58, CHCl3,
85% ee). The enantiomeric excess of 4gd was determined
by HPLC analysis (DAICEL CHIRALPAK AD-H, 2-pro-
panol/hexane 5/95, flow rate 0.5 mL/min, tR 26.9 min
(minor isomer) and 39.8 min (major isomer), detection at
254 nm).
4.2.8. 2-(3-Fluorophenyl)-2-cyclohexen-1-yl malonic acid
dibenzyl ester 4ed. Colorless oil. IR (ATR): m 3035,
4.2.11. 2-(2-Methoxyphenyl)-2-cyclohexen-1-yl malonic acid
dibenzyl ester 4hd. Colorless oil. IR (ATR): m 2930, 1749,
2933, 1741, 1731, 1581, 1456, 1271, 1220, 1157, 696 cmꢁ1
;
1H NMR (CDCl3): d 1.57–1.66 (m, 2H), 1.83–1.99 (m,
2H), 2.11–2.15 (m, 2H), 3.52–3.56 (m, 1H), 3.62 (d, J =
6.4 Hz, 1H), 4.71 (d, J = 12.4 Hz, 1H), 4.79 (d,
J = 12.4 Hz, 1H), 5.01 (d, J = 12.0 Hz, 1H), 5.09 (d, J =
12.0 Hz, 1H), 5.88–5.91 (m, 1H), 6.85–6.98 (m, 3H),
7.16–7.31 (m, 11H); 13C NMR (CDCl3): d 19.0, 25.6,
25.6, 36.2, 54.2, 66.8, 66.8, 113.5 (d, J = 21.0 Hz), 113.7
(d, J = 21.4 Hz), 122.4 (d, J = 2.7 Hz), 127.9 (ꢂ2), 128.1,
128.2, 128.3 (ꢂ2), 128.4 (ꢂ2), 128.4 (ꢂ2), 129.5, 129.5,
1729, 1242, 1136, 1118, 1025, 749, 695 cmꢁ1 1H NMR
;
(CDCl3): d 1.55–1.92 (m, 4H), 2.10–2.20 (m, 2H), 3.51 (d,
J = 6.0 Hz, 1H), 3.72 (s, 3H), 4.80 (d, J = 12.4 Hz, 1H),
4.93 (d, J = 12.4 Hz, 1H), 4.96 (d, J = 12.4 Hz, 1H), 5.02
(d, J = 12.4 Hz, 1H), 5.71–5.76 (m, 1H), 6.74–6.83 (m,
2H), 6.96–6.99 (m, 1H), 7.16–7.30 (m, 11H); 13C NMR
(CDCl3): d 20.6, 25.3, 25.7, 37.3, 54.3, 55.2, 66.6, 66.6,
110.1, 120.6, 127.9 (ꢂ2), 128.1, 128.1, 128.3, 128.3 (ꢂ2),
128.4 (ꢂ2), 128.4 (ꢂ2), 129.9, 131.0, 131.1, 135.4, 135.5,

L. Jin et al. / Tetrahedron: Asymmetry 19 (2008) 1106–1113
1111
138.4, 156.5, 168.2, 169.0; FAB-LRMS m/z 471 (MH+);
20/80, flow rate 0.5 mL/min, tR 54.2 min (minor isomer)
and 66.1 min (major isomer), detection at 254 nm).
FAB-HRMS. Calcd for C30H31O5 (MH+): 471.2171.
19
Found: 471.2155; ½aꢀD ¼ þ3:0 (c 0.79, CHCl3, 71% ee).
The enantiomeric excess of 4hd was determined by HPLC
analysis (DAICEL CHIRALCEL OD-H, 2-propanol/
hexane 3/97, flow rate 0.5 mL/min, tR 23.7 min (minor
isomer) and 28.0 min (major isomer), detection at 254 nm).
4.2.15. (1S)-2-Cyclohexen-1-yl malonic acid dibenzyl ester
4ld. Colorless oil. IR (ATR): m 2930, 1752, 1729, 1261,
1213, 1135, 1002, 734, 694 cmꢁ1 1H NMR (CDCl3): d
;
1.32–1.42 (m, 1H), 1.48–1.58 (m, 1H), 1.64–1.80 (m, 2H),
1.93–1.98 (m, 2H), 2.92–2.97 (m, 1H), 3.38 (d,
J = 9.2 Hz, 1H), 5.14 (s, 2H), 5.15 (s, 2H), 5.51–5.54 (m,
1H), 5.71–5.76 (m, 1H), 7.26–7.35 (m, 10H); 13C NMR
(CDCl3): d 20.9, 24.9, 26.5, 35.4, 57.0, 66.9, 66.9, 127.3,
128.1 (ꢂ2), 128.1 (ꢂ2), 128.2, 128.3, 128.5 (ꢂ2), 128.5
(ꢂ2), 129.6, 135.4, 135.4, 168.1, 168.2; FAB-LRMS m/z
4.2.12.(1R)-2-Phenyl-2-cyclopenten-1-ylmalonicaciddibenz-
yl ester 4id. Colorless oil. IR (ATR): m 2947, 1745, 1728,
1236, 1213, 1180, 1140, 1021, 982, 749, 693 cmꢁ1; 1H NMR
(CDCl3): d 2.13–2.34 (m, 2H), 2.38–2.47 (m, 2H), 3.72 (d,
J = 6.0 Hz, 1H), 3.92–3.98 (m, 1H), 4.84 (d, J = 12.4 Hz,
1H), 4.94 (d, J = 12.4 Hz, 1H), 5.01 (d, J = 12.4 Hz, 1H),
5.08 (d, J = 12.4 Hz, 1H), 5.95–5.99 (m, 1H), 7.18–7.35
(m, 15H); 13C NMR (CDCl3): d 27.5, 31.6, 45.5, 53.6,
66.7, 66.8, 126.4 (ꢂ2), 127.2, 128.0 (ꢂ2), 128.1, 128.2,
128.2 (ꢂ2), 128.3 (ꢂ2), 128.3, 128.4 (ꢂ2), 128.4 (ꢂ2),
130.1, 135.3, 135.7, 142.9, 168.2, 168.8; FAB-LRMS m/z
365 (MH+); FAB-HRMS. Calcd for C23H25O4 (MH+):
17
365.1753. Found: 365.1740; ½aꢀD ¼ ꢁ21:4 (c 0.85, CHCl3,
53% ee). The enantiomeric excess of 4ld was determined
by HPLC analysis (DAICEL CHIRALPAK AD, 2-propa-
nol/hexane 5/95, flow rate 0.4 mL/min, tR 31.2 min [(S)-
isomer] and 35.7 min [(R)-isomer], detection at 254 nm).
The absolute configuration of 4ld was determined after
converting into the known carboxylic acid [Reaction condi-
tions: (1) NaOH, MeOH–H2O. (2) AcOH, reflux.].
427 (MH+); FAB-HRMS. Calcd for C28H27O4 (MH+):
19
427.1909. Found: 427.1890; ½aꢀD ¼ ꢁ43:2 (c 0.87, CHCl3,
89% ee). The enantiomeric excess of 4id was determined
by HPLC analysis (DAICEL CHIRALCEL OD-H, 2-pro-
panol/hexane 5/95, flow rate 0.5 mL/min, tR 16.2 min [(S)-
isomer] and 19.2 min [(R)-isomer], detection at 254 nm).
19
20
½aꢀD ¼ ꢁ31:3 (c 1.08, CHCl3, 53% ee), Lit.13 ½aꢀD ¼ ꢁ59:5
(c 2.6, CHCl3, 94% ee).
4.3. Determination of the absolute configuration of 4ad and
4id
4.2.13. 2-Methoxycarbonyl-2-cyclohexen-1-yl malonic acid
dibenzyl ester 4jd. Colorless oil. IR (ATR): m 3032, 2951,
4.3.1. (1R)-2-Phenyl-2-cyclohexen-1-yl acetic acid 5. To a
stirred solution of 4ad (404.3 mg, 0.918 mmol) in MeOH
(9.18 mL) was added 3.3 N NaOH (1.53 mL), and the reac-
tion mixture was heated in oil bath and refluxed for 8 h.
After cooling down to room temperature, the reaction mix-
ture was evaporated. The obtained residue was dissolved in
AcOH (4.59 mL) and the solution was refluxed for 12 h.
After cooling down to room temperature, the reaction mix-
ture was evaporated. After the addition of H2O to the res-
idue, the mixture was extracted with ethyl acetate (ꢂ3),
washed with H2O and brine, and then dried over Na2SO4.
After concentration under reduced pressure, the residue
was purified by flash column chromatography (SiO2,
hexane/ethyl acetate: 10/1 to 4/1) to give 5 (182.8 mg,
92%) as a white solid. Mp: 99–101 °C; IR (ATR): m 2926,
1747, 1732, 1716, 1456, 1257, 1147, 752, 698 cmꢁ1 1H
;
NMR (CDCl3): d 1.45–1.60 (m, 2H), 1.74–1.85 (m, 2H),
2.08–2.16 (m, 2H), 3.38–3.46 (m, 1H), 3.64 (s, 3H), 4.00
(d, J = 6.4 Hz, 1H), 5.09 (d, J = 12.0 Hz, 2H), 5.14 (d,
J = 12.0 Hz, 2H), 7.05 (dt, J = 1.6 Hz, 4.0 Hz, 1H), 7.24–
7.34 (m, 10H); 13C NMR (CDCl3): d 18.2, 25.2, 25.4,
33.4, 51.4, 53.9, 66.8, 66.9, 128.0 (ꢂ2), 128.1, 128.2 (ꢂ2),
128.3 (ꢂ2), 128.4 (ꢂ2), 128.4, 130.3, 135.2, 135.3, 142.7,
167.2, 168.2, 168.4; FAB-LRMS m/z 423 (MH+); FAB-
HRMS. Calcd for C25H27O6 (MH+): 423.1808. Found:
17
423.1797; ½aꢀD ¼ ꢁ9:3 (c 1.32, CHCl3, 71% ee). The enan-
tiomeric excess of 4jd was determined by HPLC analysis
(DAICEL CHIRALCEL OD-H, 2-propanol/hexane 5/95,
flow rate 0.4 mL/min, tR 29.7 min (major isomer) and
34.3 min (minor isomer), detection at 254 nm).
1692, 1404, 1280, 1196, 916, 878, 756, 693 cmꢁ1 1H
;
NMR (CDCl3): d 1.60–1.78 (m, 4H), 1.84–1.93 (m, 1H),
2.15–2.22 (m, 2H), 2.22 (dd, J = 10.8 Hz, 16.0 Hz, 1H),
2.41 (dd, J = 2.8 Hz, 16.0 Hz, 1H), 3.20–3.30 (m, 1H),
5.98–6.00 (m, 1H), 7.22–7.32 (m, 5H), a carboxylic acid
proton could not be detected in 1H NMR (CDCl3 and
C6D6); 13C NMR (CDCl3): d 18.2, 26.0, 27.5, 32.4, 38.1,
126.2 (ꢂ2), 126.9, 127.5, 128.4 (ꢂ2), 139.8, 141.4, 179.5;
4.2.14. 2-Benzylcarbamoyl-2-cyclohexen-1-yl malonic acid
dibenzyl ester 4kd. Colorless oil. IR (ATR): m 3406, 3032,
2935, 1747, 1731, 1660, 1622, 1520, 1281, 1147, 696 cmꢁ1
;
1H NMR (CDCl3): d 1.46–1.80 (m, 3H), 1.85–2.15 (m,
3H), 3.42–3.51 (m, 1H), 3.95 (d, J = 4.8 Hz, 1H), 4.26
(dd, J = 5.6 Hz, 14.8 Hz, 1H), 4.40 (dd, J = 6.0 Hz,
14.8 Hz, 1H), 4.97 (d, J = 12.0 Hz, 1H), 5.11 (s, 2H), 5.15
(d, J = 12.0 Hz, 2H), 5.76 (dd, J = 5.6 Hz, 6.0 Hz, 1H),
6.22–6.25 (m, 1H), 7.20–7.35 (m, 15H); 13C NMR (CDCl3):
d 19.5, 24.9, 25.1, 34.3, 43.5, 53.4, 66.9, 67.0, 127.4, 127.8
(ꢂ2), 128.2 (ꢂ2), 128.4, 128.4, 128.5 (ꢂ2), 128.5 (ꢂ2),
128.5 (ꢂ2), 128.6 (ꢂ2), 133.7, 135.4, 135.4, 136.3, 138.3,
168.4, 168.4, 169.1; FAB-LRMS m/z 498 (MH+); FAB-
EI-LRMS m/z 216 (M+); EI-HRMS. Calcd for C14H16O2
24
(M+): 216.1150. Found: 216.1135; ½aꢀD ¼ ꢁ135:2 (c 1.03,
CHCl3, 86% ee).
4.3.2. (1R)-2-Phenyl-2-cyclohexen-1-yl ethanol 6. To a
stirred suspension of LiAlH4 (41.2 mg, 1.086 mmol) in
THF (7.24 mL) at 0 °C was added
5 (156.6 mg,
HRMS. Calcd for C31H32NO5 (MH+): 498.2280. Found:
0.724 mmol). The resulting suspension was heated on an
oil bath and refluxed for 16 h. After cooling down to room
temperature, the reaction was quenched by the addition of
water and 1 M NaOH. The obtained white solid was
17
498.2267; ½aꢀD ¼ þ11:7 (c 1.00, CHCl3, 79% ee). The enan-
tiomeric excess of 4kd was determined by HPLC analysis
(DAICEL CHIRALPAK AD-H, 2-propanol/hexane

1112
L. Jin et al. / Tetrahedron: Asymmetry 19 (2008) 1106–1113
1
filtered, and refluxed in THF (7.24 mL) for 3 h. After filtra-
tion, the combined organic layers were washed with brine,
dried over Na2SO4, and then evaporated in vacuo. The res-
idue was purified by flash column chromatography (SiO2,
hexane/ethyl acetate: 20/1 to 10/1) to give 6 as a colorless
oil (136.1 mg, 93%). IR (ATR): m 3309, 2927, 2859, 1492,
902, 769, 747, 699 cmꢁ1; H NMR (CDCl3): d 1.50–1.58
(m, 1H), 1.71–1.77 (m, 1H), 1.88–1.97 (m, 1H), 2.06–2.14
(m, 1H), 2.12–2.25 (m, 2H), 2.35 (dd, J = 4.4 Hz,
17.2 Hz, 1H), 2.54 (dd, J = 6.8 Hz, 17.2 Hz, 1H), 3.14–
3.21 (m, 1H), 4.66–4.69 (m, 1H), 7.32–7.48 (m, 5H); 13C
NMR (CDCl3): d 21.2, 27.0, 32.7, 36.3, 37.2, 37.3, 88.0,
126.0 (ꢂ2), 128.1 (ꢂ2), 128.5, 142.4, 175.3; EI-LRMS
1444, 1055, 1013, 756, 695 cmꢁ1 1H NMR (CDCl3): d
;
1.26 (broad peak (OH), 1H), 1.42–1.87 (m, 6H), 2.12–
2.20 (m, 2H), 2.82–2.91 (m, 1H), 3.55–3.61 (m, 2H),
5.90–5.92 (m, 1H), 7.20–7.31 (m, 5H); 13C NMR (CDCl3):
d 18.5, 26.0, 27.3, 32.0, 36.4, 61.1, 126.2 (ꢂ2), 126.4, 126.5,
128.2 (ꢂ2), 141.7, 142.6; EI-LRMS m/z 202 (M+); EI-
m/z 342 (M+); EI-HRMS. Calcd for C14H15IO2 (M+):
21
342.0117. Found: 342.0110; ½aꢀD ¼ þ26:1 (c 0.28, CHCl3,
86% ee).
4.4.2. (3aR,7aS)-7a-Phenyl-3a,4,5,7-tetrahydro-3H-benzo-
furan-2-one 10. Iodolactone 9 (71.8 mg, 0.210 mmol)
was dissolved in dry toluene (2.10 mL) containing freshly
distilled 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (48.0 mg,
0.315 mmol), and the mixture was refluxed for 12 h,
cooled to room temperature, and then filtered. After the
filtrate was concentrated under reduced pressure, the
obtained residue was purified by flash column chromato-
graphy (SiO2, hexane/ethyl acetate: 10/1 to 5/1) to give 8
as a colorless oil (38.8 mg, 86%). IR (ATR): m 2926, 1769,
HRMS. Calcd for C14H18O (M+): 202.1358. Found:
23
202.1360; ½aꢀD ¼ ꢁ118:6 (c 0.84, CH2Cl2, 86% ee).
4.3.3. (1R)-2-Phenyl-2-cyclopenten-1-yl acetic acid 7.
Compound 7 was prepared using the same procedure for
the transformation of 4ad to 5. White solid. Mp: 68 °C;
IR (ATR): m 2935, 2843, 1686, 1403, 1285, 1203, 936,
1
754, 691 cmꢁ1; H NMR (CDCl3): d 1.82–1.89 (m, 1H),
2.18 (dd, J = 10.8 Hz, 16.0 Hz, 1H), 2.27–2.35 (m, 1H),
2.48–2.60 (m, 2H), 2.67 (dd, J = 2.8 Hz, 16.0 Hz, 1H),
3.56–3.65 (m, 1H), 6.10–6.12 (m, 1H), 7.22–7.41 (m, 5H),
a carboxylic acid proton could not be detected in 1H
NMR (CDCl3 and C6D6); 13C NMR (CDCl3): d 30.0,
31.2, 38.2, 41.6, 126.1 (ꢂ2), 127.2, 127.6, 128.5 (ꢂ2),
135.4, 144.8, 179.5; EI-LRMS m/z 202 (M+); EI-HRMS.
1243, 1213, 1171, 1007, 981, 944, 903, 757, 698 cmꢁ1; H
1
NMR (CDCl3): d 1.62–1.72 (m, 1H), 1.82–1.90 (m, 1H),
2.17–2.30 (m, 2H), 2.42–2.51 (m, 1H), 2.59–2.68 (m, 2H),
5.77 (dt, J = 10.0 Hz, 2 Hz, 1H), 6.17 (dt, J = 10.0 Hz,
4 Hz, 1H), 7.26–7.41 (m, 5H); 13C NMR (CDCl3): d 21.0,
22.1, 33.5, 42.0, 85.6, 125.2 (ꢂ2), 127.3, 127.8, 128.4
(ꢂ2), 131.2, 142.4, 176.2; EI-LRMS m/z 214 (M+); EI-
Calcd for C13H14O2 (M+): 202.0994. Found: 202.0994;
23
HRMS. Calcd for C14H14O2 (M+): 214.0994. Found:
½aꢀD ¼ ꢁ57:2 (c 0.82, CHCl3, 89% ee).
24
214.0983; ½aꢀD ¼ þ98:2 (c 1.59, CHCl3, 86% ee).
4.3.4. (1R)-2-Phenyl-2-cyclopenten-1-yl ethanol 8. Com-
pound 8 was prepared using the same procedure for the
transformation of 5 to 6. Colorless oil. IR (ATR): m
4.4.3. (3aR,6aS)-6a-Phenyl-3,3a,4,6a-tetrahydro-2H-cyclo-
penta[b]furan 11. Compound 8 (24.4 mg, 0.130 mmol)
was dissolved in DMSO (0.52 mL) and the vessel was
purged with O2. Next 5 mol % of Pd(OAc)2 was added
and the vessel was sealed, evacuated and filled with oxygen
twice. After the reaction mixture was stirred for 24 h at
room temperature, the reaction was quenched with 5 mL
of water. The aqueous phase was extracted four times with
ethyl acetate. The organic layer was dried over Na2SO4 and
the solvent was carefully distilled off. The crude residue was
purified by flash column chromatography (SiO2, hexane/
ethyl acetate: 30/1 to 10/1) to give 13 as a colorless oil
(21.2 mg, 88%). IR (ATR): m 2961, 2923, 2851, 1446,
3311, 2932, 2843, 1494, 1444, 1054, 752, 692 cmꢁ1 1H
;
NMR (CDCl3): d 1.31 (broad peak (OH), 1H), 1.41–1.54
(m, 1H), 1.74–1.93 (m, 2H), 2.15–2.25 (m, 1H), 2.40–2.56
(m, 2H), 3.22–3.32 (m, 1H), 3.63–3.77 (m, 1H), 6.06 (dd,
J = 2.4 Hz, 4.0 Hz, 1H), 7.20–7.42 (m, 5H); 13C NMR
(CDCl3): d 29.8, 31.5, 36.4, 41.5, 61.6, 126.1 (ꢂ2), 126.7,
126.8, 128.3 (ꢂ2), 136.2, 146.2; EI-LRMS m/z 188 (M+);
EI-HRMS. Calcd for C13H16O (M+): 188.1201. Found:
21
188.1203; ½aꢀD ¼ ꢁ51:0 (c 0.58, CH2Cl2, 89% ee).
4.4. Experimental procedure for the transformation of 5 and
8
1269, 1058, 1030, 752, 728, 697 cmꢁ1; H NMR (CDCl3):
1
d 1.65–1.72 (m, 1H), 2.17–2.28 (m, 2H), 2.71–2.76 (m,
1H), 2.80–2.86 (m, 1H), 3.80 (ddd, J = 5.6 Hz, 8.4 Hz,
8.8 Hz, 1H), 4.05 (ddd, J = 3.6 Hz, 6.8 Hz, 8.4 Hz, 1H),
5.66 (dt, J = 5.6 Hz, 2.0 Hz, 1H), 6.03 (dt, J = 5.6 Hz,
2.4 Hz, 1H), 7.20–7.38 (m, 5H); 13C NMR (CDCl3): d
35.6, 39.9, 48.6, 66.9, 98.9, 124.9 (ꢂ2), 126.7, 128.1 (ꢂ2),
133.6, 133.8, 145.6; EI-LRMS m/z 186 (M+); EI-HRMS.
4.4.1.
(3aR,7S,7aR)-7-Iodo-7a-phenyl-hexahydrobenzo-
furan-2-one 9. Compound 5 (50.0 mg, 0.231 mmol) was
added to a solution of NaHCO3 (58.2 mg, 0.693 mmol) in
water (0.58 mL), and the resulting mixture was stirred until
it became homogeneous. The flask was then protected from
light, and the mixture was treated with a solution of KI
(230.1 mg, 1.386 mmol) and iodine (30.8 mg, 0.243 mmol)
in water (0.58 mL) in one portion. The reaction mixture
was stirred at room temperature for 24 h and then
extracted with CHCl3 (ꢂ3). The organic extracts were com-
bined, washed with 10% aqueous Na2S2O3, 10% aqueous
NaHCO3, and water, and then dried Na2SO4. After con-
centration under reduced pressure, the residue was purified
by flash column chromatography (SiO2, hexane/ethyl ace-
tate: 20/1 to 5/1) to give 9 (73.6 mg, 93%) as a white solid.
Mp 76 °C; IR (ATR): m 2924, 1771, 1233, 1155, 1131, 932,
Calcd for C13H14O (M+): 186.1045. Found: 186.1026;
23
½aꢀD ¼ þ65:4 (c 0.55, CHCl3, 89% ee).
Acknowledgments
This work was supported by Grant-in-aid for Scientific
Research on Priority Areas, Chemistry of Concerto
Catalysis, and Grant-in Aid for Encouragement of Young

L. Jin et al. / Tetrahedron: Asymmetry 19 (2008) 1106–1113
1113
Saito, Y.; Takahashi, K.; Hongo, H. Tetrahedron: Asymmetry
2005, 16, 2551; (g) Hilgraf, R.; Pfaltz, A. Adv. Synth. Catal.
2005, 347, 61; (h) Chapsal, B. D.; Ojima, I. Org. Lett. 2006, 8,
Scientist (A), from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
´
1395; (i) Pei, Y.; Brule, E.; Moberg, C. Org. Biomol. Chem.
´
2006, 4, 544; (j) Raluy, E.; Claver, C.; Dieguez, M. Org. Lett.
2007, 9, 49; (k) Liu, D.; Xie, F.; Zhang, W. J. Org. Chem.
2007, 72, 6992.
References
7. For other asymmetric reactions using the transition metal-
DIAPHOX catalyst systems, see: (a) Nemoto, T.; Matsu-
moto, T.; Masuda, T.; Hitomi, T.; Hatano, K.; Hamada, Y. J.
Am. Chem. Soc. 2004, 126, 3690; (b) Nemoto, T.; Masuda, T.;
Matsumoto, T.; Hamada, Y. J. Org. Chem. 2005, 70, 7172; (c)
Nemoto, T.; Fukuda, T.; Matsumoto, T.; Hitomi, T.;
Hamada, Y. Adv. Synth. Catal. 2005, 347, 1504; (d) Nemoto,
T.; Jin, L.; Nakamura, H.; Hamada, Y. Tetrahedron Lett.
2006, 47, 6577; (e) Nemoto, T.; Sakamoto, T.; Matsumoto,
T.; Hamada, Y. Tetrahedron Lett. 2006, 47, 8737; (f) Nemoto,
T.; Sakamoto, T.; Fukuyama, T.; Hamada, Y. Tetrahedron
Lett. 2007, 48, 4977; (g) Nemoto, T.; Harada, T.; Matsumoto,
T.; Hamada, Y. Tetrahedron Lett. 2007, 48, 6304.
8. For reviews on phosphine oxide preligands in transition metal
catalysis, see: (a) Dubrovina, N. V.; Bo¨rner, A. Angew.
Chem., Int. Ed. 2004, 43, 5883; (b) Ackermann, L. Synthesis
2006, 1557; (c) Ackermann, L. Synlett 2007, 507; (d) Nemoto,
T.; Hamada, Y. Chem. Rec. 2007, 7, 150.
9. When this reaction was performed in other solvents, the
product was obtained with lower enantiomeric excess.
CH2Cl2: 65% yield, 60% ee; toluene: 5% yield, 55% ee;
THF: 53% yield, 56% ee.
1. For reviews on Pd-catalyzed asymmetric allylic substitution,
see: (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996,
96, 395; (b) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1; (c)
Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921; (d)
Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
2. For examples using carbon nucleophiles, see: (a) Hamada, Y.;
Sakaguchi, K.; Hatano, K.; Hara, O. Tetrahedron Lett. 2001,
42, 1297; (b) Stang, A. Q.; Helmchen, G. Helv. Chim. Acta
2005, 88, 2738.
3. For examples using nitrogen nucleophiles, see: (a) Mori, M.;
Kuroda, S.; Zhang, C.-S.; Sato, Y. J. Org. Chem. 1997, 62,
3263; (b) Trost, B. M.; Oslob, J. D. J. Am. Chem. Soc. 1999,
121, 3057; (c) Mori, M.; Nishimata, T.; Nagasawa, Y.; Sato,
Y. Adv. Synth. Catal. 2001, 343, 34; (d) Mori, M.; Nakanishi,
D.; Kajishima, D.; Sato, Y. J. Am. Chem. Soc. 2003, 125,
9801.
4. For examples using oxygen nucleophiles, see: (a) Trost, B.
M.; Machacek, M. R.; Tsui, H. C. J. Am. Chem. Soc. 2005,
127, 7014; (b) Trost, B. M.; Tang, W.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 14785.
5. (a) Nemoto, T.; Masuda, T.; Akimoto, Y.; Fukuyama, T.;
Hamada, Y. Org. Lett. 2005, 7, 4447; (b) Nemoto, T.;
Fukuyama, T.; Yamamoto, E.; Tamura, S.; Fukuda, T.;
Matsumoto, T.; Akimoto, Y.; Hamada, Y. Org. Lett. 2007, 9,
927.
10. When a lithium enolate prepared from dibenzyl malonate and
LiH was used as the nucleophile, 4ad was obtained in 99%
yield with 86% ee. This result indicates that LiOAc is likely
related to the generation of lithium enolate in situ, resulting in
increased enantioselectivity.
6. For recent representative examples of Pd-catalyzed asymmet-
ric allylic substitution of cycloalkenyl alcohol derivatives
using malonate nucleophiles, see: (a) Zhao, D.; Ding, K. Org.
Lett. 2003, 5, 1249; (b) Greenfield, S.; Agarkov, A.; Gilbert-
son, S. R. Org. Lett. 2003, 5, 3069; (c) Seemann, M.; Scho¨ller,
M.; Kudis, S.; Helmchen, G. Eur. J. Org. Chem. 2003, 2122;
´
11. Ebner, D. C.; Novak, Z.; Stoltz, B. M. Synlett 2006, 3533.
12. (a) Ro¨nn, M.; Ba¨ckvall, J.-E.; Anderson, P. G. Tetrahedron
Lett. 1995, 36, 7749; (b) Trend, R. M.; Ramtohul, Y. K.;
Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2003,
42, 2892.
13. Fuchs, S.; Berl, V.; Lepoittevin, J.-P. Eur. J. Org. Chem. 2007,
1145.
´
`
(d) Dieguez, M.; Pamies, O.; Claver, C. J. Org. Chem. 2005,
`
´
70, 3363; (e) Pamies, O.; Dieguez, M.; Claver, C. J. Am.
Chem. Soc. 2005, 127, 3646; (f) Okuyama, Y.; Nakano, H.;