Polymer-supported chiral phosphinooxazolidine ligands for palladium-catalyzed asymmetric allylic alkylations and Diels-Alder reactions

Article abstract of DOI:10.1016/j.tetasy.2005.05.017

Polymer-supported chiral phosphinooxazolidine (POZ) ligands 9a-c and cationic palladium-POZ catalysts 16a-c have been prepared. The former ligands were used in the Pd-catalyzed asymmetric allylic alkylation, while the latter catalysts were used in the Die

Full text of DOI:10.1016/j.tetasy.2005.05.017

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2133–2140
Polymer-supported chiral phosphinooxazolidine ligands
for palladium-catalyzed asymmetric allylic alkylations and
Diels–Alder reactions
Hiroto Nakano,* Kouichi Takahashi and Reiko Fujita
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Received 16 April 2005; accepted 14 May 2005
Abstract—Polymer-supported chiral phosphinooxazolidine (POZ) ligands 9a–c and cationic palladium-POZ catalysts 16a–c have
been prepared. The former ligands were used in the Pd-catalyzed asymmetric allylic alkylation, while the latter catalysts were used
in the Diels–Alder reaction to afford good to excellent enantioselectivities (Pd-catalyzed allylation: up to 99% ee, Diels–Alder reac-
tion: up to 92% ee).
Ó 2005 Published by Elsevier Ltd.
2+
1. Introduction
Ph
Ph
Ph
Ph
An increasing number of applications are being found
for enantiomerically pure compounds for economic,
environmental and social reasons. Of the various meth-
ods used to obtain single enantiomers, a catalytic asym-
metric reaction is one of the most attractive from an
atom-economic perspective. Several efficient chiral
ligands and catalysts have been investigated with regard
to their use in these reactions.1 We recently reported that
chiral phosphinooxazolidine (POZ) 1 and cationic Pd-
complex 2 are an effective ligand and catalyst, respec-
tively, for asymmetric Pd-catalyzed allylic alkylations2
and Diels–Alder reactions,3 respectively (Fig. 1). Never-
theless, despite the huge amount of work on homoge-
neous chiral ligands and catalysts in these reactions,
the use of heterogeneous ligands and catalysts has not
been studied extensively.4 In particular, only a few
successful studies of the Diels–Alder reaction have been
reported.5,6 Furthermore, to the best of our knowledge,
a polymer-supported N–P type ligand has never been
used in the Diels–Alder reaction.
N
O
N
-
O
+2SbF6
Pd
P
Ph
Ph
P
Ph
Ph
2
1
Figure 1. Chiral POZ ligand 1 and cationic Pd–POZ complex 2.
of 16a–c to the Diels–Alder reaction. Good to excellent
enantioselectivities (allylic alkylation: up to 99% ee,
Diels–Alder reaction: up to 92% ee) were observed in
these reactions.
2. Results and discussion
Polymer-supported POZ ligands 9a–c, PdCl2–POZ com-
plexes 10a–c, and their homogeneous analogues, 7a and
7b and 8a and 8b, were synthesized via the route shown
in Scheme 1. Precursor 5 for linking to resins was
synthesized via the condensation of (S)-(ꢀ)-1,1-diphen-
yl-2-pyrrolidinemethanol 3 with 2-diphenylphosphino-
5-hydroxybenzaldehyde5 4 in 58% yield, and converted
to PdCl2-complex 6 by the reaction with PdCl2. The ste-
reochemical outcome of ligand 5 and PdCl2-complex 6
were determined using NOE difference spectra
(NOEDS) in 1H NMR. NOE enhancement was not
observed for the hydrogens at the 2- and 5-positions
Herein, we report the synthesis of new N–P type poly-
mer-supported chiral POZ ligands 9a–c and their cat-
ionic Pd–POZ catalysts 16a–c, and the applications of
9a–c to Pd-catalyzed asymmetric allylic alkylation and
*
Corresponding author. Tel.: +81 22 234 4181; fax: +81 22 275
2013; e-mail: hnakano@tohoku-pharm.ac.jp
0957-4166/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2005.05.017

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H. Nakano et al. / Tetrahedron: Asymmetry 16 (2005) 2133–2140
PPh2
Ph
Ph
CHO
5
Ph
Ph
Cl
N
O
N
O
2
Ph
Pd
PdCl2
4
Cl
OH
Ph
OH
P
P
Ph
Ph
Ph
Ph
N
ClCH2CH2Cl
rt, 72 h
cat. TsOH
benzene
reflux, 24 h
H
OH
OH
58%
3
5
6
58%
Ph
Ph
Ph
Ph
Cl
N
O
N
O
PdCl2
Pd
Cl
P
ClCH2CH2Cl
rt, 72 h
Ph
Ph
P
Ph
Ph
7a: TES-Cl
imidazole
CH2Cl2, rt, 1 h
OR
OR
8a,b
7b: AcCl
7a,b
a: R = TES, 96%
b: R = Ac, 72%
DMAP
CH2Cl2, rt, 5 h
a: R = TES, 60%
b: R = Ac, 91%
5
Ph
Ph
N
O
P
Ph
Ph
9a: PS-DES-Cl
imidazole
OR
CH2Cl2, rt, 4 h
9b and 9c:
9a-c
a: R = PS-DES
b: R = PS-Et-CO
c: R = Tenta Gel-MB-CO
PS-Et-COOH or
Tenta Gel MB-COOH
DIC, CH2Cl2
rt, 48 h
Ph
Ph
10a-c
a: R = PS-DES
b: R = PS-Et-CO
c: R = Tenta Gel-MB-CO
Cl
N
O
Pd
Cl
6
P
Ph
Ph
10a: PS-DES-Cl
imidazole
OR
CH2Cl2, rt, 4 h
10b and 10c:
PS-Et-COOH or
Tenta Gel MB-COOH
DIC, CH2Cl2
rt, 48 h
Scheme 1. Synthesis of monomeric and polymer-supported chiral POZ ligands and Pd–POZ complexes.
when these respective positions were irradiated (Scheme
2).
plex 6 with PS–DES–Cl in the presence of imidazole in
dichloromethane for 4 h at room temperature gave the
desired PS–DES-supported POZ ligand 9a or PdCl2–
POZ complex 10a. Furthermore, the reaction of 5 or 6
with PS–Et–COOH or TentaGel–COOH in the presence
of diisopropylcarbodiimide (DIC) in dichloromethane
for 48 h at room temperature gave the desired PS–Et-
or TentaGel-supported ligands 9b and c and PS–Et- or
TentaGel-supported PdCl2-complexes 10b and c. In
addition, to comparing the catalytic efficiency, homoge-
neous analogues 7a and 7b or 8a and 8b were also pre-
pared by reacting ligand 5 or complex 6 with TES–Cl
or AcCl.
Polystyrene–diethylsilyl (PS–DES),6 polystyrene–ethyl
(PS–Et), and polystyrene–poly(ethylene glycol-OC2H4-
NHCO-C2H5) (TentaGel) were used as resins. PS–DES
and PS–Et were constituted from styrene and DVB
(divinylbenzene) only and had a good solvent-swollen
state in dichloromethane. In contrast, TentaGel is a
graft-copolymer of gel-type polystyrene; catalysts bound
to this support behave like homogeneous rather than
heterogeneous catalysts in a wide range of solvents
because of the long, flexible poly(ethylene glycol) linker.
POZ ligand 5 and PdCl2–POZ complex 6 were linked via
ester and ether bond formation, respectively, to the PS–
DES–Cl, PS–Et–COOH or TentaGel–COOH resins
(Scheme 2). The reaction of POZ ligand 5 or PdCl2-com-
The efficiencies of the polymer-supported ligands 9a–c
were examined with the Pd-catalyzed asymmetric allylic
alkylation7,8 of 1,3-diphenyl-2-propenyl acetate 11 with

H. Nakano et al. / Tetrahedron: Asymmetry 16 (2005) 2133–2140
2135
2+
2+
Ph
Ph
Ph
Ph
-
N
N
O
-
O
+2SbF6
+2SbF6
Pd
Pd
P
P
Ph
Ph
Ph
Ph
OR
OH
14
15a,b
a: R = TES
b: R = Ac
6
8a,b
AgSbF6
CH2Cl2, rt
1 h
10a-c
2+
Ph
Ph
N
-
O
+2SbF6
Pd
a: R = PS-DES
b: R = PS-Et-CO
P
Ph
Ph
c: R = Tenta Gel-MB-CO
OR
16a-c
Scheme 2. Preparations of cationic POZ complexes.
dimethyl malonate 12a in the presence of [PdCl(g3-
C3H5)]2 and N,O-bis(trimethylsilyl)acetamide (BSA)9
to give allylation product 13a (Table 1). Initially, the
activities of monomer ligands 5, 7a, and 7b were tested
as a controlled experiment. The reaction using ligand 5
with a hydroxy group gave product 13 in 97% yield
and 58% enantiomeric excess (ee) (entry 1). Ligand 7a
with a triethylsilyloxy group afforded product 13a in
quantitative yield and good ee (89%) (entry 2). Further-
more, ligand 7b with an acetoxy group gave an excellent
ee (98%) with a reasonable chemical yield (93%) (entry
3).
in this reaction (Table 1). The use of PS–DES-supported
ligand 9a gave a poor chemical yield (25%) but a good ee
(93%) (entry 4). PS–Et-supported ligand 9b brought
about high asymmetric induction (98%) in a moderate
chemical yield (67%) (entry 5). Extending the reaction
time from 6 to 12 h led to a substantial increase in the
chemical yield to 99% (entry 6). However, decreasing
the catalytic loading from 5 to 2 mol % led to a substan-
tial decrease in the enantioselectivity to 77% ee (entry 7).
Furthermore, TentaGel-supported ligand 9c also affor-
ded product 13a in a satisfactory ee (96%) in a moderate
chemical yield (78%) (entry 8). The superior ligand 9b
was also applied to the reaction with a bulkier diethyl
methylmalonate 12b as a nucleophile. However, the
reaction gave product 13b in only 51% ee, although
With these results in hand, we investigated the efficien-
cies of the polymer-supported chiral POZ ligands 9a–c
Table 1. Pd-catalyzed asymmetric allylic alkylation of acetate 11 with dialkylmalonates 12a,b
R1
O
O
Ligand
R2 [PdCl(η3-C3H5)]2
R2O2C CO2R2
OAc
Ph
R2
O
O
+
Ph
R1
base/BSA
CH2Cl2
Ph
Ph
*
12a: R1=H, R2=Me
12b: R1=Me, R2=Et
13a: R1=H, R2=Me
13b: R1=Me, R2=Et
11
Entrya
Ligand
Ligand (mol %)
Nucleophile
Temperature (°C)
Time (h)
Yieldb (%)
% eec (config)d
1
2
5
2
2
2
5
5
5
2
5
5
5
12a
12a
12a
12a
12a
12a
12a
12a
12b
12b
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
3
3
97
99
93
25
67
99
67
78
98
98
58 (R)
89 (R)
98 (R)
93 (R)
98 (R)
99 (R)
77 (R)
96 (R)
51 (S)
19 (S)
7a
7b
9a
9b
9b
9b
9c
9b
9b
3
3
4
6
5
6
6
12
12
6
7
8
9
10
3
12
a Molar ratio for entries 1–10: [PdCl(g3-C3H5)]2 (0.001 equiv) for 1–3, 7 or [PdCl(g3-C3H5)]2 (0.025 equiv) for 4–6, 8–10, dimethyl malonate (3 equiv),
N,O-bis-(trimethylsilyl)acetoamide (BSA) (3 equiv), potassium acetate (0.02 equiv).
b Isolated yields.
c Determined by HPLC analysis using a DAICEL Chiralcel OD-H.
d R Configurations based on the specific rotation with literature data.3

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H. Nakano et al. / Tetrahedron: Asymmetry 16 (2005) 2133–2140
the chemical yield was excellent (entry 9). Furthermore,
the enantioselectivity at 0 °C was poor (19% ee) (entry
10).
experiment in the reaction of cyclopentadiene 17 with
acryloyl-1,3-oxazolidin-2-one 18 (Table 2). The Diels–
Alder reactions were attempted at 0 °C using 10 mol %
of the antimonate catalysts 14 and 15a and 15b. The
reaction using catalyst 14 did not proceed (entry 1) at
all. By contrast, catalysts 15a and 15b both showed good
catalytic activity (entries 2 and 3); in particular, catalyst
15b with an acetoxy group gave excellent enantioselec-
tivity (98% ee) when the reaction temperature was re-
duced to ꢀ45 °C (entry 4).
From these results, PS–Et-supported POZ ligand 9b was
more effective than the PS–DES- and TentaGel-sup-
ported POZ ligands 9a and c for this allylic alkylation,
while 9b gave a higher enantioselectivity than both the
corresponding monomer ligand 7b and the previously
reported monomer ligand 1.2 Although it is unclear
why ligand 9b gave an excellent yield and enantioselec-
tivity, it seemed to be dependent on the advantageous
steric and electronic interactions of the nucleophile
and p–allyl complex with its bulky polymeric backbone.
In addition, low enantioselectivities using bulkier car-
bon nucleophiles (entries 9 and 10) might result from
the interfering effects of the polymer backbone on ligand
9b to the attack of bulkier carbon nucleophiles.
Next, the Diels–Alder reactions using polymer-sup-
ported POZ catalysts 16a–c were examined under the
same reaction conditions as entries 2–4 (Table 2). The
PS–DES- and TentaGel-supported catalysts, 16a and
16c, did not show effective catalytic activity (16a: 27%
yield, 5% ee; 16c: 34% yield, 0% ee) (entries 5 and 7).
Conversely, PS–Et-supported catalyst 16b gave compar-
atively good results (64% yield, 83% ee) (entry 6). We
examined the effects of the molar ratio and reaction tem-
perature on the reaction using the superior catalyst 16b.
The use of 5 mol % 16b decreased both the chemical
yield and ee (entry 8), while increasing 16b to
20 mol % gave the best chemical yield (79%) and ee
(92% ee) (entry 9). Unfortunately, with 20 mol % 16b,
decreasing the temperature to ꢀ30 °C led to a substan-
tial decrease in the chemical yield along with a slight
decrease in ee (86% ee) (entry 10).
Finally, recycling experiments examined the allylic alkyl-
ation of 12a with 11 using ligand 9b. After the first run,
which gave 99% yield and 99% ee of product 13a, the
mixture was decanted off, and the solution of reactants
for the next cycle then added without any further addi-
tion of Pd. This process was repeated three times. Con-
sequently, 9b was recycled with 57% loss in activity
(from 99% to 42% yield) and with 33% loss in enantio-
selectivity (from 99% to 66% ee).
For application to other reactions, the catalytic activities
of cationic polymer-supported Pd–POZ catalysts 16a–c
in the Diels–Alder reaction10,11 were examined. Cationic
catalysts 14, 15a and 15b, and 16a–c, with a hexafluoro-
antimonate counterion, were prepared by reacting 6, 8a
and 8b, and 10a–c, respectively, with AgSbF6 in dry
CH2Cl2 at rt for 1 h under argon (Scheme 2).
The superior cationic antimonate catalyst 16b was then
tested using other dienes such as cyclohexadiene 20 or
2,3-dimethyl-1,3-butadiene 21, and dienophiles, such as
crotonyl-1,3-oxazaolidin-2-one 22a or fumaroyl-1,3-
oxazolidin-2-one 22b (Table 3). The reactions were car-
ried out with 20 mol % catalyst 16b at 0 °C (Table 3).
However, the reaction of diene 17 with dienophile 22a
was sluggish and only gave the Diels–Alder adduct 23a
in poor chemical yield and low enantioselectivity (entry
1). In contrast, the reaction with 22b proceeded in
Initially, the catalytic activities of the cationic monomer
catalysts 14 and 15a and b were tested as a control
Table 2. Diels–Alder reactions with cationic POZ catalysts
O
O
catalyst
O
N
O
+
N
O
CH2Cl2
O
17
19
18
Entry
Catalyst (mol %)
Temperature (°C)
Time (h)
Yielda (%)
endo/exob
% eec
1
2
3
4
5
6
7
8
9
10
14 (10)
0
24
3
No reaction
—
—
90
93
98
5
15a (10)
15b (10)
15b (10)
16a (10)
16b (10)
16c (10)
16b (5)
0
0
99
97
86
27
64
34
43
79
29
93:3
93:7
98:2
95:5
94:6
83:17
94:6
93:7
97:3
3
ꢀ45
0
24
24
24
24
24
24
48
0
83
0
0
0
28
92
86
16b (20)
16b (20)
0
ꢀ30
a Isolated yields.
b endo/exo Ratio was determined by HPLC.
c Ee of endo-isomer was determined by chiral HPLC using a Daicel OD-H column.

H. Nakano et al. / Tetrahedron: Asymmetry 16 (2005) 2133–2140
Table 3. Substrate generality in the Diels–Alder reaction with cationic catalyst 16b
2137
(
)
n
R
23a: n=1, R=Me
23b: n=1, R=CO2Et
23c: n=2, R=H
O
(
)
n
O
N
O
catalyst 16b
O
17: n=1
20: n=2
(20mol%)
N
O
R
+
CH2Cl2
0 °C, 48 h
R
18: R=H
24a: R=H
24b: R=CO2Et
22a: R=Me
O
N
22b: R=CO2Et
O
O
21
Entry
Diene
Substrate
Yield (%)a
endo/exob
% eec (config)
1
2
3
4
5
17
17
20
21
21
22a
22b
18
12
99
82:18
67:33
—
56 (R)
17 (S)d
—
No reaction
18
22b
11
14
—
—
35 (R)
44 (R)
a Isolated yield.
b endo/exo Ratios were determined by HPLC or 1H NMR.
c Ee of endo-isomers were determined by chiral HPLC.
d After conversion to the corresponding iodolactone (I2, KI, NaHCO3, yield 63%), the ee and absolute configuration were determined by comparison
with known specific rotation.
excellent chemical yield, although the enantioselectivity
was poor (entry 2). Furthermore, the reaction of rela-
tively unreactive diene 20 with dienophile 18 did not
proceed at all (entry 3). In addition, catalyst 16b was ap-
plied to the reactions of acyclic diene 21 with dienophiles
18 and 22b, although poor results were obtained for
both the chemical yield and enantioselectivity (entries
4 and 5). Although it is unclear why catalyst 16b gave
good enantioselectivity, it seemed to be dependent on
the advantageous steric and electronic interactions of
diene 17 and the Pd–POZ complex with the bulky poly-
meric backbone of the coordinating dienophile. These
results suggest that the linking of POZ on PS–Et resin
was the most effective for giving good chemical yield
and enantioselectivity, similar to the results of the allylic
alkylation. However, this polymer-supported catalyst
16b did not work as efficiently as either of the monomer
catalysts 15b and 23 in the Diels–Alder reaction.
POZ ligand 9b and Pd–POZ catalyst with antimonate
counterion 16b had good activity and enantioselectivity
(allylation with 9b: 99% yield, 99% ee, Diels–Alder reac-
tion with 16b: 80% yield, 92% ee) in the reactions. In
particular, 9b gave a superior chemical yield and enantio-
selectivity than that of monomer 12 in Pd-catalyzed allylic
alkylation. Studies to optimize the reaction conditions for
continuous processing, recycling, and application to
other asymmetric reactions are currently in progress.
4. Experimental
4.1. General methods
Melting points are uncorrected. IR spectra were re-
corded as KBr pellets (solids) or thin films (liquids).
1
The H and 13C NMR spectra were recorded at 270
and 67.5 MHz, and at 400 and 100 MHz, respectively.
The chemical shifts are reported in ppm downfield to
TMS (d = 0) for H NMR and relative to the central
We conducted recycling experiments for the Diels–Alder
reaction of diene 17 with dienophile 18 catalyzed using
the PS–Et-supported Pd–POZ catalyst 16b. After the
first run, which gave 92% ee of Diels–Alder adduct 19,
the mixture was decanted, and a solution containing
the reactants for the next cycle added. This process
was carried out three times. Consequently, 15b was recy-
cled with approximately 30% losses in both activity
(from 79% to 45% yield) and enantioselectivity (from
92% to 62% ee).
1
CDCl3 resonance (d = 77.0) for 13C NMR. Mass spectra
were obtained by EI. The enantiomeric excess (ee) of the
products were determined by chiral HPLC. Optical rota-
tions were recorded at the sodium D line with a polari-
meter at room temperature. Commercially available
compounds were used without further purification. Sol-
vents were dried according to standard procedures.
Chromatography refers to flash chromatography on sil-
ica gel (230–400 mesh), unless otherwise noted.
3. Conclusion
4.2. (2R,5S)-1-Aza-4,4-diphenyl-2-(50-hydroxy-20-di-
phenylphosphino)phenyl-3-oxobicyclo[3.3.0]octane 5
In conclusion, we have prepared six new chiral, poly-
mer-supported POZ ligands 9a–c and their cationic
Pd–POZ catalysts 16a–c, and applied them to heteroge-
neous Pd-catalyzed allylic alkylation and the Diels–
Alder reaction, respectively. The PS–Et-supported
A solution of (S)-(ꢀ)-a,a-diphenyl-2-pyrrolidinemetha-
nol 3 (41 mg, 0.16 mmol), 2-diphenylphosphanyl-5-
hydroxybenzaldehyde 4 (50 mg, 0.16 mmol) and p-tolu-
enesulfonic acid monohydrate (6 mg, 0.03 mmol) in

2138
H. Nakano et al. / Tetrahedron: Asymmetry 16 (2005) 2133–2140
benzene (20 mL) was heated under reflux using a Dean-
Stark trap. After 24 h, the solvent was evaporated under
reduced pressure. The residue was purified by prepara-
tive TLC on silica gel (1:1 hexane–AcOEt) to give prod-
(NaCl) 699, 735, 1216, 1733, 2931 cmꢀ1 1H NMR
;
(CDCl3): d 1.45–1.69 (m, 4H), 2.20 (s, 3H), 2.69–2.78
(m, 1H), 2.93–3.02 (m, 1H), 4.27 (t, J = 6.7 Hz, 1H),
6.34 (d, J = 5.8 Hz, 1H), 6.90 (s, 2H), 7.05–7.24 (m,
10H), 7.28–7.36 (m, 10H), 7.50–7.70 (m, 1H); 13C NMR
(CDCl3): d 21.11, 24.52, 27.82, 50.92, 73.29, 89.16,
94.72, 120.83, 121.34, 125.09, 126.28, 126.44, 126.66,
127.74, 128.38, 128.43, 128.48, 128.54, 128.80, 131.65,
131.89, 133.21, 133.68, 133.81, 133.94, 134.05, 134.08,
134.18, 135.06, 135.31, 137.04, 137.56, 144.04, 146.76,
147.67, 151.36, 169.02; MS m/z 583 (M+); HRMS calcd
for C38H34NO3P (M+) 583.2277. Found: 583.2244.
uct 5 (50 mg, 58%) as colorless prism: mp 76 °C;
20
½aꢁ ¼ þ15.0 (c 0.16, CHCl3); IR (KBr) 698, 746,
D
1
1226, 1434, 1598 cmꢀ1; H NMR (CDCl3): d 1.44–1.62
(m, 2H), 1.64–1.73 (m, 2H), 2.71–2.77 (m, 1H), 2.84–
2.91 (m, 1H), 4.34 (t, J = 6.9 Hz, 1H), 6.36 (d,
J = 6.6 Hz, 1H), 6.50 (dd, J = 2.6, 8.4 Hz, 1H), 6.73
(dd, J = 4.3, 8.4 Hz, 1H), 7.04–7.46 (m, 21H); 13C
NMR (CDCl3): d 24.62, 27.88, 50.72, 73.35, 88.97,
94.46, 114.98, 115.07, 116.06, 125.97, 126.15, 126.28,
126.39, 126.52, 126.71, 127.75, 127.85, 128.05, 128.24,
128.28, 128.34, 128.37, 128.49, 133.51, 133.65, 133.80,
133.93, 135.60, 137.66, 137.82, 137.97, 143.75, 146.57,
146.69, 147.02, 157.00; MS m/z 541 (M+); HRMS calcd
for C36H32NO2P (M+) 541.2171. Found: 541.2188.
4.5. Dichloro[(2R,5S)-1-aza-4,4-diphenyl-2-(20-
diphenylphosphino-50-hydroxy)-phenyl-3-oxobicyclo-
[3.3.0]octane]palladium 6
A suspension of POZ ligand 5 (30 mg, 0.06 mmol) and
PdCl2 (10 mg, 0.06 mmol) in 1,2-dichloroethane (5 mL)
was stirred at room temperature for 72 h. Then the sol-
vent was evaporated under reduced pressure. The residue
was chromatographed on a column of silica gel (1:1
4.3. (2R,5S)-1-Aza-4,4-diphenyl-2-(20-diphenylphosphino-
50-triethylsilyloxy)phenyl-3-oxobicyclo[3.3.0]octane 7a
To a solution of 5 (30 mg, 0.06 mmol) and imidazole
(8 mg, 0.11 mmol) in CH2Cl2 (3 mL) was added chlo-
rotriethylsilane (0.02 mL, 0.11 mmol) at room tempera-
ture. The reaction was carried out at room temperature
for 1 h. Then the reaction mixture was quenched with
water and extracted twice with ether. The combined or-
ganic layer was dried over anhydrous MgSO4 and con-
centrated. The residue was chromatographed on a
AcOEt–CHCl3) to give complex 6 (23 mg, 58%) as a yel-
20
low prism: mp 229 °C; ½aꢁ ¼ ꢀ95.0 (c 0.20, DMSO); IR
D
1
(KBr) 692, 1438, 1600 cmꢀ1; H NMR (DMSO-d6): d
1.41–1.56 (m, 1H), 1.88–1.93 (m, 1H), 2.07–2.10 (m,
1H), 2.23–2.44 (m, 1H), 2.88–2.99 (m, 1H), 4.03 (t,
J = 9.7 Hz, 1H), 4.97 (s, 1H), 6.54–6.28 (m, 1H), 6.66
(t, J = 9.1 Hz, 1H), 6.91–7.03 (m, 3H), 7.08–7.56 (m,
19H), 10.76 (br s, 1H); 13C NMR (DMSO-d6): 27.31,
28.21, 54.48, 78.69, 87.79, 92.45, 109.02, 109.79,
118.70, 118.34, 121.64, 121.77, 124.86, 125.55, 126.71,
127.53, 127.90, 128.10, 128.26, 128.51, 128.69, 128.84,
129.17, 130.42, 130.85, 130.95, 133.05, 133.21, 134.26,
135.01, 137.06, 139.28, 139.53, 143.32, 143.46, 160.84;
MS m/z 646 ([Mꢀ1H2Cl]+); HRMS calcd for
C36H31NO2PPd ([Mꢀ1H2Cl]+) 646.1128. Found:
646.1235 (FAB with p-nitrobenzylalcohol added).
column of silica gel (1:10 AcOEt–hexane) to give the
20
D
(c 0.20, CHCl3); IR (NaCl) 698, 749, 1292, 1469, 1592,
product 7a (35 mg, 96%) as colorless oil: ½aꢁ ¼ ꢀ65.0
1
2957 cmꢀ1; H NMR (CDCl3): d 0.58 (q, J = 8.1 Hz,
6H), 0.89 (t, J = 8.1 Hz, 9H), 1.31–1.38 (m, 1H), 1.48–
1.55 (m, 1H), 1.67 (dd, J = 6.2, 13.2 Hz, 2H), 2.68–
2.72 (m, 1H), 2.90–2.95 (m, 1H), 4.22–4.29 (m, 1H),
6.38 (d, J = 6.2 Hz, 1H), 6.64 (dd, J = 2.2, 8.4 Hz, 1H),
6.76 (dd, J = 4.4, 8.4 Hz, 1H), 7.12–7.15 (m, 2H),
7.17–7.20 (m, 5H), 7.21–7.28 (m, 4H), 7.29–7.32 (m,
5H), 7.34–7.39 (m, 5H); 13C NMR (CDCl3): d 4.90,
6.61, 24.30, 27.70, 50.56, 73.18, 89.01, 94.90, 118.95,
119.90, 126.25, 126.35, 126.49, 126.58, 126.65, 126.81,
126.88, 126.97, 127.69, 127.86, 128.25, 128.34, 128.47,
131.92, 131.99, 133.66, 133.79, 133.88, 134.01, 135.34,
137.91, 137.98, 138.08, 138.14, 144.30, 146.88, 147.53,
156.63; MS m/z 655 (M+); HRMS calcd for
C42H46NO2PSi (M+) 655.3035. Found: 655.3078.
4.6. Dichloro[(2R,5S)-1-aza-4,4-diphenyl-2-(20-
diphenylphosphino-50-triethylsilyloxy)-phenyl-3-
oxobicyclo[3.3.0]octane]palladium 8a
A suspension of 7a (30 mg, 0.05 mmol) and PdCl2 (8 mg,
0.05 mmol) in 1,2-dichloroethane (5 mL) was stirred at
room temperature for 72 h. Then the solvent was evap-
orated under reduced pressure. The residue was chro-
matographed on a column of silica gel (AcOEt only)
to give the product 8a (23 mg, 60%) as yellow prism:
20
4.4. (2R,5S)-2-(50-Acetoxy-20-diphenylphosphino)phenyl-
1-aza-4,4-diphenyl-3-oxobicyclo-[3.3.0]octane 7b
mp 213 °C; ½aꢁ ¼ ꢀ235.55 (c 0.90, DMSO); IR (KBr)
D
1
689, 1437, 1600, 2345 cmꢀ1; H NMR (CDCl3): d 0.82
(q, J = 8.1 Hz, 6H), 0.85–0.94 (m, 1H), 1.05 (t,
J = 8.1 Hz, 9H), 1.39–1.46 (m, 1H), 1.86–1.91 (m, 1H),
2.06–2.08 (m, 1H), 2.60–2.65 (m, 1H), 2.90 (dt, J = 8.1,
12.5 Hz, 1H), 4.43 (dt, J = 3.7, 11.2 Hz, 1H), 4.79 (d,
J = 1.5 Hz, 1H), 6.69–6.72 (m, 1H), 6.86 (dd, J = 7.7,
10.6 Hz, 1H), 6.91 (ddd, J = 0.7, 1.8, 8.4 Hz, 1H), 7.00
(t, J = 7.7 Hz, 2H), 7.03–7.04 (m, 1H), 7.08 (t,
J = 7.3 Hz, 3H), 7.11–7.14 (m, 2H), 7.17 (t, J = 7.3 Hz,
1H), 7.24–7.36 (m, 7H), 7.38 (dd, J = 1.5, 7.3 Hz, 4H);
13C NMR (CDCl3): d 5.07, 6.60, 26.96, 28.83, 54.99,
77.37, 89.15, 94.46, 133.68, 114.01, 122.16, 122.22,
124.89, 125.39, 125.46, 126.58, 127.05, 127.30, 127.99,
To a mixture of 5 (70 mg, 0.13 mmol), DMAP (8 mg,
0.06 mmol) and Et3N (0.04 mL, 0.26 mmol) in CH2Cl2
(5 mL) was added acetylchloride (0.02 mL, 0.26 mmol)
at 0 °C. The reaction was carried out at room tempera-
ture for 5 h. Then the reaction mixture was quenched
with saturated aqueous NaHCO3 and extracted
twice with AcOEt. The combined organic layers were
washed with brine, dried over MgSO4 and concentrated.
The residue was chromatographed on a column of silica
gel (1:10 AcOEt–hexane) to give product 7b (54 mg,
20
D
72%) as colorless oil: ½aꢁ ¼ ꢀ52.0 (c 1.00, CHCl3); IR

H. Nakano et al. / Tetrahedron: Asymmetry 16 (2005) 2133–2140
2139
128.07, 128.42, 128.49, 128.57, 128.60, 130.56, 130.58,
130.69, 132.50, 132.69, 133.31, 133.92, 137.66, 137.68,
139.29, 139.40, 142.13, 143.59, 158.92; MS m/z 761
([Mꢀ2Cl]+); HRMS calcd for C42H46NO2PSiPd
([Mꢀ2Cl]+) 761.2069. Found: 761.2272 (FAB with
p-nitrobenzylalcohol added).
Pd–POZ 10b (159 mg). Elemental analysis of 9b: Found:
C, 85.25; H, 7.42; N, 1.10, containing 1.10% N, corre-
sponding to 0.78 mmol ligand/g of polymer. Elemental
analysis of 10b: Found: C, 82.89; H, 7.48; N, 1.07, con-
taining 1.07% N, corresponding to 0.76 mmol complex/g
of polymer.
4.7. Dichloro[(2R,5S)-2-(50-acetoxy-20-diphenylphos-
phino)phenyl-1-aza-4,4-diphenyl-3-oxobicyclo-
[3.3.0]octane]palladium 8b
4.10. TentaGel-supported POZ ligand 9c and Pd–POZ
complex 10c
A mixture of 5 or 6 (0.06 mmol), TentaGel MB–COOH
(100 mg, 0.04 mmol) and DIC (0.01 mL, 0.8 mmol) in
CH2Cl2 (2 mL) was stirred at room temperature for
48 h. The reaction mixture was filtered and the polymer
washed with CHCl3, MeOH, acetone, and ether. The
polymer was dried under reduced pressure to give Ten-
taGel-supported POZ ligand 9c (128 mg) or TentaGel-
supported Pd–POZ 10c (124 mg). Elemental analysis
of 9c: Found: C, 69.13; H, 8.30; N, 1.03, containing
1.03% N, corresponding to 0.37 mmol ligand/g of poly-
mer. Elemental analysis of 10c: Found: C, 66.15; H,
7.76; N, 0.98, containing 0.98% N, corresponding to
0.35 mmol complex/g of polymer.
A suspension of 7b (50 mg, 0.09 mmol) and PdCl2
(15 mg, 0.09 mmol) in 1,2-dichloroethane (5 mL) was
stirred at room temperature for 72 h. Then the solvent
was evaporated under reduced pressure. The residue
was chromatographed on a column of silica gel (AcOEt
only) to give product 8b (59 mg, 91%) as yellow prism:
20
D
mp 214 °C; ½aꢁ ¼ ꢀ260.9 (c 0.46, DMSO); IR (KBr)
690, 1437, 1763, 2983 cmꢀ1
;
1H NMR (CDCl3): d
1.32–1.48 (m, 1H), 1.81–1.91 (m, 1H), 2.05–2.13 (m,
1H), 2.37 (s, 3H), 2.556–2.67 (m, 1H), 2.93 (dt,
J = 7.9, 16.0 Hz, 1H), 4.41 (dt, J = 3.3, 9.1 Hz, 1H),
4.89 (s, 1H), 6.83–6.91 (m, 2H), 6.97–7.19 (m, 9H),
7.22–7.36 (m, 7H), 7.39–7.44 (m, 6H); 13C NMR
(CDCl3): d 21.12, 26.93, 28.71, 54.92, 77.31, 89.16,
93.99, 120.04, 120.72, 124.67, 124.91, 125.04, 125.42,
126.44, 126.56, 126.68, 127.00, 127.22, 127.96, 128.15,
128.37, 128.46, 128.62, 130.67, 130.80, 131.74, 132.76,
133.11, 133.26, 133.37, 133.84, 137.30, 138.85, 139.09,
141.89, 143.23, 152.98, 168.43; MS m/z 689 ([Mꢀ2Cl]+);
HRMS calcd for C38H34NO3PPd ([Mꢀ2Cl]+) 689.1311.
Found: 689.1375 (FAB with p-nitrobenzylalcohol
added).
4.11. General procedure for the Pd-catalyzed allylic
alkylation using nonsupported ligand
A
mixture of nonsupported ligand (0.004 mmol,
2 mol %) and [(g3-C3H5)PdCl]2 (0.7 mg, 0.002 mmol,
1 mol %) in CH2Cl2 (1 mL) was stirred at room temper-
ature under argon for 1 h. The resulting yellow solution
was added to a mixture of 1,3-diphenyl-2-propenyl ace-
tate 11 (50 mg, 0.2 mmol) and KOAc (0.4 mg,
0.004 mmol, 2 mol %) in CH2Cl2 (1 mL) via a cannula,
followed by the addition of malonate 12a (0.07 mL,
0.59 mmol) and BSA (0.15 mL, 0.59 mmol). The reac-
tion was carried out at room temperature after 3 h.
The reaction mixture was quenched with saturated
NH4Cl solution and extracted twice with ether. The
combined organic layer was washed with brine, dried
over anhydrous MgSO4, and concentrated. The crude
product was purified by preparative TLC on silica gel
(2:1 hexane–AcOEt) to give the alkylated product 13a.
4.8. PS–DES-supported POZ ligand 9a and Pd–POZ
complex 10a
A mixture of POZ ligand 5 or Pd–POZ complex 6
(0.21 mmol), chlorodiethylsilyl polystyrene (PS–DES–
Cl, 100 mg, 0.14 mmol) and imidazole (33 mg,
0.49 mmol) in CH2Cl2 (2 mL) was stirred at room tem-
perature for 4 h. The reaction mixture was filtered and
the polymer washed with CHCl3, MeOH, acetone and
ether. The polymer was dried under reduced pressure
to give PS–DES-supported POZ ligand 9a (100 mg) or
PS–DES-supported Pd–POZ 10a (121 mg). Elemental
analysis of 9a: Found: C, 82.74; H, 8.40; N, 0.16, con-
taining 0.16% N, corresponding to 0.11 mmol ligand/g
of polymer. Elemental analysis of 10a: Found: C,
81.40; H, 8.39; N, 0.79, containing 0.79% N, corre-
sponding to 0.56 mmol complex/g of polymer.
4.12. General procedure for the Pd-catalyzed allylic
alkylation using polymer-supported ligand
A mixture of polymer-supported ligand (0.01 mmol,
5 mol %), [(g3-C3H5)PdCl]2 (2 mg, 0.005 mmol, 2.5 mol %),
1,3-diphenyl-2-propenyl acetate 11 (50 mg, 0.2 mmol)
and KOAc (0.4 mg, 0.004 mmol, 2 mol %) in CH2Cl2
(1 mL) was stirred at room temperature under argon
for 1 h. To this mixture, cooled to the desired reaction
temperature, was added malonate 12a or 12b
(0.59 mmol) and BSA (0.15 mL, 0.59 mmol). The reac-
tion was then carried out at the same temperature. After
a certain time had elapsed, the mixture was quenched
with saturated NH4Cl solution, filtered, and extracted
twice with ether. The combined organic layer was
washed with brine, dried over anhydrous MgSO4, and
concentrated. The crude product was purified by
preparative TLC on silica gel (2:1 hexane–AcOEt) to
give alkylated product 13a or 13b.
4.9. PS–Et-supported POZ ligand 9b and Pd–POZ
complex 10b
A mixture of 5 or 6 (0.17 mmol), carboxyethylpolysty-
rene (PS–Et–COOH, 100 mg, 0.11 mmol) and diisopro-
pylcarbodiimide (DIC, 0.04 mL, 0.23 mmol) in CH2Cl2
(2 mL) was stirred at room temperature for 48 h. The
reaction mixture was filtered and the polymer washed
with CHCl3, MeOH, acetone, and ether. The polymer
was dried under reduced pressure to give PS–Et-sup-
ported POZ ligand 9b (123 mg) or PS–Et-supported

2140
H. Nakano et al. / Tetrahedron: Asymmetry 16 (2005) 2133–2140
2. Okuyama, Y.; Nakano, H.; Hongo, H. Tetrahedron:
Asymmetry 2000, 11, 1193–1198.
4.13. General procedure for the Diels–Alder reaction
using nonsupported Pd–POZ complex
3. Nakano, H.; Takahashi, K.; Okuyama, Y.; Senoo, C.;
Tsugawa, N.; Suzuki, Y.; Fujita, R.; Sasaki, K.; Kabuto,
C. J. Org. Chem. 2004, 69, 7092–7100.
4. For recent reviews on heterogeneous asymmetric catalysis,
see: (a) Chiral Catalyst Immobilization and Recycling;
DeVos, D. E., Vankelecom, I. F. J., Jacobs, P. A., Eds.;
Wiley-VCH: Weinheim, 2000; (b) Fan, Q.-H.; Li, Y.-M.;
Chan, A. S. C. Chem. Rev. 2002, 102, 3385–3466; (c)
Brase, S.; Lauterwasser, F.; Ziegert, R. E. Adv. Synth.
Catal. 2003, 345, 869–929.
A
suspension of nonsupported Pd–POZ complex
(0.034 mmol) and AgSbF6 (30 mg, 0.089 mmol) in
CH2Cl2 (1 mL) was stirred at room temperature under
argon for 1 h. The suspension was cooled to the desired
reaction temperature and to which were added cyclo-
pentadiene 17 (0.057 mL, 0.84 mmol) and CH2Cl2
(1 mL) solution of N-acryloyloxazolidinone 18 (25 mg,
0.18 mmol). The reaction was carried out at the same
temperature. After a certain time had elapsed, the reac-
tion mixture was quenched with saturated NH4Cl solu-
tion and extracted twice with ether. The combined
organic layer was washed with brine, dried over anhy-
drous MgSO4, and concentrated. The crude product
was purified by preparative TLC on silica gel (1:1 hex-
ane–AcOEt) to give Diels–Alder adduct 19.
5. Laue, S.; Greiner, L.; Woltinger, J.; Liese, A. Adv. Synth.
Catal. 2001, 343, 711–720.
6. Hu, Y.; Porco, J. A., Jr.; Labadie, J. W.; Gooding, O. W.
J.; Trost, B. M. J. Org. Chem. 1998, 63, 4518–4521.
7. For some recent successful publications on polymer-
supported chiral ligands in Pd-catalyzed allylic alkyla-
tions: (a) Nakano, H.; Takahashi, K.; Fujita, R. Hetero-
cycles 2004, 64, 407–416; (b) Nakano, H.; Takahashi, K.;
Suzuki, Y.; Fujita, R. Tetrahedron: Asymmetry 2005, 16,
609–614; (c) Uozumi, Y.; Danjo, H.; Hayashi, T. Tetra-
hedron Lett. 1998, 39, 8303–8306; (d) Uozumi, Y.;
Shibatomi, K. J. Am. Chem. Soc. 2001, 123, 2919–2920;
(e) Aoki, K.; Shimada, T.; Hayashi, T. Tetrahedron:
Asymmetry 2004, 15, 1771–1777; (f) Hallman, K.; Mac-
edo, E.; Nordstrom, K.; Moberg, C. Tetrahedron: Asym-
metry 1999, 10, 4037–4046; (g) Hallman, K.; Moberg, C.
Tetrahedron: Asymmetry 2001, 12, 1475–1478; (h) Belda,
O.; Lundgren, S.; Moberg, C. Org. Lett. 2003, 5, 2275–
2278; (i) Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2046–
2048; (j) Gamez, P.; Dunjic, B.; Fache, F.; Lemaire, M.
Tetrahedron: Asymmetry 1995, 6, 1109–1116; (k) Gilbert-
son, S. R.; Lan, P. Org. Lett. 2001, 3, 2237–2240; (l)
Greenfield, S. J.; Agarkov, A.; Gilbertson, S. R. Org. Lett.
2003, 5, 3069–3072.
8. For a recent review on asymmetric allylic substitution, see:
(a) Hayashi, T. In Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; VCH: Weinheim, 1993, p 325; (b) Trost, B. M.; van
Vranken, D. L. Chem. Rev. 1996, 96, 395; (c) Helmchen, G.;
Pfaltz, A. Acc. Chem. Res. 2000, 33, 336; (d) Seebach, D.;
Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40, 92;
(e) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
9. Trost, B. M.; Murphy, D. J. Organometallics 1985, 4,
1143–1145.
4.14. General procedure for the Diels–Alder reaction
using polymer-supported Pd–POZ complex
A suspension of polymer-supported Pd–POZ complex
(0.034 mmol) and AgSbF6 (30 mg, 0.089 mmol) in
CH2Cl2 (1 mL) was stirred at room temperature under
argon for 1 h. The suspension was cooled to the desired
reaction temperature and to which were added diene 17,
20, or 21 (0.84 mmol) and CH2Cl2 (1 mL) solution of
dienophile 18, 22a, or 22b (0.18 mmol). The reaction
was carried out at the same temperature. After a certain
time had elapsed, the reaction mixture was filtered,
quenched with saturated NH4Cl solution and extracted
twice with ether. The combined organic layer was
washed with brine, dried over anhydrous MgSO4, and
concentrated. The crude product was purified by pre-
parative TLC on silica gel (1:1 hexane–AcOEt) to give
Diels–Alder adduct 19, 23a–c, 24a, or 24b.
4.15. Recycling experiments with supported ligand and
catalyst
10. For some successful publications on polymer-supported
chiral catalysts in Diels–Alder reactions: (a) Kamahori, K.;
Ito, K.; Itsuno, S. J. Org. Chem. 1996, 61, 8321–8324; (b)
Itsuno, S.; Kamahori, K.; Watanabe, K.; Koizumi, T.; Ito,
K. Tetrahedron: Asymmetry 1994, 5, 523–526; (c) Altava,
B.; Burguete, M. I.; Escuder, B.; Luis, S. V.; Salvador, R. V.
J. Org. Chem. 1997, 62, 3126–3134; (d) Altava, B.; Burgu-
ete, M. I.; Fraile, J. M.; Garcia, J. I.; Luis, S. V.; Mayoral, J.
A.; Vicent, M. J. Angew. Chem., Int. Ed. 2000, 39, 1503–
1505; (e) Annunziata, R.; Benaglia, M.; Cinquini, M.;
Cozzi, F.; Pitillo, M. J. Org. Chem. 2001, 66, 3160–3166; (f)
Rechavi, D.; Lemaire, M. Org. Lett. 2001, 3, 2493–2496; (g)
OÕLeary, P.; Krosveld, N. P.; De Jong, K. P.; Koten, G.;
Gebbink, K. Tetrahedron Lett. 2004, 45, 3177–3180.
11. For a recent overview, see: Lewis Acids in Organic
Synthesis; Yamamoto, H., Ed.; Wiley-VCH: Weinheim,
2001; Vols. 1 and 2.
After allylic alkylation or Diels–Alder reaction, the reac-
tion mixture was decanted off by using a cannula, and
the solution of the reactants (allylic alkylation: acetate,
malonate, and BSA, Diels–Alder reaction: diene and
dienophile) for the next cycle added to the polymer.
References
1. For a recent overview, see: (a) Oppolzer, W. Comprehen-
sive Organic Syntheses: Selectivity, Strategy and Effi-
ciency. In Modern Organic Chemistry; Trost, B. M.; Ed.;
Pergamon Press: Oxford, 1991; Vol. 5, p 315, and
references cited therein; (b) Comprehensive Asymmetric
Catalysis; Jacobsen, E. J., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999.