Novel chiral xylofuranose-based phosphinooxathiane and phosphinooxazinane ligands for palladium-catalyzed asymmetric allylations

Article abstract of DOI:10.1016/S0957-4166(03)00495-6

Novel chiral xylofuranose-based phosphinooxathiane and phosphinooxazinane ligands were found to provide high levels of enantioselectivity (up to 94% ee) in palladium-catalyzed asymmetric allylic alkylations and aminations.

Full text of DOI:10.1016/S0957-4166(03)00495-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2361–2368
Novel chiral xylofuranose-based phosphinooxathiane and
phosphinooxazinane ligands for palladium-catalyzed asymmetric
allylations
Hiroto Nakano,* Jun-ichi Yokoyama, Yuko Okuyama, Reiko Fujita and Hiroshi Hongo
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Received 22 April 2003; accepted 17 May 2003
Abstract—Novel chiral xylofuranose-based phosphinooxathiane and phosphinooxazinane ligands were found to provide high
levels of enantioselectivity (up to 94% ee) in palladium-catalyzed asymmetric allylic alkylations and aminations.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
type of chiral phosphinooxathiane8 2 and phosphinoox-
azinane ligands 3a–d by fusing a xylofuranose ring and
have shown their utility in palladium-catalyzed tandem
allylations9 (Scheme 1). Herein, we report the applica-
tion of these ligands to Pd-catalyzed allylic alkylations
and aminations.
Palladium-catalyzed allylation1 is one of the most
important methods for carbonꢀcarbon bond formation
in synthetic organic chemistry. As such its asymmetric
version using a chiral ligand has also been extensively
studied over the last decade.2,3 Generally, the combina-
tion of a donor atom and a rigid backbone in a ligand
is very important for realizing high levels of asymmetric
2. Results and discussion
induction in the reaction. 1,2-O-Isopropylidene-D-xylo-
furanose 1 is a readily available and highly functional-
ized compound with several stereogenic centers,
allowing for a systematic regio- and stereoselective
introduction of different functionalities in the synthesis
of a series of chiral ligands. For this reason, several
xylofuranose-based chiral ligands have recently been
explored and their potential utility in asymmetric reac-
tions such as palladium-catalyzed allylation,4 hydro-
genation,5 hydroformylation,6 and copper-catalyzed
addition7 of dialkylzinc to enones has been demon-
strated. More recently, we have also explored a new
2.1. Synthesis of phosphinooxathiane and phosphinoox-
azinane ligands
Phosphinooxathiane 2 and phosphinooxazinane 3a–d
ligands were synthesized easily from commercially
available
(Scheme 2). Diol
1,2-O-isopropylidene-
D
-xylofuranose
1
1
was converted to
4
by
monotosylation10 followed by acetylation. The displace-
ment of the tosylate group with potassium thioacetate
and the treatment of 6 with potassium carbonate
afforded the mercapto-alcohol 7. The condensation of 7
Scheme 1.
* Corresponding author. Tel.: +81-22-234-4181; fax: +81-22-275-2013; e-mail: hnakano@tohoku-pharm.ac.jp
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00495-6

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H. Nakano et al. / Tetrahedron: Asymmetry 14 (2003) 2361–2368
Scheme 2.
with 2-(diphenylphosphino)benzaldehyde 8 gave the
desired chiral phosphinooxathiane ligand 2 in 43%
yield. Similarly, chiral ligands 3a–d were also easily
prepared by the reaction of tosylate 4 with the corre-
sponding amines followed by the condensations of 9a–d
with 8 in good yields (63–89%). In all five cases 2 and
3a–d, the assigned stereochemistry at the a-position of
the 1,3-oxathiane ring was determined by the NOE
difference spectrum (NOEDS). Enhancements were
observed between the hydrogen at the a-position and
the hydrogen at the b-position when the a- and b-pro-
tons were irradiated, respectively (Scheme 2).8,9
2.2. Palladium-catalyzed asymmetric allylic alkylations
The palladium-catalyzed allylic alkylation of 1,3-
diphenyl-2-propenyl acetate 10 with dimethyl malonate
using chiral phosphinooxathiane ligand 2 and phosphi-
nooxazinane ligands 3a–d were examined in the pres-
ence
of
p-allylpalladium
chloride
dimmer
[PdCl(h3-C3H5)]2,
N,O-bis(trimethylsilyl)acetamide
(BSA),11 and potassium acetate (entries 1–8) in
dichloromethane to give the allylation product 11. The
results are summarized in Table 1. The reaction using
phosphinooxathiane ligand
2 (5 mol%) gave the
Table 1. Asymmetric Pd-catalyzed allylic alkylation of acetate 10
Entry
Ligand
Ligand (mol%)
Temp. (°C)
Time (h)
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
2
2
2
2
3a
3b
3c
3d
5
2
1
2
2
2
2
2
rt
rt
rt
0
rt
rt
rt
rt
6
93
91
87
90
67
64
75
17
90
91
84
70
46
75
49
73
24
24
48
24
24
24
24
a(S)-Configurations based on the specific rotation with literature data.3b
bIsolated yields.
cDetermined by HPLC analysis using a DAICEL Chiralcel OD-H.

H. Nakano et al. / Tetrahedron: Asymmetry 14 (2003) 2361–2368
2363
product 11 in 93% yield and 90% enantiomeric excess
2.3. Palladium-catalyzed asymmetric allylic aminations
(ee) (entry 1). Decreasing the catalyst loading of 2 from
5 mol% to 2 mol% afforded almost the same results as
entry 1 (91%, 91% ee) (entry 2). However, a further
decrease in catalyst loading to 1 mol% led to a decrease
in ee (entry 3). In addition, decreasing the temperature
also brought about a decrease in ee (70% ee) (entry 4).
Reactions with chiral phosphinooxazinane ligands 3a–d
under the same conditions as entry 2 using ligand 2
gave only low to moderate yields and enantioselectivi-
ties (entries 5–8). The best result was obtained when the
reaction was carried out with N-benzylated ligand 3b
(64%, 75% ee) (entry 5). Based on the above results,
chiral phosphinooxathiane ligand 2 was more effective
than phosphinooxazinane ligands 3a–d for this allylic
alkylation.
We next examined the palladium-catalyzed allylic
amination13 of acetate 10 with benzylamine 12 acting as
the nucleophile using the chiral phosphinooxathiane
ligand 2, which showed an efficient ability in allylic
alkylation. The reaction was carried out in CH2Cl2
using a catalyst generated by mixing 1 or 2.5 mol% of
[PdCl(h3-C3H5)]2 with 2 or 5 mol% of chiral ligand 2,
respectively, to give the aminated product 14a. The
results are summarized in Table 2. When the reaction
was carried out at room temperature using 2 mol% of
ligand 2 and 2.5 equiv. of benzylamine 12 to a substrate
10, the product 14a was obtained in low chemical yield
(43%), but with good ee (89% ee) (entry 1). Increasing
the nucleophile loading of 12 from 2.5 to 25 equiv. at
room temperature did not give a significant increase in
the chemical yield (53%, entry 2). At 45°C the reaction
proceeded almost to completion (98%), but with a low
enantioselectivity (52% ee) (entry 3). Decreasing the
temperature to 0°C led to a substantial decrease in both
chemical yield (13%) and enantioselectivity (79% ee,
entry 4). However, varying the catalyst loading to 5
mol% of chiral ligand 2 brought about an increase in
chemical yield (60%) without the substantial decrease in
the enantioselectivity (85% entry 5). Furthermore, the
same reaction was examined using potassium phthal-
imide 13 as a bulky, reactive nitrogen nucleophile
(entries 6–8). The reaction at room temperature gave
the product 14b an excellent chemical yield (98%) and
enantioselectivity (94% ee entry 6). Cooling to 0°C led
to a decrease in chemical yield (31%) (entry 7). Varying
It is considered that the enantiodifferentiation step in
Pd-catalyzed allylic alkylation and amination involves
the substitution of p-allyl complexes with nucleophiles,
and nucleophilic attack occurs predominantly at the
allyl terminus from trans to the better p-acceptor (P>
S).8b,12 Due to the (S)-product being obtained as the
major enantiomer, the reaction probably proceeded
through an M-type A rather than a W-type B interme-
diate (Scheme 3). In addition, the differentiation of
chemical yields and enantiomeric excesses for the
oxathiane ligand 2 and oxazinane ligands 3a–d may be
explained by steric differences. Thus, the ligands 3a–d
have bulky alkyl- or arylmethyl groups on the nitrogen
atom in the oxazinane ring that obstructs construction
of the p-allyl palladium complex C.
Scheme 3.

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H. Nakano et al. / Tetrahedron: Asymmetry 14 (2003) 2361–2368
Table 2. Asymmetric Pd-catalyzed allylic amination of acetate 10
Entry
Nucleophile
Ligand (mol%)
Nucleophile (equiv. to 10)
Temp. (°C)
Time (h)
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
12
12
12
12
12
13
13
13
2
2
2
2
5
2
2
5
2.5
25
25
25
25
3
rt
rt
45
0
rt
rt
0
48
48
6
96
48
48
48
48
43
53
98
13
60
98
31
90
89
88
52
79
85
94
92
90
3
3
0
a(R)-Configurations based on the specific rotation with literature data.3b
bIsolated yields.
cDetermined by HPLC analysis using a DAICEL Chiralcel OD-H column.
the catalyst loading to 5 mol% of chiral ligand 2 gave a
good chemical yield (90%) and enantioselectivity (90%
ee), even at 0°C (entry 8). From these results, it appears
that the chemical yield and the enantioselectivity
depend on both the amount of catalyst and the reaction
temperature in the reactions using nucleophiles 12 and
13. Increasing the reaction temperature gave an excel-
lent chemical yield, but enantioselectivity was poorer.
However, increasing the catalyst loading of 2 acceler-
ated the reaction rate without the substantial decrease
in the enantioselectivity. In particular, this was
observed in the reaction using imide 13 as the nucleo-
phile. For reasons that are not clear, it might be
considered that imide 13 has both weaker basicity and
more rigid structure when compared to amine 12.
The 1H and 13C NMR spectra were recorded at 270 and
67.5 MHz, respectively. The chemical shifts are
reported in ppm downfield to TMS (l=0) for 1H NMR
and relative to the central CDCl3 resonance (l=77.0)
for 13C NMR. Mass spectra were obtained by EI. The
enantiomeric excesses (ee) of the products were deter-
mined by chiral HPLC. Optical rotations were recorded
at the sodium D line with a polarimetar at room
temperature. Commercially available compounds were
used without further purification. Solvents were dried
according to standard procedures. Chromatography
refers to flash chromatography on silica gel (230–400
mesh), unless otherwise noted.
4.2. 3-O-Acetyl-1,2-O-isopropylidene-5-p-toluenesul-
fonyl-3,5-dioxy-a-D-xylofuranose 5
3. Conclusions
To a solution of 414 (1.0 g 2.91 mmol) in anhydrous
pyridine (15 mL) was added acetic anhydride (0.33 mL,
3.49 mmol) at 0°C. After being stirred at room temper-
ature for 24 h, the reaction mixture was concentrated
under reduced pressure. The residue was diluted with
EtOAc and washed with saturated aqueous NaHCO3,
and brine. The organic layer was dried over anhydrous
MgSO4 and filtered. The filtrate was concentrated
under reduced pressure to give a residue, which was
chromatographed on silica gel (hexane/EtOAc=2/1 as
eluent) to give the pure product 5 (1.1 g, 97%): [h]2D3=
−16.4 (c 1.9, CHCl3). IR (film) cm−1: 3021, 1749, 1375,
The chiral xylofuranose-based phosphinooxathiane 2
and phosphinooxazinane 3a–d ligands have been
exploited, and applied to Pd-catalyzed asymmetric
alkylations and aminations. From these results it can be
seen that the SꢀP type chiral oxathiane ligand 2 was
effective in both reactions. In particular an excellent
chemical yield and high enantiomeric excess were
obtained when chiral ligand 2 was used in Pd-catalyzed
aminations. It is expected that both 2 and 3 could act as
good ligands in other catalytic asymmetric reactions.
Further applications and modifications of these ligands
are in progress.
1
1216, 1178. H NMR (CDCl3) l 1.29 (s, 3H), 1.47 (s,
3H), 2.03 (s, 3H), 2.45 (s, 3H), 4.11–4.26 (m, 2H),
4.40–4.46 (m, 1H), 4.49 (d, J=3.6 Hz, 1H), 5.19 (d,
J=3.1 Hz, 1H), 5.86 (d, J=3.6 Hz, 1H), 7.35 (d, J=8.4
Hz, 2H), 7.79 (d, J=8.4 Hz, 2H). 13C NMR (CDCl3) l
21.13, 22.18, 26.72, 27.18, 66.31, 76.15, 76.51, 83.63,
105.23, 112.88, 128.37, 130.26, 132.96, 145.42, 169.81.
HRMS m/z calcd for C17H22O8S (M+): 386.1035.
Found: 386.1037.
4. Experimental
4.1. General methods
Melting points are uncorrected. IR spectra were
recorded as KBr pellets (solids) or thin films (liquids).

H. Nakano et al. / Tetrahedron: Asymmetry 14 (2003) 2361–2368
2365
4.3. 3-O-Acetyl-5-deoxy-1,2-O-isopropylidene-5-
thioacetyl-a- -xylofuranose 6
127.23, 128.45, 128.48, 128.55, 128.59, 128.72, 128.82,
129.06, 129.48, 133.56, 133.78, 133.85, 133.98, 134.06,
142.39, 142.73. HRMS m/z calcd for C27H27O4PS (M+):
478.1368. Found: 478.1390.
D
To a solution of 5 (1.0 g, 2.59 mmol) in DMF (5 mL)
was added potassium thioacetate (592 mg, 5.18 mmol)
under Ar. After being stirred at 65°C for 6 h under Ar,
the reaction mixture was quenched with water and
extracted with ether. The organic layer was washed
with saturated aqueous Na2CO3, dried over anhydrous
MgSO4 and filtered. The filtrate was concentrated
under reduced pressure to give a residue, which was
chromatographed on silica gel (hexane/EtOAc=2/1 as
eluent) to give the pure product 6 (633 mg, 84%):
[h]2D3=−13.2 (c 1.7, CHCl3). IR (film) cm−1: 1746, 1695,
4.6. General procedure for synthesis of 5-deoxy-1,2-O-
isopropylidene-5-N-monoalkylamino-a-
D-xylofuranoses
9a–d
To a solution of 410 (1.0 g, 2.91 mmol) in 2-propanol (6
mL) was added amines (11.62 mmol) and the reaction
mixture refluxed for 24 h. The solvent was removed
under reduced pressure. The residue was diluted with
EtOAc and washed with saturated aqueous Na2CO3.
The organic layer was dried over anhydrous MgSO4
and filtered. The filtrate was concentrated under
reduced pressure to give a residue, which was chro-
matographed on silica gel (hexane/EtOAc=1/1 as elu-
ent) to give the pure products 9a–d.
1
1224. H NMR (CDCl3) l 1.30 (s, 3H), 1.50 (s, 3H),
2.12 (s, 3H), 2.34 (s, 3H), 3.15 (dd, J=7.1 Hz, 1.6 Hz,
2H), 4.35 (dt, J=7.1 Hz, 2.9 Hz, 1H), 4.50 (d, J=3.8
Hz, 1H), 5.19 (d, J=3.0 Hz, 1H), 5.90 (d, J=3.8 Hz,
1H). 13C NMR (CDCl3) l 20.82, 26.24, 26.66, 26.70,
30.51, 76.20, 77.88, 83.43, 104.64, 112.12, 169.52,
194.29. HRMS m/z calcd for C12H18O6S (M+):
290.0824. Found: 290.0847.
4.6.1. 5-Deoxy-5-isopropylamino-1,2-O-isopropylidene-
a-D
-xylofuranose 9a14. Yield 53%.
4.6.2. 5-Benzylamino-5-deoxy-1,2-O-isopropylidene-a-
D-
4.4. 5-Deoxy-1,2-O-isopropylidene-5-mercapto-a-D-xylo-
xylofuranose 9b14. Yield 86%.
furanose 7
4.6.3. 5-Deoxy-1,2-O-isopropylidene-5-naphthylmethyl-
amino-a-
D
-xylofuranose 9c. Yield 83%; [h]2D3=+6.7 (c
A mixture of 6 (500 mg, 1.72 mmol) and K2CO3 (1.2 g,
8.62 mmol) in MeOH (9 mL) was stirred at room
temperature for 4 h under Ar, and filtered. The filtrate
was concentrated under reduced pressure to give a
residue, which was chromatographed on silica gel (hex-
ane/ether=1/2 as eluent) to give the pure product 7
(313 mg, 88%): mp 66–68°C. [h]2D3=−50.0 (c 1.2,
1.3, CHCl3). IR (film) cm−1: 770. H NMR (CDCl3) l
1.30 (s, 3H), 1.47 (s, 3H), 3.12 (dd, J=12.9 Hz, 1.2 Hz,
1H), 3.49 (dd, J=12.9 Hz, 3.5 Hz, 1H), 4.22–4.27 (m,
4H), 4.46 (d, J=3.6 Hz, 1H), 5.90 (d, J=3.6 Hz, 1H),
7.40–7.58 (m, 4H), 7.79 (m, 1H), 7.84 (d, J=9.1 Hz,
1H), 8.00 (d, J=8.2 Hz, 1H). 13C NMR (CDCl3) l
26.11, 26.81, 48.26, 51.44, 78.00, 85.80, 104.84, 111.28,
123.02, 125.05, 125.89, 126.24, 126.42, 128.20, 128.59,
131.38, 133.66, 133.87. HRMS m/z calcd for
C19H21NO4 (M+): 329.1627. Found: 329.1607.
1
1
CHCl3). IR (KBr) cm−1: 3366, 2580. H NMR (CDCl3)
l 1.32 (s, 3H), 1.51 (s, 3H), 2.06 (d, J=5.7 Hz, 1H),
2.70–2.93 (m, 2H), 4.21–4.28 (m, 1H), 4.31–4.34 (m,
1H), 4.53 (d, J=3.6 Hz, 1H), 5.93 (d, J=3.6 Hz, 1H).
13C NMR (CDCl3) l 21.97, 26.28, 26.81, 74.75, 81.50,
85.12, 104.79, 111.77. HRMS m/z calcd for C8H14O4S
(M+): 206.0613. Found: 206.0585. Anal. calcd for
C8H14O4S: C, 46.58; H, 6.84. Found: C, 46.63; H, 6.67.
4.6.4.
5-(R)-Phenylmethylamino-5-deoxy-1,2-O-iso-
-xylofuranose 9d. Yield 80%; [h]2D3=
propylidene-a-
D
+40.8 (c 2.2, CHCl3). IR (film) cm−1: 3320, 770. 1H
NMR (CDCl3) l 1.32 (s, 3H), 1.38 (d, J=6.6 Hz, 3H),
1.45 (s, 3H), 2.79 (dd, J=12.9 Hz, 1.3 Hz, 1H), 3.23
(dd, J=12.9 Hz, 3.5 Hz, 1H), 3.70 (q, J=6.6 Hz, 1H),
4.12–4.17 (m, 2H), 4.49 (d, J=3.6 Hz, 1H), 5.99 (d,
J=3.6 Hz, 1H), 7.22–7.37 (m, 5H). 13C NMR (CDCl3)
l 24.33, 26.20, 26.86, 46.44, 58.69, 77.12, 77.99, 85.89,
104.95, 111.33, 126.62, 127.31, 128.58, 143.33. HRMS
m/z calcd for C16H23NO4 (M+): 293.1627. Found:
293.1603.
4.5. (1S,3R,6R,8R,9R)-2,7-Dioxa-3-(2-diphenylphos-
phino)phenyl-8,9-O-isopropylidenethiabicyclo[4.3.0]-
nonane 2
Compound 7 (100 mg, 0.49 mmol), 2-(diphenylphos-
phino)benzaldehyde 8 (140 mg 0.49 mmol), camphor-
10-sulfonic acid (15 mg) and benzene (10 mL) were
placed in a flask equipped with a Dean–Stark trap and
the mixture refluxed for 48 h. The solvent was removed
under reduced pressure and the residue purified by
preparative TLC (hexane/EtOAc=15/1) to give the
product 2 (181 mg, 43%): mp 78–80°C. [h]2D3=−78.0 (c
1.0, CHCl3). IR (KBr) cm−1: 746, 697. 1H NMR
(CDCl3) l 1.27 (s, 3H), 1.48 (s, 3H), 3.13 (dd, J=14.8
Hz, 3.0 Hz, 1H), 3.45 (dd, J=14.8 Hz, 2.6 Hz, 1H),
4.03 (d, J=2.1 Hz, 1H), 4.10 (d, J=3.6 Hz, 1H),
4.12–4.15 (m, 1H), 5.98 (d, J=3.6 Hz, 1H), 6.35 (d,
J=7.6 Hz, 1H), 6.92–6.97 (m, 1H), 7.20–7.41 (m, 12H),
7.67–7.72 (m, 1H). 13C NMR (CDCl3) l 25.97, 26.58,
29.76, 68.15, 80.93, 81.30, 83.71, 105.18, 111.52, 127.16,
4.7. General procedure for synthesis of phosphinooxazi-
nane ligands 3a–d
Amino alcohols (0.5 mmol), 2-(diphenylphos-
phino)benzaldehyde (130 mg 0.45 mmol), and benzene
(10 mL) were placed in a flask equipped with a Dean–
Stark trap and the mixture refluxed for 24–36 h. The
reaction mixture was passed through on celite 454 and
the filtrate concentrated under reduced pressure to give
the producs 3a–d. Compounds 3b and 3c were recrystal-
lized from hexane. Compound 3d was purified by
preparative alumina TLC (hexane/EtOAc=15/1).

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H. Nakano et al. / Tetrahedron: Asymmetry 14 (2003) 2361–2368
4.7.1. (1S,3S,6R,8R,9R)-4-Aza-2,7-dioxa-3-(2-diphenyl-
phosphino)phenyl - 4 - isopropyl - 8,9 - O - isopropylidene-
bicyclo[4.3.0]nonane 3a. Yield 63%; mp 66–69°C. [h]2D31=
+17.9 (c 1.2, CHCl3). IR (KBr) cm−1: 746, 745, 698. H
NMR (CDCl3) l 0.65 (d, J=6.6 Hz, 3H), 0.99 (d,
J=6.6 Hz, 3H), 1.28 (s, 3H), 1.47 (s, 3H), 2.69 (m, 1H),
2.93 (dd, J=14.0 Hz, 2.7 Hz, 1H), 3.34 (d, J=14.0 Hz,
1H), 3.78 (d, J=2.0 Hz, 1H), 4.16 (d, J=2.0 Hz, 1H),
4.32 (d, J=3.6 Hz, 1H), 5.68 (d, J=7.7 Hz, 1H), 5.98
(d, J=3.6 Hz, 1H), 6.90–6.94 (m, 1H), 7.12–7.72 (m,
12H), 7.75–7.79 (m, 1H). 13C NMR (CDCl3) l 16.18,
16.27, 26.27, 26.83, 42.90, 47.44, 73.26, 79.21, 83.80,
89.56 (Jpc=26.8 Hz), 105.62, 111.31, 127.81, 128.11,
128.13, 128.24, 128.38, 128.42, 128.50, 128.67, 128.92,
129.15, 133.35, 133.64, 133.84, 134.13, 135.56, 136.31,
142.81, 143.13. HRMS m/z calcd for C30H34NO4P (M+
): 503.2226. Found: 503.2196. Anal. calcd for
C30H34NO4P: C, 71.55; H, 6.81; N, 2.78. Found: C,
71.80; H, 6.91; N, 2.66.
4.7.4. (1S,3S,6R,8R,9R)-4-Aza-2,7-dioxa-3-(2-diphenyl-
phosphino)phenyl-8,9-O-isopropylidene-4-((R)-phenyl-
ethyl)bicyclo[4.3.0]nonane 3d. Yield 76%; mp 70–73°C.
[h]2D3=+46.9 (c 1.3, CHCl3). IR (KBr) cm−1: 763, 747,
1
723, 698. H NMR (CDCl3) l 1.21–1.27 (m, 6H), 1.43
(s, 3H), 2.81 (dd, J=13.5 Hz, 2.5 Hz, 1H), 3.04 (dd,
J=13.5 Hz, 1.9 Hz, 1H), 3.74 (d, J=1.8 Hz, 1H), 3.87
(q, J=6.8 Hz, 1H), 4.13 (d, J=2.1 Hz, 1H), 4.28 (d,
J=3.6 Hz, 1H), 5.84 (d, J=7.7 Hz, 1H), 6.00 (d, J=3.6
Hz, 1H), 6.87–6.92 (m, 1H), 7.14–7.41 (m, 15H), 7.46
(d, J=8.1 Hz, 2H), 7.88–7.93 (m, 1H). 13C NMR
(CDCl3) l 26.21, 26.75, 43.55, 54.07, 73.67, 78.65,
83.53, 88.96 (d, Jpc=27.9 Hz), 105.68, 111.27, 126.10,
127.06, 127.61, 127.82, 128.10, 128.15, 128.19, 128.36,
128.46, 128.48, 128.63, 128.74, 129.49, 133.34, 133.63,
133.78, 134.08, 135.55, 136.20, 136.50, 136.64, 142.58,
142.92, 143.23. HRMS m/z calcd for C35H36NO4P
(M+): 565.2382. Found: 565.2412. Anal. calcd for
C35H36NO4P: C, 74.32; H, 6.42; N, 2.48. Found: C,
74.04; H, 6.47; N, 2.45.
4.7.2. (1S,3S,6R,8R,9R)-4-Aza-4-benzyl-2,7-dioxa-3-(2-
diphenylphosphino)phenyl - 8,9 - O - isopropylidenebicyclo-
[4.3.0]nonane 3b. Yield 76%; mp 79–81°C. [h]2D3=+79.8
(c 1.3, CHCl3). IR (KBr) cm−1: 746, 697. 1H NMR
(CDCl3) l 1.33 (s, 3H), 1.46 (s, 3H), 2.91 (dd, J=15.0
Hz, 2.6 Hz, 1H), 3.06 (d, J=12.9 Hz, 1H), 3.17 (d,
J=15.0 Hz, 1H), 3.78 (d, J=12.9 Hz, 1H), 4.03 (d,
J=1.3 Hz, 1H), 4.20 (d, J=2.0 Hz, 1H), 4.59 (d, J=3.6
Hz, 1H), 5.99 (d, J=6.6 Hz, 1H), 6.08 (d, J=3.6 Hz,
1H), 6.70–6.73 (m, 2H), 7.00–7.15 (m, 4H), 7.17–7.42
(m, 12H), 7.80–7.84 (m, 1H). 13C NMR (CDCl3) l
26.31, 26.81, 47.85, 51.57, 73.34, 80.23, 84.16, 89.71 (d,
Jpc=25.2 Hz), 105.14, 111.42, 126.25, 127.20, 127.28,
127.75, 128.11, 128.19, 128.28, 128.55, 128.66, 128.76,
128.80, 128.88, 128.92, 133.05, 133.33, 134.14, 134.45,
135.36, 136.02, 138.24, 138.26, 142.93, 143.26. HRMS
m/z calcd for C34H34NO4P (M+): 551.2225. Found:
551.2241. Anal. calcd for C34H34NO4P: C, 74.03; H,
6.21; N, 2.54. Found: C, 74.31; H, 6.47; N, 2.36.
4.8. General procedure for the palladium-catalyzed
allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate
10 with dimethyl malonate
A mixture of the ligand (0.008 mmol) and [PdCl(h3-
C3H5)]2 (0.004 mmol) in dry CH2Cl2 (1 mL) was stirred
at room temperature for 1 h under Ar. The solution
was added to a mixture of 1,3-diphenyl-2-propenyl
acetate 10 (0.4 mmol) and potassium acetate (0.008
mmol) in dry CH2Cl2 (1 mL) followed by the addition
of dimethyl malonate (1.2 mmol) and BSA (1.2 mmol).
The reaction mixture was stirred at a temperature and
reaction time as shown in Table 1. The mixture was
diluted with ether and quenched with saturated
aqueous NH4Cl. The organic layer was washed with
brine and dried over anhydrous MgSO4 and filtered.
The filtrate was concentrated under reduced pressure
and the residue purified by preparative TLC (hexane/
ether=5/1) to give the product 11. The enantiomeric
excess was determined by HPLC (Chiralcel OD-H, 0.5
mL/min, hexane/2-propanol=98/2). The absolute
configuration was determined by the specific rotation.8b
4.7.3. (1S,3S,6R,8R,9R)-4-Aza-2,7-dioxa-3-(2-diphenyl-
phosphino)phenyl - 8,9 - O - isopropylidene - 4 - naphthyl-
methylbicyclo[4.3.0]nonane 3c. Yield 89%; mp 90–93°C.
[h]2D3=+73.5 (c 1.2, CHCl3). IR (KBr) cm−1: 793, 747,
699. 1H NMR (CDCl3) l 1.33 (s, 3H), 1.45 (s, 3H), 2.92
(dd, J=14.8 Hz, 2.4 Hz, 1H), 3.37 (d, J=14.8 Hz, 1H),
3.68 (d, J=13.9 Hz, 1H), 4.06 (s, 1H), 4.12 (d, J=1.8
Hz, 1H), 4.27 (d, J=13.9 Hz, 1H), 4.57 (d, J=3.6 Hz,
1H), 5.93 (d, J=5.6 Hz, 1H), 6.13 (d, J=3.6 Hz, 1H),
6.97–7.01 (m, 1H), 7.13–7.57 (m, 16H), 7.63 (d, J=8.1
4.9. General procedure for the palladium-catalyzed
allylic amination of rac-1,3-diphenyl-2-propenyl acetate
10 with benzylamine 12
Hz 1H), 7.75 (d, J=8.2 Hz, 2H), 7.87–7.91 (m, 1H). 13
C
A mixture of the ligand (0.008 mmol) and [PdCl(h3-
C3H5)]2 (0.004 mmol) in dry CH2Cl2 (1 mL) was stirred
at room temperature for 1 h under Ar. To this was
added a solution of 1,3-diphenyl-2-propenyl acetate 10
(0.4 mmol) in CH2Cl2 (1 mL) and benzylamine 12 (10
mmol). The reaction mixture was stirred at a tempera-
ture and reaction time as shown in Table 2. The
mixture was subjected directly to column chromatogra-
phy on silica gel (hexane/EtOAc=5/1 as eluent) to give
the product 14a. The enantiomeric excess was deter-
mined by HPLC (Chiralcel OD-H, 0.5 mL/min, hexane/
NMR (CDCl3) l 26.20, 26.68, 49.13, 49.35, 73.26,
80.02, 83.95, 90.18 (d, Jpc=22.9 Hz), 105.13, 111.34,
123.75, 124.94, 125.18, 125.24, 126.61, 126.80, 127.49,
127.57, 128.21, 128.31, 128.37, 128.42, 128.52, 128.67,
128.76, 131.82, 133.13, 133.37, 133.42, 133.76, 133.99,
134.28, 135.46, 135.71, 135.99, 137.20, 142.36, 142.68.
HRMS m/z calcd for C38H36NO4P (M+): 601.2382.
Found: 601.2352. Anal. calcd for C38H36NO4P: C,
75.86; H, 6.03; N, 2.33. Found: C, 75.79; H, 6.15; N,
2.35.

H. Nakano et al. / Tetrahedron: Asymmetry 14 (2003) 2361–2368
2367
2-propanol=199/1). The absolute configuration was
determined by the specific rotation.8b
Tanaka, K.; Kawabata, T.; Tsubaki, K. Synlett 2000, 3,
351–352; (o) Deng, W.-P.; You, S.-L.; Hou, X.-L.; Dai,
L.-X.; Yu, Y.-H.; Xia, W.; Sun, J. J. Am. Chem. Soc.
2001, 123, 6508–6519; (p) Ogasawara, M.; Yoshida, K.;
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4.10. General procedure for the palladium-catalyzed
allylic amination of rac-1,3-diphenyl-2-propenyl acetate
10 with potassium phthalimide 13
A mixture of the ligand (0.008 mmol) and [PdCl(h3-
C3H5)]2 (0.004 mmol) in dry CH2Cl2 (1 mL) was stirred
at room temperature for 1 h under Ar. The solution
and the CH2Cl2 solution (1 mL) of 1,3-diphenyl-2-pro-
penyl acetate 10 (0.4 mmol) were added to the suspen-
sion of potassium phthalimide 13 (1.2 mmol) in CH2Cl2
(1 mL). The reaction mixture was stirred at a tempera-
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mixture was quenched with water and extracted with
ether. The organic layer was dried over anhydrous
MgSO4 and filtered. The filtrate was concentrated
under reduced pressure to give a residue, which was
chromatographed on silica gel (hexane/EtOAc=5/1 as
eluent) to give the pure product 14b. The enantiomeric
excess was determined by HPLC (Chiralcel OD-H, 0.5
mL/min, hexane/2-propanol=98/2). The absolute
configuration was determined by the specific rotation.8b
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