New chiral ligands, pyridinooxathianes, for palladium-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.3987/com-02-s(m)44

New types of pyridinooxathiane ligands have been synthesized and their abilities as chiral catalysts examined in the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate.

Full text of DOI:10.3987/com-02-s(m)44

HETEROCYCLES, Vol. 58, 2002, pp. 457-469, Received, 8th April, 2002
NEW CHIRAL LIGANDS, PYRIDINOOXATHIANES, FOR
PALLADIUM-CATALYZED ASYMMETRIC ALLYLIC ALKYLATION
Yuko Okuyama,a Hiroto Nakano,*,a Chizuko Kabuto,b Erica Nozawa,a Kouichi
Takahashi, a and Hiroshi Hongoa
a Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-Ku, Sendai
981-8558, Japan
b Instrumental Analysis Center for Chemistry, Graduate School of Science,
Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Abstract - New types of pyridinooxathiane ligands have been synthesized and
their abilities as chiral catalysts examined in the palladium-catalyzed allylic
alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate.
Carbon–carbon bond formation is one of the most fundamental transformations in synthetic organic
chemistry. In this effect, one useful method involves the palladium-catalyzed allylation reaction, which
has been studied extensively over the last decade.1 In earlier exhaustive surveys, phosphorus containing
ligands were found to be the most effective in various palladium catalyzed reactions. More recently,
mixed P-N and N-S ligands have gathered increasing attention for their superior reactivity in different
palladium mediated reactions and for their ease in prepartion and handling.2 We have demonstrated that
phosphinooxathianes (1 and 2) are effective ligands for the palladium catalyzed allylation reaction3 and
herein report the synthesis of chiral norbornane-based pyridinooxathianes as a new class of S-N ligands
and their application to the allylation reaction.
Syntheses of the chiral ligands (12-19a,b) are described in Scheme 1. 6-Hydroxymethyl-2-
pyridinecarboxaldehyde (4) was prepared conveniently by the selective NaBH4 reduction of 2,6-
pyridinedicarboxaldehyde (3). Monoketalization of 3, followed by alkylation with ethylmagnesium
bromide and acidic deprotection provided 6-(1-hydroxypropyl)-2-pyridinecarboxaldehyde (7) as a
racemic mixture. Condensation of the pyridinecarboxaldehydes (4 and 7) with (-)-(1S)-10-
* Dedicated to Professor Albert I. Meyers on the occasion of his 70th birthday.

mercaptoisoborneol (8) or (-)-(1S)-10 mercaptoborneol furnished ligands (12-16) in good yields (12 :
93%, 13 : 84%, 14 : 96%, 15 : 78%, 16 : 78%). Silylation of 16 with TBDMSCl or TBDPSCl gave
ligands (17 and 18) in moderate yields (17: 76%, 18: 55%).
H
Ligand (1) or (2)
[PdCl(η3-C3H5)]2
OAc
Nu
O
O
S
H
S
H
H
Ph
R
Ph
*
R
-
Nu
Ph2P
Ph2P
1
2
HO
NaBH4
N
MeOH
0 ˚C, 5 min
CHO
CHO
N
4: 54%
HO Et
*
Et
N
CHO
HO
*
CHO
N
EtMgBr
10% HCl
OH OH
3
N
benzene
reflux
15 min
THF
rt, 1 h
O
THF
reflux
1 h
O
CHO
O
O
5 : 42%
7 : 88%
6 : 78%
R1
HO R1
N
N
or
β
β
H
O
OH
CHO
CHO
O
α
H
S
H
SH
10 : R1 = H
11 : R1 = Me
O
H
N
S
4
7
: R1 = H
: R1 = Et
α
H
8
H
S
R1
N
N
benzene or toluene
reflux, 6-14 h
R2
R1
OH
R1
12 : R1 = H, 93%
13 : R1 = Me, 84%
16 : R1 = R2 = H, 78%
19a : R1 = Et, R2 = H, 22%
19b : R1 = H, R2 = Et, 32 %
14 : R1 = H, 96%
15 : R1 = Me, 78%
OH
HS
9
TBDMSCl
or TBDPSCl
O
O
S
H
N
S
H
N
H
H
imidazole, CH2Cl2
0 ˚C → rt
17 : 1.5 h
18 : 24 h
O Y
OH
16
17 : Y = TBDMS, 76%
18 : Y = TBDPS, 55%
Scheme 1
The reaction of racemic pyridinecarboxaldehyde (7) with (-)-(1S)-10 mercaptoisoborneol (8) gave a
diastereomeric mixture of pyridinooxathianes (19a and 19b) which were readily separated by

preparative TLC (19a: 22%, 19b: 32%). The absolute stereochemistry of the carbinol center was
established by X-Ray diffraction analysis of 19b (Figure 1). In all cases (12-18 and 19a,b), the assigned
stereochemistry at the a-position of the 1,3-oxathiane ring was determined by analysis of their NOE
difference spectra; enhancements were observed between the a- and the b-position protons when the
respective a- or b-proton resonances were irradiated.
We then investigated the palladium-catalyzed allylic substitution of 1,3-diphenyl-2-propenyl acetate (20)
with dimethyl malonate using the chiral ligands (12-19a,b). The reaction was carried out in the presence
of p-allylpalladium chloride dimer [PdCl(h3-C3H5)]2 and N,O-bis(trimethylsilyl)acetamide (BSA)5 to
give the allylation product (21) (Entries 1-18). The results are summarized in Table 1. When the
Table 1. Asymmetric Pd-catalyzed allylation of acetate (20)
Ligand [PdCl(h3-C3H5)]2
OAc
Ph
MeO2C CO2Me
Ph
CH2(CO2Me)2
CH3CO2K, BSA
CH2Cl2
Ph
*
Ph
20
21
Yield c
(%)
Ligand
(mol%)
Temp.
(°C)
Time
(h)
Eed
(%)
Config.e
Entry
Ligand
1a
2
12
12
5
5
3
100
83
38
42
53
62
37
51
30
40
59
49
65
74
83
82
77
44
88
85
S
rt
0
48
6
S
rt
0
3
13
5
100
78
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
4
13
5
48
18
24
18
48
18
72
24
24
72
24
96
48
72
72
rt
0
5
14
5
100
100
100
92
6
14
5
rt
0
7
15
5
8
15
5
rt
0
9
16
5
97
10
11
12b
13
14
15
16
17
18
16
5
53
rt
rt
0
17
5
60
17
2.1
2.1
2.1
2.1
2.1
2.1
2.1
80
17
50
rt
0
18
42
18
48
rt
rt
0
19a
19b
19b
40
60
31
a) Molar ratio for Entries 1-11 : [PdCl(h3 -C3H5 )]2 (0.025 equiv.), dimethyl malonate (3 equiv.),
N,O-bis(trimethylsilyl)acetamide (BSA) (3 equiv.), potassium acetate (0.02 equiv.), 20 (1 equiv.), ligands
(12-17) (0.05 equiv.). b) Molar ratio for Entries 12-18 : [PdCl(h3-C3H5)]2 (0.01 equiv.), dimethyl malonate
(3 equiv.), BSA (3 equiv.), potassium acetate (0.02 equiv.), 20 (1 equiv.), ligands (17-19a,b) (0.021 equiv.).
c) Isolated yields. d) Determined by chiral HPLC using a Daicel OD-H column. e) R or S configuration
based on the specific rotation with literature data.2a,b,e

reactions were carried out at room temperature (or 0 °C) using 2.5 mol% of [PdCl(h3-C3H5)]2 and
5 mol% of ligand (12) linking pyridine ring, the alkylation product [(S)-21] was obtained in high
o
yield (rt : 100%, 0 °C : 83%) but in low enantiomeric purity (rt: 38% ee, 0 C : 42% ee)(Entries 1, 2).
Employing chiral ligand (13) gave the antipodal alkylation product [(R)-21] in good chemical yields
(rt : 100%, 0 °C : 78%) and the enantioselectivity improved marginally (rt : 53% ee, 0 °C : 62% ee)
(Entries 3, 4). Ligands (14 and 15), the epimeric analogues of 12 and 13, were also examined under
the same reaction conditions, but this change did not give any improvements in enantioselectivity
(Entries 5-8). Likewise, the hydroxymethyl ligand (16) did not afford any significant changes in
enantioselectivity (Entries 9,10). Next, the effect of substituents on the 6-position of the pyridine
ring were examined, and the chiral ligands (17 and 18), with bulkier TBDMS and TBDPS ethers as
siloxyalkyl substituents on 6-position of pyridine ring, were therefore employed in this reaction
(Entries 11-15). The results indicated that these ligands gave superior levels of enantioselectivity
[17: 83% ee, 18: 82% ee], albeit in poor chemical yields (Entries 13 and 14). Finally, we tested the
effectiveness of the diastereomeric chiral ligands (19a and 19b) (Entries 16-18). Although ligand
(19a) was ineffective in this reaction (Entry 16), its epimer (19b) gave the best result (60% yield
and 88% ee) by using 1 mol% of [PdCl(h3-C3H5)]2 and 2.1 mol% of ligand at room temperature for
72 h (Entry 17).
From the above results, it is clear that pyridinooxathiane (19a) is a good ligand for the allylation reaction
as described above. Further, the bulky substituent on the 6-position of the pyridine ring would be
expected to increase the stabilization of the sterically favored diastereomeric transition state to afford the
enantiomerically enriched product. In this description, we assume that the palladium-catalyzed reaction
proceeds via one of two diastereomeric palladium-allyl complexes (22 and 23) in the reaction involving
the chiral ligand (19b). Considering that nucleophilic attack usually occurs predominantly at the allyl
terminus from trans to the better p-acceptor (N in imine >S)6 and that the (R) product was obtained as
the major enantiomer, the reaction likely proceeds through an M-type (22) rather than a W-type (23)
intermediate. Furthermore, the reason that the ligand (19b) is more effective than the ligand (19a) is
considered as follows: by having a bulkier ethyl group in the intermediate (23) (cf. the hydroxyl group in
24) on the same side of the coordination site, this would favor the diastereomeric transition state (22)

leading to (R)-enantiomeric product. Such a consideration is supported from the X-Ray structure of 19b,
which shows the close contact between the N-atom of pyridine and the H-atom of ethyl group.
O
O
O
S
H
H
N
N
3.00 Å
H
H
S
Et
OH
19b
Figure 1. ORTEP drawing of 19b
O
O
S
H
S
H
N
N
Nu
Et
Pd
Et
Ph
Pd
OH
OH
PhH
H
Ph
Ph
Nu
22
23
Major enantiomer
Minor enantiomer
88% ee
MeO2C CO2Me
MeO2C CO2Me
Ph
Ph
Ph
Ph
(S)
(R)
44% ee
O
O
S
H
S
H
N
HO
N
Nu
HO
Pd
Ph
Pd
Et
Et
PhH
H
Ph
Ph
Nu
24
Figure 2. Assumed conformation of π-allyl palladium complexes with ligands (19a and 19b)
In summary, we have prepared new pyridinooxathiane ligands (12-19a,b) and disclose the chiral ligand
(19b) as a new and effective ligand in the asymmetric allylic alkylation reaction.
EXPERIMENTAL
1
General. IR spectra were measured with a PERKIN ELMER 1725X spectrophotometer. H-NMR
spectra were recorded on a JEOL JNM-GSX 270 and a JEOL JNM-LA 600 spectrometers with TMS as

an internal standard. MS was taken on a JEOL-JNM-DX 303 spectrometers and elemental analysis was
performed by a PERKIN-ELMER 2400 CHN Elemental Analyzer. Optical rotations were measured
with a JASCO-DPI-370 digital polarimeter.
6-Hydroxymethyl-2-pyridinecarboxaldehyde (4).
To a solution of 2,6-pyridinedicarboxaldehyde (3) (100 mg, 0.74 mmol) in MeOH (7 mL) was added
NaBH4 (7 mg, 0.19 mmol) at 0 ˚C, and the mixture was stirred for 5 min. The reaction was quenched
with H2O (10 mL) and extracted with ether. The organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by column chromatography on silica gel with
hexane/AcOEt (1 : 3) as an eluent to give a white solid (4) (54.8 mg) in 54% yield. mp 66-68 ˚C
1
(hexane-CHCl3). IR (film) cm-1: 3156, 1713, 1601. H-NMR (CDCl3) δ: 10.08 (s, 1H), 7.87-7.91 (m,
2H), 7.56 (m, 1H), 4.89 (s, 2H), 3.76 (br s, 1H). 13C-NMR (CDCl3) δ : 193.07, 160.30, 151.64, 137.79,
124.90, 120.57, 64.15. Ms m/z : 137 (M+). HRMS calcd for C7H7NO2 : 137.0477, found : 137.0498.
2,6-Pyridinedicarboxaldehyde monoethylene acetal (5).
2,6-Pyridinedicarboxaldehyde (3) (410 mg, 3 mmol), ethylene glycol (93 mg, 1.5 mmol), p-
toluenesulfonic acid monohydrate (29 mg, 0.15 mmol) and benzene (15 mL) were placed in a flask
equipped with a Dean-Stark trap. The mixture was refluxed for 15 min. The solvent was evaporated
under a reduced pressure and the residue was subjected to column chromatography on silica gel with
hexane/ether (3 : 1) as an eluent to give a colorless oil (5) (228 mg) in 42% yield. IR (film) cm-1: 1713,
1593. 1H-NMR (CDCl3) δ: 10.11 (s, 1H), 7.94-7.96 (m, 2H), 7.79 (dd, J = 2.7 Hz, 6.5 Hz, 1H), 5.94 (s,
1H), 4.10-4.24 (m, 4H). 13C-NMR (CDCl3) δ : 193.00, 157.73, 152.04, 137.73, 124.68, 121.47, 102.84,
65.48, 65.48. Ms m/z : 178 (M+-1). HRMS calcd for C9H9NO2 : 179.0582, found : 179.0586.
6-(1-Hydroxypropyl)-2-pyridinecarboxaldehyde monoethylene acetal (6).
To a solution of compound (5) (330 mg, 1.84 mmol) in THF (6 mL) was added ethylmagnesium
bromide [2 mL (3 mol/L ether), 6 mmol] at rt, and the reaction mixture was stirred for 1 h at the same
temperature. The reaction mixture was quenched with sat. NH4Cl and extracted with CHCl3. The organic

layer was dried over MgSO4. The solvent was evaporated under a reduced pressure and the residue was
purified by preparative TLC (ether) to give a colorless oil (6) (300 mg) in 78% yield. IR (film) cm-1:
1
1597. H-NMR (CDCl3) δ: 7.74 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H),
13
5.86 (s, 1H), 4.71 (m, 1H), 4.04-4.23 (m, 5H), 1.64-1.96 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). C-NMR
(CDCl3) δ : 161.70, 155.67, 137.40, 120.67, 119.01, 103.69, 73.65, 65.59, 65.58, 31.24, 9.43. Ms m/z :
208 (M+-1). HRMS calcd for C11H15NO3 : 209.1052, found : 209.1081.
6-(1-Hydroxypropyl)-2-pyridinecarboxaldehyde (7).
A mixture of compound (6) (300 mg, 1.43 mmol), 10% HCl (3 mL) and THF (6 mL) was refluxed for 1
h. The reaction mixtures were quenched with sat. NaHCO3 at 0 ˚C and extracted with CHCl3. The
organic layer was dried over MgSO4 and the solvent was evaporated under a reduced pressure to give
the crude product that was purified by preparative TLC (ether) to give a colorless oil (7) (208 mg) in
1
88% yield. IR (film) cm-1: 1716. H-NMR (CDCl3) δ: 10.09 (s, 1H), 7.88-7.90 (m, 2H), 7.53 (m, 1H),
4.81 (dd, J = 4.7 Hz, 7.2 Hz, 1H), 3.94 (br s, 1H), 1.69-2.03 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C-NMR
(CDCl3) δ : 193.16, 163.09, 151.36, 137.70, 124.79, 120.28, 73.87, 31.28, 9.37. Ms m/z : 165 (M+).
HRMS calcd for C9H11NO2 : 165.0790, found : 165.0814.
General procedure for preparations of chiral ligands (12-16).
(1S)-(-)-10-Mercaptoisoborneol (8) (50 mg, 0.27 mmol) and (1S)-(-)-10-Mercaptoborneol (9) (50 mg,
0.27 mmol), 2-pyridinecarboxaldehydes (4, 10, 11) (32 mg, 0.30 mmol), p-toluenesulfonic acid
monohydrate (10 mg, 0.054 mmol) and benzene (12-15: 10 mL) or toluene (16: 10 mL) respectively,
were placed in a flask equipped with a Dean-Stark trap. The mixture was refluxed for 6 h (12-15) or 14
h (16). The solvent was evaporated under a reduced pressure and the residue was purified by preparative
TLC (hexane : ether = 3 : 1) to give the corresponding products (12-16).
(1R,3R,5R,8S)-11,11-Dimethyl-4-oxa-5-pyridinyl-6-thiatricyclo[6.2.1.03,8]undecane (12).
Obtained (69 mg, 93%) as a white solid, mp 71-73 °C (hexane-ether). [α] D24= -58.92˚ (c 1.68, CHCl3).
IR (KBr) cm-1: 1590, 750, 726. 1H-NMR (CDCl3) δ: 8.53 (d, J = 4.5 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H),

7.57 (d, J = 7.7 Hz, 1H), 7.20 (m, 1H), 5.85 (s, 1H), 3.81 (dd, J = 3.1 Hz, 7.9 Hz, 1H), 3.31 (d, J = 14.2
Hz, 1H), 2.85 (d, J = 14.2 Hz, 1H), 2.04 (m, 1H), 1.70-1.82 (m, 3H), 1.54 (m, 1H), 1.45 (s, 3H), 0.98-
1.09 (m, 2H), 0.95 (s, 3H). 13C-NMR (CDCl3) δ : 158.24, 148.51, 136.66, 122.86, 120.94, 85.60, 84.15,
46.76, 45.53, 42.21, 37.85, 34.35, 29.57, 27.24, 23.40, 20.44. Anal. Calcd for C16H21NOS : C, 69.78; H,
7.69; N, 5.09. Found : C, 69.49; H, 7.96; N, 5.09. Ms m/z : 275 (M+).
(1R,3R,5R,8S)-11,11-Dimethyl-4-oxa-5-(5-methyl)pyridinyl-6-thiatricyclo[6.2.1.03,8]undecane (13).
Obtained (65 mg, 84%) as a white solid, mp 144-146 °C (hexane-ether). [α]D24= -51.36˚ (c 1.46, CHCl3).
IR (KBr) cm-1: 1589, 757, 712. 1H-NMR (CDCl3) δ: 7.59 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H),
7.05 (d, J = 7.7 Hz, 1H), 5.79 (s, 1H), 3.79 (dd, J = 3.1 Hz, 8.1 Hz, 1H), 3.29 (d, J = 14.2 Hz, 1H), 2.83
(d, J = 14.2 Hz, 1H), 2.53 (s, 3H), 2.02 (m, 1H), 1.71-1.78 (m, 3H), 1.54 (m, 1H), 1.45 (s, 3H), 1.02-
1.09 (m, 2H), 0.96 (s, 3H). 13C-NMR (CDCl3) δ : 157.70, 157.16, 136.89, 122.53, 117.89, 85.53, 84.36,
46.74, 45.54, 42.14, 37.87, 34.38, 29.64, 27.25, 24.35, 23.37, 20.42. Anal. Calcd for C17H23NOS : C,
70.54; H, 8.01; N, 4.84. Found : C, 70.27; H, 8.26; N, 4.88. Ms m/z : 289 (M+).
(1R,3R,5S,8S)-11,11-Dimethyl-4-oxa-5-pyridinyl-6-thiatricyclo[6.2.1.03,8]undecane (14).
Obtained (71 mg, 96%) as a white solid, mp 123 °C (hexane-ether). [α] D24= -50.80˚ (c 1.24, CHCl3). IR
(KBr) cm-1: 1590, 748, 719. 1H-NMR (CDCl3) δ: 8.54 (d, J = 3.4 Hz, 1H), 7.66-7.76 (m, 2H), 7.21 (m,
1H), 5.97 (s, 1H), 3.95-4.02 (m, 1H), 3.26 (d, J = 14.2 Hz, 1H), 2.72 (m, 1H), 2.56 (d, J = 14.2 Hz, 1H),
2.28 (m, 1H), 1.69-1.77 (m, 2H), 1.25-1.47 (m, 2H), 1.20 (dd, J = 4.8 Hz, 13.5 Hz, 1H), 0.97 (s, 3H),
13
0.96 (s, 3H). C-NMR (CDCl3) δ : 157.69, 148.62, 136.64, 123.00, 121.17, 85.77, 84.37, 47.03, 44.80,
44.35, 34.36, 32.94, 27.87, 25.84, 19.58, 18.64. Anal. Calcd for C16H21NOS : C, 69.78; H, 7.69; N, 5.09.
Found : C, 69.50; H, 7.88; N, 5.04. Ms m/z : 275 (M+).
(1R,3R,5S,8S)-11,11-Dimethyl-4-oxa-5-(6-methyl)pyridinyl-6-thiatricyclo[6.2.1.03,8]undecane (15).
24
Obtained (61 mg, 78%) as a colorless oil. [α] D = -47.77˚ (c 0.9, CHCl3). IR (film) cm-1: 1594. 1H-NMR
(CDCl3) δ: 7.62 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 5.91 (s, 1H), 3.96
(m, 1H), 3.24 (d, J = 14.2 Hz, 1H), 2.69 (m, 1H), 2.54 (d, J = 14.2 Hz, 1H), 2.54 (s, 3H), 2.26 (m, 1H),

1.74-1.77 (m, 2H), 1.30-1.46 (m, 2H), 1.18 (dd, J = 4.7 Hz, 13.8 Hz, 1H), 0.96 (s, 3H), 0.95 (s, 3H). 13C-
NMR (CDCl3) δ : 157.35, 157.25, 137.02, 122.80, 118.22, 86.26, 84.43, 47.11, 44.91, 44.45, 34.50,
33.11, 28.00, 25.98, 24.47, 19.70, 18.74. Ms m/z : 289 (M+). HRMS calcd for C17H23NOS : 289.1500,
found : 289.1518.
(1R,3R,5R,8S)-11,11-Dimethyl-4-oxa-5-(6-hydroxymethyl)pyridinyl-6-thiatricyclo[6.2.1.03,8]-
undecane (16).
Obtained (64 mg, 78%) as a white solid, mp 120 °C (hexane-ether). [α] D24= -55.00˚ (c 1.0, CHCl3). IR
(KBr) cm-1: 1591, 759, 718. 1H-NMR (CDCl3) δ: 7.71 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.17
(d, J = 7.8 Hz, 1H), 5.83 (s, 1H), 4.73 (br s, 2H), 3.80 (dd, J = 3.1 Hz, 7.9 Hz, 1H), 3.70 (br s, 1H), 3.30
(d, J = 14.2 Hz, 1H), 2.84 (d, J = 14.2 Hz, 1H), 2.04 (m, 1H), 1.70-1.82 (m, 3H), 1.54 (m, 1H), 1.45 (s,
13
3H), 0.99-1.09 (m, 2H), 0.96 (s, 3H). C-NMR (CDCl3) δ : 158.10, 157.54, 137.60, 119.89, 119.89,
85.67, 84.08, 64.01, 46.84, 45.59, 42.24, 37.92, 34.39, 29.58, 27.28, 23.38, 20.45. Anal. Calcd for
C17H23NO2S : C, 66.85; H, 7.59; N, 4.59. Found : C, 66.56; H, 7.61; N, 4.31. Ms m/z : 305 (M+).
(1R,3R,5R,8S)-11,11-Dimethyl-4-oxa-5-(6-tert-butyldimethylsilyloxymethyl)pyridinyl-6-
thiatricyclo[6.2.1.03,8]undecane (17).
To a mixture of 16 (64 mg, 0.21 mmol) and imidazole (108 mg, 1.59 mmol) in dry dichloromethane (3
mL) was added TBDMSCl (100 mg, 0.67 mmol) at rt and the reaction mixture was stirred at same
temperature for 1.5 h. The solvent was evaporated under a reduced pressure and the residue was
subjected to column chromatography on silica gel with hexane/AcOEt (5 : 1) as an eluent to give a white
solid (17) (67 mg) in 76% yield. mp 71 ˚C (hexane-ether). [α] D24= -36.89˚ (c 1.03, CHCl3). IR (KBr)
cm-1: 1592, 778, 755. 1H-NMR (CDCl3) δ: 7.73 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 5.78 (s, 1H),
4.82 (s, 2H), 3.79 (dd, J = 3.0 Hz, 7.9 Hz, 1H), 3.29 (d, J = 14.2 Hz, 1H), 2.83 (d, J = 14.4 Hz, 1H),
1.98-2.08 (m, 1H), 1.74-1.81 (m, 3H), 1.59 (m, 1H), 1.45 (s, 3H), 0.98-1.09 (m, 1H), 0.96 (s, 3H), 0.95
(s, 9H), 0.85-0.94 (m, 1H), 0.11 (s, 6H). 13C-NMR (CDCl3) δ : 160.53, 157.43, 137.54, 119.32, 119.16,
85.70, 84.38, 66.01, 46.84, 45.64, 42.24, 37.94, 34.45, 29.68, 27.31, 25.93, 23.42, 20.47, 18.36, -5.37.
Anal. Calcd for C23H37NO2SSi : C, 65.82; H, 8.89; N, 3.34. Found : C, 65.61; H, 9.16; N, 3.07. Ms m/z :

419 (M+).
(1R,3R,5R,8S)-11,11-Dimethyl-4-oxa-5-(6-tert-butyldiphenylsilyloxymethyl)pyridinyl-6-
thiatricyclo[6.2.1.03,8]undecane (18).
To a mixture of 16 (64 mg, 0.21 mmol) and imidazole (43 mg, 0.63 mmol) in dry dichloromethane (3
mL) was added TBDPSCl (115 mg, 0.42 mmol) at rt and the reaction mixture was stirred at rt for 24 h.
The solvent was evaporated under a reduced pressure and the residue was subjected to column
chromatography on silica gel with hexane/AcOEt (5 : 1) as an eluent to give a light yellow oil (18)
24
(63mg) in 55% yield. [α]D = -31.03˚ (c 1.45, CHCl3). IR (KBr) cm-1: 1595, 758, 703. 1H-NMR (CDCl3)
δ: 7.61-7.80 (m, 6H), 7.31-7.47 (m, 7H), 5.73 (s, 1H), 4.86 (s, 2H), 3.76 (dd, J = 3.1 Hz, 7.9 Hz, 1H),
3.25 (d, J = 14.2 Hz, 1H), 2.80 (d, J = 14.4 Hz, 1H), 1.97-2.06 (m, 1H), 1.68-1.80 (m, 3H), 1.47-1.67 (m,
1H), 1.45 (s, 3H), 1.13 (s, 9H), 1.06 (m, 1H), 0.90-1.01 (m, 4H). 13C-NMR (CDCl3) δ : 160.09, 157.47,
137.59, 135.48, 134.78, 133.19, 133.16, 129.75, 129.72, 129.59, 127.74, 127.73, 127.68, 119.25, 119.16,
85.65, 84.31, 66.65, 46.79, 45.59, 42.18, 37.89, 34.39, 29.62, 27.26, 26.88, 26.53, 23.38, 20.42, 19.32.
Ms m/z : 543 (M+). HRMS calcd for C33H41NO2SSi : 543.2628, found : 543.2675.
(1R,3R,5R,8S)-11,11-Dimethyl-4-oxa-5-[6-(R)-1-hydroxypropyl]pyridinyl-6-thiatricyclo-
[6.2.1.03,8]undecane (19a) and (1R,3R,5R,8S)-11,11-Dimethyl-4-oxa-5-[6-(S)-1-hydroxypropyl]-
pyridinyl-6-thiatricyclo[6.2.1.03,8]undecane (19b).
(1S)-(-)-10-Mercaptoisoborneol (8) (100 mg, 0.54 mmol), aldehyde (7) (90 mg, 0.60 mmol), p-
toluenesulfonic acid monohydrate (20 mg, 0.11 mmol) and benzene (10 mL) were placed in a flask
equipped with a Dean-Stark trap. The mixture was refluxed for 12 h. The solvent was evaporated under
a reduced pressure and the residue was purified by preparative TLC (hexane : ether = 10 : 1) to give
pure 19a (40 mg, 22%) and 19b (58 mg, 32%). 19a : A white solid. mp 96-98 °C (hexane-ether).
24
[α]D = -50.45˚ (c 1.1, CHCl3). IR (KBr) cm-1: 3428, 1591. 1H-NMR (CDCl3) δ: 7.71 (t, J = 7.6 Hz, 1H),
7.47 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 5.83 (s, 1H), 4.67 (dd, J = 4.9 Hz, 11.7 Hz, 1H), 4.07
(d, J = 5.4 Hz, 1H), 3.81 (dd, J = 3.1 Hz, 7.9 Hz, 1H), 3.31 (d, J = 14.2 Hz, 1H), 2.84 (d, J = 14.2 Hz,
1H), 2.02 (m, 1H), 1.50-1.91 (m, 6H), 1.46 (s, 3H), 0.99-1.12 (m, 2H), 0.96 (s, 3H), 0.94 (t, J = 7.4 Hz,

13
3H). C-NMR (CDCl3) δ : 161.05, 157.20, 137.58, 119.78, 119.78, 85.61, 84.04, 73.61, 46.83, 45.59,
42.20, 37.91, 34.38, 31.31, 29.55, 27.28, 23.36, 20.44, 9.41. Anal. Calcd for C19H27NO2S : C, 68.43; H,
8.16; N, 4.20. Found : C, 68.20; H, 7.86; N, 4.15. Ms m/z : 333 (M+). 19b : A white solid. mp 127 °C
24
(hexane-ether). [α]D = -59.09˚ (c 1.2, CHCl3). IR (KBr) cm-1: 3292, 1596. 1H-NMR (CDCl3) δ: 7.70 (t,
J = 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 5.84 (s, 1H), 4.67 (dd, J = 4.6 Hz,
7.1 Hz, 1H), 4.16 (br s, 1H), 3.81 (dd, J = 3.0 Hz, 7.9 Hz, 1H), 3.30 (d, J = 14.2 Hz, 1H), 2.84 (d, J =
14.2 Hz, 1H), 2.02 (m, 1H), 1.66-1.89 (m, 5H), 1.55 (m,1H), 1.46 (s, 3H), 0.98-1.12 (m, 2H), 0.96 (s,
13
3H), 0.93 (t, J = 7.4 Hz, 3H). C-NMR (CDCl3) δ : 160.99, 157.16, 137.52, 119.79, 119.77, 85.64,
84.14, 73.49, 46.85, 45.62, 42.25, 37.95, 34.41, 31.27, 29.57, 27.30, 23.39, 20.46, 9.40. Anal. Calcd for
C19H27NO2S : C, 68.43; H, 8.16; N, 4.20. Found : C, 68.15; H, 8.19; N, 4.12. Ms m/z : 333 (M+).
X-Ray crystal structure determination of 19b.
A single crystal with sizes of 0.35 x 0.2 x 0.08 mm was mounted on a Rigaku/MSC Mercury CCD
diffractometer using MoKα radiation (λ = 0.71069 Å) at the temperature of -50°C. Crystal data are as
follows; MF = C19H27NO2S, MW = 333.49, monoclinic, P21, a = 9.086(3), b = 6.553(2), c = 16.058(6) Å,
β = 106.726(5) °, V=915.7(5) Å 3, Z=2, D(calcd)=1.209g/cm3. A total of 6943 intensity data were
measured up to 2θ = 55°, of which 3875 reflections including Freidel pairs were assigned as unique
reflections(Rint = 0.022). The structure was solved by the direct method and refined by the full-matrix
least-squares method. Final refinement for all non-hydrogen atoms anisotropically and all hydrogen
atoms fixed isotropically were converged to give R of 0.046 and Rw of 0.047 for 3459 observed data [Io
> 3σ(Io)], and GOF of 1.61. The flack parameter indicating the correctness of absolute configuration is
0.05(7). The crystallographic data have been deposited at the Cambridge Crystallographic Data Centre
(CCDC 186853) in CIF format.
Typical procedure of Pd-catalyzed asymmetric allylation of ( )-1,3-diphenyl-2-propenyl acetate
±
(20) with dimethyl malonate.
A mixture of the ligands (12-19a,b) [ 0.02 mmol (5 mol%) or 0.0084 mmol (2.1 mol%) ] and [PdCl(η3-
C3H5)]2 (0.01 mmol or 0.0042 mmol), respectively, in dry dichloromethane (1 mL) was stirred at room

temperature for 1 h and the resulting yellow solution was added to a mixture of acetate (20) (100 mg,
0.40 mmol) and potassium acetate (0.8 mg, 0.008 mmol) in dry dichloromethane (1 mL), followed by
the addition of dimethyl malonate (160 mg, 1.2 mmol) and BSA (240 mg, 1.2 mmol). The reaction was
carried out an ambient temperature. The reaction mixtures were diluted with ether and quenched with sat.
NH4Cl. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated
under a reduced pressure and the residue was purified by preparative TLC (hexane : ether = 5 : 1) to give
a pure product (21). 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.2a,b,e
ACKNOWLEDGMENT
We are grateful to Dr. Martin J. Lear (Tohoku University) for helpful discussions.
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