Synthesis of chiral pyridylphenols for the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1002/jccs.201100474

Chiral 8-substituted 2-(8,10,10-trimethyl-6-aza-tricyclo[7.1.1.0 ^2,7]undeca-2(7),3,5-trien-5-yl)-phenols were prepared from a high enantiopurity (>97% ee) of (1R)-(+)-α-pinene, and assessed in the enantioselective addition of diethylzinc to substituted benzaldehydes, giving the (S)-alcohols with enantiomeric excess ranging from 33% to 89%. Interestingly, in all cases, except for those of ortho-chlorobenzaldehyde, ortho- and para-methoxybenzaldehydes, the ee was >71%. The plot of the Hammett substitution constants vs. enantiomeric excess of the diethylzinc addition to either the ortho- or para-substituted benzaldehydes shows a linear correlation.

Full text of DOI:10.1002/jccs.201100474

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Synthesis of Chiral Pyridylphenols for the Enantioselective Addition of Diethylzinc to
Aldehydes
Pei-Shan Wu and Chinpiao Chen*
Department of Chemistry, National Dong Hwa University, Shoufeng, Hualien 974, Taiwan, Republic of China
(Received: Aug. 2, 2011; Accepted: Dec. 8, 2011; Published Online: Mar. 13, 2012; DOI: 10.1002/jccs.201100474)
Chiral 8-substituted 2-(8,10,10-trimethyl-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-trien-5-yl)-phenols
were prepared from a high enantiopurity (>97% ee) of (1R)-(+)-a-pinene, and assessed in the enantio-
selective addition of diethylzinc to substituted benzaldehydes, giving the (S)-alcohols with enantiomeric
excess ranging from 33% to 89%. Interestingly, in all cases, except for those of ortho-chlorobenzalde-
hyde, ortho- and para-methoxybenzaldehydes, the ee was >71%. The plot of the Hammett substitution
constants vs. enantiomeric excess of the diethylzinc addition to either the ortho- or para-substituted ben-
zaldehydes shows a linear correlation.
Keywords: Enantioselective catalyst; Diethylzinc; Asymmetric alkylation; Chiral ligand;
Enantiomeric excess.
INTRODUCTION
Asymmetric catalysis provides enantiomerically-en-
ordinate one molecule of aldehyde and one molecule of
diethylzinc to assemble the key species (C) where the ethyl
group transfer occurs (Scheme I). Recently, we demon-
strated that bipyridyl alcohols (D) and (E) act as interesting
chiral catalysts in the enantioselective addition of diethyl-
zinc to various substituted benzaldehydes, provided that
the alcohols of the (S)-configuration and enantiomeric ex-
cess generally range from 45% to 79%.13 The moderate de-
gree of asymmetric induction encouraged us to modify the
5-pyridyl ring of the ligand (D) for various aldehydes.
riched products in organic reactions, which is very impor-
tant in modern synthetic and pharmaceutical chemistry.1
Notably, enantioselective catalysis is one of the most effi-
cient environmentally benign processes. Therefore, the de-
velopment of enantioselective catalysts is the greatest chal-
lenges in modern organic chemistry. The most promising
candidates for such enantioselective catalysts are metal
complexes that bear chiral organic ligands. The enantio-
selective addition of diorganozinc reagents to aldehydes is
one of the most important and fundamental asymmetric re-
actions2 among the asymmetric catalysis of C-C bond-
forming reactions. Since the initial report by Oguni,3 vari-
ous chiral ligands including a-amino alcohols,4 BINOL,5
diamine,6 diol,7 pyridyl alcohol,8 salen,9 TADDOL,10 and
others11 have been used in this type of reaction. Chiral lig-
ands with diol generally need a Lewis acid such as Ti(O-i-
Pr)4 to form a chiral environment to induce an asymmetric
addition of diethylzinc to aldehydes. While chiral ligands
with amino alcohol or pyridyl alcohol form an asymmetric
environment with two molecules of diethylzinc, one per-
forms as a Lewis acid, and another performs as a nucleo-
phile.12 The interaction between diethylzinc and an amino
alcohol produces a chelated ethylzinc alkoxide (A) which
is in equilibrium with a dimeric species (B).12d Only the
monomer is catalytically active, and the adjacent Zn and O
ring atoms, displaying complementary Lewis acid and
Lewis base characteristics, are believed to respectively co-
Scheme I
RESULTS AND DISCUSSION
Synthesis of ligands 10-13
The synthesis of ligands 10–13 is outlined in Scheme
II. 1-(2-Hydroxy-phenyl)-ethanone (1) readily converts to
methyl ether in the presence of LiOH and dimethylsulfate
to yield 2. Moreover, 2-methoxyacetophenone was heated
with iodine in pyridine at 100–110 ºC for 3 hr and recrys-
tallized from ethanol to produce pyridinium salt 3. Com-
* Corresponding author. Tel: +886-3-8633597; Fax: +886-3-8630475; E-mail: chinpiao@mail.ndhu.edu.tw
768
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Pyridylphenol Enantioselective Addition Et2Zn Aldehyde
Scheme II
Scheme IV
at room temperature with various solvents (Table 1): tolu-
ene (57%), dichloromethane (56%), hexane (53%), aceto-
nitrile (43%) and tetrahydrofuran (33%). Toluene was
therefore selected as the reaction solvent in the following
reactions. The asymmetric addition of benzaldehyde using
diethylzinc in toluene at room temperature in the presence
of 5% of ligands yielded enantiomeric excesses of 1-phen-
yl-1-propanol, as shown in Table 2. The stereochemical
outcome depends mainly on the stereogenic centres in the
8-position of the pyridyl-pinane-ring (ligand 10). In fact,
the other substituent on the 8-position of the ligands did not
pounds 3 and 4 were heated with ammonium acetate in gla-
cial acetic acid at 100–110 ºC overnight to yield 2-anisolyl-
pyridine 5. Compounds 6–9 were prepared by treating
compound 5 with LDA and alkyl halides. The methyl ether
of compounds 6–9 were cleaved by treating them with
phenyl thiol and K2CO3 in NMP solution to produce com-
pounds 10–13.14
Synthesis of ligand 16
Table 1. Asymmetric addition of diethylzinc to benzaldehyde
The synthesis of ligand 16 is outlined in Scheme III.
Compound 5 was oxidized using potassium permanganate
to form ketone 14. Compound 15 was prepared by reacting
compound 14 with the Grignard reagent (MeMgI). An effi-
cient protocol reported in the literature for the demethyl-
ation of 15 to 16 in good purity using KOPh14 was therefore
attempted.
using ligand 13 in various solvents
OH
*
O
chiral ligand 13 (5 mol%), r.t.
H
solvent, Et2Zn
Entry
Slovent
Ee (%)
Yield (%)
1
2
3
4
5
Hexane
Toluene
CH2Cl2
CH3CN
THF
53
57
56
43
33
85
90
75
76
62
Scheme III
Table 2. Asymmetric addition of benzaldehyde using diethylzinc,
in the presence of various chiral ligands
OH
*
O
chiral ligand (5 mol%) , r.t.
Toluene, Et2Zn
H
Synthesis of ligands 17 and 19
The synthesis of ligands 17 and 19 is outlined in
Scheme IV. Compound 17 was prepared by treating com-
pound 5 with LDA and acetone. The methyl ether of com-
pound 5 was cleaved by treating it with BBr3 to produce
compound 18. Compound 19 was obtained by treating
compound 18 with LDA and acetone.
Entry
Chiral ligand
Ee (%)
Yield (%)
1
2
3
4
5
6
7
8
9
10
64
57
55
57
9
0
40
2
63
66
90
90
41
53
75
40
84
11
12
13
16
16/Ti(OiPr)4
17
Application in asymmetric catalytic reaction
The enantiomeric excesses of 1-phenyl-1-propanol
were acquired through the asymmetric addition of benzal-
dehyde using diethylzinc in the presence of chiral ligand 13
19
19/Ti(OiPr)4
35
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769

Article
Wu and Chen
Table 3. Enantiomeric excess of the addition of benzaldehyde in
Table 4. Enantiomeric excess of the addition of benzaldehyde in
the presence of 10 at various temperatures
the presence of various amount of ligand 10
O
OH
*
chiral ligand 10, -40 o
C
H
toluene, Et2Zn
Entry
Temp (ºC)
Ee (%)
Yield (%)
Entry
Ligand mol %
Ee (%)
Yield (%)
1
2
3
4
5
6
40
rt
4
- 20
- 40
- 78
72
64
67
73
79
78
93
63
72
81
42
46
1
2
3
4
5
1
5
10
15
20
79
79
79
78
78
37
42
85
80
86
enantioselectivities obtained using the 8-methyl-substi-
tuted ligand 10 were in the range of 33–89% ee. All prod-
ucts were S-configuration determined by comparing the
signs of specific rotations (aD) in the literature. Notably,
similarly high levels of reactivity and enantioselectivity
were observed for aliphatic aldehydes under identical reac-
tion conditions (Table 5, entries 14 and 15).
increase the stereoselectivity. The optimized ligands were
10 (64% ee). Therefore, the following asymmetric reac-
tions were performed in the presence of ligand 10. The
same reactions were conducted in toluene at various tem-
peratures (Table 3), and the enantimeric excesses of 1-
phenyl-1-propanol were acquired at –78 ºC (78%), –40 ºC
(79%), –20 ºC (73%), 4 ºC (67%), rt (64%), and 40 ºC
(72%). Therefore the following asymmetric reactions were
performed in toluene at –40 ºC. The asymmetric addition of
benzaldehyde, using diethylzinc in the presence of various
amounts of ligand 10, yielded enantiomeric excesses of
1-phenyl-1-propanol, as shown in Table 4. The optimal
amount catalyst was 10 mol% of ligand 10 (79% ee).
The plot of Hammett substituent constants vs. en-
antiomeric excess of the addition of para-substituted ben-
zaldehydes using diethylzinc shows a linear correlation.
Importantly the moderate electron-releasing substituents
on the para-position exhibited higher enantiomeric ex-
cesses (p-CH3, 89%), while the stronger electron-with-
drawing substituents on the para-position showed lower
enantiomeric excesses (p-Cl, 75%; p-CN, 71%) (Fig. 1).
On the other hand, the substituents on the meta-position did
not exhibit high correlation of Hammett substituent con-
stants and enantiomeric excesses of the alkylation of sub-
stituted benzaldehydes using diethylzinc (enantiomeric ex-
The enantioselective formation of carbon-carbon
bonds via the asymmetric addition of dialkylzinc to alde-
hydes continues to be very important in the development of
the enantioselective method. Numerous pyridine-alcohol
derivatives have been established to be effective chiral cat-
alysts so, following research in this area, the authors have
evaluated the potential utility of new ligands 10–13 in this
catalytic process. Substituted benzaldehyde was asymmet-
rically alkylated in the presence of catalyst 10 as described
below. Diethylzinc was added to a solution of ligand 10 (10
mol%) in toluene at –40 ºC and stirred for 30 h. The reac-
tion was quenched by adding 1N HCl. Following purifica-
tion by flash chromatography, the enantiomeric excess of
the product was determined by HPLC, and the yields, %ee,
and the specific rotation were as shown in Table 5. The ab-
solute configurations of all products were determined by
comparing the signs of specific rotations (aD).15 The ster-
eochemical outcome mainly depends on the stereogenic
centers in the 8-position of the pyridyl-pinane-ring (ligand
10). In fact, the ligands with further substituents at the
8-position did not exhibit higher stereoselectivity. The
Fig. 1. The correlation of substituent constants (sp)
and the enantiomeric excess of the alkylation of
para-substituted benzaldehydes in the presence
of 10.
770
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Pyridylphenol Enantioselective Addition Et2Zn Aldehyde
Table 5. Asymmetric addition of substituted benzaldehyde using diethylzinc, in the presence
of ligand 10
OH
*
O
chiral ligand 10 (5 mol%), -40 o
C
R
R
H
toluene, Et2Zn
Entry
R
Yield (%)
ee (%)d
[a]D (c) CH2Cl3 Cofiguration
1
2
3
4
5
6
7
8
C6H5 (20)
85
70
64
52
51
86
40
72
91
93
94
91
87
77
56
66
79
-44.8 (1.25)
-44.8 (1.25)
-31.9 (1.20)
-37.6 (1.00)
-9.8 (1.00)
-29.5 (1.20)
-15.1 (1.10)
-23.4 (1.05)
-29.8 (0.95)
-31.4 (1.00)
-18.4 (1.05)
-26.0 (1.00)
-25.7 (1.15)
-5.3 (1.00)
+4.3 (1.00)
-3.6 (1.25)
S
S
2-Me-C6H4 (21)
3-Me-C6H4 (22)
4-Me-C6H4 (23)
75 a
77
S
89
S
2-MeO-C6H4 (24)
3-MeO-C6H4 (25)
4-MeO-C6H4 (26)
2-Cl-C6H4 (27)
3-Cl-C6H4 (28)
4-Cl-C6H4 (29)
3-CN-C6H4 (30)
4-CN-C6H4 (31)
3-(Me)2N-C6H4 (32)
c-C6H11 (33)
41
S
75 a
33
S
S
39 b
83
S
9
S
10
11
12
13
14
15
16
75
S
79 a
71 b
77
NA
NA
NA
S
81 c
65 c
39
n-C6H13 (34)
(E)-cinnamyl (35)
S
S
a The ee% was determined by converting the alcohols to acetates.
b The ee% was determined by converting the alcohols to benzoyates.
c The ee% was determined by converting the alcohols to Mosher’s ester and determined by
19F NMR.
d The ee% was determined by Chiracel OD-H HPLC column and the absolute configuration
was assigned based on comparison with the literature data.
cesses ranged from 75% to 83%) (Fig. 2). The stronger
sition showed higher enantiomeric excesses (o-Me, 75%)
electron-releasing substituents on the para- and ortho-po-
sition displayed lower enantiomeric excesses (p-OCH3,
33%; o-OCH3, 41%) (Fig. 1 and 3). Moreover, the stronger
electron-withdrawing substituents on the ortho-position
displayed lower enantiomeric excesses (o-Cl, 39%), while
the weaker electron-releasing substituents on the ortho-po-
(Fig. 3).
CONCLUSIONS
In summary, a new class of chelating ligands of type
10 was prepared. Their catalytic activity in the asymmetric
addition of diethylzinc to substituted benzaldehydes was
demonstrated. These ligands were prepared from highly
Fig. 2. The correlation of substituent constants (sm)
and the enantiomeric excess of the alkylation of
meta-substituted benzaldehydes in the presence
of 10.
Fig. 3. The correlation of substituent constants (so)
and the enantiomeric excess of the alkylation of
ortho-substituted benzaldehydes in the pres-
ence of 10.
J. Chin. Chem. Soc. 2012, 59, 768-781
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Article
Wu and Chen
enantiopure (1R)-(+)-a-pinene (>97% ee). Pridylphenol
10 acts as an interesting chiral catalyst in the enantioselec-
tive addition of diethylzinc to various substituted benzalde-
hydes, affording the (S)-alcohols with ee ranging from 33%
to 89%.
1486, 1437, 1358, 1292, 1247, 1163, 1126, 1023, 967, 805,
758, 595, 534 cm–1.
1-[2-(2-Methoxyphenyl)-2-oxoethyl]pyridinium iodide 3
To a solution of 2-methoxyphenyl methyl ketone 2
(45.0 mL, 300.0 mmol) in pyridine (328 mL) was added a
solution of iodine (83.0 g, 327 mmol) in pyridine (75.0
mL), and the resulting solution was heated at 100–110 ºC
for 3 h. The reaction solution was stood for 10 h, filtered,
washed with ethanol, and then recrystallized twice in etha-
nol. The crystal was dried under vacuum yielding com-
pound 3 (43.8 g, 123.0 mmol). Yield: 41%.
EXPERIMENTAL
General Chemical Procedures
All reactions were carried out in anhydrous solvents.
THF and diethyl ether were distilled from sodium-benzo-
phenone under argon. Toluene, CH3CN, CH2Cl2, xylene
1
and hexane were distilled from CaH2. H NMR spectra
(5S,7S)-(+)-5,6,7,8-Tetrahydro-6,6-dimethyl-2-(2-meth-
oxyphenyl)-5,7-methanoquinoline 5
were obtained at 300 or 400 MHz (as indicated), and 13
C
NMR spectra were obtained at 75.5 or 100.6 MHz using a
Bruker NMR spectrometer. Chemical shifts (d) are re-
ported in ppm relative to CDCl3 (7.26 and 77.0 ppm). Mass
spectra (MS) and high resolution mass spectra (HRMS)
were determined on a Finnigan/Thermo Quest MAT 95XL
mass spectrometer. Infrared spectra were recorded using a
JASCO FT/IR 410 spectrometer. All asymmetric reactions
were conducted in dry glassware under nitrogen using a
standard glovebox. Enantiomeric excesses were deter-
mined using Lab Alliance Series III high performance liq-
uid chromatography (HPLC) with a Chiracel OD-H chiral
column (Daicel Chemical Industries, LTD). Optical rota-
tions were measured using a JASCO P-1010 polarimeter at
the indicated temperature using a sodium lamp (D line, 589
nm). Flash column chromatography was performed using
MN silica gel 60 (70–230 mesh) purchased from Macherey-
Nagel.
A mixture of compound 4 (1.2 g, 8.0 mmol), com-
pound 3 (4.72 g, 13.0 mmol), and ammonium acetate (4.14
g, 53.0 mmol) in glacial acetic acid (8.8 mL) under argon
atmosphere was heated at 100–110 ºC for 20 h. After cool-
ing to room temperature, the reaction mixture was trans-
ferred to a 1-L Erlenmeyer flask, ethyl acetate (200 mL)
and water (200 mL) were added, and the mixture was
basified by 6 M sodium hydroxide until the aqueous solu-
tion become basic. The aqueous solution was extracted
with ethyl acetate three times, and the combined extracts
were dried over anhydrous magnesium sulfate. After filter-
ing and concentration, the resulting residue was purified by
flash column chromatography using silica gel as the sta-
tionary phase and using ethyl acetate-hexane (1:19) as the
mobile phase producing compound 5 (0.74 g, 2.6 mmol).
Yield: 33%. mp: 110-111 ºC. [a]23.4D +71.0º (c 1.03, CHCl3).
1H NMR (400 MHz, CDCl3, d): 7.80-7.78 (dd, J1 = 7.5, 1.3
Hz, 1H), 7.51-7.49 (d, J = 7.8 Hz, 1H), 7.34-7.30 (t, J = 7.8
Hz, 1H), 7.22-7.20 (d, J = 7.8 Hz, 1H), 7.08-7.04 (t, J = 7.4
Hz, 1H), 6.98-6.96 (d, J = 8.2 Hz, 1H), 3.83 (s, 3H), 3.19-
3.18 (d, J = 2.0 Hz, 2H), 2.79-2.76 (t, J = 5.6 Hz, 1H),
2.71-2.66 (m, 1H), 2.40-2.38 (m, 1H), 1.42 (s, 3H),
1.34-1.32 (d, J = 9.5 Hz, 1H), 0.70 (s, 3H). 13C NMR (100.6
MHz, CDCl3, d): 156.8, 156.3, 152.9, 139.7, 132.6, 131.1,
129.6, 121.5, 121.0, 111.3, 55.6, 46.3, 40.3, 39.5, 36.7,
32.0, 26.15, 21.4. IR (KBr): 3045, 2931, 2832, 1600, 1583,
1492, 1444, 1423, 1263, 1240, 1120, 1068, 1025, 944, 821,
752 cm–1. MS m/z: 279 (M+, 100), 279 (100), 264 (68), 250
(28), 236 (45), 221 (23), 126 (28), 77 (7). HRMS-EI (m/z):
[M]+ calcd for C19H21NO, 279.1623; found, 279.1614.
(1S,8R,9S)-8-Isopropyl-5-(2-methoxy-phenyl)-10,10-di-
methyl-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene 9
To a solution of diisopropylamine (121 mL, 1.2 mmol)
in THF (5 mL) at 0 ºC was added n-BuLi (0.76 mL, 1.2
Synthesis of ligands 10–13
2-Methoxyphenyl methyl ketone 2
A solution of 1-(2-hydroxy-phenyl)-ethanone (1)
(35.2 mL, 300 mmol) and LiOH×H2O (24.8 g, 590 mmol) in
THF (400 mL) was stirred at room temperature for 1 h, and
then dimethyl sulfate (42 mL, 293 mmol) was added. After
completion of the reaction (TLC, 60 h), the solvent was re-
moved under reduced pressure. The residue was dissolved
in 2 M NaOH, and the resulted solution was extracted with
diethyl ether (3 ×). The combined extracts were dried over
anhydrous MgSO4, filtered and concentrated under re-
duced pressure to afford compound 2 (38.5 g, 256.0 mmol,
86%). 1H NMR (400 MHz, CDCl3, d): 7.71-7.69 (dd, J =
7.7, 1.8 Hz, 1H), 7.44-7.40 (m, 1H), 6.97-6.92 (m, 2H),
3.86 (s, 3H), 2.58 (s, 3H). 13C NMR (100.6 MHz, CDCl3,
d): 199.8, 158.9, 133.7, 130.3, 128.2, 120.5, 111.6, 55.5,
31.8. IR (KBr): 3074, 3003, 2944, 2840, 1674, 1598, 1578,
772
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Pyridylphenol Enantioselective Addition Et2Zn Aldehyde
mmol, 1.6 M in hexane) and stirred for 30 min. The pre-
pared LDA solution was cooled to -78 ºC, and a solution of
5 (0.28 g, 1.0 mmol) in THF (6 mL) was transfered to LDA
solution by cannula. The solution became a blue color and
was stirred at -78 ºC for 2 h. A solution of 2-bromopropane
(113 mL, 3.0 mmol) in THF (10 mL) was added and stirred
overnight at room temperature. The solution became or-
ange color and quenched by adding water. The resulting so-
lution was extracted with ethyl acetate three times, and the
combined extracts were dried over anhydrous MgSO4. Af-
ter filtering and concentration, the residue was purified by
flash column chromatography using silica gel as the sta-
tionary phase and ethyl acetate-hexane (1:19) as the mobile
phase, thus producing compound 9 (0.18 g, 0.6 mmol,
56%). [a]16.8D +17.2º (c 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 7.94-7.91 (dd, J = 7.6, 1.4 Hz, 1H), 7.62-7.60
(d, J = 7.8 Hz, 1H), 7.35-7.31 (m, 1H), 7.22-7.20 (d, J = 7.8
Hz, 1H), 7.10-7.07 (t, J = 7.4 Hz, 1H), 7.01-6.99 (d, J = 8.2
Hz, 1H), 3.87 (s, 3H), 3.00 (s, 1H), 2.96-2.92 (m, 1H),
2.76-2.73 (t, J = 5.6 Hz, 1H), 2.62-2.57 (m, 1H), 2.40-2.37
(m, 1H), 1.44 (s, 3H), 1.41-1.42 (d, J = 5.7 Hz, 2H), 1.22-
1.20 (d, J = 6.9 Hz, 3H), 0.89-0.87 (t, J = 6.9 Hz, 3H), 0.68
(s, 3H). 13C NMR (100.6 MHz, CDCl3, d): 158.7, 157.1,
152.3, 140.2, 132.4, 131.2, 129.7, 129.2, 121.5, 121.1,
111.6, 55.6, 49.1, 46.6, 42.0, 41.3, 30.3, 29.6, 26.5, 22.3,
21.2, 20.0. IR (KBr): 2953, 2923, 2868, 1599, 1582, 1492,
1463, 1434, 1385, 1294, 1259, 1239, 1121, 1067, 1026,
853, 828, 751 cm–1. MS m/z: 321 (M+, 9), 306 (20), 278
(100), 264 (21), 250 (18), 236 (68), 221 (16). HRMS-EI
(m/z): [M]+ calcd for C22H27NO, 321.2093; found,
321.2096.
(dd, J = 7.9, 1.4 Hz, 1H), 7.63-7.61 (d, J = 8.1 Hz, 1H),
7.37-7.35 (d, J = 8.1 Hz, 1H), 7.28-7.23 (m, 1H), 7.01-6.98
(dd, J = 9.3, 0.8 Hz, 1H), 6.90-6.86 (m, 1H), 2.99-2.98 (m,
1H), 2.82-2.78 (m, 1H), 2.76-2.74 (t, J = 5.8 Hz, 1H),
2.63-2.58 (m, 1H), 2.40-2.36 (m, 1H), 1.57-1.39 (d, J = 7.0
Hz, 1H), 1.43 (s, 3H), 1.15-1.13 (d, J = 7.0 Hz, 3H), 0.83-
0.81 (d, J = 7.1 Hz, 3H), 0.63 (s, 3H). 13C NMR (100.6
MHz, CDCl3, d): 159.6, 156.0, 154.7, 141.0, 134.8, 130.7,
125.8, 119.5, 118.7, 118.3, 115.9, 48.6, 46.6, 42.2, 40.7,
30.3, 29.7, 26.3, 22.0, 21.0, 19.7. IR (KBr): 2956, 2931,
2862, 1584, 1503, 1470, 1411, 1292, 1255, 1117, 853, 760,
747, 608 cm–1. MS m/z: 307 (M+, 35), 292 (11), 264 (100),
236 (20), 222 (76), 128 (8). HRMS-EI (m/z): [M]+ calcd for
C21H25NO, 307.1936; found, 307.1947.
(1S,8R,9S)-5-(2-Methoxy-phenyl)-8,10,10-trimethyl-6-
aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene 6
Compound 6 was prepared following the same proce-
dure as in the preparation of 9 using CH3I (187 mL, 3.0
mmol) to produce 6 (0.22 g, 0.7 mmol, 75%). mp: 68-70 ºC.
1
[a]17.5 +47.6º (c 1.00, CHCl3). H NMR (400 MHz,
D
CDCl3, d): 7.89-7.87 (dd, J = 7.6, 1.8 Hz, 1H), 7.56-7.54
(dd, J = 7.8, 0.5 Hz, 1H), 7.35-7.30 (m, 1H), 7.20-7.18 (d, J
= 7.8 Hz, 1H), 7.09-7.05 (m, 1H), 7.00-6.98 (dd, J = 6.2,
0.6 Hz, 1H), 3.86 (s, 3H), 3.29-3.23 (m, 1H), 2.78-2.76 (t, J
= 5.6 Hz, 1H), 2.59-2.53 (m, 1H), 2.18-2.15 (m, 1H), 1.46-
1.44 (d, J = 7.1 Hz, 3H), 1.43 (s, 3H), 1.37-1.34 (d, J = 9.8
Hz, 1H), 0.69 (s, 3H). 13C NMR (100.6 MHz, CDCl3, d):
160.2, 157.0, 152.6, 139.6, 132.3, 131.2, 129.6, 129.2,
121.6, 121.1, 111.5, 55.6, 47.0, 46.9, 41.4, 39.0, 28.7, 26.4,
21.0, 18.4. IR (KBr): 2955, 2927, 2869, 1600, 1583, 1492,
1434, 1300, 1240, 1179, 1123, 1026, 857, 831, 753 cm–1.
MS m/z: 293 (M+, 24), 278 (100), 250 (41), 234 (20), 115
(7). HRMS-EI (m/z): [M]+ calcd for C20H23NO, 293.1780;
found, 293.1776.
(1S,8R,9S)-8-Isopropyl-10,10-dimethyl-6-aza-tricyclo-
[7.1.1.02,7]undeca-2(7),3,5-trien-5-yl)-phenol 13
To a solution of 9 (0.09 g, 0.3 mmol) in anhydrous
NMP (0.53 mL) was added PhSH (28 mL, 0.6 mmol) and
K2CO3 (2.0 mg, 0.03 mmol), and heated to 250 ºC for
refluxing 30 min (TLC). The reaction mixture was cooled
to room temoerature and a 5% NaOH (25 mL) was added,
then the aqueous solution was neutralized by adding 1 M
HCl to pH = 8. The aqueous phase was extracted with di-
ethyl ether three times, and the combined extracts were
dried over anhydrous MgSO4. After filtering and concen-
tration, the residue was purified by flash column chroma-
tography using silica gel as the stationary phase and ethyl
acetate-hexane (1:19) as the mobile phase, thus producing
compound 13 (0.08 g, 0.25 mmol, 86%). [a]20.7D -17.5º (c
(1S,8R,9S)-2-(8,10,10-Trimethyl-6-aza-tricyclo-
[7.1.1.02,7]undeca-2(7),3,5-trien-5-yl)-phenol 10
Compound 10 was prepared following the same pro-
cedure as in the preparation of 13 to produce 10 (0.17 g, 0.6
mmol, 61%). [a]20.1D +31.3º (c 1.00, CHCl3). 1H NMR (400
MHz, CDCl3, d): 7.78-7.76 (dd, J = 8.0, 1.5 Hz, 1H), 7.62-
7.60 (d, J = 8.1 Hz, 1H), 7.37-7.34 (d, J = 8.1 Hz, 1H),
7.29-7.25 (m, 1H), 7.03-7.00 (dd, J = 8.2, 1.1 Hz, 1H),
6.91-6.89 (m, 1H), 6.89-6.87 (t, J = 7.0 Hz, 1H), 3.25-3.23
(m, 1H), 2.82-2.78 (dd, J = 10.2, 5.6 Hz, 1H), 2.61-2.58 (m,
1H), 2.17-2.15 (m, 1H), 1.43 (s, 3H), 1.34-1.31 (d, J = 9.9
Hz, 1H), 0.67 (s, 3H). 13C NMR (100.6 MHz, CDCl3, d):
159.7, 157.4, 154.9, 140.2, 134.7, 130.7, 125.7, 119.4,
1
1.15, CHCl3). H NMR (400 MHz, CDCl3, d): 7.78-7.76
J. Chin. Chem. Soc. 2012, 59, 768-781
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Article
Wu and Chen
118.7, 118.4, 115.8, 46.9, 46.7, 41.5, 38.2, 28.8, 26.3, 20.9,
18.0. IR (KBr): 3675, 3329, 2967, 2928, 2868, 1585, 1500,
1467, 1458, 1411, 1289, 1254, 1215, 852, 749, 611 cm–1.
MS m/z: 279 (M+, 56), 264 (96), 250 (13), 236 (100), 222
(21), 210 (14), 115 (11), 77 (8). HRMS-EI (m/z): [M]+
calcd for C19H21NO, 279.1623; found, 279.1632.
(m/z): [M]+ calcd for C20H23NO, 293.1780; found,
293.1770.
(1S,8R,9S)-5-(2-Methoxy-phenyl)-10,10-dimethyl-8-
propyl-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene 8
Compound 8 was prepared following the same proce-
dure as in the preparation of 9 using 1-bromopropane (273
mL, 3.0 mmol) to produce 8 (0.11 g, 0.4 mmol, 34%). mp:
107-109 ºC. [a]17.1D +21.8º (c 1.00, CHCl3). 1H NMR (400
MHz, CDCl3, d): 7.91-7.89 (dd, J = 7.6, 1.7 Hz, 1H), 7.56-
7.54 (d, J = 7.8 Hz, 1H), 7.33-7.31 (m, 1H), 7.19-7.18 (d, J
= 7.8 Hz, 1H), 7.10-7.06 (m, 1H), 6.99-6.97 (d, J = 8.2 Hz,
1H), 3.86 (s, 3H), 3.08-3.06 (dd, J = 6.5, 2.9 Hz, 1H),
2.77-2.75 (t, J = 5.7 Hz, 1H), 2.62-2.52 (m, 1H), 2.35-2.32
(m, 2H), 1.52-1.48 (m, 3H), 1.43 (s, 3H), 1.36-1.34 (d, J =
(1S,8R,9S)-8-Ethyl-5-(2-methoxy-phenyl)-10,10-di-
methyl-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene 7
Compound 7 was prepared following the same proce-
dure as in the preparation of 9 using 1-bromoethane (224
mL, 3.0 mmol) to produce 7 (0.11 g, 0.4 mmol, 36%). mp
1
87-89 ºC. [a]18.0D +31.3º (c 1.00, CHCl3). H NMR (400
MHz, CDCl3, d): 7.90-7.88 (dd, J = 7.6, 1.8 Hz, 1H),
7.57-7.55 (d, J = 7.8 Hz, 1H), 7.34-7.30 (m, 1H), 7.20-7.18
(d, J = 7.8 Hz, 1H), 7.10-7.06 (t, J = 7.5 Hz, 1H), 6.99-6.97
(d, J = 8.2 Hz, 1H), 3.86 (s, 3H), 2.99-2.96 (m, 1H), 2.78-
2.75 (t, J = 5.6 Hz, 1H), 2.57-2.53 (m, 1H), 2.51-2.44 (m,
1H), 2.39-2.36 (m, 1H), 1.57-1.47 (m, 1H), 1.45 (s, 3H),
1.35-1.33 (d, J = 9.7 Hz, 1H), 1.09-1.06 (t, J = 7.4 Hz, 3H),
0.68 (s, 3H). 13C NMR (100.6 MHz, CDCl3, d): 159.7,
157.0, 152.5, 139.6, 132.3, 131.2, 129.6, 129.2, 121.5,
121.1, 111.5, 55.6, 46.8, 46.1, 42.8, 41.1, 28.6, 26.5, 25.3,
21.1, 12.5. IR (KBr): 2956, 2928, 2869, 1600, 1583, 1492,
1463, 1436, 1398, 1302, 1261, 1240, 1180, 1123, 1068,
1027, 942, 831, 752, 605 cm–1. MS m/z: 307 (M+, 10), 292
(18), 278 (100), 264 (35), 250 (16), 236 (22). HRMS-EI
(m/z): [M]+ calcd for C21H25NO, 307.1936; found,
307.1932.
9.7 Hz, 1H), 1.02-0.98 (t, J = 6.9 Hz, 3H), 0.67 (s, 3H). 13
C
NMR (100.6 MHz, CDCl3, d): 159.8, 157.1, 152.5, 139.6,
132.3, 131.3, 129.6, 129.2, 121.4, 121.1, 111.5, 55.6, 46.8,
44.2, 43.4, 41.0, 34.7, 28.5, 26.5, 21.1, 20.9, 14.4. IR
(KBr): 2950, 2928, 2868, 1599, 1582, 1492, 1462, 1436,
1396, 1300, 1259, 1239, 1174, 1123, 1026, 828, 751 cm–1.
MS m/z: 321 (M+, 10), 279 (51), 278 (100), 264 (18), 250
(14), 236 (36), 221 (12). HRMS-EI (m/z): [M]+ calcd for
C22H27NO, 321.2093; found, 321.2085.
(1S,8R,9S)-2-(10,10-Dimethyl-8-propyl-6-aza-tricyclo-
[7.1.1.02,7]undeca-2(7),3,5-trien-5-yl)-phenol 12
Compound 12 was prepared following the same pro-
cedure as in the preparation of 13 to produce 12 (0.22 g, 0.7
mmol, 72%). [a]20.7D -11.8º (c 1.00, CHCl3). 1H NMR (400
MHz, CDCl3, d): 7.78-7.75 (dd, J = 8.0, 1.5 Hz, 1H), 7.60-
7.58 (d, J = 8.0 Hz, 1H), 7.35-7.34 (d, J = 3.2 Hz, 1H),
7.29-7.25 (m, 1H), 7.05-7.02 (dd, J = 8.2, 1.0 Hz, 1H),
6.91-6.87 (m, 1H), 3.08-3.04 (m, 1H), 2.80-2.77 (t, J = 5.6
Hz, 1H), 2.60-2.54 (m, 1H), 2.36-2.32 (m, 1H), 2.19-2.11
(m, 1H), 1.60-1.52 (m, 2H), 1.44 (s, 3H), 1.34-1.31 (d, J =
(1S,8R,9S)-2-(8-Ethyl-10,10-dimethyl-6-aza-tricyclo-
[7.1.1.02,7]undeca-2(7),3,5-trien-5-yl)-phenol 11
Compound 11 was prepared following the same pro-
cedure as in the preparation of 13 to produce 11 (0.17 g, 0.6
mmol, 60%). [a]20.6D +9.5º (c 1.00, CHCl3). 1H NMR (400
MHz, CDCl3, d): 7.78-7.76 (dd, J = 8.0, 1.5 Hz, 1H), 7.62-
7.60 (d, J = 8.1 Hz, 1H), 7.36-7.34 (d, J = 8.1 Hz, 1H),
7.29-7.25 (m, 1H), 7.02-7.00 (dd, J = 8.2, 1.1 Hz, 1H),
6.91-6.87 (m, 1H), 2.98-2.94 (m, 1H), 2.81-2.78 (t, J = 5.6
Hz, 1H), 2.60-2.55 (m, 1H), 2.39-2.31 (m, 1H), 2.30-2.25
(m, 2H), 1.58-1.52 (m, 1H), 1.45 (s, 3H), 1.42-1.40 (d, J =
6.8 Hz, 1H), 1.33-1.31 (d, J = 9.9 Hz, 3H), 1.09-1.05 (t, J =
7.4 Hz, 3H), 0.69 (s, 3H). 13C NMR (100.6 MHz, CDCl3,
d): 159.6, 156.0, 154.8, 140.2, 134.6, 125.7, 119.4, 118.7,
118.3, 115.8, 46.8, 45.3, 42.6, 41.2, 28.6, 26.4, 25.1, 20.9,
12.3. IR (KBr): 2961, 2931, 2873, 1585, 1503, 1471, 1411,
1377, 1292, 1256, 1218, 1149, 1094, 1019, 851, 823, 801,
749, 606 cm–1. MS m/z: 293 (M+, 58), 278 (25), 264 (100),
250 (58), 236 (22), 222 (37), 128 (8), 77 (5). HRMS-EI
9.9 Hz, 1H), 1.04-1.00 (t, J = 7.2 Hz, 3H), 0.69 (s, 3H). 13
C
NMR (100.6 MHz, CDCl3, d): 159.6, 157.2, 154.8, 140.2,
134.6, 130.6, 125.8, 119.5, 118.7, 118.3, 115.8, 46.7, 43.3,
43.2, 41.1, 34.5, 28.6, 26.4, 20.9, 20.8, 14.2. IR (KBr):
2950, 2931, 2862, 1585, 1503, 1471, 1411, 1380, 1292,
1256, 1218, 1149, 1124, 1015, 852, 823, 749, 606 cm–1.
MS m/z: 307 (M+, 37), 292 (10), 278 (17), 264 (100), 236
(24), 222 (64), 128 (11). HRMS-EI (m/z): [M]+ calcd for
C21H25NO, 307.1936; found, 307.1929.
(1S,9R)-5-(2-Methoxy-phenyl)-10,10-dimethyl-6-aza-
tricyclo[7.1.1.02,7]undeca-2(7),3,5-trien-8-one 14
A solution of compound 5 (4.00 g, 14.0 mmol), tert-
butyl alcohol (143 mL) and water (28.6 mL) was heated at
774
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J. Chin. Chem. Soc. 2012, 59, 768-781

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Pyridylphenol Enantioselective Addition Et2Zn Aldehyde
80 ºC, and added potassium permanganate (12.3 g, 77.7
mmol). After stirred for 12 hr, the hot reaction mixture was
filtrated through celite to remove the manganese dioxide,
and washed with 20% tert-butyl alcohol in water (20 mL).
The filtrate was added 20% aqueous solution of sodium
bisulfite (10.0 mL) to reduce the remained potassium per-
manganate, and then the tert-butyl alcohol was removed by
rotary evaporator. The remained aqueous solution was ex-
tracted with ethyl acetate three times, and the combined ex-
tracts were dried over anhydrous magnesium sulfate. After
filtering and concentration, the resulting residue was puri-
fied by flash column chromatography using silica gel as the
stationary phase and using ethyl acetate-hexane (1:19, 1:4,
3:7) as the mobile phase producing compound 14 (3.00 g,
10.2 mmol). Yield: 72%. mp 187–188 ºC. [a]23.5D +152.6º
(c 1.01, CHCl3). 1H NMR (400 MHz, CDCl3, d): 7.92-7.89
(d, J = 10.6 Hz, 1H), 7.89-7.87 (d, J = 8.3 Hz, 1H), 7.59-
7.57 (d, J = 8.0 Hz, 1H), 7.35-7.32 (t, J = 7.6 Hz, 1H),
7.20-7.18 (d, J = 8.2 Hz, 1H), 7.15-7.11 (t, J = 7.5 Hz, 1H),
5.19 (s, 2H), 3.43 (s, 3H), 3.12-3.10 (d, J = 9.1 Hz, 3H),
CDCl3, d): 7.94-7.92 (dd, J = 7.7, 1.8 Hz, 1H), 7.69-7.67
(d, J = 7.8 Hz, 1H), 7.38-7.34 (m, 1H), 7.29-7.26 (d, J = 7.8
Hz, 1H), 7.11-7.07 (m, 1H), 7.02-6.99 (d, J = 8.4 Hz, 1H),
3.88 (s, 3H), 2.92 (br, 1H), 2.83-2.74 (m, 2H), 2.41-2.38 (t,
J = 6.2 Hz, 1H), 1.65 (s, 3H), 1.58-1.55 (d, J = 9.9 Hz, 1H),
1.49 (s, 3H), 0.82 (s, 3H). 13C NMR (100.6 MHz, CDCl3,
d): 160.0, 157.0, 153.2, 138.2, 132.7, 131.2, 129.6, 129.1,
123.2, 121.0, 111.5, 76.1, 55.6, 51.9, 47.1, 43.2, 34.7, 29.0,
27.1, 24.1. IR (KBr): 3564, 3445, 2926, 2868, 1600, 1583,
1569, 1493, 1463, 1437, 1367, 1302, 1244, 1098, 1025,
923, 751 cm–1. MS m/z: 309 (M+, 16), 307 (10), 294 (100),
276 (67), 266 (48), 252 (36), 236 (39), 128 (4), 77 (5).
HRMS-EI (m/z): [M]+ calcd for C20H23NO2, 309.1729;
found, 309.1721.
(1S,8S,9R)-5-(2-Hydroxy-phenyl)-8,10,10-trimethyl-6-
aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-trien-8-ol 16
To a solution of 15 (0.18 g, 0.5 mmol) in anhydrous
NMP (1.10 mL) was added PhSH (58 mL, 0.5 mmol) and
K2CO3 (4.0 mg, 0.03 mmol), and heated to 250 ºC for
refluxing 30 min (TLC). The reaction mixture was cooled
to room temperature and a 5% NaOH (25 mL) was added,
then the aqueous solution was neutralized by adding 1 M
HCl to pH = 8. The aqueous phase was extracted with di-
ethyl ether three times, and the combined extracts were
dried over anhydrous MgSO4. After filtering and concen-
tration, the residue was purified by flash column chroma-
tography using silica gel as the stationary phase and ethyl
acetate-hexane (1:19) as the mobile phase, thus producing
2.21-2.19 (t, J = 4.6 Hz, 1H), 1.61 (s, 3H), 0.84 (s, 3H). 13
C
NMR (100.6 MHz, CDCl3, d): 200.0, 156.9, 155.1, 147.7,
144.4, 133.7, 131.7, 130.1, 128.3, 128.0, 121.2, 111.2,
58.2, 55.6, 52.8, 47.1, 39.5, 26.7, 22.7. IR (KBr): 2954,
2836, 1708, 1585, 1492, 1442, 1303, 1257, 1189, 1066,
1022, 860, 754, 725, 582 cm–1. MS m/z: 293 (M+, 33), 278
(26), 264 (100), 250 (78), 236 (28), 77 (9). HRMS-EI (m/z):
[M]+ calcd for C19H19NO2, 293.1416; found, 293.1414.
(1S,8S,9R)-5-(2-Methoxy-phenyl)-8,10,10-trimethyl-6-
aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-trien-8-ol 15
A mixture of magnesium (72.0 mg, 3.0 mmol) in di-
ethyl ether (30.0 mL) equipped with a reflux condenser and
under argon atmosphere, was added iodomethane (0.46
mL, 3.0 mmol) drop wisely, and after 1 hr, all magnesium
was consumed. A solution of compound 14 (0.3 g, 1.0
mmol) in tetrahydrofuran (30.0 mL) was added to the fresh
prepared MeMgI drop wisely at 0 ºC, and then stirred at
room temperature. After completion of the reaction (TLC,
1 h), the reaction was quenched by ammonium chloride so-
lution, and the aqueous solution was extracted with diethyl
ether three times, and the combined extracts were dried
over anhydrous magnesium sulfate. After filtering and con-
centration, the resulting residue was purified by flash col-
umn chromatography using silica gel as the stationary
phase and using ethyl acetate-hexane (1:19) as the mobile
phase producing compound 15 (0.22 g, 0.7 mmol). Yield:
88%. [a]21.3D +107.0º (c 1.00, CHCl3). 1H NMR (400 MHz,
compound 16 (0.22 g, 0.7 mmol). Yield: 84%. [a]20.7
D
+103.0º (c 1.25, CHCl3). 1H NMR (400 MHz, CDCl3, d):
7.78-7.75 (dd, J = 8.0, 1.4 Hz, 1H), 7.70-7.68 (d, J = 8.2
Hz, 1H), 7.46-7.43 (d, J = 8.2 Hz, 1H), 7.30-7.26 (m, 1H),
7.03-7.01 (dd, J = 8.2, 1.0 Hz, 1H), 6.93-6.89 (m, 1H),
2.85-2.77 (m, 2H), 2.44 (br, 1H), 2.40-2.37 (t, J = 6.2 Hz,
1H), 1.65 (s, 3H), 1.54-1.51 (d, J = 9.8 Hz, 1H), 1.49 (s,
3H), 0.83 (s, 3H). 13C NMR (100.6 MHz, CDCl3, d): 159.4,
157.0, 155.7, 138.9, 135.1, 130.9, 125.9, 119.4, 118.9,
118.4, 117.7, 75.9, 52.6, 47.1, 43.1, 35.0, 28.5, 27.0, 24.0.
IR (KBr): 3468, 2927, 1586, 1471, 1411, 1368, 1290, 1251,
1221, 1151, 1102, 1059, 845, 752, 620 cm–1. MS m/z: 295
(M+, 22), 266 (39), 250 (80), 240 (100), 235 (12).
HRMS-EI (m/z): [M]+ calcd for C19H21NO2, 295.1572;
found, 295.1570.
(1S,8R,9S)-2-[5-(2-Methoxy-phenyl)-10,10-dimethyl-6-
aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-trien-8-yl]-pro-
pan-2-ol 17
To a solution of diisopropylamine (121 mL, 1.2
J. Chin. Chem. Soc. 2012, 59, 768-781
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775

Article
Wu and Chen
mmol) in THF (5 mL) at 0 ºC was added n-BuLi (0.90 mL,
1.2 mmol, 1.33 M in hexane) and stirred for 30 min. The
prepared LDAsolution was cooled to -78 ºC, and a solution
of 5 (0.28 g, 1.0 mmol) in THF (6 mL) was transfered to
LDAsolution by cannula. The solution became a blue color
and was stirred at -78 ºC for 2 h. A solution of acetone (128
mL, 1.75 mmol) in THF (10 mL) was added and stirred
overnight at room temperature. The solution became or-
ange color and quenched by adding water. The resulting so-
lution was extracted with ethyl acetate three times, and the
combined extracts were dried over anhydrous MgSO4. Af-
ter filtering and concentration, the residue was purified by
flash column chromatography using silica gel as the sta-
tionary phase and ethyl acetate-hexane (1:19) as the mobile
phase, thus producing compound 17 (0.22 g, 0.7 mmol).
Yield: 61%. [a]20.8D -0.9º (c 1.10, CHCl3). 1H NMR (400
MHz, CDCl3, d): 8.05 (br, 1H), 7.74-7.72 (d, J = 7.4 Hz,
1H), 7.61-7.59 (d, J = 7.8 Hz, 1H), 7.35-7.28 (m, 1H), 7.06-
7.02 (t, J = 7.5 Hz, 1H), 6.99-6.97 (d, J = 8.2 Hz, 1H), 3.87
(s, 3H), 3.26 (s, 1H), 2.79-2.77 (t, J = 5.4 Hz, 1H), 2.63-
2.58 (m, 1H), 2.37-2.35 (t, J = 5.4 Hz, 1H), 1.44 (s, 3H),
1.43-1.38 (d, J = 9.3 Hz, 1H), 1.33 (s, 3H), 1.14 (s, 3H),
0.73 (s, 3H). 13C NMR (100.6 MHz, CDCl3, d): 157.9,
157.0, 151.5, 140.9, 133.3, 130.8, 129.7, 128.4, 122.0,
121.1, 111.4, 74.2, 55.5, 52.9, 46.4, 42.7, 42.2, 29.5, 29.2,
27.5, 26.4, 21.2. IR (KBr): 3306, 2974, 2939, 2867, 1703,
1584, 1464, 1417, 1241, 1163, 1122, 1024, 860, 752, 646
cm–1.
1H), 2.75-2.70 (m, 1H), 2.41-2.38 (m, 1H), 1.43 (s, 3H),
1.31-1.29 (d, J = 9.6 Hz, 1H), 0.67 (s, 3H). 13C NMR (100.6
MHz, CDCl3, d): 159.5, 154.8, 153.4, 140.2, 134.7, 130.6,
125.7, 119.3, 118.6, 118.4, 115.6, 46.2, 40.0, 39.7, 35.8,
32.1, 26.0, 21.2. IR (KBr): 2938, 1586, 1497, 1469, 1425,
1382, 1294, 1254, 1154, 946, 850, 768, 751, 625 cm–1. MS
m/z: 265 (M+, 100), 250 (66), 236 (24), 222 (75), 210 (13),
128 (9), 91 (3), 77 (6). HRMS-EI (m/z): [M]+ calcd for
C18H19ON, 265.1647; found, 265.1458.
(1S,8R,9S)-2-[8-(1-Hydroxy-1-methyl-ethyl)-10,10-di-
methyl-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-trien-5-
yl]-phenol 19
To a solution of diisopropylamine (253 mL, 1.2
mmol) in THF (6 mL) at 0 ºC was added n-BuLi (1.5 mL,
2.4 mmol, 1.6 M in hexane) and stirred for 30 min. The pre-
pared LDA solution was cooled to -78 ºC, and a solution of
18 (0.26 g, 1.0 mmol) in THF (6 mL) was transfered to
LDAsolution by cannula. The solution became a blue color
and was stirred at -78 ºC for 2 h. A solution of acetone (108
mL, 1.5 mmol) in THF (20 mL) was added and stirred over
night at room temperature. The reaction was quenched by
adding water. The resulting solution was extracted with
ethyl acetate three times, and the combined extracts were
dried over anhydrous MgSO4. After filtering and concen-
tration, the residue was purified by flash column chroma-
tography using silica gel as the stationary phase and ethyl
acetate-hexane (1:19) as the mobile phase, thus producing
compound 19 (0.22 g, 0.7 mmol). Yield: 68%. [a]20.4
D
1
(5S,7S)-(+)-5,6,7,8-Tetrahydro-6,6-dimethyl-2-(2-hy-
droxyphenyl)-5,7-methanoquinoline 18
-43.3º (c 1.10, CHCl3). H NMR (400 MHz, CDCl3, d):
7.71-7.68 (dd, J = 7.9, 1.4 Hz, 1H), 7.60-7.58 (d, J = 8.1
Hz, 1H), 7.40-7.38 (d, J = 8.0 Hz, 1H), 7.28-7.24 (m, 1H),
7.02-6.99 (dd, J = 8.2, 0.9 Hz, 1H), 6.92-6.88 (m, 1H),
3.25-3.22 (m, 1H), 2.78-2.75 (t, J = 5.6 Hz, 1H), 2.61-2.56
(m, 1H), 2.45-2.41 (m, 1H), 1.57-1.55 (d, J = 9.8 Hz, 1H),
1.43 (s, 3H), 1.40 (s, 3H), 1.21 (s, 3H), 0.64 (s, 3H). 13C
NMR (100.6 MHz, CDCl3, d): 158.1, 155.5, 154.4, 141.3,
135.2, 130.6, 126.5, 120.7, 119.0, 118.2, 117.4, 74.3, 53.3,
46.5, 43.2, 42.5, 30.8, 28.3, 26.2, 20.9. IR (KBr): 3393,
2953, 2869, 1583, 1471, 1384, 1293, 1253, 1122, 898, 852,
761, 749, 608 cm–1. MS m/z: 323 (M+, 71), 290 (23), 264
(84), 250 (87), 236 (46), 222 (100), 210 (14), 128 (10), 59
(23). HRMS-EI (m/z): [M]+ calcd for C21H25NO2,
323.1885; found, 323.1876.
To a solution of 5 (1.2 g, 4.3 mmol) in dichloro-
methane (40 mL) was added BBr3 (8.1 mL, 32.0 mmol, 1 M
in dichloromethane) slowly under argon and the mixture
was stirred at room temperature for 60 h (TLC). A 2 M
NaOH solution was added, and neutralized by acetic acid to
pH = 8. The resulting solution was extracted with ethyl ace-
tate three times, and the combined extracts were dried over
anhydrous MgSO4. After filtering and concentration, the
residue was purified by flash column chromatography us-
ing silica gel as the stationary phase and ethyl acetate-hex-
ane (1:19) as the mobile phase, thus producing compound
18 (1.02 g, 3.8 mmol). Yield: 90%. mp: 130-131 ºC.
1
[a]22.0 +114.0º (c 1.0, CHCl3). H NMR (400 MHz,
D
CDCl3, d): 7.78-7.75 (dd, J= 8.0, 1.5 Hz, 1H), 7.62-7.60 (d,
J = 8.1 Hz, 1H), 7.37-7.35 (d, J = 8.1 Hz, 1H), 7.28-7.24
(m, 1H), 7.02-7.00 (dd, J = 8.2, 1.2 Hz, 1H), 6.90-6.86 (m,
1H), 3.14-3.13 (d, J = 2.8 Hz, 2H), 2.81-2.78 (t, J = 5.6 Hz,
Typical procedure for the enantioselective addition of
diethylzinc to aldehydes catalyzed by the ligand 10
Aldehyde (0.5 mmol) was added to a solution of
ligand 10 (14.0 mg, 2.5 mmol) in toluene (1.0 mL) at room
776
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© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 768-781

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Pyridylphenol Enantioselective Addition Et2Zn Aldehyde
temperature, and then a solution of diethylzinc (1.0 mL, 1
M in hexane) was added and stirred for 30 h. The reaction
was quenched by adding 1 M HCl (0.5 mL), and the reac-
tion mixture was extracted three times with ethyl acetate.
The combined extracts then were dried over anhydrous
magnesium sulfate. After filtering and concentration, the
residue was purified by flash column chromatography us-
ing silica gel as the stationary phase and ethyl acetate–hex-
ane (1:19) as the mobile phase, thus producing products.
The enantiomeric excess of products was determined by
HPLC (Chiralcel OD-H column, flow rate 0.25 mL/min,
10% 2-propanol in hexane, 254 nm UV detector).
1H), 4.59-4.56 (t, J = 6.5 Hz, 1H), 2.16 (br, 1H), 1.86-1.71
(m, 2H), 0.94-0.90 (t, J = 7.4 Hz, 3H). 13C NMR (100.6
MHz, CDCl3, d): 144.6, 128.4, 127.5, 126.0, 76.0, 31.9,
10.2. IR (KBr): 3374, 2982, 2964, 2876, 1492, 1453, 1330,
1200, 1095, 1012, 973, 761, 699, 544 cm–1. HPLC (Daicel
Chiralcel OD-H, hexane/i-PrOH = 90:10, flow rate 0.25
mL/min), tR of R isomer 23.20 min, tR of S isomer 24.76
min, R : S = 10.49 : 89.50, ee%: 79%.
(S)-1-o-Tolyl-propan-1-ol 21
Yield: 70%. [a]20.5D -44.8º (c 1.25, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.47-7.45 (d, J = 7.4 Hz, 1H), 7.26-
7.13 (m, 3H), 4.87-4.84 (t, J = 6.4 Hz, 1H), 2.35 (s, 3H),
1.99 (br, 1H), 1.80-1.73 (m, 2H), 1.01-0.97 (t, J = 7.4 Hz,
3H). 13C NMR (100.6 MHz, CDCl3, d): 142.8, 134.6,
130.3, 127.1, 126.2, 125.3, 72.0, 30.9, 19.1, 10.4. IR
(KBr): 3368, 3065, 3024, 2964, 2876, 1487, 1461, 1379,
1091, 1052, 973, 750, 726 cm–1.
The enantiomeric excesses of products were deter-
mined by the following methods.
Method A: To a solution of product (0.05 mmol) in
dichloromethane (2 mL) was added acetic anhydride (0.07
mL) and pyridine (0.03 mL), and stirred for 3 h. After con-
centration, the residue was purified by flash column chro-
matography using silica gel as the stationary phase and
ethyl acetate-hexane (1:19) as the mobile phase, thus pro-
ducing the product. The enantiomeric excess of products
were determined by HPLC (Chiralcel OD-H column, flow
rate 0.25 mL/min, 10% 2-propanol in hexane, 254 nm UV
detector, and EZChromTM Chromatography Data System.)
Method B: To a solution of product (0.05 mmol) in di-
chloromethane (2 mL) was added benzoyl chloride (0.07
mL) and pyridine (0.03 mL), and stirred for 12 h. After con-
centration, the residue was purified by flash column chro-
matography using silica gel as the stationary phase and
ethyl acetate-hexane (1:19) as the mobile phase, thus pro-
ducing the product. The enantiomeric excess of products
were determined by HPLC (Chiralcel OD-H or OJ-H col-
umn, flow rate 0.25 or 0.5 mL/min, 10% 2-propanol in hex-
ane, 254 nm UV detector, and EZChromTM Chromatogra-
phy Data System.)
(S)-1-o-Tolylpropyl acetate 21-1
Yield: 75.4%. [a]20.1 -67.5º (c 0.85, CHCl3). H
1
D
NMR (400 MHz, CDCl3, d): 7.35-7.33 (dd, J = 7.3, 2.1 Hz,
1H), 7.22-7.17 (m, 2H), 7.16-7.13 (m, 1H), 5.92-5.88 (m,
1H), 2.41 (s, 3H), 2.08 (s, 3H), 1.95-1.75 (m, 2H), 0.94-
0.90 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d):
170.5, 155.9, 139.2, 135.2, 130.3, 127.5, 126.1, 125.8,
108.9, 78.0, 74.0, 65.2, 30.6, 29.7, 28.9, 21.3, 19.3, 10.1.
IR (KBr): 2923, 2851, 1736, 1459, 1371, 1237, 1078,
1017, 801, 757, 721 cm–1. HPLC (Daicel Chiralcel OD-H,
hexane/i-PrOH = 90:10, flow rate 0.25 mL/min), tR of R
isomer 15.80 min, tR of S isomer 16.92 min, R : S = 12.07 :
87.92, ee%: 75%.
(S)-1-m-Tolylpropan-1-ol 22
Yield: 65%. [a]20.7D -31.9º (c 1.20, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.26-7.23 (t, J = 7.2 Hz, 1H),
7.17-7.09 (m, 3H), 4.56-4.53 (t, J = 6.5 Hz, 1H), 2.37 (s,
3H), 2.09 (br, 1H), 1.86-1.71 (m, 2H), 0.94-0.91 (t, J = 7.4
Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d): 144.6, 138.0,
128.3, 128.2, 126.7, 123.1, 76.1, 31.9, 21.5, 10.2. IR
(KBr): 3370, 3026, 2963, 2931, 2875, 1608, 1488, 1456,
1378, 1322, 1158, 1085, 1044, 1015, 975, 784, 703 cm–1.
HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH = 90:10,
flow rate 0.25 mL/min), tR of R isomer 20.87 min, tR of S
isomer 22.84 min, R : S =11.16: 88.83, ee%: 77%.
(S)-1-p-Tolylpropan-1-ol 23
Method C: To a solution of product (0.05 mmol) in di-
chloromethane (2 mL) was added (+)-MTPA (21.1 mg,
0.09 mmol), DMAP (cat.) and DCC (41.3 mg, 0.2 mmol),
and stirred for 12 h. After filtration and concentration, the
residue was purified by flash column chromatography us-
ing silica gel as the stationary phase and ethyl acetate-hex-
ane (1:19) as the mobile phase, thus producing the product.
The enantiomeric excesses of products were determined by
19F NMR spectrum.
Yield: 52%. [a]21.1D -37.6º (c 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.24-7.22 (d, J = 8.1 Hz, 2H), 7.18-
7.16 (d, J = 8.0 Hz, 2H), 4.56-4.53 (t, J = 6.6 Hz, 1H), 2.36
(s, 3H), 2.09 (br, 1H), 1.87-1.68 (m, 2H), 0.93-0.90 (t, J =
(S)-1-Phenyl-propan-1-ol 20
Yield: 86%. [a]20.6D -44.9º (c 1.25, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.38-7.32 (m, 4H), 7.31-7.25 (m,
J. Chin. Chem. Soc. 2012, 59, 768-781
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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777

Article
Wu and Chen
7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d): 141.7,
137.1, 129.1, 126.0, 75.9, 31.8, 21.1, 10.2. IR (KBr): 3378,
2963, 2875, 1903, 1614, 1514, 1455, 1378, 1098, 1403,
1012, 973, 902, 816, 538 cm–1. HPLC (Daicel Chiralcel
OJ-H, hexane/i-PrOH = 90:10, flow rate 0.25 mL/min), tR
of R isomer 32.70 min, tR of S isomer 30.74 min, R : S =
5.31 : 94.67, ee%: 89%.
1H), 1.84-1.64 (m, 2H), 0.89-0.85 (t, J = 7.4 Hz, 3H). 13
C
NMR (100.6 MHz, CDCl3, d): 158.9, 136.9, 127.2, 113.7,
75.6, 55.2, 31.8, 10.2. IR (KBr): 3400, 2962, 2934, 2875,
2054, 1888, 1612, 1585, 1513, 1463, 1301, 1097, 1037,
974, 830, 548 cm–1. HPLC (Daicel Chiralcel OD-H, hex-
ane/i-PrOH = 90:10, flow rate 0.25 mL/min), tR of R isomer
28.56 min, tR of S isomer 30.61 min, R : S = 33.95 : 66.05,
ee%: 33%.
(S)-1-(2-Methoxyphenyl)propan-1-ol 24
Yield: 52%. [a]20.8D -9.8º (c 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.32-7.30 (dd, J = 7.5, 1.6 Hz, 1H),
7.27-7.22 (m, 1H), 6.98-6.94 (t, J = 7.5 Hz, 1H), 6.79-6.77
(d, J = 8.2 Hz, 1H), 4.82-4.79 (t, J = 6.6 Hz, 3H), 3.83 (s,
3H), 2.79 (br, 1H), 1.85-1.78 (m, 2H), 0.98-0.94 (t, J = 7.4
Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d): 156.6, 132.5,
128.2, 127.1, 120.7, 110.5, 72.2, 55.3, 30.2, 10.5. IR
(KBr): 3406, 2963, 2876, 2030, 1601, 1491, 1464, 1438,
1287, 1237, 1089, 1046, 1028, 974, 901, 754 cm–1. HPLC
(Daicel Chiralcel OD-H, hexane/i-PrOH = 90:10, flow rate
0.25 mL/min), tR of R isomer 26.82 min, tR of S isomer
25.33 min, R : S = 29.71: 70.29, ee%: 41%.
(S)-1-(2-Chlorophenyl)propan-1-ol 27
Yield: 72%. [a]20.8D -23.4º (c 1.05, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.53-7.51 (dd, J = 7.7, 1.7 Hz, 1H),
7.33-7.30 (dd, J = 7.9, 1.2 Hz, 1H), 7.29-7.25 (m, 1H),
7.20-7.16 (m, 1H), 5.06-5.03 (m, 1H), 2.37 (br, 1H), 1.85-
1.68 (m, 2H), 0.99-0.96 (t, J = 7.4 Hz, 3H). 13C NMR
(100.6 MHz, CDCl3, d): 142.0, 132.0, 129.3, 128.3, 127.2,
127.0, 71.9, 30.5, 10.1. IR (KBr): 3367, 3067, 2967, 2877,
1573, 1590, 1466, 1437, 1102, 1048, 1032, 976, 752, 702,
460 cm–1.
(S)-1-(2-Chlorophenyl)propyl benzoate 27-1
Yield: 81%. [a]20.8D +51.7º (c 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 8.13-8.11 (dd, J = 5.0, 1.3 Hz, 2H),
7.60-7.56 (m, 1H), 7.49-7.45 (m, 3H), 7.39-7.37 (dd, J =
7.6, 1.5 Hz, 1H), 7.27-7.19 (m, 2H), 6.35-6.32 (t, J = 6.4
Hz, 3H), 2.07-1.99 (m, 2H), 1.06-1.02 (t, J = 7.4 Hz, 3H).
13C NMR (100.6 MHz, CDCl3, d): 165.7, 138.7, 133.1,
132.3, 130.3, 129.7, 129.7, 128.7, 128.5, 128.3, 127.0,
127.0, 74.5, 28.6, 9.9. IR (KBr): 3065, 2971, 2936, 1720,
1601, 1451, 1314, 1268, 1177, 1109, 1069, 1026, 944, 754,
712, 463 cm–1. HPLC (Daicel Chiralcel OD-H, hexane/i-
PrOH = 90:10, flow rate 0.25 mL/min), tR of R isomer
16.56 min, tR of S isomer 18.61 min, R : S = 30.31 : 69.69,
ee%: 39%.
(S)-1-(3-Methoxyphenyl)propan-1-ol 25
Yield: 87%. a]20.6D -29.5º (c 1.20, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.27-7.23 (m, 1H), 6.92-6.90 (m,
2H), 6.82-6.79 (m, 1H), 4.57-4.53 (t, J = 6.6 Hz, 3H), 3.80
(s, 3H), 2.10 (br, 1H), 1.86-1.68 (m, 2H), 0.93-0.90 (t, J =
7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d): 159.7,
146.4, 129.4, 118.3, 112.9, 111.5, 75.9, 55.2, 31.8, 10.2. IR
(KBr): 3408, 2963, 2876, 1929, 1602, 1487, 1485, 1318,
1261, 1156, 1084, 1043, 978, 858, 782, 699, 563, 468 cm–1.
(S)-1-(3-Methoxyphenyl)propyl acetate 25-1
Yield: 91%. [a]19.9D -65.2º (c 1.10, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.28-7.24 (d, J = 7.9 Hz, 1H), 6.92-
6.90 (d, J = 7.8 Hz, 1H), 6.88-6.87 (t, J = 2.3 Hz, 1H),
6.84-6.81 (m, 1H), 5.66-5.62 (t, J = 6.9 Hz, 1H), 3.81 (s,
3H), 2.10 (s, 3H), 1.94-1.74 (m, 2H), 0.90-0.87 (t, J = 7.4
Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d): 170.4, 159.6,
142.2, 129.4, 118.9, 113.0, 112.3, 76.8, 55.2, 29.3, 21.3,
9.9. IR (KBr): 2968, 2938, 2878, 1735, 1603, 1587, 1491,
1456, 1436, 1371, 1238, 1160, 1083, 1042, 1020, 967, 876,
783, 699 cm–1. HPLC (Daicel Chiralcel OD-H, hex-
ane/i-PrOH = 90:10, flow rate 0.25 mL/min), tR of R isomer
19.31 min, tR of S isomer 20.91 min, R : S = 12.43 : 87.57,
ee%: 75%.
(S)-1-(3-Chlorophenyl)propan-1-ol 28
Yield: 91%. [a]21.0D -29.8º (c 0.95, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.33-7.32 (m, 1H), 7.28-7.24 (t, J =
7.9 Hz, 1H), 7.24-7.21 (m, 1H), 7.20-7.18 (m, 1H), 4.56-
4.53 (t, J = 6.5 Hz, 3H), 2.22 (br, 1H), 1.81-1.66 (m, 2H),
0.92-0.88 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz,
CDCl3, d): 146.7, 134.3, 129.7, 127.6, 126.2, 124.2, 75.3,
31.9, 10.0. IR (KBr): 3366, 3065, 2966, 2877, 1942, 1869,
1598, 1575, 1477, 1462, 1432, 1261, 1198, 1084, 1044,
1015, 977, 881, 785, 698, 508 cm–1. HPLC (Daicel Chiralcel
OD-H, hexane/i-PrOH = 90:10, flow rate 0.25 mL/min), tR
of R isomer 22.84 min, tR of S isomer 21.81 min, R : S =
8.17 : 91.82, ee%: 83%.
(S)-1-(4-Methoxyphenyl)propan-1-ol 26
Yield: 40%. [a]21.0D -15.1º (c 1.10, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.25-7.21 (m, 2H), 6.88-6.85 (m,
2H), 4.51-4.47 (t, J = 6.7 Hz, 1H), 3.78 (s, 3H), 2.28 (br,
(S)-1-(4-Chlorophenyl)propan-1-ol 29
Yield: 93%. [a]21.3D -31.4º (c 1.00, CHCl3). 1H NMR
778
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© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 768-781

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Pyridylphenol Enantioselective Addition Et2Zn Aldehyde
(400 MHz, CDCl3, d): 7.30-7.28 (dd, J = 6.5, 1.8 Hz, 2H),
7.24-7.22 (dd, J = 2.8, 1.8 Hz, 2H), 4.55-4.51 (t, J = 6.6 Hz,
1H), 2.31 (br, 1H), 1.81-1.63 (m, 2H), 0.90-0.86 (t, J = 7.4
Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d): 143.0, 133.0,
128.5, 127.4, 75.2, 31.9, 10.0. IR (KBr): 3366, 2966, 2933,
2877, 1902, 1597, 1492, 1463, 1409, 1090, 1013, 975, 902,
824, 548, 527, 461 cm–1. HPLC (Daicel Chiralcel OD-H,
hexane/i-PrOH = 90:10, flow rate 0.25 mL/min), tR of R
isomer 22.60 min, tR of S isomer 21.49 min, R : S = 12.48 :
87.51, ee%: 75%.
128.5, 128.3, 127.0, 118.7, 111.7, 29.5, 9.8. IR (KBr):
3063, 2972, 2936, 2229, 1720, 1610, 1451, 1314, 1270,
1176, 1110, 1069, 1025, 842, 711, 561 cm–1. HPLC (Daicel
Chiralcel OJ-H, hexane/i-PrOH = 90:10, flow rate 0.25
mL/min), tR 33.15 and 38.18 min. ee%: 71%.
1-(3-(Dimethylamino)phenyl)propan-1-ol 32
Yield: 87%. [a]21.9D -25.7º (c 1.15, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.24-7.20 (t, J = 7.8 Hz, 2H), 6.74-
6.64 (m, 3H), 4.56-4.53 (t, J = 6.6 Hz, 1H), 2.96 (s, 6H),
1.87-1.74 (m, 3H), 0.96-0.92 (t, J = 7.4 Hz, 3H). 13C NMR
(100.6 MHz, CDCl3, d): 150.8, 145.7, 129.1, 114.3, 111.8,
110.1, 76.6, 40.7, 31.8, 10.4. IR (KBr): 3390, 2961, 2874,
1604, 1581, 1498, 1438, 1350, 1228, 1138, 1046, 997, 965,
909, 853, 776, 698, 467 cm–1. HPLC (Daicel Chiralcel
OD-H, hexane/i-PrOH = 90:10, flow rate 0.50 mL/min), tR
19.83 and 28.23 min ee%: 77%.
3-(1-Hydroxypropyl)benzonitrile 30
Yield: 94%. [a]20.4D -27.4º (c 1.05, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.61-7.60 (s, 1H), 7.56-7.54 (m,
1H), 7.53-7.50 (m, 1H), 7.44-7.40 (t, J = 7.6 Hz, 1H),
4.63-4.60 (t, J = 6.4 Hz, 1H), 2.61 (br, 1H), 1.79-1.67 (m,
2H), 0.91-0.87 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz,
CDCl3, d): 146.2, 131.0, 130.5, 120.6, 129.1, 118.9, 112.2,
74.7, 32.0, 9.8. IR (KBr): 3437, 3068, 2967, 2934, 2877,
2231, 1965, 1903, 1583, 1434, 1320, 1229, 1149, 1089,
1047, 981, 901, 801, 693, 490 cm–1.
(S)-1-Cyclohexylpropan-1-ol 33
Yield: 77%. [a]19.9D -5.3º (c 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 3.30-3.25 (m, 1H), 1.80-1.65 (m,
5H), 1.55-0.98 (m, 9H), 0.97-0.93 (t, J = 7.4 Hz, 3H). 13
C
1-(3-Cyanophenyl)propyl acetate 30-1
NMR (100.6 MHz, CDCl3, d): 77.5, 43.2, 29.3, 27.8, 26.8,
26.6, 26.4, 26.2, 10.2. IR (KBr): 3371, 2926, 2852, 1449,
1123, 971, 892 cm–1.
Yield: 89%. [a]21.5D -57.5º (c 0.50, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.61-7.53 (m, 3H), 7.46-7.43 (t, J =
8.0 Hz, 1H), 5.66-5.63 (t, J = 6.2 Hz, 1H), 2.10 (s, 3H),
1.96-1.75 (m, 2H), 0.90-0.87 (t, J = 7.4 Hz, 3H). 13C NMR
(100.6 MHz, CDCl3, d): 170.1, 142.3, 131.4, 130.9, 130.0,
129.2, 118.6, 112.7, 76.1, 29.2, 21.0, 9.6. IR (KBr): 2971,
2930, 2230, 1737, 1372, 1235, 1085, 1043, 1021, 903, 800,
694, 517, 488 cm–1. HPLC (Daicel Chiralcel OD-H, hex-
ane/i-PrOH = 90:10, flow rate 0.25 mL/min), tR 23.55 and
24.81 min. ee%: 79%.
(S,2R)-1-Cyclohexylpropyl 3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate 33-1
Yield: 57%. [a]21.7D +15.9º (c 1.15, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.58-7.57 (m, 2H), 7.41-7.38 (m,
4H), 4.91-4.89 (m, 1H), 3.58-3.56 (m, 3H), 1.76-1.58 (m,
8H), 1.23-1.00 (m, 7H), 0.93-0.89 (t, J = 7.4 Hz, 2H),
0.81-0.78 (t, J = 7.4 Hz, 2H). 13C NMR (100.6 MHz,
CDCl3, d): 129.4, 128.2, 127.4, 82.6, 55.7, 55.4, 40.2, 34.9,
28.6, 27.5, 26.3, 26.1, 26.0, 25.5, 24.7, 23.5, 9.8. IR (KBr):
3031, 2932, 2855, 1743, 1496, 1451, 1256, 1183, 1121,
1081, 1055, 1018, 994, 898, 765, 716, 645 cm–1. 19F NMR
(376 MHz, CDCl3, d): -71.19 (R) and -71.23 (S); R : S =
1.00 : 9.63, ee%: 81%.
4-(1-Hydroxypropyl)benzonitrile 31
Yield: 91%. [a]19.7D -26.0º (c 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.57-7.55 (d, J = 7.8 Hz, 2H),
7.42-7.40 (d, J = 8.3 Hz, 2H), 4.64-4.61 (t, J = 6.4 Hz, 1H),
2.74 (br, 1H), 1.73-1.67 (m, 2H), 0.89-0.86 (t, J = 7.4 Hz,
3H). 13C NMR (100.6 MHz, CDCl3, d): 150.2, 132.2,
126.7, 119.0, 110.8, 74.9, 32.0, 9.8. IR (KBr): 3435, 2967,
2934, 2877, 2229, 1608, 1503, 1460, 1408, 1202, 1097,
1046, 1016, 980, 965, 847, 564 cm–1.
(S)-Nonan-3-ol 34
Yield: 57%. [a]22.0D +4.3º (c 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 3.52-3.47 (m, 1H), 1.51-1.27 (m,
13H), 0.93-0.89 (t, J = 7.4 Hz, 3H), 0.87-0.84 (m, 4H). 13
C
1-(4-Cyanophenyl)propyl benzoate 31-1
NMR (100.6 MHz, CDCl3, d): 73.3, 36.9, 31.8, 30.1, 29.4,
25.6, 22.6, 14.0, 9.8. IR (KBr): 3348, 2950, 2858, 1464,
1378, 1337, 1123, 1057, 966, 724, 599 cm–1.
Yield: 90%. [a]20.6D +35.4º (c 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 8.09-8.07 (dd, J = 8.4, 1.3 Hz, 2H),
7.66-7.64 (d, J = 8.4 Hz, 2H), 7.61-7.57 (t, J = 7.5 Hz, 1H),
7.52-7.45 (m, 4H), 5.93-5.90 (t, J = 7.0 Hz, 1H), 2.10-1.92
(m, 2H), 1.00-0.97 (t, J = 7.5 Hz, 3H). 13C NMR (100.6
MHz, CDCl3, d): 165.7, 146.1, 133.3, 132.4, 129.9, 129.7,
((S,2R)-)-Nonan-3-yl 3,3,3-trifluoro-2-methoxy-2-phen-
ylpropanoate 34-1
Yield: 38%. [a]22.1D +3.6º (c 1.15, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.57-7.55 (m, 2H), 7.41-7.39 (m,
J. Chin. Chem. Soc. 2012, 59, 768-781
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.jccs.wiley-vch.de
779

Article
Wu and Chen
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4H), 5.06-5.03 (m, 1H), 3.58-3.56 (m, 3H), 1.70-1.56 (m,
4H), 1.28-1.20 (m, 8H), 0.95-0.82 (m, 6H). 13C NMR
(100.6 MHz, CDCl3, d): 166.4, 132.6, 129.5, 128.3, 127.4,
78.8, 55.4, 33.0, 31.6, 29.0, 26.7, 24.8, 22.5, 14.0, 9.6. IR
(KBr): 3307, 3065, 2932, 2857, 2119, 1961, 1744, 1496,
4. (a) Wilken, J.; Winter, M.; Stahl, I.; Martens, J. Tetrahedron:
Asymmetry 2000, 11, 1067. (b) Dimitrov, V.; Dobrikov, G.;
Genov, M. Tetrahedron: Asymmetry 2001, 12, 1323. (c)
Chen, Y. K.; Costa, A. M.; Walsh, P. J. J. Am. Chem. Soc.
2001, 123, 5378. (d) Dahmen, S.; Braese, S. Chem. Commun.
2002, 26. (e) Nugent, W. A. Org. Lett. 2002, 4, 2133. (f) Li,
M.; Yuan, K.; Li, Y.-Y.; Cao, B.-X.; Sun, J.; Hou, X.-L. Tet-
rahedron: Asymmetry 2003, 14, 3347. (g) Dahmen, S. Org.
Lett. 2004, 6, 2113–2116. (h) Wu, X.-W.; Zhang, T.-Z.;
Yuan, K.; Hou, X.-L. Tetrahedron: Asymmetry 2004, 15,
2357. (i) Huang, J.; Ianni, J. C.; Antoline, J. E.; Hsung, R. P.;
Kozlowski, M. C. Org. Lett. 2006, 8, 1565. (j) Lauterwasser,
F.; Gall, J.; Hoefener, S.; Braese, S. Adv. Syn. Catal. 2006,
348, 2068. (k) Sokeirik, Y. S.; Omote, M.; Sato, K.;
Kumadaki, I.; Ando, A. Tetrahedron: Asymmetry 2006, 17,
2654. (l) Chai, Z.; Liu, X.-Y.; Zhang, J.-K.; Zhao, G. Tetrahe-
dron: Asymmetry 2007, 18, 724. (m) Chang, T.-C.; Chen, C.
J. Chin. Chem. Soc. 2008, 55, 606. (n) Yang, X.-F.; Hirose,
T.; Zhang, G.-Y. Tetrahedron: Asymmetry 2008, 19, 1670. (o)
Pisani, L.; Superchi, S. Tetrahedron: Asymmetry 2008, 19,
1784. (p) Stivala, C. E.; Zakarian, A. J. Am. Chem. Soc.
2008, 130, 3774. (q) Wu, Z.-L.; Wu, H.-L.; Wu, P.-Y.; Uang,
B.-J. Tetrahedron: Asymmetry 2009, 20, 1556. (r) Ananthi,
N.; Balakrishnan, U.; Velmathi, S.; Vinu, A.; Ariga, K. Tet-
rahedron: Asymmetry 2009, 20, 1731. (s) Banerjee, S.;
Groeper, J. A.; Standard, J. M.; Hitchcock, S. R. Tetrahe-
dron: Asymmetry 2009, 20, 2154. (t) Lesniak, S.; Rachwalski,
M.; Sznajder, E.; Kielbasinski, P. Tetrahedron: Asymmetry
2009, 20, 2311. (u) Cheng, K.; Kelly, A. R.; Kohn, R. A.;
Dweck, J. F.; Walsh, P. J. Org. Lett. 2009, 11, 2703. (v)
Blocka, E.; Jaworska, M.; Welniak, M.; Kozakiewicz, A.;
Wojtczak, A. Tetrahedron: Asymmetry 2010, 21, 571. (w)
Kim, H.; Hong, J. Org. Lett. 2010, 12, 2880.
1452, 1256, 1168, 1122, 994, 765, 716, 644, 508 cm–1. 19
F
NMR (376 MHz, CDCl3, d): -71.29 (R) and -71.37 (S); R : S
= 1.00 : 4.86, ee%: 65%.
(E,S)-1-Phenylpent-1-en-3-ol 35
Yield: 67%. [a]21.6D -3.6º (c 1.25, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.40-7.39 (d, J = 7.4 Hz, 2H),
7.35-7.31 (t, J = 7.2 Hz, 2H), 7.27-7.24 (t, J = 7.2 Hz, 1H),
6.60-6.56 (d, J = 6.8 Hz, 1H), 6.26-6.20 (dd, J = 15.9, 6.8
Hz, 1H), 4.23-4.18 (m, 1H), 2.50 (br, 1H), 1.73-1.63 (m,
2H), 1.01-0.98 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz,
CDCl3, d): 136.9, 132.5, 130.3, 128.6, 127.6, 126.5, 74.3,
30.3, 9.8. IR (KBr): 3655, 3026, 2964, 2875, 1946, 1876,
1803, 1599, 1493, 1450, 1331, 1130, 1058, 1006, 965, 896,
747, 693, 551 cm–1. HPLC (Daicel Chiralcel OD-H, hex-
ane/i-PrOH = 90 : 10, flow rate 0.25 mL/min), tR of R iso-
mer 7.71 min, tR of S isomer 11.03 min, R : S = 30.69 :
69.31, ee%: 39%.
ACKNOWLEDGEMENTS
The authors thank Ms. L. M. Hsu, at the Instruments
Center, National Chung Hsing University, for her help in
obtaining HRMS, and the National Science Council of the
Republic of China, for financially supporting this research
under contract NSC 97-2113-M-259-002-MY3.
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
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J. Chin. Chem. Soc. 2012, 59, 768-781
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