Asymmetric reduction of substituted indanones and tetralones catalyzed by chiral dendrimer and its application to the synthesis of (+)-sertraline

Article abstract of DOI:10.1016/j.tetasy.2006.07.010

A recoverable dendrimeric supported prolinol was used as a catalyst in the asymmetric reduction of indanones and tetralones to give separable cis and trans isomers up to 97% ee. This method was also applied in the enantioselective synthesis of the antidepressant drug (+)-sertraline.

Full text of DOI:10.1016/j.tetasy.2006.07.010

Tetrahedron: Asymmetry 17 (2006) 2074–2081
Asymmetric reduction of substituted indanones and tetralones
catalyzed by chiral dendrimer and its application to
the synthesis of (+)-sertraline
Guangyin Wang, Changwu Zheng and Gang Zhao*
Laboratory of Modern Organic Synthetic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, PR China
Received 7 June 2006; accepted 11 July 2006
Abstract—A recoverable dendrimeric supported prolinol was used as a catalyst in the asymmetric reduction of indanones and tetralones
to give separable cis and trans isomers up to 97% ee. This method was also applied in the enantioselective synthesis of the antidepressant
drug (+)-sertraline.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
their biological activities.3 There are only a few approaches
to introduce chirality onto the indanone and tetralone ring
systems. Tetralone ring systems are obtained through the
preparation of chiral aryl carboxylic acids either by resolu-
tion or by asymmetric synthesis followed by Friedel–Crafts
cyclization onto an aromatic ring.4 The kinetic resolution
of racemic substrates has also been employed.5
An indane ring framework1 or a tetrahydronaphthalene
core2 is often found in a large number of bioactive and
pharmaceutically interesting substances. Molecules that
contain a substructure of indanones or tetralones possess-
ing stereogenic centers are even more useful as they can
be used as starting materials for the synthesis of biologi-
cally active compounds or drugs, such as etoposide,
SB209670, and sertraline (Fig. 1). These products are of
current interest in the pharmaceutical industry and, there-
fore, their derivatives have been extensively evaluated for
Recently, we have developed a new class of chiral dendri-
mers containing a prolinol core (Fig. 2) and applied them
to the enantioselective reduction of ketones via BH3ÆMe2S.6
OMe
O
OGlu
NHMe
CO2H
O
O
O
O
O
PrO
O
CO2H
O
N
O
O
H
MeO
OMe
Cl
HO
O
O
OH
Cl
Etoposide
SB209670
Sertraline
O
1 (n = 2)
Figure 1. Molecules that contain the indanone or tetralone substructure.
*
Figure 2. Chiral dendrimer containing a prolinol core.
Corresponding author. E-mail: zhaog@mail.sioc.ac.cn
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.010

G. Wang et al. / Tetrahedron: Asymmetry 17 (2006) 2074–2081
2075
In our studies, we found that they are as efficient as the
unsupported parent catalyst in the reactions and among
these different generation dendrimers, the second genera-
tion (n = 2) 1 is an optimization of the availability and
reusability. Herein, we report our work to obtain optically
active substituted indane and tetrahydronaphthalene struc-
tures via asymmetric reduction catalyzed by a chiral
dendrimer, including the enantioselective preparation of
(+)-sertraline, an important antidepressant.
reduction than the 3-substituent. When the indanone had
no substituent, the ee of the product was 94%, which was
as high as the matched reaction (entry 7). Finally, a cyclo-
pentanone substituted by an ester group was subjected to
the reduction and the result was similar to that of above.
An interesting phenomenon was that the c-ester group
was also reduced to an hydroxy group, which was same
as the results for an a-keto ester and b-keto ester.
The relative configuration of the products was determined
1
by 2D H–1H NOESY of 5a–7a and 5b–7b (Fig. 3). The
absolute configuration at the 3-position in the trans isomer
was confirmed by the comparison of the specific rotation of
(S)-2a derived from 3a with the literature value.7 The
results are consistent with a prediction via the mechanism
of the CBS reaction. Although the configurations of the
remaining compounds could not be assigned, in view of
the same reaction mechanism, we assumed their configura-
tions were as described in the Experimental.
2. Results and discussion
Various substituted indanones and tetralones were sub-
jected to the chiral dendrimer catalyzed asymmetric reduc-
tion, which was previously developed by us. When racemic
substrates were employed, the products were two cis and
trans diastereoisomers that could be isolated by column
chromatography. After the derived alcohols were oxidized
to ketones, the optically active indanones or tetralones
were acquired (Scheme 1).
The results of the reductions of the tetralones are shown in
Table 2. Similarly, except for the 2-substituted tetralone, 4-
substituted tetralones were reduced to two cis and trans iso-
mers in almost a 1:1 ratio (entries 1–7). Although the
reduction that produced trans isomer was a mismatched
reaction and the reduction that produced cis isomer was
a matched reaction, which was different with indanone,
the difference in ee between the trans isomer and cis isomer
was small. The 4-substituent was too far from the carbonyl
group to affect the stereoselectivity of the reduction. Simi-
lar to the 2-substituted indanone, 2-substituted tetralones
had a more increased cis/trans ratio, 5.8:1, and difference
in ee (entry 8). When the tetralone had no substituent,
the ee of product was 98%, slightly higher than the substi-
tuted substrates (entry 7). While tetralone was replaced by
substituted cyclohexanone, the reduction that produced the
cis isomer was a matched reaction and the reduction that
produced the trans isomer was a mismatched reaction.
Compared with cyclopentanone, the difference between
their ees was less obvious. The relative and absolute config-
urations of the products were determined by comparison of
1H NMR and specific rotation of 17b and (S)-11f with the
literature.4c,8 The configurations of the other compounds,
in view of the same reaction mechanism, were assumed as
described in the Experimental.
O
OH
OH
+
(CH2)n
1
(CH2)n
R
(CH2)n
BH3·Me2S
R
= 1, 2
R
cis
/
trans 1:1
n
up to 98% ee
up to 95% ee
[O]
[O]
O
O
(CH2)n
R
(CH2)n
R
Scheme 1.
Indanone could be substituted at the 2- and 3-positions
and, therefore, we initially studied the effect of various sub-
stituents at these positions. The results are shown in Table
1. When the substituent at the 3-position was varied from a
small methyl group to either a large tert-butyl or cyclo-
hexyl group (entries 1, 3, 4, and 5), the reaction gave two
cis and trans isomers in almost a 1:1 ratio. The cis isomers
had an ee of about 80%, whereas the trans isomers had an
ee of about 95%. The difference in ee between cis and trans
isomers indicated that the preexistent stereogenic center
had an influence on the reaction. The reduction that pro-
duced the trans isomer was a matched reaction while the
reduction that produced the cis isomer was a mismatched
reaction. When the substituent at the 3-position was an
aromatic group, for example, phenyl (entry 2), the differ-
ence in ee between the cis and trans isomers was almost
the same as for the alkyl substituent. The ratio of the cis
and trans products increased to 1.5:1 when 2-substituted
indanone was reduced (entry 6). However, the difference
of ee was enlarged, with the cis isomers being 31% whereas
trans isomers were 85%. The 2-substituent was closer to the
carbonyl group, and as a result had a greater impact on the
After the reduction was complete, the dendrimer-supported
catalysts were precipitated by adding methanol and then
recovered by filtration. The recovered dendrimers were re-
used after being dried and no loss of catalytic activity was
observed. Tests on the reduction of 11f (Table 3) show that
the chiral dendrimer-supported catalyst can be recycled at
least five times with little or no loss of performance.
Since the reduction of 4-substituted tetralones resulted in
two separable diastereoisomers with high ee’s, the method
could be used for asymmetric synthesis of compounds,
which contained the chiral tetralone structure. (+)-Sertra-
line 23, an antidepressant sold by Pfizer under the trade
name Zoloft, is a competitive inhibitor of synaptosomal
serotonin uptake. It is produced commercially by the reso-
lution of the racemate with D-mandelic acid.2a Even though

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G. Wang et al. / Tetrahedron: Asymmetry 17 (2006) 2074–2081
Table 1. Asymmetric reduction of substituted indanonesa
O
OH
OH
BH3.Me2S
+
1 (5 mol%)
R
R
R
cis-isomer
trans-isomer
Entry
1
Substrate
cis Isomer
trans Isomer
Yield (%)b
ee (%)c
82
Yield (%)b
ee (%)c
95
O
46 (3a)
46 (3b)
Me
O
2a
2b
2
47 (4a)
78
48 (4b)
91
Ph
O
3
4
46 (5a)
45 (6a)
80
80
46 (5b)
46 (6b)
94
96
n
-Bu
2c
2d
O
t
-Bu
O
5
6
7
45 (7a)
53 (8a)
75 (9)
78
31
94
46 (7b)
36 (8b)
—
93
85
—
c
-Hex
2e
2f
O
Me
O
2g
O
8
12 (10a)d
50e
50 (10b)d
87e
CO2Me
2h
a Molar ratio: ketone/BMS/Cat. 1 = 1.0:1.1:0.05.
b After column chromatography.
c Determined by chiral HPLC.
d The product was 1,4-diol.
e Analytical sample was converted to its phenylcarbamate.
a few synthetic routes to the sertraline 23 have been re-
ported,4 a classical resolution method is still the feasible
means of its production. In view of the structural resem-
blance of sertraline 23 to 17b, we decided to synthesize ser-
traline using our developed method (Scheme 2). Pure trans
isomer 17b derived from asymmetric reduction of ( )-11f

G. Wang et al. / Tetrahedron: Asymmetry 17 (2006) 2074–2081
2077
HO
HO
H
H
O
H
NOE
no NOE
PCC
3a
(S)
H
R
R
Me
5a-7a
(S)-2a
5b-7b
Figure 3. NOE of 5a–7a and 5b–7b.
Table 2. Asymmetric reduction of substituted tetralonesa
O
OH
OH
R
BH3·Me2S
+
1 (5 mol%)
R
R
cis-isomer
trans-isomer
Entry
Substrate
cis Isomer
trans Isomer
Yield (%)b
ee (%)c
Yield (%)b
ee (%)c
O
1
46 (12a)
95
45 (12b)
88
Ph
11a
O
2
49 (13a)
97
48 (13b)
94
p
-F-Ph
11b
O
3
— (14)f
97
— (14)f
95
m
-F-Ph
11c
O
4
42 (15a)
95
42 (15b)
95
p
-Cl-Ph
11d
O
5
41 (16a)
96
41 (16b)
94
m
-Cl-Ph
11e
O
6
49 (17a)
97
49 (17b)
94
3,4-di-Cl-Ph
11f

2078
G. Wang et al. / Tetrahedron: Asymmetry 17 (2006) 2074–2081
Table 2 (continued)
Entry
Substrate
cis Isomer
trans Isomer
Yield (%)b
ee (%)c
Yield (%)b
ee (%)c
O
7
8
49 (18a)
94
48 (18b)
91
p
-Me-Ph
O
Me
73 (19a)
18
12 (19b)
98
11h
O
9
93 (20a)
98
—
—
11i
O
51 (21a)d
94e
42 (21b)d
88e
CO2Et
10
11j
a Molar ratio: ketone/BMS/Cat. 1 = 1.0:1.1:0.05.
b After column chromatography.
c Determined by chiral HPLC.
d The product was a 1,4-diol.
e Analytical sample was converted to its phenylcarbamate.
f Two isomers could not be separated.
4. Experimental
Table 3. Recycling of chiral dendrimer 1 for the reduction of 11f
Run (no.)
Yield
(%)a
ee of cis isomer
(%)b
ee of trans isomer
(%)b
4.1. General procedure for the asymmetric reduction of
indanone and tetralone
1
2
3
4
5
98
98
96
98
97
97.0
97.6
96.9
97.5
97.3
94.0
94.6
95.6
95.3
95.9
Cat. 1 (0.05 mmol) was added to a 50 mL three-necked
flask after which were added 8 mL THF and 0.5 mL
BH3ÆMe2S (2.0 M in THF). The solution was heated at
reflux and stirred for 0.5 h. Then a THF (8 mL) solution
of indanone or tetralone (1.0 mmol) was added at a rate
of 10 mL/h by a syringe pump. After the addition was com-
pleted, the mixture was treated with 10 mL methanol and
filtered. The dendrimeric catalyst could be recovered by
more than 95%. The resulting solution was evaporated
and purified by Silica gel chromatography to give the cor-
responding cis (eluted first) and trans products.
a After column chromatography.
b Determined by HPLC using a chiral stationary.
was oxidized to optically active tetralone (S)-11f. Imine 22
was obtained by the reaction of methylamine with (S)-11f
in the presence of TiCl4. Hydrogenation of 22 was cata-
lyzed by Raney-Ni to produce sertraline 23 and its trans
isomer in a 3:1 ratio. The physical and spectroscopic data
of 23 are in agreement with the literature data.5h
4.2. (1R,3S)-3-Butyl-indan-1-ol 5a
28
White solid, mp = 64–65 °C, ½aꢀD ¼ ꢁ56:8 (c 0.75, CHCl3).
1H NMR (CDCl3, 300 MHz): d 7.39–7.36 (m, 1H), 7.27–
7.23 (m, 3H), 5.14 (t, J = 7.0 Hz, 1H), 3.00–2.91 (m, 1H),
2.74–2.65 (m, 1H), 2.12 (s, 1H), 2.00–1.94 (m, 1H), 1.54–
1.36 (m, 6H), 0.93 (t, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 146.6, 145.1, 128.1, 126.8, 123.8,
123.6, 75.2, 43.1, 41.8, 35.2, 29.8, 22.9, 14.1. IR (film) m
3329, 3025, 2956, 2925, 2856, 1607, 1475, 1458, 1330,
1095, 1053 cmꢁ1. EIMS (m/z, abundance): 190 (M+,
3. Conclusions
In summary, the results reported here offer a practical and
highly stereoselective methodology for the synthesis of
optically active indanone and tetralone derivatives. Finally,
we applied this method to the enantioselective synthesis of
the antidepressant drug (+)-sertraline.

G. Wang et al. / Tetrahedron: Asymmetry 17 (2006) 2074–2081
2079
O
OH
OH
1
+
BH3-Me2S
Cl
Cl
Cl
Cl
Cl
Cl
(+)-11f
17a cis- 97% ee
trans
- 94% ee
17b
PCC
O
NHMe
NMe
NH2Me
H2
Raney Ni
Cl
Cl
Cl
Cl
Cl
Cl
23
(S)-11f
22
Scheme 2. Reagents and conditions: (a) BH3ÆMe2S, 1 (5 mol %), THF, reflux; (b) PDC, CH2Cl2, rt; (c) MeNH2, TiCl4, Et2O, ꢁ78 °C; (d) H2, Raney-Ni,
MeOH.
13.61), 133 (100), 115 (26.94), 105 (34.71), 91 (20.85), 77
(21.07). Anal. Calcd for C13H18Ol: C, 82.06; H, 9.53.
Found: C, 81.89; H, 9.45. HPLC: 80% ee, Chiralcel OJ,
20 °C, 254 nm, 90:10 hexane/i-PrOH, 0.75 mL/min;
tR = 7.47 min (1S,3R), tR = 7.97 min (1R,3S).
1098, 1054 cmꢁ1. EIMS (m/z, abundance): 190 (M+,
0.22), 173 (11.50), 133 (21.92), 116 (100), 105 (11.05), 91
(7.88), 77 (11.81), 57 (47.22). HRMS Calcd for C13H18O:
190.1358, Found: 190.1357. HPLC: 80% ee, Chiralcel
AD, 20 °C, 254 nm, 90:10 hexane/i-PrOH, 0.75 mL/min;
tR = 9.80 min (1R,3R), tR = 10.63 min (1S,3S).
4.3. (1R,3R)-3-Butyl-indan-1-ol 5b
4.5. (1R,3S)-3-tert-Butyl-indan-1-ol 6b
29
Colorless oil, ½aꢀD ¼ ꢁ36:5 (c 0.95, CHCl3), 1H NMR
19
Colorless oil, ½aꢀD ¼ ꢁ57:9 (c 0.75, CHCl3). 1H NMR
(CDCl3, 300 MHz): d 7.41–7.38 (m, 1H), 7.31–7.21 (m,
3H), 5.24 (dd, J = 4.2 and 5.5 Hz, 1H), 3.35–3.27 (m,
1H), 2.23–2.15 (m, 1H), 2.11–2.02 (m, 1H), 1.82–1.75 (m,
1H), 1.72 (s, 1H), 1.40–1.32 (m, 5H), 0.92 (t, J = 6.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): d 147.6, 144.7, 128.5,
126.9, 124.4, 124.2, 75.3, 42.7, 42.2, 35.2, 29.9, 22.8, 14.1.
IR (film) m 3324, 3024, 2956, 2925, 2856, 1606, 1477,
1458, 1332, 1054, 1022 cmꢁ1. EIMS (m/z, abundance):
190 (M+, 9.78), 173 (17.04), 133 (100), 115 (40.91), 105
(34.59), 91 (19.11), 77 (18.46). Anal. Calcd for C13H18Ol:
C, 82.06; H, 9.53. Found: C, 82.01; H, 9.42. HPLC: 94%
ee, Chiralcel OJ, 20 °C, 254 nm, 90:10 hexane/i-PrOH,
0.75 mL/min; tR = 7.39 min (1S,3S), tR = 8.73 min
(1R,3R).
(CDCl3, 300 MHz): d 7.40–7.38 (m, 1H), 7.31–7.23 (m,
3H), 5.29 (t, J = 6.6 Hz, 1H), 3.08 (dd, J = 1.5 and
8.7 Hz, 1H), 2.56–2.48 (m, 1H), 1.97–1.87 (m, 1H), 1.76
(br, 1H), 0.92 (s, 9H). 13C NMR (100 Hz, CDCl3): d
146.4, 144.30, 127.47, 127.08, 126.78, 123.85, 75.73,
53.94, 40.12, 34.36, 27.94. IR (film) m 3239, 2976, 2952,
2881, 1477, 1460, 1365, 1060 cmꢁ1. EIMS (m/z, abun-
dance): 190 (M+, 2.51), 173 (9.05), 133 (68.22), 116
(65.69), 105 (23.69), 91 (14.80), 77 (20.85), 57 (100). HRMS
Calcd for C13H18O: 190.1358, Found: 190.1365. HPLC:
96% ee, Chiralcel AD, 20 °C, 254 nm, 90:10 hexane/
i-PrOH, 0.75 mL/min; tR = 10.59 min (1S,3R), tR =
11.93 min (1R,3S).
4.4. (1R,3R)-3-tert-Butyl-indan-1-ol 6a
4.6. (1R,3R)-3-Cyclohexyl-indan-1-ol 7a
19
23
Colorless oil, ½aꢀD ¼ ꢁ59:1 (c 0.90, CHCl3). 1H NMR
Colorless oil, ½aꢀD ¼ ꢁ31:9 (c 0.80, CHCl3). 1H NMR
(CDCl3, 300 MHz): d 7.45–7.39 (m, 2H), 7.24–7.23 (m,
2H), 5.06 (t, J = 6.6 Hz, 1H), 2.94 (t, J = 7.8 Hz, 1H),
2.60–2.51 (m, 1H), 1.94 (br, 1H), 1.76–1.67 (m, 1H), 1.04
(s, 9H). 13C NMR (100 MHz, CDCl3): d 146.1, 144.4,
127.7, 126.8, 126.0, 124.3, 74.3, 53.1, 38.8, 33.3, 28.3. IR
(film) m 3336, 3069, 3037, 2962, 2867, 1606, 1475, 1366,
(CDCl3, 300 MHz): d 7.40–7.38 (m, 1H), 7.30–7.22 (m,
3H), 5.13 (dd, J = 6.3 and 12.7 Hz, 1H), 3.01 (dd, J = 7.8
and 12.5 Hz, 1H), 2.55–2.45 (m, 1H), 1.94–1.66 (m, 6H),
1.45 (d, J = 13.5 Hz, 1H), 1.34–1.11 (m, 6H). 13C NMR
(100 MHz, CDCl3): d 145.5, 145.0, 127.9, 126.8, 124.3,
124.0, 75.2, 47.7, 40.5, 37.9, 32.1, 27.9, 26.9, 26.6, 26.5.

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G. Wang et al. / Tetrahedron: Asymmetry 17 (2006) 2074–2081
IR (film) m 3322, 3024, 2924, 2850, 1601, 1476, 1448, 1329,
1095, 1056 cmꢁ1. EIMS (m/z, abundance): 216 (M+, 1.38),
198 (7.38), 133 (34.34), 116 (100), 105 (9.01), 91 (7.57), 77
(7.88), 55 (17.32). HRMS Calcd for C15H20O: 216.1514,
Found: 216.1519. HPLC: 78% ee, Chiralcel AD, 20 °C,
254 nm, 90:10 hexane/i-PrOH, 0.75 mL/min; tR =
10.75 min (1S,3S), tR = 11.70 min (1R,3R).
4.10. (1R,4R)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetra-
hydronaphthalen-1-ol 17a
24
Colorless oil, ½aꢀD ¼ ꢁ52:5 (c 1.14, CHCl3). 1H NMR
(CDCl3, 300 MHz): d 7.45 (d, J = 7.5 Hz, 1H), 7.34 (d,
J = 5.4 Hz, 1H), 7.26–7.15 (m, 3H), 6.99–6.96 (m, 1H),
6.83 (d, J = 7.5 Hz, 1H), 4.83 (t, J = 4.2 Hz, 1H), 3.98 (t,
J = 7.8 Hz, 1H), 2.29 (br, 1H), 2.10–1.96 (m, 4H). IR (film)
m 3356, 2939, 2867, 1557, 1488, 1467, 1396, 1264, 1030,
739 cmꢁ1. HPLC: 97% ee, Daicel Chiralcel AD column,
20 °C, k = 254 nm, hexane/i-PrOH = 90:10, flow = 0.75
mL/min; tR = 10.04 min (1S,4S), tR = 10.09 min (1R,4R).
4.7. (1R,3S)-3-Cyclohexyl-indan-1-ol 7b
23
White solid, mp = 54–56 °C, ½aꢀD ¼ ꢁ35:9 (c 0.80, CHCl3).
1H NMR (CDCl3, 300 MHz): d 7.40–7.37 (m, 1H), 7.28–
7.20 (m, 3H), 5.25 (t, J = 6.3 Hz, 1H), 3.27–3.21 (m, 1H),
2.40–2.32 (m, 1H), 1.99–1.60 (m, 1H), 1.77–1.57 (m, 6H),
1.42 (d, J = 14.4 Hz, 1H), 1.26–0.88 (m, 5H). 13C NMR
(100 MHz, CDCl3): d 145.6, 145.5, 128.1, 126.9, 125.0,
124.1, 75.8, 48.4, 41.9, 39.1, 31.6, 28.7, 26.7, 26.5, 26.5.
4.11. (1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetra-
hydronaphthalen-1-ol 17b8
24
25
Colorless oil, ½aꢀD ¼ þ1:6 (c 1.00, CHCl3) {lit.8 ½aꢀD ¼ 5:0
1
IR (film)
m
3211, 2923, 2850, 1474, 1449, 1098,
(c 0.5, CHCl3)}. H NMR (CDCl3, 300 MHz): d 7.55 (d,
1061 cmꢁ1. EIMS (m/z, abundance): 216 (M+, 5.09), 198
(10.97), 133 (100), 116 (44.97), 105 (16.75), 91 (35.66), 77
(72.11), 55 (46.06). HRMS Calcd for C15H20O: 216.1514,
Found: 216.1521. HPLC: 93% ee, Chiralcel AD, 14 °C,
254 nm, 90:10 hexane/i-PrOH, 0.75 mL/min; tR = 11.03
min (1S, 3R), tR = 112.34 min (1R,3S).
J = 7.5 Hz, 1H), 7.34–7.44 (m, 4H), 6.87–6.82 (m, 2H),
4.86 (t, J = 5.1 Hz, 1H), 4.13 (t, J = 6.3 Hz, 1H), 2.38–
2.30 (m, 1H), 2.14–2.06 (m, 1H), 1.97 (br, 1H), 1.82–1.73
(m, 2H). IR (film) m 3361, 3059, 2939, 2862, 1557, 1468,
1265, 1131, 1030, 738 cmꢁ1. HPLC: 94% ee, Daicel Chiral-
cel OJ column, 20 °C, k = 254 nm, hexane/i-PrOH = 90:10,
flow = 1.0 mL/min; tR = 10.68 min (1R,4S), tR = 11.88 min
(1S,4R).
4.8. (1R,4S)-4-(2-Chlorophenyl)-1,2,3,4-tetrahydronaphtha-
len-1-ol 16a
4.12. (S)-4-(3,4-Dichlorophenyl)-3,4-dihydronaphthalen-
1(2H)-one 11f4c
24
Colorless oil, ½aꢀD ¼ ꢁ43:4 (c 0.92, CHCl3). 1H NMR
(CDCl3, 300 MHz): d 7.47 (d, J = 7.5 Hz, 1H), 7.40–7.37
(m, 1H), 7.26–7.12 (m, 3H), 6.94–6.91 (m, 1H), 6.82 (d,
J = 7.5 Hz, 1H), 4.86 (t, J = 5.1 Hz, 1H), 4.14 (t,
J = 6.6 Hz, 1H), 2.17–1.96 (m, 5H). 13C NMR (CDCl3,
100 MHz): d 143.9, 139.3, 138.9, 134.0, 130.8, 129.7,
129.5, 128.8, 128.1, 127.5, 126.9, 126.8, 68.2, 41.9, 30.0,
26.1. IR (film) m 3347, 3061, 3021, 2936, 2863, 1569,
1472, 1437, 1079, 1035 cmꢁ1. EI-MS (m/z, abundance):
258 (11.25, M+), 240 (100), 205 (76.13), 178 (29.10), 165
(23.18), 120 (95.65), 101 (53.99), 89 (34.64). HRMS Calcd
for C16H14OCl (MꢁH+): 257.0733, Found: 257.0734.
HPLC: 96% ee, Daicel Chiralcel OJ column, 20 °C,
k = 254 nm, hexane/i-PrOH = 90:10, flow = 0.75 mL/min;
tR = 10.34 min (1R,4S), tR = 11.01 min (1S,4R).
Compound 17b (600 mg, 2.06 mmol) was dissolved in
5.0 mL dichloromethane and cooled to 0 °C in an ice-water
bath. PCC (1.2 g) was added to the solution and stirred
overnight at room temperature. Celite and ether were
added with complete stirring. The mixture was filtrated
and the filtrate concentrated. The residue was purified by
silica gel chromatography to give a white solid (S)-11f in
24
23
98% yield. ½aꢀD ¼ þ65:8 (c 1.20, benzene) {lit.4c ½aꢀD
¼
1
þ71:3 (c 1.1, benzene)}. H NMR (CDCl3, 300 MHz): d
8.12 (d, J = 7.8 Hz, 1H), 7.49–7.36 (m, 3H), 7.26–7.22
(m, 1H), 6.96–6.94 (m, 2H), 4.28 (dd, J = 4.5 and 7.8 Hz,
1H), 2.76–2.57 (m, 2H), 2.51–2.48 (m, 1H), 2.31–2.21 (m,
1H). IR (film) m 2941, 2859, 1686, 1596, 1468, 1284,
1030 cmꢁ1. HPLC: 97% ee, Daicel Chiralcel OD column,
20 °C, k = 254 nm, hexane/i-PrOH = 90:10, flow =
1.0 mL/min; tR = 10.68 min (S), tR = 11.92 min (4R).
4.9. (1R,4R)-4-(2-Chlorophenyl)-1,2,3,4-tetrahydronaphtha-
len-1-ol 16b
24
Colorless oil, ½aꢀD ¼ ꢁ24:7 (c 0.92, CHCl3). 1H NMR
4.13. (S)-N-(4-(3,4-Dichlorophenyl)-3,4-dihydronaphthalen-
1(2H)-ylidene)methanamine 225h
(CDCl3, 300 MHz): d 7.54 (d, J = 8.1 Hz, 1H), 7.40–7.05
(m, 5H), 6.85 (d, J = 8.1 Hz, 1H), 6.68–6.65 (m, 1H),
4.89 (m, 1H), 4.69 (t, J = 6.3 Hz, 1H), 2.40–2.28 (m, 1H),
2.15–2.01 (m, 1H), 1.92–1.75 (m, 3H). 13C NMR (CDCl3,
100 MHz): d 143.7, 140.0, 138.5, 133.9, 130.6, 129.9,
129.6, 128.2, 127.9, 127.5, 126.9, 126.7, 68.3, 41.6, 29.9,
26.3. IR (film) m 3413, 3061, 3021, 2931, 2862, 1604,
1569, 1473, 1265, 1080 cmꢁ1. EI-MS (m/z, abundance):
258 (6.59, M+), 240 (100), 205 (57.06), 178 (23.80), 165
(18.54), 120 (79.17), 101 (41.80), 89 (23.92). HRMS Calcd
for C16H14OCl (MꢁH+): 257.0733, Found: 257.0731.
HPLC: 94% ee, Daicel Chiralcel OJ column, 20 °C,
k = 254 nm, hexane/i-PrOH = 90:10, flow = 0.75 mL/min;
tR = 11.47 min (1S,4S), tR = 12.06 min (1R,4R).
Compound (S)-11f (0.54 g, 1.85 mmol) was placed in a dry
Schlenk flask under argon. Anhydrous ether (5 mL) was
added, and the reaction flask cooled to ꢁ78 °C. Condensed
methylamine (1.0 mL, 34 mmol) was introduced via can-
nula, followed by the addition of TiCl4 (0.30 mL). The
reaction mixture was allowed to warm to room tempera-
ture slowly and stirred overnight. The reaction mixture
was filtered through a pad of Celite and washed with ether.
The combined filtrates were concentrated to give a white
solid that could be used without purification in 93% yield:
24
½aꢀD ¼ þ91:9 (c 1.05, CHCl3). 1H NMR (CDCl3,
300 MHz): d 8.22–8.18 (m, 1H), 7.36–7.19 (m, 4H), 6.91–

G. Wang et al. / Tetrahedron: Asymmetry 17 (2006) 2074–2081
2081
2. (a) Williams, M.; Quallich, G. Chem. Ind. 1990, 315; (b)
Kamal, A.; Gayatri, N. L. Tetrahedron Lett. 1996, 37,
3359.
6.88 (m, 2H), 4.16 (dd, J = 4.2 and 6.7 Hz, 1H), 3.32 (s,
3H), 2.60–2.46 (m, 2H), 2.34–2.23 (m, 1H), 2.18–2.07 (m,
1H). IR (film) m 3059, 2926, 2852, 1688, 1633, 1595, 1470,
1284 cmꢁ1
.
3. (a) Welch, W. M.; Kraska, A. R.; Sarges, R.; Coe, K. B. J.
Med. Chem. 1984, 27, 1508; (b) Lowe, J. A.; Hageman, D. L.;
Drozda, S. E.; McLean, S.; Bryce, D. K.; Crawford, R. T.;
Zorn, S.; Morrone, J.; Bordner, J. J. Med. Chem. 1994, 37,
3789; (c) Miyano, S.; Tatsuoka, T.; Suzuki, K.; Imao, K.;
Satoh, F.; Ishihara, T.; Hirotsu, I.; Kihara, T.; Hatta, M.;
Horikawa, Y.; Sumoto, K. Chem. Pharm. Bull. 1990, 38, 1570.
4. (a) Poras, H.; Stephan, E.; Pourcelot, G.; Cresson, P. Chem.
Ind. 1993, 206; (b) Quallich, G. J.; Woodall, T. M. Tetrahedron
1992, 48, 10239; (c) Corey, E. J.; Gant, T. G. Tetrahedron Lett.
1994, 35, 5373; (d) Davies, H. M. L.; Stafford, D. G.; Hansen,
T. Org. Lett. 1999, 1, 233; (e) Lautens, M.; Rovis, T. J. Org.
Chem. 1997, 62, 5246; (f) Chen, C. Y.; Reamer, R. A. Org.
Lett. 1999, 1, 293; (g) Cho, B. T.; Choi, O. K. Tetrahedron:
Asymmetry 2001, 12, 903; (h) Schmalz, H.; Jope, H. Tetrahe-
dron 1998, 54, 3457; (i) Quallich, G. J. Chirality 2005, 17,
S120.
5. (a) Adam, W.; Diaz, M. T.; Fell, R. T.; Saha-Moller, C. R.
Tetrahedron: Asymmetry 1996, 7, 2207; (b) Kajiro, H.;
Mitamura, S.; Mori, A.; Hiyama, T. Tetrahedron: Asymmetry
1998, 9, 907; (c) Genet, J. P.; Pfister, X.; Ratovelomanana-
Vidal, V.; Pinel, C.; Laffitte, J. A. Tetrahedron Lett. 1994, 35,
4559; (d) Kabuto, K.; Ziffer, H. J. Org. Chem. 1975, 40, 3467;
(e) Schmalz, H.-G.; Jope, H. Tetrahedron 1998, 54, 3457; (f)
Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T. Chem.
Lett. 1996, 1081; (g) Begue, J.-P.; Cerceau, C.; Dogbeavou, A.;
Mathe, L.; Sicsic, S. J. Chem. Soc., Perkin Trans. 1 1992,
3141; (h) Yun, J.; Buchwald, S. L. J. Org. Chem. 2000, 65,
767.
4.14. (+)-Sertraline 235h
Imine 22 (109 mg, 0.35 mmol) was dissolved in methanol
and hydrogenated over Raney-Ni. When the imine dis-
appeared (detected by TLC), the catalyst was filtered, and
the methanol was evaporated. The residue was purified
by silica gel chromatography to give (+)-sertraline 23 as
26
a yellow oil in 98% yield: ½aꢀD ¼ þ36:5 (c 1.00, MeOH)
25
{lit.8 ½aꢀD ¼ 39:7 (c 0.3, MeOH)}. 1H NMR (CDCl3,
300 MHz): d 7.45 (d, J = 7.7 Hz, 1H), 7.33–7.10 (m, 4H),
6.86–6.81 (m, 2H), 4.13 (t, J = 5.4 Hz, 1H), 3.78 (t,
J = 5.0 Hz, 1H), 2.52 (s, 3H), 2.40–2.31 (m, 1H), 2.00–
1.91 (m, 1H), 1.80–1.69 (m, 2H), 1.49 (br, 1H). IR (film)
m 3024, 3060, 2935, 2857, 2790, 1469, 1394, 1130,
1029 cmꢁ1
.
Acknowledgements
We are grateful to the National Natural Science Founda-
tion of China for financial support (Nos. 20525208,
203900502, 20532040). We are also grateful to the QT pro-
gram and Shanghai Natural Science Council.
6. (a) Liu, X. Y.; Wu, X. Y.; Chai, Z.; Zhao, G. J. Org. Chem.
2005, 70, 7432; (b) Wang, G. Y.; Liu, X. Y.; Zhao, G. Synlett
2006, 1150.
References
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1. Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.;
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