Asymmetric syntheses of trans-3,4-disubstituted 2-piperidinones and piperidines

Article abstract of DOI:10.1016/S0957-4166(01)00069-6

A convenient and practical method for the preparation of chiral 4-aryl-2-piperidinone from 3-arylglutaric anhydride and (S)-methylbenzylamine is described. Acylation or alkylation at the α-carbon of the chiral 4-aryl-2-piperidinone product afforded chiral trans-3,4-disubstituted 2-piperidinone derivatives and reduction of the chiral 2-piperidinones with lithium aluminum hydride provided the corresponding enantiomerically pure trans-3,4-disubstituted piperidines. This methodology has been successfully applied to the synthesis of the anti-depressant paroxetine.

Full text of DOI:10.1016/S0957-4166(01)00069-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 419–426
Asymmetric syntheses of trans-3,4-disubstituted 2-piperidinones
and piperidines
Lee Tai Liu,a,* Pao-Chiung Hong,a Hsiang-Ling Huang,a Shyh-Fong Chen,a Chia-Lin Jeff Wanga
and Yuh-Sheng Wenb
aDevelopment Center for Biotechnology, 102, Lane 169, Kang-Ning St., Hsi-Chih 221, Taipei, Taiwan, ROC
bInstitute of Chemistry, Academia Sinica, Nan-Kang, Taipei, Taiwan, ROC
Received 21 December 2000; accepted 6 February 2001
Abstract—A convenient and practical method for the preparation of chiral 4-aryl-2-piperidinone from 3-arylglutaric anhydride
and (S)-methylbenzylamine is described. Acylation or alkylation at the a-carbon of the chiral 4-aryl-2-piperidinone product
afforded chiral trans-3,4-disubstituted 2-piperidinone derivatives and reduction of the chiral 2-piperidinones with lithium
aluminum hydride provided the corresponding enantiomerically pure trans-3,4-disubstituted piperidines. This methodology has
been successfully applied to the synthesis of the anti-depressant paroxetine. © 2001 Elsevier Science Ltd. All rights reserved.
diastereomeric salts,3a–d,4 the biocatalytic kinetic resolu-
1. Introduction
tion of racemic or prochiral esters,3e–f and a chiral
auxiliary assisted asymmetric Michael addition3g,h,5
Chiral piperidine derivatives constitute many natural
products and pharmacologically active compounds.1,2
For example, as a trans-3,4-disubstituted piperidine
derivative, paroxetine is a potent selective serotonin
(5-hydroxytryptamine) re-uptake inhibitor and has been
widely used as an anti-depressant and anti-Parkinson
agent.2,3 Chiral 2-piperidinones have been generally
regarded as the precursors of the corresponding pipe-
ridines and d-amino acids.
have been reported. However, some racemic trans-3,4-
piperidine derivatives could not be easily resolved
because their diastereomeric salts did not form good
enough crystals to be selectively crystallised,4 and
although enzymatic processes gave enantiomerically
pure 3-substituted piperidine derivatives, the requisite
use of chromatography for purification reduces the
viability of large-scale processes.6
Recently, the asymmetric synthesis of specific chiral 3-
or 4-substituted and 3,4-disubstituted 2-piperidinones
has been published in the literature.3g,h,5 These method-
ologies include the chiral auxiliary assisted Michael
addition and the transformation of natural products.
However, the synthetic methods available for the
Several procedures have been used for the preparation
of these chiral trans-3,4-disubstituted piperidines and
their precursors. Physical and enzymatically assisted
kinetic resolution are still the most common methods
employed. For the preparation of homochiral parox-
etine, methods such as the selective recrystallisation of
* Corresponding author. Fax: 886-2-26953404; e-mail: ltliu@mail.dcb.org.tw
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00069-6

420
L. T. Liu et al. / Tetrahedron: Asymmetry 12 (2001) 419–426
Scheme 1.
preparation of chiral 3,4-disubstituted 2-piperidinones
and piperidines are still limited. Therefore, we decided
to develop a convenient method for the preparation of
chiral 2-piperidinones and their corresponding pipe-
ridine derivatives.
2. Results and discussion
The synthetic procedure is shown in Scheme 2. Diacid
5a was prepared from 4-fluorocinnamic acid methyl
ester 2 in three steps (Michael addition to ester 2,
hydrolysis of triester 3, and decarboxylation of acid
4).7,8 The prochiral 3-substituted glutaric anhydrides
6a–6c were then obtained by dehydration of the com-
mercially available diacids 5a–5c in acetyl chloride.9
The anhydrides 6a and 6b were purified by recrystallisa-
tion and 6c was purified by distillation.
Herein, we report a chiral auxiliary assisted diastereose-
lective synthesis of chiral 4-substituted and trans-3,4-
disubstituted 2-piperidinones from 3-substituted
glutaric anhydrides and (S)-methylbenzylamine. As
shown in Scheme 1, this new method can be used for
the synthesis of chiral 4-aryl-2-piperidinones, trans-3,4-
disubstituted 2-piperidinones and piperidines. The
methodology developed was subsequently applied to
the synthesis of homochiral paroxetine.
Desymmetrisation of meso-3-substituted glutaric anhyd-
rides 6a–6c with (S)-methylbenzylamine (99% e.e.)
was effected in toluene at −78°C (Scheme 2 and Table
Scheme 2. Reagents and conditions: (a) sodium methoxide, dimethyl malonate, methanol, reflux, 20 h, 70%; (b) 1N sodium
hydroxide, reflux, 20 h; (c) concentrated hydrochloric acid, reflux, 20 h, 70% (two steps); (d) acetyl chloride, reflux, 20 h, 90%;
(e) (S)-methylbenzylamine, triethylamine, toluene, −78°C, 10 h, room temperature 10 h, 70%; (f) triethylamine, isobutyl
chloroformate, tetrahydrofuran, −78 to 0°C, 20 h; then, sodium borohydride, water, 0–25°C, 20 h, 86%; (g) phosphorus
tribromide, concentrated hydrobromic acid, 0–25°C, 4 days, 70%; (h) sodium hydride, tetrahydrofuran, refluxed, 20 h, 85%.
Table 1. Yields and diastereoselectivities in the reactions of 6a–6c with (S)-methylbenzylamine
Entry
Anhydrides
Major product
Yield (%)
Diastereoselectivity (de%)
1
2
3
6a
6b
6c
7a
7c
7e
70a
67a
76a
95a
94a
\99a,b
a The first crop of the recrystallised product.
b The crude product.

L. T. Liu et al. / Tetrahedron: Asymmetry 12 (2001) 419–426
421
Figure 1. X-Ray crystal structures of compounds 11a (left) and 11b (right). Only hydrogens on the stereogenic carbon centres are
displayed.
1) according to the procedure described by Kara-
newsky.10 In the amidation of 3-arylglutaric anhydrides
6a–6b, mixtures of hemiamides 7a (or 7c) and 7b (or 7d)
were obtained in 98% yield. The major product was
assigned as the hemiamides 7a and 7c according to a sim-
ilar compound in the literature,10 and the absolute
configuration was later identified by X-ray crystallogra-
phy of compounds 11a–11b (Fig. 1). The proton NMR
spectrum showed that the ratio of the two diastereo-
mers 7a and 7b in the crude product was about 4.5–5.5:1
(60–70% d.e., measured by relative integration of the
methyl doublet). We found that selectivity was not
improved even if 2 equivalents of (S)-methylbenzyl-
amine was used, but the ratio of 7a:7b was lowered to 2:1
if excess triethylamine (based on (S)-methylbenzyl-
amine) was added. The diastereoselectivity of the crude
7c was slightly lower, with a d.e. of 50–55%. The
diastereomeric purity of the major products 7a and 7c
was enhanced to a d.e. of 94–95% (67–70% yield) by one
recrystallisation. The second and third crops which con-
tained mixtures of diastereomers (e.g. 7a and 7b, 28%
yield) were treated with concentrated hydrochloric acid,
and the corresponding starting diacids 5a and 5b were
recovered.
bromide and hydrobromic acid then gave bromide 9 in
moderate yield. Treatment of 9 with sodium hydride sus-
pended in refluxing tetrahydrofuran afforded chiral
2-piperidinone 10 in 85% yield after recrystal-
lisation. The proton NMR spectrum showed that the
recrystallised 2-piperidinone 10 was diastereomerically
pure with a d.e. of >99%.
Alkylation or acylation at the a-carbon of 2-piperidinone
10 was effected by treatment with an excess of lithium
diisopropylamide and 1.4–1.5 equivalents of methyl chlo-
roformate or benzyl bromide. trans-3,4-Disubstituted 2-
piperidinones 11a–11c were obtained in good to
moderate yields with excellent diastereoselectivity
1
(Scheme 3). X-Ray crystallography and the H NMR
spectra of 11a–11b (Fig. 1) showed that only the trans-
diastereomer was obtained in each case. However, reac-
tions with halides such as 4-substituted benzyl halides,
methyl iodide and other alkyl iodides were unsatisfac-
tory. For example, the yield was low if 4-chlorobenzyl
bromide was used as an electrophile. Mixtures of 3-
methyl and 3,3-dimethyl substituted 2-piperidinones
11e–11g were obtained if 1.4 equivalents of methyl iodide
was used, whilst only 3,3-dimethyl-2-piperidone 11g was
obtained if 2.4 equivalents of methyl iodide was added.
Amidation of 3-methylglutaric anhydride 6c was much
more selective under the same reaction conditions. No
diastereomer 7f was detected in the proton NMR spec-
trum of the crude product, and the hemiamide 7e was
obtained as the sole product with >99% d.e. in 76% yield
after a single recrystallisation.
These homochiral trans-3,4-disubstituted 2-piperidi-
nones 11 can be used as the precursors for the prepara-
tion of the corresponding chiral 3,4-disubstituted
piperidines and d-amino acids. The synthesis of chiral
paroxetine, a 3,4-disubstituted piperidine derivative,
exemplified the study (Scheme 4). Reduction of 2-pipe-
ridinone 11a with lithium aluminum hydride provided 3-
hydroxymethyl piperidine 12. Protection of the hydroxyl
group of compound 12, followed by transformation of
the resulting methanesulfonate 13 with sesamol and
The carboxyl group of hemiamide 7a was converted to
the primary alcohol 8 in satisfactory yield by reduction of
the corresponding mixed anhydride with sodium borohy-
dride.11 Bromination of alcohol 8 with phosphorus tri-

422
L. T. Liu et al. / Tetrahedron: Asymmetry 12 (2001) 419–426
Scheme 3.
Scheme 4. Reagents and conditions: (a) lithium aluminum hydride, tetrahydrofuran, reflux, 72 h, 65%; (b) methanesulfonyl
chloride, dichloromethane, rt, 20 h; (c) (i) sesamol, sodium, propanol, reflux, 36 h; (ii) hydrochloric acid, 64%; (d) H2, Pd–C,
methanol, 68%.
sodium propoxide, provided aryl ether 14a as an oily
product. Ether 14a was treated with hydrochloric acid,
and hydrochloride salt 14b was purified by recrystallisa-
tion. Hydrogenolysis removed the chiral auxiliary in
ether 14b to provide paroxetine hydrochloride salt 15 as
an oily form. Although the recrystallised hydrochloride
salt could be obtained from methanol and ether in 68%
yield, some of the salt remained in the mother liquor.
the preparation of the corresponding chiral piperidines
and d-amino acids. For example, reduction of 2-pipe-
ridinone 11a with lithium aluminum hydride provided
chiral piperidine 12. This methodology has been suc-
cessfully applied to the synthesis of the anti-depressant
paroxetine, which was obtained in high enantiomeric
purity using this methodology.
1
The recrystallised compound 15 had identical H NMR
spectrum and specific rotation value ([h]2D5 −88.6 (c 1.0,
CH3OH)) to an authentic sample of paroxetine
extracted from commercial Seroxat® ([h]D22 −89.4 (c 1.6,
CH3OH)). It is notable that the specific rotation value
of paroxetine 15 obtained in this procedure is higher
than that of Amat’s compound ([h]2D2 +81.7 (c 1.3,
CH3OH)).5a,b
4. Experimental
4.1. General
All reactions were carried out under nitrogen unless
otherwise stated. Tetrahydrofuran was dried by distilla-
tion from potassium benzophenone ketyl under a nitro-
gen atmosphere before use. Thin layer chromatography
was performed on 0.2 mm aluminum sheets precoated
with silica gel 60. Visualisation was achieved with UV
light, 5% ninhydrin or 5% vanillin ethanolic solution.
Flash chromatography was carried out using 0.040–
0.063 mm (230–400 mesh) silica gel 60. The specific
rotation values were measured at the sodium D-line
(589 nm) and reported as [h]2D5 (c g/100 mL, solvent).
Chemical shifts of proton and carbon-13 NMR spectra
were reported in ppm relative to Si(CH3)4. Coupling
constants are reported in Hz.
3. Conclusion
We have developed a convenient and practical four-step
method for the preparation of diastereomerically pure
4-aryl-2-piperidinones 10 from 3-arylglutaric anhydride
6 and (S)-methylbenzylamine. Acylation or alkylation
of 10 provided chiral trans-3,4-disubstituted 2-piperid-
inones 11a–11c in good yield and excellent diastereo-
selectivity. These chiral trans-3,4-disubstituted 2-piperi-
dinone derivatives can then be used as precursors for

L. T. Liu et al. / Tetrahedron: Asymmetry 12 (2001) 419–426
423
4.2. Dimethyl 3-(4-fluorophenyl)-2-methoxycarbonylpen-
tanedioate 3
1H), 2.83 (dd, J=11.1, 17.0 Hz, 1H). Anal. calcd for
C11H9FO3: C, 63.46; H, 4.36. Found: C, 63.37; H, 4.34%.
To a suspension of 4-fluorocinnamic acid 1 (25 g, 0.15
mol) in methanol (300 mL) at room temperature was
added dropwise thionyl chloride (40 mL, 0.55 mol). The
brown solution was stirred at room temperature for 18 h,
and then evaporated to dryness. The crude compound
was diluted with ethyl acetate, washed with saturated
sodium hydrocarbonate and brine, and dried over mag-
nesium sulfate. The viscous mass was distilled in vacuo
to give the pure ester 2 (27 g, 99%).
4.5. (3S,1%S)-3-(4-Fluorophenyl)-5-oxo-5-(1%-phenylethyl-
amino)pentanoic acid 7a
To a solution of (S)-methylbenzylamine (99% e.e., Acros
or Aldrich 5.25 mL, 40.72 mmol) in toluene (200 mL) at
−78°C was added dropwise a solution of anhydride 6a
(5.0 g, 24.02 mmol) in toluene (100 mL). Triethylamine
(3.5 mL, 25.11 mmol) was then added dropwise. The
mixture was stirred and allowed to warm to room tem-
perature overnight. After evaporation of toluene, the
mixture was stirred with a solution of 1N hydrochloric
acid (50 mL), and then extracted with hot ethyl acetate.
The organic extracts were combined, washed with brine,
dried over magnesium sulfate and evaporated to dryness.
The crude product was recrystallised to furnish the title
compound as a colourless solid in the first crop (5.50 g,
70% yield, 95% d.e.): mp 195.0–195.5°C; [h]2D5 −78.8 (c
To a solution of sodium (4.60 g, 0.20 mol) in methanol
(100 mL) in an ice bath was added dropwise dimethyl
malonate (27.0 g, 0.20 mol) in methanol (30 mL). After
stirring for 20–30 min, a solution of ester 2 (27.0 g, 0.15
mol) in methanol (30 mL) was added dropwise into the
solution at room temperature. The mixture was gently
refluxed overnight, and then concentrated to dryness.
The viscous mass was diluted with ethyl acetate and
washed with a 1N hydrochloric acid solution. The
aqueous solution was back extracted several times with
ethyl acetate. The organic layer was combined, washed
with brine solution, dried over magnesium sulfate and
concentrated to afford the crude product 3 which was
used directly for the next step or recrystallised from ethyl
acetate and hexanes to afford a white solid (31.5 g, 67%):
mp 77.5–78.0°C; 1H NMR (200 MHz, CDCl3) l 7.25 (m,
2H), 6.97 (t, J=8.6 Hz, 2H), 3.93 (td, J=5.0, 9.7 Hz,
1H), 3.74 (d, J=9.9 Hz, 1H), 3.75 (s, 3H), 3.54 (s, 3H),
3.50 (s, 3H), 2.86 (dd, J=4.9, 15.7 Hz, 1H), 2.72 (dd, J=
9.4, 15.7 Hz, 1H).
1
1.0, CH3OH); H NMR (200 MHz, CDCl3) l 7.30–7.00
(m, 7H), 6.95 (t, J=8.7 Hz, 2H), 5.60 (m, 1H), 4.94
(quint, J=6.9 Hz, 1H), 3.58 (m, 1H), 2.75–2.25 (m, 4H),
1.26 (d, J=6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3/
CD3OD) l 176.8, 173.6, 164.3, 145.8, 140.8, 131.6, 131.0,
129.7, 128.6, 117.8, 51.1, 45.3, 43.0, 41.1, 23.9. Anal.
calcd for C19H20FNO3: C, 69.29; H, 6.12; N, 4.25.
Found: C, 69.07; H, 6.09; N, 3.83. The second and third
crops were treated with concentrated hydrochloric acid
to recover diacid 5a (2.25 g, 28%).
4.6. (3S,1%S)-5-Oxo-3-phenyl-5-(1%-phenylethyl-
amino)pentanoic acid 7c
4.3. 3-(4-Fluorophenyl)pentanedioic acid 5a
Synthesised according to the procedure for 7a, 67%
yield, 94% d.e., colourless solid: mp 181.0–181.2°C; [h]D25
−81.2 (c 1.0, CH3OH); H NMR (500 MHz, CDCl3) l
A suspension of triester 3 (31.5 g, 0.10 mol) in 2N
aqueous sodium hydroxide (80 mL) was gently refluxed
overnight. The solution was cooled to room temperature
and acidified with concentrated hydrochloric acid to pH
0–1, and then refluxed overnight to effect complete
decarboxylation. The aqueous solution was distilled to
remove most of the water, then extracted with ethyl ace-
tate. After drying over magnesium sulfate and evaporat-
ing the solvent, the crude product was recrystallised from
ethyl acetate and hexanes to afford diacid 5a (15.5 g,
68%): mp 146.0–146.5°C; 1H NMR (200 MHz, CDCl3) l
7.23 (m, 2H), 6.96 (t, J=8.6 Hz, 2H), 5.47 (bs, 1H), 3.62
(m, 1H), 2.72 (dd, J=6.8, 15.6 Hz, 1H), 2.56 (dd, J=8.2,
15.7 Hz, 1H).
1
7.35–7.20 (m, 6H), 7.17 (d, J=6.9 Hz, 2H), 7.13 (d, J=
7.1 Hz, 2H), 5.49 (d, J=7.8 Hz, 1H), 5.00 (quint, J=7.3
Hz, 1H), 3.61 (quint, J=6.3 Hz, 1H), 2.81 (dd, J=8.4,
14.9 Hz, 1H), 2.70–2.60 (m, 2H), 2.52 (dd, J=8.4, 13.9
Hz, 1H), 1.25 (d, J=6.8 Hz, 3H); 13C NMR (125 MHz,
CDCl3/CD3OD) l 174.1, 170.8, 142.8, 142.2, 128.2,
128.1, 126.7, 126.5, 126.1, 125.7, 48.2, 42.4, 40.1, 38.9,
20.9. Anal. calcd for C19H21NO3: C, 73.29; H, 6.80; N,
4.50. Found: C, 73.52; H, 6.78; N, 4.41%.
4.7. (3S,1%S)-3-Methyl-5-oxo-5-(1%-phenylethyl-
amino)pentanoic acid 7e
4.4. 4-(4-Fluorophenyl)dihydropyran-2,6-dione 6a
Synthesised according to the procedure for 7a, 76%
yield, 99% d.e., colourless solid: mp 118.6–118.8°C; [h]D25
−88.8 (c 1.0, CH3OH); H NMR (500 MHz, CDCl3) l
A suspension of diacid 5a (40 g, 0.18 mol), in acetyl chlo-
ride (50 mL, 0.68 mol) was gently refluxed overnight.
After evaporation of acetyl chloride, the viscous mass
was dissolved in ethyl acetate, and then filtered through
a silica gel pad. The solution was concentrated and
diluted with ethyl acetate and hexanes, then kept in a
freezer overnight. The white solid was collected and
dried in vacuo to give the title compound (33 g, 90%):
1
7.40–7.26 (m, 5H), 6.03 (d, J=7.4 Hz, 1H), 5.16 (quint,
J=7.3 Hz, 1H), 2.50–2.38 (m, 2H), 2.35 (dd, J=6.2, 14.2
Hz, 1H), 2.31 (dd, J=6.6, 14.2 Hz, 1H), 2.23 (dd, J=6.7,
13.9 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.07 (d, J=6.6
Hz, 3H); 13C NMR (125 MHz, CDCl3/CD3OD) l 175.2,
171.9, 143.3, 128.4, 127.1, 125.9, 48.6, 42.6, 40.6, 28.2,
21.7, 19.4. Anal. calcd for C14H19NO3: C, 67.45; H, 7.68;
N, 5.62. Found: C, 67.59; H, 7.66; N, 5.49%.
1
mp 98.5–99.0°C; H NMR (200 MHz, CDCl3) l 7.25–
7.00 (m, 4H), 3.40 (m, 1H), 3.11 (dd, J=4.5, 17.2 Hz,

424
L. T. Liu et al. / Tetrahedron: Asymmetry 12 (2001) 419–426
4.8. (3R)-3-(4-Fluorophenyl)-5-hydroxypentanoic acid
(1S)-1-phenylethylamide 8
4.10. (4R,1%S)-4-(4-Fluorophenyl)-1-(1%-phenylethyl)-
piperidin-2-one 10
To a solution of 7a (5 g, 15.85 mmol) in tetra-
hydrofuran (200 mL) at room temperature was added
triethylamine (3 mL, 21.52 mmol). The solution was
stirred for 60 min at room temperature and then cooled
to −78°C in a dry ice-acetone bath. To this solution was
added dropwise isobutyl chloroformate (2.6 mL, 20.04
mmol). The suspension was stirred from −78°C to room
temperature overnight. The mixture was filtered
through a Celite and silica gel pad and washed with a
small amount of tetrahydrofuran. To this solution in an
ice bath was added sodium borohydride (2.0 g, 52.87
mmol), followed by dropwise addition of water (10
mL). Carbon dioxide gas was evolved violently. The
reaction mixture was stirred for 2–4 h and filtered
through a Celite pad. After evaporation of the solvent,
the aqueous layer was extracted several times with ethyl
acetate. The organic extracts were combined, washed
with brine, dried over magnesium sulfate and concen-
trated. The solid was recrystallised from ethyl acetate
and hexanes to afford the title compound as a colour-
less solid (4.3 g, 86%): mp 170.0–170.5°C; [h]2D5 −86.4 (c
To a solution of 9 (3.5 g (9.25 mmol) in dry tetra-
hydrofuran (40 mL) at room temperature was added a
suspension of sodium hydride (80% dispersion in min-
eral oil, 0.7 g, 23.33 mmol) in dry tetrahydrofuran (10
mL). The mixture was heated at 65–75°C overnight.
After cooling to room temperature, the reaction mix-
ture was slowly quenched in an ice bath with methanol
(10 mL). After evaporation of solvent, the residue was
diluted with ethyl acetate and then washed with brine.
The organic layer was collected and filtered through a
silica gel pad. After removal of solvent, the crude solid
was recrystallised from ethyl acetate and hexanes to
afford the title compound as colourless crystals (2.4 g,
87%): mp 163.5–164.0°C; [h]2D5 −108.4 (c 1.0, CHCl3);
1H NMR (200 MHz, CDCl3) l 7.36–7.25 (m, 5H), 7.13
(m, 2H), 7.00 (m, 2H), 6.18 (q, J=7.08 Hz, 1H),
3.16–2.87 (m, 2H), 2.87–2.69 (m, 2H), 2.55 (dd, J=
10.1, 17.4 Hz, 1H), 2.05–1.78 (m, 2H), 1.51 (d, J=7.1
Hz, 3H); 13C NMR (125 MHz, CDCl3) l 168.7, 161.6,
140.0, 139.3, 128.5, 128.0, 127.6, 127.4, 115.5, 49.8,
40.3, 39.6, 37.5, 30.3, 15.1. Anal. calcd for C19H20FNO:
C, 76.74; H, 6.78; N, 4.71. Found: C, 76.93; H, 6.82; N,
4.30%.
1
1.0, CH3OH); H NMR (200 MHz, CDCl3) l 7.40–7.10
(m, 7H), 6.98 (t, J=8.7 Hz, 2H), 5.51 (br d, J=7.7 Hz,
1H), 5.00 (quint, J=7.4 Hz, 1H), 3.60–3.50 (m, 2H),
3.33 (m, 1H), 2.55 (dd, J=6.6, 14.2 Hz, 1H), 2.38 (dd,
J=8.6, 14.2 Hz, 1H), 1.95–1.75 (m, 2H), 1.27 (d, J=6.9
Hz, 3H); 13C NMR (125 MHz, CDCl3) l 170.6, 161.6,
142.9, 139.6, 128.9, 128.6, 127.4, 126.1, 115.4, 60.1,
48.6, 44.0, 38.9, 38.4, 21.3. Anal. calcd for
C19H22FNO2: C, 72.36; H, 7.03; N, 4.44. Found: C,
72.35; H, 6.83; N, 4.33%.
4.11. (3S,4R,1%S)-4-(4-Fluorophenyl)-3-methoxycar-
bonyl-1-(1%-phenylethyl)piperidin-2-one 11a
To a stirred solution of lactam 10 (2 g, 6.72 mmol) in
tetrahydrofuran (50 mL) at −78°C was added dropwise
a solution of lithium diisopropylamide in cyclohexane
(1.5 M, 19.5 mL, 29.25 mmol). After 1 h, methyl
chloroformate (0.8 mL, 10.35 mmol) was added drop-
wise. The resultant solution was stirred at −78°C for 4
h and quenched at this temperature with aqueous
ammonium chloride. The mixture was concentrated and
the aqueous layer was extracted with ethyl acetate. The
combined organic extract was washed with brine, dried
over magnesium sulfate, filtered and concentrated to
afford a yellow viscous oil which slowly solidified on
standing. Recrystallisation from ethyl acetate and hex-
anes gave the title compound as white needles (1.85 g,
4.9. (3S)-5-Bromo-3-(4-fluorophenyl)pentanoic acid
(1S)-1-phenylethylamide 9
To a solution of alcohol 8 (4.5 g, 14.27 mmol) in dry
ethyl ether (250 mL) in an ice bath was added dropwise
phosphorous tribromide (1.7 mL, 17.90 mmol). After
stirring for 3 days in an ice bath, conc. hydrobromic
acid (0.5 mL) was added to the mixture. The resulting
solution was allowed to stir at room temperature
overnight. Ice (100 mL) was added to quench the
reaction. The white solid precipitate was collected, dis-
solved in ethyl acetate, washed with saturated sodium
hydrogen carbonate solution and saturated brine. The
organic layer was filtered through a silica gel pad. After
evaporation of solvent, the crude solid was recrys-
tallised from ethyl acetate and hexanes to afford the
title compound as a white solid (3.8 g, 70%): mp
78%): mp 73.5–74.5°C; [h]2D5 −181.2 (c 1.0, CHCl3); H
1
NMR (500 MHz, CDCl3) l 7.45–7.30 (m, 5H), 7.20–
7.16 (m, 2H), 7.06–7.00 (m, 2H), 6.17 (q, J=7.0 Hz,
1H), 3.70 (s, 3H), 3.64 (d, J=10.2 Hz, 3H), 3.39 (td,
J=3.5, 10.7 Hz, 1H), 3.17 (dt, J=4.9, 12.6 Hz, 1H),
2.88 (m, 1H), 2.05 (m, 1H), 1.96 (m, 1H), 1.57 (d,
J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) l 170.6,
165.4, 161.9, 139.4, 137.4, 128.6, 128.3, 127.5, 115.7,
56.6, 52.3, 50.4, 41.4, 40.5, 29.4, 15.0. Anal. calcd for
C21H22FNO3: C, 70.97; H, 6.24; N, 3.94. Found: C,
70.97; H, 6.17; N, 4.01%.
1
156.5–157.5°C; [h]2D5 −38.2 (c 1.0, CH3OH); H NMR
(200 MHz, CDCl3) l 7.40–7.10 (m, 7H), 6.99 (m, 2H),
5.52 (br d, J=7.6 Hz, 1H), 4.98 (m, 1H), 3.35–3.20 (m,
2H), 3.05 (m, 1H), 2.51 (dd, J=6.3, 14.0 Hz, 1H), 2.37
(dd, J=8.7, 14.0 Hz, 1H), 2.25–2.05 (m, 2H), 1.25 (d,
J=6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) l 169.7,
161.8, 142.8, 137.7, 129.1, 128.6, 127.4, 126.1, 115.7,
48.6, 44.0, 40.6, 38.7, 30.9, 21.3. Anal. calcd for
C19H21BrFNO: C, 60.33; H, 5.60; N, 3.70. Found: C,
60.57; H, 5.54; N, 3.82%.
4.12. (3S,4R,1%S)-4-(4-Fluorophenyl)-1-(1%-phenylethyl)-
3-phenylmethylpiperidin-2-one 11b
Synthesised according to the procedure for 11a. Recrys-
tallisation from ethyl acetate and hexanes gave the title
compound as colourless crystals (78% yield): mp 156.8–
157.0°C; [h]2D5 −90.0 (c 1.0, CHCl3); 1H NMR (500

L. T. Liu et al. / Tetrahedron: Asymmetry 12 (2001) 419–426
425
MHz, CDCl3) l 7.32–7.13 (m, 12H), 7.05 (t, J=8.5 Hz,
2H), 6.17 (q, J=7.0 Hz, 1H), 3.47 (dd, J=5.2, 13.7 Hz,
1H), 3.03–2.96 (m, 2H), 2.76–2.71 (m, 2H), 2.55 (m,
1H), 1.83–1.72 (m, 2H), 1.54 (d, J=7.1 Hz, 3H); 13C
NMR (125 MHz, CDCl3) l 171.2, 162.0, 140.2, 139.7,
139.4, 130.4, 129.1, 128.7, 128.6, 127.9, 127.6, 127.2,
126.6, 115.9, 50.9, 49.5, 41.4, 41.0, 35.5, 31.3, 15.3.
Anal. calcd for C26H26FNO: C, 80.59; H, 6.76; N, 3.61.
Found: C, 80.77; H, 6.76; N, 3.48%.
7.40–7.10 (m, 7H), 7.05–6.90 (m, 2H), 3.51 (q, J=6.78
Hz, 1H), 3.45–3.34 (m, 2H), 3.23 (m, 1H), 2.89 (m, 1H),
2.20 (m, 1H), 2.05–1.80 (m, 4H), 1.80–1.65 (m, 2H),
1.44 (d, J=6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3)
l 161.4, 143.2, 140.3, 128.8, 128.2, 127.8, 127.0, 115.3,
65.1, 63.9, 54.7, 50.6, 44.4, 34.6, 19.6. Anal. calcd for
C20H24FNO: C, 76.65; H, 7.72; N, 4.47. Found: C,
76.86; H, 7.77; N, 4.58%.
4.16. (3S,4R,1%S)-3-(1,3-Benzodioxol-5-yloxy)methyl-4-
(4-fluorophenyl)-1-(1%-phenylethyl)piperidine hydrochlo-
ride 14b
4.13. (3S,4R,1%S)-4-(4-Fluorophenyl)-3-(4-fluorophenyl)-
methyl-1-(1%-phenylethyl)piperidin-2-one 11c
Synthesised according to the procedure for 11a. Recrys-
tallisation from ethyl acetate and hexanes gave the title
compound as colourless crystals (40% yield): mp 124.6–
125.0°C; [h]2D5 −89.6 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3) l 7.32–7.26 (m, 3H), 7.16 (d, J=7.1 Hz,
2H), 7.13–7.08 (m, 4H), 7.03 (t, J=8.6 Hz, 2H), 6.92 (t,
J=8.7 Hz, 2H), 6.13 (q, J=7.0 Hz, 1H), 3.42 (dd,
J=4.9, 13.8 Hz, 1H), 3.00–2.95 (m, 2H), 2.69–2.62 (m,
2H), 2.55 (m, 1H), 1.80–1.76 (m, 2H), 1.54 (d, J=7.1
Hz, 3H); 13C NMR (125 MHz, CDCl3) l 170.5, 161.6,
161.6, 139.8, 139.2, 134.6, 131.4, 128.7, 128.4, 127.4,
127.3, 115.7, 114.9, 50.6, 49.2, 41.2, 40.7, 34.1, 31.2,
15.2. Anal. calcd for C26H25F2NO: C, 77.01; H, 6.21; N,
3.45. Found: C, 77.07; H, 6.21; N, 3.27%.
To
a
solution of 12 (2 g, 6.38 mmol) in
dichloromethane (60 mL) in an ice bath was added
dropwise triethylamine (1.65 mL, 11.84 mmol) and
methanesulfonyl chloride (0.86 mL, 11.11 mmol). The
mixture was stirred in an ice bath for 3 h and quenched
with saturated sodium hydrogen carbonate solution (30
mL). The aqueous layer was extracted with
dichloromethane. The combined organic extract was
washed with brine, dried over magnesium sulfate and
concentrated to furnish the mesylate 13 as a yellow
viscous oil.
To a solution of sodium (0.28 g, 12.17 mmol) in
propanol (20 mL) was added a solution of sesamol (3 g,
21.72 mmol) in propanol (30 mL). After gently reflux-
ing for 30 min, the above prepared solution of mesylate
13 in propanol (50 mL) was added. The mixture was
refluxed for 36 h, cooled to room temperature, and then
quenched with ice water (30 mL). After evaporation of
propanol, the aqueous layer was extracted with ethyl
ether. The combined organic layer was washed with 1N
sodium hydroxide solution, brine, dried over magne-
sium, filtered and then concentrated to afford the free
amine 14a as a red–brown viscous oil. The free amine
was diluted with methanol (50 mL) and treated with
concentrated hydrochloric acid (0.5 mL). The resultant
solution was allowed to stand for several days and a
yellow solid precipitate was collected, recrystallised
from methanol and ethyl acetate to afford the hydro-
chloride salt as white needles (1.92 g, 64%). mp >250°C
4.14. (4R,1%S)-3,3-Dimethyl-4-(4-fluorophenyl)-1-(1%-
phenylethyl)piperidin-2-one 11g
Synthesised according to the procedure for 11a (with
2.4 equiv. of methyl iodide used as electrophile).
Recrystallisation from ethyl acetate and hexanes gave
the title compound as a colourless solid (75% yield): mp
102.2–102.6°C; [h]2D5 −31.6 (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) l 7.40–7.25 (m, 5H), 7.12 (dd,
J=5.5, 8.5 Hz, 2H), 7.01 (t, J=8.6 Hz, 2H), 6.16 (q,
J=7.0 Hz, 1H), 3.18 (m, 1H), 2.84 (dd, J=2.7, 11.5 Hz,
1H), 2.78 (m, 1H), 2.17 (m, 1H), 1.90 (m, 1H), 1.56 (d,
J=7.1 Hz, 3H), 1.30 (s, 3H), 1.07 (s, 3H); 13C NMR
(125 MHz, CDCl3) l 175.4, 162.6, 140.3, 136.9, 130.3,
128.5, 127.5, 127.3, 114.7, 50.4, 48.6, 42.9, 40.6, 27.0,
25.3, 22.2, 15.0. Anal. calcd for C21H24FNO: C, 77.51;
H, 7.43; N, 4.30. Found: C, 77.90; H, 7.43; N, 4.18%.
1
(decomposed); [h]D25 −87.4 (c 1.0, CH3OH); H NMR
(500 MHz, CDCl3) l 7.65–7.60 (m, 2H), 7.55–7.45 (m,
3H), 7.30–7.20 (m, 2H), 6.97 (t, J=8.7 Hz, 2H), 6.66
(d, J=8.5 Hz, 1 Hz), 6.34 (d, J=2.5 Hz, 1 Hz), 6.14
(dd, J=2.5, 8.5 Hz, 1H), 5.92 (s, 2H), 4.23 (quintet,
J=6.0 Hz, 1H), 3.86 (m, 1H), 3.64 (dd, J=2.3, 9.6 Hz,
1H), 3.49 (dd, J=3.9, 9.6 Hz, 1H), 3.32 (m, 1H),
2.90–2.80 (m, 3H), 2.57 (m, 1H), 2.02 (d, J=6.9 Hz,
3H), 1.90 (m, 1H); 13C NMR (125 MHz, CDCl3) l
161.8, 153.7, 148.2, 142.0, 136.9, 133.9, 123.0, 129.4,
129.2, 115.7, 107.9, 105.5, 101.2, 97.9, 67.6, 67.5, 54.6,
49.5, 41.2, 39.3, 29.9, 17.5. Anal. calcd for
C27H29ClFNO3: C, 69.00; H, 6.22; N, 2.98. Found: C,
69.36; H, 6.22; N, 3.07%.
4.15. (3S,4R,1%S)-4-(4-Fluorophenyl)-3-hydroxymethyl-
1-(1%-phenylethyl)piperidine 12
To a suspension of lithium aluminum hydride (6 g,
158.10 mmol) in tetrahydrofuran (150 mL) under nitro-
gen in an ice bath was added dropwise a solution of
ester 11a (5.6 g, 15.67 mmol) in tetrahydrofuran (50
mL). The mixture was stirred under reflux for 3 days
and treated with water (10 mL), 15% sodium hydroxide
solution (6 mL), and water (25 mL) in an ice bath.
After filtration of precipitates, the organic solution was
washed with brine, dried over magnesium sulfate,
filtered and concentrated in vacuo to afford the crude
product as a pale yellow solid. Recrystallisation from
ethyl acetate and hexanes gave the title compound as
colourless crystals (3.2 g, 65%): mp 130.0–131.0°C; [h]D25
4.17. Paroxetine hydrochloride or (3S,4R)-3-(1,3-benzo-
dioxol-5-yloxy)methyl-4-(4-fluorophenyl)-piperidine
hydrochloride 15
1
−17.4 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) l
A suspension of 14b (1.6 g, 3.49 mmol) and 10% Pd–C

426
L. T. Liu et al. / Tetrahedron: Asymmetry 12 (2001) 419–426
(20 mg) in anhydrous methanol (140 mL) was stirred at
room temperature under 1 atm. hydrogen gas for 48 h.
The resulting suspension was filtered through Celite,
washed with methanol and concentrated in vacuo.
Crude paroxetine hydrochloride was obtained as a red
viscous mass. Purification was accomplished by recrys-
tallisation from methanol, ethyl ether and hexanes to
afford paroxetine hydrochloride as pink crystals (0.85
g, 68%): mp 123–124°C (lit.3c 129–131°C); [h]D25 −88.6 (c
1.0, CH3OH); lit.5 [h]D22 −89.4 (c 1.6, CH3OH)); 1H
NMR (500 MHz, CDCl3) l 7.35–7.25 (m, 2H), 7.05 (t,
J=8.5 Hz, 2H), 6.68 (d, J=8.4 Hz, 1H), 6.40 (d, J=2.3
Hz, 1H), 6.18 (dd, J=2.3, 8.5 Hz, 1 Hz), 5.95 (s, 2H),
3.83 (d, J=10.3 Hz, 1H), 3.75 (d, J=12.4 Hz, 1H), 3.68
(d, J=9.5 Hz, 1H), 3.24 (m, 1H), 3.12 (m, 1H), 2.97 (td,
J=3.3, 12.9 Hz, 1H), 2.75 (m, 1H), 2.50 (m, 1H), 2.01
(d, J=13.1 Hz, 1H); 13C NMR (125 MHz, CDCl3)
l 161.9, 153.7, 148.2, 142.0, 137.1, 128.9, 115.8,
107.9, 105.6, 101.2, 97.9, 67.5, 46.8, 44.5, 41.7, 39.4,
30.1.
0.037. These data are available in Supporting Informa-
tion.
Acknowledgements
The financial support from the Ministry of Economic
Affairs of ROC and the NMR analytical support pro-
vided by Ms. Ying Chen are greatly appreciated.
References
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4.18. X-Ray crystallography for compounds 11a and
11b
The crystals were grown from
a
mixture of
dichloromethane and ethyl acetate at 25°C. Diffraction
measurements were made on a Nonius CAD-4 diffrac-
tometer using graphite-monochromatised Mo Ka radia-
,
tion (u=0.7107 A). Unit cell parameters were obtained
by a least-squares fit to the automatically centred set-
tings for 25 reflections. Intensity data were collected by
using ꢀ/2q scan mode. Corrections were made for
Lorentz and polarisation effects. The structures were
solved by direct methods SOLVER.12a All non-hydro-
gen atoms were located from the difference Fourier
maps and were refined by full-matrix least-squares pro-
cedures. Hydrogen atoms were calculated and refined
with an overall isotropic temperature factor. Calcula-
tions and full-matrix least-squares refinements were per-
formed utilising the NRCVAX program package.12b
4. Kozikowski, A. P.; Araldi, G. L.; Boja, J.; Meil, W. M.;
Johnson, K. M.; Flippen-Anderson, J. L.; George, C.;
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Canto´, M.; Pe´rez, M.; Llor, N.; Molins, E.; Miravitlles,
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N.; Nielsen, B.; Krogsgaard-Larsen, P. J. Med. Chem.
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4.18.1. Crystal data for 11a. Crystal dimensions 0.46×
0.58×0.58 mm were used for data collection.
C21H22FNO3, fw=355.41, monoclinic C2, a=
,
16.2213(22), b=9.191(4), c=13.022(3) A, i=
96.887(16)°, V=1927.4(10) A , Z=4, Dcalcd=1.225 g
3
,
cm−3, v(Mo Ka)=0.825 cm−1. Unique reflections
(3370) were obtained and 1994 observed reflections
(I>1|(I)) were used for refinement to give R=0.080
and Rw=0.080. These data are available in Supporting
Information.
9. Fieser, L. F.; Martin, E. L. Org. Synth. Collect. 1943, 2,
560.
10. Karanewsky, D. S.; Malley, M. F.; Gougoutas, J. Z. J.
Org. Chem. 1991, 56, 3744.
11. Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Mar-
4.18.2. Crystal data for 11b. Crystal dimensions 0.49×
0.42×0.31 mm were used for data collection.
C26H26FNO, fw=355.41, orthorhombic P212121, a=
tinez, J. Tetrahedron Lett. 1991, 32, 923.
12. (a) Gabe, E. J.; Le Page, Y.; Charland, J. P.; Lee, F. L.;
White, P. S.; Charland, J. P.; White, P. S. J. Appl. Cryst.
1989, 22, 384; (b) Gabe, E. J.; Lee, F. L.; Le Page, Y. In
Crystallographic Computing 3: Data Collection, Structure
Determination, Proteins, and Databases; Sheldrick, G. M.;
Kru¨ger, C.; Goddard, R., Eds.; Clarendon Press: Oxford,
1985; pp. 167–174.
,
10.1484(14), b=10.294(4), c=20.040(3) A, V=
3
,
2093.6(8) A , Z=4,
Dcalcd=1.229 g
cm−3, v(Mo
Ka)=0.750 cm−1. Unique reflections (3677) were
obtained and 2577 observed reflections (I>1|(I))
were used for refinement to give R=0.035 and Rw=