Chemoenzymatic synthesis2 of both enantiomers of fluoxetine, tomoxetine and nisoxetine: Lipase-catalyzed resolution of 3-aryl-3-hydroxypropanenitriles

Article abstract of DOI:10.1016/S0957-4166(02)00537-2

A facile preparation of (±)-3-hydroxy-3-phenylpropanenitrile has been carried out by ring-opening of styrene oxide with NaCN in aqueous ethanol. Subsequent kinetic resolution of this material via lipase-mediated transesterification gave the S-alcohol and R-acetate in excellent yields and high enantioselectivities, particularly with lipase PS-C 'Amano' II. The effect of solvents and immobilization of the lipase has also been investigated. It is interesting to note that the use of immobilized lipase for this transesterification process in hydrophobic solvents (diisopropyl ether, toluene and hexane) enhanced the reaction rate drastically and gave optimal yields with high enantioselectivity (>99%). Moreover, enantiopure 3-hydroxy-3-phenylpropanenitrile products have been converted via enantioconvergent routes into the (R)- and (S)-enantiomers of the important anti-depressants fluoxetine, tomoxetine, nisoxetine and norfluoxetine.

Full text of DOI:10.1016/S0957-4166(02)00537-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2039–2051
Chemoenzymatic synthesis2 of both enantiomers of fluoxetine,
tomoxetine and nisoxetine: lipase-catalyzed resolution of
3-aryl-3-hydroxypropanenitriles
Ahmed Kamal,* G. B. Ramesh Khanna and R. Ramu
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
Received 22 July 2002; accepted 29 August 2002
Abstract—A facile preparation of ( )-3-hydroxy-3-phenylpropanenitrile has been carried out by ring-opening of styrene oxide with
NaCN in aqueous ethanol. Subsequent kinetic resolution of this material via lipase-mediated transesterification gave the S-alcohol
and R-acetate in excellent yields and high enantioselectivities, particularly with lipase PS-C ‘Amano’ II. The effect of solvents and
immobilization of the lipase has also been investigated. It is interesting to note that the use of immobilized lipase for this
transesterification process in hydrophobic solvents (diisopropyl ether, toluene and hexane) enhanced the reaction rate drastically
and gave optimal yields with high enantioselectivity (>99%). Moreover, enantiopure 3-hydroxy-3-phenylpropanenitrile products
have been converted via enantioconvergent routes into the (R)- and (S)-enantiomers of the important anti-depressants fluoxetine,
tomoxetine, nisoxetine and norfluoxetine. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
macology of (R)-fluoxetine offers the potential for more
rapid onset of relief, greater efficacy in the treatment of
depression and fewer side effects such as sexual dys-
function. (R)-Fluoxetine also offers the potential for
the treatment of additional indications, including anxi-
ety. Improvement in pharmacokinetic profile of such
compounds allows shorter washout and reduced drug–
drug interactions. Presently, (R)-fluoxetine, an
‘improved chemical entity’ version of the drug, is in
phase III clinical trials under a collaborative program
between Eli Lilly and Company and Sepracor. How-
ever, many differences have been reported in the litera-
ture with regard to the pharmacological potencies of
the isomers of fluoxetine.3c Some studies suggest that
the (S)-isomer is more potent than the (R)-isomer,
while some suggest that the (R)-isomer is more potent
and some studies suggest that the eudismic ratio for the
isomers is unity.3b In the case of tomoxetine, the (R)-
enantiomer is twice more potent than the racemate and
nine times more potent than the (S)-form. This has led
many research groups to explore the preparation of
enantiomerically pure building blocks for these com-
pounds via enantioselective epoxidation followed by
stereoselective opening, asymmetric reduction, micro-
bial reductions and enzymatic resolutions (Fig. 1).
The anti-depressants (selective serotonin reuptake
inhibitors/norepinephrine reuptake inhibitors) with a
3-aryloxy-3-phenylpropylamine
sub-structure,
e.g.
fluoxetine1 12, tomoxetine2 16 and nisoxetine 18 are
among the most important pharmaceuticals for the
treatment of psychiatric disorders and metabolic
problems.
Fluoxetine offers the potential for treatment of addi-
tional indications such as anxiety, alcoholism, chronic
pain, migraine headache, obsessive compulsive disor-
ders, memory disorders, sleep disorders and bulimia.
Fluoxetine in its racemic form (prozac) is the worlds
leading anti-depressant with the sales of approximately
US $3 billions per annum. In view of the different
pharmacological activities displayed by the individual
enantiomers of the above racemates,3 differences in
metabolic behavior and also in recent years the impor-
tance of preparing drugs in enantiomerically pure form,
the preparation of these anti-depressants in enantiomer-
ically pure form is highly desirable. The unique phar-
* Corresponding author. Fax: +91-40-7160512, +91-40-7160757;
e-mail: ahmedkamal@iict.ap.nic.in
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00537-2

2040
A. Kamal et al. / Tetrahedron: Asymmetry 13 (2002) 2039–2051
b-hydroxy nitriles has been developed by the regioselec-
tive ring-opening of styrene oxide with NaCN in
aqueous–alcoholic medium. The presence of water in
the reaction media not only facilitates the availability of
the cyanide nucleophile but also assists complete
regioselective opening in good yields (Eq. (1)).
(1)
Figure 1.
2.2. Lipase-catalyzed resolution of b-hydroxy nitriles,
1–4
History shows that b-hydroxy nitriles have importance
both as reagents and as technical products in organic
chemistry. These have been extensively investigated and
employed4 in the preparation of various intermediates
for naturally occurring bioactive compounds.5 More-
over, as the cyano group can be readily transformed
into different functional groups by simple methods,
chiral b-hydroxy nitriles have enormous synthetic
potential for the preparation of optically active b-
hydroxy amides,6 b-hydroxy acids,7 b-hydroxy esters,7c,8
diols,7c,9 and amino alcohols.10 These compounds,
derived from optically active b-hydroxy nitriles, are
synthetically interesting highly functionalized chiral
synthons and versatile intermediates in both asymmet-
ric synthesis and medicinal chemistry. Moreover, the
stereogenicity at the hydroxyl group in these com-
pounds can be used to control the generation of new
stereocenters thus offering a potential diastereoselective
route to 1,3-diols11 and 1,3-amino alcohols,12 intermedi-
A number of biologically important compounds con-
tain chiral b-hydroxy nitrile components in their struc-
tures. However, there are very few reports on the
preparation of optically active b-hydroxy nitriles, and
most of them are based on enzymatic approaches.
Earlier attempts to reduce 3-oxo-3-phenylpropanenitrile
by employing bakers’ yeast23 gave the required (S)-3-
hydroxy-3-phenylpropanenitrile in very low yields
(10%), while the major product formed was the alkyl-
ated compound ( )-2-ethyl-3-oxo-3-phenylpropaneni-
trile. Recently, it has been demonstrated24 that on
performing this reaction at low temperature (S)-3-
hydroxy-3-phenylpropanenitrile is formed exclusively in
moderate yield. However, this bakers’ yeast-mediated
reaction had to be carried out at 4°C for 7 days to give
the desired reduction product. Another recent enan-
tioselective bioreduction of b-ketonitriles has been car-
ried out with fungus Curvularia lunata25 and even this
organism produced the ethylated b-hydroxy nitrile on
employing ethanol as well as DMF as co-solvent. How-
ever, use of methanol as a co-solvent improved the
yield (55%) and ee of the b-hydroxy nitrile product.
Lipase-catalyzed hydrolysis has been extensively uti-
lized for the resolution of various optically active
hydroxy substituted substrates and this has also been
applied to the resolution of b-hydroxy nitriles. As most
of the enzymatic hydrolytic processes are substrate
specific, the enantioselectivity depends on both the acid
and the ester components. However, enzymatic hydrol-
ysis by employing lipases failed to resolve the b-
hydroxy nitriles. With a view to improving the enantio-
selectivity of the resolution process, sulphur-con-
taining bulky esters26 have been hydrolyzed with
various lipases. It is further observed from the
literature26e,f that not much attention has been given to
the resolution of 3-hydroxy-3-phenylpropanenitrile 1 by
lipase-catalyzed transesterification. Therefore, we
became interested in the transesterification of these
substrates (1–4) (Eq. (2)) employing various lipases to
prepare optically active 3-aryl-3-hydroxy propaneni-
triles and these results are discussed in Table 2.
Although the maximum yield of this resolution process
is only 50%, the reaction holds high importance if
certain criteria are met with: if both isomers obtained
after resolution are easily separable and have high
enantiomeric purities, the lipase used can be recovered
ates for
a
large number of natural products,
antibiotics13 and chiral auxillaries.14 In view of the need
for development of practical efficient methodologies for
the preparation of enantiomerically pure anti-depres-
sant drugs such as fluoxetine, tomoxetine and nisox-
etine, we have considered enantiomerically pure
b-hydroxy nitriles as suitable precursors for the synthe-
sis of these compounds. In continuation of our earlier
efforts towards the synthesis of biologically important
compounds employing enzymes,15 we wish to report
herein a successful enzymatic resolution of b-hydroxy
nitriles and their application in the synthesis of opti-
cally active antipsychic drugs, viz. fluoxetine, tomox-
etine, and nisoxetine.
2. Results and discussion
2.1. Preparation of b-hydroxy nitriles, 1–2
In the literature, b-hydroxy nitriles have been prepared
by the ring-opening of styrene oxide with HCN,16 alkali
metal cyanides in the presence of perchlorates,17
Yb(CN)3,17,18 acetone cyanohydrin,19 alkylaluminum
cyanides,20 Ce(OTf)4,21 TMSCN.18,20b,22 Most of these
methods have some limitations such as poor chemose-
lectivity, and the use of volatile toxic substances and
expensive reagents. In order to overcome these prob-
lems, a new practical method for the preparation of

A. Kamal et al. / Tetrahedron: Asymmetry 13 (2002) 2039–2051
2041
and reused, and the substrate for the resolution process
can be readily obtained. In this context, we investigated
the potential of different lipases for the transesterifica-
tion of 3-hydroxy-3-phenylpropanenitrile.27
faster than when the non-immobilized form is used
(Table 1, entry 3). In this investigation the effect of
solvents on the rate of conversion and enantioselectivity
has been examined. It was also observed that diiso-
propyl ether, toluene and hexane are the solvents of
choice, offering remarkable enantioselectivities (Table
3, entries 1, 2 and 3). Whereas in hydrophilic solvents
like acetone, THF and acetonitrile the reaction did not
proceed, or proceeded with negligible formation of the
product and no significant enantioselectivity (Table 3,
entries 5, 6, and 7). The generality of the process has
been extended to various aryl substituted 3-aryl-3-
It was observed from the results (Table 1) that lipase
PS-C ‘Amano’ II gave excellent yields and high enan-
tioselectivity. Moreover, this led us to examine the
effect of immobilization (Table 2) and solvent effects in
this transesterification process (Table 3). It is interesting
to observe that in the transesterification of 1 with
immobilized PS lipase (Table 1, entry 1) is 14 times
(2)
Table 1. Transesterification of 3-hydroxy-3-phenylpropanenitrile with various lipases in diisopropyl ether at 40°C
Entry
Lipasesa
Time (h)
Alcohol
eec (%)
Acetate
Yieldb (%)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
PS-C
PS-D
PS
13
75
46
45
46
98
81
65
80
90
60
\99
\99
\99
–
21
33
16
–
55
46
46
44
–
15
28
14
5
\99
\99
\99
–
\99
78
\99
–
\99
180
240
216
139
216
220
216
PPL
CCL
CRL
Lipozyme
CAL
P
32
a Pseudomonas cepacia lipase immobilized on modified ceramic particals (PS-C) (Amano Pharmaceutical company), Pseudomonas cepacia lipase
immobilized on diatomite (PS-D) (Amano Pharmaceutical company), Psedomonas cepacia (PS) (Amano Pharmaceutical company), Porcine
pancreas lipase (PPL) (Sigma), Candida cylindracea lipase (CCL) (Sigma), Candida rugosa lipase (CRL) (Sigma), lipase immobilized from Mucor
meihei (Lipozyme) (Fluka), Candida antartica lipase immobilized in Sol-Gel-AK on sintered glass (CAL) (Fluka), Pseudomonas fluorescens lipase
immobilized in Sol-Gel-AK on sintered glass(P) (Fluka).
b Isolated yields.
c Determined by chiral HPLC (chiral OJ-H column; Diacel) employing hexane–isopropanol (90:10) as the mobile phase at 0.5 mL/min and
monitored by UV (254 nm).
Table 2. Transesterification of various substrates using both immobilized (PS-C) and non-immobilized lipase (PS) in diiso-
propyl ether
Entry
Substrate (R)
Lipase
Time (h)
Alcohol
eeb (%)
Acetate
Yielda (%)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
H
H
PS-Cc
PSd
16
180
8
93
7.5
72
46
46
45
59
46
60
45
55
\99
\99
\99
74
\99
74
46
44
46
35
47
34
46
34
\99
\99
\99
\99
\99
\99
\99
\99
3-Cl
3-Cl
4-Cl
4-Cl
4-CH3
4-CH3
PS-Cc
PSd
PS-Cc
PSd
PS-Cc
PSd
10
170
\99
78
a Isolated yields.
b Determined by chiral HPLC (chiral OJ-H column; Diacel) employing hexane–isopropanol (90:10) as mobile phase at 0.5 mL/min and monitored
by UV (254 nm).
c Reaction carried out at 27°C.
d Reaction carried out at 40°C.

2042
A. Kamal et al. / Tetrahedron: Asymmetry 13 (2002) 2039–2051
Table 3. Effects of solvents on the transesterification of 3-hydroxy-3-phenylpropanenitrile by lipase PS-C ‘Amano’ II
Entry
Solvent
Time (h)
Alcohol
eeb (%)
Acetate
Yielda (%)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
Diisopropyl ether
Toluene
Hexane
Chloroform
Acetonitrile
Acetone
Tetrahydrofuran
t-Butyl methyl ether
16
18
17
24
25
24
30
20
46
44
45
70
80
95
96
96
\99
\99
\99
30
46
44
46
24
14
–
\99
\99
\99
\99
B10
–
17
–
–
–
–
–
–
–
a Isolated yields.
b Determined by chiral HPLC (chiral OJ-H column; Diacel) employing hexane–isopropanol (90:10) as mobile phase at 0.5 mL/min and monitored
by UV (254 nm).
hydroxypropanenitriles, as illustrated in Table 2. The
absolute configuration of these compounds has been
assigned by the comparison of the specific rotation
value for the authentic (S)-3-hydroxy-3-phenylpro-
panenitrile24 (S)-1. From our earlier experience15a with
Pseudomonas cepacia lipase and by the empirical rule
for the enantiopreference of this lipase the absolute
configuration of acetates (R)-6-(R)-8 has been assumed
to be R.
enantiomerically pure fluoxetine and tomoxetine. It was
observed that most of the methods reported in the
literature have either employed expensive chiral
reagents or the yields and enantioselectivities of the
desired precursors are not very high. Therefore, in the
present investigation we have employed both enan-
tiomeric forms of 3-hydroxy-3-phenylpropanenitrile,
(S)-1 and (R)-5, which have been obtained in very good
yields and high enantioselectivity by lipase-mediated
transesterification, for the synthesis of fluoxetine,
tomoxetine and nisoxetine.
2.3. Synthesis of both enantiomers of fluoxetine,
tomoxetine, nisoxetine and norfluoxetine
Attempts to couple (S)-1 with aryl halides in the pres-
ence of a base and Mitsunobu coupling with phenols
did not afford the desired ether (in the Mitsunobu
coupling cinnamonitrile is formed as a major product
as a result of dehydration of (S)-1). Therefore, to
overcome this problem the nitrile functionality of (S)-1
was reduced to an amine by employing borane–methyl
sulphide37 without any loss in enantiomeric purity. It
has been observed that during the workup of this
reaction using conc. HCl and aqueous NaOH, most of
the reduced product decomposed. Therefore, treatment
of the reaction mixture with methanol upon completion
provides the required (S)-3-amino-1-phenyl-1-propanol,
(S)-9 in high yields. In contrast (R)-3-amino-1-phenyl-
1-propanol, (R)-9 was obtained by the simultaneous
reduction of the nitrile functionality and hydrolysis of
the acetate of (R)-3-acetyloxy-3-phenylpropanenitrile
(R)-5 on treatment with borane–methyl sulphide.
Again, the Mitsunobu coupling of (S)-9 or (R)-9 did
not give satisfactory results, as such (S)-9 and (R)-9
were converted to their carbamates (S)-N-(ethoxycar-
bonyl)-3-amino-1-phenyl-1-propanol ((S)-10) and (R)-
N - (ethoxycarbonyl) - 3 - amino - 1 - phenyl - 1 - propanol
((R)-10), respectively, by their reaction with ethyl chlo-
roformate in the presence of K2CO3. Importantly, these
carbamates provide the monomethylated product (S)-
N-methyl-3-amino-1-phenyl-1-propanol ((S)-11) and
Introduction of chirality in these non-tricyclic anti-
depressants fluoxetine, tomoxetine, nisoxetine has been
described in the literature by employing different meth-
ods and various substrates. One of the methods
involves Sharpless epoxidation28 of cinnamyl alcohol
followed by regioselective reduction (Red-Al) to pro-
duce the corresponding (S)- or (R)-1-phenyl-1,3-
propanediol which were subsequently utilized for the
preparation of enantioselective forms of fluoxetine and
tomoxetine. Another method deals with the ring-open-
ing of optically active styrene oxide29 with acetone
cyanohydrin to provide chiral 3-hydroxy-3-phenyl-
propanenitrile which has been utilized as the key inter-
mediate in the preparation of optically active fluoxetine
and norfluoxetine. Optically active 3-chloro-1-phenyl-1-
propanol has been extensively used as the key interme-
diate for the preparation of these drugs. This
intermediate was either prepared by enzymatic kinetic
resolution30 of the chlorohydrin or by asymmetric
reduction of the corresponding ketone with
diisopinocamphenylchloroborane,31 borane in the pres-
ence of chiral oxazaborolidine32 and baker’ yeast.33
Ethyl benzoylacetate34 is another substrate which has
been subjected to asymmetric reduction by bakers’
yeast and later employed for the preparation of enan-
tiomeric fluoxetine and tomoxetine. Similarly, asym-
metric hydrogenation of benzoylamide in the presence
of chiral BINAP-ruthenium(II)35 catalyst under 200 psi
pressure of hydrogen afforded hydroxyamide which has
been used in the preparation of chiral fluoxetine.
Another substrate is allyl alcohol,36 which has been
resolved by lipase and employed in the preparation of
(R)-N-methyl-3-amino-1-phenyl-1-propanol
((R)-11)
upon reduction with LAH. Upon treatment with NaH
and 4-chlorobenzotrifluoride in DMSO (R)-11 and (S)-
11 gave the corresponding (R)-fluoxetine ((R)-12) and
(S)-fluoxetine ((S)-12) (Scheme 1). In a similar manner,
both enantiomers of norfluoxetine, (R)-13 and (S)-13

A. Kamal et al. / Tetrahedron: Asymmetry 13 (2002) 2039–2051
2043
Scheme 1. Reagents: (i) BH3-Me2S, THF; (ii) ethyl chloroformate, K2CO3, DCM; (iii) LAH, THF; (iv) 4-chlorobenzotrifluoride,
NaH, dry DMSO.
have been prepared by etherification of (S)-9 and (R)-9
with 4-chlorobenzotrifluoride/NaH in DMSO.
its acid 20, ester34 21 and 1,3-diol28,36 22. Interestingly,
all of these intermediates have not only been employed
in the enantioselective preparation of fluoxetine and
tomoxetine but are also useful building blocks for the
construction of chiral organic frameworks. Various
attempts to perform this hydrolysis with a large number
of literature methods produced undesired products.
Alkaline or acid hydrolysis of (S)-1, at elevated temper-
ature and room temperature, produced cinnamic acid
and cinnamamide, respectively. To overcome this prob-
lem, hydrolysis of (S)-1 has been carried out using
K2CO3/H2O2 in DMSO and the corresponding acid,
ester and diol have been prepared in the usual manner
as shown in Scheme 3.
This approach was not successful in etherification reac-
tions with 2-chlorotoluene and 2-chloroanisole to
obtain tomoxetine and nisoxetine. Therefore, another
approach was investigated for the preparation of both
the enantiomers of these drugs. Mitsunobu coupling of
the carbamate with phenols such as 4-hydroxy benzo-
trifluoride, 2-methylphenol, and 2-methoxyphenol gave
the corresponding products with inversion at the stereo-
genic center, as depicted in Scheme 2. Reduction of
these ethers with LAH then afforded both isomers of
fluoxetine, tomoxetine and nisoxetine.
The carbamate appears to be a versatile intermediate in
this process: etherification with various phenols to
provide the required products such as (S)-N-(ethoxy-
carbonyl)-3-(4-(trifluoromethyl)phenoxy)-3-phenyl-1-
propanamine ((S) - 14), (S) - N - (ethoxycarbonyl) - 3-
(2-(methyl)-phenoxy)-3-phenyl-1-propanamine ((S)-15)
and (S)-N-(ethoxycarbonyl)-3-(2-(methoxy)-phenoxy)-
3-phenyl-1-propanamine ((S)-17) and, importantly, to
afford the monomethylated product selectively upon
hydride reduction.
3. Conclusion
We have developed an efficient method for the prepara-
tion of b-hydroxy nitriles and their resolution in good
yields and with high enantioselectivities employing
lipase-catalyzed transesterifications. Further, we have
utilized these b-hydroxy nitriles for practical prepara-
tion of both enantiomers of fluoxetine, tomoxetine,
nisoxetine and norfluoxetine. The transformation of
(S)-3-hydroxy-3-phenylpropanenitrile to its correspond-
ing acid, ester, and 1,3-diol has also been investigated.
In conclusion, efficient chemoenzymatic syntheses of
the important anti-depressants fluoxetine, tomoxetine
and nisoxetine have been carried out starting from
simple racemic styrene oxide.
2.4. Transformation of (S)-3-hydroxy-3-phenyl-
propanenitrile to useful chiral intermediates
(S)-3-Hydroxy-3-phenylpropanenitrile provides an
entry to a wide range of chiral synthons. Therefore,
(S)-1 has been transformed to its amide 19 followed by

2044
A. Kamal et al. / Tetrahedron: Asymmetry 13 (2002) 2039–2051
Scheme 2. Reagents: (i) PPh3, DIAD, 4-hydroxy benzotrifluoride, diethyl ether; (ii) PPh3, DIAD, 2-methyl phenol, diethyl ether;
(iii) PPh3, DIAD, 2-methoxy phenol, diethyl ether; (iv) LAH, THF.
Scheme 3. Reagents: (i) H2O2, DMSO, K2CO3; (ii) dil. HCl; (iii) ethyl iodide, K2CO3, acetone; (iv) LAH, THF.

A. Kamal et al. / Tetrahedron: Asymmetry 13 (2002) 2039–2051
2045
4. Experimental
mmol) was added and stirring was continued overnight
at room temperature. On completion of the reaction, as
indicated by the TLC, the reaction mixture was concen-
trated to about 25% of the total volume under reduced
pressure. The residue was extracted with ethyl acetate
(3×30 mL), the organic layer was washed with brine
and dried over anhydrous Na2SO4. Evaporation of the
solvent and purification of the residue by column chro-
matography employing EtOAc–hexane (25:75) as eluent
afforded the required product in 82% yield. IR (Neat)
3441, 3085, 3000, 2256, 1064 cm−1; 1H NMR (400
MHz, CDCl3) l 2.72 (d, 2H, J=6.23 Hz), 2.97 (s, 1H),
5.00 (t, 1H, J=6.23 Hz), 7.26–7.38 (m, 4H); mass (EI)
161, 141, 113, 77, 50; anal. calcd for C9H8ClNO: C,
59.52; H, 4.44; N, 7.71. Found C, 59.71; H, 4.38; N,
7.63%.
4.1. General
Unless specified all solvents and reagents were reagent
grade and used without purification. THF and ether
were dried and distilled from sodium benzophenone
ketyl under nitrogen while DMSO was vacuum distilled
,
and dried on 4 A molecular sieves. Reactions involving
moisture-sensitive reagents were performed under an
inert atmosphere of nitrogen in glassware that has been
oven dried. Melting points have been recorded on an
electrothermal melting point apparatus and are uncor-
rected. Infrared spectra were recorded on Perkin–Elmer
model 683 or 1310 spectrometers and are reported in
1
wave numbers (cm−1). H NMR spectra were recorded
as solutions in CDCl3, CD3OD or DMSO (d6) and
chemical shifts are reported in parts per million (PPM,
l) on Gemini 200 MHz, AV 300 MHz, Unity 400 MHz
instrument using tetramethylsilane (TMS) as an inter-
nal standard. Spectral patterns are designated as s,
singlet; d, doublet; dd, double doublet; t, triplet; br,
broad; m, multiplet. 13C NMR spectra were recorded as
solutions in CDCl3 at an operational frequency of 50
MHz. Coupling constants are reported in hertz (Hz).
Low resolution mass spectra were recorded on CEC-21-
100B Finnigan Mat 1210 or VG 7070H Micromass
mass spectrometers. Analytical TLC of all reactions
was performed on Merck prepared plates (silica gel 60
F-254 on glass). Column chromatography was per-
formed using Acme silica gel (100–200 mesh). Percent-
age yields are given for compounds. HPLC analysis was
performed on an instrument that consisted of a Shi-
madzu LC-6A system controller, SPD-6A fixed wave-
length UV monitor as detector, FCV-100B fraction
collector and chromatopac C-R4A data processor as a
recording integrator.
4.2.3. ( )-3-(4-Chlorophenyl)-3-hydroxypropanenitrile, 3.
A
solution of 2-chloro-1-(4-chlorophenyl)-1-ethanol
(1.24 g, 6.50 mmol) in methanol (24 mL) was added
dropwise to NaCN (0.95 g, 19.50 mmol) in water (8
mL) at room temperature. After complete addition the
reaction mixture was heated under reflux for 6 h while
monitoring the progress of the reaction by TLC. On
completion of the reaction the reaction mixture was
allowed to reach room temperature and the reaction
mixture was concentrated to about 25% of the total
volume. The residue was extracted with ethyl acetate
(3×20 mL) and the organic layer was washed with brine
and dried over anhydrous Na2SO4. Evaporation of the
solvent and purification of the residue by column chro-
matography employing EtOAc–hexane (25:75) as the
eluent afforded the product in 71% yield. Mp 58–60°C;
1
IR (KBr) 3444, 3074, 2936, 2904, 2234, 1069 cm−1; H
NMR (200 MHz, CDCl3) l 2.73 (d, 2H, J=5.85 Hz),
2.86 (s, 1H), 5.00 (t, 1H, J=5.85 Hz), 7.32–7.39 (m,
4H); mass (EI) 181, 141, 113, 77, 51; anal. calcd for
C9H8ClNO: C, 59.52; H, 4.44; N, 7.71. Found C, 59.80;
H, 4.43; N, 7.68%.
4.2. Preparation of 3-aryl-3-hydroxypropanenitriles
4.2.1. ( )-3-Hydroxy-3-phenylpropanenitrile, 1. To a
solution of styrene oxide (12.00 g, 100.00 mmol) in
ethanol (100 mL) was added water (300 mL). After
stirring for 5 min sodium cyanide (7.35 g, 150.00 mmol)
was added and stirring was continued overnight at
room temperature. On completion of the reaction, as
indicated by TLC, the reaction mixture was concen-
trated to about 25% of the total volume under reduced
pressure. The residue was extracted with ethyl acetate
(3×150 mL) washed with brine and dried over anhy-
drous Na2SO4. Evaporation of the solvent and purifica-
tion of the residue by column chromatography
employing EtOAc–hexane (25:75) as eluent afforded 1
in 80% yield. IR (Neat) 3438, 3046, 3015, 2954, 2923,
2892, 2238, 1115, 1092 cm−1; 1H NMR (200 MHz,
CDCl3) l 2.67 (d, 2H, J=7.23 Hz), 3.15 (br s, 1H), 4.94
(t, 1H, J=5.78), 7.35 (s, 5H); mass (EI) 147, 121, 107,
105, 91, 79, 77.
4.2.4. ( )-3-Hydroxy-3-(4-methylphenyl)propanenitrile,
4. To a solution of 4-methylstyrene (1.77 g, 15.00
mmol) in THF (30 mL) was added water (6 mL) and
NBS (4.00 g (recrystallized), 22.50 mmol) at room
temperature and stirred for 30 min. After completion of
the reaction as indicated by TLC, THF was evaporated
under reduced pressure and the residue was extracted
twice with DCM (15 mL). The organic layer was
washed with hypo and then with brine, dried over
Na2SO4 and the solvent was evaporated under reduced
pressure to leave a residue which on purification
afforded 2-bromo-1-(4-methylphenyl)-1-ethanol in 70%
yield.
The above obtained bromohydrin was dissolved in
methanol (25 mL) and added dropwise to NaCN (1.50
g, 31.35 mmol) in water (8 mL) at room temperature.
After complete addition the reaction mixture was
heated under reflux for 4 h, cooled to room tempera-
ture and the reaction mixture was concentrated to
about 25% of the total volume. The residue was
extracted with ethyl acetate (3×20 mL), washed with
brine, dried over Na2SO4 and concentrated. The residue
4.2.2. ( )-3-(3-Chlorophenyl)-3-hydroxypropanenitrile, 2.
To a solution of 3-chlorostyrene oxide (1.54 g, 10.00
mmol) in ethanol (20 mL) was added water (60 mL).
After stirring for 5 min, sodium cyanide (0.74 g, 15.10

2046
A. Kamal et al. / Tetrahedron: Asymmetry 13 (2002) 2039–2051
was subjected to purification by column chromatogra-
phy employing EtOAc–hexane (25:75) as eluent to
afford the required product in 76% yield. Mp 62–64°C;
70.92; H, 6.45; N, 6.89. Found C, 70.98; H, 6.41; N,
6.69%.
1
IR (KBr) 3443, 3011, 2924, 2253, 1063 cm−1; H NMR
4.4. General procedure for resolution of 3-aryl-3-
hydroxypropanenitriles 1–4
(200 MHz, CDCl3) l 2.38 (s, 3H), 2.72 (d, 2H, J=8.60
Hz), 4.97 (t, 1H, J=8.60 Hz), 7.13–7.30 (m, 4H); mass
(EI) 161, 121, 91, 77, 65, 41; anal. calcd for C10H11NO:
C, 74.51; H, 6.88; N, 8.69. Found C, 74.34; H, 6.81; N,
8.71%.
To a solution of the b-hydroxy nitrile (0.20 g) in
diisopropyl ether (20 mL) were successively added
lipase (0.15 g) and vinyl acetate (6 equiv.) and the
mixture was shaken at 40°C in an orbital shaker. After
about 50% completion of the reaction as indicated by
the HPLC analysis, the reaction mixture was filtered
and the residue was washed three times with diiso-
propyl ether. The combined organic layers were evapo-
rated under reduced pressure and purification was
accomplished by column chromatography employing
EtOAc–hexane (20:80) as eluent to afford the corre-
sponding (R)-acetate followed by (S)-alcohol.
4.3. General procedure for preparation of 3-acetyloxy-
3-arylpropanenitriles 5–8
To 3-aryl-3-hydroxy propanenitrile (5.00 mmol) under
N2 was added acetic anhydride (20.00 mmol) and pyri-
dine (5.50 mmol) and the resultant mixture was stirred
at room temperature overnight. After completion of the
reaction (TLC) the reaction mixture was diluted with
ethyl acetate (25 mL) and treated with 1N HCl (20
mL). The organic layer was separated, washed with
brine and dried over anhydrous Na2SO4. The solvent
was evaporated and the residue was purified by column
chromatography employing EtOAc–hexane (15:85) as
eluent to afford the required 3-acetyloxy-3-aryl
propanenitrile in nearly quantitative yield.
4.4.1. (R)-3-Acetyloxy-3-phenylpropanenitrile, (R)-5.
Mp 121–124°C; [h]3D0=+71.9 (c 1.0, CHCl3); NMR, IR,
and mass spectral data are identical to 5.
4.4.2.
(S)-3-Hydroxy-3-phenylpropanenitrile,
(S)-1.
[h]3D0=−60.5 (c 1.0, CHCl3), lit.26b [h]2D0=+58.0 (c 1.0,
EtOH) (R enantiomer); NMR, IR, and mass spectral
data are identical to 1.
4.3.1. ( )-3-Acetyloxy-3-phenylpropanenitrile, 5. 1 (0.73
g) was acetylated using the above general procedure to
obtain the product as white solid in 92% yield. Mp
97–100°C; IR (KBr) 3054, 3008, 2961, 2923, 2254, 1738,
4.4.3. (R)-3-Acetyloxy-3-(3-chlorophenyl)propanenitrile,
(R)-6. Mp 77–79°C; [h]3D0=+68.0 (c 1.0, CHCl3); NMR,
IR, and mass spectral data are identical to 6.
1
1238, 1200, 1046 cm−1; H NMR (200 MHz, CDCl3) l
2.15 (s, 3H), 2.86 (d, 2H, J=5.52 Hz), 5.94 (t, 1H,
J=5.52 Hz), 7.35 (s, 5H); mass (EI) 189, 162, 149, 130,
120, 107, 77.
4.4.4. (S)-3-(3-Chlorophenyl)-3-hydroxypropanenitrile,
(S)-2. [h]3D0=−50.5 (c 2.0, CHCl3); NMR, IR, and mass
spectral data are identical to 2.
4.3.2. ( )-3-Acetyloxy-3-(3-chlorophenyl)propanenitrile,
6. 2 (0.20 g) was acetylated using the above general
procedure to obtain the product as a white solid in 95%
yield. Mp 76–78°C; IR (KBr) 3065, 3021, 2933, 2250,
4.4.5. (R)-3-Acetyloxy-3-(4-chlorophenyl)propanenitrile,
(R)-7. Mp 99–103°C; [h]3D0=+80.5 (c 1.0, CHCl3);
NMR, IR, and mass spectral data are identical to 7.
1
1746, 1052 cm−1; H NMR (200 MHz, CDCl3) l 2.20
(s, 3H), 2.87 (d, 2H, J=6.67 Hz), 5.90 (t, 1H, J=6.67
Hz), 7.23–7.40 (m, 4H); mass (EI) 223, 183, 181, 164,
154, 141, 111, 77, 51, 43; anal. calcd for C11H10ClNO2:
C, 59.07; H, 4.51; N, 6.26. Found C, 59.12; H, 4.47; N,
6.28%.
4.4.6. (S)-3-(4-Chlorophenyl)-3-hydroxypropanenitrile,
(S)-3. [h]3D0=−54.5 (c 2.0, CHCl3); NMR, IR, and mass
spectral data are identical to 3.
4.4.7. (R)-3-Acetyloxy-3-(4-methylphenyl)propanenitrile,
(R)-8. Mp 88–91°C; [h]3D0=+106.5 (c 1.0, CHCl3);
NMR, IR, and mass spectral data are identical to 8.
4.3.3. ( )-3-Acetyloxy-3-(4-chlorophenyl)propanenitrile
7. 3 (0.20 g) was acetylated using the above general
procedure to obtain the product as a white solid in 90%
yield. Mp 95–98°C; IR (KBr) 2967, 2945, 2252, 1750,
4.4.8. (S)-3-Hydroxy-3-(4-methylphenyl)propanenitrile,
(S)-4. [h]3D0=−52.6 (c 2.0, CHCl3); NMR, IR, and mass
spectral data are identical to 4.
1
1094, 1051 cm−1; H NMR (300 MHz, CDCl3) l 2.15
(s, 3H), 2.75–2.94 (m, 2H), 5.90 (t, 1H, J=5.76 Hz),
7.30–7.40 (m, 4H); mass (EI) 223, 196, 183, 154, 141,
77, 43; anal. calcd for C11H10ClNO2: C, 59.07; H, 4.51;
N, 6.26. Found C, 58.92; H, 4.49; N, 6.28%.
4.5. Preparation of enantiomers of 3-amino-1-phenyl-1-
propanol, (S)- and (R)-9
4.5.1. (S)-3-Amino-1-phenyl-1-propanol, (S)-9. Borane–
methyl sulphide complex (1.34 g, 17.68 mmol) was
slowly added to a solution of (S)-1 (2.00 g, 13.60 mmol)
in dry THF (20 mL) at room temperature. After com-
pletion of the addition, the reaction mixture was heated
under reflux and the progress of the reaction was
monitored by TLC. On completion of the reaction (2 h
reflux) the reaction mixture was cooled and methanol
was slowly added at 0°C to decompose the unreacted
4.3.4. ( )-3-Acetyloxy-3-(4-methylphenyl)propanenitrile,
8. 4 (0.10 g) was acetylated using the above general
procedure to obtain the product as a white solid in 95%
yield. Mp 72–74°C; IR (KBr) 2979, 2940, 2250, 1744,
1
1051 cm−1; H NMR (200 MHz, CDCl3) l 2.15 (s, 3H),
2.38 (s, 3H), 2.87 (d, 2H, J=8.79 Hz), 5.92 (t, 1H,
J=8.79 Hz), 7.15–7.34 (m, 4H); mass (EI) 203, 163,
143, 121, 93, 91, 77, 43; anal. calcd for C12H13NO2: C,

A. Kamal et al. / Tetrahedron: Asymmetry 13 (2002) 2039–2051
2047
borane complex. The organic solvents were evaporated
and the purification of the residue by column chro-
was heated under reflux for 1 h. After completion of the
reaction the mixture was cooled to room temperature
and ethyl acetate was slowly added. The resultant reac-
tion mixture was filtered, the residue was treated with
ethyl acetate and filtered three times. The filtrates were
combined and evaporated under reduced pressure to
leave a residue which was purified by column chro-
matography
employing
NH4OH–MeOH–EtOAc
(1:9:90) afforded (S)-amino alcohol, (S)-9 in 85% yield.
[h]3D0=−42.8 (c 1.0, MeOH); IR (Neat) 3346, 3277,
3169, 3054, 3015, 2923, 2869, 1554, 1477, 1438, 1315,
1
1046 cm−1; H NMR (200 MHz, CDCl3) l 1.64–1.85
(m, 2H), 2.60 (br s, 3H), 2.86–3.12 (m, 2H), 4.91 (dd,
1H, J1=5.00 Hz, J2=10.00 Hz), 7.15–7.35 (m, 5H); 13C
NMR (50 MHz, CDCl3) l 39.24, 39.50, 73.54, 125.50,
126.87, 128.08, 144.84; mass (EI) 134, 107, 104, 91, 77;
FABMS 152, 151, 134, 107, 91, 77.
matography
employing
NH4OH–MeOH–EtOAc
(1:9:90) as eluent to afford the product in 88% yield.
[h]3D0=−36.2 (c 0.85, CHCl3); 1H NMR (200 MHz,
CDCl3) l 1.74–1.86 (m, 1H), 1.90–1.95 (m, 1H), 2.50 (s,
3H), 2.86–2.93 (m, 2H), 4.92 (dd, 1H, J1=3.33 Hz,
J2=7.14 Hz), 7.27–7.36 (m, 5H); mass (EI) 165, 133,
117, 104, 91, 77, 43.
4.5.2. (R)-3-Amino-1-phenyl-1-propanol, (R)-9. Prepared
from (R)-5 (2.00 g, 10.60 mmol) using borane–methyl
sulphide complex (1.61 g, 21.20 mmol) by employing a
similar procedure to that used in the preparation of
(S)-9 (88%). [h]3D0=+41.8 (c 1.0, MeOH); NMR, IR,
and mass spectral data are identical to (S)-9.
4.7.2. (R)-N-Methyl-3-amino-1-phenyl-1-propanol, (R)-
11. Prepared from (R)-10 in 89% yield using a proce-
dure analogous to that used for (S)-11. [h]3D0=+37.1 (c
1, CHCl3); NMR, and mass spectral data are identical
to (S)-11.
4.6. Preparation of enantiomers of N-(ethoxycarbonyl)-
3-amino-1-phenyl-1-propanol, (S)- and (R)-10
4.8. Preparation of enantiomers of norfluoxetine, (S)-
and (R)-13
4.6.1.
(S)-N-(Ethoxycarbonyl)-3-amino-1-phenyl-1-
propanol ((S)-carbamate), (S)-10. Ethyl chloroformate
(0.56 g, 5.16 mmol) was added to a solution of (S)-
amino alcohol ((S)-9) (0.60 g, 3.97 mmol) in DCM (8
mL) at room temperature and stirred vigorously. To
this vigorously stirred mixture was added K2CO3 (2.74
g, 19.85 mmol) in H2O (8 mL) over a period of 5 min
and stirring was then continued for 30 min. After
completion of the reaction as indicated by the TLC, the
reaction mixture was extracted with DCM. The solvent
was evaporated and the residue was purified by column
chromatography employing EtOAc–hexane (10:90) as
the eluent to afford the (S)-carbamate, (S)-10 in 90%
yield. Mp 67–69°C; [h]3D0=−25.0 (c 1.0, CHCl3); IR
(KBr) 3423, 3300, 3254, 3046, 3015, 2961, 2923, 2877,
1692, 1546, 1269, 1007 cm−1; 1H NMR (200 MHz,
CDCl3) l 1.25 (t, 3H, J=7.33 Hz), 1.81–1.91 (m, 2H),
3.17–3.27 (m, 1H), 3.45–3.65 (m, 1H), 4.10 (q, 2H,
J=7.33 Hz), 4.74 (t, 1H, J=7.33 Hz), 5.05 (br s, 1H),
7.20–7.33 (m, 5H); 13C NMR (50 MHz, CDCl3) l
14.47, 37.89, 38.99, 60.76, 71.78, 76.68, 76.99, 77.31,
125.53, 127.53, 128.28, 144.21, 157.27; mass (EI) 223,
133, 117, 107, 102, 91, 77.
4.8.1.
(S)-3-Phenyl-3-(4-trifluoromethylphenoxy)-1-
propanamine, ((S)-norfluoxetine), (S)-13. To a solution
of (S)-9 (0.45 g, 2.98 mmol) in dry DMSO (8 mL) at
room temperature was added NaH (0.18 g (60%), 4.50
mmol) and heated at 55°C for 45 min to form a sodium
alkoxide of the amino alcohol. To the above-formed
alkoxide was added 4-chlorobenzotrifluoride (0.81 g,
4.48 mmol) taken in DMSO (2 mL) and the resultant
mixture was heated for 1 h at 90–100°C. After comple-
tion of the reaction as indicated by the TLC, the
reaction mixture was allowed to reach room tempera-
ture, diluted with cool water (10 mL) and then
extracted with diethyl ether (3×25 mL). The combined
ether layers were concentrated to leave a residue, which
was purified by column chromatography to afford the
required product 13S in 65% yield. [h]3D0=−3.5 (c 1,
1
CHCl3); H NMR (200 MHz, DMSO) l 2.05–2.36 (m,
2H), 2.93–3.05 (m, 2H), 5.38–5.55 (m, 1H), 6.88–7.00
(d, 2H, J=4.76 Hz), 7.12–7.50 (m, 7H).
4.8.2.
(R)-3-Phenyl-3-(4-trifluoromethylphenoxy)-1-
propanamine, ((R)-norfluoxetine), (R)-13. Prepared from
(R)-9 in 68% yield using the procedure described for
(S)-norfluoxetine. [h]3D0=+3.0 (c 1, CHCl3); NMR spec-
tral data is identical to (S)-13.
4.6.2.
(R)-N-(Ethoxycarbonyl)-3-amino-1-phenyl-1-
propanol, ((R)-carbamate), (R)-10. Prepared in 88%
yield from (R)-amino alcohol (R)-9 by employing a
similar procedure to that used for the preparation of
(S)-10. Mp 67–69°C; [h]3D0=+24.1 (c 1.0, CHCl3);
NMR, IR, and mass spectral data are identical to
(S)-10.
4.9. Preparation of enantiomers of N-(ethoxycarbonyl)-
3-(4-(trifluoromethyl)-phenoxy)-3-phenyl-1-propanamine,
(S)- and (R)-14
4.9.1.
(S)-N-(Ethoxycarbonyl)-3-(4-(trifluoromethyl)-
4.7. Preparation of enantiomers of N-Methyl-3-amino-
1-phenyl-1-propanol, (S)- and (R)-11
phenoxy)-3-phenyl-1-propanamine, (S)-14. Diisopropyl
azodicarboxylate (0.41 g, 2.03 mmol) in dry ether (1
mL) was slowly added to a solution of triphenyl phos-
phine (0.79 g, 3.01 mmol) in dry ether (6 mL) at 0°C to
form a betaine complex, after 20 min at 0°C 4-hydroxy
benzotrifluoride (0.39 g, 2.41 mmol) taken in dry ether
(2 mL) was added. To this resultant mixture was added
(R)-10 (0.45 g, 2.02 mmol) in dry ether (5 mL) and
4.7.1. (S)-N-Methyl-3-amino-1-phenyl-1-propanol, (S)-
11. To a solution of LAH (0.17 g, 4.48 mmol) in dry
THF (15 mL) under N2 at room temperature was
added dropwise a solution of (S)-10 (0.50 g, 2.24 mmol)
in dry THF (3 mL) and the resultant reaction mixture

2048
A. Kamal et al. / Tetrahedron: Asymmetry 13 (2002) 2039–2051
allowed to warm to room temperature. After comple-
tion of the reaction as indicated by the TLC (2 h), the
ether solvent was evaporated from the reaction mixture
and the residue was purified by column chromatogra-
phy employing EtOAc–hexane (5:95) as eluent to afford
the required product in 71% yield. [h]3D0=−7.1 (c 1.0,
CHCl3); IR (Neat) 3420, 3310, 3059, 3027, 2964, 2918,
7.20–7.33 (m, 5H), 7.40 (d, 2H, J=7.79 Hz); 13C NMR
(50 MHz, CDCl3) l 32.97, 34.76, 45.87, 76.99, 115.68,
123.14, 125.54, 126.63, 126.66, 128.19, 128.91, 139.41,
159.74; mass (EI) 309 (M+), 164, 162, 148, 104, 91, 77,
44.
4.10.2. (R)-N-Methyl-3-phenyl-3-(4-trifluoromethylphe-
noxy)-1-propanamine, (R)-fluoxetine, (R)-12. Using
method (A) described for the preparation of (S)-fluox-
etine, (R)-fluoxetine (R)-12 was prepared from (R)-14
in 85% yield and also using procedure (B) (R)-fluox-
etine (R)-12 was prepared from (R)-11 in 70% yield.
[h]3D0=+4.3 (c 0.7, CHCl3); NMR, IR, and mass spec-
tral data are identical to (S)-12.
1
1694, 1498, 1318, 1231, 1161, 1114 cm−1; H NMR (200
MHz, CDCl3) l 1.24 (t, 3H, J=7.32 Hz), 2.15–2.20 (m,
2H), 3.37 (q, 2H, J=5.86 Hz), 4.09 (q, 2H, J=7.32
Hz), 4.76 (br s, 1H), 5.22 (dd, 1H, J1=4.39 Hz, J2=
8.06 Hz), 6.87 (d, 2H, J=8.79 Hz), 7.26–7.35 (m, 5H),
7.44 (d, 2H, J=8.79 Hz); 13C NMR (50 MHz, CDCl3)
l 14.54, 37.83, 38.67, 60.74, 78.44, 115.69, 123.00,
125.62, 126.70, 126.74, 127.95, 128.83, 140.39, 156.67,
160.20; mass (EI) 209, 164, 145, 104, 44; FABMS 390
(M++Na), 366 (M+−1), 206, 117, 102, 91.
4.11. Preparation of enantiomers of N-(ethoxycar-
bonyl)-3-(2-(methyl)-phenoxy)-3-phenyl-1-propanamine,
(S)- and (R)-15
4.9.2.
(R)-N-(Ethoxycarbonyl)-3-(4-(trifluoromethyl)-
phenoxy)-3-phenyl-1-propanamine, (R)-14. Prepared
from (S)-10 using the same procedure as for (S)-14 in
78% yield with inversion at the stereogenic center.
[h]3D0=+7.4 (c 1.0, CHCl3); NMR, IR, and mass spec-
tral data are identical to (S)-14.
4.11.1. (S)-N-(Ethoxycarbonyl)-3-(2-(methyl)-phenoxy)-
3-phenyl-1-propanamine, (S)-15. Diisopropyl azodicar-
boxylate (0.41 g, 2.03 mmol) in dry ether (1 mL) was
slowly added to a solution of triphenylphosphine (0.79
g, 3.01 mmol) in dry ether (6 mL) at 0°C to form a
betaine complex, after 20 min at 0°C a solution of
2-methyl phenol (0.26 g, 2.41 mmol) in dry ether (2 mL)
was added. To this resultant mixture was added (R)-10
(0.45 g, 2.02 mmol) in dry ether (5 mL) and allowed to
reach to room temperature. After completion of the
reaction as indicated by the TLC (2 h), the ether solvent
was evaporated from the reaction mixture and the
residue was purified by column chromatography
employing EtOAc–hexane as eluent to afford the
required product in 76% yield. [h]3D0=+10.2 (c 1.0,
CHCl3); IR (Neat) 3443, 3333, 3059, 3012, 2965, 2918,
4.10. Preparation of enantiomers of fluoxetine, (S)- and
(R)-12
4.10.1. (S)-N-Methyl-3-phenyl-3-(4-trifluoromethylphe-
noxy)-1-propanamine ((S)-fluoxetine) (S)-12. Method A:
To a solution of LAH (0.08 g, 2.18 mmol) in dry THF
(8 mL) under N2 at room temperature was added
dropwise a solution of (S)-14 (0.40 g, 1.09 mmol) in dry
THF (4 mL) and the resultant reaction mixture was
heated under reflux for 1 h. After completion of the
reaction the mixture was cooled to room temperature
and ethyl acetate was slowly added. The mixture was
filtered, the residue was thrice treated with ethyl acetate
and filtered. The filtrates were combined and evapo-
rated under reduced pressure to leave a residue, which
was purified by column chromatography employing
NH4OH–MeOH–EtOAc (1:9:90) as eluent to afford the
product in 85% yield.
1
1686, 1600, 1506, 1475, 1223, 1027 cm−1; H NMR (200
MHz, CDCl3) l 1.22 (t, 3H, J=6.40 Hz), 2.14 (q, 2H,
J=5.33), 2.30 (s, 3H), 3.34 (q, 2H, J=5.33 Hz), 4.06 (q,
2H, J=6.40 Hz), 4.85 (br s, 1H), 5.20 (t, 1H, J=5.50
Hz), 6.49 (d, 1H, J=8.00 Hz), 6.72 (t, 1H, J=6.40 Hz),
6.90 (t, 1H, J=8.00 Hz), 7.06 (d, 1H, J=6.40 Hz),
7.20–7.32 (m, 5H); 13C NMR (50 MHz, CDCl3) l
14.51, 16.48, 38.01, 38.56, 60.58, 77.91, 112.63, 120.36,
125.56, 126.25, 126.48, 127.51, 128.56, 130.60, 141.26,
155.61, 156.58; mass (EI) 205, 115, 43; FABMS 312
(M+−1), 206, 197, 117, 102, 91.
Method B: To a solution of (S)-11 (0.20 g, 1.21 mmol)
in dry DMSO (5 mL) at room temperature was added
NaH (0.08 g (60%), 2.00 mmol) and heated at 55°C for
45 min to form the sodium alkoxide of the amino
alcohol. To the above formed alkoxide was added
4-chlorobenzotrifluoride (0.33 g, 1.82 mmol) taken in
DMSO (3 mL) and the resultant mixture was heated for
1 h at 90–100°C. After completion of the reaction as
indicated by the TLC, the reaction mixture was allowed
to come to room temperature, diluted with cool water
(8 mL) and then extracted with diethyl ether (3×20
mL). The combined ether layers were concentrated to
leave a residue, which was purified by column chro-
matography to afford the required product (S)-fluox-
etine (S)-12 in 71% yield. [h]3D0=−4.1 (c 1.0, CHCl3); IR
(Neat) 3369, 3031, 2954, 2931, 2731, 1600, 1323, 1254,
4.11.2. (R)-N-(Ethoxycarbonyl)-3-(2-(methyl)-phenoxy)-
3-phenyl-1-propanamine, (R)-15. Prepared from (S)-10
in 70% yield with inversion at the stereogenic center
analogous to (S)-15. [h]3D0=−10.7 (c 1.0, CHCl3);
NMR, IR, and mass spectral data are identical to
(S)-15.
4.12. Preparation of enantiomers of tomoxetine, (S)-
and (R)-16
4.12.1. (S)-N-Methyl-3-(2-methylphenoxy)-3-phenyl-1-
propanamine ((S)-tomoxetine), (S)-16. To a solution of
LAH (0.07 g, 1.92 mmol) in dry THF (8 mL) under N2
at room temperature was added dropwise a solution of
15S (0.30 g, 0.96 mmol) taken in dry THF (2 mL) and
1
1108 cm−1; H NMR (200 MHz, CDCl3) l 2.00–2.32
(m, 2H), 2.46 (s, 3H), 2.73–2.88 (m, 2H), 5.32 (dd, 1H,
J1=5.19 Hz, J2=7.79 Hz), 6.86 (d, 2H, J=7.79 Hz),

A. Kamal et al. / Tetrahedron: Asymmetry 13 (2002) 2039–2051
2049
the resultant reaction mixture was heated under reflux
for 1 h. After completion of the reaction the reaction
mixture was cooled to room temperature and ethyl
acetate was slowly added. The resultant reaction mix-
ture was filtered, residue was thrice treated with ethyl
acetate and filtered. Solvent in all the combined filtrates
was evaporated under reduced pressure to leave a
residue, which was purified by column chromatography
employing NH4OH–MeOH–EtOAc (1:9:90) as eluent
to afford the product in 88% yield. [h]3D0=+42.2 (c 0.56,
MeOH); IR (Neat) 3341, 3004, 2925, 2886, 1584, 1561,
1474, 1388, 1224, 1108, 1038 cm−1; 1H NMR (200
MHz, CDCl3) l 2.07–2.17 (m, 1H), 2.23–2.29 (m, 1H),
2.33 (s, 3H), 2.49 (s, 3H), 2.80–2.89 (m, 2H), 5.24–5.31
(m, 1H), 6.57 (d, 1H, J=5.70 Hz), 6.75 (t, 1H, J=4.70
Hz), 6.92 (t, 1H, J=5.70 Hz), 7.07 (d, 1H, J=4.70 Hz),
7.30–7.35 (m, 5H); 13C NMR (50 MHz, CDCl3) l
16.42, 32.86, 34.76, 46.02, 76.47, 112.65, 120.60,
125.566, 126.568, 126.73, 127.88, 128.75, 130.65, 140.32,
155.22; mass (EI) 255 (M+), 148, 104, 91, 77, 44.
4.13.2.
(R)-N-(Ethoxycarbonyl)-3-(2-(methoxy)-
phenoxy)-3-phenyl-1-propanamine, (R)-17. Prepared
from (S)-10 in 60% yield with inversion at the stereo-
genic center analogous to (S)-17. [h]3D0=+9.0 (c 1.0,
CHCl3); NMR, IR, and mass spectral data are identical
to (S)-17.
4.14. Preparation of enantiomers of nisoxetine, (S)-
and (R)-18
4.14.1. (S)-N-Methyl-3-(2-methoxyphenoxy)-3-phenyl-1-
propanamine ((S)-nisoxetine) (S)-18. To a solution of
LAH (0.06 g, 1.52 mmol) in dry THF (9 mL) under N2
at room temperature was added dropwise a solution of
(S)-17 (0.25 g, 0.76 mmol) taken in dry THF (3 mL)
and the resultant reaction mixture was heated under
reflux for 1 h. After completion of the reaction the
mixture was cooled to room temperature and ethyl
acetate was slowly added. The resultant mixture was
filtered and the residue was thrice treated with ethyl
acetate and filtered. The filtrates were combined and
evaporated under reduced pressure to leave a residue,
which was purified by column chromatography employ-
ing NH4OH–MeOH–EtOAc (1:9:90) as eluent to afford
the product in 80% yield. [h]3D0=−34.6 (c 1.0, CHCl3);
IR (Neat) 3385, 3146, 3062, 2962, 2923, 2838, 1492,
1246, 1215, 1108, 1015 cm−1; 1H NMR (200 MHz,
CDCl3) l 2.13–2.40 (m, 2H), 2.62 (s, 3H), 3.07–3.24 (m,
2H), 3.87 (s, 3H), 5.09–5.20 (m, 1H), 6.49 (d, 1H,
J=9.75 Hz), 6.54–6.68 (m, 1H), 6.77–6.87 (m, 2H),
7.20–7.35 (m, 5H); 13C NMR (50 MHz, CDCl3) l
32.77, 34.07, 46.81, 55.82, 81.21, 111.69, 116.64, 120.78,
122.36, 125.72, 128.05, 128.68, 140.17, 146.52, 149.59;
mass (EI) 141, 124, 109, 91, 44; FABMS 272 (M++1),
160, 113, 91, 58.
4.12.2. (R)-N-Methyl-3-(2-methylphenoxy)-3-phenyl-1-
propanamine ((R)-tomoxetine), (R)-16. (R)-Tomoxetine
was prepared in 84% yield by subjecting (R)-15 to LAH
reduction, similar to the preparation of (S)-tomoxetine.
[h]3D0=−43.0 (c 0.8, MeOH); NMR, IR, and mass spec-
tral data are identical to (S)-16.
4.13. Preparation of enantiomers of N-(ethoxycar-
bonyl)-3-(2-(methoxy)phenoxy)-3-phenyl-1-propanamine,
(S)- and (R)-17
4.13.1.
(S)-N-(Ethoxycarbonyl)-3-(2-(methoxy)-
phenoxy)-3-phenyl-1-propanamine, (S)-17. Diisopropyl
azodiarboxylate (0.41 g, 2.03 mmol) in dry ether (1 mL)
was slowly added to a solution of triphenyl phosphine
(0.79 g, 3.01 mmol) in dry ether (6 mL) at −20°C to
form a betaine complex, after 20 min at −20°C, 2-
methoxy phenol (0.30 g, 2.41 mmol) taken in dry ether
(2 mL) was added. To this resultant mixture was added
(R-carbamate) (R)-10 (0.45 g, 2.02 mmol) in ether (5
mL) and allowed to reach to room temperature. After
completion of the reaction as indicated by the TLC (2
h), the ether solvent was evaporated from the reaction
mixture and the residue was purified by column chro-
matography employing EtOAc–hexane (5:95) as eluent
to afford the required product in 60% yield. [h]3D0=−8.7
(c 1.0, CHCl3); IR (Neat) 3385, 3061, 3031, 2985, 2946,
2838, 1715, 1569, 1485, 1246, 1215, 1115, 1046, 1015
cm−1; 1H NMR (200 MHz, CDCl3) l 1.25 (t, 3H,
J=7.30 Hz), 2.14 (q, 2H, J=5.86), 3.22–3.35 (m, 1H),
3.49–3.67 (m, 1H), 3.94 (s, 3H), 4.12 (q, 2H, J=7.30
Hz), 5.12 (t, 1H, J=6.59 Hz), 6.5 (br s, 1H), 6.55 (d,
1H, J=10.25 Hz), 6.60–6.70 (m, 1H), 6.82–6.85 (m,
2H), 7.25–7.35 (m, 5H); 13C NMR (50 MHz, CDCl3) l
14.67, 38.49, 38.68, 55.41, 60.37, 82.02, 111.18, 115.26,
120.53, 121.44, 125.54, 127.62, 128.57, 141.25, 147.13,
149.46, 156.87; mass (EI) 206, 124, 108, 102, 91, 77;
FABMS 352 (M++Na), 330 (M++1), 245, 206, 159, 117,
102, 91.
4.14.2. (R)-N-Methyl-3-(2-methoxyphenoxy)-3-phenyl-1-
propanamine ((R)-nisoxetine), (R)-18. Prepared in 80%
yield by subjecting (R)-17 to LAH reduction, using a
method analogous to the preparation of (S)-nisoxetine.
[h]3D0=+36.1 (c 1.0, CHCl3); NMR, IR, and mass spec-
tral data are identical to (S)-18.
4.15. (S)-3-Hydroxy-3-phenyl propanamide, 19
To a stirred solution of (S)-1 (0.44 g, 3 mmol) in
DMSO (3 mL) was added H2O2 (1 mL, 100 vol) and
K2CO3 (0.07 g, 0.50 mmol) while keeping the tempera-
ture below 30°C. After stirring the reaction mixture for
15 min, H2O (5 mL) was added and the mixture was
extracted with diethyl ether (3×10 mL). Evaporation of
ether and purification of the residue afforded (S)-3-
hydroxy-3-phenyl propanamide in 70% yield with >99%
ee (chiral HPLC). Mp 101–103°C; [h]3D0=−32.1 (c 1.0,
EtOH); IR (KBr) 3377, 3300, 3177, 2961, 2900, 2761,
1623, 1431, 1392, 1331, 1046 cm−1; 1H NMR (200
MHz, CD3OD) l 2.41–2.70 (m, 2H), 4.93–5.11 (m, 1H),
7.20–7.40 (m, 5H); mass (EI) 165, 141, 120, 105, 91, 77,
59.

2050
A. Kamal et al. / Tetrahedron: Asymmetry 13 (2002) 2039–2051
4.16. (S)-3-Hydroxy-3-phenylpropanoic acid, 20
Pharmaceutical Company (Japan) is gratefully
acknowledged. Two of the authors G.B.R.K. and R.R.
are thankful to CSIR, New Delhi, for the award of
research fellowship.
To (S)-3-hydroxy-3-phenyl propanamide (0.30 g, 1.82
mmol) was slowly added 6N HCl (3 mL) and the
mixture was stirred overnight. The reaction mixture
was diluted with water and then extracted with ethyl
acetate (2×10 mL). Treatment of the EtOAc layer with
10% Na2CO3 and then acidification of the resulting
mixture to pH 5–6 gave 20 in 60% yield. Mp 112–
114°C; [h]3D0=−18.1 (c 1, EtOH), lit.7c [h]2D2=−18.9 (c
2.27, EtOH); IR (KBr) 3292, 2969, 2915, 2846, 2631,
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4.17. (S)-Ethyl 3-hydroxy-3-phenyl propanoate, 21
To a solution of 20 (0.33 g, 1.99 mmol) in dry acetone
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4.18. (S)-1-Phenyl-1,3-propanediol, 22
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To a stirred solution of LAH (0.06 g, 1.65 mmol) in dry
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of 21 (0.32 g, 1.65 mmol) in dry THF (3 mL) at room
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99). The generous gift of Pseudomonas cepacia lipases
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