Asymmetric dihydroxylation route to (R)-isoprenaline, (R)-norfluoxetine and (R)-fluoxetine

Article abstract of DOI:10.1016/j.tetasy.2004.11.005

An efficient asymmetric synthesis of enantiomerically pure (R)-isoprenaline, (R)-norfluoxetine and (R)-fluoxetine is described using Sharpless asymmetric dihydroxylation as the key step.

Full text of DOI:10.1016/j.tetasy.2004.11.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3955–3959
Asymmetric dihydroxylation route to (R)-isoprenaline,
(R)-norfluoxetine and (R)-fluoxetine
*
Pradeep Kumar, Rajesh Kumar Upadhyay and Rajesh Kumar Pandey
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune-411008, India
Received 7 October 2004; accepted 1 November 2004
Available online 24 November 2004
Abstract—An efficient asymmetric synthesis of enantiomerically pure (R)-isoprenaline, (R)-norfluoxetine and (R)-fluoxetine is
described using Sharpless asymmetric dihydroxylation as the key step.
ꢀ
2004 Elsevier Ltd. All rights reserved.
1. Introduction
atric disorders (depression, anxiety, alcoholism) and
5
also metabolic problems (obesity and bulimia). In view
Due to the high demand and preference for the use of
enantiomerically pure drugs, there has been an upsurge
of interest in the asymmetric synthesis of pharmaceutical
products. (R)-Isoprenaline 1 (Fig. 1) is a clinically
potent b-adrenoreceptor agonist and sympathomimetic
drug that dilates the bronchioles (small air passages in
the lungs) and improves the transmission of electrical
of different pharmacological activities displayed by the
individual enantiomers and differences in metabolic
behaviour, the asymmetric synthesis of both enantio-
mers of fluoxetine and related compounds has received
growing interest in recent years. Most of these ap-
proaches start with a three-carbon-chain segment and
6
establish the configuration by enzymatic resolution,
7
1
8
signals in the heart. It is used as a bronchodilator to re-
lieve the bronchopasm associated with asthma, bronch-
asymmetric reduction, asymmetric epoxidation, chem-
9
ical resolution and an asymmetric carbonyl-ene reac-
1
0
itis and emphysema. The (R)-form of isoprenaline is
2
tion. Recently a four-carbon-chain segment has been
employed to make fluoxetine and its analogues by incor-
porating asymmetric reduction and Hofmann rearrange-
approximately 90 times more potent than the (S)-form.
Presently (R)-isoprenaline is produced by a resolution
3
11
process. To our knowledge there has been only one re-
4
port of its asymmetric synthesis using the CBS catalyst.
ment. As part of our research program aimed at
developing enantioselective synthesis of naturally occur-
1
2
ring lactones and amino alcohols, the Sharpless asym-
1
3
metric dihydroxylation was envisaged as a powerful
tool to chiral dihydroxy compounds offering consider-
able opportunities for synthetic manipulation. Herein
we report a new and highly enantioselective synthesis
of (R)-isoprenaline, (R)-norfluoxetine and (R)-fluoxetine
by employing Sharpless asymmetric dihydroxylation as
the key step.
CF3
OH
O
H
N
HO
HO
NHR
1
(R)-(-)-Isoprenaline
2 R = H, (R)-Norfluoxetine
R = CH , (R)-Fluoxetine
3
3
2. Results and discussion
Figure 1.
Norfluoxetine 2 and fluoxetine 3 are among the most
important pharmaceuticals for the treatment of psychi-
The synthesis of (R)-isoprenaline started from commer-
cially available 3,4-dimethoxybenzaldehyde 4 as de-
picted in Scheme 1. Compound 4 was subjected to
Wittig olefination with methylenetriphenylphosphorane
generated by the reaction of triphenylmethylphospho-
*
Corresponding author. Fax: +91 20 25893614; e-mail: tripathi@
dalton.ncl.res.in
1
4
nium iodide and n-BuLi to give styrene 5 in 90% yield.
0
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.005

3956
P. Kumar et al. / Tetrahedron: Asymmetry 15 (2004) 3955–3959
OH
CF3
CF3
O
MeO
MeO
MeO
MeO
OH
MeO
MeO
b
Ref. 14
OTs
a
H
OH
5
6
a
b
4
NH2
O
O
OH
OH
OH
H
NH2
NHCH3
MeO
MeO
I
MeO
MeO
N
MeO
MeO
d
c
14
2
3
(R)-Norfluoxetine
(R)-Fluoxetine
7
8
9
CF3
OH
H
N
HO
HO
e
c
O
1
NHCH .HCl
3
Scheme 1. Reagents and conditions: (a) (DHQD)
CO , t-BuOH–H O, OsO
0.2mol%), TsCl, NEt , CH
reflux, 6h, 95%; (d) isopropylamine, sealed tube, 80ꢁC, 7h, 90%; (e)
AlCl , EtSH, CH Cl , rt, 3h, 80%.
2
PHAL, K
3
6
Fe(CN) ,
K
2
3
2
4
, 0ꢁC, 24h, 97%; (b) dibutyltin oxide
Cl , rt, 45min, 95%; (c) NaI, acetone,
(R)-Fluoxetine hydrochloride
(
3
2
2
Scheme 3. Reagents and conditions: (a) NaH, DMSO, 55ꢁC, 30min,
then 4-chlorobenzotrifluoride, 90ꢁC, 1h, 90%; (b) (i) ClCO Me,
CH Cl , aq K CO , 30min, (ii) LiAlH
, THF, 65ꢁC, 2h, 90%; (c)
HCl gas, ether, 95%.
2
3
2
2
2
2
2
3
4
The dihydroxylation of 5 with osmium tetroxide and
potassium ferricyanide as co-oxidant under Sharpless
1
3
asymmetric dihydroxylation conditions gave the diol
in 97% yield with 97% ee. Selective conversion of the
primary hydroxyl group of 6 into a tosylate was carried
styrene 10. We planned to incorporate the amine
functionality early in the synthesis via cyanide addition.
Towards this end, the asymmetric dihydroxylation of
styrene 10 gave the diol 11 essentially in quantitative
yield with 97% ee. The diol 11 was first treated with
dibutyltin oxide (0.2mol%) followed by addition of
tosyl chloride and triethylamine in dichloromethane to
give the monotosyl compound 12 in quantitative yield.
6
out using tosyl chloride in the presence of a catalytic
1
5
amount (0.2mol%) of dibutyltin oxide to afford 7 in
5% yield.
9
Our initial attempt to synthesize 1 either by the direct
nucleophilic displacement of tosylate 7 with isopropyl-
amine or by the conversion to epoxide and subsequent
opening with isopropylamine was not very satisfactory.
Hence, we attempted the following sequence of reac-
tions. The nucleophilic displacement of tosylate 7 with
sodium iodide in acetone under reflux furnished the iodo
compound 8 in essentially quantitative yield. Compound
The nucleophilic displacement of tosylate 12 with so-
dium cyanide furnished the cyano compound 13 in
9
0% yield. While the reduction of nitrile 13 with lithium
aluminium hydride was not very satisfactory, the reac-
tion proceeded smoothly with the use of borane dimeth-
ylsulfide as reducing agent to give the 1,3-amino alcohol
8
was reacted with isopropylamine at 80ꢁC in a sealed
tube to afford 9 in 90% yield. Subsequent cleavage of
1
4 in 96% yield.
the methoxy groups using aluminium chloride and ethane-
1
The key intermediate 1,3-amino alcohol 14 was then
used to prepare the optically active (R)-norfluoxetine 2
and fluoxetine 3. Thus, the arylation of 14 was carried
out by nucleophilic aromatic substitution employing
NaH as a base and 4-chlorobenzotrifluoride as an electro-
phile in DMSO to afford (R)-norfluoxetine in 90% yield
as a viscous liquid. Conversion of (R)-norfluoxetine 2 to
6
thiol furnished the target compound 1 in 80% yield
as a white solid.
The synthesis of (R)-norfluoxetine and (R)-fluoxetine is
illustrated in Scheme 3. The 1,3-amino alcohol 14 is
envisaged as a common building block from which
(
(
R)-fluoxetine and norfluoxetine can be synthesized
Scheme 2). The synthesis of intermediate 14 starts from
(R)-fluoxetine 3 was achieved via carbamate formation.
Thus, the treatment of 2 with methyl chloroformate in
aq K CO afforded the carbamate, which on subsequent
2
3
reduction with lithium aluminium hydride furnished
R)-fluoxetine 3. This was treated with hydrogen chlo-
ride to form the colourless, crystalline hydrochloride
(
OH
OH
OH
OTs
a
b
of 3 in 95% yield.
11
12
10
OH
OH
3. Conclusion
CN
c
d
NH2
In summary, a practical and highly enantioselective syn-
thesis of (R)-isoprenaline 1, (R)-norfluoxetine 2 and (R)-
fluoxetine 3 has been achieved using the Sharpless asym-
metric dihydroxylation as the key step and source of chi-
rality. The synthetic strategy described can be further
extended to other enantiomers and related analogues.
1
3
14
Scheme 2. Reagents and conditions: (a) (DHQ)
CO , t-BuOH–H O, OsO
0.2mol%), p-TsCl, NEt , CH
O (4:1), rt, 24h, 90%; (d) BH
2
PHAL, K
, 0ꢁC, 24h, 97%; (b) dibutyltin oxide
Cl , rt, 45min, 99% (c) NaCN, EtOH–
ÆSMe , THF, reflux, 2h, 96%.
3 6
Fe(CN) ,
K
2
3
2
4
(
3
2
2
H
2
3
2

P. Kumar et al. / Tetrahedron: Asymmetry 15 (2004) 3955–3959
3957
4. Experimental
(Na SO ) and concentrated. Silica gel column chroma-
2 4
tography of crude product using petroleum ether–
EtOAc (6:4) as eluent afforded monotosyl compound 7
4
.1. General experimental
25
(
4.88g, 95%) as a viscous liquid: ½aŠ ¼ À21:0 (c 2.64,
D
1
The solvents were purified and dried by the standard
procedures prior to use; petroleum ether of boiling range
6
sodium D line on a JASCO-P-1020-polarimeter. Infra-
red spectra were recorded on Perkin Elmer FT-IR
spectrometer. Mass spectra were recorded either by
GC–MS or with a Finnigan LCMS mass spectrometer.
Enantiomeric excess was measured using either the
chiral HPLC or by comparison with optical rotation.
The enantiomeric excess determined for the diols was
MeOH). H NMR (200MHz, CDCl ): d 2.89 (s, 3H),
3
3.77 (s, 1H, OH), 4.28 (s, 3H), 4.31 (s, 3H), 4.54 (d,
J = 3Hz, 2H), 5.30 (t, J = 3Hz, 1H), 7.27–7.30 (m,
0–80ꢁC was used. Optical rotation was measured using
1
3
3H), 7.77 (d, J = 9Hz, 2H) 8.20 (d, J = 9Hz, 2H);
NMR (50MHz, CDCl ): 21.12. 55.48, 71.26, 73.80,
C
3
109.05, 110.94, 118.23, 127.48, 129.40, 130.71, 132.48,
144.57, 148.87; IR (CHCl3): 3509, 2939, 1733,
1517cm ; mass (ESI): 370 (M + H O). Anal. Calcd
À1
+
2
for C H O S: C, 57.94; H, 5.72; S, 9.10. Found: C,
7
1
20
6
57.98; H, 5.80, S, 9.20.
9
7%. HPLC model: Merck-Hitachi Lachrom Photo
Diode Array detector (PDA); column: Astec Cyclobond
I (4.6mm ID · 250mmL); mobile phase: methanol–
water: (40:60); flow: 1mL/min.
4.2.4. (R)-1-(3,4-Dimethoxyphenyl)-2-iodo-ethanol 8.
To a solution of tosyl compound 7 (0.25g, 0.71mmol)
in acetone (3mL) was added sodium iodide (1.06g,
7.0mmol) and reaction mixture was refluxed for 6h.
4
4
.2. Synthesis of isoprenaline
The reaction mixture was cooled to room temperature
and solvent was evaporated and water (2.0mL) was
added and extracted with ethyl acetate (3 · 20mL); the
combined organic layer were washed with water and
dried over sodium sulfate (Na SO ) and concentrated.
.2.1. 3,4-Dimethoxystyrene 5. Prepared from 3,4-
dimethoxy benzaldehyde in 90% yield following a litera-
1
ture procedure.
4
2
4
Silica gel column chromatography of crude product
using petroleum ether–EtOAc (4:1) as eluent gave the
4.2.2. (R)-1-(3,4-Dimethoxyphenyl)ethane-1,2-diol 6.
To a mixture of K Fe(CN) (30.07g, 91.33mmol) and
25
iodo compound 8 (0.207g, 95%); ½aŠ ¼ À27:9 (c
3
6
D
1
K CO (12.62g, 91.33mmol) and (DHQD) PHAL
2
1.74, CHCl ); H NMR (200MHz, CDCl ): d 3.38–
3
2
3
3
(
238mg, 0.304mmol) in t-BuOH–H O (1:1, 152mL)
2
3.48 (m, 2H), 3.84 (s, 3H), 3.87 (s, 3H), 4.77–4.81 (m,
1H), 6.82–6.91 (m, 3H); C NMR (50MHz, CDCl3):
d 14.98, 55.60, 73.53, 108.42, 110.77, 117.90, 133.56,
1
3
cooled to 0ꢁC was added osmium tetroxide (1.3mL,
0
0
.1M solution in toluene). After stirring for 5min at
ꢁC, olefin 5 (5.0g, 30.45mmol) was added in one por-
148.59; IR (CHCl ): 3401, 3020, 2936, 1720, 1595,
3
À1
+
1516cm ; GC–MS (ESI): 308 (M ), C H IO : C,
tion. The reaction mixture was stirred at 0ꢁC for 24h
and then quenched with solid sodium sulfide (7g). The
stirring was continued for an additional 45min and then
solution was extracted with ethyl acetate (3 · 50mL).
The combined organic phase were dried (Na SO ) and
concentrated. Silica gel column chromatography of the
crude product using petroleum ether–EtOAc (3:7) as
eluent gave 6 (5.85g, 97%) as a white solid, mp 89–
1
0
13
3
38.98; H, 4.25; I, 41.19. Found: C, 39.02; H, 4.20; I,
41.11.
4.2.5. (R)-1-(3,4-Dimethoxyphenyl)-2-isopropyl amino-
ethanol 9. A solution of iodo compound 8 (0.2g,
0.65mmol) and freshly distilled isopropylamine
(0.383g, 6.5mmol) was kept under sealed tube at
MR 80ꢁC for 7h. Removal of the excess isopropylamine
afforded crude compound 9, which on purification by
silica gel column chromatography using ethyl acetate–
methanol (9:1) as eluent afforded a yellow coloured
2
4
2
5
1
9
0ꢁC; ½aŠ ¼ À32:2 (c 1.4, MeOH).
H
N
D
(
200MHz, CDCl ): d 2.05 (br s, 2H, OH), 3.61 (dd,
3
J = 10.0, 8.0Hz, 2H), 3.79 (s, 6H), 4.00–4.03 (m, 1H),
1
3
6
5
1
1
.73–7.32 (m, 3H); C NMR (50MHz, CDCl ): d
3
1
7
6.17, 68.30, 74.66, 109.83, 111.65, 118.67, 133.49,
49.10, 149.47; IR (CHCl ): 3410, 2938, 2839, 1608,
product, mp 127ꢁC (lit. mp 126–128ꢁC). The spectro-
scopic data were in full agreement with the literature
17
values.
3
À1
+
595cm ; mass (ESI): 198 (M ). Anal. Calcd for
C H O : C, 60.59; H, 7.12. Found: C, 60.49; H, 7.09.
1
0
14
4
The ee obtained was 97% as determined by chiral
HPLC.
4.2.6. (R)-(À)-Isoprenaline 1. To a mixture of dry ethane-
thiol (1mL) in dichloromethane was added alumin-
ium chloride (0.8g, 6.0mmol) at 0ꢁC. The resulting
solution was warmed to room temperature, and com-
pound 9 (0.079g, 0.313mmol) was added with stirring.
After stirring overnight, the reaction mixture was
poured into water, acidified with dilute HCl and
extracted with dichloromethane. The organic layer was
evaporated to give a crude product. Chromatography
over a silica gel column using chloroform–methanol
(9.5:0.5) as eluent gave 1 (0.055g, 80%) as a white solid.
4
.2.3. (R)-Toluene-4-sulfonic acid 2-(3,4-dimethoxyphen-
yl)-2-hydroxyethyl ester 7. To a mixture of diol 6
2.9g, 14.63mmol), in dry dichloromethane (30mL)
(
was added dibutyltin oxide (8.0mg, 0.2mol% of diol)
followed by the addition of p-toluensulfonyl chloride
(
1
3.03g, 15.93mmol) and triethylamine (2.2mL,
5.70mmol) and the reaction was stirred at room tem-
perature under nitrogen. The reaction was monitored
by TLC. After completion of reaction (45min), the mix-
ture was quenched by adding water. The solution was
extracted with dichloromethane (3 · 25mL) and then
combined organic phase were washed with water, dried
4
25
Mp 160ꢁC (lit. 163–164ꢁC), ½aŠ ¼ À42:3 (c 1, 2M
D
4
23
HCl) [lit. ½aŠ ¼ À43:5 (c 1, 2M HCl)]. The spectro-
D
scopic data of 1 were in full agreement with the litera-
4
ture values.

3958
P. Kumar et al. / Tetrahedron: Asymmetry 15 (2004) 3955–3959
4
4
.3. Synthesis of norfluoxetine and fluoxetine
methyl sulfide complex (0.84g, 11.0mmol) at room
temperature. Methyl sulfide was then distilled from the
reaction vessel and the resulting THF solution refluxed
for 2.5h. After cooling to room temperature, methanolic
HCl (6.25mL, 1.0M) was added to the reaction mixture.
Methanol and methyl borate were removed by distilla-
tion and the reaction mixture neutralized with sodium
hydroxide (6.0mL, 5N). Extraction of the mixture with
dichloromethane followed by concentration provided
the crystalline (R)-3-phenyl-3-hydroxypropylamine 14
.3.1. (S)-1-Phenylethane-1,2-diol 11. To a mixture of
K Fe(CN) (47g, 144mmol), K CO (19.88g, 144mmol)
3
and (DHQ) PHAL (0.378g, 0.48mmol) in t-BuOH–
2
3
6
2
H O (1:1, 240mL:240mL) cooled to 0ꢁC was added
2
OsO (1.94mL, 0.4mol%, 0.1M solution in toluene).
After stirring for 5min at 0ꢁC, styrene 10 (5.0g,
4
4
8.0mmol) was added in one portion. The reaction mix-
ture was stirred at 0ꢁC for 24h and then quenched with
solid sodium sulfite. The stirring was continued for 1h
and the solution was extracted with ethyl acetate. The
combined organic phase were washed with brine, dried
25
(1.23g, 96%). ½aŠ ¼ þ40:5 (c 1, CHCl ). The spectro-
D
scopic data were in full agreement with the literature
3
6
j
values.
(
tography of crude product using petroleum ether–
Na SO ) and concentrated. Silica gel column chroma-
2 4
4.3.5. (R)-Norfluoxetine 2. A solution of (R)-3-phenyl-
3-hydroxypropylamine 14 (1.0g, 6.6mmol) in DMSO
(2.0mL) was stirred with sodium hydride (0.47g, 9.9
mmol 50% in oil) at 55ꢁC for 30min under nitrogen
atmosphere. 4-Chlorobenzotrifluoride (1.8g, 9.9mmol)
in 1.0mL DMSO was then slowly added to the above
reaction mixture and the resulting solution heated to
90ꢁC for 1h. The resulting mixture was cooled to room
temperature and diluted with NaOH (10.0mL, 2N aq
solution). Toluene (4 · 3mL) was used to extract the
product 2 from the hydroxide solution as viscous liquid
EtOAc (3.5:1.5) as eluent gave (S)-phenylethylene glycol
1
25
1 as a white solid. (6.6g, 99%). Mp 65ꢁC ½aŠ ¼ þ54:9
D
(
ment with the literature values.
c 1, CHCl ). The spectroscopic data were in full agree-
3
1
8
4
.3.2. (S)-Toluene-4-sulfonic acid 2-hydroxy-2-phenyl-
ethyl ester 12. To a mixture of (S)-phenylethane-1,2-
diol 11 (4.42g, 32.02 mmol), in dry dichloromethane
(65mL) was added dibutyltin oxide (15mg, 0.2mol%
of diol) followed by the addition of p-toluenesulfonyl
25
1
chloride (6.17g, 32.02mmol) and triethylamine
(
(1.96g, 90%). ½aŠ ¼ þ10:2 (c 0.62, CHCl ). H N MR
D
3
4.4mL, 32.02mmol) and reaction was stirred at room
(200MHz, CDCl ): d 1.90–2.20 (m, 2H), 2.1 (br s,
3
temperature under nitrogen. The reaction was moni-
tored by TLC. After completion of reaction (45min),
the mixture was quenched by adding water. The solution
was extracted with dichloromethane (3 · 25mL) and
then combined organic phase were washed with water,
dried (Na SO ) and concentrated. Silica gel column
2H), 2.90 (t, J = 7.35Hz, 2H), 5.35 (dd, J = 3.45,
8.55Hz, 1H), 6.90 (d, J = 8.6Hz, 2H), 7.20–7.35 (m,
5H), 7.45 (d, J = 8.6Hz, 2H); IR (CHCl ): 3369, 3298,
3
À1
+
1613, 1500cm ; MS (m/z, rel int.%): (M À2) 295
(0.4), 278 (0.2), 251 (1), 197 (18), 162 (15), 134 (100),
104 (85), 91 (40), 77 (67).
2
4
chromatography of crude product using petroleum
ether–EtOAc (4:1) as eluent gave the monotosyl com-
pound 12 (9.27g, 99%) as a white solid. Mp 63–64ꢁC
4.3.6. (R)-Norfluoxetine hydrochloride. (R)-Norfluoxe-
tine (1.9g) was dissolved in toluene (4.0mL) and hep-
tane (10.0mL) was added, HCl gas was passed to form
(R)-norfluoxetine hydrochloride (1.92g, 90%). Solid;
2
5
1
½
aŠ ¼ þ49:9 (c 1, CHCl ); H NMR (200MHz,
D
3
CDCl ): d 2.45 (s, 3H), 2.75 (br s, 1H), 4.00–4.25 (m,
3
8
b
25
2
H), 5.00 (dd, J = 3.5, 8.0Hz, 1H), 7.30 (s, 5H), 7.31
d, J = 8.2Hz, 2H), 7.75 (d, J = 8.2Hz, 2H). IR
mp 129–130ꢁC [lit.
131ꢁC] ½aŠ ¼ À36:0 (c 1.5,
D
+36.3 (c 2, MeOH) for (S)-
8
b
25
D
(
(
MeOH) [lit.
enantiomer].
½aŠ
À1
CHCl ): 3529, 1598, 1360cm ; MS (m/z, rel int.%):
3
+
M
(
292 (0.2), 262 (4), 155 (3), 107 (100), 91 (38), 79
45), 77 (31).
4.3.7. (R)-Fluoxetine 3. To a solution of norfluoxetine
(1.0g, 3.38mmol) and methyl chloroformate
2
4
.3.3. (R)-3-Hydroxy-3-phenylpropanenitrile 13. To a
(0.29mL, 3.72mmol) in dichloromethane (15.0mL)
was added aqueous K CO (2.33g, 16.89 mol in
30mL water). The reaction was rapidly stirred for
stirring mixture of monotosyl compound 12 (3.0g,
0.26mmol) in ethanol–H O (35mL:25mL) at 0ꢁC
2
3
1
2
was added NaCN (1.76g, 35.92mmol) in one portion.
The reaction mixture was stirred at room temperature
for 24h, then concentrated at 50ꢁC on rotatory evapora-
tor and extracted with ethyl acetate. The combined
organic phases were washed with brine, dried (Na SO )
20min and then diluted with H O. The organic phase
2
was separated and the aqueous phase was extracted
with dichloromethane. The combined organic phase
were dried (Na SO ) and concentrated to give carba-
2
4
mate as a pale yellow oil. To a stirring suspension of
lithium aluminum hydride (0.25g) in dry THF
(15.0mL) at 0ꢁC was added a solution of carbamate
in dry THF (5.0mL) under nitrogen. The ice bath
was removed and then the reaction mixture was re-
fluxed for 2h. Excess lithium aluminium hydride was
2
4
and concentrated. Silica gel column chromatography of
crude product using petroleum ether–EtOAc (3:1) as
eluent gave (R)-3-phenyl-3-hydroxypropanenitrile 13
25
(
1.351g, 90%) as a pale yellow oil. ½aŠ ¼ þ60:2 (c 1,
D
1
9
20
CHCl ) [lit. ½aŠ ¼ þ58:0 (c 1, EtOH)]. The spectro-
3
D
scopic data were in full agreement with the literature
destroyed by adding H O and EtOAc. The white
2
6
j
values.
precipitate obtained was filtered and washed with
MeOH. The combined filtrate was concentrated to
give (R)-fluoxetine 3 (0.94g, 90%) as an viscous oil
4
(
.3.4. (R)-3-Amino-1-phenylpropane-1-ol 14. To a THF
10.0mL) solution of (R)-3-phenyl-3-hydroxypropane-
nitrile 13 (1.25g, 8.5mmol) was slowly added borane di-
25
½aŠ ¼ þ5:0 (c 1, CHCl ). The spectroscopic data were
D
in full agreement with the literature values.
3
6
j

P. Kumar et al. / Tetrahedron: Asymmetry 15 (2004) 3955–3959
3959
4
.3.8. (R)-Fluoxetine hydrochloride. Fluoxetine (0.90g)
Tetrahedron: Asymmetry 1992, 3, 525–528; (e) Kumar, A.;
Ner, D. H.; Dike, S. Y. Indian J. Chem. 1992, 31B, 803–
was dissolved in ether (15mL). HCl gas was passed
through until a pH of 3–4 was achieved and no precipi-
tate was formed. The solution was concentrated at room
temperature to give a yellow solid, which was washed
with ether and recrystallized from CH Cl /EtOAc to
8
09; (f) Kumar, A.; Ner, D. H.; Dike, S. Y. Tetrahedron
Lett. 1991, 32, 1901–1904; (g) Chenevert, R.; Fortier, G.
Chem Lett. 1991, 1603–1606; (h) Fronza, G.; Fuganti, C.;
Grasselli, P.; Mele, A. J. Org. Chem. 1991, 56, 6019–6023;
2
2
(
i) Master, H. E.; Newadkar, R. V.; Rane, R. A.; Kumar,
give pure (R)-fluoxetine hydrochloride (0.91g, 90%)
7
A. Tetrahedron Lett. 1996, 37, 9253–9254; (j) Kamal, A.;
Khanna, G. B. R.; Ramu, R. Tetrahedron: Asymmetry
2002, 13, 2039–2051.
a
as 25
a
solid; mp 139–140ꢁC [lit.
142–143ꢁC]
7a
25
½
aŠ ¼ À13:6 (c 1, CHCl ) [lit. ½aŠ ¼ À13:8 (c 1,
D
CHCl )]. The spectroscopic data were in full agreement
3
D
3
7. (a) Corey, E. J.; Reichard, G. A. Tetrahedron Lett. 1989,
30, 5207–5210; (b) Sakuraba, S.; Achiwa, K. Synlett 1991,
8
a
with the literature.
6
89–690; (c) Devocelle, M.; Agbossou, F.; Mortreux, A.
Synlett 1997, 1306–1308; (d) Srebnik, M.; Ramachandran,
P. V.; Brown, H. C. J. Org. Chem. 1988, 53, 2916–
Acknowledgements
2
920.
8
. (a) Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 53,
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R.K.P. thanks CSIR New Delhi for award of senior re-
search fellowship. We are grateful to Dr. M. K. Gurjar
for his support and encouragement. The financial sup-
port from DST, New Delhi is gratefully acknowledged.
This is NCL communication No 6673.
9. Koenig, T.; Mitchell, D. Tetrahedron Lett. 1994, 35, 1339–
342.
1
1
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