Preparation of enantiomerically pure (R)- and (S)-3-amino-3-phenyl-1- propanol via resolution with immobilized penicillin G acylase

Article abstract of DOI:10.1016/j.tetasy.2005.12.022

Ethyl 2,4-dioxo-4-phenylbutyrate, obtained by condensation of acetophenone with diethyl oxalate, was converted to 3-oxo-3-phenyl-1-propanol in 90% yield by reaction with baker's yeast. Reductive amination with sodium cyanoborohydride in the presence of ammonium acetate gave the racemic 3-amino-3-phenyl-1-propanol in 65% yield. Enzymatic resolution of the corresponding N-phenylacetyl derivative with penicillin G acylase, immobilized on an epoxy resin gave (S)-amide and (R)-amino alcohol in high enantiomeric purity (ee >99%) and >45% yields for each enantiomer.

Full text of DOI:10.1016/j.tetasy.2005.12.022

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 240–244
Preparation of enantiomerically pure
(R)- and (S)-3-amino-3-phenyl-1-propanol via resolution
with immobilized penicillin G acylaseq
Nitin W. Fadnavis,* Kasiraman R. Radhika and A. Vedamayee Devi
Biotransformations Laboratory, Indian Institute of Chemical Technology, Uppal Road, Habsiguda, Hyderabad 500 007, India
Received 11 November 2005; accepted 29 December 2005
Available online 23 January 2006
Abstract—Ethyl 2,4-dioxo-4-phenylbutyrate, obtained by condensation of acetophenone with diethyl oxalate, was converted to
3-oxo-3-phenyl-1-propanol in 90% yield by reaction with baker’s yeast. Reductive amination with sodium cyanoborohydride in
the presence of ammonium acetate gave the racemic 3-amino-3-phenyl-1-propanol in 65% yield. Enzymatic resolution of the corre-
sponding N-phenylacetyl derivative with penicillin G acylase, immobilized on an epoxy resin gave (S)-amide and (R)-amino alcohol
in high enantiomeric purity (ee >99%) and >45% yields for each enantiomer.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
we report the conversion of keto alcohol 2 to the corre-
sponding racemic [N-phenylacetyl]amino alcohol 5 and
its resolution using immobilized penicillin G acylase
(E.C. 3.5.1.11) (Scheme 1).
Enzymes and microbial cells are finding increasing
applications in the fine chemical industries such as phar-
maceuticals, agrochemicals, and health care products
due to their high chemo- and stereospecificity.1 We have
recently described the preparation of ethyl (R)-2-hydr-
oxy-4-phenylbutyrate (HPB) ester using ethyl 2,4-dioxo-
4-phenylbutyrate 1 with baker’s yeast (Saccharomyces
cerevisiae).2 During these investigations, the unexpected
formation of 3-oxo-3-phenyl-1-propanol 2 was observed
as a side reaction. In fact, the compound could be pre-
pared in high yields if the reaction with baker’s yeast
was allowed to continue for a longer period. The single
pot synthesis of 2 in 90% yield is an interesting route
since it is an intermediate for the synthesis of enantio-
merically pure 1-phenyl-1,3-propanediol, an important
intermediate to drugs such as fluoxetine.3 Since the
methodologies of the synthesis of 1-phenyl-1,3-propane-
diol 3 from 2 and its subsequent conversion to fluoxetine
are quite well known,2,4–8 we did not attempt the synthe-
sis of fluoxetine. Intermediate 2 can also be used for the
preparation of chiral 1,3-amino alcohols 6 and 7. Herein
2. Results and discussion
Known methods for the synthesis of 2 include the selec-
tive oxidation of 1-phenyl-1,3-propanediol with oxidiz-
ing agents;9 chemoselective reduction of b-keto esters
to b-keto alcohols;10 condensation of acetophenone with
formaldehyde;11 the oxidative ring-opening reaction of a
1,3-dioxane derivative;12 aldol reaction of silyl enol
ethers with aldehydes in the presence of lanthanide cat-
alysts;13 reduction of epoxides with Bu3SnH–Bu3SnI
complexes;14 electron-transfer reactions of aromatic
a,b-epoxy ketones,15 and aldol reaction under high-
intensity ultrasound.16 Compared to the above known
methods, the method of preparing 2 by reaction of 1
with baker’s yeast in a biphasic system is much simpler.
Chiral 1,3-amino alcohols have potential applications
both as pharmaceutically active compounds, agricul-
tural chemicals, chiral intermediates, and chiral auxi-
liary agents. For example, U.S. Pat. No. 3,668,199
describes novel 1,3-amino alcohols having potential
applications as anti-diabetic agents and diuretics.17
The most well-known example is dapoxetine hydro-
chloride and its derivatives, which are useful for the
q IICT Communication No. 051109.
Corresponding author. Tel.: +91 40 27160123x2631; fax: +91 40
27160512; e-mail addresses: fadnavisnw@yahoo.com; fadnavis@
iictnet.org; fadnavis@iict.res.in
*
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.022

N. W. Fadnavis et al. / Tetrahedron: Asymmetry 17 (2006) 240–244
241
O
O
O
OH
OEt
Baker's yeast
Diisopropyl ether/
phosphate buffer
O
pH 4.5
NaBH4
2 (90%)
NaBH3CN
NH4OAc
1
NHCOCH2Ph
OH
OH
NH2
OH
NaOH
PhCH2COCl
HO
5 (80%)
4 (65%)
3
PenG acylase
phosphate buffer
pH 7.5
F3C
Me
O
N
H
Fluoxetine
NHCOCH2Ph
NH2
+ PhCH2COOH
+
HO
HO
7 (47.5%, ee >99%)
6 (45%, ee >99%)
Scheme 1. Biocatalytic preparation of enantiomerically pure 3-amino-3-phenyl-1-propanol.
treatment of premature ejaculation.18 Chiral c-amino
alcohols can be prepared by (a) classical resolution of
the amino alcohol;19 (b) reduction of an optically active
b-amino acid;20 (c) reduction of a keto-oxime with a
chiral reducing agent such as a metal borohydride
complexed to a different optically active amine21 or a
chiral oxaborolidine–BH3–THF complex;22 (d) stereo-
selective oxidation of a 1,4-diol to a c-lactone using an
alcohol dehydrogenase, the conversion of the c-lactone
to the corresponding 4-hydroxyamide, 4-hydroxyhydr-
oxamic acid, or 4-hydroxyhydrazide, followed by
stereospecific rearrangement to the corresponding chiral
1,3-amino alcohol,23 and (e) enzymatic resolution of the
amino alcohol using lipases or amino acylases.24 The
processes involving chiral catalysts are expensive and
require specialized skills while the methodology of
kinetic resolution using a hydrolase is very useful, since
it provides both (R)- and (S)-enantiomers and can be
performed easily.
reduced to obtain 6. Since penicillin G acylase is com-
mercially available in an immobilized form at a reason-
able price and is generally useful for the resolution of
amino compounds,25 we attempted the resolution of
racemic c-amino alcohol 2 to obtain (R)-6 using this
enzyme. Herein the synthesis of the enantiomerically
pure isomers of both (R)- and (S)-3-amino-3-phenyl-1-
propanol was carried out in the following manner.
Reaction of 1 with baker’s yeast in a phosphate buffer
(pH 4)/diisopropyl ether 2-phase system for 48 h gave
2 in 90% yield in 48 h. Earlier, we had used citrate buffer
for the reaction under similar conditions,2 but it
required 4–7 days for the completion of the reaction.
The facilitation using a phosphate is unsurprising since
we expected the involvement of thiamine pyrophosphate
(TPP) adduct in the decarboxylation of a keto acid
formed during the reaction.2,26 Reductive amination of
2 with sodium cyanoborohydride in the presence of
ammonium acetate gave the racemic amino alcohol 4
in 65% yield. The amino group was protected with
phenylacetyl chloride under Schotten–Baumann condi-
tions to give racemic N-phenylacetyl derivative 5 in
80% yield, and then resolved by enantioselective hydro-
lysis of the racemic amide catalyzed by penicillin G
acylase (immobilized on epoxy resin) in phosphate
buffer (0.05 M, pH 7.5). The hydrolytic reaction was
followed by reverse phase HPLC. The reaction practi-
cally stopped at 50% conversion showing very high
enantioselectivity. After the reaction, the enzyme was
filtered off and the aqueous reaction mixture acidified
to convert the (R)-amino alcohol into a water soluble
hydrochloride. Phenyl acetic acid produced during
Although several methods already exist for preparing
enantiomerically pure c-amino alcohols as described
above, we could find only two reported chemo-enzy-
matic routes to 6. The one described in the US patent23
is rather complex needing several steps and NADH recy-
cling strategies. The second route is via reduction of the
chiral b-amino acid. The racemic b-amino acid was
obtained in 67% yield by refluxing malonic acid, benzal-
dehyde and ammonium acetate in ethanol.20d,e It was
then converted to its racemic N-phenylacetyl derivative
and enantioselectively hydrolyzed with penicillin G
acylase to obtain the (R)-amino acid,20f which can be

242
N. W. Fadnavis et al. / Tetrahedron: Asymmetry 17 (2006) 240–244
hydrolysis and the unreacted (S)-amide was extracted
with dichloromethane. Separation of the (S)-amide
and phenylacetic acid was achieved by evaporating the
dichloromethane and extracting the phenylacetic acid
from the residue with cyclohexane. HPLC analysis on
chiral stationary phase (Chiralcel OD, Daicel, Japan)
showed that the amide was enantiomerically pure
(ee >99%). The (R)-amine present in the aqueous reac-
tion mixture after enzymatic hydrolysis and acidification
was recovered after basification with 4 M NaOH and
extraction with dichloromethane. HPLC analysis on
the chiral stationary phase (Crownpack CR(+), Daicel,
Japan) showed that the amine was also enantiomerically
pure (ee >99%). Thus, from the yields (>45%) and enan-
tiomeric purities (>99%) the reaction was found to be
completely enantioselective and only the (R)-enantiomer
was hydrolyzed by the enzyme.
washed with brine, dried over anhydrous magnesium
sulfate and concentrated on rotavapor to give a yellow
viscous oil consisting mainly of keto alcohol 2. This
was purified by column chromatography using hex-
ane–ethyl acetate (25%) as the eluent. The alcohol 2
was obtained as a fraction eluting with rf = 0.31
(1.35 g, 90%); IR (neat) m (cmꢀ1) 460, 580, 665, 720,
780, 810, 880, 940, 1000, 1040, 1155, 1200, 1240, 1340,
1410, 1595, 1705, 3045, 3495. 13C NMR (CDCl3,
1
200 MHz): dppm 200, 136, 132, 128, 57, 40. H NMR
(CDCl3, 200 MHz): dppm 3.2 (t, 2H, J1,2 = 7.00 Hz,
J1,3 = 9.0 Hz), 4.00 (t, 2H, J1,2 = 7.5 Hz, J1,3 = 9.5 Hz),
7.45–7.62 (m, 3H), 8.01 (d, 2H, J = 8 Hz).
4.2. 3-Amino-3-phenyl-1-propanol 4
To a stirred solution of 2 (2.0 g, 10 mmol) and ammo-
nium acetate (10.2 g, 0.10 mol) in absolute ethanol
(35 mL) was added sodium cyanoborohydride (570 mg,
9 mmol) in one portion at room temperature. The result-
ing solution was stirred at room temperature for 36 h.
Concentrated HCl (1 mL) was added carefully in a fume
cupboard, ethanol evaporated, and the resulting white
residue dissolved in water (25 mL). The aqueous solution
was extracted with diethyl ether to remove unreacted
starting materials (3 · 10 mL). The aqueous phase was
then basified with powdered KOH to pH >10, saturated
with NaCl and extracted with dichloromethane
(3 · 10 mL). The combined extracts were dried over
sodium sulfate and evaporated to dryness to obtain a
semi-solid, which was recrystallized from chloroform–
hexane to yield 4 as a pale yellow solid (1.3 g, 65%, mp
72–73 ꢁC; lit.27 mp 72–73 ꢁC). IR (neat) (cmꢀ1): 3282,
3. Conclusion
Herein we have provided a simple and environmentally
friendly biocatalytic route to both (R)- and (S)-enantio-
mers of 3-amino-3-phenyl-1-propanol with high enan-
tiomeric purity (ee >99%) and yield of 45–50% in four
steps. The starting materials are easy to prepare while
the immobilized enzyme can be recycled several times.
Conversion of the amino alcohol to Dapoxetine is cur-
rently in progress.
4. Experimental
1
Immobilized penicillin G acylase (150 units/g) was a
gift from M/s KOPRAN, Mumbai. Preparation of
diketo ester 1 and baker’s yeast mediated synthesis of
keto-alcohol 2 has been described earlier.2 Sodium
cyanoborohydride was obtained from Fluka. All other
reagents were obtained from SD Fine Chem, India.
HPLC analyses were carried out on a Hewlett Packard
HP1090 unit with diode array detector and HP Chem
Station software.
1610, 1595, 1059, 755. H NMR: (CDCl3 + DMSO-d6,
200 MHz) dppm 1.70–1.90 (m, 2H), 3.4–3.6 (m, 2H),
4.19 (t, 1H), 7.20 (m, 5H). Mass: 151 (M+).
4.3. 3-[N-(Phenylacetyl)amino]-3-phenyl-1-propanol 5
Phenylacetyl chloride (2.6 mL, 19 mmol) and 2 M
NaOH (21 mL) were alternately added dropwise to a
stirred solution of 4 (2 g, 13 mmol) in ice cold 2 M
NaOH (21 mL). The reaction mixture was stirred for a
further 4 h at room temperature. The reaction mixture
was then cooled to 0 ꢁC, acidified with 10% aqueous
HCl to pH ꢁ 2 and extracted with ethyl acetate
(2 · 25 mL). The combined organic layer was washed
with water and brine, dried over anhydrous Na2SO4
and evaporated to dryness under reduced pressure.
The crude residue was extracted several times with
cyclohexane to remove phenylacetic acid and the crude
product was recrystallized from ethyl acetate–hexane
to afford the solid racemic 3-phenyl-3-(N-phenyl-
acetyl)-1-propanol 5 (4.3 g, 80%, mp 124.5–125 ꢁC). IR
(neat) (cmꢀ1): 3310, 3235, 3062, 2946, 2884, 1641,
1559, 1232, 1061, 761, 701, 564. 1H NMR:
(CDCl3 + DMSO-d6, 200 MHz) dppm 1.71–2.10 (m,
2H), 3.31–3.61 (m, 4H), 4.0–4.20 (m, 1H), 4.90–5.10
(m, 1H), 7.0–7.40 (m, 10H), 7.9 (br s, 1H, NH).
4.1. 3-Phenyl 3-oxo propanol 2
Yeast cells (20 g) were suspended in sodium phosphate
buffer (0.05 M, pH 4.5, 50 mL) containing glucose
(5 g). The cells were allowed to activate for 3 h, then
diisopropyl ether was added (200 mL) followed by the
addition of phenacyl chloride (150 mg) dissolved in
diisopropyl ether (10 mL). The contents were vigorously
stirred on a magnetic stirrer at room temperature for
3 h. Substrate 1 was prepared from the condensation
of diethyl oxalate with acetophenone, as described previ-
ously,1 (2.2 g, 0.1 mol) dissolved in diisopropyl ether
(50 mL) was added and the contents were stirred for
48 h at room temperature with intermittent addition of
glucose (2 g/day). The starting ester disappeared and
the decomposition of intermediate 2-hydroxy ester to
form the keto alcohol 2 was complete in 48 h. The cells
were centrifuged at 10,000 rpm, the aqueous phase and
the yeast cells were separately extracted with ethyl ace-
tate (3 · 50 mL). The combined organic layer was
13C NMR: (CDCl3 + DMSO-d6, 200 MHz) dppm 170,
141, 136, 129, 128.7, 128.1, 127.9, 126.7, 126.1, 57, 50,
43, 38. Mass: 270 (M+1).

N. W. Fadnavis et al. / Tetrahedron: Asymmetry 17 (2006) 240–244
243
4.4. Enzymatic hydrolysis of 5
4.6. HPLC with chiral stationary phase
A solution of 5 (1.0 g, 3.7 mmol) dissolved in ethanol
(3 mL) was added to phosphate buffer (0.05 M,
pH 7.5, 20 mL) and immobilized penicillin G acylase
(1 g, 150 units). The reaction mixture was shaken in
a conical flask at 80 rpm (25 ꢁC) and the reaction fol-
lowed by reverse phase HPLC analysis. The reaction
virtually stopped at 50% hydrolysis (1 h). The enzyme
was filtered and washed with water (5 mL). The aque-
ous phase was acidified with concd HCl to pH ꢁ2 and
extracted with dichloromethane (3 · 5 mL). The com-
bined organic layer was washed with brine, dried over
anhydrous Na2SO4 and concentrated under reduced
pressure to obtain a mixture of unreacted (S)-amide
and phenylacetic acid. The crude residue was extracted
with cyclohexane (4 · 5 mL), in which only phenylace-
tic acid was highly soluble. The crude amide residue
The enantiomeric purity of amino alcohol 6 was deter-
mined by HPLC analysis on Crownpack CR(+) column
(150 · 4 mm), Daicel Chemical Industries, Japan.
Mobile phase: water containing 0.1% perchloric acid;
flow rate 0.7 mL/min; detection wavelength 210 nm;
retention times: (S)-amino alcohol 7.98 min, (R)-amino
alcohol 9.32 min. The enantiomeric purity of the amide
7 was determined by HPLC analysis on Chiralcel OD
column (250 · 5 mm), Daicel Chemical Industries,
Japan. Mobile phase: 10% isopropanol in hexane con-
taining 0.1% trifluoroacetic acid; flow rate: 0.7 mL/
min; and detection wavelength 210 nm. Retention times:
(S)-amide 28.87 min, (R)-amide 30.31 min.
Acknowledgements
was recrystallized from ethyl acetate–hexane to afford
25
(S)-7 {0.48 g, 95%; ½aꢂD ¼ ꢀ51:6 (c 1, ethanol)}.
We thank CSIR, New Delhi, for grant of SRF to
K.R.R. and financial support.
Amide 7 was hydrolyzed by refluxing with 6 M HCl
(10 mL), liberated phenylacetic acid removed by
extraction with cyclohexane and the amino alcohol
recovered as a hydrochloride after evaporation of
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