An efficient formal synthesis of (S)-dapoxetine from enantiopure 3-hydroxy azetidin-2-one

Article abstract of DOI:10.1016/j.tet.2008.11.042

An efficient formal synthesis of S-(+) dapoxetine starting from 3-hydroxy azetidin-2-one is described. The intermediate (S)-3-(dimethyl amino)-3-phenylpropan-1-ol was synthesized in enantiopure form starting with 3-hydroxy azetidin-2-one in seven steps.

Full text of DOI:10.1016/j.tet.2008.11.042

Tetrahedron 65 (2009) 2605–2609
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An efficient formal synthesis of (S)-dapoxetine from enantiopure 3-hydroxy
azetidin-2-one
,
Pinak M. Chincholkar a, Ajaykumar S. Kale a, Vikas K. Gumaste a, Abdul Rakeeb A.S. Deshmukh b
*
a Organic Chemistry Division, National Chemical Laboratory, Pune 411 008, India
b Research Support International Ltd., DIL-Complex, Ghodbander Road, Majiwada, Thane West-400610, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2008
Received in revised form 11 November 2008
Accepted 14 November 2008
Available online 24 November 2008
An efficient formal synthesis of S-(þ) dapoxetine starting from 3-hydroxy azetidin-2-one is described.
The intermediate (S)-3-(dimethyl amino)-3-phenylpropan-1-ol was synthesized in enantiopure form
starting with 3-hydroxy azetidin-2-one in seven steps.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective synthesis
b
-Lactams
Azetidin-2-ones
Reduction
Staudinger reaction
1. Introduction
a cure for premature ejaculation,10 a sexual disorder in men, which
is another fall-out of high stress. Phase III clinical trials on patients
Substituted azetidin-2-ones have been of sustained interest to
the synthetic and medicinal chemists, as they are part structures
of the penicillin antibiotics,1–3 which have been proved to be a boon
with premature ejaculation have shown (S)-dapoxetine to be
effective in delaying ejaculation without any major side effect ex-
cept nausea. (S)-Dapoxetine thus, is a strong contender to join the
class of ViagraÒ, LevittraÒ, CialisÒ, and DostinexÒ as a drug intended
to better male sexual health. Very few reports are available in the
literature for the synthesis of this potentially useful molecule.
Recently, a report illustrated use of Sharpless asymmetric dihy-
droxylation for enantioselective synthesis of (S)-dapoxetine.11 An-
other synthesis of (S)-dapoxetine by Gotor et al. uses enzymatic
resolution of 3-amino-3-phenylpropan-1-ol with Candida antarc-
tica lipase A (CAL-A) as the key step.12 Use of radiochemical reaction
has also been employed for the synthesis of (S)-dapoxetine from
to the mankind. Apart from this, another field of b-lactam chem-
istry, which has shown an astonishing growth is their use as syn-
thons for molecules of biological and medicinal interest.4–6 The
field has been reviewed7c extensively and continues to be an active
area of research. We have been engaged in the use of enantiopure
b
-lactams as synthons for biologically important molecules and
intermediates.7,8 As a part of this research program, we herein
present our work on an enantioselective formal synthesis of (S)-
dapoxetine from an optically pure 3-hydroxy b-lactam.
Stress related ailments have seen a precipitous rise world over,
with life becoming faster paced than ever. Depression is one such
psychiatric disorder affecting people of all ages and genders around
the globe. Treatment of depression, among other methods, involves
use of selective serotonin re-uptake inhibitors (SSRI’s). Prozac,
Paxil, and Zoloft (Fig. 1) are few such SSRI’s. (S)-Dapoxetine (1)
(Fig. 2) is another such SSRI, which is structurally related to Prozac
and is widely recommended against depression and bulimia.9 In
addition to its use as an SSRI, (S)-dapoxetine is now being tested as
(S)-(þ)-N-methyl-
a-[2-(1-naphthalenyloxy)ethyl]benzene meth-
anamine hydrochloride using methyl iodide.13 Koizumi et al. have
reported a formal synthesis of (S)-dapoxetine, wherein they
achieved the synthesis of intermediate (S)-3-(dimethyl amino)-3-
phenylpropan-1-ol (15) using 1,3-dipolar cycloaddition of (R)-
(þ)-p-tolyl vinyl sulfoxide with acyclic nitrones as the asymmetry
inducing step with high yield and high enantiomeric excess.14 We
herein report for the first time, synthesis of 15, a crucial in-
termediate for (S)-dapoxetine, from an enantiopure, substituted,
3-hydroxy
Scheme 1. We envisaged that intermediate 15 can be obtained from
carbamate substituted -lactam 12, which in turn can be accessed
from the 3-hydroxy -lactam 8. The starting 3-hydroxy -lactam 8
b-lactam. The retro-synthetic strategy is shown in
b
* Corresponding author. Tel.: þ91 22 67980938; fax: þ91 22 67980999.
E-mail address: Abdul.Deshmukh@rsil.biz (A.R.A.S. Deshmukh).
b
b
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.042

2606
P.M. Chincholkar et al. / Tetrahedron 65 (2009) 2605–2609
H
N
HN
HN
O
O
Cl
Cl
O
O
CF3
Paxil
Zoloft
H3C
Prozac
F
Figure 1. Zoloft, Paxil, and Prozac.
CO2Et
CO2Et
CO2Et
COCl
CO2Et
CO2Et
HO
HO
O
O
O
O
a)
b)
CH3
N
O
4
2
3 (90%)
O
CO2Et
O
H
Ph
N
CO2Et
O
Figure 2. (S)-Dapoxetine (1).
c)
+
PMP
N
PMP
O
O
H
Ph
H
H
5a
O
5b
NMe2
H
5a:5b = 60:40, 70%
HO
H
Ph
N
H
COOEt
N
O
Ph
OH
e)
d)
O
BOC
PMP
5b
PMP
H
12
15
OH
N
O
PMP
7 (88%)
H
O
H
H
N
H
6 (84%)
HO
H
HO
O
Ph
N
f)
O
PMP
O
N
10
8
PMP
8 (90%)
PMP = p-methoxy phenyl
Scheme 2. Reagents and conditions: (a) 2,2-dimethoxy propane benzene, PTSA, reflux,
5 h; (b) (i) NaOH, THF/H2O, rt, 4–6 h, (ii) (COCl)2, DCM, reflux, 5 h; (c) PMP–N]CH–Ph,
Et3N, DCM, ꢀ40 ꢁC to rt, 15 h; (d) FeCl3, DCM, rt, 2 h; (e) NaIO4, acetone/water, rt, 6–
8 h; (f) NaBH4, MeOH, 0 ꢁC, 2 h.
Scheme 1.
can be obtained from easily available chiral starting material
(þ)-diethyl -tartrate in good yield.
L
2. Results and discussion
HO
MeS
O
a
We started the synthesis of intermediate 15 with enantiopure 3-
N
S
N
hydroxy
b-lactam 8, which was prepared easily by a reported
O
PMP
O
PMP
method using stereoselective reduction of corresponding azetidin-
2,3-dione.15 We recently reported a method for an enantioselective
synthesis of azetidin-2,3-diones bearing aromatic substituents on
8
9 (75%)
N-1 and C-4 of the
b-lactam, from (þ)-diethyl
L L-
-tartrate.5d Diethyl
b
d
c
tartrate 2 was protected as its acetonide 3 using a reported pro-
tocol16 (Scheme 2). Compound 3 was subjected to partial hydrolysis
to afford mono acid, which was further converted to its acid chlo-
ride 4 by refluxing with oxalyl chloride in anhydrous dichloro-
methane in very good yield. This acid chloride 4 was used as such
for Staudinger cycloaddition reaction with the imine derived from
benzaldehyde and p-anisidine, to furnish diastereomeric mixture
N
NH
O
PMP
O
10 (92%)
11 (60%)
NHBOC
e
HO
N
O
BOC
(60:40)5d of
was obtained in enantiopure form by column chromatography.
Spiro -lactam 5b was then subjected to the deprotection of ace-
b-lactams 5a and 5b. The required diastereomer 5b
12 (70%)
13 (80%)
b
NH2
tonide using ferric chloride to obtain diol 6, which on periodate
cleavage yielded azetidin-2,3-dione 7 in excellent yield. Stereo-
selective reduction of the keto group of azetidin-2,3-dione 7 was
g
f
HO
14 (89%)
achieved using sodium borohydride to get 3-hydroxy
in very good yield. The 3-hydroxy -lactam (8) was converted to its
b
-lactam (8)15
H3C
CH3
b
N
xanthate derivative 9 using NaH, CS2, and CH3I, which was further
subjected to reduction with n-Bu3SnH and AIBN in toluene under
Ref.12
1
HO
reflux condition to furnish deoxygenated
b-lactam 10 in excellent
15 (80%)
yield (Scheme 3). -Lactam 10 was subjected to oxidative removal
b
Scheme 3. Reagents and conditions: (a) NaH, CS2, CH3I, THF, 0 ꢁC to rt, 6 h; (b) Bu3SnH,
AIBN, toluene, reflux, 3–4 h; (c) CAN, CH3CN/H2O, 0 ꢁC, 1 h; (d) (Boc)2O, DMAP, DCM,
0 ꢁC to rt, 6 h; (e) LAH, THF, 0 ꢁC to rt, 4 h; (f) TFA, DCM, 0 ꢁC to rt, 2 h; (g) HCHO,
NaBH3CN, CH3COOH, CH3CN,rt, 2 h.
of the p-methoxy-phenyl group on the lactam nitrogen using ceric
ammonium nitrate (CAN) to obtain compound 11 in 60% yield. This
was then protected as its carbamate derivative with (Boc)2O in

P.M. Chincholkar et al. / Tetrahedron 65 (2009) 2605–2609
2607
presence of DMAP in DCM to obtain
b
-lactam 12. It was further
7.23 (7H, m, Ar), 6.80 (d, 2H, J¼8.8 Hz, Ar), 5.27 (1H, d, J¼5.4 Hz, CH–
N), 5.20 (1H, d, J¼5.4 Hz, CH–OH), 3.76 (3H, s, OCH3), 2.67 (1H, br s,
–OH); dC (50 MHz, CDCl3) 165.4, 156.5, 133.2, 130.6, 129.1, 129.0,
127.5, 118.8, 114.5, 77.2, 62.1, 55.5; MS (m/z): 270 (Mþ1).
reduced by LAH to get Boc protected amino alcohol 13 with desired
stereochemistry in pure form after column chromatography. It has
been shown that the reduction of substituted azetidinone with LAH
yields corresponding amino alcohol in good yield.17a The reaction
proceeds via an alkoxyalanate intermediate, which further breaks
4.3. (3S,4R) Dithiocarbonic acid O-[1-(4-methoxy-phenyl)-2-
oxo-4-phenyl-azetidin-3-yl] ester S-methyl ester (9)
down to amino alcohol.17b In case of
b-lactam 12, we too got the
reduced amino alcohol 13 in very good yield. Intermediate 13 was
further subjected to Boc deprotection with TFA to get amino alcohol
14. Although, bismethylation of 14 to furnish 15 using formic acid
and formaldehyde under reflux conditions is known,11 we adopted
milder reaction conditions using formaldehyde and sodium cya-
noborohydride at room temperature to deliver the desired N-bis-
methylated amino alcohol 15 in better yield. The spectral data and
specific rotation of intermediate 15 were in good agreement with
To a cooled suspension of NaH (60%; 0.47 g, 11.8 mmol) in an-
hydrous THF (5 mL) was added 3-hydroxy-b-lactam 8 (0.80 g,
2.97 mmol) as a solution in THF (5 mL) slowly. After the addition
was complete, the reaction mixture was stirred at room tempera-
ture for 30 min. The solution was cooled to 0 ꢁC and a solution of
CS2 (0.53 mL, 8.91 mmol) in THF (5 mL) was added. The reaction
mixture was stirred for 1.5 h at 0 ꢁC, MeI (1.10 mL, 17.8 mmol) was
then added at the same temperature, and the reaction mixture was
stirred at room temperature for 3 h. After the reaction was com-
plete (TLC), a saturated aq solution of NH4Cl (10 mL) was added,
and THF was removed under reduced pressure. The residue was
dissolved in CH2Cl2 (50 mL) and the organic layer was washed with
H2O (20 mL), brine (20 mL), and dried over Na2SO4. The solvent was
removed under reduced pressure to afford the crude product,
which was then purified by flash column chromatography (10%
EtOAc/pet. ether) to furnish compound 9 (0.79 g, 75%) as a white
solid. Mp 135 ꢁC. [Found: C, 60.12; H, 4.72; N, 3.96; S, 17.86%.
25
25
reported values [
a
]
þ39.0 (c 6, CHCl3); lit.11
[
a
]
þ39.2 (c 0.6,
D
D
CHCl3). Further elaboration of 15 to (S)-dapoxetine is a well
established synthetic protocol.12 Thus, enantioselective synthesis of
intermediate 15, in 17% overall yield, constitutes a formal synthesis
of (S)-dapoxetine.
3. Conclusion
In conclusion, an enantioselective formal synthesis of (S)-
dapoxetine, an SSRI type of drug against depression and a potential
cure of premature ejaculation in men, was achieved from
C18H17NO3S2 requires C, 60.14; H, 4.77; N, 3.90; S, 17.84%.] Rf (20%
30
a substituted 3-hydroxy
b
-lactam in 17% overall yield. The synthesis
EtOAc/pet. ether) 0.4; [
a]
þ33.3 (c 0.9, CHCl3); nmax (CHCl3)
D
illustrates the use of
medicinal interest.
b
-lactam synthon method for molecules of
1755 cmꢀ1
; dH (200 MHz, CDCl3) 7.37–7.27 (7H, m, Ar), 6.81 (2H, d,
J¼8.9 Hz, Ar), 6.68 (1H, d, J¼4.8 Hz, CH–OC]S), 5.42 (1H, d,
J¼4.8 Hz, CH–N), 3.76 (3H, s, OCH3), 2.29 (3H, s, SCH3); dC (50 MHz,
CDCl3) 213.6, 160.5, 156.5, 131.8, 130.0, 128.7, 128.3, 128.1, 118.8,
114.3, 81.6, 61.6, 55.3, 18.8; MS: (m/z)¼360 (Mþ1).
4. Experimental
4.1. General
4.4. (S)-1-(4-Methoxy-phenyl)-4-phenyl-azetidin-2-one (10)
1H NMR and 13C NMR spectra were recorded in CDCl3 solutions
on Bru¨ker AV 200, AV 400 spectrometers, and chemical shifts are
reported in parts per million, downfield from tetramethylsilane for
1H NMR. Infrared spectra were recorded on Perkin Elmer Infrared
Spectrophotometer, Model 599-B or Shimadzu FTIR-8400 using
sodium chloride optics. Melting points were determined on a Buchi
melting point apparatus and are uncorrected. The microanalyses
were performed on a Carlo-Erba, CHNS-O EA 1108 elemental ana-
lyzer available in Division of Organic Chemistry, National Chemical
Laboratory, Pune. Optical rotations were recorded on ADP 220 po-
larimeter BellinghamþStanley Ltd. under standard conditions.
Mass spectra were recorded on API QSTAR PULSAR using electron
spray ionization (ESI) method.
A solution of Bu3SnH (0.58 mL, 2.15 mmol) and AIBN (15 mg) in
anhydrous toluene (5 mL) was added drop wise to a refluxing so-
lution of xanthate (0.26 g, 0.72 mmol) in anhydrous toluene
(10 mL) under argon atmosphere. The reaction mixture was then
refluxed for 3 h (TLC). The solvent was removed under reduced
pressure and the residue was purified by flash column chroma-
tography (10% EtOAc/pet. ether) to afford 10 (0.168 g, 92%) as
a white fluffy solid. Mp 98 ꢁC. [Found: C, 75.95; H, 6.09; N, 5.60%.
C16H15NO2 requires C, 75.87; H, 5.97; N, 5.53%.] Rf (20% EtOAc/pet.
30
ether) 0.3; [
a
]
ꢀ40 (c 0.2, CHCl3); nmax (CHCl3) 1755 cmꢀ1
; dH
D
(200 MHz, CDCl3) 7.28–7.13 (7H, m, Ar), 6.69 (2H, d, J¼8.9 Hz, Ar),
4.90–4.86 (1H, m, CH–N), 3.64 (3H, s, OCH3), 3.45 (1H, dd, J¼5.5,
0
15 Hz, OCCH2 ), 2.83 (1H, dd, J¼2.5, 15 Hz, OCCH); dC (50 MHz,
4.2. (3S,4R)-3-Hydroxy-1-(4-methoxy-phenyl)-4-phenyl-
CDCl3) 163.9,155.8,138.2,131.3,129.0,128.4,125.8,118.0,114.1, 55.3,
azetidin-2-one (8)
53.9, 46.8; MS: (m/z)¼254 (Mþ1).
To a solution of dione 7 (0.037 g, 0.14 mmol) in methanol (3 mL)
was added sodium borohydride (0.008 g, 0.21 mmol) in portion
wise manner at 0 ꢁC. After addition was complete, the reaction
mixture was stirred at 0 ꢁC for 2 h (TLC). Ice was then added care-
fully to the reaction mixture at 0 ꢁC and stirred for half an hour at
same temperature. Methanol was then evaporated on the rotary
evaporator and to the residue was added CH2Cl2 (15 mL). Organic
layer was then washed with H2O (3ꢂ5 mL) and brine (5 mL). Or-
ganic extracts were then dried over anhydrous Na2SO4 and con-
centrated in vacuo to obtain crude compound 8, which was purified
by column chromatography (50% EtOAc/pet. ether) to get pure 3-
4.5. (S)-4-Phenyl-azetidin-2-one (11)
A solution of (NH4)2Ce(NO3)6 (0.97 g,1.77 mmol) in water (7 mL)
was added drop wise to a solution of (S)-1-(4-Methoxy-phenyl)-4-
phenyl-azetidin-2-one (10) (0.15 g, 0.59 mmol) in acetonitrile
(7 mL) at 0 ꢁC. The mixture was stirred at this temperature for 1 h.
Water (10 mL) was added, it was extracted with ethyl acetate
(3ꢂ15 mL), and washed with saturated solution of NaHCO3
(2ꢂ10 mL). The aqueous layer of NaHCO3 was extracted again with
ethyl acetate (1ꢂ10 mL), and the combined organic extracts were
washed with 40% NaHSO3 (3ꢂ10 mL) and brine (10 mL). It was
dried over anhydrous Na2SO4 and the solvent was removed under
reduced pressure to get crude product, which was purified by flash
column chromatography (70% EtOAc/pet. ether) to furnish 11
(0.052 g, 60%) as a very viscous liquid. [Found: C, 73.39; H, 6.09; N,
hydroxy
[Found C, 71.50; H, 5.69; N, 5.03%. C16H15NO3 requires C, 71.36; H,
b
-lactam 8 (0.033 g, 90%) as a white solid. Mp 201–201 ꢁC.
30
5.61; N 5.20%.] Rf (50% EtOAc/pet. ether) 0.3; [
a
]
D
ꢀ179.0 (c 1.0,
CHCl3); nmax (CHCl3) 3315, 1715 cmꢀ1
;
dH (200 MHz, CDCl3) 7.55–

2608
P.M. Chincholkar et al. / Tetrahedron 65 (2009) 2605–2609
9.61%. C9H9NO requires C, 73.45; H, 6.16; N, 9.52%.] Rf (70% EtOAc/
m, OCH2, CH–N), 2.32–1.77 (2H, m, CCH2C); dC (50 MHz, CDCl3)
128.9, 128.6, 126.9, 126.2, 58.9, 55.1, 35.9; MS: (m/z)¼152 (Mþ1).
30
pet. ether) 0.3; [
a
]
ꢀ40 (c 0.1, CHCl3); nmax (CHCl3) 3411,
D
1765 cmꢀ1
;
dH (200 MHz, CDCl3) 7.30–7.19 (5H, m, Ar), 6.23 (1H, br
0
s, NH), 4.66 (1H, m, CH-N), 3.44–3.32 (1H, m, OCCH2 ), 2.81 (1H, dd,
J¼2.09, 14.09 Hz, OCCH2); dC (50 MHz, CDCl3) 167.9, 140.2, 128.4,
127.6, 125.3, 49.7, 47.4; MS: (m/z)¼148 (Mþ1).
4.9. (S)-3-Dimethylamino-3-phenyl-propan-1-ol (15)
To a solution of 14 (0.12 g, 0.807 mmol) in acetonitrile was
added, 30% aq formaldehyde solution (0.325 mL) followed by so-
dium cyanoborohydride (0.081 g, 1.29 mmol) and it was allowed to
stir at room temperature. A few drops of glacial acetic acid were
added to maintain the pH near neutrality. The solution was stirred
at room temperature for 2 h. After completion of the reaction (TLC),
the reaction mixture was concentrated in vacuo. To the residue was
added 2 N aq KOH (10 mL). It was then extracted with ethyl acetate
(3ꢂ10 mL). The ethyl acetate layer was then washed with 1 N HCl
(3ꢂ5 mL). The combined HCl extracts were basified with solid KOH
and then extracted with ethyl acetate (3ꢂ10 mL). Combined or-
ganic extracts were washed with brine (10 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo to afford crude product,
which was purified by column chromatography (40% EtOAc/MeOH)
to furnish 15 (0.115 g, 80%) as a hygroscopic solid. [Found: C, 73.78;
4.6. (S)-2-Oxo-4-phenyl-azetidine-1-carboxylic acid tert-butyl
ester (12)
(Boc)2O (0.94 mL, 4.08 mmol) and DMAP (0.398 g, 3.26 mmol)
were added to a solution of azetidin-2-one 11 (0.400 g, 2.72 mmol)
in CH2Cl2 (10 mL) at 0 ꢁC, and the reaction mixture was stirred for
6 h. Then, CH2Cl2 (10 mL) was added, and it was washed with
a saturated solution of NaHCO3 (5 mL) and brine (5 mL). The or-
ganic layer was dried over anhydrous Na2SO4 and the solvent was
removed under reduced pressure to get crude product, which was
purified by column chromatography (20% EtOAc/pet. ether) to
furnish title
b-lactam 12 (0.470 g, 70%) as a viscous liquid. [Found:
C, 68.05; H, 6.91; N, 5.60%. C14H17NO3 requires C, 68.00; H, 6.93; N,
30
5.66%.] Rf (20% EtOAc/pet. ether) 0.2; [
a]
ꢀ33.3 (c 0.3, CHCl3); nmax
D
H, 9.48; N, 7.88%. C11H17NO requires C, 73.70; H, 9.56; N, 7.81%.] Rf
(CHCl3) 1805 cmꢀ1
;
dH (200 MHz, CDCl3) 7.36–7.25 (5H, m, Ar), 4.85
30
(40% EtOAc/MeOH) 0.3; [
a
]
þ39.0 (c 6.0, CHCl3); nmax (CHCl3)
D
0
(1H, m, CH–N), 3.36 (1H, dd, J¼6.1, 16 Hz, OCCH2 ), 2.85 (1H, dd,
J¼3.15, 16 Hz, OCCH2), 1.31 (9H, s, OC(CH3)3); dC (50 MHz, CDCl3)
164.9, 147.3, 138.1, 128.7, 128.4, 125.8, 83.1, 53.6, 45.9, 27.7; MS: (m/
z)¼248 (Mþ1).
3335 cmꢀ1
;
dH (200 MHz, CDCl3) 7.32–7.15 (5H, m, Ar), 5.16 (1H, br
s, OH), 3.90–3.80 (2H, m, OCH2), 3.80–3.69 (1H, m, CH–N), 2.48–
0
2.32 (1H, m, CCH2 C), 2.18 (6H, s, N(CH3)2), 1.76–1.66 (1H, m,
CCH2C); dC (50 MHz, CDCl3) 136.1, 129.0, 128.8, 128.3, 127.9, 127.1,
70.0, 63.1, 41.0, 32.1; MS: (m/z)¼180 (Mþ1).
4.7. S-(3-Hydroxy-1-phenyl-propyl)-carbamic acid tert-butyl
ester (13)
Acknowledgements
To a suspension of LAH (0.204 g, 5.37 mmol) in THF (5 mL) was
added b-lactam 12 (0.332 g, 1.33 mmol) in THF (5 mL) drop wise at
Authors, P.M.C. and A.S.K., thank University Grants Commission
and Council of Scientific and Industrial Research, New Delhi re-
spectively for research fellowships.
0 ꢁC under inert atmosphere. The reaction mixture was allowed to
attain room temperature and stirred for total 4 h. After completion
of reaction (TLC), a saturated solution of Na2SO4 was added to the
reaction mixture at 0 ꢁC and it was stirred for an hour. THF was then
evaporated on rotary evaporator and to the residue was added ethyl
acetate (15 mL). It was washed with water (10 mL). The aqueous
layer was washed with ethyl acetate (2ꢂ5 mL). Combined organic
extracts were washed with brine (5 mL) and dried over anhydrous
Na2SO4 and concentrated in vacuo to get the crude product, which
was purified by column chromatography using (40% EtOAc/pet.
ether) to furnish 13 (0.269 g, 80%) as a white solid. Mp 104 ꢁC.
References and notes
1. For reviews on
Lattrell, R.; Scheunemann, K. H. Angew. Chem., Int. Ed. Engl. 1985, 24, 180; (b)
Chemistry and Biology of -lactam antibiotics; Morin, R. B., Gorman, M., Eds.;
b-lactam antibiotics see: (a) Du¨rkheimer, W.; Blumbach, J.;
b
Academic: New York, NY, 1982; Vols. 1–3; (c) Coulton, S.; Hunt, E. In Recent
Progress in the Chemical Synthesis of Antibiotics and Related Microbial Products;
Lucaks, G., Ed.; Springer: Berlin, 1993; Vol. 2, p 621; (d) Southgate, R. Contemp.
Org. Synth. 1994, 1, 417.
2. The Chemistry of b-lactams; Page, M. I., Ed.; Chapman and Hall: London, 1992.
3. For comprehensive general reviews, see: (a) Koppel, G. A. In Small Ring Het-
erocycles; Hasner, A., Ed.; Wiley: New York, NY, 1983; Vol. 42, p 219; (b) Backes,
J. In Houben-Weyl, Methoden der Organischen Chemie; Klamann, D., Ed.; Thieme:
Stuttgart, 1991; Vol. E16B, p 31; (c) de Kimpe, N. In Comprehensive Heterocyclic
Chemistry II; Katrizky, A. R., Rees, C. W., Scriven, E. F. V., Padwa, A., Eds.; Per-
gamon: Oxford, 1996; Vol. 1B, p 507.
[Found: C, 66.81; H, 8.57; N, 5.65%. C14H21NO3 requires C, 66.91; H,
30
8.42; N, 5.57%.] Rf (30% EtOAc/pet. ether) 0.2; [
a
]
ꢀ53.1 (c 7.0,
D
acetone); nmax (CHCl3) 3337 cmꢀ1
;
dH (200 MHz, CDCl3) 7.38–7.27
(5H, m, Ar), 4.99 (1H, m, CH–N), 3.72–3.65 (2H, m, OCH2), 2.7 (2H, br
s, OH, NH), 2.17–1.79 (2H, m, CCH2C), 1.44 (9H, s, OC(CH3)3); dC
(50 MHz, CDCl3) 156.3, 141.9, 128.7, 127.4, 126.3, 79.9, 58.9, 51.5,
39.3, 28.2; MS: (m/z)¼252 (Mþ1).
4. (a) Ojima, I. In The Chemistry of
1993; p 197; (b) Palomo, C.; Aizpurua, J.; Ganboa, I. In Enantioselective Synthesis
of -Amino Acids I; Juaristi, E., Ed.; Wiley-VCH: New York, NY, 1997; p 279; and
b-Lactams; Georg, G. I., Ed.; VCH: New York, NY,
b
references cited therein; (c) For a review on this subject, see: Ojima, I.; Dela-
loge, F. Chem. Soc. Rev. 1997, 26, 377; (d) Alcaide, B.; Almendros, P. Chem. Soc.
Rev. 2001, 30, 226; (e) Alcaide, B.; Almendros, P. Synlett 2002, 381.
4.8. (S)-3-Amino-3-phenyl-propan-1-ol (14)
5. Nagahara, T.; Kametani, T. Heterocycles 1987, 25, 729; (b) Thomas, R. C. In Recent
Progress in the Chemical Synthesis of Antibiotics; Lucaks, G., Ohno, M., Eds.;
Springer: Berlin, 1990; p 553; (c) Palomo, C. In Recent Progress in the Chemical
Synthesis of Antibiotics; Lucaks, G., Ohno, M., Eds.; Springer: Berlin, 1990; p 565;
(d) Palomo, C.; Arrieta, A.; Cossio, F. P.; Aizpurua, J. M.; Mielgo, A.; Aurrekoetxea,
N. Tetrahedron Lett. 1990, 31, 6429; (e) Palomo, C.; Cabre, F.; Ontario, J. M. Tet-
rahedron Lett. 1992, 33, 4819; (f) Annunziata, R.; Benaglia, M.; Cinquini, M.;
Cozzi, F.; Ponzini, F. J. Org. Chem. 1993, 58, 4746.
6. (a) Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M. J. Org. Chem. 1994, 59,
932; (b) Jayaraman, M.; Nandi, M.; Sathe, K. M.; Deshmukh, A. R. A. S.; Bhawal,
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A. S.; Bhawal, B. M. Tetrahedron 1996, 52, 8989; (d) Banik, B. K.; Mathur, C.;
Wagle, D. R.; Manhas, M. S.; Bose, A. K. Tetrahedron 2000, 56, 5603.
To a solution of 13 (0.030 g, 0.12 mmol) in DCM (2 mL) was
added TFA (0.3 mL) drop wise at 0 ꢁC. It was kept at 0 ꢁC for half an
hour and then allowed to come to room temperature and stirred for
further 1.5 h. After completion (TLC), the reaction mixture was
concentrated in vacuo to remove DCM and TFA. The residue was
then dissolved in methanol (3 mL) and Et3N (0.016 mL, 0.12 mmol)
was added and the resultant solution was passed through a short
column of silica gel with methanol as an eluent. The methanol
fractions were concentrated in vacuo to furnish 14 as a white hy-
7. (a) Jayaraman, M.; Puranik, V. G.; Bhawal, B. M. Tetrahedron 1996, 52, 9005; (b)
Srirajan, V.; Deshmukh, A. R. A. S.; Puranik, V. G.; Bhawal, B. M. Tetrahedron:
Asymmetry 1996, 7, 2733; (c) Deshmukh, A. R. A. S.; Bhawal, B. M.; Krish-
naswamy, D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A. Curr. Med. Chem. 2004,
11, 1889; (d) Shirode, N. M.; Kulkarni, K. C.; Gumaste, V. K.; Deshmukh, A. R. A. S.
groscopic solid (0.016 g, 89%). [Found: C, 71.32; H, 8.80; N, 9.35%.
30
C9H13NO requires C, 71.49; H, 8.67; N, 9.26%.] Rf (MeOH) 0.3; [a]
D
ꢀ11.4 (c 2.0, CHCl3); nmax (CHCl3) 3200–3380 cmꢀ1
; dH (200 MHz,
CDCl3) 7.38–7.15 (5H, m, Ar), 3.86 (3H, br s, NH2, OH), 3.69–3.63 (3H,

P.M. Chincholkar et al. / Tetrahedron 65 (2009) 2605–2609
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