Stereoselective synthesis of (S)-dapoxetine: A chiral auxiliary mediated approach

Article abstract of DOI:10.1016/j.tetlet.2013.08.059

An imidazolidin-2-one chiral auxiliary mediated acetate aldol reaction was explored in the enantioselective synthesis of (S)-dapoxetine (SSRI). The diastereoselective aldol adduct was transformed to highly enantiopure (S)-dapoxetine with overall good yield.

Full text of DOI:10.1016/j.tetlet.2013.08.059

Accepted Manuscript
Stereoselective synthesis of (S)-dapoxetine: A chiral auxiliary mediated ap‐
proach
Gopal L. Khatik, Ratnesh Sharma, Varun Kumar, Mangilal Chouhan, Vipin A.
Nair
PII:
S0040-4039(13)01432-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.059
TETL 43422
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 July 2013
13 August 2013
17 August 2013
Please cite this article as: Khatik, G.L., Sharma, R., Kumar, V., Chouhan, M., Nair, V.A., Stereoselective synthesis
of (S)-dapoxetine: A chiral auxiliary mediated approach, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/
j.tetlet.2013.08.059
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Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
Stereoselective synthesis of (S)-dapoxetine: A chiral auxiliary
mediated approach
Gopal L. Khatika*, Ratnesh Sharmab, Varun Kumarb, Mangilal Chouhanb, Vipin A. Nairb*
aDepartment of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, G.T. Road, Phagwara,
Punjab 144402, India.
bDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, Mohali, Punjab
160062, India.
Abstract— An imidazolidin-2-one chiral auxiliary mediated acetate aldol reaction was explored in the enantioselective synthesis of (S)-
dapoxetine (SSRI). The diastereoselective aldol adduct was transformed to highly enantiopure (S)-dapoxetine with overall good yield.
© 2013 Elsevier Science. All rights reserved
Several drugs possess one or more chiral centres and are
found to interact stereoselectively with their receptors.
Hence asymmetric synthesis of drugs always outweighs the
nonstereoselective methods. Selective Serotonin Reuptake
Inhibitors (SSRIs) are most widely prescribed for treating
depression and have been proven to be safer as well as
effective than other classes of antidepressants by virtue of
their high specificity.1 SSRIs increase the concentration of
serotonin selectively by inhibiting its reuptake at the
neuronal junction.2 Some of the commercially well known
SSRI medications are illustrated in Figure 1. Based on our
interests in chiral auxiliary mediated synthesis of natural
products and drug scaffolds,3 we had recently reported the
stereoselective synthesis of (R)- and (S)-fluoxetine.3h
Herein, we further extend our inquisitions on another SSRI
by exploring a stereoselective synthesis of (S)-dapoxetine.
Dapoxetine, initially marketed as an antidepressant, has
been recently used for the treatment of premature
ejaculation.4 It is reported to have a rapid absorption and
elimination from the body and was evaluated safe when
used in combination with other existing drugs for erectile
dysfunction such as sildenafil (Viagra), tadalafil (Cialis),
and vardenafil (Levittra).5
asymmetric C-H amination reactions of a prochiral
sulfamate,11 reduction12
oxazaborolidine of 3-
chloropropiophenone or ketone and recently reported
Carica papaya lipase (CPL) catalyzed enantioselective
alcoholysis.13
Figure 1. Selective Serotonin Reuptake Inhibitors (SSRIs).
The above mentioned methods are undermined by poor
yields/low
enantio
selectivities/complex
synthetic
procedures. We therefore envisioned a simple asymmetric
induction strategy through a chiral auxiliary mediated
acetate aldol reaction. The resulting aldol adduct could be
subjected to undergo functional group transformations to
yield (S)-dapoxetine.
The (S) enantiomer of dapoxetine is 3.5 times more
potent than its counterpart.6 However, there are only a few
reports available on its stereoselective synthesis. The earlier
methods include chiral/enzymatic resolution,7 and
radiochemical synthesis8 whereas the newer approaches
encompass asymmetric dihydroxylation of trans methyl
cinnamate or cinnamyl alcohol,9 chiral azetidin-2,3-dione,10
———
The retrosynthetic analysis is illustrated in Scheme 1.
The preferential selection of N-acetyl-(S)-4-isopropyl-1-
*Corresponding authors. Tel.: +91-9256336645 (G.L.K.); +91-172-2292045 (V.A.N.).
E-mail addresses: gopal.16803@lpu.co.in; gopal_niper@rediffmail.com (G.L.K.), vnair@niper.ac.in (V.A.N.)

2
Tetrahedron Letters
[(R)-1-phenylethyl]imidazolidin-2-one (1) as
a chiral
situ upon treatment with triethylamine, and further react
with the mesylated adduct.
auxiliary was based on our previous investigations.3h The
chiral auxiliary was subjected to reaction with N,N-
diisopropylethylamine (DIPEA) and titanium tetrachloride
at -78 °C under anhydrous conditions for enolate
generation. Subsequent reaction with benzaldehyde
afforded the syn:anti acetate aldol product with a
1
diasteroselectivity of 99:01 respectively (determined by H
NMR of the crude product).3h
Scheme 2. Stereoselective synthesis of (S)-dapoxetine.
Accordingly an aq. solution of dimethylamine was
reacted with conc. HCl in equimolar amounts and dried
under vacuum to yield the dimethylamine hydrochloride
salt (Me2NH.HCl) as a white solid. Further its reaction, in
the presence of triethylamine, with the in situ generated
mesylate product had improved the yield to 70% (Scheme
2).16 The product was confirmed by the spectral data and
specific rotation [α]D20 +65.9 (c 1.00, CHCl3), which were
in complete agreement with the reported values.9a
Scheme 1. Retrosynthetic analysis.
Cleavage of the auxiliary from the syn aldol adduct with
aq. NaOH afforded (R)-3-hydroxy-3-phenylpropanoic acid
(3) with high enantiopurity without any racemization. The
absolute configuration of the acid was confirmed by
20
comparing the optical rotation {[α]D +55.9 (c 1.00,
CHCl3)} with the reported value.4h,14 (R)-3-Hydroxy-3-
phenylpropanoic acid (3) was then subjected to
esterification using thionyl chloride in methanol and
subsequently reduction with NaBH4 afforded (R)-1-
phenylpropan-1,3-diol (4). A selective primary hydroxyl
tosylation15 using TsCl succeeded by a nucleophilic
substitution with 1-naphthol in the presence of K2CO3
afforded (R)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol
(6) in excellent yield.
In conclusion, the stereoselective synthesis of (S)-
dapoxetine was successfully achieved in 50% overall good
yield by utilizing a chiral auxiliary mediated approach
through an asymmetric acetate aldol reaction as the key
steps.
Acknowledgments
Attempts to isolate the O-mesylated derivative of 6 failed
due to the product instability. However, in situ generation
of the mesylated product at 0 °C under anhydrous
atmosphere followed by reaction with dimethyl amine
solution in THF afforded (S)-dapoxetine (7) in 42% yield.
Volatility of dimethylamine was reasoned for the low yield.
We assumed that this problem could be resolved by using a
dimethyl amine salt that would release the free amine in
We are thankful to the University Grants Commission; and
the Department of Science & Technology, Government of
India for research funding.

Tetrahedron Letters
3
16. Experimental:
Synthesis of (R)-3-hydroxy-3-phenylpropanoic acid (3).
To solution of (S)-3-acetyl-4-isopropyl-1-[(R)-1-
Supplementary Material
a
Supplementary data associated with this article can be
found, in the online version, at www.elsevier.com/
locate/tetlett.
phenylethyl]imidazolidin-2-one (1, 3 g, 11 mmol, 1.0 equiv)
in anhydrous DCM (50 mL, dried over calcium hydride) and
under N2 environment, was added TiCl4 solution (22 mL, 22
mmol, 2.0 equiv, 1 M in DCM) at –78 °C. The reaction
mixture was warmed to 0 °C, stirred for 10 min and again
cooled to –78 °C. To this reaction mixture, DIPEA (2 mL, 11
mmol, 1.0 equiv) was added and stirred for 1 h. Further
benzaldehyde (1.25 mL, 12 mmol, 1.1 equiv) was introduced
into it and stirred for 30 min. The reaction mixture was
quenched with water and extracted with DCM, further
product was purified (yield 3.8 g) and dissolved in THF (50
mL) was added aq NaOH (0.8 g, 20 mmol, 2.0 equiv, 20 mL
H2O) and refluxed for 2 h. The reaction mixture was extracted
with DCM to remove auxiliary, and then aqueous layer was
acidified upto pH ~3 with dil. HCl. The resulting solution was
extracted with ethyl acetate, dried and concentrated to afford
3 (yield 2 g, 87%).
References and Notes
1. Isbister, G.; Bowe, S.; Dawson, A.; Whyte, I. J. Toxicol. Clin.
Toxicol. 2004, 42, 277.
2. Preskorn, S. H.; Ross, R.; Stanga, C. Y. Antidepressants:
Past, Present and Future. Berlin: Springer. 2004, pp. 241.
3. (a) Kumar, V.; Pal, A.; Khatik, G. L.; Nair, V. A.
Tetrahedron: Asymmetry 2012, 23, 434; (b) Kumar, V.;
Raghavaiah, P.; Mobin, S. M.; Nair, V. A. Org. Biomol.
Chem. 2010, 8, 4960; (c) Kumar, V.; Khatik, G. L.; Nair, V.
A. Synlett 2011, 2997; (d) Kumar, V.; Nair, V. A.
Tetrahedron Lett. 2010, 51, 966; (e) Khatik, G. L.; Pal, A.;
Mobin, S. M.; Nair, V. A. Tetrahedron Lett. 2010, 51, 3654;
(f) Khatik, G. L.; Khurana, R.; Kumar, V.; Nair, V. A.
Synthesis 2011, 3123; (g) Kumar, V.; Khatik, G. L.; Pal, A.;
Praneeth, M. R.; Bhattarai, S.; Nair, V. A. Synlett 2012, 2357;
(h) Khatik, G. L.; Kumar, V.; Nair, V. A. Org. Lett. 2012, 14,
2442; (i) Chouhan, M.; Sharma, R.; Nair, V. A. Org. Lett.
2012, 14, 5672; (j) Chouhan, M.; Kumar, K.; Sharma, R.;
Grover, V.; Nair, V. A. Tetrahedron Lett. 2013, 54, 4540; (k)
Gahtory, D.; Chouhan, M.; Sharma, R.; Nair, V. A. Org. Lett.
2013, 15, 3942.
4. (a) McCarty, E.; Dinsmore, W. Core Evid. 2012, 7, 1; (b)
McMahon, C. G.; McMahon, C. N.; Leow, L. J.
Neuropsychiatr. Dis. Treat. 2006, 2, 489; (c) Shabsigh, R.;
Broderick, G. A.; Miloslavsky, M.; Bull, S. J. Urol. 2006,
175, 297; (d) Wong, D. T.; Perry, K. W.; Bymaster, F. P. Nat.
Rev. Drug Discovery 2005, 4, 764.
5. (a) Sotomayor, M. J. Sex. Med. 2005, 2, 110; (b) Dresser, M.
J.; Desai, D.; Gidwani, S.; Seftel, A. D.; Modi, N. B. Int. J.
Impot. Res. 2006, 18, 1040; (c) Andersson, K. E.; Mulhall, J.
P.; Wyllie, M. G. BJU Int. 2006, 97, 311.
White solid; Mp 115–119 °C; [α]D20 +55.9 (c 1.00, CHCl3. 1H
NMR (400 MHz, CDCl3) δ 2.72–2.85 (m, 2H), 5.15 (dd, J =
9.29, 3.76 Hz, 1H), 7.28–7.37 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 43.04, 70.24, 125.69, 128.00, 128.66, 142.18,
176.55; HRMS (ESI-TOF) calcd for C9H10O3 [M]+:166.0630;
found: 166.1227; and C9H10O3Na [M+Na]+: 189.0528; found:
189.1081.
Synthesis of (R)-1-phenylpropane-1,3-diol (4).
A solution of 3 (1.2 g, 7.23 mmol, 1.0 equiv.) in methanol (20
mL) was cooled to 0 °C and SOCl2 (0.53 mL, 7.23 mmol, 1.0
equiv) was added to it. The reaction mixture was stirred for
1h and then
NaBH4 (0.21 g, 5.54 mmol, 1.0 equiv) was
added to it and then stirred for another 30 min. The reaction
was quenched with water, and methanol was evaporated
under reduced pressure. The crude product was extracted into
ethyl acetate, dried over anhydrous sodium sulfate and
concentrated to afford 4 (yield 0.78 g, 92%).
20
1
White solid; Mp 60–64 °C; [α]D +59.1 (c 1.00, CHCl3; H
NMR (400 MHz, CDCl3) δ 1.83–1.93 (m, 2H), 3.65–3.88 (m,
2H), 4.92 (dd, J = 8.78, 3.76 Hz, 1H), 5.32 (brs, 2H), 7.19–
7.29 (m, 1H) 7.29–7.39 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 40.35, 61.01, 73.79, 125.67, 127.49, 128.46,
144.23; HRMS (ESI-TOF) calcd for C9H12O2 ([M+Na]+):
175.0735; found: 175.0733.
6. Anon, N. Z. Drugs Res. Dev. 2005, 6, 307.
7. (a) Torre, O.; Gotor-Fernandez, V.; Gotor, V. Tetrahedron:
Asymmetry 2006, 17, 860; (b) Alt, O. A. Robey, R. L.; Meter,
E. E. V. U.S. Pat. 5292962, 1994.
8. (a) Robertson, D. W.; Thompson, D. C.; Wong, D. T. Eur.
Pat. Appl. EP 288188 A1 19881026, 1988; (b) Livni, E.;
Satterlee, R. W.; Robey, R. L.; Alt, C. A.; Van Meter, E. E.;
Babich, J. W.; Wheeler, W. J.; O’Bannon, D. D.; Thrall, J. H.;
Fischman, A. J. Nucl. Med. Biol. 1994, 21, 669.
9. (a) Siddiqui, S. A.; Srinivasan, K. V. Tetrahedron:
Asymmetry 2007, 18, 2099; (b) Venkatesan, K.; Srinivasan,
K. V. Arkivoc 2008, XVI, 302.
10. Chincholkar, P. M.; Kale, A. S.; Gumaste, V. K.; Rakeeb, A.;
Deshmukh, A.S. Tetrahedron 2009, 65, 2605.
11. Kang, S.; Lee, H.-K. J. Org. Chem. 2010, 75, 237.
12. Kim, S. J.; Tae, H. J.; Im S. M.; In S. K.; Young, H. J.
Tetrahedron Lett. 2012, 53, 3680; (b) Mahale, R. D.;
Chaskar, S. P. ; Patil, K. E. ; Maikap, G. C.; Gurjar, M. K.
Org. Process Res. Dev. 2012, 16, 710.
13. You, P.; Qiu, J.; Su, E.; Wei, D. Eur. J. Org. Chem. 2013,
557.
14. Yan, T. H.; Hung, H. C.; Hung, A. W.; Lee, H. C.; Chang, C.
S. J. Org. Chem. 1994, 59, 8187.
15. (a) Ali, A. I.; Sudalai, A. Tetrahedron Lett. 2002, 43, 5435;
(b) Bosse, K.; Marineau, J.; Nason, D. M.; Fliri, A. J.;
Segelstein, B. E.; Desai, K.; Volkmann, R. A. Tetrahedron
Lett., 2006, 47, 7285.
Synthesis
methylbenzenesulfonate (5).
of
(R)-3-hydroxy-3-phenylpropyl
4-
To a solution of 4 (0.7 g, 4.59 mmol, 1.0 equiv.) in DCM (20
mL) at 0 °C was added triethylamine (1.27 mL, 9.18 mmol,
2.0 equiv) and a solution of tosyl chloride (0.96 g, 5.04
mmol, 1.1 equiv) in DCM (10 mL). The reaction mixture was
allowed to stir at rt for 24 h. It was then extracted with ethyl
acetate, washed with aq NaHCO3, dried over anhydrous
sodium sulfate and concentrated under vacuum to afford 5
(yield 1.44 g, 95%).
Gummy; [α]D – 16.4 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ 2.00–2.04 (m, 3H), 2.45 (s, 3H), 4.03–4.08 (m, 1H),
4.25– 4.31 (m, 1H), 4.80 (t, J = 6.6 Hz, 1H), 7.26– 7.31 (m,
5H), 7.34 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 7.7 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 21.67, 38.07, 67.63, 70.18,
125.55, 127.95, 128.50, 128.61, 129.90, 132.92, 143.54,
144.86; HRMS (ESI-TOF) calcd for C16H18O4SNa [M+Na]+:
329.0823; found: 329.0826.
20
1
Synthesis of (R)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol
(6).
A mixture of 5 (1.0 g, 3.26 mmol, 1.0 equiv.), 1-naphthol
(0.51 g, 3.59, 1.1 equiv) and K2CO3 (1.35 g, 7.78 mmol, 3.0
equiv) in acetone (50 mL) was refluxed for 12 h. The

4
Tetrahedron Letters
reaction mixture was cooled and acetone was evaporated. It
was extracted with ethyl acetate, dried over anhydrous
sodium sulphate and concentrated to afford the crude product
which was purified by column chromatography [silica gel
(60-120 mesh), eluent hexanes:EtOAc = 9:1] to afford the 6
(yield 0.89 g, 94%).
20
1
White solid; Mp 71–74 °C; [α]D –30.5 (c 0.5, CHCl3); H
NMR (400 MHz, CDCl3) δ 2.31–2.41 (m, 2H), 2.42 (d, J =
3.1 Hz, 1H), 4.16–4.23 (m, 1H), 4.31–4.36 (m , 1H), 5.12–
5.14 (m, 1H), 6.79 (d, J = 7.5 Hz, 1H), 7.28–7.31 (m, 1H),
7.33–7.37 (m, 3H), 7.41–7.43 (m, 3H), 7.45–7.53 (m, 2H),
7.79–7.81 (m, 1H), 8.23–8.25 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 29.72, 38.50, 65.39, 104.79, 120.08, 121.97,
125.09, 125.60, 125.85, 126.32, 127.45, 127.64, 128.38,
128.67, 134.44, 138.76, 154.52; HRMS (ESI-TOF) calcd for
C19H18O2Na [M+Na]+: 301.1204; found: 301.1204.
Synthesis of (S)-dapoxetine 7.
A solution of 6 (0.5 g, 1.8 mmol, 1.0 equiv.), triethylamine
(0.75 mL, 5.4 mmol, 3.0 equiv) and DMAP (0.02 g, 0.18
mmol, 0.1 equiv) in THF (20 mL) was cooled to 0 °C. To this
reaction mixture, mesyl chloride (0.41 mL, 3.6 mmol, 2.0
equiv) was added and stirred for 12 h at rt. The reaction
mixture was cooled to 0 °C and to this excess triethyl amine
(0.75 mL, 5.4 mL, 3.0 equiv) followed by Me2NH.HCl (0.44
g, 5.4 mmol, 3.0 equiv,) was added. The reaction mixture was
then stirred at rt for another 24 h. It was extracted with ethyl
acetate, dried over anhydrous sodium sulfate and concentrated
to afford crude which was purified by column
chromatography [silica gel (60-120 mesh), eluent
DCM:MeOH = 9:1] to afford an oily compound 7 (yield 0.38
g, 70%).
Me2NH.HCl was prepared from aq. dimethylamine solution
(5.0 mL, 40%) by the addition of conc. HCl (5.0 mL, 35%) at
0°C. The reaction mixture was stirred for 0.5 h and then the
water was evaporated.The solid fraction was azeotroped thrice
with toluene to afford white solid compound (3.0 g), which
was stored under inert atmosphere.
20
25
Liquid; [α]D +65.9 (c 1.00, CHCl3), lit9a [α]D +64:2 (c
0.3,CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.03 (s, 6H),
2.33–2.35 (m, 1H), 2.65–2.70 (m, 1H), 3.68 (dd, J = 9.4, 5.1
Hz, 1H), 3.85–3.91 (m, 1H), 4.05–4.10 (m, 1H), 6.63 (d, J =
7.6 Hz, 1H), 7.28–7.35 (m, 6H), 7.38 (d, J = 8.2 Hz, 1H),
7.44–7.50 (m, 2H), 7.76–7.79 (m, 1H), 8.20–8.22 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 32.79, 42.69, 65.46, 67.87,
104.57, 120.08, 121.97, 125.09, 125.60, 125.85, 126.32,
127.45, 127.64, 128.38, 128.67, 134.44, 138.36, 154.52;
HRMS (ESI-TOF) calcd for C21H24NO [M+H]+: 306.1858;
found: 306.1860; and C21H23NONa [M+Na]+: 328.1677;
found: 328.1677.

Tetrahedron Letters
1
Graphical Abstract
Leave this area blank for abstract info.
Stereoselective synthesis of (S)-dapoxetine: A
chiral auxiliary mediated approach
Gopal L. Khatika, Ratnesh Sharma b, Varun Kumarb Mangilal Chouhanb, Vipin A. Nairb
aDepartment of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, G.T. Road, Phagwara,
Punjab 144 402, India; bDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER),
Sector 67, Mohali, Punjab 160 062, India;