Asymmetric total synthesis of (S)-dapoxetine

Article abstract of DOI:10.1016/j.tetlet.2012.05.037

A concise asymmetric total synthesis of (S)-dapoxetine from commercially available 3-chloropropiophenone is described. The key step includes a highly stereoselective amination of chiral benzylic ether, with the retention of stereochemistry, using chlorosu

Full text of DOI:10.1016/j.tetlet.2012.05.037

Tetrahedron Letters 53 (2012) 3680–3682
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric total synthesis of (S)-dapoxetine
Sun Joo Kim a, Tae Hong Jeon a, Im Sook Min a, In Su Kim b, , Young Hoon Jung a,
⇑
⇑
a School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
b College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise asymmetric total synthesis of (S)-dapoxetine from commercially available 3-chloropropiophe-
none is described. The key step includes a highly stereoselective amination of chiral benzylic ether, with
the retention of stereochemistry, using chlorosulfonyl isocyanate.
Received 6 April 2012
Revised 30 April 2012
Accepted 7 May 2012
Available online 12 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Dapoxetine
Chlorosulfonyl isocyanate
Amination
Asymmetric
Selective serotonin reuptake inhibitors (SSRIs) are the most fre-
quently prescribed agents for the treatment of depression and
other psychiatric disorders such as bulimia or anxiety due to their
pharmacological effect of increasing the extracellular level of the
neurotransmitter serotonin by inhibiting its reuptake into the pre-
synaptic cell (Fig. 1).1 Delayed-ejaculation is a common side effect
of SSRI antidepressants.2 In the last decade, clinical evidence has
emerged indicating a beneficial effect of SSRIs for the treatment
of patients with premature ejaculation (PE),3 which is considered
the most common male sexual disorder with a prevalence of
9–31% of men worldwide.4
Dapoxetine (1, (S)-(+)-N,N-dimethyl[3-(naphthalen-1-yloxy)-1-
phenylpropyl]amine hydrochloride, PriligyÒ), a short-acting SSRI
with a unique pharmacokinetic profile,5 is currently used in several
European countries, New Zealand, and South Korea as an on-demand
oral treatment for premature ejaculation. The (S)-enantiomer of
dapoxetine is 3.5 times more potent than the (R)-enantiomer.6
The commercial production of (S)-dapoxetine relies on the tartaric
acid-promoted chiral resolution of racemic dapoxetine. Due to its
potent pharmacological activity and unique structural features,
asymmetric synthetic approaches for (S)-dapoxetine have been
developed. Gotor described the asymmetric total synthesis of (S)-
dapoxetine (1) starting from chiral 1,3-amino alcohol, which was
obtained by enzyme-catalyzed resolution of racemic 1,3-amino
alcohols.7 Srinivasan reported enantioselective syntheses of (S)-
dapoxetine from trans-methyl cinnamate8 and cinnamyl alcohol9
via respective sharpless asymmetric dihydroxylation and epoxida-
tion as the key steps. A formal synthesis of (S)-dapoxetine based on
radical deoxygenation of enantiopure 3-hydroxyazetin-2-one was
also reported.10 In an elegant example, Lee demonstrated a highly
enantioselective synthesis of both enantiomers of dapoxetine via
Rh-catalyzed asymmetric amination reaction of C–H bond in a
prochiral sulfamate ester.11 Recently, Zhang described the highly
efficient Ir-catalyzed asymmetric hydrogenation of unprotected
b-enamine esters to afford b-amino esters, that can be easily con-
verted to (S)-dapoxetine.12
F3C
Me
Me
N
O
Me
O
N
H
dapoxetine (1)
fluoxetine
H
N
O
O
Me
Cl
Cl
O
N
H
paroxetine
sertraline
Figure 1. Selective serotonin reuptake inhibitors (SSRIs).
⇑
Corresponding authors. Tel.: +82 2 961 0475; fax: +82 2 966 3885 (I.S.K.);
tel.: +82 31 290 7711; fax: +82 31 290 7773 (Y.H.J.).
As part of an ongoing research program aimed at developing
asymmetric total synthesis of biologically active compounds,13
E-mail addresses: insukim@khu.ac.kr (I.S. Kim), yhjung@skku.edu (Y.H. Jung).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.037

S. J. Kim et al. / Tetrahedron Letters 53 (2012) 3680–3682
3681
OBn
OH
O
a
b
Cl
Cl
Cl
79%
77%
2
3
4
NHCbz
NHCbz
c
see Table 1
Cl
O
O
91%
5
6
Me
Me
N
NH2
d
e
65%
O
90%
7
1
Scheme 1. Reagents and conditions: (a) (R)-(+)-2-methyl-CBS-oxazaborolidine, N,N-diethylaniline borane, toluene, rt, 6 h; (b) NaH, BnBr, THF/DMF (4:1), rt, 3 h; (c) (i) CSI,
Na2CO3, n-hexane, 0 °C, 6 h; (ii) 25% Na2SO3, rt, 12 h; (d) H2, 10% Pd/C, MeOH/EtOAc (1:1), rt, 24 h; (e) HCO2H, 30% HCOH, reflux, 8 h.
we recently reported a facile strategy for the preparation of (+)-
sertraline based on stereoselective amination of various chiral
benzylic ethers using chlorosulfonyl isocyanate (CSI).14 In connec-
tion with our previous work on the regioselective and diastereose-
lective allylic or benzylic amination using CSI, we became
interested in developing an efficient synthetic route for the total
synthesis of (S)-dapoxetine (1). Herein, we describe the concise to-
tal synthesis of 1 starting from readily available 3-chloropropio-
phenone (2), via highly stereoselective amination of chiral
benzylic ether using chlorosulfonyl isocyanate as the key step.
Our initial investigations focused on the enantioselective reduc-
tion of prochiral ketone to synthesize the chiral alcohol 3 according
to previous reports (Scheme 1).15 After optimization of the reaction
conditions, we found 3-chloropropiophenone was converted into
the alcohol 3 with excellent enantioselectivity (>99.9% ee via chiral
HPLC analysis). Benzylation of 3 under standard conditions (benzyl
bromide, NaH, THF/DMF) proceeded cleanly to afford the ether 4 in
77% yield. The stereoselective reaction of 4 with chlorosulfonyl iso-
cyanate was carried out in anhydrous n-hexane at 0 °C for 6 h, fol-
lowed by desulfonylation with aqueous 25% sodium sulfite
solution to give the desired carbamate 5 with excellent enantiose-
lectivity (99.8% ee via chiral HPLC analysis) in 91% yield. The reten-
tion of stereochemistry can be explained by SNi mechanism
through a four-centered transition state.16 This observation is con-
sistent with the formation of a tight ion pair in nonpolar n-hexane
solvent, compared to relatively polar methylene chloride solvent.17
To introduce the naphthoxy moiety into 5 using 1-naphthol by
nucleophilic substitution, several reaction conditions were investi-
gated and the selected results are summarized in Table 1. The use of
NaH as a base afforded the desired product 6 in moderate to good
yields (Table 1, entries 1 and 2). However, other bases, such as
KOH, K2CO3, and KOtBu, were less effective (Table 1, entries 3–5).
Since carbamate and chloro moieties are sensitive to some bases,
the choice of base is crucial for this transformation. After further
optimization, the best results were obtained by the treatment of
Cs2CO3 (500 mol %) and 1-naphthol (300 mol %) in the presence of
THF and DMF at 60 °C for 20 h, affording the desired product 6 in
high yield (88%), as shown in entry 6. Deprotection of the carbamate
group of 6 using palladium-catalyzed hydrogenation provided the
amine 7 in 90% yield. Finally, reductive amination of 7 under
Eschweiler-Clarke conditions furnished (S)-dapoxetine (1) with
excellent enantiopurity (>99.7%) in 65% yield. The spectral data
(1H NMR and 13C NMR) and specific rotation of 1 were in full agree-
ment with the reported values.11
In conclusion, we have described the concise total synthesis of
(S)-dapoxetine starting from readily available 3-chloropropiophe-
none in six linear steps (28.5% overall yield) via stereoselective
introduction of an NHCbz group into chiral benzylic ether using
chlorosulfonyl isocyanate. It is believed that this synthetic strategy
can be applied to the preparation of a broad range of biologically
active compounds containing a chiral amine moiety.
Acknowledgments
This work was supported by the National Research Foundation
of Korea (NRF-2009-0074658), funded by the Ministry of Educa-
tion, Science and Technology.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
05.037.
References and notes
1. (a) Preskorn, S. H.; Ross, R.; Stanga, C. Y. Selective Serotonin Reuptake Inhibitor
In Preskorn, S. H., Ross, R., Stanga, C. Y., Feighner, J. P., Eds.; Antidepressants:
Past, Present, and Future; Springer-Velarg: Berlin, Germany, 2004; p 242; (b)
Wong, D. T.; Perry, K. W.; Bymaster, F. P. Nat. Rev. Drug Discovery 2005, 4, 764;
(c) Katzman, M. A. CNS Drug 2009, 23, 103.
2. Montejo-González, A. L.; Llorca, G.; Izquierdo, J. A.; Ledesma, A.; Bousoño, M.;
Calcedo, A.; Carrasco, J. L.; Ciudad, J.; Daniel, E.; De la Gandara, J.; Derecho, J.;
Franco, M.; Gomez, M. J.; Macias, J. A.; Martin, T.; Perez, V.; Sanchez, J. M.;
Sanchez, S.; Vicens, E. J. Sex Marital Ther. 1997, 23, 176.
3. (a) Kara, H.; Aydin, S.; Yucel, M.; Agargun, M. Y.; Odabas, O.; Yilmaz, Y. J. Urol.
1996, 156, 1631; (b) Waldinger, M. D.; Hengeveld, M. W.; Zwinderman, A. H.
Am. J. Psychiatry 2004, 151, 1377.
4. Lewis, R. W.; Fugl-Meyer, K. S.; Bosch, R.; Fugl-Meyer, A. R.; Laumann, E. O.;
Lizza, E.; Martin-Morales, A. J. Sex Med. 2004, 1, 35.
Table 1
Selected optimization for the coupling of 5 and 1-naphthola
Entry
Conditions
Yieldb (%)
1
2
3
4
5
6
NaH, DMF, 40 °C
NaH, THF/DMF (2:1), 80 °C
50% KOH, DMF, 40 °C
K2CO3, KI, acetonitrile, 80 °C
KOtBu, 18-crown-6, DMF, 80 °C
Cs2CO3, THF/DMF (2:1), 60 °C
51
64
29
40
39
88
a
Reaction conditions: 5 (0.3 mmol), 1-naphthol (0.9 mmol), base (1.5 mmol), and
5. Modi, N. B.; Dresser, M. J.; Simon, M.; Lin, D.; Desai, D.; Gupta, S. J. Clin.
Pharmacol. 2006, 46, 301.
6. Robertson, D. W.; Wong, D. T.; Thompson, D. C. U.S. Patent 5,135,947, 1992.
solvent (1.2 mL) for 20 h under N2.
b
Isolated yield by column chromatography.

3682
S. J. Kim et al. / Tetrahedron Letters 53 (2012) 3680–3682
7. Torre, O.; Gotor-Fernádez, V.; Gotor, V. Tetrahedron: Asymmetry 2006, 17, 860.
8. Siddiqui, S. A.; Srinivasan, K. V. Tetrahedron: Asymmetry 2007, 18, 2099.
9. Venkatesan, K.; Srinivasan, K. V. ARKIVOC 2008, xvi, 302.
10. Chincholkar, P. M.; Kale, A. S.; Gumaste, V. K.; Deshmukh, A. R. A. S. Tetrahedron
2009, 65, 2605.
Lee, J. K.; Lee, S. H.; Lim, J. K.; Zee, O. P.; Jung, Y. H. Synlett 2007, 1711; (h) Kim, I.
S.; Ryu, C. B.; Li, Q. R.; Zee, O. P.; Jung, Y. H. Tetrahedron Lett. 2007, 48, 6258; (i)
Kim, I. S.; Li, Q. R.; Dong, G. R.; Woo, S. H.; Park, H.-j.; Zee, O. P.; Jung, Y. H.
Synlett 2008, 2985.
14. Lee, S. H.; Kim, I. S.; Li, Q. R.; Dong, G. R.; Jeong, L. S.; Jung, Y. H. J. Org. Chem.
2011, 76, 10011.
11. Kang, S.; Lee, H.-K. J. Org. Chem. 2010, 75, 237.
12. Hou, G.; Li, W.; Ma, M.; Zhang, X.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 12844.
13. (a) Kim, J. D.; Kim, I. S.; Jin, C. H.; Zee, O. P.; Jung, Y. H. Org. Lett. 2005, 7, 4025;
(b) Kim, I. S.; Kim, J. D.; Ryu, C. B.; Zee, O. P.; Jung, Y. H. Tetrahedron 2006, 62,
9349; (c) Kim, I. S.; Ji, Y. J.; Jung, Y. H. Tetrahedron Lett. 2006, 47, 7289; (d) Kim,
I. S.; Oh, J. S.; Zee, O. P.; Jung, Y. H. Tetrahedron 2007, 63, 2622; (e) Kim, I. S.;
Kim, S. J.; Lee, J. K.; Li, Q. R.; Jung, Y. H. Carbohydr. Res. 2007, 342, 1502; (f) Kim,
I. S.; Lee, H. Y.; Jung, Y. H. Heterocycles 2007, 71, 1787; (g) Kim, I. S.; Li, Q. R.;
15. (a) Salunkhe, A. M.; Burkhardt, E. R. Tetrahedron Lett. 1997, 38, 1523; For a
typical review, see: (b) Corey, E. J.; Helal, C. Angew. Chem., Int. Ed. 1998, 37,
1986.
16. For a detailed reaction mechanism, see: Ref. 14.
17. The reaction in methylene chloride under otherwise identical conditions
furnished the corresponding product
enantioselectivity (92.8%) in 76% yield.
5
with slightly decreased