A short formal synthesis of paroxetine. Diastereoselective cuprate addition to a chiral racemic olefinic amido ester

Article abstract of DOI:10.1016/S0040-4039(01)01666-5

A diastereoselective conjugate addition of an organocopper reagent to a chiral racemic olefinic amido ester has been used as the key step in a formal total synthesis of paroxetine.

Full text of DOI:10.1016/S0040-4039(01)01666-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7805–7807
A short formal synthesis of paroxetine. Diastereoselective
cuprate addition to a chiral racemic olefinic amido ester
Janine Cossy,a,* Olivier Mirguet,a Domingo Gomez Pardoa and Jean-Roger Desmursb
aLaboratoire de Chimie Organique ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
bRhodia, 190 avenue Thiers, 69457 Lyon Cedex 06, France
Received 26 June 2001; accepted 4 September 2001
Abstract—A diastereoselective conjugate addition of an organocopper reagent to a chiral racemic olefinic amido ester has been
used as the key step in a formal total synthesis of paroxetine. © 2001 Published by Elsevier Science Ltd.
Drugs that modulate the physiological and pathophysio-
logical actions of serotonin are useful or potentially
useful in the treatment of a variety of human diseases,
including depression, anxiety, alcoholism, chronic pain,
emesis and eating disorders.1
diastereomers 3a and 3b was obtained in 50% yield.
Phenylselenation of the mixture of 3a/3b gave a mixture
of diastereomeric selenides 4a and 4b (75/25) which
were not separated but oxidized with H2O2 (CH2Cl2,
0°C) to furnish the oxidative deselenation product 5 in
quantitative yield. The addition of lithium di(4-
fluorophenyl)cuprate (4 equiv., THF, −78°C) to the
asymmetric olefinic amido ester 5 led to the conjugate
addition product 6 in 80% yield (Scheme 2).
For example, paroxetine which is an enantiomerically
pure (−)-trans-3,4-disubstituted piperidine, is used in
the treatment of depression, obsessive compulsive disor-
der and panic disorder.2 Moreover, it has a reduced
propensity to cause the side effects usually associated
with tricyclic antidepressants.3 Due to the importance
of its biological properties, several syntheses of this
compound have been achieved.4
It is worth noting that the NMR spectrum of the
unpurified conjugate addition product indicated excel-
F
F
F
Here we report the formal synthesis of paroxetine
according to the following retrosynthetic scheme
(Scheme 1). The key step for obtaining paroxetine was
the conjugate addition of an organocopper compound
to a chiral olefinic amido carboxylate of the concave
chiral racemic alcohol A,5 which can be easily prepared
from N-Boc protected d-valerolactam 1.
O
O
O
OH
OR*
ref. 4g,4l
N
N
H
N
O
O
O
O
The treatment of N-Boc d-valerolactam 1 with Li-
HMDS at −78°C (1.3 equiv., THF) followed by the
addition of methyl chloroformate afforded the corre-
sponding methyl amidocarboxylate 26 in 93% yield. The
asymmetric shielded amido ester 3 was readily available
by a transesterification reaction of 2 with the chiral
racemic auxiliary A (1 equiv.) mediated by DMAP (2
equiv., toluene, reflux).7 A 65/35 mixture of two
7
6
Paroxetine
O
O
OR*
N
SO2Ph
N
O
N
OH
O
O
O
O
A (R*OH)
N-Boc δ-valerolactam, 1
5
* Corresponding author. Tel.: 00.33.1.40.79.46.63; fax: 00.33.1.40.79.
46.60; e-mail: janine.cossy@espci.fr
Scheme 1. Retrosynthetic analysis.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01666-5

7806
J. Cossy et al. / Tetrahedron Letters 42 (2001) 7805–7807
CO2Me
CO2R*
O
1/ LiHMDS (1.3 equiv.)
THF, -78 °C
A (1 equiv.)
DMAP (2 equiv.)
N
O
N
O
N
2/ ClCO2Me
-78 °C to rt
powdered MS 4 Å
Toluene, reflux
O
O
O
O
O
O
50 %
93 %
N-Boc δ-valerolactam, 1
2
3a/3b
68 %
based on recovered
starting material
F
1/ NaH, sonication
THF, rt
2/ PhSeCl, HMPA
O
O
O
CO2R*
SePh
OR*
OR*
(4 equiv.)
CuLi
2
F
H2O2 (excess)
CH2Cl2, 0 °C
N
O
N
O
N
THF, -78 °C
80 %
O
O
O
O
O
O
100 %
6
5
4a/4b
LAH (7 equiv.)
85 %
THF, 0 °C to rt
then reflux
N
F
SO2Ph
OH
A (R*OH)
ref. 4g,4l
OH
paroxetine
N
7
Scheme 2. Formal total synthesis of paroxetine.
1
lent diastereoselectivity (>98:2). However, the H and
13C NMR spectroscopic data of 68 did not reveal the
relative stereochemistry between the newly introduced
groups and the chiral auxiliary. Fortunately 6 was
crystalline (mp=215–217°C) and its structure could be
determined by X-ray diffraction spectroscopy (Fig. 1).9
Since piperidine 7 has been converted into parox-
etine,4g,4l the present transformation of the N-Boc pro-
tected d-valerolactam (six steps, 21% overall yield)
constitutes a formal synthesis of paroxetine. As the
auxiliary A can be prepared enantiomerically pure,
(−)-paroxetine can be obtained by using this synthetic
route. Furthermore, our work demonstrates for the first
time that highly diastereoselective addition of cuprates
can be performed on chiral facially shielded cyclic
olefinic amido ester.
Attack of the organocopper reagent to the asymmetric
olefinic amido ester 5 occured from the less hindered
face of the s-trans enoate double bond leading to the
formation of 6 with a very high level of diastereoselec-
tivity (Fig. 2).5
Acknowledgements
Cleavage of the chiral auxiliary from the sterically
crowded olefinic amido ester 6 was accomplished by
reduction with LAH in THF (7 equiv., 0°C to rt, then
reflux), which gave the known amino alcohol 7 in 85%
yield.
The authors would like to thank Rhoˆne-Poulenc-Rho-
dia for financial support and Dr. Lee Tai LIU for
sending us the H NMR spectrum of compound 7.4f
1
One of us, O.M. thanks the MRET for a grant.

J. Cossy et al. / Tetrahedron Letters 42 (2001) 7805–7807
7807
C19
C14
(f) Shih, K.-S.; Liu, C.-W.; Hsieh, Y.-J.; Chen, S.-F.; Ku,
H.; Liu, L.-T.; Lin, Y.-C.; Huang, H.-L.; Wang, C.-L. J.
Heterocycles 1999, 51, 2439–2444; (g) Murthy, K. S. K.;
Rey, A. W. WO Patent 9907680, 1999; Chem. Abstr. 1999,
130, 182361; (h) Patil, V. D.; Viswanathan, C. L. Indian
Drugs 1998, 35, 686–692; (i) Kreidl, J.; Czibula, L.;
Deutschne´, J.; Werkne´ Papp, E.; Nagyne´ Bagdy, J.;
Dobay, L.; Hegedus, I.; Harsanyi, K.; Borza, I. WO
Patent 9801424, 1998; Chem. Abstr. 1998, 128, 127941; (j)
Sugi, K.; Itaya, N.; Katsura, T.; Igi, M.; Yamazaki, S.;
Ishibashi, T.; Yamaoka, T.; Kawada, Y.; Tagami, Y. Eur.
Patent 0812827 A1, 1997; Chem. Abstr. 1998, 128, 75308;
(k) Adger, B. M.; Potter, G. A.; Fox, M. E. WO Patent
9724323, 1997; Chem. Abstr. 1997, 127, 149075; (l) Engel-
stoft, M.; Hansen, J. B. Acta Chem. Scand. 1996, 50,
164–169; (m) Zepp, C. M.; Gas, Y.; Heefner, D. L. US
Patent 5,258,517, 1993; Chem. Abstr. 1994, 120, 217289;
(n) Willcocks, K.; Barnes, R. D.; Rustidge, D. C.; Tidy, D.
J. D. J. Label. Cmpds. Radiopharm. 1993, 33, 783–794; (o)
Christensen, J. A.; Squires, R. F. US Patent 4,007,196,
1977; Chem. Abstr. 1974, 81, 152011; (p) Stemp, J. A.;
Miller, D.; Martin, R. T. Eur. Patent 0190496, 1985.
5. (a) Helmchen, G.; Wegner, G. Tetrahedron Lett. 1985, 26,
6051–6054; (b) Urban, E.; Riehs, G.; Knu¨hl, G. T. Tetra-
hedron 1995, 41, 11149–11164.
C15
C20
C21
C16
O4
O6
N2
C17
O7
C26
C18
C12
F1
C13
C11
O5
C23
C22
C25
O3
C24
C3
C2
N1
C4
C8
O2
C9
C7
C27
O1
C1
S1
C5
C6
C29
C36
C28
C41
C34
C37
C30
C40
C33
C38
C31
C32
C39
C35
Figure 1. ORTEP plot for compound 6.
N
SO2Ph
O
N
SO2Ph
O
O
6. Imbroisi, D. O.; Simpkins, N. S. J. Chem. Soc., Perkin
O
Trans. 1 1991, 1815–1823.
7. Taber, D. F.; Amedio, Jr., J. C.; Patel, Y. K. J. Org.
Chem. 1985, 50, 3618–3619.
O
R
O
N
N
Boc
8. Compound 6: mp 215–217°C; IR (KBr): 1742, 1730, 1708,
Boc
R2CuLi
1332, 1297, 1185, 1163 cm−1; H NMR (CDCl3, 300 MHz)
1
5
l 7.54 (m, 1H), 7.48–7.27 (5H), 7.06 (br s, 1H), 7.03 (m,
2H), 6.81 (br s, 1H), 5.86 (br s, 1H), 5.43 (d, 1H, J=8.5
Hz), 4.23 (dd, 1H, J=8.5 and 3.3 Hz), 4.08 (m, 1H), 3.93
(d, 1H, J=5.1 Hz), 3.83 (ddd, 1H, J=13.2, 6.6 and 4.8
Hz), 3.66 (ddd, 1H, J=13.2, 9.2 and 4.0 Hz), 2.44 (m, 1H),
2.27 (s, 3H), 2.00 (s, 3H), 1.99–1.82 (2H), 1.67 (m, 1H),
1.54 (s, 9H), 1.34–0.99 (3H), 1.03 (s, 3H), 0.89 (s, 3H), 0.81
(s, 3H); 13C NMR (CDCl3, 75 MHz) l 168.8 (s), 167.3 (s),
161.7 (d, J=244.8 Hz), 152.1 (s), 138.8 (s), 138.7 (d, J=3.7
Hz), 138.3 (s), 137.1 (s), 136.9 (s), 132.5 (d), 130.1 (d),
129.4 (d), 128.8 (dd, J=7.9 Hz), 128.2 (d), 127.5 (d), 115.6
(dd, J=21.4 Hz), 83.1 (d), 78.0 (s), 59.0 (d), 57.4 (d), 51.2
(s), 49.2 (d), 45.8 (s), 43.5 (t), 39.7 (d), 30.5 (t), 28.0 (q),
26.7 (t), 21.1 (q), 20.9 (q), 19.5 (q), 19.4 (t), 19.3 (q), 14.4
(q); MS CI+ (NH3) (relative intensity): 750 (M+NH4+, 11),
634 (37), 633 (92), 593 (20), 493 (40), 415 (29), 414 (100),
274 (23), 174 (20); HRMS (CI+, NH3): calcd for
C41H50FN2O7S (M+H+): 733.3323. Found: 733.3317.
9. Crystallographic data (excluding structural factors) for the
structure in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication numbers CCDC 162939. Copies of the data
can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
Figure 2.
References
1. Robertson, D. W.; Krushinski, J. H.; Fuller, R. W.; Lean-
der, J. D. J. Med. Chem. 1988, 31, 1412–1417.
2. Mathis, C. A.; Gerdes, J. M.; Enas, J. D.; Whitney, J. M.;
Taylor, S. E.; Zhang, Y.; McKenna, D. J.; Havlik, S.;
Peroutka, S. J. J. Pharm. Pharmacol. 1992, 44, 801–805.
3. Gunasekara, N. S.; Noble, S.; Benfield, P. Drugs 1998, 55,
85–120.
4. For other asymmetric synthesis of paroxetine, see: (a)
Cossy, J.; Mirguet, O.; Gomez Pardo, D.; Desmurs, J.-R.
Tetrahedron Lett. 2001, 42, 5705–5707; (b) Liu, L. T.;
Hong, P.-C.; Huang, H.-L.; Chen, S.-F.; Wang, C.-L. J.;
Wen, Y.-S. Tetrahedron: Asymmetry 2001, 12, 419–426; (c)
Johnson, A. J.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc.
2001, 123, 1004–1005; (d) Yu, M. S.; Lantos, I.; Peng,
Z.-Q.; Yu, J.; Cacchio, T. Tetrahedron Lett. 2000, 41,
5647–5651; (e) Amat, M.; Bosch, J.; Hidalgo, J.; Canto,
M.; Pe´rez, M.; Llor, N.; Molins, E.; Miravitlles, C.;
Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074–3084;