Ring expansion: Formal total synthesis of (-)-paroxetine

Article abstract of DOI:10.1016/S0040-4039(01)01096-6

A ring expansion and a radical dehalogenation have been used as the key steps in a formal total synthesis of (-)-paroxetine. A stereoselective ring expansion of prolinol generated the substituted piperidine ring precursor of (-)-paroxetine.

Full text of DOI:10.1016/S0040-4039(01)01096-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5705–5707
Ring expansion: formal total synthesis of (−)-paroxetine
Janine Cossy,a,* Olivier Mirguet,a Domingo Gomez Pardoa,* and Jean-Roger Desmursb
aLaboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
bRhodia, 190 avenue Thiers, 69457 Lyon Cedex 06, France
Received 5 May 2001; accepted 19 June 2001
Abstract—A ring expansion and a radical dehalogenation have been used as the key steps in a formal total synthesis of
(−)-paroxetine. A stereoselective ring expansion of prolinol generated the substituted piperidine ring precursor of (−)-paroxetine.
© 2001 Elsevier Science Ltd. All rights reserved.
4-Arylpiperidine is an important structural element in a
number of biologically active compounds, possibly due
to the similarity to aryl alkylamine pharmacophore
common to neurotransmitters like serotonin [5-hydroxy-
tryptamine (5-HT)], dopamine (DA), noradrenaline
(NA) and to antagonists of opiate receptors. Drugs that
modulate the physiological and pathophysiological
actions of 5-HT are useful or potentially useful in the
treatment of a variety of human diseases, including
depression, anxiety, alcoholism, chronic pain, emesis
and eating disorders such as obesity and bulimia.1 Such
compounds can be exemplified by the antipsychotic
5-HT- and DA-antagonists, haloperidol,2 the analgesic
opioid agonist, meperidine,3 and the selective serotonin
usually associated with tricyclic antidepressants.5
Paroxetine is an enantiomerically pure (−)-trans-3,4-di-
substituted piperidine. Due to its biological importance,
several enantiocontrolled syntheses have been
disclosed.6
In the context of our studies on ring expansion
reactions7 of enantiomerically pure substituted prolinols
to enantiomerically pure substituted 3-hydroxy-
piperidines7,8 or substituted 3-chloropiperidines7,9
(Scheme 1), we report here a formal enantioselective
synthesis of the (−)-paroxetine.
The retrosynthetic analysis shown in Scheme 2 envi-
sions aminoalcohol (−)-9, a known precursor of the
(−)-paroxetine 1,6a arising from optically pure substi-
tuted 3-chloropiperidine (−)-7, which would be derived
reuptake inhibitor (SSRI), paroxetine
1
[Paxil®,
Seroxat®] (Fig. 1).4
This drug is used in the treatment of depression, obses-
sive compulsive disorder and panic disorder. Moreover,
it had a reduced propensity to cause the side-effects
from (L)-pyroglutamic acid via the known bicyclic lac-
tam (+)-2.10
Enantiomerically pure bicyclic lactam (+)-2 ([a]D=
+237, c 1.2, CHCl3), obtained in three steps from (L)-
pyroglutamic acid,10 was treated with an excess of
LiHMDS (2.1 equiv., THF, −78°C, 40 min) which
Figure 1. Selected 4-arylpiperidines.
* Corresponding
00.33.1.40.79.46.60; e-mail: janine.cossy@espci.fr
authors.
Tel.:
00.33.1.40.79.46.63;
fax:
Scheme 1. Ring expansion reactions.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01096-6

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J. Cossy et al. / Tetrahedron Letters 42 (2001) 5705–5707
allowed the formation of the selenoesters (−)-3 and (+)-3%
in a one-pot reaction (ratio (−)-3/(+)-3%=62/38) involving
successive addition of isobutyl chloroformate (1 equiv.,
−78°C, 45 min) and phenylselenyl chloride (1 equiv.,
−78°C to −20°C, 1.2 h). The phenylselenoesters were not
purified but treated directly with H2O2 (5 equiv., CH2Cl2,
0°C, 30 min)11 and the unsaturated bicyclic lactam (+)-4
was isolated in 99% yield (overall yield from the bicyclic
lactam (+)-2). The unsaturated bicyclic lactam (+)-4 was
allowed to react diastereoselectively with lithium di(4-
fluorophenyl)cuprate (5.7 equiv., −78°C, 2 h) to give the
conjugate addition product, the all-trans trisubstituted
pyrrolidinone (+)-5, in 97% yield.12 Reduction of (+)-5
with BH3·THF (10 equiv., THF, 0°C, 1.5 h), which also
causes the cleavage of the CꢀO bond of the oxazolidine
ring, led to the prolinol (−)-6 (44% yield). Ring expansion
of prolinol (−)-6 by addition of mesyl chloride (1.1 equiv.,
DCE, 0°C to rt, 1 h) followed by the addition of Et3N
(3.1 equiv., reflux, 2 days) provided the expected trisub-
stituted 3-chloropiperidine (−)-713 in 84% yield. The
relative stereochemistry of the chloride and the aryl
Scheme 2. Retrosynthetic analysis.
Scheme 3. Formal total synthesis of paroxetine.

J. Cossy et al. / Tetrahedron Letters 42 (2001) 5705–5707
5707
1
group was determined by examination of the H NMR
coupling constants between the C-4 and C-5 protons.14
Reduction of (−)-7 with n-Bu3SnH (1.1 equiv., toluene,
reflux, 2h)inthepresenceofacatalyticamountofAIBN15
gavetheaminoester(−)-8in71%yield. Finally, theknown
precursor (−)-916 of the (−)-paroxetine was obtained by
reducing (−)-8 by LAH (2 equiv., THF, 0°C to rt, 50 min)
in quantitative yield (Scheme 3).
127941; (h) 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; (i) Adger, B. M.; Potter, G. A.; Fox, M.
E. WO Patent 9724323, 1997; Chem. Abstr. 1997, 127,
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1996, 50, 164–169; (k) Zepp, C. M.; Gas, Y.; Heefner, D.
L. US Patent 5,258,517, 1993; Chem. Abstr. 1994, 120,
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7. Cossy, J.; Dumas, C.; Gomez Pardo, D. Eur. J. Org. Chem.
1999, 1693–1699 and references cited therein.
Since the piperidine (−)-9 has been converted into (−)-
paroxetine,6a the present transformation of the known
bicyclic lactam (+)-2 into the aminoalcohol (−)-9 (seven
steps, 25% overall yield) constitutes a new formal synthe-
sis of (−)-paroxetine.
8. (a) Cossy, J.; Dumas, C.; Michel, P.; Gomez Pardo, D.
Tetrahedron Lett. 1995, 36, 549–552; (b) Cossy, J.; Dumas,
C.; Gomez Pardo, D. Synlett 1997, 905–906; (c) Cossy, J.;
Dumas, C.; Gomez Pardo, D. Bioorg. Med. Chem. Lett.
1997, 7, 1343–1344; (d) Wilken, J.; Kossenjans, M.; Saak,
W.; Haase, D.; Pohl, S.; Martens, J. Liebigs Ann. 1997,
573–579; (e) Langlois, N.; Calvez, O. Synth. Commun. 1998,
28, 4471–4477; (f) Davis, P. W.; Osgood, S. A.; He´bert, N.;
Sprankle, K. G.; Swayze, E. E. Biotechnol. Bioeng. 1999,
61, 143–154; (g) Michel, P.; Rassat, A. J. Org. Chem. 2000,
65, 2572–2573.
Our work demonstrates that trans-3,4-disubstituted pipe-
ridinescanbeobtainedwithhighstereoselectivityemploy-
ing a stereospecific ring expansion applied to prolinol
which uses a mesyl chloride–Et3N process and a n-
Bu3SnHmediated reduction of3-chloropiperidine. Appli-
cation of this procedure to other complex products is
currently underway.
Acknowledgements
The authors would like to thank Rhoˆne-Poulenc-Rhodia
for financial support and Dr. Marvin S. Yu (Smithkline
Beecham) for sending us the 1H NMR spectra of
compound (−)-9. One of us, O.M., thanks the MRET for
a grant.
9. Calvez, O.; Chiaroni, A.; Langlois, N. Tetrahedron Lett.
1998, 39, 9447–9450 and references cited therein.
10. Thottathil, J. K.; Moniot, J. L.; Mueller, R. H.; Wong, M.
K. Y.; Kissick, T. P. J. Org. Chem. 1986, 51, 3140–3143.
For a review on pyroglutamic acid as building block in
asymmetric synthesis, see: Na`jera, C.; Yus, M. Tetrahedron:
Asymmetry 1999, 8, 2245–2303.
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1
12. Only one isomer could be detected by H and 13C NMR
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13. (−)-7: Rf=0.35 (petroleum ether/EtOAc, 95/5). [h]D=−5.2
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1150, 750 cm−1. 1H NMR l 7.44–7.28 (5H), 7.23 (m, 2H),
7.03 (m, 2H), 4.09 (ddd, 1H, J=10.7, 10.7 and 4.4 Hz), 3.67
(dd, 1H, J=10.7 and 6.6 Hz), 3.66 (s, 2H), 3.57 (dd, 1H,
J=10.7 and 6.6 Hz), 3.37 (ddd, 1H, J=11.4, 4.4 and 1.5
Hz), 3.15(ddd, 1H, J=11.0, 3.3and1.5Hz), 3.07–2.85(2H),
2.48–2.31 (2H), 1.64 (m, 1H), 0.71 (d, 3H, J=6.6 Hz), 0.70
(d, 3H, J=6.6 Hz). 13C NMR l 171.5 (s), 162.0 (d, J=245.4
Hz), 137.1 (s), 135.2 (d, J=3.0 Hz), 129.6 (dd, J=7.9 Hz),
128.9 (d), 128.4 (d), 127.4 (d), 115.2 (dd, J=31.4 Hz), 70.6
(t), 62.0 (t), 61.0 (t), 59.6 (d), 55.4 (t), 52.8 (d), 50.0 (d),
+
’
27.4 (d), 18.7 (q). EI MS m/z (relative intensity): 405 (M ,
+
’
1), 403 (M , 3), 369 (14), 368 (56), 354 (39), 314 (11), 312
(31), 276 (25), 91 (100). HRMS (CI+, CH4) calcd for
28
C23H ClFNO2 [(M+H)+]: 404.1793; found: 404.1788.
35
Calcd for C23H ClFNO2 [(M+H)+]: 406.1773; found:
37
28
406.1765.
14. The trans stereochemistry was assigned on the basis of
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J
H5ax-H6eq=4.4 Hz).
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16. (−)-9·HCl: [h]D=−10.6 (c 1, MeOH) [Ref. 6e: [h]D=−10.3
(c 1, MeOH)].