Enantioselective synthesis of 3-substituted-4-aryl piperidines useful for the preparation of paroxetine

Article abstract of DOI:10.1016/S0040-4039(03)01192-4

The asymmetric conjugate addition reaction between 4-fluorophenylmagnesium bromide and various chiral α,β-unsaturated esters and enoylsultam substrates was explored to prepare a key intermediate useful in the preparation of paroxetine. The most selective auxiliary was found to be Oppolzer's (1S)-(-)-camphorsultam. Interestingly, the diastereoselection was opposite to that reported for acyclic enoylsultams.

Full text of DOI:10.1016/S0040-4039(03)01192-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5355–5358
Enantioselective synthesis of 3-substituted-4-aryl piperidines
useful for the preparation of paroxetineꢀ
K. S. Keshava Murthy,* Allan W. Rey* and Michael Tjepkema
Brantford Chemicals Inc., 34 Spalding Drive, Brantford, Ontario, Canada N3T 6B8
Received 27 March 2003; revised 7 May 2003; accepted 8 May 2003
Abstract—The asymmetric conjugate addition reaction between 4-fluorophenylmagnesium bromide and various chiral a,b-unsat-
urated esters and enoylsultam substrates was explored to prepare a key intermediate useful in the preparation of paroxetine. The
most selective auxiliary was found to be Oppolzer’s (1S)-(−)-camphorsultam. Interestingly, the diastereoselection was opposite to
that reported for acyclic enoylsultams. © 2003 Elsevier Science Ltd. All rights reserved.
The growth in the number of chiral pharmaceuticals
coupled with both the need to reduce the cost of drug
substances and to minimize waste streams has moti-
vated research into finding more selective synthetic
procedures. Paroxetine (1, Paxil®) is a good illustration
of a chiral pharmaceutical that is useful for the treat-
ment of depression and obsessive compulsive
disorders.2
mon deficiency of all the latter approaches is that 50%
of the material is lost as the wrong isomer, which
greatly diminishes their synthetic utility for scale-up.
To overcome these deficiencies and develop a scalable
method to control the chirality at C-4 of the piperidine
ring, we have explored the asymmetric conjugate addi-
tion reaction6 between 4-fluorophenylmagnesium bro-
mide and various chiral a,b-unsaturated esters and
enoylsultams with the general formula 2 (Scheme 1).
This reaction produced compounds 3, a key intermedi-
ate in the synthesis of paroxetine, together with varying
amounts of 4. Compounds having the structure 3 can
be elaborated into (−)-paroxetine using known chem-
istry.5a,c Various chiral auxiliaries were examined in
order to achieve optimum selectivity. The results are
summarized in Table 1.
The menthol-based Michael precursors of formula 2
(Table 1, entries 1–4) were prepared in near-quantita-
tive yields by a modification of the procedure described
by Meth-Cohn7 via transesterification of arecoline in a
toluene reaction medium using the requisite menthol or
menthol-derived auxiliary (1.0 equiv.) together with
Numerous syntheses of this potent and selective sero-
tonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor
have been reported by various workers.3 Other methods
to achieve the desired chirality at the C-3 and C-4
positions of the piperidine ring include biocatalytic
methods, which rely on diastereoselective enzymatic
hydrolyses of the ester functionality of various ester
precursors,4a,c–f alcohol acylation4b and classical resolu-
tion of diastereomeric hydrobromide salts.5a,c A com-
Keywords: Michael reaction; asymmetric synthesis; paroxetine; Grig-
nard addition; camphorsultam.
ꢀ A patent covering aspects of this work has been issued. See Ref. 1.
* Corresponding authors. E-mail: kmurthy@brantfordchemicals.com;
arey@brantfordchemicals.com
Scheme 1. Conjugate addition reaction.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01192-4

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K. S. K. Murthy et al. / Tetrahedron Letters 44 (2003) 5355–5358
Table 1. Ratio of 3:4 for various auxiliaries
1
potassium tert-butoxide (0.05 equiv.). The reaction was
driven to completion by distillation to azeotropically
remove methanol. For the isoborneol-based auxiliary
(entry 5), it was necessary to transesterify 10-dicyclo-
hexylsulfamoylisoborneol with methylnicotinate (n-
BuLi, THF) followed by quaternization (iodomethane)
and reduction (NaBH4).8 The camphorsultam-based
auxiliary (entry 6) was obtained using the procedure
described by Ho and Mathre.9
The degree of asymmetric induction was assessed by H
NMR or HPLC analysis of the diastereomeric mix-
tures. For entries 1–4, the absolute stereochemistry at
C-3 and C-4 of the piperidine rings was confirmed by
comparison of their measured optical rotations with
that of the known (3S,4R)-alcohol.11 Thus, after
epimerization, the compounds were reduced to trans-3-
hydroxymethyl-4-(4%-fluorophenyl)piperidine (LiAlH4
or REDAL®) and their optical rotations compared. For
entry 5, the absolute stereochemistry was established by
determination of the crystal structures of the major
(3S,4R)- and minor (3R,4S)-diastereomers by single
crystal X-ray analysis (Figs. 1 and 212). For the cam-
phorsultam auxiliary (entry 6), the absolute stereo-
chemistry was determined by conversion to paroxetine
hydrochloride using standard methodology.5 The
(3S,4R)-absolute configuration was confirmed by opti-
cal rotation comparison (−82.8°; lit.:13 −88°).
For the 1,4-addition reactions a diethyl ether solution
of 4-fluorophenylmagnesium bromide was typically
added to a toluene solution of the Michael acceptor at
0 to −10°C. After the addition was complete, the reac-
tion was quenched using saturated aqueous NH4Cl and
the organic phase was then washed with brine.10 In
terms of further elaboration to paroxetine, the stereo-
chemistry at the C-3 position of the piperidine ring was
controlled by the stereochemistry at C-4 by epimeriza-
tion to the thermodynamically more stable C-3, C-4-
trans isomer using catalytic potassium tert-butoxide in
toluene. The only exception was when the camphorsul-
tam auxiliary (entry 6) was used, where the C-3, C-4
cis-isomer was formed. All efforts to epimerize this
compound were unsuccessful. However, other work has
shown that the C-3, C-4 cis-compound can also be
elaborated to paroxetine.3n,5a,b
Many different reaction conditions were examined to
try to improve the yield and diasteroselection of these
conjugate additions. For instance, in the case of the
menthyl ester analog of arecoline (entry 1), the com-
bined yield of the 1,4-adduct stereoisomers 3 and 4
(Scheme 1) was typically in the 65–75% range. For all
of the auxiliaries examined, improvement of the

K. S. K. Murthy et al. / Tetrahedron Letters 44 (2003) 5355–5358
5357
has been achieved by the asymmetric conjugate addi-
tion reaction.
Acknowledgements
The authors would like to thank Mr. Peter Blazecka
and Ms. Jillian Drage for technical help, Drs. B. Hu
and Nick Taylor for NMR and single cell X-ray sup-
port, Dr. Derek McPhee for assistance preparing the
manuscript, and Drs. Sajan Joseph, Stephen Horne,
Gamini Weeratunga, and Professor Derrick Clive for
helpful discussions.
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Figure 2. (3R,4S).
diastereoselection by changing the solvents (toluene,
THF, ether), reaction temperatures (20 to −50°C), addi-
tives (copper(I) bromide–dimethylsulfide complex,
TMEDA), nucleophiles, and Lewis acids used (TMS-
Cl, BF3·Et2O) was generally unsuccessful. However, it
was found that by increasing the steric bulk of the
auxiliary (cf. entries 2 and 3 versus entry 1), the selec-
tivity increased significantly.
Even higher diastereoselection was achieved using the
Oppolzer (1S)-(−)-(2,10)-camphorsultamoyl chiral aux-
iliary (entry 6), which afforded a high degree of stereo-
control. Surprisingly, the induction was the opposite
of that predicted by the model developed by Oppolzer
for similar acyclic unsaturated N-enoylsultams.14
A
similar observation was recently made by Cook15 for
the addition of p-tolylmagnesium bromide to the simi-
lar enoylsultam Michael precursor, N-ethyl-1,2,5,6-tetra-
hydropyridine-4-carboxylic acid. Also it is of interest
to note that a conjugate addition strategy was used for
the stereocontrolled synthesis of various 2-substituted-
4-aryl piperidines from the corresponding 4,5-
unsaturated-6-piperidinones.16
In conclusion, a highly stereoselective method for the
preparation of a key synthetic precursor of paroxetine

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K. S. K. Murthy et al. / Tetrahedron Letters 44 (2003) 5355–5358
6. For a comprehensive review, see: Rossiter, B. E.; Swingle,
(m, 4H), 0.82 (s, 3H), 0.43 (s, 3H); 13C NMR (CDCl3, 75
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J=7.8 Hz), 114.7 (d, J=21.0 Hz), 65.3, 56.4, 55.9, 53.1,
47.7 47.3, 46.6, 45.3, 44.5, 42.1, 38.3, 32.8, 26.3 (2C),
20.0, 19.7; MS (DCI, NH3): 435 (M+H+, 100%), 371
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diethyl ether (4.42 mL, 8.84 mmol, 2.0 equiv.) was added
to a solution of the N-enoyl camphorsultam 2 (R=2,10-
camphorsultamoyl, 1.50 g, 4.42 mmol) in toluene (30 mL)
over a 10 minute period, while maintaining the tempera-
ture between 0 to −10°C. After a further 1 h at this
temperature, the reaction mixture was quenched using
saturated aqueous NH4Cl. The layers were separated and
the organic phase was washed with brine, filtered through
Celite®, and the volatiles removed under reduced pres-
sure. This afforded a crude solid which was further
purified by silica gel chromatography (EtOAc) to provide
1.44 g (75% yield) of the cis-(3R,4R)-adduct. IR (CHCl3):
12. Crystallographic data for these structures have been
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
196924 and CCDC 196925. These data can be obtained
free of charge from the CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033;
e-mail:
deposit@ccdc.cam.ac.uk
or
via
http://
www.ccdc.cam.ac.uk/conts/retrieving.html
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;
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2H), 3.72 (dd, 1H, J=7.3, 5.0 Hz), 3.60 (br s, 1H), 3.32
(s, 2H), 3.25 (d, 1H, J=12.5 Hz), 3.11 (d, 1H, J=5.9
Hz), 3.01–2.74 (m, 2H), 2.48–2.18 (m, 2H), 2.28 (s, 3H),
2.01 (t, 1H, J=10.1 Hz), 1.92–1.58 (m, 3H), 1.46–0.92
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