Synthesis of (-)-paroxetine via enantioselective phase-transfer catalytic monoalkylation of malonamide ester

Article abstract of DOI:10.1021/ol100928v

(Figure presented) A new enantioselective synthetic method of (-)-paroxetine is reported. (-)-Paroxetine could be obtained in 15 steps (95% ee and 9.1% overall yield) from N,N-bis(p-methoxyphenyl)malonamide tert-butyl ester via the enantioselective phase-transfer catalytic alkylation and the diastereoselective Michael addition as the key steps.

Full text of DOI:10.1021/ol100928v

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2826-2829
Synthesis of (-)-Paroxetine via
Enantioselective Phase-Transfer
Catalytic Monoalkylation of Malonamide
Ester
Mi-hyun Kim,† Yohan Park,† Byeong-Seon Jeong,‡ Hyeung-geun Park,*,† and
Sang-sup Jew*,†
Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul
National UniVersity, Seoul 151-742, Korea, and College of Pharmacy, Yeungnam
UniVersity, Gyeongsan 712-749, Korea
hgpk@snu.ac.kr
Received April 22, 2010
ABSTRACT
A new enantioselective synthetic method of (-)-paroxetine is reported. (-)-Paroxetine could be obtained in 15 steps (95% ee and 9.1% overall
yield) from N,N-bis(p-methoxyphenyl)malonamide tert-butyl ester via the enantioselective phase-transfer catalytic alkylation and the
diastereoselective Michael addition as the key steps.
The piperidine ring system has been regarded as one of the
most important pharmacophore units in biologically active
natural products as well as in synthetic drugs.1 Their
biological activities are often quite dependent on the types
and locations of their substituents and their chirality. Ac-
cordingly, enantioselective synthetic methodologies for the
construction of piperidine ring systems with 3- and 4-sub-
stituents have been studied greatly thus far.2 The usefulness
of the newly developed synthetic methodologies has fre-
quently been evaluated via their application in the enanti-
oselective synthesis of (-)-paroxetine which possesses chiral
centers at C(3) and C(4).
(-)-Paroxetine (Paxil) is a selective serotonin reuptake
inhibitor that is used for the treatment of depression, anxiety,
and panic disorders.3 There have been a number of enanti-
oselective synthetic methods for its construction. The (3S)-
and (4R)-chiral centers have been introduced by resolutions,4
chiral auxiliaries,5 chiral bases,6 resort to the chiral pool,7
enantioselective catalysis,8 and enzymatic asymmetrizations.9
Most of them generally incorporate the (4R)-p-fluorophenyl
group earlier than the (3S)-hydroxymethyl group, whose
† Seoul National University.
‡ Yeungnam University.
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(2) For reviews on the enantioselective synthesis of piperidines, see:
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633. (b) Laschat, S.; Dickner, T. Synthesis 2000, 1781. (c) Buffat, M. G. P.
Tetrahedron 2004, 60, 1701. (d) Cossy, J. Chem. Rec. 2005, 5, 70.
(3) For a review on the biological activities of (-)-paroxetine, see:
Gunasekara, N. S.; Noble, S.; Benfield, P. Drugs 1988, 55, 85.
10.1021/ol100928v  2010 American Chemical Society
Published on Web 05/25/2010

stereochemistry is often controlled by the C(4R) chirality.
Herein, we present a novel synthetic approach to (-)-
paroxetine that introduces the C(3S)-center first by asym-
metric phase-transfer catalytic alkylation,10 before installing
the C(4)-stereocenter by diastereoselective Michael addition.
in the presence of a catalytic amount of (S,S)-3,4,5-
trifluorophenyl-NAS bromide (4) to afford R-monoalkylated
products 3 in high chemical (up to 95%) and optical yields
(up to 96% ee).
The low acidity of the second R-hydrogen of 3 and the
A1,3-strain between the N-aryl-substituents (Ar) and R-sub-
stituents (R) contributed to the resistance toward racemization
of 3 during the alkylation reaction. Chiral mono-R-alkyl
malonamide esters could be converted to various useful chiral
synthetic intermediates, such as R-alkyl-ꢀ-hydroxy acids,
ꢀ-alkyl-γ-amino alcohols, and R-alkyl-ꢀ-amino acids, by
successive chemoselective reductions. Given this, we at-
tempted to apply our method to the synthesis of one of the
representative chiral 3,4-disubstituted piperidines, (-)-par-
oxetine (1).
Recently, we reported on the asymmetric catalytic “mono”-
R-alkylation of 1,3-dicarbonyl systems (Scheme 1).11 Mal-
As shown in the retrosynthetic strategy (Scheme 2), the
C(4S) chirality can, in principle, be induced by diastereo-
Scheme 2. Retrosynthesis of (-)-Paroxetine (1)
Scheme 1
.
Enantioselective Monoalkylation of 1,3-Dicarbonyls
(Malonamide Esters)
onamide esters 2 were designed as racemization-resistant
malonyl substrates and were successfully applied to the
enantioselective R-alkylations under phase-transfer conditions
selective conjugate addition of a p-fluorophenyl anionic
nucleophile to chiral enone 5, which can be obtained by
lactamization and olefination of 6. Optically active C(3S)-6
can be derived from enantioselective phase-transfer catalytic
alkylation of N,N-bis(p-methoxyphenyl) malonamide tert-
butyl ester (7).
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Org. Lett., Vol. 12, No. 12, 2010
2827

First, the phase-transfer catalytic Michael addition was
carried out with 7 and methyl acrylate to introduce an
R-carbomethoxyethyl moiety under the previously reported
optimal reaction conditions. (S,S)-3,4,5-Trifluorophenyl-NAS
bromide (4, 1 mol %) and 50% aqueous KOH (13.0 equiv)
in toluene at -40 °C were used for this purpose (entry 1 in
Table 1). However, much to our disappointment, quite low
Scheme 3. Transformation of 8c to Chiral Michael Acceptor 12
Table 1. Enantioselective Phase-Transfer Catalytic Alkylationa
with benzyl chloroformate. This was followed by alcohol
protection with a TBDPS group to provide 10 (54% for 3
steps). Hydroboration of 10 using 9-BBN, followed by
oxidation using TEMPO/(diacetoxyiodo)benzene, directly
gave the lactam 11 (83% for 2 steps). Addition of phenylse-
lenium bromide to 11 and LiHMDS provided the corre-
sponding R-phenylselenylated product, which was readily
converted to the R,ꢀ-unsaturated lactam 12 with hydrogen
peroxide (60% for 2 steps).
a The reaction was carried out with 1.2 equiv of electrophile and 13.0
equiv of 50% aq KOH in the presence of catalyst 4 (1 mol %) in toluene.
b Isolated yields. c Enantiopurity was determined by HPLC analysis of 8
using a chiral column (Chiralcel OD) with hexane/2-propanol as an eluent;
in this case, it was established by analysis of the racemate, of which the
enantioisomers were fully resolved. d Absolute configuration was determined
by comparison of the optical rotation of (-)-paroxetine (1) transformed
from 8c with the reported value.5b e The reaction was conducted by s-CsOH
(1 equiv).
enantioselectivity was observed alongside low chemical
yields (60%, 35% ee). Our strategy needed modification to
enhance enantioselectivity, and we chose allylation as an
alternate pathway which could convert to a carbomethoxy-
ethyl moiety by further chemical transformations. The phase-
transfer catalytic allylation with allyl bromide and 2-bro-
moallyl bromide under the same reaction conditions afforded
the corresponding allylated products 8b and 8c with quite
enhanced enantioselectivities. Notably, a higher enantiose-
lectivity was obtained with 2-bromoallyl bromide (entry 3,
92%, 95% ee), compared to that of allyl bromide (entry 2,
86%, 90% ee). The bulkier electrophile could more selec-
tively approach the re-face of the enolate of 7 when
complexed with quaternary ammonium catalyst 4, thus
affording higher enantioselectivity. The absolute configura-
tion of 8c was determined as S by comparison of the optical
Scheme 4. Completion of the Synthesis of (-)-Paroxetine (1)
22
rotation of (-)-paroxetine (1) {[R]D ) -75.6 (c 1.00,
22
MeOH)} obtained from 8c with the reported values {[R]D
) -80.8 (c 1.25, MeOH)}.5b
Six-membered lactam intermediate 12 was prepared from
the allylated product 8c (95% ee) in eight steps (Scheme 3).
The debromination of 8c using tributyltin hydride in the
presence of a catalytic amount of AIBN in toluene, followed
by reduction with LiAlH4 in dibutyl ether, provided 9 (85%
from 8c). The PMP groups of 9 were removed with CAN to
afford crude 3-amino-2-allylpropanol. Without purification,
the amino group was protected with a Cbz group by treatment
2828
Org. Lett., Vol. 12, No. 12, 2010

Next, diastereoselective Michael addition of 12 was
performed to introduce the C(4R) chirality of 1. The Michael
addition of p-fluorophenyl cuprate to 12 in THF at -78 °C
afforded (3S,4R)-13 in 88% chemical yield with an excellent
diastereomeric ratio of 49:1 in favor of the trans-lactam
(Scheme 4). The trans relationship of the substituents at C(3)
and C(4) was confirmed by the coupling constant of the
protons at C(3) and C(4) in the 1H NMR (500 MHz, CDCl3)
spectrum of 13, showing a value of 10.5 Hz. The TBDPS
group of 13 was deprotected with 0.1 M TBAF in THF
(99%). Interestingly, we could only obtain the 3,4-cis-lactone
14 instead of the deprotected alcohol.12 The alcohol generated
by the TBDPS deprotection displaced the N-Cbz group of
the imide 13 to give the lactone 14. The removal of the
N-Cbz group by catalytic hydrogenation readily furnished
the lactam 15 (>99%). The etherification of 15 with sesamol
was accomplished by the coupling of sodium sesamolate with
the mesylate prepared from 15 by treatment with methane-
sulfonyl chloride (56% for 2 steps). Finally, (-)-paroxetine
(1) was obtained by amide reduction of 16 with LiAlH4
(90%).
In conclusion, (-)-paroxetine (1) has been synthesized in
15 steps (9.1% overall yield, 95% ee) by enantioselective
phase-transfer catalytic alkylation and diastereoselective
Michael addition from N,N-bis(p-methoxyphenyl)malona-
mide tert-butyl ester (7). Further applications to the synthesis
of similar compounds with a phenyl piperidine core structure
having two trans-substituents at C(3) and C(4), such as (+)-
femoxetine and Roche-1, are now under investigation.
Acknowledgment. This work was supported by the National
Research Foundation (NRF) grant funded by the Korea govern-
ment (MEST) (No. 201000017) and by the Midcareer Re-
searcher Support Programs of National Research Foundation
of Korea (2009-0078814).
Note Added after ASAP Publication. Scheme 4 and the
SI file contained errors in the version published ASAP May
25, 2010; the correct versions reposted May 27, 2010.
Supporting Information Available: Spectroscopic char-
acterizations of compounds 1 and 8c-16. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) Lillelund, V. H.; Liu, H.; Liang, X.; Sehoel, H.; Bols, M. Org.
Biomol. Chem. 2003, 1, 282.
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