Highly enantioselective organocatalytic synthesis of piperidines. Formal synthesis of (-)-Paroxetine

Article abstract of DOI:10.1016/j.tetlet.2009.02.049

A highly enantioselective organocatalytic synthesis of piperidines is reported. The reaction is catalyzed by simple and commercially available secondary amines, affording the corresponding adducts with high yields and enantioselectivities. Moreover, this

Full text of DOI:10.1016/j.tetlet.2009.02.049

Tetrahedron Letters 50 (2009) 1943–1946
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly enantioselective organocatalytic synthesis of piperidines. Formal
synthesis of (ꢀ)-Paroxetine
a,
a,
*
Guillem Valero a, Jiri Schimer b, Ivana Cisarova c, Jan Vesely b, , Albert Moyano , Ramon Rios
*
*
a Department of Organic Chemistry, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Spain
b Department of Organic Chemistry, Charles University, Hlavova 2030, 128 00 Prague, Czech Republic
c Department of Inorganic Chemistry, Charles University, Hlavova 2030, 128 00 Prague, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective organocatalytic synthesis of piperidines is reported. The reaction is catalyzed by
simple and commercially available secondary amines, affording the corresponding adducts with high
yields and enantioselectivities. Moreover, this reaction is used for the formal synthesis of (ꢀ)-Paroxetine,
a blockbuster drug, in only three steps.
Received 9 January 2009
Revised 4 February 2009
Accepted 6 February 2009
Available online 12 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The discovery of new reactions that allow us to build complex
molecular scaffolds in an efficient way from readily available start-
ing materials remains a challenging goal in chemical synthesis.
However, a limited number of catalytic enantioselective cascade
reactions,1 which enable the facile construction of complex scaf-
folds, have been developed thus far.
the pyrrolidine moiety. The same authors have shown in their
synthesis of 5-hydroxyisoxazolidines9 that the intramolecular
formation of hemiacetals or hemiaminals could push the organ-
ocatalytic reaction and exert an important positive effect in
terms of conversion and enantioselectivity.
With these ideas in mind, we envisioned an easy and direct
Due to the widespread occurrence of the piperidine ring in
biologically active compounds,2 the development of efficient
methods for its diastereoselective or enantioselective synthesis
is a subject of considerable practical importance. It is widely ac-
cepted that the biological properties of piperidines are highly
dependent on the type and location of substituents in the het-
erocycle. Accordingly, great attention has been paid to the con-
struction of functionalized piperidines. It is well documented
that piperidin-2-ones are common synthetic precursors for bio-
logically important polycyclic alkaloids, such as indolo[2,3-
entry to piperidines by coupling of imidomalonates 1 and a,b-
unsaturated aldehydes 2, as shown in Scheme 1, which could
be used for the facile synthesis of valuable compounds such as
(ꢀ)-Paroxetine5,7 and (+)-Femoxetine5 in a highly enantioselec-
tive fashion.
In our initial experiments (Table 1), we selected the TMS-pro-
tected diphenylprolinol I as the catalyst, and we screened different
solvents and additives in order to achieve high enantioselectivities
and yields in the addition of imidomalonate 1a to 4-nitrocinnam-
aldehyde (2a).
a
]quinolizidines and benzo[
a
]quinolizidines. In the literature,
To our delight, when polar protic solvents such as MeOH and
EtOH (entries 6 and 8) were used, the reaction performed well
but with moderate enantioselectivities. Interestingly, when non-
polar or non-protic solvents (entries 2, 3, 9 and 10) were used,
no reaction was observed. The reaction is simply catalyzed by sec-
ondary amines, but requires an additional base such as KOAc to af-
ford high yields. Surprisingly when 2,2,2-trifluoroethanol, a more
acidic solvent (entry 11), was used as a solvent we achieved very
high enantioselectivities and yields.10
Once we determined the optimal conditions to perform the
reaction, we screened several secondary amines as catalysts. As
is shown in Table 2, catalyst I gave us the best enantioselectivities,
while proline (II) or catalyst III or IV afforded worse enantioselec-
tivities and yields.
we can find several methodologies that allow us to obtain this
privileged structure. In 2005, Takasu et al. reported a synthesis
of racemic piperidines from
molecular aza-double Michael addition.3 In the realm of organ-
ocatalysis,4 Jorgensen and coworkers reported
Michael
addition5 of malonates to
,b-unsaturated aldehydes that could
be used to obtain piperidines in only three steps in excellent
yields and enantioselectivities.6,7 In 2007, Rios and Córdova8 re-
ported a synthesis of pyrrolidines from 2-amidomalonates and
a,b-unsaturated amides by an inter-
a
a
a
,b-unsaturated aldehydes, catalyzed by simple secondary
amines with excellent enantioselectivities and yields. In this Let-
ter, the authors developed a malonate addition to ,b-unsatu-
a
rated aldehydes followed by a hemiacetal formation to furnish
Next, we screened different a,b-unsaturated aldehydes in order
to study the scope of the process (Table 3). In all the examples
screened, the reaction furnished the desired piperidines in moder-
ate to excellent yields and excellent enantioselectivities (90–99%).
* Corresponding author. Tel.: +34 934021257; fax: +34 933097878 (R.R.).
E-mail addresses: jxvesely@post.cz (J. Vesely), amoyano@ub.edu (A. Moyano),
rios.ramon@icrea.cat (R. Rios).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.049

1944
G. Valero et al. / Tetrahedron Letters 50 (2009) 1943–1946
R2
CO2R1
O
O
PG
R2
R1O
N
H
CHO
HO
N
PG
O
3
2
1
Scheme 1. Amidomalonate addition.
Table 1
Table 3
Conditions screeninga
Aldehyde screeninga
O
O
Ph
R
O
O
Solvent
r.t
O2N
CO2Et
CO2Et
CF3CH2OH
EtO
NH
EtO
NH
KOAc, r.t
R
CHO
CHO
Ph
HO
N
O
HO
N
Bn
O
Ph
1a
Ph
2a
Ph
2a-g
Bn
1a
I
3a-g
3a
N
H
OTMS
20%
N
I
OTMS
H
20%
Entry
Solvent
Additive
Yieldb (%)
drc
eed (%)
Entry
1
Compound
R
Product
Yieldb (%)
drc
eed (%)
95
1
2
3
4
5
6
7
8
9
CHCl3
CHCl3
CHCl3
MeOH
MeOH
MeOH
MeOHe
EtOH
—
0
0
—
—
—
—
5:1
5:1
5:1
5:1
—
—
—
—
—
57
74
96
62
—
Et3N
KOAc
—
Et3N
KOAc
KOAc
KOAc
Et3N
Et3N
KOAc
2a
3a
92
94
84
90
93
71
84
86
5:1
Traces
0
O2N
NC
Cl
67
86
72
75
0
2
3
4
5
6
7
2b
2c
2d
2e
2f
3b
3c
3d
3e
3f
5:1
4:1
3:1
5:1
5:1
5:1
3:1
94e
90e
98
AcOEt
Toluene
CF3CH2OH
10
11
0
92
—
5:1
95
a
The experimental conditions: A mixture of 1a (0.30 mmol), catalyst I (20%,
0.05 mmol), 2a (0.25 mmol) and additive (0.30 mmol) in solvent (1 mL) was stirred
at rt overnight. Crude product 3a was purified by column chromatography.
b
Isolated yield.
Determined by NMR analysis of crude reaction.
Determined by chiral HPLC analysis.
Reaction run at 0 °C.
c
d
94e
96
e
Br
Br
Table 2
2g
2h
3g
3h
90e
99
Catalyst screeninga
F
O
O
Ph
CF3CH2OH
KOAc 1.2 equiv. r.t
O2N
CO2Et
EtO
NH
8
CHO
Catalyst 20%
HO
N
O
1a
2a
Bn
3a
a–d
Same as Table 1.
ee of dehydrated product.
e
CF3
Ph
Ph
Ph
Ph F3C
CF3
CO2H
(II)
N
N
H
N
OTMS
(I)
OH
tion works also fine with halogen substituents in the aromatic ring
such as chloro, bromo or fluoro in 4-position (Table 3, entries 3, 5
and 7) or in 2-position (Table 3, entry 6).
H
H
(III)
N
H
CF3
(IV)
OTMS
In all the examples, we obtained a mixture of diastereomers
with 3:1 to 5:1 ratio. This diastereoselectivity corresponds to the
equatorial or axial position of the hemiaminal hydroxyl of the
piperidine. This can be easily confirmed by elimination of the
Entry
Catalyst
Yieldb (%)
drc
eed (%)
1
2
3
4
I
II
III
IV
92
76
0
5:1
5:1
—
95
22
—
56
5:1
58
a
The experimental conditions:
A mixture of 1a (0.30 mmol), catalyst (20%,
0.05 mmol), 2a (0.25 mmol) and KOAc (0.30 mmol) in CF3CH2OH (1 mL) was stirred
at rt overnight. Crude product 3a was purified by column chromatography.
R
R
b–d
CHCl3, AcOH
Same as in Table 1.
CO2Et
CO2Et
O
HO
N
O
N
4a-g
Bn
Bn
3a-g
When electron-withdrawing substituents were used in the aro-
matic ring, the yields and enantioselectivies were excellent (Table
3, entries 1 and 2) and the reaction times were shorter. The reac-
quantitative yield, 1 diastereomer
Scheme 2. Dehydration of compounds 3.

G. Valero et al. / Tetrahedron Letters 50 (2009) 1943–1946
1945
Ph
Catalyst I 20%
KOAc 1.2 equiv
CF3CH2OH, r.t.
O
O
CO2Et
Me
Ph
EtO
N
H
CHO
HO
N
Me
O
2d
3i
1b
yield: 50%
67% ee
Scheme 3. Reaction with imidomalonate 1b.
ate 1b was used instead of ethyl 3-(benzylamino)-3-
oxopropanoate 1a, the reaction furnished the corresponding piper-
idine derivative 3i with lower yields and enantioselectivities (50%
yield, 67% ee) (Scheme 3).
In order to elucidate the structure of the major diastereomer of
compound 3d, we performed an X-ray diffraction analysis as
shown in Figure 1.
On the other hand, the absolute configuration of the adducts
was ascertained by chemical correlation. Thus, reduction of com-
pound (ꢀ)-3g (obtained by using ent-I as the catalyst) gave the
corresponding piperidine 5g as shown in Scheme 4. Comparison
with the literature data revealed that the absolute configuration
of compound 5g is (3R,4S) (½a D25
ꢀ23.4 (c 1.2, CHCl3), lit. (Ref. 5)
ꢁ
(½a 2D5
ꢀ21.2 (c 0.5, CHCl3). This compound is described as a chiral
ꢁ
intermediate in the synthesis of (ꢀ)-Paroxetine, a blockbuster anti-
depressive drug.5,7,11
The stereochemical outcome could be rationalized by the mech-
anistic proposal outlined in Scheme 5. Thus, efficient shielding of
the Re-face of the chiral iminium intermediate by the bulky aryl
groups of I leads to stereoselective Si-facial nucleophilic conjugate
attack on the b-carbon of 2. This is in accordance with other amine-
catalyzed reactions between malonates and enals. Next, intermedi-
ate 7 cyclizes spontaneously to afford the hemiacetal 3. It should
be noticed that epimerization of the stereochemically labile stereo-
centre at C3 will establish the thermodynamically more stable
(3S,4R) trans-configuration.
In summary, we have reported an organocatalytic, highly
enantioselective conjugate addition of amidomalonates to
a,b-
unsaturated aldehydes, that furnishes chiral piperidines after
hemiaminal formation in excellent yields and enantioselectivi-
ties. Furthermore, we have developed a simple synthesis of
(ꢀ)-Paroxetine in only three steps from commercially starting
materials in high yields and enantioselectivities. This new syn-
thesis improves the reported procedures by the reduced number
of steps and the high levels of enantioselectivity achieved.11
Mechanistic studies, synthetic applications and the discovery
of new reactions based on this concept are ongoing in our
laboratory.12
Figure 1. X-ray structure of 3d.13
hydroxyl to furnish compounds 4 in acid media. In all the cases, we
obtained only one product in quantitative yield and without loss of
enantioselectivity, as shown in Scheme 2.
The use of amidomalonates other than 1a was briefly investi-
gated. For example, when ethyl 3-(methylamino)-3-oxopropano-
F
F
F
O
O
OH
CO2Et
O
Ref. 5 and 7
O
BH3, THF
76%
HO
N
N
N
(-)-Paroxetine
5g
6
(-)-3g
Scheme 4. Formal synthesis of (ꢀ)-Paroxetine.

1946
G. Valero et al. / Tetrahedron Letters 50 (2009) 1943–1946
-H+
N
N
Ar
Ar
CO2Et
OEt
BnHNOC
O
H+
BnHN
O
H2O
OHC
H2O
Ar
N
N
Ar
CO2Et
H2
BnHNOC
O
Ar
(4R)
EtO2C
Bn
CO2Et
(3S)
N
H
CHO
(7)
HO
(6R)
N
O
(3)
Ar
Bn
Scheme 5. Mechanism of the reaction.
A.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47, 8703–8706; (g) Shaikh, R. R.;
Mazzanti, A.; Petrini, M.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47,
8707–8710; (h) Zhao, G.-L.; Rios, R.; Vesely, J.; Eriksson, L.; Cordova, A. Angew.
Chem., Int. Ed. 2008, 47, 8468–8472; (i) Zhao, G.-L.; Ibrahem, I.; Dziedzic, P.; Sun,
J.; Bonneau, C.; Cordova, A. Chem. Eur. J. 2008, 14, 10007–10011; (j) Gianelli, C.;
Sambri, L.; Carlone, A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47,
8700–8702; (k) Valero, G.; Balaguer, A.-N.; Moyano, A.; Rios, R. Tetrahedron Lett.
2008, 49, 6559–6562; (l) Balaguer, A.-N.; Companyó, X.; Calvet, T.; Font-Bardía,
M.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2009, 199–203.
Acknowledgements
We thank the Spanish Ministry of Science and Education (Pro-
ject AYA2006-15648-C02-01), the Grant Agency of Czech Republic
(203/09/P193) and the Ministry of Education of Czech Republic for
financial support.
5. Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jorgensen, K. A. Angew. Chem.,
Int. Ed. 2006, 45, 4305–4309.
References and notes
6. For recent reviews of asymmetric organocatalytic 1,4-conjugated additions,
see: (a) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716; (b) Vicario, J. L.;
Badía, D.; Carrillo, L. Synthesis 2007, 2065–2092; (c) Erkkilä, A.; Majander, I.;
Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470.
7. Rubidium and potassium salts of proline has been used in the synthesis of
piperidines. De Ferra, L.; Massardo, P.; Piccolo, O.; Cignarella G. U.S. 6,444,822,
B1.
8. Rios, R.; Vesely, J.; Ibrahem, I.; Sunden, H.; Cordova, A. Tetrahedron Lett. 2007,
48, 8695–8699.
9. Ibrahem, I.; Rios, R.; Vesely, J.; Zhao, G.-L.; Cordova, A. Chem. Commun. 2007,
849–852.
10. Typical experimental procedure for the synthesis of compound 3d: To a stirred
solution of catalyst I (16 mg, 0.05 mmol, 20 mol %) in CF3CH2OH (1.0 mL) were
added 4-nitrocinnamaldehyde 2a (33 mg, 0.25 mmol, 1 equiv), KOAc (30 mg,
0.3 mmol, 1.2 equiv) and amidomalonate 1a (64 mg, 0.3 mmol, 1.2 equiv). The
reaction was vigorously stirred at rt overnight. Next, the crude product was
purified by silica gel chromatography (hexane/EtOAc mixtures) to give the
corresponding piperidine derivative 3a. Compound 3d: 1H NMR (400 MHz.
CDCl3, TMSint): d (ppm) = 8.26 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.44–
7.37 (m, 5H), 5.30–5.12 (m, 2H), 4.43 (d, J = 15.0 Hz, 1H), 4.30–4.10 (m, 3.72–
3.66 (m, 2H), 2.30–2.12 (m, 2H), 1.19 (t, 3H, J = 7.1 Hz). 13C NMR (100 MHz.
CDCl3): d (ppm) = 169.6, 165.5, 148.1, 136.6, 129.0, 128.8, 128.3, 128.2, 128.1,
127.8, 124.3, 78.0, 61.8, 56.7, 48.0, 37.1, 37.0, 14.2. HRMS: Calculated for
1. For two excellent summaries on the concept of domino and tandem reactions
see: (a) Tietze, L. F. Chem. Rev., 1996, 96, 115–136; (b) Wasilke, J. C.; Obrey, S. J.;
Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001–1020; For selected
examples in the literature: (c) Ibrahem, I.; Córdova, A. Angew. Chem., Int. Ed.
2006, 45, 1952–1956; (d) Vesely, J.; Rios, R.; Ibrahem, I.; Zhao, G.-L.; Eriksson,
L.; Córdova, A. Chem. Eur. J. 2008, 14, 2693–2698; (e) Zhao, G.-L.; Córdova, A.
Tetrahedron Lett. 2006, 47, 7417–7421; (f) Halland, N.; Aburel, P. S.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2004, 43, 1272–1277; (g) Huang, Y.; Walji, A. M.;
Larsen, C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051–15052; (h)
Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. J. Am. Chem. Soc. 2005, 127,
15036–15037; (i) Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 15710–15711; (j) Yamamoto, Y.; Momiyama, N.;
Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962–5963; (k) Ramachary, D. B.;
Chowdari, N. S.; Barbas, C. F., III Angew. Chem., Int. Ed. 2003, 42, 4233–4235; (l)
Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 6964–6965; (m) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe,
G. Nature 2006, 441, 861; (n) Sundén, H.; Ibrahem, I.; Córdova, A. Tetrahedron
Lett. 2006, 47, 99–103; (o) Rios, R.; Sundén, H.; Ibrahem, I.; Zhao, G.-L.; Córdova,
A. Tetrahedron Lett. 2006, 47, 8679–8682; (p) Rios, R.; Sundén, H.; Ibrahem, I.;
Córdova, A. Tetrahedron Lett. 2007, 48, 2181–2184; (q) Rios, R.; Ibrahem, I.;
Vesely, J.; Zhao, G.-L.; Córdova, A. Tetrahedron Lett. 2007, 48, 5701–5705; (r)
Rios, R.; Vesely, J.; Sundén, H.; Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2007,
48, 5835–5839.
2. (a) Elbein, D. A.; Molineux, R. In Alkaloids; Chemical and Biological Prospective;
Pelletier, S. W., Ed.; Vol. 57; John Wiley & Sons: New York, 1987; (b) O’Hagan,
D. Nat. Prot. Rep. 2000, 17, 435.
3. Takasu, K.; Nishida, N.; Tomimura, A.; Ihara, M. J. Org. Chem. 2005, 70, 3957–
3962.
4. For recent examples in organocatalysis: (a) Cabrera, S.; Reyes, E.; Alemán, J.;
Mielli, A.; Kobbelgaard, S.; Jorgensen, K. A. J. Am. Chem. Soc. 2008, 130, 12031–
12037; (b) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am. Chem. Soc. 2008, 130,
15786–15787; (c) Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2008, 47,
10090–10093; (d) Goia, C.; Haauville, A.; Bernardi, L.; Fini, F.; Ricci, A. Angew.
Chem., Int. Ed. 2008, 47, 9236–9239; (e) Hayashi, Y.; Okano, T.; Itoh, T.; Urushima,
T.; Ishikawa, H.; Uchimaru, T. Angew. Chem., Int. Ed. 2008, 47, 9053–9058; (f)
Pescaioli, F.; Da Vicentis, F.; Galzerano, P.; Bencivenni, G.; Bartoli, G.; Mazzanti,
[C21H22N2O6Na]+: 421.1370; found: 421.1372. (½a 2D5
ꢁ
+5.3 (95% ee). HPLC:
ChiralpakÒ IA hexane/IPA 90:10 1 mL/min. Time: 19.3 min and 35.4 min.
11. For an ecellent review of syntheses of Paroxetine: (a) De Risi, C.; Fanton, G.;
Pollini, G. P.; Trapella, C.; Zanirato, V. Tetrahedron: Asymmetry 2008, 19, 131–
155; For recent synthesis of Paroxetine: (b) Nemoto, T.; Sakamoto, T.;
Fukuyama, T.; Hamada, Y. Tetrahedron Lett. 2007, 48, 4977–4981; (c)
Yamada, S.; Jahan, I. Tetrahedron Lett. 2005, 46, 8673–8676; (d) Hynes, P. S.;
Stupple, P. A.; Dixon, D. J. Org. Lett. 2008, 10, 1389–1391; (e) Pastre, J. C.;
Correia, C. R. D. Org. Lett. 2006, 8, 1657–1660.
12. During preparation of this Letter, Dr. J. Franzén reported an excellent synthesis
of quinolizilidine derivatives based on this concept: Franzén, J.; Fisher, A.
Angew. Chem., Int. Ed. 2009. doi:10.1002/anie.200805130.
13. Crystallographic data for structural analysis have been deposited with the
Cambridge Crystallographic Data Centre, CCDC No. 719613.