Highly enantioselective organocatalytic cascade reaction for the synthesis of piperidines and oxazolidines

Article abstract of DOI:10.1016/j.tet.2011.08.079

The synthesis of piperidines and piperidines derivatives in enantiopure fashion has been a challenging goal for organic chemists. In this report we developed a nice cascade reaction for piperidine derivatives based in an amidomalonate Michael addition to enals followed by an intramolecular hemiaminal formation with good yields and enantioselectivities. Moreover we studied the 'in situ' intramolecular cyclization of this hemiaminals with alcohols forming fused piperidine-oxazolidines.

Full text of DOI:10.1016/j.tet.2011.08.079

Tetrahedron 67 (2011) 8942e8950
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly enantioselective organocatalytic cascade reaction for the synthesis of
piperidines and oxazolidines
b
a
a
b
ꢁ a
*
ꢀ
ꢀ
ꢁ a
ꢀ
Sylva Cíhalova , Guillem Valero , Jirí Schimer , Marek Humpl , Martin Dracínsky , Albert Moyano ,
Ramon Rios b , Jan Vesely
,
c
,
a,
*
a Department of Organic and Nuclear Chemistry, Faculty of Science, Charles University in Prague, Hlavova 2030, 12840 Prague, Czech Republic
b
ꢁ
Universitat de Barcelona, Department of Organic Chemistry, c/Martí i Franques 1-11, 08028 Barcelona, Spain
c ICREA, Passeig Lluis Companys 23, 08010 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 June 2011
Received in revised form 25 August 2011
Accepted 26 August 2011
Available online 12 September 2011
The synthesis of piperidines and piperidines derivatives in enantiopure fashion has been a challenging
goal for organic chemists. In this report we developed a nice cascade reaction for piperidine derivatives
based in an amidomalonate Michael addition to enals followed by an intramolecular hemiaminal
formation with good yields and enantioselectivities. Moreover we studied the ‘in situ’ intramolecular
cyclization of this hemiaminals with alcohols forming fused piperidineeoxazolidines.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Paroxetine
Enantioselective
Cascade reaction
Diastereoselective
1. Introduction
The importance of piperidine analogs in medicinal chemistry is
well established due to the blockbuster drug paroxetine and the
In the last decades, the development of new asymmetric
methodologies that allow building complex structures has been
a highly pursued target for organic chemists.
related analog femoxetine (Fig. 1).4
With the renaissance of organocatalysis in 2000,1 new and
powerful cascade or tandem reactions have emerged for the syn-
thesis of heterocycles.2 In these processes, highly complex and
functionalized organic scaffolds are easily accessed from simple
starting materials by combining two or more reaction steps, where
at least one involves an asymmetric process, to take place in the
same reaction mixture. These processes are commonly environ-
mentally friendly, since the generation of chemical waste is reduced
and avoids time-consuming and costly processes, including the
purification of intermediates and steps involving the protection and
deprotection of functional groups in addition to high efficiency.3
Heterocycles, and more concretely, aza-heterocycles, such as
piperidines, have a great importance in biological and pharma-
ceutical chemistry due to its presence as structural motif in nu-
merous natural alkaloids, such as the fire ant toxin solenopsin, the
nicotine analog anabasine, or the famous Socrates’ poison coniine.
Fig. 1. Examples of biologically active piperidines.
Aza-heterocycles have attracted much attention from several
research groups. For example the synthesis of pyrrolidines has been
achieved via [3þ2] cycloadditions of azomethine ylides with enals,5
* Corresponding authors. Tel.: þ34 934021257; fax: þ34933397878 (R.R.);
tel.: þ420 221 951 305; fax: þ420 221 951 326 (J.V.); e-mail addresses: riosramon@
yahoo.com, rios.ramon@icrea.cat (R. Rios), jxvesely@natur.cuni.cz (J. Vesely).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.079

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S. Cíhalova et al. / Tetrahedron 67 (2011) 8942e8950
8943
nitroalkenes6 or other activated alkenes;7 a different approxima-
tion was made by Rios and Cordova consisting on the addition of 2-
aminomalonates to enals.8 Soon after, Carter and Fustero reported
the highly enantioselective synthesis of pyrrolidines via an intra-
molecular aza-Michael addition.9
Despite all these efforts the synthesis of piperidine moieties
has been limited to few examples of intramolecular aza-Michael
reactions described by Fustero and Carter,9 and aza-DielseAlder
reaction reported by Bode,10 Cordova,11 Chen,12 and others.13
In 2009, based on the previous synthesis of pyrrolidines via
a malonate addition followed by an intramolecular aminal forma-
tion, Franzen,14 and soon after us15 developed a similar strategy to
the synthesis of highly substituted piperidines (Scheme 1). During
the preparation of this manuscript, several research groups have
found similar results base on similar strategies.16
enantioselectivities and yields in the addition of amidomalonate
6a to 4-nitrocinnamaldehyde (7a).
To our delight, when polar protic solvents, such as MeOH or
EtOH were used (entries 6 and 8), the reaction performed well but
with moderate enantioselectivities. Interestingly, when non-polar
or non-protic solvents were used (entries 2, 3, 9, and 10), no re-
action was observed. The reaction is simply catalyzed by secondary
amines, but it requires an additional base, such as KOAc to afford
high yields. Surprisingly when 2,2,2-trifluoroethanol, which is
more acidic, was used as a solvent (entry 11), we achieved very high
enantioselectivities and yields.
This effect could probably be explained by the increment in the
nucleophilicity of the amidomalonate in more acidic solvents.
Once we determined the optimal conditions to perform the
reaction, we screened several secondary amines as catalysts. As it is
ꢁ
Scheme 1. Reaction reported by Franzen.
Here we wish to present our work in the synthesis of piperidines
and related bicycles and the application of this methodology to the
formal synthesis of blockbuster drug paroxetine and its related
analog femoxetine.
shown in Table 2, catalyst I gave us the best enantioselectivities,
while proline (II) or catalysts III or IV afforded worse enantiose-
lectivities and yields.
Table 2
Catalyst screeninga
2. Results and discussion
Based in our previous experience in organocatalysis,17 we
selected the TMS-protected diphenylprolinol I as the catalyst in
our initial experiments (Table 1), and we screened different
solvents
and
additives
in
order
to
achieve
high
Table 1
Solvent and additive screeninga
O
O
Ar
Solvent
r.t..
O2N
CO2Et
EtO
NH
CHO
Ph
HO
N
Bn
O
Ph
OTMS
1a
2a
Entry
Catalyst
Yieldb (%)
drc
eed (%)
3a
N
H
1
2
3
4
I
II
III
IV
92
76
0
5:1
5:1
d
95
22
d
I
20%
Entry
Solvent
Additive
Yieldb (%)
drc
eed (%)
56
5:1
58
1
2
3
4
5
6
7
8
CHCl3
CHCl3
CHCl3
d
0
0
d
d
d
d
d
57
74
96
62
d
d
95
a
Experimental conditions: A mixture of 1a (0.30 mmol), catalyst I (20 mol %,
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.
Et3N
KOAc
d
d
Traces
0
d
MeOH
MeOH
MeOH
MeOHe
EtOH
AcOEt
Toluene
CF3CH2OH
d
b
Isolated yield.
Determined by NMR analysis of crude reaction.
Determined by chiral HPLC analysis.
Et3N
KOAc
KOAc
KOAc
Et3N
Et3N
KOAc
67
86
72
75
0
5:1
5:1
5:1
5:1
d
c
d
Next, we screened different a,b-unsaturated aldehydes in order
9
10
11
to study the scope of the process (Table 3). In all the examples
screened, the reaction furnished the desired piperidines in
moderate to excellent yields and excellent enantioselectivities
(90e99%). When electron-withdrawing substituents were used on
the aromatic ring, the yields and enantioselectivies were excellent
(entries 1 and 2; Table 3) and the reaction times were shorter. The
reaction also works fine with halogen substituents on the aromatic
ring, such as chloro, bromo or fluoro in 4-position (entries 3, 5, and
7; Table 3) or in 2-position (entry 6; Table 3). It should be noticed
0
92
d
5:1
a
Experimental conditions: A mixture of 1a (0.30 mmol), catalyst I (20 mol %,
0.05 mmol), 2a (0.25 mmol), and additive (0.30 mmol) in the corresponding 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
e

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8944
S. Cíhalova et al. / Tetrahedron 67 (2011) 8942e8950
Table 3
Enal screeninga
R
O
O
CO2Et
CF3CH2OH
KOAc, r.t.
EtO
NH
R
CHO
2a-i
HO
N
Bn
O
Ph
Ph
1a
I
3a-i
N
H
OTMS
20%
Entry
1
Compound
R
Product
Yieldb (%)
drc
eed (%)
95
2a
3a
92
94
84
5:1
5:1
4:1
O2N
2
3
2b
2c
3b
3c
94e
90e
NC
Cl
4
5
2d
2e
3d
3e
90
93
3:1
5:1
98
94e
Br
6
7
8
2f
3f
71
84
5:1
5:1
96e
90e
Br
Fig. 2. X-ray ORTEP of compound 3d.18
2g
3g
amidomalonate and enals. Thus, when we use ethyl 3-(methyl-
amino)-3-oxopropanoate (1b) this reaction will render us a direct
access to femoxetine (5).
To our delight the reaction renders the final piperidine derivatives
with good yields and enantioselectivities as it is shown in Table 4.
Only when bulky substituents like tert-butyl or isopropyl were used
the yield decreases dramatically probably due to the steric hin-
derance that avoids the hemiaminal forming reaction. Remarkably,
these compounds are quite unstable and during slow purification by
column chromatography dehydrates to furnish compound 4.
F
2h
2i
3h
3i
86
0
3:1
99
9
Me
d
d
a
Experimental conditions: A mixture of 1a (0.30 mmol), catalyst I (20 mol %,
0.05 mmol), 2aei (0.25 mmol), and AcONa (0.30 mmol) in CF3CH2OH (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.
Determined by chiral HPLC analysis of dehydrated compound.
c
d
e
Table 4
Amidomalonate screeninga
that the reaction with aliphatic aldehydes, such as crotonaldehyde
did not render the final compound in any of the conditions tested,
probably due to the presence of side reactions.
In all the examples we obtained a mixture of diastereomers with
3:1 to 5:1 ratio. This diastereoselectivity corresponds to the equa-
torial or axial position of the hemiaminal hydroxyl group of the
piperidine. This can be easily confirmed by elimination of the hy-
droxyl 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.
Entry
1
R1
R2
Product
Yieldb (%)
drc
eed (%)
1e
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1b
1b
1c
1d
1e
Me
Me
Me
Me
Me
Me
Et
H
Me
F
Cl
Br
No2
H
3j
3k
3l
3m
3n
3o
3p
3q
3r
66
66
52
82
68
95
14
10
d
19:1
9:1
9:1
9:1
9:1
19:1
19:1
10:7
d
95
92
69
94
94
95
89
91
d
R
R
CHCl3, AcOH
CO2Et
CO2Et
O
HO
N
Bn
O
N
Bn
4a-g
3a-g
i-Pr
t-Bu
H
H
quantitative yield,1 diastereomer
Scheme 2. Dehydration of compounds 3aeg.
a
Experimental conditions: A mixture of 1bee (0.30 mmol), catalyst I (20 mol %,
0.05 mmol), 2aef (0.25 mmol), and AcOK (0.30 mmol) in CF3CH2OH (1 mL) was
stirred at rt overnight. Crude product 3 was purified by column chromatography
that dehydrates during the column to furnish product 4.
In order to elucidate the structure of the major diastereomer of
compound 3d, we performed an X-ray diffraction analysis as shown
in Fig. 2.
Next, we focused our efforts on the reaction between amido-
malonates bearing different substituents in the nitrogen of the
b
Isolated yield of 4.
Determined by NMR analysis of crude reaction.
Determined by chiral HPLC analysis of 4.
Reaction run with the opposite enantiomer of I.
c
d
e

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S. Cíhalova et al. / Tetrahedron 67 (2011) 8942e8950
8945
In order to show the broad utility of this reaction and to ascer-
tain the absolute configuration of the compounds obtained we
decided to do a formal synthesis of (ꢁ)-paroxetine19 and femox-
etine. As it is shown in Scheme 3, reduction of compound 3g, gave
the corresponding piperidine 5g. Comparison with the literature
data revealed that the absolute configuration of compound 5g is
(3R,4S) ½a 2D5
ꢂ
ꢁ23.4 (c 1.2, CHCl3), ½a D25
ꢂ
ꢁ21.2 (c 0.5, CHCl3).20 This
compound 5g is described as a chiral intermediate in the synthesis
of (ꢁ)-paroxetine, a blockbuster antidepressive drug. In a similar
way, femoxetine unit was synthesized starting from amidomalo-
nate 1b and cinnamaldehyde. The reaction catalyzed by ent-I ren-
der the compound 3j in 92% yield and 95% ee. Next 3j was reduced
with BH3 in THF to render the piperidine 8 that should be further
transformed to femoxetine (9) as shown in Scheme 3.20
The stereochemical outcome could be rationalized by the mech-
anistic proposal outlined in Scheme 4. Thus, efficient shielding of the
Re-face of the chiral iminium intermediate by the bulkyaryl 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 re-
actions between malonates and enals. Next, intermediate 7 cyclizes
spontaneously via a favored 6-exo-trig ring closure to afford the
hemiacetal 3. It should be noticed that epimerization of the stereo-
chemically labile stereocenter at C3 will establish the thermody-
namically more stable (3S,4R) trans-configuration.
Scheme 4. Proposed mechanism.
Next, we decided to study the formation of oxazolidines via
a cascade reaction taking advantage of the easy imine formation of
Scheme 3. Synthesis of paroxetine and femoxetine.

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S. Cíhalova et al. / Tetrahedron 67 (2011) 8942e8950
8946
the resulting pyridines 3 in acid media. As it is shown in Scheme 5,
initially, the cascade reaction of the rationally designed hydrox-
yamide 1f and enal (2) was carried out at room temperature by
using catalysts I, to form the desired piperidine. Next the piperidine
was treated in acid media to furnish the desired oxazolidine via an
intramolecular acetal formation through the formed ‘in situ’ imine
(Scheme 5).
The relative configuration of these products was determined by
X-ray analysis of compound 10a. As shown in Fig. 3, the relative
configuration will be (6S,7R,8aS).
Scheme 5. Proposed mechanism for the oxazolidine formation.
The first step works fine in exactly the same reaction conditions
that were used previously. The reaction rendered the final piperi-
dine 3seu in good yields, enantio and diastereoselectivities as it is
illustrated in Table 5.
Fig. 3. X-ray of 10a.21
This configuration corresponds to the thermodynamic product
where all the substituents of the cyclohexyl ring are in equatorial
position.
Table 5
Cascade reactiona
3. Conclusions
In summary, we have reported an organocatalytic, highly
enantioselective conjugate addition of amidomalonates to a,b-un-
saturated aldehydes, that furnishes chiral piperidines after hemi-
aminal formation in excellent yields and enantioselectivities.
Furthermore, we have developed a simple synthesis of (ꢁ)-parox-
etine and femoxetine in only three steps from commercially start-
ing materials in high yields and enantioselectivities. This new
synthesis improves the reported procedures by the reduced num-
ber of steps and the high levels of enantioselectivity achieved.22
Moreover, we have expanded the scope of the reaction de-
veloping a new cascade reaction that renders highly interesting
oxazolidines in excellent yields and enantioselectivities in two-step
processes or even in one-pot procedure.
Entry
R1
Compound
Yieldb (%)
drc
eed (%)
1
2
3
H
Br
No2
3s
3t
3u
73
44
56
9:1
9:1
9:1
98
90
95
a
The experimental conditions: A mixture of 1f (0.30 mmol), catalyst I (20 mol %,
0.05 mmol), 2aec (0.25 mmol), and AcOK (0.30 mmol) in CF3CH2OH (1 mL) was
stirred at rt overnight. Crude product 3seu was purified by column
chromatography.
b
Isolated yield.
Determined by NMR analysis of crude reaction.
Determined by chiral HPLC analysis.
c
d
4. Experimental section
4.1. General
Next, the addition of acid to the reaction media rendered the
final oxazolidines in quantitative yields as it is shown in Scheme 6.
Chemicals and solvents were either purchased puriss p.A. from
commercial suppliers or purified by standard techniques. For thin-
layer chromatography (TLC), silica gel plates Merck 60 F254 were
used and compounds were visualized by irradiation with UV light
and/or by treatment with a solution of phosphomolybdic acid
(25 g), Ce(SO4)2$H2O(10 g) followed by heating. Flash chroma-
tography was performed using silica gel Merck 60 (particle size
0.063e0.200 mm), 1H NMR, 13C NMR spectra were recorded on
Scheme 6. Oxazolidine formation.
Interestingly, the cascade reaction can also proceed in a ‘one pot’
fashion, rendering the final compounds in good yields and with
slightly lower enantioselectivities (10a 93% ee, 10b and 10c<90% ee).
Varian
INOVA-300. Chemical shifts for protons are given in
UNITY
d
relative to tetramethylsilane (TMS) and are referenced to residual
protium in the NMR solvent (CDCl3:
d¼7.26 ppm). Chemical shifts

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S. Cíhalova et al. / Tetrahedron 67 (2011) 8942e8950
8947
for carbon are given in
referenced to the carbon resonances in the solvent (CDCl3:
d
relative to tetramethylsilane (TMS) and are
1H), 5.06 (dt, J¼7.2, 6.3 Hz, 1H), 4.45 (d, J¼15 Hz, 1H), 4.12 (q,
J¼9.9 Hz, 2H), 3.85 (dt, J¼11.7, 3.9 Hz, 1H), 3.63 (d, J¼11.7 Hz, 1H),
d
¼77.0 ppm). The coupling constants J are given in hertz. Chiral
2.78 (t, J¼7.2 Hz, 1H), 2.06e2.23 (m, 2H), 1.12 (t, J¼7.2 Hz, 3H). 13
C
HPLC was carried out using an LCP 5020 Ignos liquid chromatog-
raphy pump with LCD 5000 spectrophotometric detector. High-
resolution mass spectroscopic data were obtained at the Univer-
sity of Barcelona, Department of Organic Chemistry.
NMR (CDCl3, 75.46 MHz):
d
(ppm)¼170.06, 166.25, 140.71, 137.01,
128.85, 128.42, 127.78, 127.47, 127.04, 78.34, 77.22, 61.46, 57.11,
47.48, 37.11, 13.97. HRMS (ESI): calcd for [C21H23NO4Na]þ 376.1525,
found 376.1525. The enantiomeric excess (98%) was determined
by HPLC with an AD-H column. (n-heptane/i-PrOH¼90:10,
4.2. General procedure for the preparation of 3
l¼220 nm), 1.0 mL/min; tR¼minor enantiomer 22.46 min, major
enantiomer 32.81 min.
In a round bottom flask, unsaturated aldehyde 2 (0.25 mmol,
1
equiv), amidomalonate
1
(0.3 mmol, 1.2 equiv), catalyst
4.3.5. (3S,4R,6R)-Ethyl 1-benzyl-4-(4-bromophenyl)-6-hydroxy-2-
oxopiperidine-3-carboxylate (3e). White solid (93%). Mp: 167 ꢀC.
IR (KBr): 3338, 3032, 2981, 2908, 1735, 1617, 1477, 1454, 1166, 1152,
(0.05 mmol, 20% mol), and KOAc (0.3 mmol, 1.2 equiv) were added
sequentially in 1 mL of 2,2,2-trifluoroethanol. The reaction was
stirred at room temperature overnight. Then the crude was purified
by column chromatography to furnish piperidine adducts 3.
1037, 763, 748, 701 cmꢁ1. 1H NMR (CDCl3, 299.94 MHz):
d
(ppm)¼
7.22e7.37 (m, 10H), 5.13 (d, J¼15 Hz,1H), 5.03e5.08 (m,1H), 4.45 (d,
J¼15 Hz, 1H), 4.12 (q, J¼7.2 Hz, 2H), 3.85 (dt, J¼11.6, 3.9 Hz,1H), 3.62
(d, J¼11.7 Hz, 1H), 2.78 (br d, 1H), 2.06e2.23 (m, 2H), 1.12 (t,
4.3. General procedure for the one-pot cyclization reactions
J¼7.2 Hz, 3H). 13C NMR (CDCl3, 75.43 MHz):
d
(ppm)¼170.1, 166.3,
To a stirred solution of (S)-2,2-diphenyl-2-trimethylsilanox-
ymethylpyrrolidine (0.05 mmol, 0.2 equiv, 16 mg) in 2,2,2-
trifluoroethanol (1 mL) was added E-arylprop-2-enal (0.3 mmol,
1.2 equiv), amidomalonate (0.25 mmol, 1 equiv), and potassium ac-
etate (0.25 mmol, 1 equiv, 21 mg). Reaction mixture was allowed to
stir at room temperature for 14 h. After that, p-toluenesulfinic acid
(0.5 mmol, 2 equiv, 95 mg) was added. After 1 h, crude mixture was
purified by column chromatography (EtOAc) to give the final product.
140.7,137.0,128.9,128.4,127.8,127.5,127.0, 78.3, 61.5, 57.1, 47.8, 37.1,
37.0, 14.0. ½a 2D5
þ20.0 (c 0.8, CH2Cl2, 94% ee). HRMS (ESI): calcd for
ꢂ
[MþH]þ C21H23NO4 354.1627, found 354.1632.
4.3.6. (3S,4R,6R)-Ethyl 1-benzyl-4-(2-bromophenyl)-6-hydroxy-2-
oxopiperidine-3-carboxylate (3f). Colorless oil (71%). mixture of di-
astereomers 1H NMR (400 MHz, CDCl3, TMSint):
d
(ppm)¼7.60 (dd,
J¼8.2, 1.5 Hz, 1H), 7.39e7.26 (m, 7H), 7.15 (m, 1H), 5.39e5.19 (d,
J¼15.5 Hz,1H), 5.03 (m,1H), 4.49e4.33 (m,1H), 4.15 (q, J¼7.0 Hz, 2H),
3.86e3.76 (m, 1H), 3.64e3.56 (sample, 1H (OH)), 2.28e1.92 (m, 2H),
4.3.1. (3S,4R,6R)-Ethyl 1-benzyl-6-hydroxy-4-(4-nitrophenyl)-2-
oxopiperidine-3-carboxylate (3a). Colorless oil (92%). 1H NMR
1.32e1.15 (t, J¼7.3 Hz, 3H). ½a D25
þ16.1 (c 0.6, CH2Cl2, 96% ee). HRMS
ꢂ
(400 MHz, CDCl3, TMSint
)
d
(ppm)¼8.26 (d, J¼8.8 Hz, 2H), 7.48 (d,
(ESI): calcd for [MþH]þ C21H22BrNO4 432.0804, found 432.0802.
J¼8.8 Hz, 2H), 7.44e7.37 (m, 5H), 4.43 (d, J¼15.0 Hz, 1H), 4.30e4.10
(m, 2H), 3.72e3.66 (m, 2H), 2.30e2.12 (m, 2H), 1.19 (t, J¼7.1 Hz, 3H).
4.3.7. (3S,4R,6R)-Ethyl 1-benzyl-4-(4-fluorophenyl)-6-hydroxy-2-
oxopiperidine-3-carboxylate (3g). Colorless oil (84%). 1H NMR
13C NMR (100 MHz, CDCl3):
d
(ppm)¼169.6, 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,
(400 MHz CDCl3, TMSint):
d
(ppm)¼7.36e7.10 (m, 9H), 5.10e5.00
37.1, 37.0, 14.2. ½a D25
ꢂ
þ5.3 (c 1.1, CH2Cl2). HRMS (ESI): calcd for
(m, 1H), 4.50e4.00 (m, 5H), 3.90e3.80 (m, 1H), 3.53 (d, 1H,
J¼11.7 Hz), 2.20e2.00 (m, 2H), 1.11 (t, J¼7.9 Hz, 3H). 13C NMR
[C21H22N2O6Na]þ 421.1370, found 421.1372. The enantiomeric ex-
cess (95%) was determined by HPLC with an IA column (n-hexane/i-
(100 MHz CDCl3):
d
(ppm)¼169.2, 164.6, 137.2e128.5, 62.6, 57.6,
PrOH¼90:10,
l¼220), 1.0 mL/min; tR¼minor enantiomer 19.3 min,
50.0, 41.9, 14.7. 19F NMR (100 MHz CDCl3):
d
(ppm)¼ꢁ114.1. ½a D25
ꢂ
major enantiomer 35.4 min.
þ4.0 (c 0.7, CHCl3). HRMS (ESI): calcd for [C21H21FNO4]þ: 371.1500;
found: 371.1498. (3S,4R,6S)-Ethyl 1-benzyl-4-(4-fluoroophenyl)-6-
hydroxy-2-oxopiperidine-3-carboxylate (3g0 (minor diastereomer))
4.3.2. (3S,4R,6R)-Ethyl 1-benzyl-4-(4-cyanophenyl)-6-hydroxy-2-
oxopiperidine-3-carboxylate (3b). Colorless oil (94%). 1H NMR
1H NMR (400 MHz CDCl3, TMSint):
d
(ppm)¼7.36e7.10 (m, 9H),
(400 MHz CDCl3, TMSint):
d
(ppm)¼7.60 (d, J¼8.1 Hz, 2H), 7.36e7.26
5.10e5.00 (m, 1H), 4.50e4.00 (m, 5H), 3.90e380 (m, 1H), 3.64 (d,
J¼11.3 Hz, 1H)2.20e2.00 (m, 2H), 1.36 (t, J¼7.3 Hz, 3H). 19F NMR
(m, 7H), 5.16 (d, J¼14.8 Hz,1H), 5.06e5.03 (m,1H), 4.47 (d, J¼5.8 Hz,
1H), 4.32 (d, J¼14.8 Hz, 1H), 4.20e3.90 (m, 4H), 3.57 (d, J¼11.8 Hz,
1H), 2.18e2.10 (m, 1H) 4.30e4.10 (m, 2H), 3.72e3.66 (m, 2H),
2.30e2.12 (m, 2H), 1.09 (t, 3H, J¼7.2 Hz). 13C NMR (100 MHz CDCl3):
(100 MHz CDCl3):
d
(ppm)¼ꢁ110.0.
4.3.8. (3S,4R,6R)-Ethyl 1-benzyl-6-hydroxy-4-(naphthalen-1-yl)-2-
oxopiperidine-3-carboxylate (3h). White solid (86%). Mp: 174 ꢀC
d
(ppm)¼170.1, 166.1, 146.7, 137.2, 133.2, 129.3, 129.2, 128.7, 128.6,
128.3, 118.9, 78.2, 62.2, 57.0, 48.2, 37.5, 37.2, 14.5. ½a D25
ꢂ
þ16.7 (c 0.6
½
a 2D5
ꢂ
þ20.0. IR (KBr): 3307, 3047, 2987, 2937, 1741, 1618, 1482, 1321,
CH2Cl2, 94% ee).
1153, 1035, 750, 704 cmꢁ1. 1H NMR (CDCl3, 300.13 MHz):
d
(ppm)¼
7.83e7.30 (m, 12H), 5.17 (d, J¼15 Hz, 1H), 5.08 (m, 1H), 4.20 (br d,
J¼15 Hz, 1H), 4.14e3.98 (m, 3H), 3.75 (d, J¼11.4 Hz, 1H), 3.18 (br s,
1H), 2.28e2.14 (m, 2H), 1.05 (t, J¼6.9 Hz, 3H). 13C NMR (CDCl3,
4.3.3. (3S,4R,6R)-Ethyl 1-benzyl-4-(4-chlorophenyl)-6-hydroxy-2-
oxopiperidine-3-carboxylate (3c). Colorless oil (84%). 1H NMR
(400 MHz CDCl3, TMSint):
d
(ppm)¼7.40e7.16 (m, 9H), 5.12e5.02
75.46 MHz):
d
(ppm)¼170.13, 166.24, 138.13, 136.98, 133.45, 132.72,
(m, 2H), 4.46e4.02 (m, 5H), 3.80e3.60 (m, 1H), 2.20e2.00 (m, 2H),
128.87, 128.73, 128.43, 127.81, 127.77, 127.64, 126.33, 125.97, 125.93,
1.13 (t, 3H, J¼8.0 Hz). 13C NMR (100 MHz CDCl3):
d
(ppm)¼169.8,
124.95, 78.34, 77.23, 61.54, 56.91, 47.88, 37.11, 13.96. ½a D25
þ54.3 (c
ꢂ
166.2, 139.6, 138.0, 137.1, 133.4, 129.8, 129.6, 128.9, 128.8, 128.5,
0.8, CH2Cl2, 99% ee). HRMS (ESI): calcd for [C21H23NO4Na]þ
426.1681, found 426.1680. The enantiomeric excess (99%) was de-
termined by HPLC with an AD-H column. (n-heptane/i-
128.3, 127.9, 78.2, 61.9, 56.3, 49.5, 41.2, 36.8, 14.2. ½a D25
þ7.1 (c 1.1,
ꢂ
CH2Cl2, 90% ee).
PrOH¼90:10,
l
¼254 nm), 1.0 mL/min; tR¼minor enantiomer
4.3.4. (3S,4R,6R)-Ethyl 1-benzyl-6-hydroxy-2-oxo-4-phenylpiperidine-
35.41 min, major enantiomer 58.24 min.
3-carboxylate (3d). White solid (90%). Mp: 167 ꢀC ½a D25
ꢂ
14.2 (c 0.8
CH2Cl2) IR (KBr): 3338, 3056, 3032, 2981, 2955, 2908, 1735, 1617,
4. 3. 9. (3R, 4S, 6S)-Ethyl 6-hydroxy-1-methyl-2-oxo-4-
1478, 1454, 1321, 1167, 1152, 1037, 748, 702, 644, 531 cmꢁ1. 1H NMR
phenylpiperidine-3-carboxylate (3j). Yellowish oil (66%). 1H NMR
(CDCl3, 300 MHz):
d
(ppm)¼7.37e7.22 (m, 10H), 5.13 (d, J¼14.4 Hz,
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.20e7.33 (m, 5H), 5.00 (t,

ꢀ
ꢁ
S. Cíhalova et al. / Tetrahedron 67 (2011) 8942e8950
8948
J¼3 Hz, 1H), 4.01e4.16 (q, J¼7.2 Hz, 2H), 3.71e3.89 (m, 1H), 3.53 (d,
J¼12 Hz, 1H), 3.06 (s, 3H), 2.18e2.22 (m, 2H) 1.05 (t, J¼7.2 Hz, 3H).
4.3.17. (3S,4R,6R)-Ethyl 6-hydroxy-1-(2-hydroxyethyl)-4-(4-
nitrophenyl)-2-oxopiperidine-3-carboxylate (3u). Yellow oil (56%).
13C NMR (300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼170.18, 166.38, 140.69,
1H NMR (300 MHz, DMSO, 25 ꢀC):
d
(ppm)¼8.19 (d, J¼8.7 Hz, 2H),
128.78, 127.37, 126.99, 80.84, 61.34, 56.82, 56.48, 37.17, 37.09, 33.16,
13.92.
7.58 (d, J¼8.7 Hz, 2H), 6.42 (d, J¼4.5 Hz, 1H), 5.07 (br s, 1H), 4.95 (t,
J¼4.8 Hz, 1H), 3.92 (q, J¼6.9 Hz, 2H), 3.72e3.85 (m, 2H), 3.48e3.53
(m, 3H), 2.33 (dt, J¼12.9, 2.7 Hz, 1H), 1.88 (br d, J¼13.8 Hz, 1H), 0.95
4.3.10. (3S,4R,6R)-Ethyl 6-hydroxy-1-methyl-2-oxo-4-p-tolylpiper-
(t, J¼7.2 Hz, 3H). 13C NMR (300 MHz, DMSO, 25 ꢀC):
d
(ppm)¼
idine-3-carboxylate (3k). Yellowish oil (66%). 1H NMR (300 MHz,
169.06, 165.10, 149.46, 146.61, 128.73, 123.76, 78.53, 60.26, 58.57,
55.78, 47.62, 36.90, 36.09, 13.88.
CDCl3, 25 ꢀC):
d
(ppm)¼7.07e7.13 (m, 4H), 5.0 (t, J¼3 Hz, 1H),
4.02e4.15 (m, 2H), 3.68e3.80 (m, 1H), 3.49 (d, J¼11.7 Hz, 1H), 3.05
(s, 3H), 2.31 (s, 3H), 2.15e2.18 (m, 2H), 1.07 (t, J¼7.2 Hz, 3H).
4.3.18. (3S,4R)-Ethyl 1-benzyl-4-(4-cyanophenyl)-1,2,3,4-tetrahydro-
2-oxopyridine-3-carboxylate (4b). Colorless oil. 1H NMR (400 MHz
4.3.11. (3S,4R,6R)-Ethyl 4-(4-fluorophenyl)-6-hydroxy-1-methyl-2-
oxopiperidine-3-carboxylate (3l). Dark red oil (45%). 1H NMR
CDCl3, TMSint):
d
(ppm)¼7.56 (d, J¼8.5 Hz, 2H), 7.37e7.26 (m, 7H),
6.26 (dd, J¼7.8 Hz, J0¼1.7 Hz, 1H), 5.19 (dd, J¼7.8 Hz, J0¼4.2 Hz, 1H),
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.16e7.20 (m, 2H), 6.96e7.02 (m,
4.75 (m, 2H), 4.28e4.12 (m, 3H), 3.64 (d, J¼8.3 Hz, 1H), 1.20 (t, 3H,
2H), 5.00 (br s, 1H), 4.04 (q, J¼7.2 Hz, 2H), 3.75e3.84 (m, 1H), 3.46
J¼7.1 Hz). 13C NMR (100 MHz CDCl3):
d
(ppm)¼169.0, 164.6, 146.2,
(d, J¼12 Hz, 1H), 3.04 (s, 3H), 2.13e2.17 (m, 2H), 1.05 (t, J¼7.2 Hz,
136.7, 133.2, 130.5, 129.4, 129.3, 128.9, 128.7, 128.5, 119.0, 112.0,
3H). 13C NMR (300 MHz CDCl3, 25 ꢀC):
d
(ppm)¼170.09, 166.28,
108.3, 62.4, 56.1, 49.9, 42.1, 14.5. ½a D25
þ13.8 (c 0.82 CH2Cl2, 94% ee).
ꢂ
163.72, 160.03, 136.41, 128.56 (d, J¼30.6 Hz, 1C), 115.63 (d,
J¼83.7 Hz, 1C), 80.69, 61.40, 57.00, 37.24, 36.40, 33.16, 13.89.
HRMS (ESI): calcd for [C22H21N2O3]þ: 361.1546; found: 361.1545.
½
a 2D5
determined by HPLC with an IA column. (n-hexane/i-PrOH¼90:10,
ꢂ
þ13.8 (c 0.8, CH2Cl2). The enantiomeric excess (94%) was
4.3.12. (3S,4R,6R)-Ethyl 4-(4-chlorophenyl)-6-hydroxy-1-methyl-2-
l
¼254 nm), 1.0 mL/min; tR¼minor enantiomer 26.3 min, major
oxopiperidine-3-carboxylate (3m). Colorless oil (82%). 1H NMR
enantiomer 42.1 min.
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.29 (d, J¼8.4 Hz, 2H), 7.16 (d,
J¼8.4 Hz, 2H), 5.02 (t, J¼3 Hz, 1H), 4.02e4.13 (m, 2H), 3.73e3.83 (m,
4.3.19. (3S,4R)-Ethyl 1-benzyl-4-(4-chlorophenyl)-1,2,3,4-
1H), 3.47 (d, J¼11.7 Hz, 1H), 3.06 (s, 3H), 2.15e2.18 (m, 2H), 1.09 (t,
tetrahydro-2-oxopyridine-3-carboxylate (4c). Colorless oil. 1H NMR
J¼6.9 Hz, 3H). 13C NMR (300 MHz CDCl3, 25 ꢀC):
d
(ppm)¼169.86,
(400 MHz CDCl3, TMSint):
d
(ppm)¼7.36e7.10 (m, 9H), 6.20 (dd,
166.00, 139.18, 133.25, 129.02, 128.40, 80.83, 61.53, 56.70, 37.08,
36.55, 33.22, 14.00.
J¼7.9 Hz, J0¼1.8 Hz, 1H), 5.19 (dd, J¼7.9 Hz, J0¼4.8 Hz, 1H), 4.75 (m,
J¼5.6 Hz, 2H), 4.22e4.10 (m, 3H), 3.63 (d, J¼8.7 Hz, 1H), 1.19 (t, 3H,
J¼7.1 Hz). 13C NMR (100 MHz CDCl3):
d
(ppm)¼169.2, 164.5, 130.1,
4.3.13. (3S,4R,6R)-Ethyl 4-(4-bromophenyl)-6-hydroxy-1-methyl-2-
129.8, 129.7, 129.6, 129.5128.7, 128.5, 109.8, 62.5, 56.8, 50.1, 41.8,
oxopiperidine-3-carboxylate (3n). Colorless oil (58%). 1H NMR
14.8. ½a 2D5
þ8.2 (c 1.1, CH2Cl2, 90% ee). HRMS (ESI): calcd for
ꢂ
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.44 (d, J¼8.1 Hz, 2H), 7.10 (d,
[C21H21NO3Cl]þ: 370.1204, found: 370.1212. The enantiomeric ex-
J¼8.4 Hz, 2H), 5.00 (t, J¼3.3 Hz, 1H), 3.98e4.12 (m, 2H), 3.73e3.83
(m, 1H), 3.50 (d, J¼12 Hz, 1H), 3.05 (s, 3H), 2.14e2.17 (m, 2H), 1.11 (t,
cess (90%) was determined by HPLC with an IA column. (n-hexane/
i-PrOH¼90:10,
l
¼254 nm), 1.0 mL/min; tR¼minor enantiomer
J¼7.2 Hz, 3H). 13C NMR (300 MHz CDCl3, 25 ꢀC):
d
(ppm)¼169.99,
16.1 min, major enantiomer 18.21 min.
166.14, 139.75, 131.92, 131.51, 129.13, 128.76, 121.24, 80.68, 61.52,
56.58, 37.04, 36.57, 33.22, 13.82.
4.3.20. (3S,4R)-Ethyl 1-benzyl-4-(4-bromophenyl)-1,2,3,4-
tetrahydro-2-oxopyridine-3-carboxylate (4e). White solid. 1H NMR
4.3.14. (3S,4R,6R)-Ethyl 6-hydroxy-1-methyl-4-(4-nitrophenyl)-2-
(300 MHz, CDCl3, TMSint):
d
(ppm)¼7.41e7.27 (m, 7H), 7.05 (d,
oxopiperidine-3-carboxylate (3o). Pale yellow oil (95%). 1H NMR
J¼8.5 Hz, 2H), 6.20 (dd, J¼7.9,1.8 Hz,1H), 5.19 (dd, J¼7.9, 4.1 Hz,1H),
5.21e5.17 (dd, J¼7.9, 1.8 Hz 1H), 4.75 (m, 2H), 4.20e4.15 (m, 3H),
3.63 (d, J¼8.8 Hz, 1H), 1.20 (t, J¼7.3 Hz, 3H). 13C NMR (100 MHz
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼8.19 (d, J¼7.2 Hz, 2H), 7.42 (d,
J¼7.2 Hz, 2H), 5.05 (t, J¼2.7 Hz, 1H), 3.92e4.17 (m, 3H), 3.54 (d,
J¼12 Hz, 1H), 3.07 (s, 3H), 2.19e2.24 (m, 2H), 1.09 (t, J¼7.2 Hz, 3H).
CDCl3, TMSint):
d
(ppm)¼169.1, 164.6, 139.6, 136.6, 132.1, 129.6,
13C NMR (300 MHz CDCl3, 25 ꢀC):
d
(ppm)¼169.53, 165.62, 148.13,
129.4, 129.0, 128.3, 128.1, 121.5, 109.1, 61.9, 56.1, 49.5, 41.3, 14.3.
147.29, 128.10, 127.67, 124.13, 80.53, 61.71, 56.20, 36.98, 36.85,
33.29, 13.97.
HRMS (ESI): [MþH]þ C21H20BrNO3 calcd 414.0699, found:
414.0693. ½a 2D5
þ3.5, (c 0.92, CHCl3, 94% ee). The enantiomeric ex-
ꢂ
cess (94%) was determined by HPLC with an IA column. (n-hexane/
4.3.15. (3S,4R,6R)-Ethyl 6-hydroxy-1-(2-hydroxyethyl)-2-oxo-4-
i-PrOH¼90:10,
l
¼254 nm), 1.0 mL/min; tR¼minor enantiomer
phenylpiperidine-3-carboxylate (3s). Yellowish oil (73%). 1H NMR
15.2 min, major enantiomer 17.9 min.
(300 MHz, DMSO, 25 ꢀC):
d
(ppm)¼7.20e7.34 (m, 5H), 6.34 (d,
J¼4.5 Hz, 1H), 5.04 (br s, 1H), 4.95 (t, J¼4.5 Hz, 1H), 3.90 (q, J¼7.2 Hz,
2H), 3.57e3.73 (m, 2H), 3.52 (br s, 3H), 3.29e3.40 (m, 1H), 2.27 (dt,
J¼13.2, 3.3 Hz,1H),1.85 (br d, J¼13.2 Hz,1H), 0.93 (t, J¼6.9 Hz, 3H).13C
4.3.21. (3S,4R)-Ethyl 1-benzyl-4-(2-bromophenyl)-1,2,3,4-
tetrahydro-2-oxopyridine-3-carboxylate (4f). Colorless oil. 1H
NMR (300 MHz, CDCl3, TMSint):
d
(ppm)¼7.50 (dd, J¼7.0, 2.3 Hz,
NMR (300 MHz DMSO, 25 ꢀC):
d
(ppm)¼169.35,165.65,141.71,128.52,
1H), 7.31e7.23 (m, 5H), 7.09e6.99 (m, 2H), 6.94 (dd, J¼7.3,
2.3 Hz, 1H), 6.21 (d, J¼7.6 Hz, 1H), 6.20 (dd, J¼7.9, 1.8 Hz, 1H),
5.19 (dd, J¼7.6, 5.6 Hz, 1H), 4.78e4.62 (m, 1H), 4.54 (m, 1H), 4.16
(q, J¼7.0 Hz, 2H), 3.73 (d, J¼4.4 Hz, 1H), 1.18 (t, J¼7.0 Hz, 3H). 13C
127.16, 126.95, 78.68, 59.97, 58.58, 56.57, 54.49, 47.63, 36.78, 13.86.
4.3.16. (3S,4R,6R)-Ethyl 4-(4-bromophenyl)-6-hydroxy-1-(2-
hydroxyethyl)-2-oxopiperidine-3-carboxylate (3t). Colorless oil
NMR (100 MHz CDCl3, TMSint):
d
(ppm)¼168.6, 164.4, 137.9,
(44%). 1H NMR (300 MHz, DMSO, 25 ꢀC):
d
(ppm)¼7.50 (d, J¼8.4 Hz,
136.5, 133.6, 130.1, 129.0, 128.7, 128.5, 128.3, 127.9, 127.8, 124.2,
2H), 7.23 (d, J¼8.4 Hz, 2H), 6.35 (d, J¼4.5 Hz, 1H), 5.03 (br s, 1H),
4.94 (t, J¼4.8 Hz, 1H), 3.92 (q, J¼7.2 Hz, 2H), 3.62e3.72 (m, 2H),
3.46e3.56 (m, 3H), 3.29e3.36 (m, 1H), 2.26 (t, J¼12 Hz, 1H), 1.83 (d,
J¼13.5 Hz, 1H), 0.96 (t, J¼7.2 Hz, 3H). 13C NMR (300 MHz, DMSO,
107.8, 61.9, 53.8, 49.3, 40.6, 14.1. HRMS (ESI): [MþNa]þ calcd for
C21H20BrNO3 436.0518, found: 436.0521. ½a D25
þ4.5, (c 0.99,
ꢂ
CHCl3, 96% ee). The enantiomeric excess (96%) was determined
by HPLC with an IA column (n-hexane/i-PrOH¼80:20,
25 ꢀC):
d
(ppm)¼169.22, 165.39, 141.12, 131.43, 129.50, 120.03,
l
¼254 nm), 1.0 mL/min; tR¼major enantiomer 13.3 min, minor
78.59, 60.10, 58.56, 56.29, 47.61, 36.36, 13.88.
enantiomer 15.4 min.

ꢀ
ꢁ
S. Cíhalova et al. / Tetrahedron 67 (2011) 8942e8950
8949
4.3.22. (3S,4R)-Ethyl 1-benzyl-4-(4-fluorophenyl)-1,2,3,4-
tetrahydro-2-oxopyridine-3-carboxylate (4g). Colorless oil. 1H NMR
enantiomeric excess (94%) was determined by HPLC with an IC
column (n-heptane/i-PrOH¼80:20,
l
¼230 nm), 1.0 mL/min;
(400 MHz CDCl3, TMSint):
d
(ppm)¼7.36e7.10 (m, 9H), 6.19 (dd,
tR¼major enantiomer 27.33 min, minor enantiomer 39.2 min.
J¼7.9, 1.7 Hz, 1H), 5.20 (dd, J¼7.9, 4.1 Hz, 1H), 4.75 (m, 2H),
4.22e4.10 (m, 3H), 3.64 (d, J¼8.8 Hz, 1H), 1.19 (t, 3H, J¼7.1 Hz). 13C
4.3.27. (3S,4R)-Ethyl 4-(4-bromophenyl)-1,2,3,4-tetrahydro-1-
methyl-2-oxopyridine-3-carboxylate (4n). Pale yellow oil (86%). IR
(KBr): 2977, 1737, 1640, 1486, 1324, 1174, 1011, 820 cmꢁ1. 1H NMR
NMR (100 MHz CDCl3):
d
(ppm)¼169.2, 164.57, 160.1, 159.8, 137.2,
130.1, 128.4, 129.8, 129.7, 129.6, 129.5128.7, 128.5, 109.6, 62.6, 56.7,
50.0, 41.9, 14.7. 19F NMR (100 MHz CDCl3):
d
(ppm)¼ꢁ115.1. HRMS
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.43 (d, J¼8.7 Hz, 2H), 7.11 (d,
(ESI): Calcd for [C21H22FNO3]þ: 354.1500; found: 354.1498. ½a 2D5
ꢂ
J¼8.7 Hz, 2H), 6.16 (dd, J¼7.8, 2.1 Hz,1H), 5.16 (dd, J¼8.1, 3.9 Hz, 1H),
4.12e4.21 (m, 3H), 3.57 (d, J¼10.2 Hz, 1H), 3.14 (s, 3H), 1.19 (t,
þ12.2 (c 1.02, CHCl3, 90% ee). The enantiomeric excess (90%) was
determined by HPLC with an IA column (n-hexane/i-PrOH¼95:5,
J¼7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼169.0,
l
¼254 nm), 1.0 mL/min; tR¼major enantiomer 25.5 min, minor
164.7, 139.8, 132.0, 130.8, 129.2, 121.3, 108.6, 61.6, 55.9, 41.3, 34.1,
enantiomer 29.7 min.
14.1.
½
a 2D5
ꢂ
þ43.9 (c 0.29, CHCl3). HRMS (ESI): calcd for
[MþNa]þ(C15H16BrNO3) requires 360.0211, found 360.0204. The
enantiomeric excess (94%) was determined by HPLC with an IC
4.3.23. (3R,4S)-Ethyl 1,2,3,4-tetrahydro-1-methyl-2-oxo-4-
phenylpyridine-3-carboxylate (4j). Colorless oil (54%). IR (KBr):
2980,1739, 1661,1453, 1372,1154, 1031, 761, 700, 526 cmꢁ1. 1H NMR
column (n-heptane/i-PrOH¼80:20,
l
¼221 nm), 1.0 mL/min;
tR¼major enantiomer 28.4 min, minor enantiomer 40.18 min.
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.21e7.31 (m, 5H), 6.15 (dd,
J¼7.8, 2.1 Hz, 1H), 5.21 (dd, J¼7.8, 3.9 Hz, 1H), 4.08e4.22 (m, 3H),
4.3.28. (3S,4R)-Ethyl 1,2,3,4-tetrahydro-1-methyl-4-(4-nitrophenyl)-
3.62 (d, J¼10.2 Hz, 1H), 3.14 (s, 3H), 1.16 (t, J¼7.2 Hz, 3H). 13C NMR
2-oxopyridine-3-carboxylate (4o). Pale yellow oil (72%). IR (KBr):
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼169.2, 165.0, 140.7, 130.4, 128.8,
2978, 1736, 1657, 1518, 1348, 1250, 1034, 852, 699 cmꢁ1 1H NMR
.
a 25
127.4, 127.0, 109.2, 61.4, 56.0, 41.9, 34.0, 14.0. ½ ꢂD ꢁ20.0 (c 0.05,
CHCl3). HRMS (ESI): calcd for [MþNa]þ(C15H17NO3) requires
282.1106, found 282.1101. The enantiomeric excess (95%) was de-
termined by HPLC with an IC column (n-heptane/i-PrOH¼80:20,
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼8.18 (d, J¼9 Hz, 2H), 7.42 (d,
J¼9 Hz, 2H), 6.23 (dd, J¼7.5, 2.1 Hz, 1H), 5.17 (dd, J¼7.5, 3.3 Hz, 1H),
4.31e4.36 (m, 1H), 4.07e4.25 (m, 2H), 3.61 (d, J¼10.5 Hz, 1H), 3.16
(s, 3H), 1.19 (t, J¼7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3, 25 ꢀC):
l
¼254 nm), 1.0 mL/min; tR¼major enantiomer 32.2 min, minor
d
(ppm)¼168.6, 164.3, 148.1, 147.3, 131.5, 128.5, 124.1, 107.3, 61.8,
enantiomer 49.2 min.
55.4, 41.6, 34.1, 14.0. ½a D25
ꢁ69.1 (c 0.47, CHCl3). HRMS (ESI): calcd
ꢂ
for [MþNa]þ(C15H16N2O5) requires 327.0957, found 327.0950. The
enantiomeric excess (94%) was determined by HPLC with an IC
4.3.24. (3S,4R)-Ethyl
1,2,3,4-tetrahydro-1-methyl-2-oxo-4-p-tol-
ylpyridine-3-carboxylate (4k). Pale yellow oil (66%). IR (KBr): 2976,
1728, 1623, 14,920, 1326, 1154, 1027, 814, 634, 535 cmꢁ1 1H NMR
(300 MHz, CDCl3, 25 ꢀC):
column (n-heptane/i-PrOH¼80:20,
l
¼254 nm), 1.0 mL/min;
.
tR¼major enantiomer 79.1 min, minor enantiomer 98.7 min.
d
(ppm)¼7.11 (br s, 4H), 6.13 (dd, J¼8.1,
2.1 Hz, 1H), 5.20 (dd, J¼8.1, 3.9 Hz, 1H), 4.09e4.20 (m, 3H), 3.60 (d,
4.3.29. (3S,4R)-Ethyl 1-ethyl-1,2,3,4-tetrahydro-2-oxo-4-
phenylpyridine-3-carboxylate (4p). White solid (92%). IR (KBr):
2980,1712,1643,1420,1365,1176,1095, 840, 690, 533 cmꢁ1.1H NMR
J¼10.2 Hz, 1H), 3.13 (s, 3H), 2.31 (s, 3H), 1.18 (t, J¼7.5 Hz, 3H). 13C
NMR (300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼169.3, 165.0, 137.6, 137.0,
130.2, 129.5, 127.2, 109.5, 61.4, 56.0, 41.5, 34.0, 21.0, 14.0. ½a D25
ꢂ
þ29.4
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.22e7.32 (m, 5H), 6.19 (dd,
(c 0.55, CHCl3). HRMS (ESI): calcd for [MþNa]þ(C16H19NO3) requires
296.1263, found 296.1257. The enantiomeric excess (92%) was de-
termined by HPLC with an IC column (n-heptane/i-PrOH¼80:20,
J¼7.5, 1.8 Hz, 1H), 5.24 (dd, J¼7.5 Hz, 3.6 Hz, 1H), 4.12e4.21 (m, 3H),
3.51e3.72 (m, 3H), 1.15e1.24 (m, 6H). 13C NMR (300 MHz, CDCl3,
25 ꢀC):
d
(ppm)¼169.3, 164.3, 140.7, 129.1, 128.8, 127.4, 127.4, 109.3,
l
¼254 nm), 1.0 mL/min; tR¼major enantiomer 33.6 min, minor
61.4, 56.1, 41.7, 41.4,14.0,13.5 ½a D25
þ77.3 (c 0.06, CHCl3). HRMS (ESI):
ꢂ
enantiomer 56.7 min.
calcd for [MþNa]þ(C16H19NO3) requires m/z 274.1438, found
274.1437. The enantiomeric excess (89%) was determined by HPLC
4.3.25. (3S,4R)-Ethyl 4-(4-fluorophenyl)-1,2,3,4-tetrahydro-1-
methyl-2-oxopyridine-3-carboxylate (4l). Reddish oil (85%). IR
with an IC column (n-heptane/i-PrOH¼80:20, ¼254 nm), 1.0 mL/
l
min; tR¼major enantiomer 20.3 min, minor enantiomer 31.9 min.
(KBr): 2977, 1737, 1639, 1510, 1321, 1158, 1028, 817 cmꢁ1 1H NMR
.
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.13e7.21 (m, 2H), 6.94e7.01 (m,
4.3.30. (3R,4S)-Ethyl 1,2,3,4-tetrahydro-1-isopropyl-2-oxo-4-
2H), 6.14 (dd, J¼7.8, 2.1 Hz, 1H), 5.17 (dd, J¼7.8, 3.6 Hz, 1H),
phenylpyridine-3-carboxylate (4q). White solid (92%). IR (KBr):
4.02e4.22 (m, 3H), 3.56 (d, J¼10.2 Hz, 1H), 3.12 (s, 3H), 1.15 (t,
2978, 1740, 1660, 1403, 1369, 1147, 1045, 886, 702, 533 cmꢁ1 1H
.
J¼7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼169.0,
NMR (300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.22e7.33 (m, 5H), 6.29
164.8, 136.4, 130.5, 129.0, 128.9, 115.8, 115.5, 109.0, 61.4, 56.1, 41.1,
(dd, J¼8.1, 1.8 Hz, 1H), 5.30 (dd, J¼7.8, 4.2 Hz, 1H), 4.90 (sep,
J¼6.6 Hz, 1H), 4.07e4.22 (m, 3H), 3.61 (d, J¼9 Hz, 1H), 1.15e1.25 (m,
33.9, 14.0. ½a 2D5
þ5.4 (c 0.19, CHCl3). HRMS (ESI): calcd for
ꢂ
[MþNa]þ(C15H16FNO3) requires m/z 300.1012, found 300.1007. The
9H). 13C NMR (300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼169.4, 164.2, 140.6,
enantiomeric excess (69%) was determined by HPLC with an IC
128.8, 127.4, 127.3, 124.5, 109.6, 61.4, 56.5, 44.0, 41.2, 20.5, 20.5,
column (n-heptane/i-PrOH¼80:20,
l
¼190 nm), 1.0 mL/min;
14.0.
½
a 2D5
ꢂ
ꢁ190.8 (c 0.49, CHCl3). HRMS (ESI): calcd for
tR¼major enantiomer 42.5 min, minor enantiomer 47.6 min.
[MþNa]þ(C17H21NO3) requires m/z 310.1419, found 310.1413. the
enantiomeric excess (91%) was determined by HPLC with an IC
4.3.26. (3S, 4R)-Ethyl 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1-
column (n-heptane/i-PrOH¼80:20,
l
¼230 nm), 1.0 mL/min;
methyl-2-oxopyridine-3-carboxylate (4m). Pale yellow oil (80%). IR
tR¼major enantiomer 13.8 min, minor enantiomer 20.8 min.
(KBr): 2980, 1736, 1638, 1490, 1325, 1174, 1091, 823, 657, 533 cmꢁ1
.
1H NMR (300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.28 (d, J¼8.7 Hz, 2H),
4.3.31. (6S,7R,8aS)-Ethyl hexahydro-5-oxo-7-phenyl-2H-oxazolo
7.17 (d, J¼8.7 Hz, 2H), 6.16 (dd, J¼8.1, 2.1 Hz, 1H), 5.16 (dd, J¼7.8,
3.6 Hz, 1H), 4.06e4.21 (m, 3H), 3.57 (d, J¼10.2 Hz, 1H), 3.14 (s, 3H),
[3,2-a]pyridine-6-carboxylate (10a). White solid (95%). IR (KBr):
2960, 1730, 1627, 1487, 1334, 1174, 1061, 866, 758, 513 cmꢁ1. 1H NMR
1.18 (t, J¼7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.18e7.35 (m, 5H), 4.95 (dd,
169.0, 164.7, 139.2, 133.2, 130.7, 129.0, 128.8, 108.7, 61.6, 55.9, 41.2,
J¼9.9, 4.5 Hz, 1H), 4.18e4.26 (m, 1H), 4.08 (q, J¼9 Hz, 2H),
3.86e3.99 (m, 2H), 3.44e3.50 (m, 3H), 2.44e2.50 (m,1H),1.85e1.96
(m, 1H), 1.08 (t, J¼7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3, 25 ꢀC):
34.0, 14.0. ½a 2D5
þ46.3 (c 0.27, CHCl3). HRMS (ESI): calcd for
ꢂ
[MþNa]þ(C15H16ClNO3) requires 316.0716, found 316.0709. The

ꢀ
ꢁ
8950
S. Cíhalova et al. / Tetrahedron 67 (2011) 8942e8950
5. (a) Vicario, J. L.; Reboredo, S.; Badia, D.; Carrillo, L. Angew. Chem., Int. Ed. 2007,
46, 5168e5170; (b) Ibrahim, I.; Rios, R.; Vesely, J.; Cordova, A. Tetrahedron Lett.
2007, 48, 6252e6257.
d
(ppm)¼169.7,164.0,140.5, 129.0, 127.6, 126.9, 86.7, 65.0, 61.4, 56.8,
42.8, 39.8, 34.7, 14.0. ½a D25
ꢁ40 (c 0.1, CHCl3). HRMS (ESI): calcd for
ꢂ
[MþNa]þ(C16H19NO4) requires m/z 290.1387, found 290.1385. The
enantiomeric excess (98%) was determined by HPLC with an IA
6. (a) Crovetto, L.; Rios, R. Synlett 2008, 1840e1844; (b) Xue, M. X.; Zhang, X. M.;
Gong, L.-Z. Synlett 2008, 691e694; (c) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J.
Am. Chem. Soc. 2008, 130, 5652e5653; (d) Liu, Y. K.; Liu, H.; Du, W.; Yue, L.;
Chen, Y. C. Chem.dEur. J. 2008, 14, 9873e9877; (e) Xie, J.; Yoshida, K.; Takasu,
K.; Takemoto, Y. Tetrahedron Lett. 2008, 49, 6910e6913.
7. (a) Chen, X.-H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009,
131, 13819e13825; (b) Li, N.; Song, J.; Tu, X.-F.; Liu, B.; Chen, X.-H.; Gong, L.-Z.
Org. Biomol. Chem. 2010, 8, 2016e2019; (c) Yu, J.; He, L.; Chen, X.-H.; Song, J.;
Chen, W.-J.; Gong, L.-Z. Org. Lett. 2009, 11, 4946e4949; (d) Yu, J.; Chen, W.-J.;
Gong, L.-Z. Org. Lett. 2010, 12, 4050e4053.
column (n-heptane/i-PrOH¼80:20,
l¼198 nm), 1.0 mL/min;
tR¼major enantiomer 8.5 min, minor enantiomer 17.7 min.
4.3.32. (6S,7R,8aS)-Ethyl 7-(4-bromophenyl)-hexahydro-5-oxo-2H-
oxazolo[3,2-a]pyridine-6-carboxylate (10b). White solid (95%). IR
(KBr): 2975,1734,1638,1489,1313,1155, 988, 834, 681, 517 cmꢁ1. 1H
NMR (300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼7.45 (d, J¼8.4 Hz, 2H), 7.07
8. Rios, R.; Ibrahem, I.; Vesely, J.; Sunden, H.; Cordova, A. Tetrahedron Lett. 2007,
48, 8695e8699.
(d, J¼8.7 Hz, 2H), 4.93 (dd, J¼9.6, 4.2 Hz, 1H), 4.17e4.25 (m, 1H),
4.04e4.15 (m, 2H), 3.82e3.98 (m, 2H), 3.38e3.52 (m, 3H),
2.40e2.46 (m, 1H), 1.80e1.92 (m, 1H), 1.12 (t, J¼7.2 Hz, 3H). 13C NMR
9. (a) Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett, N. D.; Carter, R. G. J. Org.
Chem. 2008, 73, 5155e5158; (b) Fustero, S.; Moscardo, J.; Jimenez, D.; Peerez-
Carrion, M. D.; Sanchez-Rosesllo, M.; del Pozo, C. Chem.dEur. J. 2008, 14,
9868e9872; (c) Fustero, S.; Jimenez, D.; Moscardo, J.; Catalan, S.; del Pozo, C.
Org. Lett. 2007, 9, 5283e5286.
10. He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418e8420.
11. Sunden, H.; Ibrahem, I.; Eriksson, L.; Cordova, A. Angew. Chem., Int. Ed. 2005, 44,
4877e4880.
12. (a) Han, B.; Li, J.-L.; Ma, C.; Zhang, S.-J.; Chen, Y.-C. Angew. Chem., Int. Ed. 2008,
47, 9971e9974; (b) He, Z.-Q.; Han, B.; Li, R.; Wu, L.; Chen, Y.-C. Org. Biomol.
Chem. 2010, 8, 755e757; (c) Han, B.; He, Z.-Q.; Li, J.-L.; Li, R.; Jiang, K.; Liu, T.-Y.;
Chen, Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5474e5477.
13. (a) Liu, H.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L.-Z. Org. Lett. 2006, 8,
6023e6026; (b) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2006, 45,
4796e4798; (c) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128,
13070e13071; (d) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science
2010, 327, 986e990.
(300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼169.4, 163.6, 142.4, 139.6, 132.1,
128.6, 86.5, 65.0, 61.6, 56.6, 42.9, 39.2, 34.6, 14.0. ½a D25
ꢁ37.4 (c 0.46,
ꢂ
CHCl3). HRMS (ESI): calcd for [MþNa]þ(C16H18N2O4) requires m/z
390.0317, found 390.0311. The enantiomeric excess (90%) was de-
termined by HPLC with an IA column (n-heptane/i-PrOH¼80:20,
l
¼230 nm), 1.0 mL/min; tR¼major enantiomer 13.0 min, minor
enantiomer 24.0 min.
4.3.33. (6S,7R,8aS)-Ethyl
oxazolo[3,2-a]pyridine-6-carboxylate (10c). Yellowish solid (95%).
hexahydro-7-(4-nitrophenyl)-5-oxo-2H-
IR (KBr): 2981, 1734, 1639, 1520, 1354, 1188, 1054, 864, 756,
14. (a) Franzen, J.; Fisher, A. Angew. Chem., Int. Ed. 2009, 48, 787e790; (b) Zhang,
W.; Franzen, J. Adv. Synth. Catal. 2010, 352, 499e503.
15. Valero, G.; Schimer, J.; Cisarova, I.; Vesely, J.; Moyano, A.; Rios, R. Tetrahedron
616 cmꢁ1
.
1H NMR (300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼8.21 (d,
J¼8.7 Hz, 2H), 7.39 (d, J¼9 Hz, 2H), 4.96 (dd, J¼9.6, 4.2 Hz, 1H),
4.18e4.29 (m,1H), 4.04e4.17 (m, 2H), 3.84e4.02 (m, 2H), 3.54e3.68
(m, 1H), 3.44e3.51 (m, 2H), 2.45e2.51 (m, 1H), 1.87e1.99 (m, 1H),
Lett. 2009, 50, 1943e1946.
16. (a) Jin, Z.; Huang, H.; Li, W.; Luo, X.; Luang, X.; Ye, J. Adv. Synth. Catal. 2011, 353,
343e348; (b) Dai, X.; Wu, X.; Fang, H.; Nie, L.; Chen, J.; Deng, H.; Cao, W.; Zhao,
G. Tetrahedron 2011, 67, 3034e3040; (c) Jin, Z.; Yu, F.; Wang, X.; Huang, H.; Lao,
X.; Liang, X.; Ye, J. Org. Biomol. Chem. 2011, 9, 1809e1816.
1.12 (t, J¼7.2 Hz, 3H). 13C NMR (300 MHz, CDCl3, 25 ꢀC):
d
(ppm)¼
169.1, 163.0, 147.8, 128.4, 128.0, 124.3, 86.3, 65.1, 61.8, 56.1, 42.9,
17. For some example of our previous experience in organocatalysis see: (a) Valero,
39.5, 34.3, 14.0. ½a D25
ꢁ10 (c 0.05, CHCl3). HRMS (ESI): calcd for
ꢂ
G.; Balaguer, A.-N.; Moyano, A.; Rios, R. Tetrahedron Lett. 2008, 49, 6559e6562;
[MþNa]þ(C16H18N2O6) requires m/z 357.1063, found 357.1056.
ꢁ
(b) Companyo, X.; Valero, G.; Crovetto, L.; Moyano, A.; Rios, R. Chem.dEur. J.
ꢁ
ꢁ
2009, 15, 6564e6568; (c) Companyo, X.; Hejnova, M.; Kamlar, M.; Vesely, J.;
The enantiomeric excess (95%) was determined by HPLC with an
ꢁ
Moyano, A.; Rios, R. Tetrahedron Lett. 2009, 50, 5021e5024; (d) Companyo, X.;
Balaguer, A.-N.; Cardenas, F.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2009,
3075e3080; (e) Alba, A.-N. R.; Companyo, X.; Moyano, A.; Rios, R. Chem.dEur. J.
2009, 15, 11095e11099; (f) Alba, A.-N. R.; Companyo, X.; Moyano, A.; Rios, R.
IB column (n-heptane/i-PrOH¼80:20,
l¼254 nm), 1.0 mL/min;
ꢁ
ꢁ
tR¼major enantiomer 43.9 min, minor enantiomer 64.8 min.
ꢁ
ꢁ
Chem.dEur. J. 2009, 15, 7035e7038; (g) Alba, A.-N. R.; Companyo, X.; Valero, G.;
Acknowledgements
Moyano, A.; Rios, R. Chem.dEur. J. 2010, 16, 5354e5361; (h) Balaguer, A.-N.;
ꢁ
Companyo, X.; Calvet, T.; Font-Bardía, M.; Moyano, A.; Rios, R. Eur. J. Org. Chem.
ꢁ
2009, 199e203; (i) Alba, A.-N. R.; Companyo, X.; Rios, R. Chem. Soc. Rev. 2010, 39,
J.V. gratefully acknowledges the Grant Agency of Czech Republic
(GACR 203/09/P193) and Ministry of Education, Youth and Sport
(No. MSM0021620857), R.R. and A.M. thank to Spanish Ministry of
Science and Innovation (MICINN) for financial support (Project
AYA2009-13920-C02-02). G.V. is also grateful to MICINN for his
ꢁ
2018e2033; (j) Valero, G.; Alba, A.-N. R.; Companyo, X.; Bravo, N.; Moyano, A.;
Rios, R. Synlett 2010, 1883e1908; (k) Alba, A.-N. R.; Valero, G.; Calvet, T.; Font-
Bardia, M.; Moyano, A.; Rios, R. Chem.dEur. J. 2010, 16, 9884e9889; (l) El-
ꢁ
Hamdouni, N.; Companyo, X.; Rios, R.; Moyano, A. Chem.dEur. J. 2010, 16,
ꢁ
1142e1148; (m) Companyo, X.; Zea, A.; Alba, A.-N. R.; Mazzanti, A.; Moyano, A.;
Rios, R. Chem. Commun. 2010, 6953e6955; (n) Alba, A.-N. R.; Zea, A.; Valero, G.;
Calbet, T.; Font-Bardia, M.; Mazzanti, A.; Moyano, A.; Rios, R. Eur. J. Org. Chem.
2011, 1318e1324.
ꢀ
ꢁ
pre-doctoral fellowship. J.V. also thanks to Dr. Císarova for X-ray
studies.
18. Crystallographic data for structural analysis have been deposited with the
Cambridge Crystallographic Data Centre, CCDC No 719613.
References and notes
19. For an excellent review of syntheses of paroxetine: (a) De Risi, C.; Fanton, G.;
Pollini, G. P.; Trapella, C.; Zanirato, V. Tetrahedron: Asymmetry 2008, 19,
131e155; (b) For recent synthesis of paroxetine: Nemoto, T.; Sakamoto, T.;
Fukuyama, T.; Hamada, Y. Tetrahedron Lett. 2007, 48, 4977e4981; (c) Yamada, S.;
Jahan, I. Tetrahedron Lett. 2005, 46, 8673e8676; (d) Hynes, P. S.; Stupple, P. A.;
Dixon, D. J. Org. Lett. 2008, 10, 1389e1391; (e) Pastre, J. C.; Correia, C. R. D. Org.
Lett. 2006, 8, 1657e1660; (f) Buchanan, J. G.; Sable, H. Z. In Selective Organic
Transformations; Thyagarajan, B. S., Ed.; Wiley-Interscience: New York, NY,
1972; Vol. 2, pp 1e95.
1. For reviews in organocatalysis see: (a) Marques-Lopez, E.; Herrera, R. P.;
Christmann, M. Nat. Prod. Rep. 2010, 27, 1138e1167; (b) MacMillan, D. W. C.
Nature 2008, 455, 304e308; (c) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta
2006, 39, 79e87; (d) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Ber-
telsen, S.; Jorgensen, K. A. Chem. Commun. 2011, 632e647.
2. For recent reviews in organocatalytic cascade and domino reactions see: (a)
Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167e178; (b) Alba, A.-N.
R.; Companyo, X.; Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13, 1432e1474; (c)
Moyano, A.; Rios, R. Chem. Rev. 2011, 111, 4703e4832.
20. Brandau, S.; Landa, A.; Franzen, J.; Marigo, M.; Jorgensen, K. A. Angew. Chem.,
Int. Ed. 2006, 45, 4305e4309.
21. Crystallographic data for structural analysis have been deposited with the
Cambridge Crystallographic Data Centre, CCDC No 831873.
22. (a) Lyle, F. R. U.S. Patent 5, 973, 257, 1985; Chem. Abstr. 1985, 65, 2870; (b)
Lassen, J. B.; Christensen, J. A.; Petersen, E. N.; Hansen, J. B. U.S. Patent 4,
593,036, 1986.
3. For two excellent papers on the concept of atom economy see: (a) Trost, B. M.
Science 1991, 254, 1471e1477; (b) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995,
34, 259e281.
4. For reviews in the organocatalytic synthesis of pyrrolidines and piperidines see:
ꢁ
(a) Companyo, X.; Alba, A. N. R.; Rios, R. Targets Heterocycl. Syst. 2009,13,147e174.