A general and enantiodivergent method for the asymmetric synthesis of piperidine alkaloids: concise synthesis of (R)-pipecoline, (S)-coniine and other 2-alkylpiperidines

Article abstract of DOI:10.1016/j.tet.2007.08.067

A simple and very efficient protocol for the preparation of highly enantioenriched 2-alkylpiperidines has been set up, which allows the preparation of the final heterocycles with any wanted configuration at the stereogenic center starting from the same starting material. The key step of the synthesis relies on a diastereodivergent aza-Michael reaction protocol using the readily available and cheap reagent (+)-(S,S)-pseudoephedrine as chiral auxiliary.

Full text of DOI:10.1016/j.tet.2007.08.067

Tetrahedron 63 (2007) 11421–11428
A general and enantiodivergent method for the asymmetric
synthesis of piperidine alkaloids: concise synthesis of (R)-
pipecoline, (S)-coniine and other 2-alkylpiperidines
*
Juan Etxebarria, Jose L. Vicario, Dolores Badıa and Luisa Carrillo
ꢀ
Departamento de Quꢀımica Orgaꢀnica II, Facultad de Ciencia y Tecnologꢀıa, Universidad del Paꢀıs Vasco/Euskal Herriko Unibertsitatea,
PO Box 644, E-48080, Bilbao, Spain
Received 18 July 2007; revised 13 August 2007; accepted 21 August 2007
Available online 25 August 2007
Abstract—A simple and very efficient protocol for the preparation of highly enantioenriched 2-alkylpiperidines has been set up, which allows
the preparation of the final heterocycles with any wanted configuration at the stereogenic center starting from the same starting material. The
key step of the synthesis relies on a diastereodivergent aza-Michael reaction protocol using the readily available and cheap reagent (+)-(S,S)-
pseudoephedrine as chiral auxiliary.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
heterocycle moiety varies across the different members of
this family of compounds. In this context, when planning the
asymmetric synthesis of any member of this family using
many of the already reported procedures, a careful election
of the chiral starting material, auxiliary, ligand or catalyst
employed in the generation of this stereocenter is necessary
in order to prepare the final compound with the right configu-
ration. This means that if one wants to employ a general and
modular route for the synthesis of a wide number of 2-alkylpi-
peridines both enantiomers of this chiral starting material,
auxiliary, ligandorcatalysthave tobecommerciallyavailable.
The piperidine ring is an ubiquitous structural feature shared
by many natural products and therapeutics. As a conse-
quence, the development of short, versatile, and efficient
procedures for their stereocontrolled preparation represents
a very important field of research for the organic chemists.1
In particular, simple 2-alkyl substituted piperidines play an
important role as key targets for the pharmaceutical industry
because they exhibit an extensive range of biological activ-
ities. For example, pipecoline and coniine (Fig. 1) are alka-
loids found as constituents of the poisonous hemlock
(Conium Maculatum L.) and have been considered as excel-
lent targets for the demonstration of the performance
achieved by the new methodologies developed for the asym-
metric synthesis of piperidines.
As a consequence, the design of enantiodivergent protocols,
which allows the stereoselective preparation of a chiral com-
pound in any wanted configuration using the same chirality
source is a challenging task for the synthetic organic chem-
ist. In this context, we have recently shown that the cheap
and commercially available chiral aminoalcohol (+)-(S,S)-
pseudoephedrine can play the role as an excellent chiral
auxiliary in asymmetric aza-Michael reactions.2 More inter-
estingly, a simple modification of its structure, such as the
derivatization of the OH group as a bulky trialkylsilyl ether,
leads to the formation of the corresponding aza-Michael
adduct with the opposite configuration at the newly created
stereogenic center, if compared with the same reaction using
the unmodified chiral auxiliary, therefore presenting a stereo-
divergent protocol for the asymmetric synthesis of b-amino
carbonyl compounds (Scheme 1).3
As it can be seen in the two examples shown in Figure 1, it is
very often found in naturally occuring 2-alkylpiperidines that
the configuration of the stereogenic center present at the
N
H
N
H
(R)-Pipecoline
(S)-Coniine
Figure 1. The structure of two relevant 2-alkylpiperidine alkaloids.
Here we report the efforts made in order to synthesize chiral
enantioenriched 2-alkylpiperidines by the transformation of
* Corresponding author. Tel.: +34 94 601 2633; fax: +34 94 601 2748;
e-mail: dolores.badia@ehu.es
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.067

11422
J. Etxebarria et al. / Tetrahedron 63 (2007) 11421–11428
Bn
R
Bn
2. Results and discussion
O
N
O
Bn2NLi
Ph
OH
Ph
R
N
2.1. Synthesis of (R)-2-alkylpiperidines5
N
OH
Yield: 60-85%
We started our investigations with the preparation of enan-
tioenriched chiral g-amino alcohols 4a–d starting from the
corresponding (S,S)-(+)-pseudoephedrine derived enamides
1a–d has been previously described by us (Scheme 3).3
The employed protocol involved an aza-Michael reaction
with lithium dibenzylamide as key step regarding the stereo-
controlled installation of the stereogenic center. In this case,
different experimental conditions had to be used depending
upon the nature of the R alkyl chain introduced at the enam-
ide precursor in order to reach to the highest possible yield
and diastereoselectivity (Table 1). Next, we needed to carry
out a protecting-group interconversion at the adducts 2a–d
in order to proceed to the removal of the chiral auxiliary
by reduction, yielding cleanly the required g-amino alcohols
4a–d. We have already demonstrated that this protecting-
group interconversion strategy was absolutely necessary in
order to avoid epimerization at the stereogenic center during
this reduction process.
de: 60->99%
TBSOTf
O
Bn
R
Bn
N
O
1) Bn2NLi
2) TBAF
Ph
OTBS
R
N
Ph
N
OH
R=Me; Yield: 80%
de: 82%
Scheme 1. Stereodivergent aza-Michael reaction using (S,S)-(+)-pseudo-
ephedrine as chiral auxiliary.
the corresponding N-protected-b-amino amides derived
from (+)-(S,S)-pseudoephedrine and prepared using our
recently reported aza-Michael reaction protocol, following
the retrosynthetic approach shown in Scheme 2.4 The dis-
connection of the C6–N bond of the piperidine ring would
lead to a d-amino aldehyde structure, which could be ob-
tained by a chain-elongation process from the corresponding,
conveniently protected b-aminoaldehyde. This could be
hypothetically prepared directly from a chiral nonracemic
g-amino alcohol, the latter being easily accessible from the
already mentioned aza-Michael b-amino amide adducts.
This strategy will allow us to synthesize two naturally occur-
ring piperidine alkaloids such as (R)-pipecoline and
(S)-coniine and other nonnatural derivatives. The preparation
of these two natural alkaloids with opposite configuration will
be approached in terms of the stereodivergent procedure
showninScheme1andalreadyoptimizedinourlaboratories.3
O
Bn2N
R
O
Bn2NLi
Ph
OH
Ph
OH
R
N
N
Method
A or B
1a-d
2a-d
1) H2, Pd/C
2) (Cbz)2O
Cbz
Cbz
R
NH
O
NH
LiBH3NH2
THF, 0 °C
Ph
OH
R
N
OH
4a-d
3a-d
Scheme 3. Asymmetric synthesis of g-amino alcohols 4a–d.
We next proceeded to carry out the oxidation of g-amino al-
cohols 4a–d under standard Swern-type conditions, isolating
the corresponding b-amino aldehydes 5a–d in good yields
(Scheme 4, Table 2). This oxidation step proceeded in an ex-
tremely clean and smooth way, rendering directly the target
compounds almost pure after work-up, which allowed us to
use these b-amino aldehydes in the following transformation
with no need of further purification. Nevertheless, as we also
found that aldehydes 5a–d showed an unexpected stability
we proceeded to purify them by flash chromatography for
better characterization process. The subsequent chain-
elongation strategy was performed by a Wittig reaction
GP
R
GP
R
NH
*
NH
*
HN
O
O
R
*
Bn
R
Bn
O
N
*
O
Ph
OH
Ph
OH
R
N
N
Scheme 2. Retrosynthetic plan for the enantiodivergent synthesis of 2-alkyl-
piperidines.
Table 1. Asymmetric synthesis of g-amino alcohols 4a–d
Entry
R
Prod.
Conditionsa
Yieldb
%
drc
Prod.
Yieldb (%)
Prod.
Yieldb (%)
eed (%)
1
2
3
4
Me
Et
t-Bu
Ph
2a
2b
2c
2d
A
B
C
A
85
88
50
15
>99:1
94:6
>99:1
98:2
3a
3b
3c
3d
70
75
64
43
4a
4b
4c
4d
85
76
72
90e
98
88
98
98
a
Method A: Bn2NLi, toluene, ꢀ90 ꢁC. Method B: Bn2NLi/TMEDA (1:1), toluene, ꢀ90 ꢁC. Method C: Bn2NLi/CuI/TMEDA (2:1:2), THF, ꢀ90 ꢁC.
Yield of pure product after flash column chromatography purification.
Determined by HPLC (Chiracel OD column, UV detector, hexanes/iso-propanol 95:5, flow rate: 1.00 mL/min).
Determined by HPLC (Chiracel OJ column, UV detector, hexanes/iso-propanol 99:1, flow rate: 1.00 mL/min).
Based on recovered 3d.
b
c
d
e

J. Etxebarria et al. / Tetrahedron 63 (2007) 11421–11428
11423
with a suitable and commercially available phosphorous
ylide reagent such as 6, which allowed us to obtain the cor-
responding conjugated d-amino aldehydes 7a–d in moderate
to good yields after flash column chromatography purifica-
tion (Scheme 4, Table 2). The Wittig olefination proceeded
with very high diastereoselectivity providing the expected
E isomers in very high purity (1H NMR analysis).
presenting opposite configuration at the newly created ste-
reogenic center (Scheme 1). With this precedent in mind en-
amide 1e, in which an n-Pr substituent was conveniently
placed at the b-carbon of the conjugate acceptor was chosen
as an appropriate precursor to the target alkaloid (S)-coniine.
The preparation of substrate 9 was carried out by standard
O-silylation of the corresponding (S,S)-pseudoephedrine
enamide 1e with TBSOTf (Scheme 5). The aza-Michael re-
action of lithium dibenzylamide with enamide 9 yielded the
corresponding b-amino amide 20e after removal of the TBS
group by treatment of the crude reaction mixture with TBAF.
HPLC analysis showed that the obtained major diastereomer
corresponded to 20e with the opposite configuration at C3
with respect to that found in adducts 2a–d, which was in
good agreement with our previously reported diastereodiver-
gent approach. Fortunately, and despite the moderate dia-
stereoselectivity obtained in this aza-Michael reaction,
compound 20e could be isolated in 98% de by flash column
Cbz
R
Cbz
R
DMSO, (COCl)2
Et3N,
NH
NH
O
OH
H
CH2Cl2, -60 °C
4a-d
5a-d
Ph3P=CHCHO
6
CH2Cl2, 70 °C
-
Cl
+
1) H2, Pd/C
EtOH, r.t.
Cbz
H2N
NH
O
H
2) HCl
R
R
TBSOTf,
O
O
8a-d
7a-d
2,6-lutidine
Ph
OH
Ph
nPr
N
nPr
N
Scheme 4. Asymmetric synthesis of (R)-2-alkylpiperidines 8a–d.
THF, r.t.
68%
OTBS
1e
9
1) Bn2NLi,
toluene, -90 ºC
Table 2. Asymmetric synthesis of 2-alkylpiperidine hydrochlorides 8a–d
Entry
R
Prod. Yielda (%) Prod. Yielda (%) Prod. Yield (%)
2) TBAF, THF, r.t.
1
2
3
4
Me 5a
Et 5b
t-Bu 5c
Ph 5d
79
62
66
77
7a
7b
7c
7d
71
56
37
84
8a
8b
8c
8d
84
78
99
91
Bn2N
O
Ph
nPr
N
OH
2'e
a
Yield of pure product after flash column chromatography purification.
d.r.: 61:39
99:1 after cromat.
Yield: 55%
Indeed, these d-amino aldehydes 7a–d represent very suit-
able precursors of the desired piperidinic structures via a cas-
cade process involving hydrogenation of the C]C double
bond, followed by removal of the N-Cbz protecting group
and a final intramolecular reductive amination step.6 There-
fore, derivatives 7a–d were treated with H2 in the presence
of 10% Pd/C, yielding cleanly the final heterocycles in ex-
cellent yield. In order to easily handle these compounds, in
particular those of high volatility, the crude reaction mixture
was treated with concentrated HCl and hence, the corre-
sponding piperidine hydrochlorides 8a–d were isolated after
crystallization (Scheme 4).
Scheme 5.
Cbz
nPr
1) H2, Pd/C
2) (Cbz)2O
Bn2N
nPr
O
NH
O
Ph
OH
Ph
OH
N
N
72%
2'e
3'e
LiBH3NH2
THF, 0 ºC
61%
It has to be mentioned that hydrochloride 8a, a derivative of
the naturally occurring alkaloid (R)-pipecoline, was ob-
tained in a 47% overall yield from the corresponding alcohol
4a and in 29% yield from the corresponding aza-Michael
adduct 2a. The recorded data for the specific rotation value
of compound 7a matched with the reported data for natural
(R)-pipecolinehydrochloride7 andthesameappliestotheother
nonnatural piperidines prepared by this synthetic pathway.8
Cbz
DMSO, (COCl)2
Et3N
Cbz
nPr
NH
O
NH
nPr
H
CH2Cl2, -60 ºC
65%
OH
ent-5e
ent-4e
e.e.: 98%
Ph3P=CHCHO
6
68%
CH2Cl2, 70 ºC
-
Cl
+
Cbz
NH
1) H2, Pd/C
EtOH, r.t.
2.2. Synthesis of (S)-coniine
O
H2N
nPr
nPr
H
2) HCl
93%
As it was previously mentioned, the aza-Michael reaction of
lithium dibenzylamide with O-TBS-protected enamides de-
rived from (+)-(S,S)-pseudoephedrine has been exploited in
our group for the preparation of b-amino amide adducts
ent-7e
ent-8e
(S)-Coniine
Scheme 6. Asymmetric synthesis of (S)-coniine.

11424
J. Etxebarria et al. / Tetrahedron 63 (2007) 11421–11428
chromatography affording the necessary diastereomerically
enriched material required in order to synthesize the desired
piperidine alkaloid.
0.46ꢂ25 cm). The synthesis of alcohols 4a–d was described
previously.
4.2. Synthesis of (R)-2-alkylpiperidines
Next, debenzylation followed by treatment with dibenzyldi-
carbonate afforded the N-protected b-amino amide 30e in
good yield and with no isomerization at C3 (Scheme 6). The
LAB-mediated reduction of 30e led to the corresponding g-
amino alcohol ent-4e in good yield and with no loss of optical
purity as confirmed by chiral HPLC. Subsequently, and
following the strategy described before, alcohol ent-4e was
oxidized to the corresponding b-amino aldehyde ent-5e,
which was transformed into the corresponding a,b-unsatu-
rated d-amino aldehyde ent-7e after Wittig reaction with com-
mercially available stabilized ylide 6. The hydrogenation/
deprotection/reductive amination sequence took place
smoothly furnishing (S)-coniine hydrochloride ent-8e after
acidic treatment. The obtained specific rotation value for a
sample of ent-8e matched with that reported in the literature.9
4.2.1. General procedure for the Swern oxidation of the
g-amino alcohols 4a–d. A solution of DMSO (5.20 mmol)
in dry CH2Cl2 (2 mL) was added dropwise over a solution
of oxalyl chloride (2.60 mmol) in CH2Cl2 at ꢀ60 ꢁC and
the mixture was stirred for 15 min at this temperature.
Then, a solution of the corresponding alcohol 4a–d
(1.30 mmol) in CH2Cl2 was added via cannula over the mix-
ture at ꢀ60 ꢁC and the reaction mixture was stirred for
30 min. Then Et3N (13.00 mmol) was added to the mixture
at ꢀ60 ꢁC and the reaction mixture was stirred for 15 min
at ꢀ60 ꢁC and for 30 min at rt. The reaction was then
quenched with water (20 mL). The mixture was extracted
with CH2Cl2 (3ꢂ15 mL), and the combined organic fractions
were collected, dried over Na2SO4, and filtered. The solvent
removed invacuo, affording the desired aldehydes 5a–d after
column chromatography purification (hexanes/AcOEt 8:2).
3. Conclusions
4.2.1.1. (D)-(3R)-3-Benzyloxycarbonylaminobutanal
(5a). This compound was obtained following the general
method from alcohol 4a (0.30 g, 1.34 mmol), DMSO
(0.58 mL, 5.36 mmol), oxalyl chloride (0.34 mL,
2.68 mmol), and Et3N (1.40 mL, 13.40 mmol) in 79% yield
(0.23 g, 1.06 mmol). Data for 5a: yellowish solid; mp: 75–
77 ꢁC; [a]D20 +16.9 (c 0.7, CH2Cl2); IR (film): 3324, 1700;
1H NMR (250 MHz, CDCl3): d 1.19 (d, J¼6.8 Hz, 3H),
2.55 (m, 2H), 4.16 (m, 1H), 5.04 (s, 2H), 5.15 (m, 1H),
7.30 (m, 5H), 9.68 (s, 1H); 13C NMR (50 MHz): d 20.7,
42.7, 50.0, 66.6, 128.0, 128.1, 128.4, 136.3, 155.5, 200.8;
MS (EI): m/z 206 (4), 137 (9), 122 (5), 108 (3), 91 (100),
87 (3), 72 (13), 65 (3), 56 (43).
To sum up, we have shown that our recently reported proto-
col for carrying out stereodivergent aza-Michael reactions
using (+)-(S,S)-pseudoephedrine as chiral auxiliary can be
a very reliable tool for the asymmetric synthesis of valuable
chiral compounds such as 2-alkylpiperidines, including
naturally occurring (R)-pipecoline and (S)-coniine. The
synthetic route presented herein is very straightforward,
employs simple transformations and furnishes the final
heterocycles in very high optical purity. The most remark-
able feature of this methodology is that the final compounds
can be obtained with any desired configuration at their
stereogenic center using in all cases the same chirality
source for exerting the desired high degree of stereocontrol,
with no need for the availability of both enantiomeric forms
of the chiral auxiliary employed.
4.2.1.2. (D)-(3R)-3-Benzyloxycarbonylaminopentanal
(5b). This compound was obtained following the general
method from alcohol 4b (0.27 g, 1.14 mmol), DMSO
(0.49 mL, 4.56 mmol), oxalyl chloride (0.29 mL,
2.28 mmol), and Et3N (1.20 mL, 11.40 mmol) in 62% yield
(0.17 g, 0.71 mmol). Data for 5b: colorless oil; [a]2D0 +23.4
4. Experimental section
4.1. General
1
(c 0.2, CH2Cl2); IR (film): 3333, 1717, 1700; H NMR
(250 MHz, CDCl3): d 0.91 (t, J¼7.5 Hz, 3H), 1.54 (m,
2H), 2.55 (m, 2H), 3.99 (m, 1H), 5.05 (s, 2H), 5.25 (m,
1H), 7.31 (m, 5H), 9.69 (s, 1H); 13C NMR (50 MHz):
d 12.2, 27.6, 48.2, 48.5, 66.6, 127.6, 127.8, 128.3, 136.2,
155.8, 201.1; MS (EI): m/z 206 (2), 137 (7), 122 (4), 101
(6), 91 (100), 79 (7), 65 (32), 57 (36).
1H NMR and 13C NMR spectra were acquired in a Bruker
AC-250 and AV-500. THF and toluene were distilled from
sodium/benzophenone and CH2Cl2 from CaH2. Melting
points were measured using a Gallenkamp apparatus in
open capillary tubes. Optical rotations were recorded in cells
with 10 cm path length on a Perkin–Elmer 241 MC polarim-
eter. Flash column chromatography was performed using sil-
ica gel Merck-60, 230–400 mesh ATMS or 70–230 mesh
ATMS. IR spectra were recorded in a Perkin–Elmer
R-1600 FTIR and Mattson Satellite FTIR. The MS spectra
were measured on electronic ionization conditions in a Hew-
lett Packard 5989B spectrometer. GC–MS analyses were
performed in a Hewlett Packard 5890II spectrometer using
a Hp-5 (5% phenylmethylpolysiloxane, 30 mꢂ0.25 mmꢂ
0.25 mm) column. Enantiomeric and diastereomeric ex-
cesses were measured by HPLC in a Waters 600A chromato-
graph using a photodiode array UV detector and a chiral
stationary phase (Chiralcel OJ and Chiralcel OD columns,
4.2.1.3. (D)-(3S)-3-Benzyloxycarbonylamino-4,4-di-
methylpentanal (5c). This compound was obtained follow-
ing the general method from alcohol 4c (0.21 g, 0.79 mmol),
DMSO (0.34 mL, 3.16 mmol), oxalyl chloride (0.20 mL,
1.58 mmol), and Et3N (0.80 mL, 7.90 mmol) in 66% yield
(0.14 g, 0.52 mmol). Data for 5c: colorless oil; [a]2D0 +45.2
(c 0.6, CH2Cl2); IR (film): 3326, 1708; 1H NMR
(250 MHz, CDCl3): d 0.85 (s, 9H), 2.26 (m, 1H), 2.55 (m,
1H), 4.03 (m, 1H), 5.02 (m, 2H), 5.24 (m, 1H), 7.26 (m,
5H), 9.64* (s, 1H), 9.65 (s, 1H); 13C NMR (50 MHz):
d 25.9, 34.4, 44.6, 54.5, 66.4, 127.6, 127.8, 128.2, 136.2,
156.0, 201.5; MS (EI): m/z 221 (6), 178 (8), 132 (2), 108
(17), 91 (100), 79 (16), 65 (8), 57 (32).

J. Etxebarria et al. / Tetrahedron 63 (2007) 11421–11428
11425
4.2.1.4. (L)-(3S)-3-Benzyloxycarbonylamino-3-phe-
nylpropanal (5d). This compound was obtained following
the general method from alcohol 4d (0.21 g, 0.74 mmol),
DMSO (0.32 mL, 2.96 mmol), oxalyl chloride (0.19 mL,
1.48 mmol), and Et3N (0.75 mL, 7.40 mmol) in 77% yield
(0.16 g, 0.57 mmol). Data for 5d: colorless oil; [a]2D0 ꢀ7.5
(c 0.4, CH2Cl2); IR (film): 3326, 1702; 1H NMR
(250 MHz, CDCl3): d 2.93 (m, 2H), 5.06 (m, 2H), 5.26 (m,
1H), 5.55 (m, 1H), 7.27 (m, 10H), 9.71 (s, 1H); 13C NMR
(50 MHz): d 49.4, 50.4, 66.9, 126.2, 127.8, 128.0, 128.1,
128.5, 136.1, 140.5, 155.6, 200.0; MS (EI): m/z 193 (2),
149 (7), 137 (8), 134 (10), 122 (4), 108 (25), 91 (100), 65
(21), 57 (32).
1H), 6.13* (d, J¼7.9 Hz, 1H), 6.78 (m, 1H), 7.31 (m, 5H),
9.39* (s, 1H), 9.42* (s, 1H); 13C NMR (50 MHz): d 26.2,
34.3, 34.7, 58.9, 66.7, 127.9, 128.1, 130.4, 130.5, 134.6,
136.4, 155.6*, 156.4*, 193.8; MS (EI): m/z 179 (3), 136
(5), 108 (100), 105 (64), 91 (20), 81 (25), 58 (42).
4.2.2.4. (5S,2E)-5-Benzyloxycarbonylamino-5-phenyl-
pent-2-enal (7d). This compound was obtained following
the general method from aldehyde 5d (0.10 g, 0.35 mmol)
and triphenylphosphoranylidenacetaldehyde
6 (0.58 g,
1.75 mmol) in 84% yield (91 mg, 0.29 mmol). Data for
7d: colorless oil; IR (film): 3313, 1710; 1H NMR
(250 MHz, CDCl3): d 2.88 (m, 2H), 5.03 (d, J¼11.9 Hz,
1H), 5.12 (d, J¼11.9 Hz, 2H), 5.29 (d, J¼6.7 Hz, 1H),
6.12 (dd, J¼15.4, 7.5 Hz, 1H), 6.68 (m, 1H), 7.28 (m,
10H), 9.40 (d, J¼7.5 Hz, 1H); 13C NMR (50 MHz):
d 39.5, 54.1, 67.0, 126.2, 128.0, 128.1, 128.2, 128.5,
128.9, 135.1, 136.1, 153.0, 193.6; MS (EI): m/z 175 (34),
108 (100), 105 (25), 98 (37), 91 (23), 79 (11), 65 (20), 51 (6).
4.2.2. General procedure for the Wittig reaction of alde-
hydes 5a–d with ylide 6. Triphenylphosphoranylidenacet-
aldehyde 6 (2.45 mmol) was added to a solution of the
corresponding aldehyde 5a–d (0.50 mmol) in CH2Cl2
(20 mL) and the mixture was stirred at reflux for 15 h.
Then, the reaction was cooled to rt and quenched with satu-
rated NH4Cl (20 mL). The mixture was extracted with
CH2Cl2 (3ꢂ15 mL), and the combined organic fractions
were collected, dried over Na2SO4, and filtered. The solvent
was removed in vacuo, affording the desired aldehydes 7a–
d after flash column chromatography purification (hexanes/
AcOEt 7:3).
4.2.3. General procedure for the cascade hydrogenation/
deprotection/intramolecular reductive amination se-
quence: synthesis of piperidines 8a–d. A catalytic amount
of Pd/C (10 mol %) was added to a solution of the corre-
sponding aldehyde 7a–d (0.30 mmol) in EtOH (20 mL)
and the mixture was stirred under a 65 psi pressure of H2
for 15 h at rt. Then, the mixture was filtered and concentrated
HCl (0.1 mL) was added to the solution and the mixture was
stirred at rt for 1 h after which the solvent was removed in
vacuo obtaining the corresponding 2-alkylpiperidine hydro-
chlorides 8a–d.
4.2.2.1. (5R,2E)-5-Benzyloxycarbonylaminohex-2-enal
(7a). This compound was obtained following the general
method from aldehyde 5a (0.11 g, 0.49 mmol) and triphenyl-
phosphoranylidenacetaldehyde 6 (0.79 g, 2.45 mmol) in 71%
yield (86 mg, 0.35 mmol). Data for 7a: colorless oil; IR
1
(film): 3324, 1704; H NMR (250 MHz, CDCl3): d 1.18 (d,
4.2.3.1. (D)-(2R)-2-Methylpiperidine hydrochloride
((D)-pipecoline hydrochloride) (8a). This compound was
obtained following the general method from aldehyde 7a
(70 mg, 0.28 mmol) in 84% yield (32 mg, 0.24 mmol).
Data for 8a: white solid; mp: 192–194 ꢁC (Et2O); [a]D20
+3.9 (c 1.1, EtOH); lit.7 +3.97 (c 1.0, EtOH); IR (film):
J¼6.7 Hz, 3H), 2.46 (m, 2H), 3.94 (m, 1H), 4.87 (m, 1H),
5.1 (s, 2H), 6.10 (dd, J¼15.4, 7.9 Hz, 1H), 6.77 (m, 1H),
7.32 (m, 5H), 9.45 (d, J¼7.9 Hz, 1H). 13C NMR (50 MHz):
d 20.7, 40.1, 46.0, 66.6, 128.1, 128.5, 134.9, 136.3, 153.8,
155.6, 193.7; MS (EI): m/z 136 (15), 108 (52), 105 (12), 91
(100), 84 (56), 79 (18), 66 (12).
1
3358; H NMR (250 MHz, CDCl3): d 1.43 (m, 4H), 1.78
(m, 5H), 2.78 (m, 1H), 3.05 (m, 1H), 3.61 (m, 1H), 9.08
(br s, 1H), 9.47 (br s, 1H); 13C NMR (50 MHz): d 19.3,
21.7, 22.3, 30.3, 44.4, 53.0; MS (EI): m/z 84 (100), 70 (4),
56 (12).
4.2.2.2. (5R,2E)-5-Benzyloxycarbonylaminohept-2-
enal (7b). This compound was obtained following the general
method from aldehyde 5b (0.10 g, 0.43 mmol) and triphenyl-
phosphoranylidenacetaldehyde 6 (0.71 g, 2.15 mmol) in 56%
yield (62 mg, 0.24 mmol). Data for 7b: colorless oil; IR
4.2.3.2. (L)-(2R)-2-Ethylpiperidine hydrochloride
(8b). This compound was obtained following the general
method from aldehyde 7b (65 mg, 0.25 mmol) in 78% yield
(29 mg, 0.19 mmol). Data for 8b: white solid; mp: 205–
206 ꢁC (Et2O); [a]D20 ꢀ1.2 (c 0.2, EtOH); lit.7 [a]2D0 ꢀ1.42
(c 0.2, EtOH). IR (film): 3356; 1H NMR (250 MHz,
CDCl3): d 0.98 (m, 3H), 1.28–2.05 (m, 8H), 2.82 (m, 2H),
3.39 (m, 1H), 9.07 (br s, 1H), 9.37 (br s, 1H); 13C NMR
(50 MHz): d 9.8, 22.1, 22.3, 26.3, 27.5, 44.7, 58.5; MS
(EI) m/z 98 (100), 84 (24), 71 (42), 67 (7), 56 (5).
1
(film): 3318, 1703; H NMR (250 MHz, CDCl3): d 0.92 (t,
J¼7.1 Hz, 3H), 1.49 (m, 2H), 2.47 (m, 2H), 3.76 (m, 1H),
4.93 (d, J¼8.3 Hz, 1H), 5.06 (s, 2H), 6.10 (dd, J¼15.8,
7.9 Hz, 1H), 6.76 (m, 1H), 7.30 (m, 5H), 9.43 (d, J¼7.9 Hz,
1H); 13C NMR (50 MHz): d 10.18, 27.7, 38.2, 51.6, 66.6,
127.9, 128.0, 128.4, 130.9, 136.3, 154.2, 156.0, 193.7; MS
(EI): m/z 151 (15), 108 (100), 105 (6), 91 (52), 79 (17), 65
(18), 51 (12).
4.2.2.3. (5S,2E)-5-Benzyloxycarbonylamino-6,6-dime-
thylhept-2-enal (7c). This compound was obtained follow-
ing the general method from aldehyde 5c (0.11 g,
0.42 mmol) and triphenylphosphoranylidenacetaldehyde 6
(0.70 g, 2.10 mmol) in 37% yield (45 mg, 0.15 mmol).
4.2.3.3. (D)-(2S)-2-tert-Butylpiperidine hydrochloride
(8c). This compound was obtained following the general
method from aldehyde 7c (62 mg, 0.22 mmol) in 99% yield
(0.37 mg, 0.21 mmol). Data for 8c: white solid; mp: 193–
195 ꢁC (Et2O); [a]2D0 +2.1 (c 0.2, EtOH); IR (film): 3358;
1H NMR (250 MHz, CDCl3): d 1.18 (s, 9H), 1.30–2.22 (m,
6H), 2.63 (m, 1H), 2.88 (m, 1H), 3.16 (m, 1H), 8.75 (br s,
2H); 13C NMR (50 MHz): d 22.0, 23.1, 24.1, 26.9, 33.3,
1
Data for 7c: colorless oil; IR (film): 3316, 1703; H NMR
(250 MHz, CDCl3): d 0.94 (s, 9H), 2.20 (m, 1H), 2.65 (m,
1H), 3.67 (td, J¼10.1, 2.4 Hz, 1H), 4.71* (s, 1H), 4.75* (s,
1H), 5.06 (dd, J¼19.0, 12.3 Hz, 2H), 6.07* (d, J¼7.9 Hz,

11426
J. Etxebarria et al. / Tetrahedron 63 (2007) 11421–11428
47.1, 67.2; MS (EI): m/z 126 (100), 113 (34), 95 (26), 83
(24), 61 (9).
for 1 h. Then, the reaction was quenched with saturated
NH4Cl (20 mL). The mixture was extracted with CH2Cl2
(3ꢂ15 mL), and the combined organic fractions were col-
lected, dried over Na2SO4, and filtered. The solvent was re-
moved in vacuo, affording the desired amide 20e after
column chromatography purification (hexanes/AcOEt 1:1)
in 55% yield (0.53 g, 1.15 mmol). Data for 20e: colorless oil;
[a]2D0 +29.4 (c 0.3, CH2Cl2); IR (film): 3378, 1615; 1H NMR
4.2.3.4. (D)-(2S)-2-Phenylpiperidine hydrochloride
(8d). This compound was obtained following the general
method from aldehyde 7d (55 mg, 0.18 mmol) in 91% yield
(32 mg, 0.16 mmol). Data for 8d: white solid; mp: 192–
195 ꢁC (Et2O); [a]2D0 +3.0 (c 0.2, EtOH); lit.8 [a]2D0 ꢀ3.1 (c
1
*
0.2, EtOH) for the R isomer; IR (film): 3360; H NMR
(250 MHz, CDCl3) (3:1 rotamer ratio; indicates minor ro-
(250 MHz, CDCl3): d 1.50–2.16 (m, 6H), 2.76 (m, 1H),
3.08 (m, 1H), 3.90 (m, 1H), 7.32 (m, 3H), 7.58 (m, 2H),
9.49 (br s, 2H); 13C NMR (50 MHz): d 21.6, 23.1, 30.1,
45.7, 61.2, 127.0, 128.0, 128.5, 129.0, 129.1, 136.4; MS
(EI) m/z 143 (10), 131 (7), 114 (23), 81 (7), 76 (100), 58 (8).
tamer resonances): d 0.68* (d, J¼6.5 Hz, 3H), 0.81 (m, 3H),
1.06 (d, J¼6.5 Hz, 3H), 1.26 (m, 2H), 1.57 (m, 2H), 2.26
(m, 1H), 2.67 (m, 1H), 2.71 (s, 3H), 2.85* (s, 3H), 3.17 (m,
1H), 3.42 (m, 2H), 3.76 (m, 2H), 4.52 (m, 3H), 7.30 (m,
15H); 13C NMR (50 MHz) (* indicates minor rotamer reso-
nances): d 14.0, 14.4*, 15.3, 19.9, 26.9, 32.9*, 33.7, 34.2*,
34.4, 53.2*, 53.5, 54.5*, 55.9, 58.2, 58.8, 75.3*, 76.5, 126.4,
126.7, 126.8, 126.9, 127.6, 128.1, 128.3, 128.6, 128.8,
139.9, 141.2*, 142.3, 173.7*, 174.6; MS (EI): m/z 460 (M+,
3), 441 (5), 365 (11), 196 (25), 170 (15), 105 (6), 91 (100),
58 (15). Anal. Calcd for C30H38N2O2: C, 78.56; H, 8.35; N,
6.11. Found: C, 78.81; H, 8.67; N, 6.43.
4.3. Asymmetric synthesis of (S)-coniine
4.3.1. (D)-(10S,20S,2E)-N-(20-tert-Butyldimethylsilyloxy-
10-methylethyl-20-phenyl)-N-methylhex-2-enamide (9).
2,6-Lutidine (1.25 mL, 10.72 mmol) was added to a solution
of the amide 1e (2.00 g, 7.66 mmol) in CH2Cl2 (25 mL) at
0 ꢁC. The mixture was stirred at 0 ꢁC for 1 h and then tert-
butyldimethyilsilyl triflate (1.79 mL, 7.70 mmol) was added
at once. Next, the reaction mixture was cooled to rt and
stirred for 12 h after which it was quenched with saturated
NH4Cl (20 mL) and diluted with water (20 mL). The mix-
ture was extracted with CH2Cl2 (3ꢂ15 mL), and the com-
bined organic fractions were collected, dried over Na2SO4,
and filtered. The solvent was removed in vacuo, affording
the desired amide 9 after column chromatography purifica-
tion (hexanes/AcOEt, 8:2) in 68% yield (1.96 g,
5.20 mmol). Data for 9: colorless oil; [a]2D0 +66.8 (c 0.4,
4.3.3. (D)-(10S,20S,3S)-3-(Benzyloxycarbonylamino)-N-
methyl-N-(20-hydroxy-10-methylethyl-20-phenyl)-hexan-
amide (30e). N,N-Dibenzyl-b-amino amide 20e (1.20 g,
2.61 mmol) was hydrogenated in EtOH under 65 psi H2
and Pd/C 10% for 18 h, after which the solvent was removed
in vacuo. The obtained slurry was dissolved in dioxane/H20
(1:1, 20 mL), treated with NaOH (1 M) (2.61 g, 2.61 mmol),
and dibenzylcarbonate (0.95 g, 3.92 mmol) at rt and stirred
for 18 h. The mixture was quenched with saturated NH4Cl
(15 mL) and extracted with CH2Cl2 (3ꢂ15 mL). The com-
bined organic fractions were collected, dried over Na2SO4,
filtered, and the solvent removed in vacuo affording the
wanted N-Cbz-b-amino amide 30e (0.78 g, 1.88 mmol) after
flash column chromatography (AcOEt/hexanes 1:1) in 72%
yield. Data for 30e: colorless oil; [a]D20 +51.7 (c 0.5, CH2Cl2);
CH2Cl2); IR (film): 1654, 1617; 1H NMR (250 MHz,
*
CDCl3) (3:1 rotamer ratio;
indicates minor rotamer
resonances): d ꢀ0.39 (s, 3H), ꢀ0.37* (s, 3H), ꢀ0.10 (s,
3H), ꢀ0.05* (s, 3H), 0.72 (s, 9H), 0.78* (s, 9H), 0.88 (m,
6H), 1.38 (m, 2H), 2.05 (m, 2H), 2.77* (s, 3H), 2.82 (s,
3H), 4.04 (m, 1H), 4.42 (d, J¼7.5 Hz, 1H), 6.08* (d,
J¼15.1 Hz, 1H), 6.19 (d, J¼15.1 Hz, 1H), 6.66 (m, 1H),
7.20 (m, 5H); 13C NMR (50 MHz) (* indicates minor ro-
tamer resonances): d ꢀ5.6*, ꢀ5.0, ꢀ3.8, 13.2*, 13.4, 15.3,
16.5, 17.6, 21.3, 25.5, 27.4*, 34.3, 58.2, 75.8*, 76.6,
121.1*, 121.6, 126.6, 127.2, 128.1, 141.9, 144.2, 145.6*,
166.6*, 167.9; MS (EI): m/z 375 (M+, 4), 261 (2), 243 (3),
166 (12), 115 (5), 70 (56), 58 (100). Anal. Calcd for
C22H37NO2: C, 70.35; H, 9.93; N, 3.73. Found: C, 70.27;
H, 9.76; N, 4.37.
1
IR (film): 3330, 1703, 1619; H NMR (250 MHz, CDCl3)
(3:1 rotamer ratio; indicates minor rotamer resonances):
*
d 0.89 (d, J¼5.5 Hz, 3H), 0.98* (d, J¼5.2 Hz, 3H), 1.32
(m, 4H), 2.43 (m, 1H), 2.54 (m, 1H), 2.77 (s, 3H), 2.83*
(s, 3H), 3.94 (m, 1H), 4.41 (m, 2H), 5.03 (s, 2H), 5.79 (m,
1H), 7.30 (m, 10H); 13C NMR (50 MHz) (* indicates minor
rotamer resonances): d 13.6, 13.9*, 15.3, 19.3, 26.6*, 32.0,
36.3, 37.7*, 38.1, 48.0, 48.4, 66.1, 74.9*, 75.5, 126.2,
126.6, 127.3, 127.6, 127.8, 128.0, 128.1, 128.2, 136.5,
141.5*, 142.0, 156.0, 171.8*, 172.3; MS (EI): m/z 396 (8),
320 (12), 291 (13), 278 (43), 171 (5), 149 (28), 107 (4), 91
(100), 58 (12). Anal. Calcd for C24H32N2O4: C, 69.88; H,
7.82; N, 6.79. Found: C, 69.57; H, 7.67; N, 6.67.
4.3.2. (D)-(10S,20S,3S)-3-Dibenzylamino-N-(20-hydroxy-
10-methylethyl-20-phenyl)-N-methylhexanamide (20e). n-
BuLi (4.24 mL of a 1.6 M solution in hexanes, 6.78 mmol)
was added to a solution of dibenzylamine (1.37 mL,
6.92 mmol) in dry toluene (20 mL) at ꢀ78 ꢁC and the mixture
was stirred at ꢀ78 ꢁC for 30 min. The mixturewas cooled and
added dropwise for 2 h over a solution of O-protected amide 9
(0.64 g, 1.71 mmol) in dry toluene (20 mL) at ꢀ90 ꢁC. Then,
the reactionmixturewas stirred atꢀ90 ꢁC for 20 h after which
it was quenched with saturated NH4Cl (15 mL). The mixture
was extracted with CH2Cl2 (3ꢂ25 mL), and the combined
organic fractions were collected, dried over Na2SO4, filtered,
and the solvent removed in vacuo. THF (1 M) solution of
TBAF (6.84 mL, 6.84 mmol) was added to a solution of this
material in THF (20 mL) and this mixture was stirred at rt
4.3.4. (D)-(3S)-3-Benzyloxycarbonylaminohexanol (ent-
4e). n-BuLi (4.83 mL of a 1.4 M solution in hexanes,
6.76 mmol) was added to a solution of di-iso-propylamine
(0.68 mL, 6.76 mmol) in dry THF (10 mL) at ꢀ78 ꢁC and
the mixture was stirred for 15 min. The reaction was warmed
to 0 ꢁC and NH3$BH3 (0.21 g, 6.76 mmol) was added at
once. The mixture was stirred for 15 min at 0 ꢁC and for
15 min at rt, after which a solution of 30e (0.70 g,
1.69 mmol) in THF (10 mL) was added via cannula at 0 ꢁC
and the reaction was stirred for 2 h. Then the reaction was
quenched with 1 N HCl (15 mL) and extracted with AcOEt
(3ꢂ15 mL). The organic fractions were collected, washed

J. Etxebarria et al. / Tetrahedron 63 (2007) 11421–11428
11427
with saturated NaHCO3, dried over Na2SO4, filtered, and the
solvent removed invacuo affording thewanted g-amino alco-
hol ent-4e (0.26 g, 1.03 mmol) after flash column chromato-
graphy purification (hexanes/AcOEt 1:1) in 61% yield. Data
for ent-4e: colorless oil; [a]2D0 +5.8 (c 0.3, CH2Cl2); IR (film):
3308, 1693; 1H NMR (250 MHz, CDCl3): d 0.91 (d,
J¼6.7 Hz, 3H), 1.41 (m, 5H), 1.77 (m, 1H), 3.60 (s, 1H),
3.61 (m, 2H), 3.79 (m, 1H), 5.03 (s, 1H), 5.08 (m, 2H),
7.32 (m, 5H); 13C NMR (50 MHz): d 13.7, 19.1, 37.4, 38.2,
47.7, 58.6, 66.7, 127.8, 127.9, 128.3, 136.3, 157.2; MS
(EI): m/z 252 (M+, 6), 233 (12), 149 (18), 142 (5), 91 (100),
84 (7). Anal. Calcd for C14H21NO3: C, 66.91; H, 8.42; N,
5.57. Found: C, 66.75; H, 8.63; N, 6.17.
9/UPV00041.310-15835/2004), the Basque Government
(a fellowship to J.E.) and the Spanish Ministerio de Educa-
ꢀ
cion y Ciencia (CTQ2005-02131/BQU) for financial sup-
port. The authors also acknowledge PETRONOR, S.A.
(Muskiz, Bizkaia) for the generous gift of hexanes.
References and notes
1. For some reviews see: (a) Pearson, M. S. M.; Mathe-Allainmat,
M.; Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159; (b)
Afarinkia, K.; Bahar, A. Tetrahedron: Asymmetry 2005, 16,
1239; (c) Dhavale, D. D.; Matin, M. M. Arkivoc 2005, 110;
(d) Buffat, M. G. P. Tetrahedron 2004, 60, 1701; (e)
Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953; (f) Felpin, F.-X.; Lebreton, J. Eur.
J. Org. Chem. 2003, 3693; (g) Bates, R. W.; Sa-Ei, K.
Tetrahedron 2002, 58, 5957; (h) Enders, D.; Thiebes, T. Pure
Appl. Chem. 2001, 73, 573; (i) Laschat, S.; Dickner, T.
Synthesis 2000, 1781; (j) Husson, H.-P.; Royer, J. Chem. Soc.
Rev. 1999, 28, 383; (k) Comins, D. L. J. Heterocycl. Chem.
1999, 36, 1491; (l) Guilloteau-Bertin, B.; Compere, D.; Gil,
L.; Marazano, C.; Das, B. C. Eur. J. Org. Chem. 2000, 1391.
2. Etxebarria, J.; Vicario, J. L.; Badia, D.; Carrillo, L. J. Org. Chem.
2004, 69, 2588.
4.3.5. (L)-(3S)-3-Benzyloxycarbonylaminohexanal (ent-
5e). This compound was obtained following the general
methoddescribedinSection4.2.1forSwernoxidationstarting
from alcohol ent-4e (0.25 g, 0.99 mmol), DMSO (0.43 mL,
3.96 mmol), oxalyl chloride (0.25 mL, 1.98 mmol),
and Et3N (1.00 mL, 9.90 mmol) in 65% yield (0.16 g,
0.65 mmol). Data for ent-5e: colorless oil; [a]2D0 ꢀ33.9 (c
1
0.3, CH2Cl2); IR (film): 3322, 1702; H NMR (250 MHz,
CDCl3): d 0.90 (dd, J¼6.7, 7.1 Hz, 3H), 1.40 (m, 4H), 2.59
(d, J¼5.6 Hz, 2H), 4.07 (m, 1H), 5.06 (m, 3H), 7.32 (m,
5H), 9.73 (s, 1H); 13C NMR (50 MHz): d 13.6, 19.1, 36.8,
46.7, 48.7, 66.6, 127.9, 128.0, 128.4, 136.3, 155.8, 201.1;
MS (EI): m/z 193 (1), 137 (21), 122 (4), 115 (4), 108 (32),
100 (1), 91 (100), 79 (5), 65 (23), 57 (25).
3. Etxebarria, J.; Vicario, J. L.; Badia, D.; Carrillo, L.; Ruiz, N.
J. Org. Chem. 2005, 70, 8790.
4. For other selected synthetic approaches to enantioenriched al-
kylpiperidines from b-amino carbonyl derivatives, see: (a)
Robertson, J.; Stafford, P. M.; Bell, S. J. J. Org. Chem. 2005,
70, 7133; (b) Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005,
127, 8398; (c) Davis, F. A.; Zhang, J.; Li, Y.; Xu, H.;
DeBrosse, C. J. Org. Chem. 2005, 70, 5413; (d) Clive,
D. L. J.; Yu, M.; Li, Z. Chem. Commun. 2005, 906; (e) Burke,
A. J.; Davies, S. G.; Garner, A. C.; McCarthy, T. D.; Roberts,
P. M.; Smith, A. D.; Rodriguez-Solla, H.; Vickers, R. J. Org.
Biomol. Chem. 2004, 2, 1387; (f) Marin, J.; Didierjean, C.;
Aubry, A.; Casimir, J.-R.; Briand, J.-P.; Guichard, G. J. Org.
Chem. 2004, 69, 130; (g) Lee, H. K.; Chun, J. S.; Pak, C. S.
Tetrahedron 2003, 59, 6445; (h) Leflemme, N.; Dallemagne,
P.; Rault, S. Tetrahedron Lett. 2001, 42, 8997; (i) Grison, C.;
4.3.6. (5S,2E)-5-Benzyloxycarbonylaminooct-2-enal (ent-
7e). This compound was obtained following the general
method described in Section 4.2.2 for Wittig reaction start-
ing from aldehyde ent-5e (0.11 g, 0.44 mmol) and triphenyl-
phosphoranylidenacetaldehyde 6 (0.73 g, 2.20 mmol) in
68% yield (82 mg, 0.30 mmol). Data for ent-7e: colorless
oil; IR (film): 3321, 1705, 1704; 1H NMR (250 MHz,
CDCl3): d 0.91 (t, J¼6.3 Hz, 3H), 1.37 (m, 4H), 2.49 (m,
2H), 3.84 (m, 1H), 4.73 (d, J¼8.7 Hz, 1H), 5.07 (m, 2H),
6.11 (dd, J¼15.7, 7.9 Hz, 1H), 6.78 (m, 1H), 7.32 (m, 5H),
9.46 (d, J¼7.9 Hz, 1H); 13C NMR (50 MHz): d 13.9, 19.0,
37.1, 38.9, 50.2, 66.8, 128.1, 128.7, 135.0, 136.5, 154.2,
156.0, 193.4; MS (EI): m/z 165 (23), 108 (56), 105 (36),
91 (100), 81 (27), 65 (12).
ꢀ
Geneve, S.; Coutrot, P. Tetrahedron Lett. 2001, 42, 3831; (j)
Ma, D.; Sun, H. J. Org. Chem. 2000, 65, 6009; (k) Davies,
S. B.; McKervey, M. A. Tetrahedron Lett. 1999, 40, 1229; (l)
Kawakami, T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada,
Y.; Murahashi, S. Org. Lett. 1999, 1, 107; (m) Davis, F. A.;
Szewczyk, J. M. Tetrahedron Lett. 1998, 39, 5951.
4.3.7. (D)-(2S)-2-Propylpiperidine hydrochloride ((D)-
coniine hydrochloride) (ent-8e). This compound was ob-
tained following the general method described in Section
4.2.3 for the cascade hydrogenation/deprotection/intramo-
lecular reductive amination process starting from aldehyde
ent-7e (71 mg, 0.26 mmol) in 93% yield (39 mg,
0.24 mmol). Data for ent-8e: white solid; mp: 213–215 ꢁC
(Et2O); [a]2D0 +9.0 (c 0.2, EtOH); lit.9 [a]2D0 +9.4 (c 0.2,
EtOH); IR (film): 3355; 1H NMR (250 MHz, CDCl3):
d 0.98 (m, 3H), 1.24–2.25 (m, 10H), 3.03 (m, 2H), 3.46
(m, 1H), 8.86 (br s, 2H); 13C NMR (50 MHz): d 14.0,
18.8, 22.5, 28.3, 29.3, 35.6, 46.4, 57.4; MS (EI): m/z 112
(100), 99 (15), 85 (42), 81 (13), 70 (25), 56 (2).
5. In some cases (S)-configurated derivatives were obtained as a
result of the application of CIP rules.
6. For some selected examples on the formation of piperidines via
intramolecular reductive amination see: (a) Masuda, Y.; Tashiro,
T.; Mori, K. Tetrahedron: Asymmetry 2006, 17, 3380; (b)
Adriaenssens, L. V.; Austin, C. A.; Gibson, M.; Smith, D.;
Hartley, R. C. Eur. J. Org. Chem. 2006, 4998; (c) Kandula,
S. R. V.; Kumar, P. Tetrahedron 2006, 62, 9942; (d) Chavan,
S. P.; Praveen, C. Tetrahedron Lett. 2004, 45, 421; (e) La
Ferla, B.; Bugada, P.; Cipolla, L.; Peri, F.; Nicotra, F. Eur. J.
Org. Chem. 2004, 2451; (f) Lee, Y.-S.; Shin, Y.-H.; Kim,
Y.-H.; Lee, K.-Y.; Oh, C.-Y.; Pyun, S.-J.; Park, H.-J.; Jeong,
J.-H.; Ham, W.-H. Tetrahedron: Asymmetry 2003, 14, 87; (g)
Randl, S.; Blechert, S. J. Org. Chem. 2003, 68, 8879; (h)
Enders, D.; Nolte, B.; Raabe, G.; Runsink, J. Tetrahedron:
Asymmetry 2002, 13, 285; (i) Yamazaki, N.; Dokoshi, W.;
Acknowledgements
The authors thank the University of the Basque Country
ꢀ
Grupos de Investigacion,
ꢀ
(Subvencion General
a

11428
J. Etxebarria et al. / Tetrahedron 63 (2007) 11421–11428
Kibayashi, C. Org. Lett. 2001, 3, 193; (j) Kim, G.; Jung, S.; Kim,
W. Org. Lett. 2001, 3, 2985; (k) Enders, D.; Kirchhoff, J. H.
Synthesis 2000, 2099. See also Ref. 4c.
8. Compound 8b: [a]2D0 ꢀ1.2 (c 0.2, EtOH); lit. [a]2D0 ꢀ1.42 (c 0.2,
EtOH): see Ref. 7. Compound 8d: [a]2D0 +3.0 (c 0.2, EtOH); [a]2D0
ꢀ3.1 (c 0.2, EtOH) for the R isomer: Katritzky, A. R.; Qiu, G.;
Yang, B.; Steel, P. J. J. Org. Chem. 1998, 63, 6699.
9. [a]2D0 +9.0 (c 0.2, EtOH) for a sample of (S)-coniine hydro-
chloride obtained by us; lit. [a]2D0 +9.4 (c 0.2, EtOH). See
Refs. 7 and 8.
7. [a]2D0 +3.9 (c 1.1, EtOH) for a sample of (R)-pipecoline hydro-
chloride obtained by us; lit. +3.97 (c 1.0, EtOH). Andres,
J. M.; Herraiz-Sierra, I.; Pedrosa, R.; Perez-Encabo, A. Eur. J.
Org. Chem. 2000, 1719.