A practical asymmetric synthesis of 2,6-cis-disubstituted piperidines

Article abstract of DOI:10.1016/S0957-4166(99)00226-8

A highly diastereoselective intramolecular Mannich reaction involving enantiopure α-methylamine 7 and achiral aldehydes is employed to prepare enantiomerically pure 2,6-cis-disubstituted piperidines. This methodology provides an efficient and selective ro

Full text of DOI:10.1016/S0957-4166(99)00226-8

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2225–2235
A practical asymmetric synthesis of 2,6-cis-disubstituted
piperidines
Stéphane Ciblat,a Pascale Besse,b Jean-Louis Canet,a,∗ Yves Troin,a,∗ Henri Veschambre b and
Jacques Gelas a
aLaboratoire de Chimie des Hétérocycles et des Glucides, EA 987, Ecole Nationale Supérieure de Chimie de
Clermont-Ferrand, Université Blaise Pascal, BP 187, 63174 Aubière Cedex, France
bLaboratoire de Synthèse, Electrosynthèse et Etude de Systèmes à Intérêt Biologique, UMR 6504 du CNRS,
Université Blaise Pascal, 63177 Aubière Cedex, France
Received 16 May 1999; accepted 4 June 1999
Abstract
A highly diastereoselective intramolecular Mannich reaction involving enantiopure α-methylamine 7 and achiral
aldehydes is employed to prepare enantiomerically pure 2,6-cis-disubstituted piperidines. This methodology
provides an efficient and selective route to 2,6-cis-disubstituted piperidines, 2,6-cis-disubstituted 4-piperidones
and 2,6-cis-disubstituted 4-piperidinols. © 1999 Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
Many natural compounds and drugs contain the piperidine ring system as a structural element. As
this class of products exhibits a wide range of biological activities,1 the elaboration of efficient regio-
and stereoselective syntheses of chiral enantiopure piperidines is of great interest for organic chemists
and pharmaceutical research. Among the numerous naturally occurring piperidines, cis- and trans-2,6-
dialkylpiperidines, either monocyclic or included in bicyclic systems, form an important class of alkaloids
isolated from amphibians, insects and plants. For example, pinidine 1 was extracted from several species
of the family Pinaceae2 while dihydropinidine 2 has been found in the Mexican bean beetle Epilachna
varivestis.3 Solenopsins 3 and isosolenopsins 4 are representative alkaloids of the fire ants’ venom of
the genus Solenopsis (Myrmicinae).4 Monomorine 5 was identified as a pheromone of the pharaoh ant
Monomorium pharaonis L5 while its C-3 epimer, indolizidine 195 B 6, was isolated from the poison frog
Dendrobates histrionicus6 (Fig. 1).
∗
Corresponding authors. Fax: 33 4 73 40 70 08; e-mail: canet@chimtp.univ-bpclermont.fr and
troin@chimtp.univ-bpclermont.fr
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00226-8

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Figure 1.
Various strategies have been proposed for the stereoselective preparation of six-membered N-
heterocyclic compounds,7 many concerning the asymmetric syntheses of 2,6-dialkylpiperidine alkaloids8
such as 1–6. Part of our research program is devoted to the asymmetric synthesis of polysubstituted
piperidines and we have recently described an access to cis- and trans-2-alkyl-4-hydroxypiperidines9 and
to trans, cis-2,3-dialkyl-4-hydroxypiperidines.10 We have defined a one-pot stereoselective cyclisation
method in which the piperidine nucleus is formed through an intramolecular Mannich-type11 reaction
involving a non-chiral amine with a planar chiral dienal iron tricarbonyl complex (Scheme 1).
Scheme 1.
Although this method permits, as shown, the asymmetric construction of diverse polysubstituted
piperidines, a limitation is apparent since it does not allow the stereoselective elaboration of a 2,6-
disubstitution pattern by the same pathway. We reasoned that this case requires the use of a chiral amine
which must be involved in the cyclisation step with an achiral aldehyde (Scheme 2).
Scheme 2.

S. Ciblat et al. / Tetrahedron: Asymmetry 10 (1999) 2225–2235
2227
Thus, homochiral amine 712 (Fig. 2) was engaged in the cyclisation step with various aromatic,
heteroaromatic, ethylenic and saturated aldehydes 8–1813 (Table 1) in order to validate our approach
and to examine the diastereoselection degree of the 2,6-disubstituted-piperidine ring formation.
Figure 2.
2. Results and discussion
Reaction of aldehydes 8–18 with amine 7 in refluxing dichloromethane in the presence of magnesium
sulphate as drying agent led quantitatively (TLC monitoring), in 1–3 h, to the corresponding imines.
These unstable compounds were treated directly, for 2–3 h, with 2 equivalents of para-toluenesulphonic
acid (previously dried under Dean–Stark conditions) at 70°C in toluene. Under these conditions, 2,6-
disubstituted piperidines 19–29 were obtained in 60 to 96% yield after chromatographic purification.
The results are collected in Table 1.
In all cases, the 2,6-cis diastereomer was formed highly predominantly. The 2,6-trans isomer was
observed, by 1H NMR spectroscopy, only in the case of the 2-furyl-6-methylpiperidine 29. The relative
configurations of the 2,6-cis-piperidines 19–29 were established unambiguously from 1H NMR spectra,
particularly with the signals corresponding to H-3 (axial and equatorial) and H-5 (axial and equatorial),
showing typical coupling constants for a 2,6-diequatorial disubstitution in a chair conformation. As the
presence of the 2,6-trans isomer was not detected by 1H NMR for compounds 19–28, we assume that the
diastereomeric excess of the cyclised products is higher than 95%. To explain such a diastereoselectivity,
we have considered a priori the transition states A and B (Scheme 3). It clearly appears that, due to a
A(1,3) strain present in A, leading to the 2,6-trans isomer, this transition state is disfavoured compared to
B, precursor of the observed 2,6-cis isomer (Scheme 3).
Scheme 3.
We then examined the enantiomeric purity of our piperidines by high performance liquid
chromatography.14 This was accomplished with the 2-phenyl-6-methylpiperidine 22. A baseline
separation was obtained for racemic 22 while only one peak was observed for (+)- and (−)-22,
demonstrating that no racemisation occurs during the cyclisation.
Cleavage of the dioxane appendage15 of piperidine (−)-22 was then cleanly realised using a con-
ventional procedure and furnished the parent 4-piperidone (−)-30 in 90% yield (Scheme 4). Piperidone

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Table 1
Diastereoselective formation of 2,6-cis-disubstituted piperidines 19–29 from amine 7 and aldehydes
8–18

S. Ciblat et al. / Tetrahedron: Asymmetry 10 (1999) 2225–2235
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Table 1 (continued)
(−)-30 was stereoselectively reduced with sodium borohydride and L-Selectride® to afford, respectively,
equatorial 4-piperidinol (−)-31 (92%, de: 80%) and its C-4 axial epimer (−)-32 (95%, de: 95%). Finally,
treatment of piperidine (−)-22 with an excess of ethanedithiol in the presence of BF3·Et2O gave in 91%
yield the dithiolane derivative (−)-33 which was quantitatively converted into the (−)-2,6-cis-2-phenyl-
6-methylpiperidine 34 by hydrogenolysis realised in the presence of W2 Raney nickel16 in refluxing
ethanol (Scheme 4). The specific rotation of (−)-34 ([α]25=−21, c 0.7, EtOH) was consistent with that
D
recently reported for its enantiomer (lit.8a: ([α]25=22.1, c 0.69, EtOH).
D
Scheme 4.

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3. Conclusion
We have described herein the enantioselective preparation of 2,6-cis-disubstituted piperidines via
a highly diastereoselective intramolecular Mannich-type reaction using the homochiral amine 7. As
demonstrated, this method is applicable to a large variety of aldehydes and permits the rapid selective syn-
thesis of 2,6-cis-disubstituted piperidines, 2,6-cis-disubstituted 4-piperidones and 2,6-cis-disubstituted
4-piperidinols (cis,cis or trans,trans, selectively). Extension of this method to other series of aldehydes,
to differently and more substituted chiral amines, as well as its application to the field of total enantio-
selective synthesis of alkaloids is currently under progress.
4. Experimental
1
Melting points are uncorrected. H and 13C NMR spectra were measured at 400.13 and 100.61 MHz,
respectively; chemical shifts are reported in ppm relative to SiMe4. J values are given in hertz. Infrared
spectra were recorded on an FTIR spectrometer. Electron impact (EI) mass spectra were obtained at 70
eV. Electron impact (EI) and fast atom bombardment (FAB) high resolution mass spectra were obtained
from the Centre Régional de Mesures Physiques, Université de Rennes. Optical rotations were measured
at 589 nm. Column chromatography was carried out on silica gel (70–230 mesh). Solvents were dried
and freshly distilled following the usual procedures. All reactions were carried out under argon. Product
solutions were dried over Na2SO4 prior to evaporation of the solvents under reduced pressure on a rotary
evaporator.
4.1. Intramolecular Mannich-type cyclisation, general procedure
To a stirred solution of aldehyde (4 mmol) in CH2Cl2 (20 mL) was added MgSO4 (1 g) followed by
a solution of amine (ꢀ)-, (+)- or (−)-7 (1 equiv.) in CH2Cl2 (5 mL). The resulting solution was heated
at reflux until complete disappearance (TLC monitoring) of the amine (1–3 h), then cooled to room
temperature and transferred via a cannula to a solution of dry para-toluenesulphonic acid (2 equiv.)
in toluene (25 mL). The resulting mixture was heated at 70°C for 3 h. After being cooled to room
temperature, saturated aqueous NaHCO3 (15 mL) was added and the protected piperidone was extracted
with ethyl acetate (4×20 mL). The combined organic extracts were dried, filtered and evaporated. The
residue was purified by column chromatography using MeOH/ethyl acetate as eluent.
4.2. (ꢀ)-(2R*,6S*)-1-Aza-2-(200 -benzyloxyethyl)-6-methyl-10 ,30-dioxaspiro[5.5]undecane 19
Following the general procedure, amine (ꢀ)-7 and aldehyde 8 gave, after chromatography
(ethyl acetate:methanol, 9:1), 70% of protected piperidone 19, as a pale yellow oil. Rf 0.40 (ethyl
acetate:methanol, 5:1); νmax (neat)/cm−1 3314, 1143, 1097, 736; δH (CDCl3) 7.33 (5H, m), 4.53 (2H, s),
3.92 (2H, t, J=5), 3.86 (2H, t, J=5), 3.59 (2H, t, J=5.5), 2.92 (2H, m, H-2 and H-6), 2.22 (2H, m), 2.00
(1H, br s, NH), 1.75 (4H, m), 1.14 (2H, m), 1.07 (3H, t, J=7); δC (CDCl3) 128.1 (d), 127.3 (d), 114.4
(s), 97.1 (s), 72.6 (t), 67.7 (t), 58.9 (t), 50.8 (d), 47.6 (d), 40.9 (t), 38.9 (t), 35.9 (t), 25.4 (t), 22.0 (q).

S. Ciblat et al. / Tetrahedron: Asymmetry 10 (1999) 2225–2235
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4.3. (−)-(2S,6S)-1-Aza-2-(non-100 -enyl)-6-methyl-10,30-dioxaspiro[5.5]undecane 20
Following the general procedure, amine (+)-7 and aldehyde 9 gave, after chromatography (ethyl
acetate:methanol, 9:1), 80% of protected piperidone (−)-20, as a pale yellow oil. Rf 0.31 (ethyl ace-
tate:methanol, 5:1); [α]25=−2.3 (c 0.97, CHCl3); νmax (neat)/cm−1 3314, 1146, 1099, 1009, 963; δH
D
(CDCl3) 5.63 (1H, m), 5.45 (1H, dd, J=15.5 and 7.0), 3.93 (4H, m), 3.29 (1H, m, H-2), 2.93 (1H, m,
H-6), 2.26 (1H, dt, J=13.5 and 3.0, H-3eq), 2.18 (1H, dt, J=13.5 and 3.0, H-5eq), 1.99 (2H, m), 1.72
(2H, m), 1.60 (1H, br s, NH), 1.45–1.00 (12H, m), 1.10 (3H, d, J=7.0), 0.85 (3H, t, J=7.0); δC (CDCl3)
132.2 (d), 131.2 (d), 97.2 (s), 59.0 (t), 54.9 (d), 49.8 (d), 41.0 (t), 38.9 (t), 32.1 (t), 31.7 (t), 29.0 (t), 28.9
(t), 25.5 (t), 22.5 (t), 22.2 (q), 14.0 (q); m/z (EI) 295 (M+·, 20), 194 (100), 235 (100), 179 (30), 101 (75);
HRMS (FAB) found: 296.2595; C18H33NO2+H+ requires: 296.2590.
4.4. (−)-(2S,6S)-1-Aza-2-(nona-100 ,300-dienyl)-6-methyl-10 ,30-dioxaspiro[5.5]undecane 21
Following the general procedure, amine (−)-7 and aldehyde 10 gave, after chromatography (ethyl
acetate:methanol, 9:1), 60% of protected piperidone (−)-21, as a pale yellow oil. Rf 0.32 (ethyl ace-
tate:methanol, 5:1); [α]25=−2.1 (c 0.85, CHCl3); νmax (neat)/cm−1 3313, 1145, 1100, 988; δH (CDCl3)
D
6.16 (1H, dd, J=15.5 and 10.0), 6.00 (1H, m), 5.67 (1H, m), 5.55 (1H, dd, J=15.5 and 7.5), 3.92 (4H, m),
3.35 (1H, m, H-2), 2.93 (1H, m, H-6), 2.31 (1H, dt, J=12.5 and 2, H-3eq), 2.17 (1H, dt, 12.5 and 2.0,
H-5eq), 2.05 (2H, m), 1.73 (2H, m), 1.52 (1H, br s, NH), 1.45–1.10 (8H, m), 1.10 (3H, d, J=8), 0.90 (3H,
t, J=7.5); δC (CDCl3) 134.9 (d), 132.9 (d), 130.6 (d), 129.6 (d), 97.2 (s), 59.1 (t), 54.8 (d), 47.7 (d), 41.2
(t), 38.5 (t), 32.5 (t), 31.3 (t), 28.9 (t), 25.5 (t), 22.4 (t), 22.2 (q), 14.0 (q); m/z (EI) 293 (M+·, 68), 101
(100), 41 (44); HRMS (FAB) found: 294.2434; C18H31NO2+H+ requires: 294.2433.
4.5. (−)-(2S,6S)-1-Aza-6-methyl-2-phenyl-10 ,30-dioxaspiro[5.5]undecane 22
Following the general procedure, amine (+)-7 and aldehyde 11 gave, after chromatography (ethyl
acetate:methanol, 9:1), 83% of protected piperidone (−)-22, as a pale yellow oil. Rf 0.24 (ethyl ace-
tate:methanol, 5:1); [α]25=−8.4 (c 1.24, CHCl3); νmax (neat)/cm−1 3307, 1602, 1135, 1101, 701; δH
D
(CDCl3) 7.45–7.25 (5H, m), 3.95 (4H, m), 3.85 (1H, dd, J=12 and 2, H-2), 3.05 (1H, m, H-6), 2.45 (1H,
td, J=12.5 and 2, H-3eq), 2.25 (1H, td, J=12.5 and 2.5, H-5eq), 1.80 (1H, m), 1.70 (1H, m), 1.60 (1H, br
s, NH), 1.52 (1H, t, J=12.5, H-3ax), 1.25 (1H, t, J=12.5, H-5ax), 1.14 (3H, d, J=7.0); δC (CDCl3) 144.1
(s), 128.4 (d), 127.2 (d), 126.8 (d), 97.6 (s), 59.1 (t), 57.5 (d), 48.4 (d), 41.6 (t), 40.3 (t), 25.6 (t), 22.4
(q); HRMS (FAB) found: 248.1651; C15H21NO2+H+ requires: 248.1651.
4.6. (+)-(2R,6R)-1-Aza-6-methyl-2-phenyl-10 ,30-dioxaspiro[5.5]undecane 22
Following the general procedure, amine (−)-7 and aldehyde 11 gave, after chromatography (ethyl
acetate:methanol, 9:1), 80% of protected piperidone (+)-22, as a pale yellow oil. [α]25=8.3 (c 1.2,
D
CHCl3). Other data were identical with those reported for (−)-22.
4.7. (ꢀ)-(2S*,6S*)-1-Aza-2-(400 -methoxyphenyl)-6-methyl-10 ,30-dioxaspiro[5.5]undecane 23
Following the general procedure, amine (ꢀ)-7 and aldehyde 12 gave, after chromatography (ethyl ace-
tate:methanol, 9:1), 75% of protected piperidone 23, as a pale yellow oil. Rf 0.26 (ethyl acetate:methanol,
5:1); νmax (neat)/cm−1 3303, 1135, 1103; δH (C6D6) 7.32 (2H, d, J=8.5), 6.78 (2H, d, J=8.5), 3.90 (1H,

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S. Ciblat et al. / Tetrahedron: Asymmetry 10 (1999) 2225–2235
dd, J=12 and 2, H-2), 3.56 (4H, m), 3.28 (3H, s), 2.97 (1H, m, H-6), 2.47 (1H, td, J=12 and 2, H-3eq),
2.24 (1H, td, J=12 and 2, H-5eq), 1.60 (1H, t, J=12, H-3ax), 1.33 (1H, t, J=12, H-5ax), 1.32 (1H, m),
1.26 (2H, m), 0.92 (3H, d, J=7.0); δC (CDCl3) 158.9 (s), 136.2 (s), 128.1 (d), 113.9 (d), 97.7 (s), 59.3
(t), 57.0 (q), 55.4 (d), 48.6 (d), 41.6 (t), 40.3 (t), 25.7 (t), 22.4 (q).
4.8. (+)-(2R,6R)-1-Aza-2-(400-bromophenyl)-6-methyl-10 ,30-dioxaspiro[5.5]undecane 24
Following the general procedure, amine (−)-7 and aldehyde 13 gave, after chromatography (ethyl
acetate:methanol, 9:1), 63% of protected piperidone (+)-24, as a pale yellow oil. Rf 0.61 (ethyl ace-
tate:methanol, 5:1); [α]25=3.6 (c 1.13, CHCl3); νmax (neat)/cm−1 3306, 1135, 1103, 831; δH (CDCl3)
D
7.41 (2H, d, J=9.5), 7.22 (2H, d, J=9.5), 3.91 (4H, m), 3.79 (1H, dd, J=11 and 2, H-2), 3.00 (1H, m,
H-6), 2.33 (1H, td, J=11 and 2, H-3eq), 2.24 (1H, td, J=11 and 2, H-5eq), 1.73 (2H, m), 1.55 (1H, br s,
NH), 1.43 (1H, t, J=11.5, H-3ax), 1.18 (1H, t, J=11.5, H-5ax), 1.10 (3H, d, J=7.0); δC (CDCl3) 143.1
(s), 131.4 (d), 128.5 (d), 120.8 (s), 97.3 (s), 59.1 (t), 56.8 (d), 48.2 (d), 41.0 (t), 40.8 (t), 25.5 (t), 22.3 (q);
HRMS (FAB) found: 326.0751; C15H20NO279Br+H+ requires: 326.0756.
4.9. (+)-(2R,6R)-1-Aza-2-(400-nitrophenyl)-6-methyl-10 ,30-dioxaspiro[5.5]undecane 25
Following the general procedure, amine (−)-7 and aldehyde 14 gave, after chromatography (ethyl
acetate:methanol, 9:1), 96% of protected piperidone (+)-25, as a yellow solid. Mp=102°C. Rf 0.64 (ethyl
acetate:methanol, 5:1); [α]25=1.7 (c 1.05, CHCl3); νmax (KBr)/cm−1 3303, 1597, 1511, 1346, 1135, 855;
D
δH (CDCl3) 8.19 (2H, d, J=8.5), 7.57 (2H, d, J=8.5), 3.96 (5H, m), 3.06 (1H, m, H-6), 2.35 (2H, m),
1.77 (2H, m), 1.60 (1H, br s, NH), 1.45 (1H, t, J=11.5, H-3ax), 1.29 (1H, t, J=11.5, H-5ax), 1.17 (3H, d,
J=7.0); δC (CDCl3) 148.7 (d), 139.2 (s), 134.4 (d), 123.4 (s), 97.2 (s), 59.2 (t), 59.1 (t), 55.0 (d), 48.3 (d),
40.8 (t), 40.6 (t), 25.4 (t), 22.2 (q); HRMS (FAB) found: 293.1499; C15H20N2O4+H+ requires: 293.1501.
4.10. (−)-(2R,6R)-1-Aza-6-methyl-2-(200 -pyridinyl)-10,30-dioxaspiro[5.5]undecane 26
Following the general procedure, amine (−)-7 and aldehyde 15 gave, after chromatography (ethyl
acetate:methanol, 5:1), 86% of protected piperidone (−)-26, as a colourless oil. Rf 0.25 (ethyl ace-
tate:methanol, 5:1); [α]25=−9.1 (c 0.95, CHCl3); νmax (neat)/cm−1 3301, 1591, 1434, 1144, 1090, 755;
D
δH (CDCl3) 8.55 (1H, m), 7.66 (1H, t, J=8.0), 7.32 (1H, d, J=8.0), 7.16 (1H, m), 3.95 (5H, m), 3.07 (1H,
m, H-6), 2.59 (1H, td, J=12.5 and 2, H-3eq), 2.24 (1H, td, J=12.5 and 2, H-5eq), 1.92 (1H, br s, NH),
1.81 (1H, m), 1.71 (1H, m), 1.52 (1H, t, J=12, H-3ax), 1.23 (1H, t, J=12.5, H-5ax), 1.18 (3H, d, J=7.0);
δC (CDCl3) 161.8 (s), 149.1 (d), 136.6 (d), 122.1 (d), 120.9 (d), 97.5 (s), 59.2 (t), 59.0 (d), 48.2 (d), 41.7
(t), 38.6 (t), 25.5 (t), 22.3 (q); HRMS (FAB) found: 249.1607; C14H20N2O2+H+ requires: 249.1603.
4.11. (+)-(2R,6R)-1-Aza-6-methyl-2-(300 -pyridinyl)-10,30-dioxaspiro[5.5]undecane 27
Following the general procedure, amine (−)-7 and aldehyde 16 gave, after chromatography (ethyl
acetate:methanol, 5:1), 65% of protected piperidone (+)-27, as a colourless oil. Rf 0.43 (ethyl ace-
tate:methanol, 1:1); [α]25=13.1 (c 1.17, CHCl3); νmax (neat)/cm−1 3303, 1578, 1511, 1345, 1104, 715;
D
δH (CDCl3) 8.63 (1H, m), 8.52 (1H, m), 7.75 (1H, m), 7.27 (1H, m), 3.94 (5H, m), 3.06 (1H, m, H-6),
2.38 (1H, td, J=11.5 and 2, H-3eq), 2.24 (1H, td, J=11.5 and 2, H-5eq), 1.75 (2H+NH, m), 1.52 (1H,
t, J=11.5, H-3ax), 1.24 (1H, t, J=11.5, H-5ax), 1.15 (3H, d, J=7.0); δC (CDCl3) 151.7 (s), 127.5 (d),

S. Ciblat et al. / Tetrahedron: Asymmetry 10 (1999) 2225–2235
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123.6 (d), 97.0 (s), 59.1 (t), 56.9 (d), 48.1 (d), 41.2 (t), 40.4 (t), 25.4 (t), 22.3 (q); HRMS (FAB) found:
249.1608; C14H20N2O2+H+ requires: 249.1603.
4.12. (−)-(2R,6R)-1-Aza-2-(200-benzofuryl)-6-methyl-10 ,30-dioxaspiro[5.5]undecane 28
Following the general procedure, amine (−)-7 and aldehyde 17 gave, after chromatography (ethyl
acetate:methanol, 9:1), 83% of protected piperidone (−)-28, as a colourless oil. Rf 0.25 (ethyl ace-
tate:methanol, 5:1); [α]25=−23.0 (c 0.97, CHCl3); νmax (neat)/cm−1 1668, 1101, 736; δH (CDCl3) 7.54
D
(1H, d, J=7.5), 7.46 (1H, d, J=7.5), 7.23 (2H, d, J=7.5), 6.57 (1H, s), 4.14 (1H, dd, J=10 and 2, H-2),
3.95 (4H, m), 3.07 (1H, m, H-6), 2.67 (1H, td, J=13.5 and 2, H-3eq), 2.28 (1H, td, J=13.5 and 2, H-5eq),
1.90–1.60 (4H, m), 1.26 (1H, t, J=13.5, H-5ax), 1.16 (3H, d, J=7.0); HRMS (FAB) found: 288.1599;
C17H21NO3+H+ requires: 288.1600.
4.13. (−)-(2R,6R)-1-Aza-2-(200-furyl)-6-methyl-10,30-dioxaspiro[5.5]undecane 29
Following the general procedure, amine (−)-7 and aldehyde 18 gave, after chromatography (ethyl
acetate:methanol, 9:1), 65% of protected piperidone (−)-29, as a colourless oil. Rf 0.43 (ethyl ace-
tate:methanol, 5:1); [α]25=−11.1 (c 1.14, CHCl3); νmax (neat)/cm−1 3311, 1145, 1101, 1007, 741; δH
D
(CDCl3) 7.29 (1H, m), 6.26 (1H, m), 6.11 (1H, m), 3.87 (5H, m), 3.00 (1H, m, H-6), 2.53 (1H, td, J=12.5
and 2, H-3eq), 2.19 (1H, td, J=12.5 and 2, H-5eq), 1.66 (3H, m), 1.55 (1H, t, J=12.5, H-3ax), 1.16 (1H, t,
J=12.5, H-5ax), 1.10 (3H, t, J=7.0); δC (CDCl3) 156.4 (s), 127.5 (d), 109.9 (d), 104.7 (d), 97.1 (s), 59.1
(t), 50.7 (d), 48.0 (d), 41.6 (t), 36.8 (t), 25.5 (t), 22.2 (q); HRMS (FAB) found: 238.1442; C13H19NO3+H+
requires: 238.1443.
4.14. (−)-(2S,6S)-6-Methyl-2-phenylpiperidin-4-one 30
To a stirred solution of protected piperidone (−)-22 (250 mg, 1 mmol) in acetone (15 mL) was
added 6% hydrochloric acid (10 mL). The resulting mixture was stirred at room temperature for 10
days. The organic solvent was eliminated under reduced pressure and the residue was diluted with an
excess of 1 M aqueous NaOH. The piperidone was then extracted with dichloromethane (4×20 mL).
The combined organic extracts were washed with brine and dried. Evaporation of the solvent, followed
by column chromatography (ethyl acetate) afforded piperidone (−)-30 (170 mg, 90%) as a white solid.
Mp=65–67°C; Rf 0.60 (ethyl acetate:methanol, 5:1); [α]25=−72.0 (c 1.19, CHCl3); νmax (KBr)/cm−1
D
3310, 1703, 1135, 1101, 700; δH (CDCl3) 7.35 (5H, m), 3.96 (1H, dd, J=8.5 and 7.5, H-2), 3.14 (1H, m,
H-6), 2.52 (2H, m), 2.42 (1H, dd, J=12.5 and 2), 2.25 (1H, t, J=12), 1.85 (1H, br s, NH), 1.27 (3H, d,
J=7.0); δC (CDCl3) 208.8 (s), 142.6 (s), 128.7 (d), 127.8 (d), 126.5 (d), 61.0 (d), 53.8 (d), 49.9 (t), 48.7
(t), 22.6 (q); HRMS (EI) found: 189.1157; C12H15NO requires: 189.1154.
4.15. (−)-(2S,4S,6S)-6-Methyl-2-phenylpiperidin-4-ol 31
To a stirred solution of piperidone (−)-30 (95 mg, 0.5 mmol) in methanol (8 mL) was added at room
temperature sodium borohydride (0.5 mmol). The resulting mixture was stirred for 10 min before addition
of saturated aqueous NH4Cl (3 mL). The piperidinol was extracted with dichloromethane (4×15 mL).
The combined organic extracts were washed with brine and dried. Evaporation of the solvents, followed
by column chromatography (ethyl acetate:methanol, 9:1), gave separated piperidinols (−)-31 (79 mg,
83%) and (−)-32 (9 mg, 9%). Piperidinol (−)-31: white solid. Mp=100°C; Rf 0.38 (ethyl acetate:methanol,

2234
S. Ciblat et al. / Tetrahedron: Asymmetry 10 (1999) 2225–2235
1:1); [α]25=−53.7 (c 0.86, CHCl3); νmax (KBr)/cm−1 3203, 1135, 1106, 1071, 1001, 704; δH (CDCl3)
D
7.30 (5H, m), 4.28 (1H, m, H-4), 4.15 (1H, dd, J=11 and 2.5, H-2), 3.29 (1H, H-6), 2.08 (2H, br s, OH
and NH), 1.80 (3H, m), 1.46 (1H, dt, J=12 and 2), 1.10 (3H, d, J=7.0); δC (CD3OD) 145.5 (s), 129.8 (d),
128.5 (d), 128.2 (d), 66.6 (d), 57.1 (d), 48.5 (d), 41.3 (t), 41.2 (t), 22.4 (q); HRMS (EI) found: 191.1317;
C12H17NO requires: 191.1310.
4.16. (−)-(2S,4R,6S)-6-Methyl-2-phenylpiperidin-4-ol 32
To a cold (−78°C) stirred solution of piperidone (−)-30 (95 mg, 0.5 mmol) in THF (5 mL) was
added dropwise L-Selectride® (550 µL of a 1 M solution in THF). After 10 min of stirring at −78°C,
methanol (1 mL) was added and the resulting solution was allowed to warm to room temperature. Water
(5 mL) was added and the piperidinol was extracted with dichloromethane (4×25 mL). Evaporation
of the solvents under reduced pressure, followed by column chromatography (ethyl acetate:methanol,
9:1), gave piperidinol (−)-32 (92 mg, 96%), exclusively, as a white solid. Mp=114°C; Rf 0.59 (ethyl
acetate:methanol, 1:1); [α]25=−33.8 (c 0.82, CHCl3); νmax (KBr)/cm−1 3251, 1086, 1036, 756, 698; δH
D
(CDCl3) 7.28 (5H, m), 3.75 (1H, m, H-4), 3.65 (1H, dd, J=11 and 2.5, H-2), 2.84 (1H, H-6), 2.15 (2H, br
s, OH and NH), 2.08 (1H, m), 1.97 (1H, m), 1.45 (1H, q, J=11.5), 1.14 (4H, m); δC (CDCl3) 143.9 (s),
128.4 (d), 127.2 (d), 126.7 (d), 69.3 (d), 59.7 (d), 50.7 (d), 43.2 (t), 43.0 (t), 22.3 (q).
4.17. (−)-(2S,6S)-1-Aza-6-methyl-2-phenyl-10 ,30-dithiaspiro[5.4]decane 33
To a stirred solution of protected piperidone (−)-22 (250 mg, 1 mmol) in dichloromethane (10 mL)
was added dropwise, at room temperature, ethanedithiol (5 equiv.) then BF3·Et2O (5 equiv.). After 1
h of stirring, an excess of 2 M aqueous NaOH was added and the resulting mixture was extracted
with dichloromethane (4×20 mL). The combined organic extracts were washed with brine and dried.
Evaporation of the solvent, followed by column chromatography (ethyl acetate:methanol, 9:1), gave
protected piperidone (−)-33 as a colourless oil (241 mg, 91%). Rf 0.79 (ethyl acetate:methanol, 5:1);
[α]25=−1.9 (c 0.9, CHCl3); δH (CDCl3) 7.31 (5H, m), 3.91 (1H, dd, J=11 and 2, H-2), 3.34 (4H, m),
D
3.04 (1H, m, H-6), 2.22 (1H, td, J=12 and 2, H-3eq), 2.13 (1H, td, J=12 and 2, H-5eq), 2.05 (1H, t, J=12,
H-3ax), 1.80 (1H, t, J=12, H-5ax), 1.60 (1H, br s, NH), 1.14 (3H, d, J=7.0). This unstable compound was
directly engaged in the next step.
4.18. (−)-(2S,6S)-6-Methyl-2-phenylpiperidine 34
To a stirred solution of protected piperidone (−)-33 (132 mg, 0.5 mmol) in absolute ethanol (10 mL)
was added freshly prepared W2 Raney nickel16 (500 mg). The resulting suspension was heated at reflux
for 30 min then cooled to room temperature. The suspension was then filtered and the filtrate was
concentrated under reduced pressure. The residue was dissolved in 1 M aqueous NaOH and the piperidine
was extracted with dichloromethane (4×10 mL). The combined organic extracts were washed with brine
and dried. Evaporation of the solvent, followed by column chromatography (ethyl acetate:methanol, 5:1),
gave piperidine (−)-34 (86 mg, 98%) as a colourless oil. [α]25=−21.0 (c 0.7, CHCl3) (lit.8a [α]25=22.2
D
D
(c 0.69, EtOH) for its enantiomer). Spectral data were identical with those recently reported for (+)-34.8a

S. Ciblat et al. / Tetrahedron: Asymmetry 10 (1999) 2225–2235
2235
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