Diastereocontrolled reduction of cyclic β-enaminones. A new diastereoselective route to 2,6-disubstituted piperidines

Article abstract of DOI:10.1016/S0040-4039(01)00770-5

A new diastereoselective synthesis of 2,6-disubstituted piperidinic alkaloids is presented. Three natural compounds, the (-)-pinidinone 1a, the (+)-dihydropinidine 1b and the (-)-pinidinol 1c were prepared from optically pure (6R)-6-methylpiperidin-2-one 2. This method is based on the chemo- and diastereocontrolled reductions of an exocyclic β-enamino ketone.

Full text of DOI:10.1016/S0040-4039(01)00770-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4609–4611
Diastereocontrolled reduction of cyclic b-enaminones.
A new diastereoselective route to 2,6-disubstituted piperidines
Ste´phanie Fre´ville, Philippe Delbecq, Vu Moc Thuy, Huguette Petit, Jean Pierre Ce´le´rier and
Ge´rard Lhommet*
Universite´ P. & M. Curie, Laboratoire de Chimie des He´te´rocycles, associe´ au CNRS, 4, place Jussieu,
F-75252 Paris Cedex 05, France
Received 10 May 2001
Abstract—A new diastereoselective synthesis of 2,6-disubstituted piperidinic alkaloids is presented. Three natural compounds, the
(−)-pinidinone 1a, the (+)-dihydropinidine 1b and the (−)-pinidinol 1c were prepared from optically pure (6R)-6-methylpiperidin-2-
one 2. This method is based on the chemo- and diastereocontrolled reductions of an exocyclic b-enamino ketone. © 2001 Elsevier
Science Ltd. All rights reserved.
Substituted piperidine systems are present in many
natural compounds and some of them exhibit an exten-
sive range of biological activities.1 During our continu-
ing studies on natural products, we have recently
reported a new enantioselective synthesis of 2-substi-
tuted piperidines from chiral 6-alkylpiperidin-2-ones.2
Our strategy to a general access to these alkaloids was
based upon the easy availability of cyclic b-enamino
ketone 4.
Two approaches were described for the preparation of
such compounds.
In this paper, we describe a diastereoselective and ver-
satile approach to three cis-2,6-disubstituted piperidine
alkaloids: the (−)-pinidinone 1a, the (+)-dihydro-
pinidine 1b and the (−)-pinidinol 1c starting from a
common chiral synthon, the (6R)-6-methylpiperidin-2-
one 2 (Scheme 1).
A ‘one-pot’ condensation of acetylacetone with a lactim
ether in the presence of triethylamine led directly to a
b-enamino ketone but this method was only used with
unsubstituted lactams.8 The second way consisted in the
condensation of a b-keto ester with lactim ether fol-
lowed by a decarboxylation with boric acid.9
This optically pure piperidinic lactam is easily prepared
in a few steps from (−)-phenylglycinol and a d-keto
acid.2 If numerous asymmetric syntheses of di-
hydropinidine 1b were described in the literature,3 only
one hemisynthesis starting from natural (−)-pinidinol 1c
was published,4 followed by one enantioselective syn-
thesis of the pinidinone 1a, which was presented by
Meyers et al. from a chiral bicyclic lactam.5 The (−)-
pinidinol 1c was non-stereoselectively synthesized firstly
by Leete et al.,6 and then a long but enantioselective
approach was proposed by Momose et al.7
We have developed a general and versatile method-
ology for preparing chiral 6-substituted-b-enamino
ketones. Direct condensation of chiral lactim ether 3
with acetylacetone in the presence of catalytic nickel
acetylacetonate gave the (Z) isomer of the b-enamino
ketone 410 stereoselectively in 60% yield (Scheme 2).
* Corresponding author Fax: (33) 01 44 27 30 56; e-mail: lhommet
@ccr.jussieu.fr
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00770-5

4610
S. Fre´6ille et al. / Tetrahedron Letters 42 (2001) 4609–4611
Scheme 2.
The reduction of the CꢀC of compound 4 was the next
step of the synthesis. Catalytic hydrogenation condi-
tions were not chemoselective irrespective of the cata-
lyst employed. Thus, we carried out a chemical
reduction with lithium aluminium hydride. Under these
conditions, (−)-pinidinone 1a was regio- and
diastereoselectively obtained in 70% yield (d.e. >98%).
Scheme 4.
In order to confirm the optical purity of our product,
we finally decided to transform compound 1a into a
well-known alkaloid, namely the (+)-dihydropinidine
1b. Direct total reduction of the carbonyl function was
effected by using Clemensen conditions and then 1b
was isolated as its hydrochloride in 30% yield and in a
good optical purity: ([h]2D0 +12 (c 1.2, EtOH);13 lit. ([h]2D0
+12.7 (c 1.0, EtOH).14 The poor yield of this step was
due to the difficulties encountered during the extraction
from the Zn–Hg amalgam. The non-epimerizing condi-
tions of this reduction confirmed the structure of (−)-
pinidinone 1a.
The chemoselectivity of this reduction of an amide
vinylogous was described earlier.11 It is a 1,4-reduction
and the keto group is transformed into its enolate salt
and released during the hydrolytic work-up.
The very high diastereoselectivity observed during the
reduction can be easily rationalized by the characteristic
structure of the b-enamino ketone 4. In fact the (Z)
geometry of 4, due to an intramolecular H-bond which
planarizes the molecule, permits an axial approach of
the hydride to furnish the syn 1,3-relationship for the
two substituents of the pinidinone 1a (Scheme 3).
The last part of our work lay in the synthesis of the
(−)-pinidinol 1c, isolated from Picea engelmannii15 and
whose absolute configuration was determined by X-ray
crystal determination.16
Starting from optically pure (6R)-6-methylpiperidin-2-
one 2, (−)-pinidinone 1a was obtained in three steps
and in 26% overall yield ([h]2D0 −41 (c 0.9, EtOH).12 This
specific rotation is higher than the value proposed by
Meyers for the same enantiomer ([h]2D0 +25 (c 0.4,
EtOH).5 It can be noted that no trace of any
diastereomer was detected during our synthesis. Only
one value was proposed for the natural product ([h]D20
−4 (c 3.5, MeOH)4 but this rotation was determined
after extraction and then chemical transformation of
the mixture.
Catalytic hydrogenation conditions of 4 using Ni
Raney or Pd/C as catalysts diastereoselectively led to
only one diastereomer of 1c (Scheme 4). The asymmet-
ric secondary alcohol was then inverted, after carba-
matation, with
a
Mitsunobu’s reaction17 using
p-nitrobenzoic acid to lead to the inverted ester. After
hydrolysis and then hydrogenolysis, the (−)-pinidinol 1c
was isolated with a very good optical purity: ([h]D20
−17.5 (c 0.63, CHCl3);18 lit. ([h]D20 −17 (c 0.99, CHCl3).15
This synthesis is a highly enantioselective route to
(−)-pinidinol starting from non-natural material.
In conclusion, we have reported a new, versatile and
diastereoselective synthesis of 2,6-disubstituted piperi-
dinic alkaloids starting from an easily available chiral
lactam.
Acknowledgements
The authors are grateful to DSM Andeno, The Nether-
lands, for the generous gift of precursor of
phenylglycinol.
Scheme 3.

S. Fre´6ille et al. / Tetrahedron Letters 42 (2001) 4609–4611
4611
References
46.9, 92.7, 163.3, 193.6; Eb (0.1 mmHg) 105°C; [h]2D0 −92
(c 1.0, EtOH).
1. (a) Bailey, P. D.; Millwood, P. A.; Smith, P. D. J. Chem.
Soc., Chem. Commun. 1998, 633–640 and references cited
therein; (b) Katritzky, A. R.; Qiu, G.; Yang, B.; Steel, P.
J. J. Org. Chem. 1998, 63, 6699–6703.
11. (a) Walker, G. N. J. Org. Chem. 1962, 27, 4227–4231; (b)
Martin, J. C.; Barton, K. R.; Gott, P. G.; Meen, R. H. J.
Org. Chem. 1966, 31, 943–945; (c) Schuda, P. F.; Ebner,
C. B.; Moargan, T. N. Tetrahedron Lett. 1986, 27, 2567–
2570; (d) Michael, J. P.; Parsons, A. S. Tetrahedron 1996,
52, 2199–2216.
2. Fre´ville, S.; Ce´le´rier, J. P.; Thuy, V. M.; Lhommet, G.
Tetrahedron: Asymmetry 1995, 6, 2651–2654.
3. (a) Hill, R. K.; Yuri, T. Tetrahedron 1997, 33, 1569–1571;
(b) Grierson, D. S.; Royer, J.; Guerrier, L.; Husson, H.
P. J. Org. Chem. 1986, 51, 4475–4477; (c) Grierson, D. S.;
Royer, J.; Guerrier, L.; Husson, H. P. Heterocycles 1992,
33, 17–20; (d) Takahata, H.; Bandoh, H.; Hanayama, M.;
Momose, T. Tetrahedron: Asymmetry 1992, 3, 607–608.
4. Tawara, J. N.; Blokhin, A.; Foderaro, T. A.; Stermitz, F.
R.; Hope, H. J. Org. Chem. 1993, 58, 4813–4818.
5. Munchhof, M. J.; Meyers, A. I. J. Am. Chem. Soc. 1995,
117, 5399–5400.
12. Spectral data for 1a: 1H NMR (250 MHz, CDCl3): l 1.10
(d, 3H, J=6.4 Hz), 1.20–1.80 (m, 6H), 2.14 (s, 3H), 2.60
(d, 2H, J=6.3 Hz), 2.72 (m, 1H), 3.05 (m, 1H), 10.51 (m,
1H); 13C NMR (62.5 MHz, CDCl3): l 22.8, 24.5, 30.6,
31.6, 33.6, 50.2, 52.1, 52.4, 208.5; [h]2D0 −41 (c 0.9, EtOH).
13. Spectral data for 1b·HCl: 1H NMR (250 MHz, CDCl3): l
0.85 (t, 3H, J=7.4 Hz), 1.10–1.24 (m, 10H), 1.53 (d, 3H,
J=6.5 Hz), 2.85 (m, 1H), 3.00 (m, 1H), 9.01 (m, 1H); 13C
NMR (62.5 MHz, CDCl3): l 13.7, 18.8, 19.5, 22.9, 27.5,
30.7, 35.2, 54.5, 58.4; F (acetonitrile) 210°C; [h]2D0 +12 (c
1.2, EtOH).
6. Leete, E.; Carver, R. A. J. Org. Chem. 1975, 40, 2151–
2153.
14. Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H. P. J.
7. Takahata, H.; Yotsui, Y.; Momose, T. Tetrahedron 1998,
54, 13505–13516.
8. Oishi, T.; Nagai, M.; Onuma, T.; Moriyama, H.; Tsutae,
K.; Ochiai, M.; Ban, Y. Chem. Pharm. Bull. Jpn. 1969,
17, 2306–2313.
Am. Chem. Soc. 1983, 105, 7754–7755.
15. Schneider, M.; Stermitz, F. R. Phytochemistry 1990, 29,
1811–1814.
16. Stermitz, F. R.; Miller, M. M.; Schneider, M. J. J. Nat.
Prod. 1990, 53, 1019–1020.
9. Delbecq, P.; Bacos, D.; Ce´le´rier, J. P.; Lhommet, G. Can.
17. Hughes, D. H. Org. React. 1992, 42, 335–656.
18. Spectral data for 1c: H NMR (250 MHz, CDCl3): l 1.00
1
J. Chem. 1991, 69, 1201–1206.
1
10. Spectral data for 4: H NMR (250 MHz, CDCl3): l 1.10
(d, 3H, J=6.2 Hz), 1.10 (d, 3H, J=6.2 Hz), 1.20–1.80
(m, 8H), 2.60 (m, 1H), 2.90 (m, 1H), 4.10 (m, 1H); 13C
NMR (62.5 MHz, CDCl3): l 22.3, 23.6, 24.2, 29.9, 32.9,
43.2, 52.9, 54.9, 64.4; [h]2D0 −18 (c 0.63, CHCl3).
(d, 3H, J=6.4 Hz), 1.25–1.87 (m, 4H), 1.92 (s, 3H), 2.20
(m, 2H), 3.41 (m, 1H), 4.85 (s, 1H), 11.0 (s, 1H); 13C
NMR (62.5 MHz, CDCl3): l 18.5, 22.4, 27.8, 28.2, 30.2,
.