Diastereoselective synthesis of trisubstituted piperidines: A versatile synthon for elaboration of uncommon poly(aza)heterocyclic structures

Article abstract of DOI:10.1016/j.tetlet.2011.09.148

Hetero Michael addition on chiral β′-amino-α,β- unsaturated ketone furnished, after some structural modifications, β,β′-diaminoketals. Mannich type reaction of these diamines with an aldehyde led, with a high diastereoselectivity, to trisubstituted piperidines. Starting from a functionalized aldehyde and after subsequent deprotection of the amino group, an intramolecular Michael addition provided octahydro-2H-pyrrolo-[3,4-b]-pyridine, an uncommon framework found in compounds exhibiting biological activity.

Full text of DOI:10.1016/j.tetlet.2011.09.148

Tetrahedron Letters 52 (2011) 6873–6876
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective synthesis of trisubstituted piperidines: a versatile synthon
for elaboration of uncommon poly(aza)heterocyclic structures
⇑
⇑
Aurélie Plas, Isabelle Abrunhosa-Thomas, Pierre Chalard , Yves Troin
Clermont Université, ENSCCF, EA 987, LCHG, BP 10448, F-63000 Clermont-Ferrand, France
a r t i c l e i n f o
a b s t r a c t
Hetero Michael addition on chiral b0-amino-
a
,b-unsaturated ketone furnished, after some structural
Article history:
Received 12 July 2011
Revised 29 September 2011
Accepted 30 September 2011
Available online 6 October 2011
modifications, b,b0-diaminoketals. Mannich type reaction of these diamines with an aldehyde led, with
a high diastereoselectivity, to trisubstituted piperidines. Starting from a functionalized aldehyde and
after subsequent deprotection of the amino group, an intramolecular Michael addition provided octahy-
dro-2H-pyrrolo-[3,4-b]-pyridine, an uncommon framework found in compounds exhibiting biological
activity.
Keywords:
b,b0-Diaminoketals
Ó 2011 Elsevier Ltd. All rights reserved.
Diastereoselective synthesis
Octahydro-2H-pyrrolo-[3,4-b]-pyridine
Intramolecular Mannich reaction
Intramolecular Michael addition
Natural products synthesis, by their structural complexity, is al-
ways the source of discovery and innovation of new selective
methods which can compete with these provided by the nature.
So, there is still a great interest in developing new synthetic path-
ways which include chemo, regio and stereoselectivity. In this con-
text, we have recently disclosed the diastereoselective synthesis of
2- and 2,6-substituted piperidines using an intramolecular Michael
synthesis of N-Boc-2-phenylpiperidine 1 is described in Scheme 1
to illustrate this approach.2
We wish to describe herein the extension of this methodology
to the diastereoselective synthesis of enantiomerically pure 2,3,6-
trisubstituted piperidines and their application in the preparation
of octahydro-2H-pyrrolo-[3,4-b]-pyridine, an uncommon frame-
work found in compounds exhibiting biological activity.4 Initially
we planned to take advantage of this newly created Michael
type reaction1 starting from b0-amino-
a,b-unsaturated ketone. The
HOCH2CH2OH
p-TsOH
CH(OMe)3
O
O
ZNH
Ph
O
ZNH
O
MgBr
60%
Me
N
Ph
Ph
N
Z
4
OMe
96%
23
3
1°)
2°)
HSCH2CH2SH
BF3.OEt2
S
S
Ni Raney
quant.
73%
(Boc)2O
DMAP
76%
[α]D25 +80.8 (c 0.95 in CHCl3)
(lit.3 +83.7)
Ph
N
Ph
N
Boc
Boc
5
1
Scheme 1. Diastereoselective synthesis of 2-substituted piperidine.
⇑
Corresponding authors. Tel.: +33 473 407 993; fax: +33 473 407 008.
E-mail address: pierre.chalard@univ-bpclermont.fr (P. Chalard).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.148

6874
A. Plas et al. / Tetrahedron Letters 52 (2011) 6873–6876
acceptor 3 to promote the intermolecular introduction of a nucle-
ophile such as various amines. Unfortunately, the use of vinylmag-
nesium bromide on Weinreb amide 2 provides always a byproduct
6, in low to moderate yield, resulting from the condensation of N,O-
dimethylhydroxylamine on the new generated double bond5
(Scheme 2). In consequence, a new pathway to obtain compound
of type 3 has to be found.
To develop a new access to b0-amino-
a,b-unsaturated ketones,
we chose the morpholine route as described in Scheme 3. So, con-
densation of morpholine with N-protected aminobutanoic acid 8,
available from the saponification of b-aminoester 7,6 in the pres-
ence of carbonyldiimidazole provided adduct 9 in very good yield.
Further alkylation with vinyl Grignard reagent gave as the only
reaction product the desired b0-amino-
a,b-unsaturated ketone 10
ZNH
Ph
O
ZNH
Ph
O
ZNH
Ph
O
MgBr
Me
Me
N
+
N
OMe
6
OMe
3
2
60%-40%
30%-10%
Scheme 2. Condensation of vinylmagnesium bromide on Weinreb amide.
ZNH
Me
O
morpholine
CDI
ZNH
Me
O
ZNH
Me
O
NaOH 1.5M
quant.
OMe
ZNH
OH
N
95%
8
7
9
O
HNPht
O
ZNH
Me
O
Triton B®
MgCl
1°) HO(CH2)3OH
Me
2°) H2NNH2
quant.
NPht
70%
60%
10
11
1°) TFAA
DMAP
H2N
O
ZNH
O
O
O
O
Me
N
H
CF3
2°) HCO2NH4
Pd/C
Me
NH2
13
12
95%
Scheme 3. Morpholine route to access b,b0-diaminoketal 13.
Figure 1. Determination of enantiomeric purity of amine 13 using chiral
a-methylbenzyl isocyanate.

A. Plas et al. / Tetrahedron Letters 52 (2011) 6873–6876
6875
O
HN
R
CF3
1°) MgSO4
O
O
H2N
O
CH2Cl2
O
O
+
RCHO
Me
N
H
CF3
2°) p-TsOH
Me
N
H
14
13
15a : 55%
15b : 60%
14a : R =
14b: R =
EtO2C
Scheme 4. Diastereoselective synthesis of the piperidines 15a and 15b by intramolecular Mannich reaction.
Table 1
Coupling constants for piperidine 15a
O
HN
CF3
H2ax
H3ax
H6ax
H2ax
O
O
O
O
O
JH2ax-Heth = 8.4 Hz
JH2ax-H3ax = 10.3 Hz
JH3ax-H2ax = 10.3 Hz
JH3ax-H11 = 7.8 Hz
JH3ax-H11 = 3.2 Hz
IRA 401
NH
Me
HN
O
0
11
MeOH
60%
Me
N
H
CO2Et
NHCOCF3
Me
N
H
H3ax
CO2Me
15b
15a
16
mixture of 2 diastereoisomers
H6ax
H5ax
H5eq
JH6ax-H5ax = 11.9 Hz
JH6ax-CH3 = 6.2 Hz
JH6ax-H5eq = 2.3 Hz
JH5ax-H5eq = 13.3 Hz
JH5ax-H6ax = 11.9 Hz
JH5eq-H5ax = 13.3 Hz
JH5eq-H6ax = 2.3 Hz
O
O
O
O
ZCl
35%
NZ
NZ
+
Me
N
Z
Me
N
Z
in a reproducible yield of 60%. Further aza-Michael addition of
phthalimide upon 10 in the presence of Triton BÒ led to adduct
11 in 70% yield. Protection of the ketone as a dioxane followed
by hydrazinolysis of the phthalimide moiety furnished the desired
amine 12 in quantitative yield. Treatment of 12 with TFAA led to
the trifluoroacetamide derivative which is deprotected by hydrog-
enolysis of the CBz appendage, realized with ammonium formate
in the presence of palladium on charcoal in refluxing methanol,6
to give amine 13, which was prepared in eight steps starting from
7 in 32% overall yield.
MeO2C
MeO2C
17b
17a
1 : 3
Scheme 5. Synthesis of octahydro-2H-pyrrolo-[3,4-b]-pyridines 17.
centres have been determined without any ambiguity by NOESY
experiments.
We have thus developed an efficient route in order to obtain
optically pure tri-substituted piperidines. This synthesis is based
on an intramolecular Mannich type reaction and furnished an ac-
cess to a stereoselective synthesis of octahydro-2H-pyrrolo-[3,4-
b]-pyridine framework. Further applications and use of compounds
15 will be described in the near future.
We have checked the enantiomeric purity of diaminoketal 13 by
1H NMR spectroscopy with
a-methylbenzylisocyanate as the chiral
derivative agent.7 Comparison of signals obtained for both methyl
groups in the racemic ( )-13 and its isomeric (ꢀ)-13 forms, demon-
strated an excellent stereoisomeric ratio, proving that no racemisa-
tion occurred throughout the synthesis (Fig. 1).
Thus, condensation of amine (ꢀ)-13 with aldehydes 14a,b un-
der conditions developed by our group (intramolecular Mannich
type cyclisation)8 gave the corresponding piperidines 15a and
15b as a single diastereomer (Scheme 4).9
Acknowledgment
We thank the Ministère de la Jeunesse, de l’Education Nationale
et de la Recherche for financial support.
As usual, the stereochemistry of piperidines 15 was confirmed
by careful examination of the coupling constants between H5/H6
3
References and notes
and H2/H3 (Table 1). For compound 15a, the value of JH2-H3
(10.3 Hz) proves that these two protons are in axial position, so,
the two substituents on C-2 and C-3 are in a trans relative position.
Moreover, the signal of H6 shows a trans diaxial coupling constant
with H5ax (11.9 Hz) proving that the substituents of the piperidine
on the C-2 and C-6 are in the cis position.9 NMR spectra of piperi-
dine 15b present the same coupling constants for H2, H5 and H6.
Treatment of 15b with IRA 401 resin10 in methanol led to the
1. Abrunhosa-Thomas, I.; Roy, O.; Barra, M.; Besset, T.; Chalard, P.; Troin, Y. Synlett
2007, 987–990.
2. Hunt, J. C. A.; Laurent, P.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 2002, 2378.
3. Enantiomeric purity of compound 2 has been previously demonstrated: see
Davies, S. G.; Brackenridge, I.; Fenwick, D. R.; Ichihara, O.; Polywka, M. E. C.
Tetrahedron 1999, 55, 533–540. and references cited therein.
4. (a) Li, Q.; Chu, D. T. W.; Claiborne, A.; Cooper, C. S.; Lee, M. C.; Raye, K.; Berst, K.
B.; Donner, P.; Wang, W.; Hasvold, L.; Fung, A.; Ma, Z.; Tufano, M.; Flamm, R.;
Shen, L. L.; Baranowski, J.; Nilius, A.; Alder, J.; Meulbroek, J.; Marsh, K.; Crowell,
D.; Hui, Y.; Seif, L.; Melcher, L. M.; Henry, R.; Spanton, S.; Faghih, R.; Klein, L. L.;
Tanaka, S. K.; Plattner, J. J. Med. Chem. 1996, 39, 3070–3088; (b) Creighton, C.;
Tari, L.; Chen, Z.; Hilgers, M.; lam, T.; Li, X.; Tazon, M.; Zhang, J.; Finn, J. PCT Int.
Appl. 2011, WO 2011032050.; (c) Tachibana, Y.; Miyagawa, M.; Masuda, T.;
Hasegawa, T. PCT Int. Appl. 2011, WO 2011013752.; (d) Black, R. A.; Gfesser, G.
A.; Gregory, G.; Cowart, M. D. PCT Int. Appl. 2010, US 0331294.; (e) Zhang, X.;
Jiang, W.; Sui, Z. J. Org. Chem. 2003, 68, 4523–4526.
intramolecular condensation of
a,b-unsaturated ester function,
furnishing compound 16 as a mixture of diastereoisomers which
could not be separated by column chromatography (Scheme 5).
Transformation of this mixture to the di-CBz derivative gave the
two diastereoisomers 17a and 17b which could be now separated
albeit in poor yield.11 The relative configurations of the stereogenic

6876
A. Plas et al. / Tetrahedron Letters 52 (2011) 6873–6876
5. Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.; Yang, B.; Bowen, K.; Lee, S.
H.; Eardley, J. H. J. Org. Chem. 2005, 70, 2184–2190.
6. Bariau, A.; Canet, J.-L.; Chalard, P.; Troin, Y. Tetrahedron: Asymmetry 2005, 16,
3650–3660.
7. (a) Gosselin, F.; Lubell, W. D. J. Org. Chem. 1998, 63, 7463–7471; (b) Ibrahim, H.
H.; Lubell, W. D. J. Org. Chem. 1993, 58, 6438–6441.
(m, 1H), 1.64 (ddd, 1H, J = 4.0, 7.4, 11.0), 1.57 (s, 1H), 1.44 (d, 1H, J = 13.9), 1.27
(t, 3H, J = 7.1), 1.10 (d, 3H, J = 6.2), 1.05 (dd, 1H, J = 11.9, 13.5); 13C NMR
(101 MHz, CDCl3) d 165.8, [156.6, 156.3] (q, J = 36.2), 146.6, 124.7, [117.4,
114.8] (q, J = 263), 99.3, 60.7, 59.5, 59.4, 56.8, 47.7, 47.3, 37.0, 36.0, 25.5, 22.3,
14.3; HR-ESI-MS: calculated for
found:395.1781; [ D = +37.8 (c 1.013, CHCl3).
C
15H26N2O5F3 (M+H)+: 395.1794,
a
]
8. (a) Ciblat, S.; Calinaud, P.; Canet, J.-L.; Troin, Y. J. Chem. Soc., Perkin Trans. 1
2000, 353–357; (b) Rougnon-Glasson, S.; Tratrat, C.; Canet, J.-L.; Chalard, P.;
Troin, Y. Tetrahedron: Asymmetry 2004, 15, 1561–1567. and references cited
therein.
10. Tietze, L. F.; Schneider, C.; Grote, A. Chem. Eur. J. 1996, 2, 139–148.
11. Compound 17a: 1H NMR (400 MHz, C6D6) d 7.34–6.97 (m, 10H), 5.16–5.00 (m,
4H), 4.60 (m, 1H), 4.28 (dd, 1H, J = 7.2, 12.0), 4.15 (m, 1H), 4.03 (m, 1H), 3.97–3.86
(m, 2H), 3.80 (t, 1H, J = 14.6), 3.46–3.16 (m, 7H), 2.48 (td, 1H, J = 7.2, 12.0), 1.79 (d,
1H, J = 13.8), 1.57 (m, 1H), 1.33 (dd, 1H, J = 4.8, 13.8), 1.25 (m, 1H), 1.16 (d, 3H,
J = 7.0), 0.56 (m, 1H); 13C NMR (101 MHz, C6D6) d 172.1, 156.4, 128.8, 128.6,
128.5, 128.4, 96.6, 67.2, 66.8, 60.3, 59.6, 59.2, 58.9, 50.9, 50.8, 49.8, 43.8, 37.0,
33.9, 25.5, 22.8; HR-ESI-MS: calculated for C30H36N2O8Na (M+Na)+: 575.2369,
9. Piperidine 15a: 1H NMR (400 MHz, CDCl3) d 1H NMR (400 MHz, CDCl3) d 7.98 (s,
1H), 5.62 (dq, 1H, J = 7.6, 15.3), 5.30 (dd, 1H, J = 8.4, 15.3), 4.10 (td, 1H, J = 2.3,
12.6), 4.00 (td, 1H, J = 2.3, 12.6), 3.85 (m, 2H), 3.57 (m, 1H), 3.48 (m, 1H), 3.19
(dd, 1H, J = 8.4, 10.3), 2.84 (dqd, 1H, J = 2.3, 6.2, 11.9), 2.78 (dd, 1H, J = 2.3, 13.3),
2.02 (m, 1H), 1.66 (d, 3H, J = 7.6), 1.52 (ddd, 1H, J = 3.2, 7.8, 10.3), 1.42 (m, 2H),
1.10 (d, 3H, J = 6.2), 1.02 (dd, 1H, J = 11.9, 13.3); 13C NMR (CDCl3, 100 MHz) d
[156.6, 156.3] (q, J = 36), 131.6, 130.2, [117.7, 114.8] (q, J = 263), 99.6, 59.5,
59.3, 58.2, 48.1, 47.3, 37.1, 36.0, 25.6, 22.4, 18.0; HR-ESI-MS: calculated for
found: 575.2378; [a]
D = +85.2 (0.94, CHCl3). Compound 17b: 1H NMR (400 MHz,
CDCl3) d 7.48–7.28 (m, 10H), 5.26–4.99 (m, 4H), 4.88 (d, 1H, J = 6.9), 4.50 (m, 1H),
4.00 (t, 1H, J = 11.2 Hz,), 3.84 (m, 4H), 3.76 (dd, 1H, J = 6.8, 13.2), 3.69–3.50 (m,
5H), 2.74 (m, 1H), 2.43 (d, 2H, J = 14.5), 2.26 (dd, 1H, J = 7.4, 13.6), 2.01 (m, 2H),
1.35 (t, 4H, J = 7.2 Hz); 13C NMR (101 MHz, CDCl3) d 171.5, 156.5, 128.7, 128.5,
128.4, 128.3, 128.1, 128.0, 95.9, 67.9, 67.2, 66.9, 59.9, 59.6, 57.9, 55.4, 52.0, 49.2,
44.2, 42.6, 35.5, 35.0, 25.7, 23.2; HR-ESI-MS : calculated for C30H36N2O8Na
C
15H24N2O3F3 (M+H)+: 337.1739, found: 337.1737;
[a]D = +16.96 (c 1.025,
CHCl3). Piperidine 15b: 7.97 (s, 1H), 6.75 (dd, 1H, J = 8.6, 15.6), 5.94 (d, 1H,
J = 15.6), 4.11 (q, 2H, J = 7.1), 4.01 (m, 2H), 3.86 (m, 2H), 3.49 (m, 2H), 3.40 (dd,
1H, J = 8.6, 11.0), 2.89 (dqd, 1H, J = 2.4, 6.2, 11.9), 2.80 (dd, 1H, J = 2.4, 13.5), 2.02
(M+Na)+: 575.2369, found: 575.2388; [
a]D = ꢀ17.3 (0.46, CHCl3).