Novel and stereocontrolled synthesis of enantiopure and polyalkyl substituted piperidines

Article abstract of DOI:10.1055/s-1998-1725

A flexible and stereodivergent synthesis of enantiopure piperidines with up to four alkyl-substituted chiral centers is reported which proceeds by way of a double nucleophilic addition of primary amines to the 7-oxo-2-enimides 1. These in turn are accessible via the silyloxy-Cope rearrangement of chiral syn-aldol products.

Full text of DOI:10.1055/s-1998-1725

652
LETTERS
SYNLETT
Novel and Stereocontrolled Synthesis of Enantiopure and Polyalkyl Substituted Piperidines
Christoph Schneider* and Christoph Börner
Institut für Organische Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, D-37077 Göttingen, Germany
Fax: +49-551-399660, e-mail: cschnei1@gwdg.de
Received 27 February 1998
Abstract: A flexible and stereodivergent synthesis of enantiopure
piperidines with up to four alkyl-substituted chiral centers is reported
which proceeds by way of a double nucleophilic addition of primary
amines to the 7-oxo-2-enimides 1. These in turn are accessible via the
silyloxy-Cope rearrangement of chiral syn-aldol products.
Nitrogen-containing heterocycles are abundant in nature and exhibit
1
diverse and important biological properties. One of the parent systems,
the piperidine ring, is contained in numerous physiologically active
2
compounds, e.g. coniine, lupetidine, and sedamine. Accordingly, novel
strategies for the stereoselective synthesis of enantiopure piperidines
continue to receive considerable attention in the field of synthetic
organic chemistry. In the past, additions of organometallic reagents to
3
4
N-acyl pyridinium salts, hetero Diels-Alder reactions with imines ,
Lewis acid- or electrophile-induced cyclizations of imines or iminium
Scheme 2
5
6
ions and reactions of bicyclic cyano piperidines and lactams have been
employed for this purpose to mention the most prominent routes.
Recently, we have established that 1,5-hexadienes with a syn-aldol
substitution pattern undergo rapid thermal Cope rearrangements with
7
excellent levels of stereocontrol (Scheme 1). The rearrangement
products 1 are highly functionalized and have been shown to be useful
8
precursors for the synthesis of enantiopure tetrahydropyrans and
9
polyols. In addition, a total synthesis of the monoterpenol (+)-lasiol has
10
been achieved using this methodology.
amine a clean and quantitative formation of the imines 5 occurred
without any indication for cyclization giving the nitrogen heterocycle
(Scheme 3). Apparently, the reactivity of the enoate towards a conjugate
addition is considerably attenuated compared to the enimides.
Subsequent addition of trimethylsilyl cyanide furnished the amino
Scheme 1
nitriles
6
as 1:1 mixtures of stereoisomers. Cyclization was
accomplished with triton B in methanol and the 2-cyano piperidines
7a,b were obtained in 75% and 81% yield, respectively. In contrast to
the piperidines 2 the cyano piperidines 7a,b have a homogenous β-
configuration at the newly formed chiral center with the C-2 alkyl group
in the equatorial position.
In our continuing efforts to devise further synthetic applications we
made the striking observation that primary amines, e. g. benzyl amine,
undergo a double nucleophilic addition to the 7-oxo-2-enimides 1
yielding initially the sensitive tetrahydropyridines which were
subsequently hydrogenated to furnish the stable 2,3,4-trisubstituted
13
11
piperidines 2 (Scheme 2). As a mechanistic rationale we propose that
the amine initially attacks the aldehyde 1 to form the imine whose
enamine tautomer rapidly adds to the α,β-unsaturated imide to form the
nitrogen heterocycle through the half chair-like transition state 3.
The stereoselectivity of the cyclization (20:1) is remarkable, the major
isomer being the piperidine with the C-2 alkyl group in the axial
position. Control experiments with the oxoenimide bearing the achiral
oxazolidinone reveal that the stereogenic centers in the chain rather than
the chiral auxiliary determine the stereochemistry at the newly formed
chiral center. Stereoelectronic reasons may be put forth to explain this
stereoselectivity with a more efficient overlap of the nitrogen lone pair
and the π*-orbital of the conjugated double bond in the pre-axial
orientation. Related intramolecular Michael additions of ester enolates
Scheme 3
to enoates in
a
synthesis of cyclohexanes exhibit the same
12
stereochemical preference, albeit less pronounced.
These observations parallel the trend seen in the tetrahydropyran
synthesis. In the case of the enimides 1 a kinetically controlled
On the contrary, when 7-oxo-2-enoates 4 readily obtained from the
imides 1 by esterification with MgClOMe were treated with benzyl
8

June 1998
SYNLETT
653
cyclization takes place to give the axially substituted piperidines 2
whereas the amino nitriles 6 bearing the enoate moiety undergo a
reversible cyclization to deliver exclusively the thermodynamically
more stable cyano piperidines 7a,b with the C-2 alkyl group in the
References and Notes
1.
2.
3.
G. M. Strunz, J. A. Findlay The Alkaloids, Academic Press, New
York 1985, 26, 89; A. R. Pinder Nat. Prod. Rep. 1993, 10, 491.
I. W. Southon, J. Buckingham Dictionary of Alkaloids, Chapman
and Hall, London 1989.
14
equatorial position. Control experiments support this conclusion.
R. Yamaguchi, M. Moriyasu, M. Yoshioka, M. Kawanisi, J. Org.
Chem. 1988, 53, 3507-3512; D. L. Comins, M. O. Killpack, J. Am.
Chem. Soc. 1992, 114, 10973-10974; D. L. Comins, S. P. Joseph,
R. R. Goehring, J. Am. Chem. Soc. 1994, 116, 4719-4728.
4.
P. A. Grieco, S. D. Larsen, J. Am. Chem. Soc. 1985, 107, 1768-
1769; M. M. Midland, J. I. McLoughlin, Tetrahedron Lett. 1988,
29, 4653-4656, H. Kunz, W. Pfrengle, Angew. Chem., Int. Ed.
Engl. 1989, 28, 1067-1068; H. Waldmann, M. Braun, M. Dräger,
ibid. 1990, 29, 1468-1470; H. Waldmann, M. Braun, J. Org.
Chem. 1992, 57, 4444-4451; M. M. Midland, R. W. Koops, ibid.
1992, 57, 1158-1161; K. Hattori, H. Yamamoto, Tetrahedron
1993, 49, 1749-1760; K. Ishihara, M. Miyata, K. Hattori, T. Tada,
H. Yamamoto, J. Am. Chem. Soc. 1994, 116, 10520-10524.
5.
C. Flann, T. C. Malone, L. E. Overman, J. Am. Chem. Soc. 1987,
109, 6097-6107; L. F. Tietze, M. Bratz, Chem. Ber. 1989, 122,
997-1002; L. E. Overman, A. K. Sarkar, Tetrahedron Lett. 1992,
33, 4103-4106; P. Castro, L. E. Overman, X. Zhang, P. S.
Mariano, ibid. 1993, 34, 5243-5246; N. deKimpe, M. Boelens, J.
Piqueur, J. Baele, ibid. 1994, 35, 1925-1928; T.-K. Yang, T.-F.
Teng, J.-Y. Lin, Y.-Y. Lay, ibid. 1994, 35, 3581-3582; S. Laschat,
R. Fröhlich, B. Wibbeling, J. Org. Chem. 1996, 61, 2829-2838.
Scheme 4
Treatment of the cyano piperidine 7a with silver triflate in acetonitrile
15
according to the strategy developed by Husson gave rise to the
iminium salt which was trapped with organozinc reagents to furnish the
2,3,4,6-tetrasubstituted piperidines 8a,b in good yields, but as 1:1
mixtures of stereoisomers (Scheme 4). The organometallic addition to
the iminium ion derived from 7b, however, proceeded with high
stereoselectivity (10:1) to deliver predominantly the 2,6-trans
6.
L. Guerrier, J. Royer, D. S. Grierson, H.-P. Husson, J. Am. Chem.
Soc. 1983, 105, 7754-7755; M. Bonin, D. S. Grierson, J. Royer,
H.-P. Husson, Org. Synth. 1991, 70, 54; M. Amat, N. Llor, J.
Bosch, Tetrahedron Lett. 1994, 35, 2223-2226; L. Micouin, T.
Varea, C. Riche, A. Chiaroni, J.-C. Quirion, H.-P. Husson, ibid.
1994, 35, 2529-2532; M. J. Munchhof, A. I. Meyers, J. Am. Chem.
Soc. 1995, 117, 5399-5400; D. Francois, M. C. Lallemand, M.
Selkti, A. Tomas, N. Kunesch, H.-P. Husson, Angew. Chem. Int.
Ed. 1998, 37, 104-105.
16
piperidines 9a,b. Their NMR spectra display the characteristic AB
system for the diastereotopic N-benzyl protons which was first
17
described by Hill for 2,6-trans-substituted N-benzyl piperidines.
To account for this high selectivity the two half-chair conformations A
and B of the iminium ion are inspected (Scheme 5). The nucleophilic
addition proceeds through conformation
A which is attacked
preferentially from the bottom side to avoid steric interactions with the
axially oriented C-3 methyl group in spite of developing A (1,2) strain
between the benzyl group and the C-2 alkyl substituent.
7.
C. Schneider, M. Rehfeuter, Synlett 1996, 212-214; C. Schneider,
M. Rehfeuter, Tetrahedron 1997, 53, 133-144; for independent
work in this area see: W. C. Black, A. Giroux, G. Greidanus,
Tetrahedron Lett. 1996, 37, 4471-4474; K. Tomooka, A.
Nagasawa, S.-Y. Wei, T. Nakai, ibid. 1996, 37, 8899-8900.
8.
9.
C. Schneider, Synlett 1997, 815-817.
C. Schneider, M. Rehfeuter, Tetrahedron Lett. 1998, 39, 9-12.
10. C. Schneider, Eur. J. Org. Chem. 1998, submitted.
Scheme 5
20
11. Spectroscopic data for compound 2a: [α]
= +10.0 (c = 0.30,
D
1
CHCl ); H NMR (500 MHz, CDCl ): δ = 0.87 (d, J= 6.8 Hz, 3 H,
3
3
CH ), 0.91 (d, J= 5.8 Hz, 3 H, CH ), 1.30-1.43 (m, 3 H, 4´-H, 5´-
In conclusion, we have developed a novel and stereoselective approach
towards the synthesis of enantiopure and highly substituted piperidines.
Studies towards the synthesis of condensed nitrogen heterocycles and
the application of this strategy towards natural product synthesis are
currently in progress and will be reported in due course.
3
3
H ), 1.74 (mc, 1 H, 3´-H), 2.58 (ddd, J= 12.5, 5.0, 3.0 Hz, 1 H, 6´-
2
H), 2.75 (dd, J= 13.5, 9.5 Hz, 1 H, benzyl-H), 2.77 (dt, J= 3.0,
12.5 Hz, 1 H, 6´-H), 2.95 (dd, J= 15.5, 4.5 Hz, 1H, CHCOX ),
c
3.32 (dd, J= 13.5, 3.5 Hz, 1 H, benzyl-H), 3.34 (dd, J= 15.5, 8.0
Hz, 1 H, CHCOX ), 3.53 (dt, J= 8.0, 4.5 Hz, 1 H, 2´-H), 3.58 (d,
c
J= 13.0 Hz, 1 H, PhCHN), 3.79 (d, J= 13.0 Hz, 1 H, PhCHN),
4.04 (dd, J= 9.0, 8.0 Hz, 1 H, 5-H), 4.10 (dd, J= 9.0, 3.5 Hz, 1 H,
Acknowledgement. This research was generously supported by the
Deutsche Forschungsgemeinschaft (Schn 441/1-1) and the Fonds der
Chemischen Industrie. We would like to thank Prof. Overman, Irvine,
and Prof. Effenberger, Stuttgart, for valuable suggestions and Prof.
Tietze for his continuous support. The donation of L-phenylalanine from
Degussa AG is gratefully acknowledged.
5-H), 4.61 (dddd, J= 9.5, 8.0, 3.0, 3.0 Hz, 1 H, 4-H), 7.20-7.30 (m,
13
5 H, phenyl-H); C NMR (50 MHz, CDCl ): δ = 15.9, 19.8, 30.3,
3
31.9, 32.0, 37.8, 38.0, 45.5, 55.5, 58.5, 60.1, 65.9, 126.7, 127.2,
128.0, 128.6, 128.9, 129.4, 135.4, 140.1, 153.3, 172.9; IR (film):
-1
+
+
v= 1786, 1700 cm ; MS (EI): m/z = 420 (6) [M ], 202 (58) [M -
CH COX ], 91 (100) [benzyl]. Anal. calcd. for C N O : C
H
26 32 2 3
2
c
74.26, H 7.67; found C 74.54, H 7.56.

654
LETTERS
SYNLETT
12. E. Yoshii, K. Hori, K. Nomura, K. Yamaguchi, Synlett 1995, 568-
and treating it again with triton B in methanol leads to a complete
epimerization at C-6.
570.
15. D. S. Grierson, M. Harris, H. P. Husson, J. Am. Chem. Soc. 1980,
102, 1064-1082; D. S. Grierson, M. Harris, H. P. Husson,
Tetrahedron 1983, 39, 3683-3694; C. Caderas, R. Lett, L. E.
Overman, M. H. Rabinowitz, L. A. Robinson, M. J. Sharp, J.
13. Typical experimental procedure: 184 mg (1.00 mmol) aldehyde 4b
are condensed with 0.11 ml (1.00 mmol) benzyl amine in 10 ml
toluene containing 1 g MgSO . The crude imine 5b is dissolved in
4
dry CH Cl and treated with 0.14 ml (1.10 mmol) TMSCN for 2 h
2
2
Zablocki, J. Am. Chem. Soc. 1996, 118, 9073-9082.
at rt. After evaporation of the solvent and chromatographic
purification on silica gel (ether/petroleum ether = 2:1) 270 mg
(90%) of the amino nitrile 6b are obtained. Cyclization of 6b is
accomplished with 0.42 ml (1.00 mmol) of triton B (40% in
methanol) in 5 ml methanol for 12 h at rt. Aqueous workup and
chromatographic purification (silica gel, ether/petroleum ether =
1:2) gave 243 mg (90%) of the cyano piperidine 7b. The
piperidine is dissolved in 5 ml dry THF and treated with 228 mg
(0.90 mmol) silver triflate for 5 min at rt. An allyl zinc bromide
solution made of 160 mg (2.43 mmol) zinc dust and 0.10 ml (1.20
mmol) allyl bromide in 5 ml DMF is added at 0°C and stirring is
continued for 10 min at 0°C. Aqueous workup and
chromatographic purification (silica gel, ether/petroleum ether =
1:2) gave 198 mg (78%) of the piperidine 9a.
20
16. Spectroscopic data for compound 9a: [α]
= +9.4 (c = 0.5,
D
1
CHCl ); H NMR (500 MHz, CDCl ): δ = 0.88 (d, J= 6.3 Hz, 3 H,
3
3
CH ), 0.99 (d, J= 6.8 Hz, 3 H, CH ), 1.32 (dt, J= 12.5, 3.0 Hz, 1
3
3
H, 5´-H), 1.48 (dt, J= 5.0, 12.5 Hz, 1 H, 5´-H), 1.59 (m, 1 H, 3´-
H), 1.95 (m, 2 H, 4´-H, H C=CH-CH), 2.38 (m, 1 H, H C=CH-
2
2
CH), 2.40 (dd, J= 15.0, 10.0 Hz, 1 H, CHCO Me), 2.63 (dd, J=
2
15.0, 3.0 Hz, 1 H, CHCO Me), 2.77 (mc, 1 H, 6´-H), 3.12 (dt, J=
2
10.0, 3.0 Hz, 1 H, 2´-H), 3.64 (s, 3 H, OMe), 3.72 (d, J= 14.5 Hz,
1 H, benzyl-H), 3.80 (d, J= 14.5 Hz, 1 H, benzyl-H), 4.94 (dq, J=
9.0, 1.5 Hz, 1 H, Z-H =CH), 4.96 (dq, J= 18.0, 1.5 Hz, 1 H, E-
2
H C=CH), 5.57 (mc, 1 H, H C=CH), 7.22-7.34 (m, 5 H, phenyl-
2
2
13
H); C NMR (50 MHz, CDCl ): δ = 13.2, 18.8, 23.3, 29.8, 34.7,
3
35.9, 36.7, 51.5, 55.9, 56.0, 61.2, 116.1, 126.7, 128.1, 128.3,
-1
137.5, 140.3, 173.6; IR (film): v = 1738 cm ; MS (DCI, NH ): m/
14. The stereoselectivity of the cyclization of 2 is independent on the
reaction time. In the case of 6, however, shorter reaction times
3
+
z = 316 (100) [M + 1]. Anal. calcd. for C
H NO : C 76.15, H
20 29 2
9.27; found C 75.92, H 9.44.
result in the formation of mixtures of C -stereoisomers. In
6
addition, isolating the C -α-configurated isomer from the mixture
17. R. K. Hill, T.-H. Chang, Tetrahedron 1965, 21, 2015-2019.
6