A stereoselective approach to 6-alkylated piperidinone & 2-piperidine via three-component vinylogous Mannich reactions (VMR) and a concise synthesis of (S)-anabasine

Article abstract of DOI:10.1016/j.tetlet.2011.01.090

A three-component diastereoselective vinylogous Mannich-type reaction (VMR) with the silyl ketene acetal (1) was developed. Adducts from the reactions provided valuable intermediates for construction of a variety of chiral 6-alkylated piperidinone and 2-piperidine compounds. The strategy was applied in a concise synthesis (S)-anabasine.

Full text of DOI:10.1016/j.tetlet.2011.01.090

Tetrahedron Letters 52 (2011) 1549–1552
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Tetrahedron Letters
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A stereoselective approach to 6-alkylated piperidinone & 2-piperidine
via three-component vinylogous Mannich reactions (VMR)
and a concise synthesis of (S)-anabasine
⇑
Yang Yang , Dean P. Phillips, Shifeng Pan
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A three-component diastereoselective vinylogous Mannich-type reaction (VMR) with the silyl ketene
acetal (1) was developed. Adducts from the reactions provided valuable intermediates for construction
of a variety of chiral 6-alkylated piperidinone and 2-piperidine compounds. The strategy was applied
in a concise synthesis (S)-anabasine.
Received 7 December 2010
Revised 11 January 2011
Accepted 18 January 2011
Available online 31 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor T. H. Chan
Keywords:
Piperidine
Piperidinone
Vinylogous Mannich reaction
Asymmetric synthesis
Anabasine
Piperidinone and piperidine rings are common moieties in alka-
loid natural products and bioactive molecules.1 New synthetic ap-
proaches for the construction of these ring systems remain an area
of intense research.2 Recently, we desired an efficient and stereose-
lective strategy for the synthesis of chiral 6-alkylated piperidinone
or 2-piperidine analogues as part of a medicinal chemistry pro-
gram. We envisaged that the vinylogous Mannich-type reaction
(VMR) would be useful for the construction of our targets. The
VMR is a versatile organic reaction and has demonstrated broad
applications in the synthesis of various nitrogen-containing natu-
ral and non-natural products in organic synthesis.3 This reaction
proceeds via the dienolate or dienolate equivalent4 addition to an
systems, either via cyclic imines or by employing heterocyclic silyl-
oxy dienolates.3 In this context, we investigated a practical ap-
proach to carry out stereoselective VMRs with an acyclic
dienolate toward highly functionalized piperidinone and piperi-
dine targets. In selecting the imine reacting partner, we decided
to explore bulky chiral benzylamines that could be easily removed.
To this end, readily available napthylamines were selected to ex-
plore the potential of the VMR for the stereoselective synthesis
of chiral piperidines and piperidinones. Herein, we describe an
asymmetric VMR employing silylketene acetal (1) mediated by
Sn(OTf)2, in the presence of (R)-(+)-1-naphthalen-1-yl-ethylamine
(3) as a chiral auxiliary (Scheme 2).
imine leading to the
c
-adduct that potentially provides key inter-
Our designed reaction sequence began with the condensation of
(R)-(+)-1-naphthalen-1-yl-ethylamine (3) with various aldehydes
(2) in the presence of 4 Å molecular sieves in one pot. The
‘in situ’ afforded imines were then treated with 1 in the presence
of Sn(OTf)2 to give the products 4.7 Diastereoselectivities of these
reactions ranged from moderate (5:1) to high (9:1) depending on
the substrate (Table 1). Aldehydes bearing steric bulky residues
(2a, 2b, 2d, and 2g) gave good diastereoselectivities as high as
9:1. The steric hindrance of the substrate seemed to be critical to
the stereoselectivity.8 In examples 2c, 2e, and 2f, moderate diaste-
reoselctivities were observed. In all of these cases, the major iso-
mers were obtained via silica gel chromatography. The purified
adducts (4) were then subjected to hydrogenation in the presence
mediates to construct 6-piperidone and 2-pipieridine compounds
(Scheme 1). The asymmetric formation of the carbon–nitrogen
bond is paramount to the construction of 6-piperidone or 2-
pipieridione compounds in a stereoselective manner.
General and stereoselective VMRs using acyclic dienolates, like
1, remains a synthetic challenge5 and asymmetric syntheses of
piperidinone and piperidine compounds via a VMR strategy are
rarely reported in the literature.6 Most references in the literature
only demonstrated the utility of the asymmetric VMR on cyclic
⇑
Corresponding author. Tel.: +1 858 812 1757.
E-mail address: yyang@gnf.org (Y. Yang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.090

1550
Y. Yang et al. / Tetrahedron Letters 52 (2011) 1549–1552
OTMS
OMe
asymmetric
VMR
R
N
O
NH
*
O
reduction
+
*
N
N
R
R
R
OMe
*
1
Scheme 1.
O
5
4AMS
H2/Pd(C)
EtOAc
OSiMe3
OMe
Sn(OTf)2
O
2
HN
HN
O
+
+
DCM
R
H
R
-78oC--20oC
H2N
R
OMe
1
4
3
Scheme 2.
Table 1
Asymmetric vinylogous Mannich reactions and the cyclizations of adducts
of palladium on carbon, leading to the concomitant reduction of
the double bond, hydrogenolysis of the chiral auxiliary, and cycli-
zation to form the 6-piperidinone product. In general, chiral 6-
piperidinones (5) were obtained in good yield9 (Scheme 2).
In order to determine if the stereoselectivity for the VMR reac-
tion is substrate or auxiliary directed, we prepared piperidinones
5c (Entry 3, Table 1) and 9 (Scheme 3) from chiral 1-(1-naph-
thyl)-ethylamines 3 and 7, respectively. The diastereoselectivity
of the VMR reactions with the two enantiomers were identical
(5:1). The analytical data suggested 5c and 9 to be the threo and er-
ythro isomers, respectively. These assignments were based on
established precedent that the J values of the Ha/Hb coupling are al-
ways larger in the threo isomers than in the erythro isomer.10 In
Entry
2 (dr)
4 (major) (yield)
5 (yield)
O
HN
HN
O
1
2a (8/1)
OMe
(92%)
(71%)
O
HN
HN
O
2
3
2b (7/1)
N
OMe
Boc
compounds 5c and 9, the JH
are 8.26 Hz and 6.39 Hz, respec-
=H
a
b
N
Boc
tively. The results indicated that the reaction was chiral auxiliary
directed and the sense of stereochemical induction of the VMR
was, therefore, determined.
The reduction of piperidinones 5a–g with lithium aluminum
hydride in THF at 50 °C proceeded well leading to the intermediate
2-piperidines. Upon workup of the reduction, the piperidines were
protected with Cbz to ease the purification and isolation of the
products (6) (Scheme 4, Table 2).
(81%)
(65%)
O
HN
HN
O
2c (5/1)
OTBS
OMe
OTBS
(89%)
(62%)
(S)-Anabasine is a tobacco alkaloid found in the Nicotiana glau-
ca11 and is a known potent agonist of the nicotinic acetylcholine
receptor (nAChRs).12 To demonstrate the utility of our acyclic
VMR strategy, we designed a concise route for the synthesis of
(S)-anabasine.13 The synthesis started with the condensation of
nicotinaldehyde 10 with 3, followed by the addition of 1 with
Sn(OTf)2 to give the VMR adduct 11 with good diastereoselectivity
(8:1). Compound 11 was then subjected to the similar hydrogena-
tion conditions leading to 12. When 12 was subjected to transfer
hydrogenation with formic acid in methanol to cleave the chiral
auxiliary, compounds 13 and 14 were obtained as a mixture.
Refluxing the mixture in toluene led to lactam 14. Finally, the
reduction of piperidinone 14 gave synthetic (S)-anabasine 15 in
moderate yield (61%) (Scheme 5).
HN
O
4
5
2d (8/1)
2e (7/1)
—
OMe
(75%)
O
HN
HN
O
OMe
(95%)
(66%)
O
HN
HN
O
In summary, starting from aldehydes and commercial chiral 1-
6
7
2f (6/1)
(1-naphthyl)-ethylamine,
a
stereoselective, three-component
N
OMe
Boc
vinylogous Mannich-type reaction (VMR) with the silyl ketene ace-
tal 1 was developed. Although the high stereoselectivities were
limited to employing sterically hindered aldehydes, the reactions
provided a valuable approach for constructing a variety of chiral
6-alkylated piperidinone and 2-piperidine compounds. The stere-
oselectivity of the reaction was chiral auxiliary controlled. This
methodology led to a concise, enantioselective synthesis of the
(S)-anabasine. The applications of this approach to other natural
alkaloid products are in progress.
N
Boc
(88%)
(70%)
O
HN
HN
O
2g (9/1)
OMe
(54%)
(78%)

Y. Yang et al. / Tetrahedron Letters 52 (2011) 1549–1552
1551
1
O
4A MS
CH2Cl2
O
HN
Pd(C)/H2
EtOAc
HN
O
+
H
Sn(OTf)2
CH2Cl2
H2N
OMe
OTBS
7
OTBS
9
OTBS
2c
8
dr: 5:1
Hb
TBSO
Ha
TBSO
Ha
N
H
O
N
O
Hb
H
9
5c
(1S, 2R)-erythro
(1S, 2S)-threo
Scheme 3.
O
Table 2
Synthesis of 2-piperidine compounds via the reduction of 6-piperidone
Cbz
R
o
1. LAH/THF/50
C
N
HN
Entry
5
6
Yield (%)
2. Cbz-Cl/TEA/DCM
R
6
Cbz
5
N
1
5a
95
85
88
Scheme 4.
Cbz
N
Acknowledgments
2
3
5b
5c
N
We are grateful to Ms. Tiffany Chuan for the assistance in 2D
NMR and Dr. Eric Peters for high resolution MS. We also thank
Dr. Xuebin Liao; Dr. Yahua Liu, and Dr. Porino Va for helpful discus-
sion and proof reading.
Cbz
N
OTBS
Cbz
N
4
5
5e
5f
96
References and notes
1. Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 3679. and reference cited
therein.
—
NA
Cbz
N
2. For recent reviews see: (a) Kallstrom, S.; Leino, R. Bioorg. Med. Chem. 2008, 681;
(b) Buffat, M. G. P. Tetrahedron 2004, 1701; (c) Felpin, F-X.; Lebreton, J. Eur. J.
Org. Chem. 2003, 3693; (d) Laschat, S.; Dickner, T. Synthesis 2000, 1781.
3. For reviews, see: (a) Martin, S. F. Acc. Chem. Res. 2002, 35, 895; (b) Bur, S. F.;
Martin, S. F. Tetrahedron 2001, 57, 3221; (c) Casiraghi, G.; Zanardi, F.;
Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929. and reference cited
therein.
6
5g
79
DCM/4A MS
CHO
Pd(C) /H2
HN
O
HN
O
EtOAc
2hrs
1
+
OMe
OMe
N
Sn(OTf)2
H2N
4
N
CH2Cl2
10
N
3
12
11
CHOOH
MeOH
Pd(C)
+
O
NH2
O
HN
OMe
HN
LAH
N
THF
N
50oC
N
Toluene
reflux
14
13
(s)-anabasine
Scheme 5.

1552
Y. Yang et al. / Tetrahedron Letters 52 (2011) 1549–1552
4. For selected recent examples: vinlyketene silyl acetal: (a) Gonzalez, A. S.;
Arrayas, G. R.; Rivero, M. R.; Carretero, J. C. Org. Lett. 2008, 10, 4335; (b) Giera,
D. S.; Sickert, M.; Schneider, C. Org. Lett. 2008, 10, 4259; (c) Sickert, M.;
Schnieider, C. Angew. Chem., Int. Ed. 2008, 47, 3631; Brassard diene: (d) Mandai,
H.; Mandai, K.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130,
17961; (e) Waldmann, H.; Braun, M.; Drager, M. Tetrahedron Asymmetry 1991,
2, 1231; Chan Diene: (f) Gu, C.-L.; Liu, L.; Wang, D.; Chen, Y.-J. J. Org. Chem.
2009, 74, 5754; Heterocyclic (furan & pyrrol) silyloxy: (g) Wieland, L. C.; Vieira,
E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 570; (h)
Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2006, 45,
72390.
5. To our knowledge, only few references described synthesizing piperidone
compounds through the vinylogous Mannich reactions by acyclic siyl enolates:
(a) Brandstadter, S. M.; Ojima, I. Tetrahedron Lett. 1987, 28, 613; (b) Midland, M.
M.; McLoughlin, J. I. Tetrahedron Lett. 1988, 29, 4653; (c) Kawecki, R.
Tetrahedron 2000, 57, 8385.
the crude product was purified by silica gel chromatography (ethyl acetate/
hexane = 5/1) to afford the product (258 mg, 71% yield). 1H NMR (400 MHz,
MeOD, 25 °C): d = 0.78–0.93(m, 1H), 0.94–1.07(m, 3H), 1.13–1.22(m, 1H,
1.32(d, J = 6.8 Hz, 3H, -CH3), 1.42(m, 1H), 1.48–1.62(m, 3H), 1.74(m, 1H),
2.17–2.23(m, 1H), 2.24–2.31(m, 2H), 3.59(s, 3H, -OCH3), 4.65(q, J = 6.8 Hz, 1H),
5.75(d, J = 15.2 Hz, 1H), 6.86(dt, Jd = 15.2 Hz, Jt = 14.8 Hz, 1H), 7.33(m, 3H),
7.55(d, J = 6.8 Hz, 1H), 7.57(d, J = 8.4 Hz, 1H), 7.71(dd, Ja = 8.0 Hz, Jb = 1.2 Hz,
1H), 8.11(d, J = 8.4 Hz, 1H). 13C-NMR (100 MHz, MeOD, 25 °C): d = 24.55, 26.51,
26.55, 26.68, 29.01, 29.66, 33.69, 41.27, 51.47, 58.66, 122.58, 123.05, 123.69,
125.31, 125.67, 125.73, 127.19, 129.02, 131.42, 134.02, 141.39, 147.53, 166.88.
LC-MS: 100% (purity), m/e: 366 (M+1). HRMS: Calcd. for C24H32NO2 (M+H):
366.24330. Found: 366.24305.
8. Very low or no stereoselectivities were observed when non-steric hinder
aldehydes were employed and diastereomeric mixtures of adducts were
difficult to be separated by conventional approaches.
9. In the case of 4d, hydrogenation led to the decomposition of the compound.
10. Solladi-Cavallo, A.; Marsol, C.; Yakoub, M.; Azyat, K.; Klein, A.; Roje, M.; Suteu,
C.; Freedman, T. B.; Can, X.; Nafie, L. A. J. Org. Chem. 2003, 68, 7308.
11. Stehl, A.; Seitz, G.; Schulz, K. Tetrahedron 2002, 58, 1343. and reference cited
therein.
6. Schneider et al reported the asymmetric vinylogous Mannich reaction of
vinylketen silyl acetal catalyzed by chiral Bronsted acid. To our knowledge, it is
the only example of asymmetric VMR using similar acylic dienolate in
literature. (a) Sickert, M.; Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631;
(b) Sickert, M.; Abels, F.; Lang, M.; Sieler, J.; Birkemeyer, C.; Schneider, C. Chem.
Eur. J. 2010, 16, 2806.
12. For the review on nAChRs in drug discovery see: Jensen, A. A.; Frolund, B.;
Lijefors, T.; Krogsgard-Larsen, P. J. Med. Chem. 2005, 48, 4705.
7. General procedure for ‘One-pot’ vinylogous Mannich reactions: (S,E)-methyl 5-
13. For the stereoselective synthesis of (S)-anabasine in literature see: (a) Giera, D.
S.; Sickert, M.; Schneider, C. Synthesis 2009, 3797; (b) Spangenberg, T.; Breit, B.;
Mann, A. Org. Lett. 2009, 11, 261; (c) Pfrengle, W.; Kunz, H. Angew. Chem., Int.
Ed. Engl. 1989, 28, 1067. Angew. Chem. 1989, 101, 1041; (d) Hattori, K.;
Yamamoto, H. J. Org. Chem. 1992, 57, 3264; (e) Hattori, K.; Yamamoto, H.
Tetrahedron 1993, 49, 1749; (f) Felpin, F.-X.; Vo-Thanh, G.; Robins, R. J.;
Villieras, J.; Lebreton, J. Synlett 2000, 1646; (g) Felpin, F.-X.; Girand, S.; Vo-
Thanh, G.; Robins, R. J.; Villieras, J.; Lebreton, J. J. Org. Chem. 2001, 66, 6305; (h)
Andres, J. M.; Herraiz- Sierra, I.; Pedrosa, R.; Perez-Encabo, A. Eur. J. Org. Chem.
2000, 1719; (i) Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.;
Zanirato, V. Eur. J. Org. Chem. 2001, 975; (j) Amat, M.; Canto, M.; Llor, N.; Bosch,
((R)-1-(naphthalen-1-yl)ethylamino)-5-cyclohexylpent-2-enoate (4a): To
a
round-bottomed flask containing (R)-1-naphthalen-1-yl-ethylamine (3)
(186 mg, 1.1 mmol, 1.1 equiv) in dried DCM (0.1 M) solution added 4AMS
(500 mg/mmol) followed by cyclohexane-carbaldehyde (2a) (112 mg, 1 mmol,
1 equiv). After stirring at room temperature for 30 mins, (1-methoxy-buta-1,3-
dienyloxy)-trimethyl-silane (1) (258 mg, 1.5 mmol, 1.5 equiv) was added and
the mixture solution was cooled to À78 °C. Tin (II) triflate (412 mg, 1 mmol,
1 equiv) was then added and the reaction was stirred at this temperature for
8 h. The reaction temperature was raised to À30 °C and kept at the same
temperature overnight. The reaction was quenched with a saturated aqueous
solution of sodium bicarbonate and removed the solid via filtration. The
reaction mixture was then extracted with ethyl acetate (15 ml  5). The
combined organic phase was dried over sodium sulfate. After concentration,
ˇ
J. Chem. Commun. 2002, 526; (k) Jurcík, V.; Arai, K.; Salter, M. M.; Yamashita, Y.;
Kobayashi, S. Adv. Synth. Catal. 2008, 350, 647.