A facile enantioselective synthesis of 2-(2-aminoethyl)allylsilanes, new synthons for piperidine synthesis

Article abstract of DOI:10.1016/S0040-4039(03)01428-X

The synthesis of chiral (2-substituted-2-aminoethyl)allylsilanes by cerium mediated trimethylsilylmethylmagnesium chloride addition to the ester group of non racemic chiral β-aminoesters is described.

Full text of DOI:10.1016/S0040-4039(03)01428-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5785–5787
A facile enantioselective synthesis of 2-(2-aminoethyl)allylsilanes,
new synthons for piperidine synthesis
Je´re´my Monfray, Yvonne Gelas-Mialhe, Jean-Claude Gramain and Roland Remuson*
´
Laboratoire de Synthe`se Et Etude de Syste`mes a` Inte´reˆt Biologique (SEESIB), CNRS UMR 6504, Universite´ Blaise Pascal
(Clermont-Ferrand), 63177 Aubie`re, France
Received 5 June 2003; revised 6 June 2003; accepted 7 June 2003
Abstract—The synthesis of chiral (2-substituted-2-aminoethyl)allylsilanes by cerium mediated trimethylsilylmethylmagnesium
chloride addition to the ester group of non racemic chiral b-aminoesters is described.
© 2003 Elsevier Ltd. All rights reserved.
The piperidine ring is a structural subunit found in a
large number of naturally occurring alkaloids. The
stereoselective synthesis of functionalized piperidines
has received considerable attention due to the broad
range of their biological activity and their versatility as
key synthetic intermediates.1 As part of our program to
expand the synthetic utility of allylsilyl functionalized
substrates for the synthesis of piperidine-containing
natural products,2,3 we have imagined a scheme where
the piperidine ring would be formed by a Mannich type
intramolecular cyclisation reaction starting from substi-
tuted aminoethylallylsilyl derivatives. In this paper, we
report the enantioselective synthesis of these
aminoallylsilanes.
The results are summarized in Table 1.
Aminoesters 1 were obtained with good to excellent
yields and high diastereoselectivity. The absolute
configuration of the new stereogenic center of the major
diastereomer was assigned by analogy with Davies’
work.5
The synthesis of the target molecules was carried out as
shown in Scheme 2
In a previous publication,4 we have described the enan-
tioselective synthesis of hydroxyethylallylsilyl deriva-
tives. They were prepared from chiral hydroxyesters,
the allylsilyl functionality was introduced by cerium
mediated trimethylsilylmethylmagnesium chloride addi-
tion to the ester group. We thought that such a reaction
could be extended to aminoesters and this article
describes the successful application of this strategy to
the synthesis of aminoethylallylsilanes.
Scheme 1. Reagents and conditions: (a) (R) or (S)-N-benzyl-
N-(a-methylbenzyl)amine, n-BuLi, THF, 0°C, 1 h.
Table 1. Preparation of b-aminoesters 1
R
R%
Yield (%)
Diastereomeric
purity
(3R,aR)-1a
(3S,aS)-1a
(3R,aR)-1b
(3S,aS)-1b
(3R,aR)-1c
(3S,aS)-1c
(3R,aR)-1d
(3S,aS)-1d
(3S,aR)-1e
(3R,aS)-1e
Me
Me
Pr
Et
Et
Et
Et
83
85
79
70
71
69
88
76
91:9
91:9
91:9
91:9
90:10
90:10
90:10
90:10
92:8
The non racemic chiral starting materials were
aminoesters 1a–e which were prepared by Michael con-
jugate addition of lithium (R) or (S)-N-benzyl-N-(a-
methylbenzyl)amide to a,b-ethylenic esters (Scheme 1)
according to Davies’ procedure.5
Pr
C9H19 Et
C9H19 Et
C11H23 Et
C11H23 Et
Ph
Ph
Keywords: allylsilane; organocerium; amine; diastereoselectivity.
* Corresponding author. Tel.: 04.73.40.76.45; fax: 04.47.40.77.17;
e-mail: remuson@chimie.univ-bpclermont.fr
Me 86
Me 79
92:8
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01428-X

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J. Monfray et al. / Tetrahedron Letters 44 (2003) 5785–5787
Scheme 2. Reagents and conditions: (a) Me3SiCH2MgCl, CeCl3, THF, rt, 3 days; (b) Pd(OH)2, H2, MeOH, H2O, AcOH, THF,
24 h; (c) HCl 1N, diethyl ether, 0°C, 1–24 h.
In a first step, the cerium reagent derived from cerium
chloride and trimethylsilylmethylmagnesium chloride4
was reacted with the ester group of the starting materials
to result in the formation of the tertiary alcohols 26 with
very good yields. The aqueous acidic workup of the
reaction had to be performed in mild conditions (HCl 1N,
t<−5°C for 1 h) to prevent elimination of trimethylsilanol.
Debenzylation of 2 was performed at room temperature
under hydrogen (3.5 atm) with Pearlman’s catalyst to give
aminoalcohols37 ingenerallygoodtoexcellentyields. The
relatively moderate yields in the phenyl substituted
compound 3e have been attributed to partial cleavage of
the molecule under the hydrogenolysis conditions. In the
last step, tertiary alcohols 3 were treated with HCl 1N
at 0°C for 1–24 h to give aminoallylsilanes 48 in good to
excellent yields. The results are summarized in Table 2.
In conclusion, we have described the enantioselective
synthesis of original 2-(2-aminoethyl)allylsilanes in three
steps with good overall yields. These compounds will be
used as new chiral starting materials for the synthesis of
piperidine natural products.
References
1. (a) Strunz, G. M.; Findlay, J. A. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1985; Vol. 26, p. 89;
(b) Angle, S. R.; Breitenbucher, J. G. In Studies in Natural
Products; Atta-ur-Rahman, Ed.; Elsevier Science: Amster-
dam, 1995; Vol. 16, p. 453; (c) Bailey, P. D.; Millwood, P.
A.; Smith, P. D. J. Chem. Soc., Chem. Commun. 1998,
633–640.
2. Cellier, M.; Gelas-Mialhe, Y.; Husson, H.-P.; Perrin, B.;
Remuson, R. Tetrahedron: Asymmetry 2000, 11, 3913–
3919.
3. Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.; Gramain,
J.-C.; Canet, I. Tetrahedron Lett. 1999, 40, 1661–1664 and
references cited therein.
4. Bardot, V.; Gelas-Mialhe, Y.; Gramain, J.-C.; Remuson,
R. Tetrahedron: Asymmetry 1997, 8, 1111–1114.
Table 2. Preparation of compounds 2, 3, and 4
Aminoester Product 2
Product 3
Product 4
1
Yield (%)
Yield (%)
92
Yield (%)
[h]D
(3R,aR)-1a
(3S,aS)-1a
(3R,aR)-1b
(3S,aS)-1b
(3R,aR)-1c
(3S,aS)-1c
(3R,aR)-1d
(3S,aS)-1d
(3S,aR)-1e
(3R,aS)-1e
90
86
76
72
82
71
51
73
71
68
93
+20
(c 0.9;
CHCl3)
−21
(c 1.1;
CHCl3)
+22
(c 1.1;
CHCl3)
−21
(c 0.9;
CHCl3)
+18
(c 1.3;
CHCl3)
−16
(c 1.9;
CHCl3)
+12
(c 1,2;
CHCl3)
−13
(c 1.0;
CHCl3)
−10a
5. Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991,
2, 183–186.
91
83
80
88
89
80
82
37
44
Quant.
75
6. General procedure for preparation of 2: Powdered
CeCl3·7H2O (4.6 equiv.) was dried under vacuum (0.05
mmHg) for 3 days at 120°C while stirring. The flask was
flushed with argon, then dry THF (110 ml) was added to
form a white suspension which was stirred at room tem-
perature for an additional 2 h. This slurry was cooled to
−78°C and trimethylsilylmethylmagnesium chloride (4.6
equiv.) in THF was added dropwise over a period of 1–2
h. The cold mixture was stirred for 1 h and the ester (0.01
mol) in THF (10 ml) was added dropwise over 30 min.
The resulting mixture was allowed to warm to room
temperature and stirred for 3 days. The reaction mixture
was then cooled to −10°C and hydrolyzed by dropwise
addition of 1 M hydrochloric acid. The layers were sepa-
rated and the aqueous layer was extracted with
diethylether. The combined organic layers were dried
(MgSO4) and concentrated. The crude product was
purified by flash chromatography. (3R,aR)-2a: 1H NMR
(400 MHz, CDCl3): l 7.18–7.50 (m, 10H); 6.35 (s, 1H);
3.97 (q, 1H, J=7.0 Hz); 3.81 (AB system, 2H, Dw=185
Hz, JAB=12.8 Hz); 3.34 (m, 1H), 2.03, (t, 1H, J=13 Hz),
1.42 (d, 3H, J=7.0 Hz), 1.14 (d, 3 H, J=6.5 Hz), 1.07 (dd,
1H, J=13 Hz, J=1.9 Hz); 0.84 (AB system, 2H, Dw=43
Hz, JAB=14.8 Hz; 0.12 (AB system, 2H, Dw=234 Hz,
89
Quant.
84
75
78
94
(c 0.7;
CHCl3)
+9a
(c 1.0;
CHCl3)
90
J
AB=14.8 Hz), 0.07 (s, 9H); −0.14 (s, 9H). 13C NMR (100
MHz, CDCl3): l 142.6; 139.2; 129.8; 129.1; 128.7; 128.4;
a The enantiomeric purity was determined by HPLC using a Chiralcel
OD column (ee(3S,aR)-1e=84%, ee(3R,aS)-1e=80%).

J. Monfray et al. / Tetrahedron Letters 44 (2003) 5785–5787
5787
127.4; 75.8; 56.2; 49.0; 48.9; 45.8; 34.9; 33.1; 18.7; 13.6; 1.1;
0.4.
Dw=42 Hz, J=14.7 Hz), 0.07 (s, 9H); 0.06 (s, 9H). 13C NMR
(100 MHz, CDCl3): l 75.6; 50.8; 45.2; 35.00; 32.7; 28.0; 0.9;
0.6.
7. General procedure for preparation of 3: To a solution of 2
(1 g) in methanol (13 ml), acetic acid (0.31 ml), water (2.7
ml) and THF (2.4 ml) was added Pearlman’s catalyst (0.3
g). The resultant mixture was stirred under 3.5 atm of
hydrogen at room temperature for 24 h in a Parr apparatus.
The mixture was filtered through Celite and concentrated.
Then, the filtrate was washed with a saturated solution of
sodium hydrogenocarbonate. Aqueous layer was extracted
with methylene chloride then the organic layers were dried
8. General procedure for preparation of 4: A solution of HCl
1N (4.4 equiv.) was added slowly to a cooled (0°C) 0.5 M
solution of 3 in ether and stirred at 0°C for 1 to 24 h. The
excess of acid was neutralized with a saturated solution of
sodium hydrogenocarbonate and the aqueous phase was
extracted with three portions of ether, organic layers were
1
collected and dried (K2CO3). (S)-4a: H NMR (400 MHz,
CDCl3) l 4.62 (s, 1H); 4.60 (s, 1H); 3.05 (m, 1H), 2.03 (dd,
1H, J=13.6 Hz, J=4.6 Hz), 1.86 (dd, 1H, J=8.8 Hz, J=13.6
Hz), 1,51 (AB system, 2H, Dw=13 Hz, JAB=13.4 Hz), 1.35
(s, 2H); 1.07 (d, 3H, J=6.4 Hz); 0.02 (s, 9H). 13C NMR (100
MHz, CDCl3): l 145.3; 109.6; 49.4; 44.6; 26.5; 23.9, −0.4.
1
(K2CO3). (S)-3a: H NMR (400 MHz, CDCl3): l 3.15 (m,
1H); 1.51 (dd, 1H, J=14.7 Hz, J=2.5 Hz), 1.45 (dd, 1H,
J=14.7 Hz, J=11.7 Hz); 1.18 (AB system, 2H, Dw=73 Hz,
J=14.6 Hz), 1.11 (d, 3H, J=6.3 Hz); 1.01 (AB system, 2H,