Short asymmetric syntheses of homoallylic, homopropargylic and allenic silylated primary amines

Article abstract of DOI:10.1016/j.tetlet.2004.03.066

Amino alcohols derived from phenylglycinol and having vinyl-, alkynyl- or allenylsilane moieties were transformed in the corresponding primary amines in two steps: oxidative cleavage of phenylglycinol and transimination with phenylhydrazine. This methodology gave general access to enantiomerically enriched amines without loss of enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2004.03.066

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3807–3809
Short asymmetric syntheses of homoallylic, homopropargylic
and allenic silylated primary amines
*
ꢀ
Sebastien Comesse, Benjamin Bertin and Catherine Kadouri-Puchot
Laboratoire de Synthꢁese Asymꢀetrique (UMR 7611), Universitꢀe P. et M. Curie, 4 place Jussieu, 75005 Paris, France
Received 22 January 2004; revised 9 March 2004; accepted 12 March 2004
Abstract—Amino alcohols derived from phenylglycinol and having vinyl-, alkynyl- or allenylsilane moieties were transformed in the
corresponding primary amines in two steps: oxidative cleavage of phenylglycinol and transimination with phenylhydrazine. This
methodology gave general access to enantiomerically enriched amines without loss of enantioselectivity.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The development of rapid, efficient and practical
asymmetric syntheses of functionalized amines1 is a
major objective for organic chemists due to their use as
synthetic precursors in the synthesis of nitrogen-con-
taining heterocycles or as ligands. Particularly, access to
enantioenriched homoallylic amines has attracted much
interest.2;3 Regarding generation of these chiral amines,
the nucleophilic 1,2-addition of organometallic reagents
to imines or oxazolidines, derived from b-amino alco-
hols, is a powerful tool.1 Such attack leads to enantio-
merically enriched primary amines bearing a stereogenic
centre at the a-position, which is a characteristic struc-
tural feature in bioactive natural products and in phar-
maceutically important compounds. On the other hand,
in this area, syntheses of amines with an unsaturated
silylated function are relatively scarce.4;5 Such com-
pounds in racemic form and, to a lesser extent, in
enantiopure form were used in the synthesis of hetero-
cycles. Owing to the b-silyl carbocation stabilization,
these syntheses consist mostly of the use of cationic
cyclizations, which occur with high levels of regiocon-
trol, via iminium or N-acyliminium ion intermediates.6
To the best of our knowledge, only enantiopure tethered
Recently, we have described7 the diastereoselective
syntheses of functionalized b-amino alcohols 2, 3a–c,
4a–c and 5 by addition of silylated and unsaturated
organometallic derivatives onto 1,3-oxazolidines 1 pre-
pared from phenylglycinol and various aldehydes
(Scheme 1).
b-Amino alcohols 2 and 3 were revealed as efficient
substrates for the synthesis of pipecolic acid derivatives8
and disubstituted proline compounds.9 As part of a
research program aimed at the enantioselective synthesis
of natural heterocyclic products, we were interested in
synthesizing a range of unsaturated primary amines
from these amino alcohols in order to check their effi-
ciency in asymmetric intramolecular cyclizations. First,
compound 2 was treated with periodic acid in aqueous
methanol containing 10 equiv of methylamine.10 Amine
6 was obtained with 39% yield, but this methodology
could not be applied to the amino alcohols 3 or 4.
Therefore, in order to develop general access to these
silylated amines, we decided to test another method to
obtain the desired amines from the amino alcohols 3, 4
and 5 (Scheme 2).
vinylsilyl or allylsilyl amines derived from L-alanine
-phenylalanine5 have been described up to now,
restricting the R-group a to the nitrogen to be methyl or
benzyl. In this paper, we report a quick, easy and gen-
eral access to various silylated unsaturated amines.
or
L
Two steps appeared necessary to isolate the primary
amines: (i) lead tetraacetate cleavage of phenylglycinol;
(ii) hydrolysis of the resulting imines. The first step
was already described by Pridgen and Mokhallalati11
and led to the imines in quantitative yields in all
studied cases. These authors also described the transfor-
mation into the corresponding amines by acidic hydrolysis.
In our hands, however, imines 7 did not react in
this medium and imines 9 underwent a desilylating
reaction. To obtain the corresponding primary amines,
Keywords: b-Amino alcohols; Phenylglycinol; Silylated and unsatu-
rated primary amines.
* Corresponding author. Tel./fax: +01-44-27-26-20; e-mail: kadouri@
ccr.jussieu.fr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.066

3808
S. Comesse et al. / Tetrahedron Letters 45 (2004) 3807–3809
OH
NH
OH
NH
TMS
Ph
Ph
TMS
R
R
2 (R = Ph)
4a (R = Ph)
4b (R = i-Pr)
O
4c (R = t-Bu)
R
N
H
Ph
1
OH
NH
OH
NH
Ph
Ph
TMS
•
3a (R = Ph)
3b (R = i-Pr)
3c (R =t-Bu)
R
R
TMS
5 (R = Ph)
Scheme 1.
Table 1. Preparation of primary amines
NH2
H5IO6
MeNH2
MeOH
2
Yield (%)a
TMS
Amino alcohol
Product
Ph
6
3a
3b
3c
4a
4b
4c
5
8a
8b
80
84
17
53
91
10
33
Scheme 2.
8c
10a
10b
10c
12
phenylhydrazine in hexane was used as a transimination
reagent.12 Thus, the imine of phenylhydrazine precipi-
tated in the medium. This reaction was very efficient
since complete disappearance of the starting material
and formation of the corresponding amines were
a Isolated yield.
observed both on the H and 13C NMR spectra in each
1
studied cases. The last purification step required careful
micro-evaporator distillation to recover the pure
amines, resulting in some low yields (Scheme 3, Table 1).
Boc
NH
HN
2
Boc O
2
TMS
TMS
3c
8c
13
To show the effectiveness of the two steps in obtaining
amine 8c, amino alcohol 3c was directly transformed
into the N-Boc protected amine 13, without any purifi-
cation except after the last step. Now, by avoiding the
distillation, compound 13 was obtained in70% yield13
(Scheme 4).
Scheme 4.
Table 2. Diastereoisomeric and enantiomeric ratios of b-amino alco-
hols and amines
Amino alcohol
Dra
Product
Era
3a
4a
5a
89/11
91/9
95/5
8a
10a
12
88/12
90/10
95/5
Chiral HPLC on compounds 8a, 10a and 12 showed
that epimerization did not occur during these two steps.
Diastereoisomeric excesses of the starting b-amino
a Diastereoisomeric and enantiomeric ratios were determined by HPLC
analysis (chiralcel OD, 250 · 4.6 mm); eluent hexane/isopropanol:
95=5, 0.6 mL/min for 15 min) by integration at 220 nm at 25 ꢁC.
Ph
N
NH
Pb(OAc)
Pb(OAc)
Pb(OAc)
TMS
TMS
PhNHNH
2
4
4
4
alcohols corresponded to the enantiomeric excesses of
the final amines, as described in Table 2.
2
TMS
8a-c
3a-c
4a-c
5
R
R
R
7a-c
Ph
In summary, we have developed a general access to
functionalized amines; studies to explore their reactivity
in cyclization reactions are actively underway in our
laboratory.
TMS
NH
2
N
PhNHNH
PhNHNH
2
R
9a-c
10a-c
Ph
N
NH
2
2
•
•
Acknowledgements
Ph
Ph
11
12
TMS
TMS
The authors gratefully acknowledge Alain Valleix
(CEA, Saclay) for performing chiral HPLC.
Scheme 3.

S. Comesse et al. / Tetrahedron Letters 45 (2004) 3807–3809
3809
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2,
p 1007.
References and notes
7. (a) Agami, C.; Comesse, S.; Kadouri-Puchot, C.; Lusinchi,
M. Synlett 1999, 1094; (b) Agami, C.; Comesse, S.;
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8. (a) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org.
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Kadouri-Puchot, C. J. Org. Chem. 2002, 67, 2424.
1. (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry
1997, 8, 1895; (b) Bloch, R. Chem. Rev. 1998, 98, 1407.
2. For a review on the homoallylamine synthesis, see:
Puentes, C. O.; Kouznetsov, V. J. Heterocycl. Chem.
2002, 39, 595.
3. For recent reports on asymmetric syntheses of homoallylic
amines: (a) van der Sluis, M.; Dalmolen, J.; de Lange, B.;
Kaptein, B.; Kellog, R. M.; Broxterman, Q. B. Org. Lett.
2001, 3, 3943; (b) Schaus, J. V.; Jain, N.; Panek, J. S.
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2827; (g) Hamada, T.; Manabe, K.; Kobayashi, S. Angew.
Chem., Int. Ed. 2003, 42, 3927.
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racemic form, see: (a) Leboutet, L.; Courtois, G.;
Miginiac, L. J. Organomet. Chem. 1991, 420, 155; (b)
Yang, T.-K.; Teng, T.-F.; Lin, J.-H.; Lay, Y.-Y. Tetrahe-
dron Lett. 1994, 35, 3581; (c) Overman, L. E.; Malone,
T. C.; Meier, G. P. J. Am. Chem. Soc. 1983, 105, 6993; (d)
Breternitz, H.-J.; Schaumann, E. J. Chem. Soc., Perkin
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13. Procedure for obtaining compound 13: Lead tetraacetate
(1.8 g, 4 mmol) was added to stirred, cooled (0 ꢁC) absolute
methanol (41 mL). To this cooled yellow solution was
added over 10 min a solution of amino alcohol 3c (1 g,
3.13 mmol) in CH2Cl2 (21 mL). After stirring for another
30 min at 0 ꢁC, the mixture was diluted with dichloro-
methane (20 mL) and stirred for 2 min. The mixture was
then quenched with a 10% aqueous sodium carbonate
solution (25 mL) and the organic layer was separated. The
aqueous layer was extracted with dichloromethane
(2 · 10 mL) and the organic layers were combined, dried
over MgSO4 and evaporated under reduced pressure. The
corresponding imine was treated directly in the next step.
Phenylhydrazine (0.3 mL, 3 mmol) was added to a solution
of imine (0.818 g, 2.84 mmol) in n-hexane (27 mL). The
solution was stirred at room temperature under argon
during 24 h. The resulting mixture was filtered through a
pad of Celite 545ꢂ, and washed with n-hexane and the
filtrate was evaporated very carefully without warming,
under reduced pressure. The crude amine 8c (0.57 g,
2.84 mmol) was directly treated with di-tertio-butyldicar-
bonate (0.682 g, 3.12 mmol.) in AcOEt (15 mL). The
mixture was stirred for 1 h 30 min and the solvent was
evaporated. The crude residue was chromatographed to
afford compound 13 as a solid (AcOEt/PE: 2/98). Yield:
ꢀ
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Coles, S. J. Synlett 2003, 1740; (h) Dobbs, A. P.; Guesne,
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J. Org. Chem. 2003, 68, 7880; (i) Furman, B.; Dziedzic, M.
Tetrahedron Lett. 2003, 44, 8249.
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enantioenriched form, see: (a) Daub, G. W.; Heerding,
D. A.; Overman, L. E. Tetrahedron 1988, 44, 3919; (b)
Castro, P.; Overman, L. E.; Zhang, X.; Mariano, P. S.
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Veerman, J. J. N.; Meester, W. J. N.; Hiemstra, H.;
Schoemaker, H. E. Eur. J. Org. Chem. 1999, 1127.
20
D
1
70%. Mp: 77 ꢁC. ½aꢀ þ 42 (c 0.7, HCCl3). H NMR: 5.96
(ddd, J ¼ 5:0, 7.5 and 18.5 Hz, 1H), 5.90 (d, J ¼ 18:5 Hz,
1H), 4.19 (d, J ¼ 10 Hz, 1H), 3.49–3.39 (m, 1H), 2.49–2.38
(m, 1H), 1.97–1.85 (m, 1H), 1.38 (s, 9H), 0.86 (s, 9H), 0.05
(s, 9H). 13C NMR: 156.1, 144.4, 132.5, 78.7, 58.3, 38.2,
34.8, 28.6, 26.5, ꢁ1.0. Anal. Calcd For C16H33NO2Si: C,
64.16; H, 11.10; N, 4.68. Found: C, 64.38; H, 11.18; N, 4.45.
6. (a) Blumenkopf, T. A.; Overman, L. A. Chem. Rev. 1986,
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