Synthesis of enantiopure azetidines: A route to new β-amino alcohols

Article abstract of DOI:10.1016/j.tetlet.2005.09.061

β-Amino alcohols possessing an E vinylsilane moiety were cyclized in the presence of N-bromosuccinimide to afford diastereoisomerically pure polyfunctional azetidines. These azetidines were then transformed into enantiopure β-amino alcohols with a Z vinyl

Full text of DOI:10.1016/j.tetlet.2005.09.061

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8023–8025
Synthesis of enantiopure azetidines: a route to new
b-amino alcohols
´
Vincent Lemau de Talance, Emilie Banide, Benjamin Bertin,
*
´
Sebastien Comesse and Catherine Kadouri-Puchot
`
´
Universite´ Pierre et Marie Curie, 4 place jussieu, 75005 Paris, France
Laboratoire de Chimie Organique-Equipe Synthese Asymetrique, UMR 7611, Institut de Chimie Moleculaire FR 2769,
´
Received 18 July 2005; revised 8 September 2005; accepted 12 September 2005
Available online 29 September 2005
Abstract—b-Amino alcohols possessing an E vinylsilane moiety were cyclized in the presence of N-bromosuccinimide to afford dia-
stereoisomerically pure polyfunctional azetidines. These azetidines were then transformed into enantiopure b-amino alcohols with a
Z vinylic bromide moiety.
Ó 2005 Elsevier Ltd. All rights reserved.
Azetidines have received much synthetic attention
during the last decade1,2 because of their utilization as
ligands,3 their detection as natural products4 and their
biological and pharmaceutical activities.5 Electrophile-
induced intramolecular cyclization of unsaturated
amines appeared as an efficient method to produce these
nitrogen heterocyclic compounds.6
cally pure azetidine derivatives and their subsequent
transformation into new b-amino alcohols.
When treated with NBS, amino alcohols 1a–d were cyc-
lized in a totally regio and diastereoselective manner to
afford azetidines 2, with some recovered unreacted start-
ing material 1 (Scheme 1).
In the course of studies of the enantioselective synthe-
sis of pipecolic acid7a and proline derivatives7b from
unsaturated and silylated b-amino alcohols 1,8 we were
interested by the synthesis of other azaheterocyclic
compounds. Thus, this letter describes a novel synthetic
application allowing a rapid access to diastereoisomeri-
As shown in Table 1, which collects the experimental
data of the cyclization performed on the amino alcohol
1d, the best conditions in order to increase the 2d/1d
ratio was the use of 1.05 equiv of N-bromosuccinimide,
at 0 °C in acetonitrile (entry 7). Whereas the tempera-
ture and the time had no significant influence on this
OH
Br
H
OH
NBS
TMS
TMS
NH
Ph
Ph
N
H
R
yields after
chromatography (%)
R
1a R = Ph
1b R = Pr
1c R = i-Pr
1d R = t-Bu
2a R = Ph
2b R = Pr
2c R = i-Pr
2d R = t-Bu
64
38
55
52
Scheme 1.
Keywords: Azetidines; b-Amino alcohols; N-Bromosuccinimide; Vinylsilane; Vinylbromide.
*
Corresponding author. Tel./fax: +33 1 44 27 26 20; e-mail: kadouri@ccr.jussieu.fr
Present address: URCOM, Universite´ du Havre, 76600 Le Havre.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.061

8024
V. L. de Talance´ et al. / Tetrahedron Letters 46 (2005) 8023–8025
Table 1.
OH
H
Br
Entry Solvent
NBS
(equiv)
Temp, time
Ratio 2d/1d
H
HF/pyr
THF
H
+
2
5
Ph
N
TMS
1
2
3
4
5
6
7
CH2Cl2
2
0 °C!rt; 20 h
0 °C!rt; 20 h
0 °C!rt; 30 min
rt; 72 h
67/33a
73/27a
77/23b
77/23b
—
-
R
F
CH2Cl2 1.05
CH2Cl2 1.05
CH2Cl2 1.05
1.05
CH3CN 1.05
CH3CN 1.05
6
Scheme 4.
THF
0 °C!rt; 72 h
0 °C!rt; 72 h
87/13b
0 °C!rt; 1 h 30 min 89/11b
a Determined after chromatography on silica gel.
b Determined by 1H NMR analysis of the crude reaction.
alcohols 5, with a Z-vinylic bromide moiety, were iso-
lated in very high yields (Scheme 3). This reaction was
very clean and no purification of the products was
necessary.14
cyclization, the reaction was governed by a solvent
effect: acetonitrile giving the best results. This solvent
was already reported as the more efficient solvent for a
4-exo-trig cyclization process.9,6b
This reaction is stereospecific and took place in the fol-
lowing way: (i) protonation of the nitrogen atom to give
the ammonium intermediate 6 and (ii) anti-elimination
of the trimethylsilyl group by the attack of the fluoride
ion with departure of ammonium (Scheme 4).15
The absolute configuration of 2d was determined by an
X-ray analysis.10 The stereoselectivity displayed by this
bromocyclization could be explained by the formation
of the intermediate bromonium 3, which was followed
by the intramolecular attack of the nitrogen atom,
according to a 4-exo-tet cyclization.11 The spatial layout
of the atoms involved in this reaction; that is, nitrogen,
carbon and bromine correspond to a minimization of
the steric interactions. The bromonium ion was formed
on the face of the double bond allowing the attack of the
doublet of the nitrogen atom in an anti position relative
to the C–Br bond, in a likely concerted process (Scheme
2). The regioselectivity was due to a dissymmetry of the
bromonium ion as a consequence of the b-effect of the
silicium.12,13
In conclusion, we have synthesized in two totally stereo-
selective steps a new class of enantiopure amino alco-
hols with a Z-vinylic bromide moiety from amino
alcohols with an E-vinylsilane terminator, via the diaste-
reoselective synthesis of highly substituted azetidines.
Works are in progress to develop the chemistry of these
new compounds: azetidines 2 and b-amino alcohols 5.
Acknowledgements
We thank Dr. Carine Guyard-Duhayon for X-ray analy-
sis of compound 2d. Dr. Louis Hamon is acknowledged
for helpful discussions.
In order to specify the synthetic utility of these azet-
idines, we attempted the cleavage of the silicon–carbon
bond. Compound 2d was first treated by tetrabutyl-
ammonium fluoride, and was thus transformed into
bicyclic product 4. Formation of compound 4 results
from a desilylation followed by a cyclization. The stereo-
chemistry of this unexpected compound has not been
determined. On the other hand, when azetidines 2a–d
were treated with fluorohydric acid in pyridine, amino
References and notes
1. For reviews, see: (a) De Kimpe, N. In Comprehensive
Heterocyclic Chemistry II; Padwa, A., Ed.; Elsevier:
Oxford, 1996; Vol. 1B, Chapter 1.18, pp 507–589; (b)
Couty, F.; Evano, G.; Prim, D. Mini-Rev Org. Chem.
2004, 1, 133.
OH
R'
TMS
H
H
R'
N
TMS
H
NH
NBS
TMS
NH
R
Ph
+
Br
R
Br
H
R
1
2
R' = CH(Ph)CH2OH
3
Scheme 2.
O
N
OH
Br
H
OH
Br
n-Bu4NF
R = t-Bu 86%
HF/pyr
5a 95%
b 82%
c 94%
d 86%
TMS
Ph
N
Ph
Ph
NH
R
R
4
2
5
Scheme 3.

V. L. de Talance´ et al. / Tetrahedron Letters 46 (2005) 8023–8025
2. Selected recent examples of asymmetric synthesis of
8025
Maguire, R. Bioorg. Med. Chem. Lett. 1999, 9, 1437; (g)
Cheng, Q.; Kiyota, H.; Yamaguchi, M.; Horiguchi, T.;
Oritani, T. Bioorg. Med. Chem. Lett. 2003, 13, 1075.
6. (a) De Kimpe, N.; De Smaele, D. J. Heterocyclic Chem.
2000, 37, 607; (b) Pannecoucke, X.; Outurquin, F.;
Paulmier, C. Eur. J. Org. Chem. 2002, 995; (c) Outurquin,
F.; Pannecoucke, X.; Berthe, B.; Paulmier, C. Eur. J. Org.
Chem. 2002, 1007.
´
azetidines: (a) Pedrosa, R.; Andres, C.; Nieto, J.; del
Pozo, S. J. Org. Chem. 2005, 70, 1408; (b) Mangelinckx,
S.; Boeykens, M.; Vliegen, M.; Van der Eycken, J.; De
Kimpe, N. Tetrahedron Lett. 2005, 46, 525; (c) Enders, D.;
Gries, J.; Kim, Z.-S. Eur. J. Org. Chem. 2004, 4471; (d)
Couty, F.; Evano, G.; Rabasso, N. Tetrahedon: Asymme-
try 2003, 14, 2407; (e) Burtoloso, A. C. B.; Correia, C. R.
D. Tetrahedron Lett. 2004, 45, 3355.
7. (a) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org.
´
3. For azetidines used as ligands, see for example: (a)
Starmans, W. A. J.; Walgers, R. W. A.; Thijs, L.; de
Gelder, R.; Smits, J. M. M.; Zwanenburg, B. Tetrahedron
1998, 54, 4991; (b) Shi, M.; Jiang, J.-K. Tetrahedron:
Asymmetry 1999, 10, 1673; (c) Hermsen, P. J.; Cremers, J.
G. O.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 2001,
42, 4243; (d) Wilken, J.; Erny, S.; Wassmann, S.; Martens,
J. Tetrahedron: Asymmetry 2000, 11, 2143; (e) Couty, F.;
Prim, D. Tetrahedron: Asymmetry 2002, 13, 2619; (f)
Keller, L.; Sanchez, M. V.; Prim, D.; Couty, F.; Evano,
G.; Marrot, J. J. Organomet. Chem. 2005, 690, 2306.
4. For azetidines as components in natural products, see, for
example: (a) Akihisa, T.; Mafune, S.; Ukiya, M.; Kimura,
Y.; Yasukawa, K.; Suzuki, T.; Tokuda, H.; Tanabe, N.;
Fukuoka, T. J. Nat. Prod. 2004, 67, 479; (b) Takikawa,
H.; Maeda, T.; Seki, M.; Koshino, H.; Mori, K. J. Chem.
Soc., Perkin Trans. 1 1997, 97; (c) Yoda, H.; Uemura, T.;
Takabe, K. Tetrahedron Lett. 2003, 44, 977; (d) Singh, S.;
Crossley, G.; Ghosal, S.; Lefievre, Y.; Pennington, M. W.
Tetrahedron Lett. 2005, 46, 1419.
Chem. 2002, 67, 2424; (b) Agami, C.; Comesse, S.; Guesne,
S.; Kadouri-Puchot, C.; Martinon, L. Synlett 2003, 1058.
8. Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org.
Chem. 2002, 67, 1496.
9. Berthe, B.; Outurquin, F.; Paulmier, C. Tetrahedron Lett.
1997, 38, 1393.
10. (a) Atomic coordinates, bond lengths and angles and
thermal parameters have been deposited at the Cambridge
Crystallographical Data Center with the deposition num-
ber CCDC 277622; (b) Spectral data for compound 2d: mp
20
1
71 °C. ½aꢀD ꢁ106 (c 0.8, CHCl3). H NMR (CDCl3): 0.00
(s, 9H), 0.67 (s, 9H), 1.43–1.53 (m, 1H), 1.76–1.90 (m, 1H),
2.66 (t, J = 8.3 Hz, 1H), 3.21 (td, J = 2.3 and 8.0 Hz, 1H),
3.28–3.43 (m, 2H), 3.55 (m, 2H), 3.75 (t, J = 10.5 Hz, 1H),
6.95–7.25 (m, 5H). 13C NMR: ꢁ2.0, 24.0, 27.0, 34.1, 48.5,
58.0, 62.7, 66.3, 68.2, 128.1, 128.5, 129.6, 138.5. Anal.
Calcd for C19H32BrNOSi: C, 57.27; H, 8.09; N, 3.52.
Found: C, 57.33; H, 8.23; N, 3.41.
11. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
12. Lambert, J. B.; Zhao, Y.; Emblidge, R. W.; Salvador, L.
A.; Liu, X.; So, J.-H.; Chelius, E. C. Acc. Chem. Res. 1999,
32, 183.
5. For synthesis and biological activities of some azetidines
derivatives, see for example: (a) Frigola, J.; Torrens, A.;
´
Castrillo, J. A.; Mas, J.; Vano, D.; Berrocal, J. M.; Calvet,
13. A similar silicon-directed 4-exo-trig electrophilic cycliza-
tion of homoallylic alcohols led to the formation of
oxetanes: Rofoo, M.; Roux, M.-C.; Rousseau, G. Tetra-
hedron Lett. 2001, 42, 2481.
˜
´
´
C.; Salgado, L.; Redondo, J.; Garcıa-Granda, S.; Valentı,
E.; Quintana, J. R. J. Med. Chem. 1994, 37, 4195; (b)
Lautar, S. L.; Rojas, C.; Slusher, B. S.; Wozniak, K. M.;
Wu, Y.; Thomas, A. G.; Waldon, D.; Li, W.; Ferraris, D.;
Belyakov, S. Brain Res. 2005, 1048, 177; (c) Morrissette,
M. M.; Stauffer, K. J.; Williams, P. D.; Lyle, T. A.; Vacca,
J. P.; Krueger, J. A.; Lewis, S. D.; Lucas, B. J.; Wong, B.
K.; White, R. B.; Miller-Stein, C.; Lyle, E. A.; Wallace, A.
A.; Leonard, Y. M.; Welsh, D. C.; Lynch, J. J.; McMas-
ters, D. R. Bioorg. Med. Chem. Lett. 2004, 14, 4161; (d)
20
14. Spectral data for compound 5b: ½aꢀD ꢁ93 (c 1.0, CHCl3).
1H NMR (CDCl3): 0.73 (t, J = 6.0 Hz, 3H), 1.19–1.37 (m,
4H), 2.31–2.23 (m, 4H), 2.57 (q, J = 5.7 Hz, 1H), 3.45 (dd,
J = 8.7 and 10.7 Hz, 1H), 3.62 (dd, J = 4.5 and 10.7 Hz,
1H), 3.86 (dd, J = 4.5 and 8.7 Hz, 1H), 6.10 (q, J = 7.5 Hz,
1H), 6.19 (d, J = 7.5 Hz, 1H), 7.12–7.35 (m, 5H). 13C
NMR: 14.2, 19.3, 33.8, 37.4, 53.2, 61.8, 67.0, 109.7, 127.3,
127.8, 128.8, 131.6, 141.1. Anal. Calcd for C15H22NOBr: C,
57.70; H, 7.10; N, 4.49. Found: C, 58.19; H, 7.40; N, 4.34.
15. A stereospecific anti elimination of b-silyl azides has been
reported: Chabaud, L.; Landais, Y. Tetrahedron Lett.
2003, 44, 6995.
Kozikowski, A. P.; Tuckmantel, W.; Reynolds, I. J.;
¨
Wroblewski, J. T. J. Med. Chem. 1990, 33, 1561; (e) Wu,
W.-L.; Caplen, M. A.; Domalski, M. S.; Zhang, H.;
Fawzi, A.; Burnett, D. A. Bioorg. Med. Chem. Lett. 2002,
12, 3157; (f) Hanessian, S.; Bernstein, N.; Yang, R.-Y.;