Synthesis of isoxazolidin-5-ones via stereocontrolled Michael additions of benzylhydroxylamine to L-serine derived α,β-unsaturated esters

Article abstract of DOI:10.1016/S0957-4166(98)00412-1

The synthesis of optically active isoxazolidin-5-ones from α,β- unsaturated esters is reported. The key features of this synthetic sequence include the stereocontrolled Michael addition of benzylhydroxylamine to alkenes 7 and 8 and the intramolecular cycl

Full text of DOI:10.1016/S0957-4166(98)00412-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3945–3949
Synthesis of isoxazolidin-5-ones via stereocontrolled Michael
additions of benzylhydroxylamine to L-serine derived
α,β-unsaturated esters
∗
Pedro Merino, Santiago Franco, Francisco L. Merchan and Tomas Tejero
Departamento de Química Orgánica, ICMA, Facultad de Ciencias, Universidad de Zaragoza, E-50009 Aragon, Spain
Received 24 September 1998; accepted 12 October 1998
Abstract
The synthesis of optically active isoxazolidin-5-ones from α,β-unsaturated esters is reported. The key features
of this synthetic sequence include the stereocontrolled Michael addition of benzylhydroxylamine to alkenes 7 and
8
and the intramolecular cyclization to the target compounds © 1998 Elsevier Science Ltd. All rights reserved.
Nitrogen containing nucleoside analogs and, in particular, isoxazolidinyl nucleosides such as 1 and
2
, have attracted considerable interest in recent years due to their potential antiviral capabilities.1,2 In
a preceding paper we described the synthesis of isoxazolidinyl thymidine 1a in enantiomerically pure
form by the nucleophilic addition of an ester enolate to a readily available D-glyceraldehyde derived
3
nitrone. As a continuation of our interest in new isoxazolidinyl nucleosides we were intrigued by more
complex compounds, e.g. 3, which bear analogous structural relationship to amino acid nucleosides.
By an extension of our nitrone-based methodology we also reported the synthesis of an isoxazolidine
4
nucleoside analog of thymine polyoxin C. Given the importance of new complex nucleoside analogs,
5–10
of both D- and L-series, in biology
interest.
the development of new strategies for their synthesis is of great
c
d
A retrosynthetic analysis for the isoxazolidinyl nucleosides 1 and 3 (type C O N according to the
3
1
notation method recently proposed by Zhao and co-workers for cyclic nucleoside analogs ) based on
nucleoside chemistry is outlined in Scheme 1. This strategy shows that isoxazolidin-5-ones 4 are obvious
precursors. In this context, the synthetic versatility of those compounds has recently been pointed out.1
1,12
∗
Corresponding author. Fax: +34 976 761194; e-mail: pmerino@posta.unizar.es
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00412-1

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P. Merino et al. / Tetrahedron: Asymmetry 9 (1998) 3945–3949
The cyclic system would need to be formed, presumably in situ, from an intramolecular cyclization of
the corresponding β-(hydroxyamino)ester, so that two key starting materials (nitrones 5 and alkenes 6)
can be considered, depending on the disconnection approach contemplated.
Scheme 1.
In our previous work the nitrone-approach (disconnection a) was used for constructing the key
3,4
intermediate 4 (X=O, NBoc). The other approach (disconnection b) was applied by Zhao and co-
13
workers for the synthesis of β-D-isoxazolidinyl nucleosides 1 (X=O).
Herein we report the stereocontrolled synthesis of isoxazolidin-5-ones 4 (X=NBoc) by a Michael
addition of benzylhydroxylamine (Scheme 1, disconnection b) to differentially protected α,β-unsaturated
esters derived from L-serine.
These alkenes 7 and 8 were regioselectively prepared from the corresponding α-amino
14
aldehydes in a straightforward manner. E-alkenes were synthesized by a Wittig–Horner reaction
†
[
(C H O) POCH CO Me] under protic conditions and Z-isomers were obtained by condensation
2
5
2
2
2
15
of the aldehydes with Still’s reagent [(CF CH O) POCH CO Me]. The Michael additions were
3
2
2
2
2
performed by adding sequentially benzylhydroxylamine hydrochloride (1.2 equiv.) and triethylamine
(
1.2 equiv.). Control experiments revealed that the reaction did not take place at low temperatures (−30
to −80°C), so all the reactions were carried out at ambient temperature.
In all cases examined, the resulting β-(hydroxyamino)esters 9 and 10 were isolated as mixtures of
diastereomers (Scheme 2) and because we were unable to purify these mixtures by column chromatogra-
phy, they were used directly in cyclization reactions. Attempts to cyclize 9 and 10 using zinc(II) chloride
13
as described were unsuccessful, the starting material being recovered in all cases. Gratifyingly, reaction
of β-(hydroxyamino)esters 9 and 10 with sodium methoxide in methanol was found to give isoxazolidin-
5
-ones 11 and 12, respectively, in good yields. The diastereoselectivity of the addition was determined by
1
H NMR on isolated mixtures of diastereomers of compounds 11, 12. The syn/anti ratios obtained with
the various alkenes employed are given in Table 1. The corresponding diastereomers 11a,b and 12a,b
†
D20
20=+21.8 (c 0.28, CHCl
); mp 50–51°C. (E)-8: [α]
20=+13.0
Data for (E)-7: [α] =−64.8 (c 0.75, CHCl
3
); oil. (Z)-7: [α]
D
3
D
2
0
(
c 0.68, CHCl
3
); oil. (Z)-8: [α]
D
=+0.5 (c 0.84, CHCl ); oil.
3

P. Merino et al. / Tetrahedron: Asymmetry 9 (1998) 3945–3949
3947
‡
were separable by flash chromatography, with the only exception of 12a which was contaminated with
1
c.a. 8% of the stereoisomer 12b, judged by the integration of the H NMR spectrum.
Scheme 2.
The stereostructure of the adducts is strongly correlated with both the protecting group arrangement at
the 1,2-aminoalcohol unit of the alkene and the configuration of the double bond. In particular, with the
Z-ester (Z)-7, the syn isomer 11a was obtained (Table 1, entries 1 and 2), whereas the E-ester (E)-7 gave a
1
:1 mixture of the syn and anti adducts (Table 1, entries 3 and 4). The diastereoselectivity of the Michael
addition was reversed when the α-amino group was monoprotected, and for the open-chain compounds
the anti isomer 12b was obtained as the major adduct. For compounds 8, the selectivity was improved
8
when the configuration of the double bond changed from Z to E (Table 1, entries 5–9). In general, the use
of diethyl ether as a solvent resulted in a slight increase of the diastereoselectivity. Thus the choice of the
Table 1
a
Stereocontrolled Michael addition of benzylhydroxylamine to alkenes 7 and 8
‡
D20
1
Data for 11a: [α] =−128.0 (c 1.40, CHCl
3 3
); H NMR (CDCl ) δ 1.44 (s, 3H), 1.47 (s, 9H), 1.51 (s, 3H), 2.62 (dd, 1H,
20
J=8.2, 17.9 Hz), 2.93 (dd, 1H, J=9.6, 17.9 Hz), 3.87–4.01 (m, 3H), 4.08–4.22 (m, 3H), 7.24–7.39 (m, 5H). 11b: [α]
D
=−13.7
1
(
c 0.63, CHCl
3 3
). H NMR (CDCl ) δ 1.48 (s, 9H), 1.50 (s, 3H), 1.52 (s, 3H), 2.68 (dd, 1H, J=8.3, 17.9 Hz), 2.78 (dd, 1H, J=3.8,
7.9 Hz), 3.52–3.69 (m, 1H), 3.80 (m, 1H), 3.90 (dd, 1H, J=5.4, 9.2 Hz), 4.00 (m, 1H), 4.17 (s, 2H), 7.29–7.41 (m, 5H). 12a:
) δ (selected signals) 1.05 (s, 9H), 1.39 (s, 9H), 2.58 (dd, 1H, J=5.3, 17.9 Hz), 2.67 (dd, 1H, J=8.1, 17.9 Hz),
.65 (dt, 1H, J=5.3, 7.6 Hz), 3.70 (dd, 1H, J=4.9, 9.9 Hz), 3.83 (m, 1H), 3.93 (dd, 1H, J=5.1, 9.9 Hz), 4.02 (d, 1H, J=13.8 Hz),
.08 (d, 1H, J=13.8 Hz), 4.59 (bd, 1H, J=9.5 Hz), 7.30 (bs, 5H), 7.35–7.49 (m, 6H), 7.60–7.72 (m, 4H). 12b: [α]
.35, CHCl ). H NMR (CDCl ) δ 1.07 (s, 9H), 1.41 (s, 9H), 2.57 (dd, 1H, J=8.3, 17.8 Hz), 2.65 (dd, 1H, J=5.6, 17.8 Hz), 3.61
1
1
H NMR (CDCl
3
3
4
0
2
0
D
=+27.9 (c
1
3
3
(
4
dt, 1H, J=5.6, 8.0 Hz), 3.74 (dd, 1H, J=4.2, 10.0 Hz), 3.80 (m, 1H), 3.91 (dd, 1H, J=3.3, 10.0 Hz), 4.00 (d, 1H, J=13.9 Hz),
.12 (d, 1H, J=13.9 Hz), 4.70 (bd, 1H, J=8.8 Hz), 7.29 (bs, 5H), 7.32–7.45 (m, 6H), 7.57–7.63 (m, 4H).

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P. Merino et al. / Tetrahedron: Asymmetry 9 (1998) 3945–3949
protecting group is crucial for the stereochemical outcome of the reaction. In fact, the sense and level of
the diastereoselectivity is surprisingly similar to those exhibited by L-serine derived nitrones 5 bearing
the same protecting groups at the 1,2-aminoalcohol subunit.1
6,17
These results reveal the importance of
having either a ring substituent, fixed firmly due to the five-membered structure of the 1,3-oxazolidine,
or a bulky open chain in α-position of the reactive centre.18
Configuration of the isoxazolidin-5-ones 11 and 12 was assigned by chemical correlation with known
structures. The absolute configuration of compounds 11 was determined by comparing the physical
1
13
(
optical rotation) and spectroscopic ( H and C NMR) properties of 11a with those reported in our
4
previous communication.
In addition, the reversal of the stereochemistry was ascertained by preparing 13 (Scheme 3) from
12b (major isomer in addition to 8; Table 1, entries 5–9) by treatment with pyridine–hydrogen fluoride
complex at 0°C. Further acetalization (DMP, acetone) of 13 gave 11b which was shown to be identical
to the minor diastereomer obtained in addition to alkenes 7 (Table 1, entries 1–4).
Scheme 3.
In summary, L-serine derived alkenes 7 and 8 add N-benzylhydroxylamine in good chemical yield
and with remarkable stereocontrol. Since they can be easily prepared from L-serine as the only chiral
source, both syn and anti isoxazolidin-5-ones 11 and 12 are accessible as homochiral building blocks in a
stereodivergent way. A synthetic application of these compounds, consisting of preparing isoxazolidinyl
4
thymine polyoxin C was outlined in a previous report from our laboratory. Further application of this
technology to the synthesis of various α-amino acid nucleoside analogs is now in progress and will be
reported in due course.
Acknowledgements
The authors gratefully acknowledge the financial support by the Direccion General de Enseñanza
Superior (Project PB97-1014, MEC, Madrid, Spain).
References
1
2
3
4
5
6
7
8
9
. For a review see: Pan, S.; Amankulor, N. M.; Zhao, K. Tetrahedron 1998, 54, 6587–6604.
. Adams, D. R.; Boyd, A. S. F.; Ferguson, R.; Grierson, D. S; Monneret, C. Nucleosides & Nucleotides 1998, 17, 1053–1075.
. Merino, P.; Franco, S.; Garces, N.; Merchan, F. L.; Tejero, T. Chem. Commun. 1998, 493–494.
. Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Tetrahedron Lett. 1998, 39, 6411–6414.
. Perigaud, C.; Gosselin, G.; Inbach, J.-L. Nucleosides & Nucleotides 1992, 11, 903–945.
. Huryn, D. M.; Okabe, M. Chem. Rev. 1995, 95, 1745–1768.
. Matteucci, M. Perspectives in Drug Discovery and Design 1996, 4, 1–16.
. Nair, V.; Jahnke, T. S. Antimicr. Agent Chemother. 1995, 39, 1017–1029.
. Crimmins, M. T. Tetrahedron 1998, 54, 9229–9272.
10. Knapp, S. Chem. Rev. 1995, 95, 1859–1876.

P. Merino et al. / Tetrahedron: Asymmetry 9 (1998) 3945–3949
3949
1
1
1
1
1
1
1
1
1. Li, P.; Gi, H.-J.; Sun, L.; Zhao, K. J. Org. Chem. 1998, 63, 366–369.
2. Niu, D.; Zhao, H.; Doshi, A.; Zhao, K. Synlett 1998, 979–980.
3. Xiang, Y.; Gi, H.-J.; Niu, D.; Schinazi, R. F.; Zhao, K. J. Org. Chem. 1997, 62, 7430–7434.
4. Jako, I.; Uiber, P.; Mann, A.; Taddei, M.; Wermuth, C.-G. Tetrahedron Lett. 1990, 31, 1011–1014.
5. Still, C. W.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
6. Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. J. Org. Chem. 1998, 63, 5627–5630.
7. Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahedron Lett. 1997, 38, 1813–1816.
8. For a detailed discussion on this topic concerning L-serine derived nitrones see: Merino, P.; Lanaspa, A.; Merchan, F. L.;
Tejero, T. Tetrahedron: Asymmetry 1998, 9, 629–646.