Modified nucleosides from nitrones: A new and efficient stereoselective approach to isoxazolidinyl thymidine derivatives

Article abstract of DOI:10.1039/a705673g

The addition of the sodium enolate of methyl acetate to the N-benzyl nitrone 4 derived from D-glyceraldehyde affords the 3-substituted isoxazolidin-5-one 6a with a high degree of syn selectivity and in quantitative chemical yield; its further elaboration

Full text of DOI:10.1039/a705673g

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Modified nucleosides from nitrones: a new and efficient stereoselective
approach to isoxazolidinyl thymidine derivatives
Pedro Merino,*† Santiago Franco, Natalia Garces, Francisco L. Merchan and Tomas Tejero
Departamento de Quimica Organica, ICMA, Universidad de Zaragoza, Zaragoza, E-50009 Aragon, Spain
The addition of the sodium enolate of methyl acetate to the
O
N-benzyl nitrone 4 derived from D-glyceraldehyde affords
RO
OM
O
+
the 3-substituted isoxazolidin-5-one 6a with a high degree of
syn selectivity and in quantitative chemical yield; its further
elaboration leads to the preparation of the important
isoxazolidine nucleoside analogue 2a in enantiomerically
pure form.
H
N
R = Me, Et
M = Li, Na
–
O
+
Bn
4
5
see Table 1
Nucleoside analogues have aroused a considerable amount of
attention because of their biological activity.1,2 In particular,
modified nucleosides, such as lamivudine 1a and its 5-fluoro
derivative 1b show potent specific, competitive anti-HIV
activities.3 Also, nucleosides 2 and 3 containing an isox-
azolidine moiety have been described to have promising
O
O
O
O
+
O
O
N
N
O
O
Bn
anti-6a
Bn
anti-6b
NH2
Scheme 1
O
N
NH2
R
F
N
NH
N
The stereochemical outcome of the reaction is in accord with
Kita’s results9 and our own previous data concerning the
nucleophilic additions to a-alkoxy nitrones.11 Efforts to
improve both the diastereoselectivity and the chemical yield by
variation of the counterion and the solvent, plus attempts of
stereocontrol of the reaction by addition of a Lewis acid, are
summarised in Table 1.
N
O
O
HO
N
O
HO
HO
S
O
N
R
N
R
O
O
1a R = H
b R = F
2a R = Me
b R = Bn
3a R = Me
b R = Bn
In all cases, sodium enolates afforded the syn adduct 6a as the
only product of the reaction (ds ! 95%) in excellent chemical
yield (Table 1, compare entries 1–4 with 5, 6 and 9), the solvent
only having a slight influence on the chemical yield of the
process. Guided by our previous results11 on nucleophilic
additions to 4 we next carried out the reaction in the presence of
1.0 equiv. of diethylaluminium chloride (Table 1, entries 7, 8
and 10). Unfortunately, the chemical yield was rather low
(20–25%) in all cases, substantial amounts of starting nitrone
being recovered. This behaviour suggests that the Lewis acid
used as a pre-complexing agent of the nitrone eliminates the
sodium enolate from the reaction mixture by forming the
corresponding aluminium enolate, which is unable to react with
4.
therapeutic utility in the development of anti-AIDS agents.4 As
a consequence, syntheses of isoxazolidinyl nucleosides of type
2 and 3 have been recently reported.5,6
Recent investigations in this laboratory have revealed that
chiral a-alkoxy and a-amino nitrones serve as versatile chiral
building blocks in the preparation of several naturally occurring
nitrogen-containing compounds.7 Here we present a successful
implementation of this strategy directed to the stereoselective
synthesis of isoxazolidinyl nucleosides 2.
The key step of our approach consists of the stepwise addition
of an ester enolate to a chiral nitrone in order to construct the
isoxazolidine ring. It had been described by Trombini and co-
workers that both ketone silyl enol ethers and vinylketene
acetals add to nitrones in the presence of trimethylsilyl triflate.8
Kita and co-workers reported that a-alkoxy nitrones undergo
nucleophilic additions with ketene silyl acetals to give the
corresponding b-(siloxyamino) esters in good yields and
stereoselectivity.9 With this background in mind we felt that the
ready availability of the enantiomerically pure nitrone derived
from 1,2-di-O-isopropylidene-d-glyceraldehyde10 and the well-
precedented stereodirecting effect of the dioxolane group7 made
4 an ideal starting material. The addition of nitrone 4 to 1.5
equiv. of the lithium enolate of methyl acetate (LDA and methyl
acetate) afforded a 75:25 mixture of diastereomeric isox-
azolidinones 6 in 60% isolated yield (Scheme 1).‡
Thus, metal exchange should proceed rapidly at the expense
of nucleophilic addition, which proceeds in only 20–25%
Table 1 Stereoselective addition of enolates to nitrone 4
Entry
R
Base (solvent)
6a:6b
75:25
Yieldb (%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Et
LDA (THF)
LDA (Et2O)
60
54
68
70
100
95
25
22
93
20
70:30
86:14
60:40
!95:5
!95:5
34:66
30:70
!95:5
32:68
LiHMDS (THF)
LiHMDS (Et2O)
NaHMDS (THF)
NaHMDS (Et2O)
NaHMDS (THF)a
NaHMDS (Et2O)a
NaHMDS (THF)
NaHMDS (Et2O)a
The b-(hydroxyamino) ester was not observed in the crude
product and only compounds 6, coming from an intramolecular
cyclization, were obtained. The stereochemistry of the obtained
isoxazolidines 6 was ascertained by an X-ray crystallographic
analysis of a single crystal of the major diastereomer syn-6a.§
10
Et
a
b
1.0 equiv. of Et2AlCl was used. Isolated yield of the crude mixture of
diastereomers.
Chem. Commun., 1998
493

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for 6a: mp 60–62 °C, [a]D + 122.6. For 6b: mp 75–77 °C, [a]D 29.7. For
9: mp 182–183 °C, [a]D 212.2 (c 0.34, MeOH). For 2b: sticky foam, [a]D
+6.1 (c 0.80, MeOH); dH (CDCl3) 1.70 (br s, 1 H, OH), 1.77 (d, 3 H, J 1.2,
CH3), 2.29 (ddd, 1 H, J 3.6, 8.5, 13.7, H2a), 2.99 (dt, 1 H, J 7.4, 13.7, H2b),
3.15 (ddt, 1 H, J 3.6, 5.2, 8.6, H3), 3.68 (dd, 1 H, J 5.0, 11.7, H4a), 3.79 (dd,
1 H, J 3.3, 11.7, H4b), 3.92 (d, 1 H, J 13.9, CH2Ph), 4.32 (d, 1 H, J 13.9,
CH2Ph), 4.32 (d, 1 H, J 13.9, CH2Ph), 5.986 (dd, 1 H, J 3.6, 7.4, H1),
7.23–7.50 (m, 6 H, ArH + CH), 8.47 (br s, 1 H, NH).
O
O
O
O
i
O
OR
N
N
O
O
Bn
anti-6a
Bn
7 R = H
8 R = Ac
ii
§
Crystal data for 6a: C15H19NO4, monoclinic, space group P21,
iii
a = 6.011(1), b = 8.039(1), c = 15.598 (2) Å, b = 92.680 (10)°,
V = 752.9(2) Å3, Z = 2, Dc = 1.223 g cm23, m = 0.089 mm21. Of the 1452
unique measured reflections, 1182 with I ! 2s(I) were used in the
refinement. R(on F2) = 3.83, Rw = 9.07. The data were collected on a
Siemens P4 diffractometer with graphite monochromated Mo-Ka radiation
w–2q scan technique (2.61 @ q @ 23.99). The structure was solved by direct
methods using the SHELXS-86 package.16 All other calculations were
accomplished by SHELXL-93.17 CCDC 182/729.
¶ Similar results were observed with other Lewis acids such as ZnCl2, ZnBr2
or MgBr2. In all cases the yield dropped considerably.
∑ The anomeric configurations were confirmed by 1H NMR (300 MHz) and
NOE experiments.
O
N
O
NH
NH
HO
HO
O
N
O
HO
iv
N
Bn
N
Bn
O
O
2b
9
Scheme 2 Reagents and conditions: i, DIBAL-H, 280 °C, CH2Cl2, 2 h,
80%; ii, Ac2O, Py, 0 °C, 1 h, 82%; iii, 2,4-bis(trimethylsilyloxy)-
5-methylpyrimidine, TMSOTf, CH2Cl2, room temp., 2 h, 63%; iv, NaIO4
(aq.), SiO2, CH2Cl2, room temp., 20 min, then NaBH4, MeOH, 0 °C, 90 min,
89%
1 D. M. Huryn and M. Okabe, Chem. Rev., 1992, 92, 1745.
2 M. Kassou and S. Castillon, J. Org. Chem., 1997, 62, 3696;
R. R. Talekar and R. H. Wightman, Tetrahedron, 1997, 53, 3831 and
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3 H. Jin, M. A. Siddiqui, C. A. Evans, H. L. A. Tse, T. S. Mansour,
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and A. Procopio, Synth. Commun., 1997, 26, 4211.
yield.¶ The lower reactivity of aluminium enolates has been
described in nucleophilic additions to imines.12 A further
confirmation of that hypothesis emerged from the fact that an
identical result was obtained when nitrone 4 was made to react
with the aluminium enolate of methyl acetate prepared in situ
from methyl acetate and diethylaluminium chloride as de-
scribed.13 Nevertheless, despite these adverse results concern-
ing the chemical yield, a reversal of the diastereofacial
selectivity was observed (Table 1, entries 7, 8 and 10) and the
anti isomer 6b could be fully characterized‡ and used in further
transformations.
Treatment of syn-6a with DIBAL-H in CH2Cl2 at 280 °C
afforded lactols 7 as a 60:40 mixture of anomers. The first order
300 MHz 1H NMR spectrum of the mixture provided un-
equivocal information on their structures.∑ Acetylation of 7 as
described6 afforded only unreacted starting material when
stoichiometric amounts of reagents were used; on the other
hand, an excess reagents led to deprotection of the acetonide
moiety. If, however, compounds 7 were treated at 0 °C with
Ac2O and pyridine a 76:24 mixture of anomeric acetates 8 was
formed in 82% combined yield, with the a anomer predominat-
ing. Coupling of 8 with 2,4-bis(trimethylsilyloxy)-5-methylpyr-
imidine14 using the glycosylation methodology developed by
Vo¨rbruggen15 afforded the N1-nucleoside 9 as a 22:78 mixture
of a/b anomers∑ in which the acetonide moiety had been
hydrolysed (Scheme 2). The major b isomer (depicted in
Scheme 2) was easily separated by column chromatography
(100% EtOAc, Rf a-isomer = 0.13, Rf b-isomer = 0.23,
visualized with UV at 254 nm). Finally, oxidative cleavage
(NaIO4) of the diol unit followed by in situ reduction with
NaBH4 generated the desired isoxazolidine nucleoside 2b in
good overall yield as summarised in Scheme 2.
6 Y. Xiang, Y. Gong and K. Zhao, Tetrahedron Lett., 1996, 37, 4877.
During the refereeing process of this manuscript a similar approach
based on the diastereoselective Michael addition of hydroxylamine to
unsaturated esters has been reported by the same authors. See Y. Xiang,
H.-J. Gi, D. Niu, R. F. Schinazi and K. Zhao, J. Org. Chem., 1997, 62,
7430.
7 P. Merino, A. Lanaspa, F. L. Merchan and T. Tejero, Tetrahedron Lett.,
1997, 38, 1813; P. Merino, A. Lanaspa, F. L. Merchan and T. Tejero,
J. Org. Chem., 1996, 61, 9028; A. Dondoni, F. Junquera, F. L. Merchan,
P. Merino and T. Tejero, J. Chem. Soc., Chem. Commun., 1995,
2127.
8 D. D. Dhavale and C. Trombini, J. Chem. Soc., Chem. Commun., 1992,
1268; C. Camiletti, D. D. Dhavale, F. Donati and C. Trombini,
Tetrahedron Lett., 1995, 36, 7293.
9 Y. Kita, F. Itoh, O. Tamura, Y. Y. Ke and Y. Tamura, Tetrahedron Lett.,
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M. Kohno and Y. Tamura, J. Chem. Soc., Chem. Commun., 1988,
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10 P. Merino, S. Franco, F. L. Merchan and T. Tejero, Tetrahedron:
Asymmetry, 1997, 8, 3489.
11 P. Merino, E. Castillo, F. L. Merchan and T. Tejero, Tetrahedron:
Asymmetry, 1997, 8, 1725; P. Merino, S. Anoro, E. Castillo, F. L.
Merchan and T. Tejero, Tetrahedron: Asymmetry, 1996, 7, 1887.
12 T. Fujisawa, Y. Koorijama and M. Shimizu, Tetrahedron Lett., 1996,
37, 3881.
13 T.-J. Sturm, A. E. Marolewski, E. S. Rezenka and S. K. Taylor, J. Org.
Chem., 1989, 54, 2039.
14 T. Niahimura and T. Iwai, Chem. Pharm. Bull., 1964, 12, 352.
15 H. Vorbruggen, K. Krolikiewicz and B. Bennua, Chem. Ber., 1981, 114,
1234.
As expected from these results, nitrone 4 behaved as an
excellent precursor to other related isoxazolidinyl nucleosides,
and thus further studies on its reactivity are underway.
This research was supported by MEC (Madrid, Spain). We
are grateful to Professor S. Castillon for helpful discussions.
One of us (S. F.) thanks the MEC (Madrid, Spain) for a
contract.
16 G. M. Sheldrick, Acta Crystallogr., 1990, A46, 467.
17 G. M. Sheldrick, SHELXL-93, Program for the Refinement of Crystal
Structures, University of Gottingen, Germany, 1993.
Notes and References
† E-mail; pmerino@posta.unizar.es
‡ All new compounds exhibited consistent spectral (1H and 13C NMR, IR)
and analytical data. Optical rotations: 20 ± 2 °C (c 1, CHCl3). Selected data
Received in Glasgow, UK, 4th August 1997; 7/05673G
494
Chem. Commun., 1998