Lewis acid stereocontrolled additions of a silyl ketene acetal to 2,3-di-O-isopropylidene-D-glyceraldehyde nitrones. Synthesis of L-isoxazolidinyl nucleosides

Article abstract of DOI:10.1016/S0040-4039(00)01674-9

The reaction of O-methyl-O-tert-butyldimethylsilyl ketene acetal with N-benzyl and N-methyl-2,3-O-isopropylidene-D-glyceraldehyde nitrones in the presence of boron trifluoride etherate afforded the corresponding isoxazolidin-5-ones in excellent yields and anti-selectivities. The obtained compounds were used as key intermediates for the synthesis of isoxazolidinyl nucleosides of the L-series. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01674-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9239–9243
Lewis acid stereocontrolled additions of a silyl ketene acetal
to 2,3-di-O-isopropylidene- -glyceraldehyde nitrones.
Synthesis of -isoxazolidinyl nucleosides
D
L
Pedro Merino,* Eva M. del Alamo, Maite Bona, Santiago Franco, Francisco L. Merchan,
Tomas Tejero and Odile Vieceli
Departamento de Quimica Organica, Facultad de Ciencias-ICMA, Universidad de Zaragoza, E-50009 Zaragoza,
Aragon, Spain
Received 22 September 2000
Abstract
The reaction of O-methyl-O-tert-butyldimethylsilyl ketene acetal with N-benzyl and N-methyl-2,3-O-
isopropylidene-D-glyceraldehyde nitrones in the presence of boron trifluoride etherate afforded the
corresponding isoxazolidin-5-ones in excellent yields and anti-selectivities. The obtained compounds were
used as key intermediates for the synthesis of isoxazolidinyl nucleosides of the
Science Ltd. All rights reserved.
L-series. © 2000 Elsevier
The Lewis acid-promoted additions of various organometallic reagents to chiral nitrones are
now well-established as powerful synthetic methods because they offer mild reaction conditions
and high stereocontrol.1 The key factor for the successful diastereoface differentiation, which we
described some years ago, is the appropriate choice of the Lewis acid. Whereas ZnBr2-promoted
additions give rise to syn-adducts, Et2AlCl-promoted reactions lead to anti-isomers preferen-
tially.2 Recently, we described the addition of both lithium and sodium enolates to N-benzyl-2,3-
O-isopropylidene- -glyceraldehyde nitrone (BIGN, 1a) and applied it successfully to the
D
efficient synthesis of novel isoxazolidine nucleosides3 of biological importance.4
* Corresponding author. E-mail: pmerino@posta.unizar.es
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01674-9

9240
A major drawback is, however, that the Lewis acid employed to induce an anti-selectivity
(Et2AlCl) also reacts with the enolate thus considerably lowering the yield of the reaction.3
In light of our synthetic interest in novel nucleoside analogues, we sought a practical
methodology for the construction of chiral isoxazolidin-5-ones with anti-selectivity (and then
L
-isoxazolidinyl nucleosides) from a-alkoxy nitrones. In this context we have recently described
an alternative approach to -isoxazolidinyl nucleosides based on the 1,3-dipolar cycloaddition
reaction between 1a and vinyl acetate.5 The synthesis of
-isoxazolidinyl nucleosides had also
L
L
been reported by Zhao et al.6 Now, we wish to report that BF3·Et2O is able to induce a highly
anti-stereoselective addition to 1, thus achieving stereodivergency in the metal ketene acetal
additions to a-alkoxy nitrones7 and enantiodivergency in the synthesis of isoxazolidinyl
nucleosides.
We examined the addition of O-tert-butyldimethylsilyl-O-methyl ketene acetal 2 to nitrones
1 in the presence of Lewis acids (Scheme 1). The results summarized in Table 1 display a marked
contrast with those observed by Kita et al.8 with ZnI2 as a Lewis acid. These authors observed
that whereas the addition of silyl ketene acetal 2 to 1a took place with a good syn-selectivity,
Scheme 1.
Table 1
Stereoselective addition of ketene acetal 2 to nitrones 1 via Scheme 1a
Entry
Nitrone
Conditions
Additive (equiv.)
3:4:5b
syn:antic
Yield (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
CH2Cl2, 1 h
THF, 1 h
Et2O, 12 h
CH2Cl2, 48 h
CH2Cl2, 30 min
CH3CN, 30 min
THF, 30 min
CH2Cl2, 30 min
CH2Cl2, 30 min
CH2Cl2, 1 h
TBSOTf (1.0)
TBSOTf (1.0)
Et2AlCl (1.0)
BF3·Et2O (0.1)
BF3·Et2O (1.0)
BF3·Et2O (1.0)
BF3·Et2O (1.0)
BF3·Et2O (2.0)
BF3·Et2O (4.0)
TBSOTf (1.0)
Et2AlCl (1.0)
BF3·Et2O (1.0)
BF3·Et2O (1.0)
BF3·Et2O (2.0)
100:0:0
100:0:0
10:90:0
100:0:0
22:33:45
17:33:50
25:25:50
0:25:75
0:40:60
100:0:0
0:0:100
0:0:100
10:0:90
0:0:100
77:23
70:30
30:70
9:91
91
94
70
12
91
78
90
93
42
87
81
85
92
90
7:93
10:90
10:90
7:93
8:92
75:25
22:78
12:88
7:93
Et2O, 12 h
THF, 30 min
CH2Cl2, 30 min
CH2Cl2, 30 min
B5:95
a All reactions were carried out at −80°C using an excess (3.0 equiv.) of enolate.
b Determined by NMR analysis of the crude reaction mixture.
c Measured over compound 5 after desilylation and cyclization.
d Calculated as the sum of the isolated yields of the diastereomeric mixtures of 3, 4, and 5.

9241
a near 1:1 mixture of diastereomers was obtained when an O-tert-butyl ketene acetal was used
as a nucleophile.9
In our experiments, the addition of 2 to nitrones 1 led to a mixture of silylated hydroxy-
lamines 3, free hydroxylamines 4 (only observed with nitrone 1a) and isoxazolidinones10 5,
depending on both the nature and stoichiometry of the Lewis acid.
When nitrone 1a was treated with TBSOTf and then with ketene acetal 2, compound 3a was
obtained in good yield and syn-selectivity (entries 1 and 2). The same result was observed with
nitrone 1b (entry 10). However, when Et2AlCl was used as a pre-complexing agent of 1a, a
mixture of hydroxylamines 3a and 4a was obtained and the anti-isomers became predominant
with acceptable diastereoselectivities (entry 3). In the case of nitrone 1b the anti-selectivity was
also observed but only cyclized compound 5b was obtained (entry 11). The use of BF3·Et2O in
a catalytic amount afforded 3a exclusively with a good level of anti-selectivity (entry 4).
Unfortunately, the yield of the reaction was only 12%, presumably due to the necessity of
stoichiometric amounts of additive; actually, nitrone 1 was recovered in nearly 80% yield. In
fact, 1.0 equiv. of BF3·Et2O increased the yield of the reaction to 91%, without a substantial lost
of selectivity (entry 5). Under these conditions, a 2:3:4 mixture of compounds 3a, 4a and 5a was
obtained. This result was only slightly affected by a change of solvent (entries 6 and 7). An
excess of 2.0 equiv. of BF3·Et2O enriched the mixture of obtained compounds into the cyclic one
5a, no silylated hydroxylamine 3a being observed (entry 8). Also, in this case both the yield and
anti-selectivity showed high values. In an attempt to obtain only the isoxazolidin-5-one 5a, we
Scheme 2. Reagents and conditions: (a) HF, Py, 0°C, 30 min; (b) NaOMe, MeOH, rt, 4 h; (c) DIBAH, CH2Cl2,
−80°C, 1 h, then Ac2O, Py, 0°C, 30 min; (d) 7a (or 7b), TMSOTf, CH2Cl2; (e) p-TosOH (cat.), MeOH, then NaIO4,
MeOH (aq.), then NaBH4, MeOH, 0°C, 45 min

9242
checked the addition in the presence of 4.0 equiv. of BF3·Et2O (entry 9). However, under these
conditions the yield of the reaction dropped considerably.11 The reversal of the stereoselectivity
by the use of BF3·Et2O was also for nitrone 1b (entries 12–14), the best result found, being
obtained when 2.0 equiv. of additive were used (entry 14).
The diastereoselectivities of the processes were measured over compounds 5 after desilylation
of 3 (HF, Py) and cyclization of 4 (NaOMe, MeOH)12 as shown in Scheme 2. The stereochem-
istry of isoxazolidinones 5a was assigned by X-ray crystallographic analysis of a single crystal of
the major isomer anti-5a.13 The structure of compounds 5b was deduced by comparison of
physical and spectroscopic data14 with those described in the literature9 for syn-5b.
With respect to the synthetic utility of compounds anti-5, they were converted into the
corresponding 5-acetoxy isoxazolidines anti-6 by reduction (DIBAH, CH2Cl2) and subsequent
acetylation (Ac2O, Py). These key intermediates were further transformed into -isoxazolidinyl
L
nucleosides 10a–d and 11a–d (Scheme 2)14 according to the Vo¨rbruggen conditions10,15 and
following our previously described protocol,5 which had been successfully applied for the
synthesis of isoxazolidinyl thymidines 10d and 11d.
In summary, the results presented here represent the first evidence that silyl ketene acetals can
be added to a-alkoxy nitrones with complete stereocontrol starting from the same substrate. The
application of this methodology has served for providing access to
in higher yields than those reported previously.5,6 In addition, both
starting from -glyceraldehyde nitrones as the only chiral sources.
L
-isoxazolidinyl nucleosides
D
- and -series are accessible
L
D
Acknowledgements
Financial support from DGES (Madrid, Spain, Project PB97-1014) and DGA (Aragon,
Spain, Project PO79/99-C) is gratefully acknowledged.
References
1. For an account, see: (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Synlett 2000, 442–454. For reviews,
see: (b) Lombardo, M.; Trombini, C. Synthesis 2000, 759–774. (c) Merino, P.; Franco, S.; Merchan, F. L.; Tejero,
T. In Recent Research and Development in Synthetic Organic Chemistry; Pandalai, S. G., Ed.; Transworld
Research Network: Trivandrum, India, 1998; Vol. 1, pp. 1091–1121. (d) Merino, P.; Tejero, T. Molecules 1999,
4, 165–175.
2. For some leading references, see: (a) Merino, P.; Castillo, E.; Franco, S.; Merchan, F. L.; Tejero, T. J. Org.
Chem. 1998, 63, 2371–2374. (b) Merino, P.; Castillo, E.; Franco, S.; Merchan, F. L.; Tejero, T. Tetrahedron:
Asymmetry 1998, 9, 1759–1769. (c) Merino, P.; Castillo, E.; Franco, S.; Merchan, F. L.; Tejero, T. Tetrahedron
1998, 54, 12301–12322. (d) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Tetrahedron: Asymmetry 1997, 8,
3489–3496.
3. Merino, P.; Franco, S.; Garces, N.; Merchan, F. L.; Tejero, T. Chem. Commun. 1998, 493+.
4. For a review, see: Pan, S.; Amankulor, N. M.; Zhao, K. Tetrahedron 1998, 54, 6587–6604.
5. Merino, P.; del Alamo, E. M.; Franco, S.; Merchan, F. L.; Simon, A.; Tejero, T. Tetrahedron: Asymmetry 2000,
11, 1543–1554.
6. Xiang, Y.; Gong, Y.; Zhao, K. Tetrahedron Lett. 1996, 47, 4877–4880.
7. For other additions of ketene acetals to nitrones, see: (a) Ohtake, H.; Imada, Y.; Murahashi, S.-I. J. Org. Chem.
1999, 64, 3790–3791. (b) Jost, S.; Gimbert, Y.; Greene, A. E.; Fotiadu, F. J. Org. Chem. 1997, 62, 6672–6677. (c)
Camiletti, C.; Dhavale, D. D.; Donati, F.; Trombini, C. Tetrahedron Lett. 1995, 36, 7293–7296.
8. Kita, Y.; Tamura, O.; Itoh, F.; Kishino, H.; Miki, T.; Kohno, M.; Tamura, Y. Chem. Commun. 1988, 761–763.

9243
9. The same authors reported, however, that when a bulky group (CH(Me)Ph or CHPh2) was attached to the
nitrone, nitrogen anti-selectivity was observed, particularly in the case of nitrones derived from 4-deoxy-L-ery-
throse. See: Kita, Y.; Itoh, F.; Tamura, O.; Ke, Y. Y.; Tamura, Y. Tetrahedron Lett. 1987, 28, 1431–1434.
10. There is a precedent for such an intramolecular cyclization in the presence of a Lewis acid. See: Xiang, Y.; Gi,
H.-J.; Niu, D.; Schinazi, R. F.; Zhao, K. J. Org. Chem. 1997, 62, 7430–7434.
11. This is presumably due to occurrence of dioxolane ring-opening promoted by an excess of Lewis acid. See:
DeGiorgis, F.; Lombardo, M.; Trombini, C. Tetrahedron 1997, 53, 11721–11730.
12. The global process consisting of desilylation and cyclization can also be carried out over crude mixtures of
compounds 3, 4 and 5 in order to obtain, in a one-flask process, isoxazolidinones 5.
13. The authors have deposited atomic coordinates for the structure of anti-5a with the Cambridge Crystallographic
Data Centre (deposition number: CCDC 149829). Data for syn-5a had also been deposited previously (see Ref.
3).
14. Selected data (solvent for optical rotations: CHCl3) for anti-5a: [h]2D0=−36 (c 1.13); anti-5b: [h]D20=−95 (c 1.11);
10a: [h]2D0=−14 (c 0.28); 10b: [h]2D0=−33.4 (c 0.40); 10c: [h]D20=−11 (c 0.8); 10d: [h]2D0=−6 (c 1.10); Ref. 5:
[h]2D0=−7 (c 1.10); 11a: [h]D20=−43 (c 0.31); 11b: [h]2D0=−98 (c 0.29); 11c: [h]D20=−23 (c 0.16); 11d: [h]D20=−38 (c
0.89); Ref. 5: [h]2D0=−36 (c 1.11). Full experimental details and characterization, data are available from the
authors upon request.
15. Vo¨rbruggen, H.; Kvolikiewicz, K.; Bennua, B. Chem. Ber. 1981, 114, 1234–1255.
.