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
references cited therein.
3 H. Jin, M. A. Siddiqui, C. A. Evans, H. L. A. Tse, T. S. Mansour,
M. D. Goodyear, P. Ravenscroft and C. D. Beels, J. Org. Chem., 1995,
60, 262 and references cited therein.
4 J. M. J. Tronchet, M. Iznaden, F. Barbalatrey, H. Dhimane, A. Ricca,
J. Balzarini and E. Declercq, Eur. J. Med. Chem., 1992, 27, 555;
J. M. J. Tronchet, M. Iznaden, F. Barbalatrey, I. Komaromi, N.
Dolatshami and G. Berbardinelli, Nucleosides Nucleotides, 1995, 14,
1737.
5 U. Chiacchio, G. Gumina, A. Rescifina, R. Romero, N. Uccella,
F. Casuscelli, A. Piperno and G. Romeo, Tetrahedron, 1996, 52, 8889;
G. Sindona, C. Siciliano, G. Giglio, A. Napoli, A. Leggio, A. Liguori
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.,
1987, 28, 1431; Y. Kita, O. Tamura, F. Itoh, H. Kishino, T. Miki,
M. Kohno and Y. Tamura, J. Chem. Soc., Chem. Commun., 1988,
761.
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