Diastereo- and enantioselective synthesis of N,O-nucleosides

Article abstract of DOI:10.1016/S0957-4166(03)00499-3

The diastereo- and enantioselective synthesis of α- and β-3′-hydroxymethyl-N,O-nucleosides is described, based on the 1,3-dipolar cycloaddition of a N-glycosyl nitrone. Two approaches have been evaluated: the one-step procedure, which uses vinyl nucleobases, showed a better stereoselectivity towards β-nucleosides.

Full text of DOI:10.1016/S0957-4166(03)00499-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2717–2723
Diastereo- and enantioselective synthesis of N,O-nucleosides
Ugo Chiacchio,a,* Antonino Corsaro,a Daniela Iannazzo,b Anna Piperno,b Venerando Pistara`,a
Antonio Rescifina,a Roberto Romeo,b Giovanni Sindonac and Giovanni Romeob,*
aDipartimento di Scienze Chimiche, Universita` di Catania, Viale Andrea Doria 6, Catania 95125, Italy
bDipartimento Farmaco-Chimico, Universita` di Messina, Viale SS. Annunziata, Messina 98168, Italy
cDipartimento di Chimica, Universita` della Calabria, Arcavacata di Rende, Cosenza 87036, Italy
Received 17 June 2003; accepted 24 June 2003
Abstract—The diastereo- and enantioselective synthesis of a- and b-3%-hydroxymethyl-N,O-nucleosides is described, based on the
1,3-dipolar cycloaddition of a N-glycosyl nitrone. Two approaches have been evaluated: the one-step procedure, which uses vinyl
nucleobases, showed a better stereoselectivity towards b-nucleosides.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
The asymmetric version has also been investigated
through the use of chiral dipoles:6,7 In this way, ADU,
ADT, ADC, ADA and ADFU have been synthesized
in enantiomerically pure form. (−)-ADFU shows
promising biological properties: in particular it appears
as a good inductor of apoptosis on lymphoid and
monocytoid cells, acting as a strong potentiator of
Fas-induced cell death.7
The improved knowledge of the HIV virus and its
replication mechanism have suggested in recent years
the synthesis of new molecules able to block the viral
replication.1 These compounds originate from chemical
modifications of the nucleic acid fragments at the level
of the sugar moiety and/or the heterocyclic base. In this
context, the design of novel ‘ribose’ rings has resulted in
the discovery of effective biological agents; promising
results have been obtained from a new generation of
nucleoside analogues where the ribose moiety has been
replaced by either carbo- or heterocyclic rings.2–4
Herein we report a successful extension of the method-
ology towards the enantioselective synthesis of 3-
hydroxymethyl derivatives of ADT, ADU, ADFU: the
presence in the molecule of the hydroxymethyl group
should promote the biological phosphorylation of the
compounds and hence their biological activity.8
The synthesis of isoxazolidinyl nucleosides 1, unsubsti-
tuted on the nitrogen atom and in racemic form, has
been recently reported:5 ADT 1 shows interesting
antiviral and anti-AIDS activity (Fig. 1).
2. Results and discussion
N-Glycosylnitrones9 have been exploited as versatile
building blocks in the preparation of the target
modified nucleosides: the chiral auxiliary is easily intro-
duced before the cycloaddition process and removed
subsequently to give N,O-nucleosides unsubstituted on
the nitrogen atom.
Thus, the reaction of (4S,5R)-5-[(1R)-2[[1-(tert-butyl)-
1,1-diphenylsilyl]oxy]-1-hydroxyethyl]-2,2-dimethyl-1,3-
dioxolane-4-carbaldehyde oxime 2, with ethyl
glyoxylate and vinyl acetate, in CHCl3 at
Figure 1. Isoxazolidinyl nucleosides.
* Corresponding authors. Tel.: +39-095-7385014; fax: +39-06-
233208980; e-mail: uchiacchio@dipchi.unict.it
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00499-3

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U. Chiacchio et al. / Tetrahedron: Asymmetry 14 (2003) 2717–2723
reflux at 60°C for 14 h gives, as previously reported,10
mixture of two homochiral isoxazolidines 4 and 5,
a
epimeric at C5, while they possess the same stereochem-
istry at C3 and C1%.
epimeric at C5, in a relative ratio trans/cis 1:1 (Scheme
1).
Thus, the cycloaddition reaction proceeds with a com-
plete diastereofacial selectivity by involving, according
to PM3 calculations,11 the attack of dipolarophile on
the re-face of nitrone in an E-exo and E-endo transi-
tion-state: in fact, an energy difference of 2.5 kcal/mol
is observed in favor of the re-face attack with respect to
the si-face one. This behaviour is also in accord with ab
initio DFT calculations on C-methoxycarbonyl nitrone
with vinyl acetate.12 On these basis, the absolute
configuration of the cycloadducts 4 and 5 can be tenta-
tively assigned as (3R,5R) and (3R,5S) respectively.
The two cycloadducts were independently converted in
the
(3R)-2-(5%-O-tert-butyldiphenylsilyl-2%,3%-O-iso-
propylidene-b-
D
-ribofuranosyl)-3-ethoxycarbonylisoxa-
zolidin-5-one10 through hydrolysis with K2CO3,
followed by oxidation with potassium permanganate.
This result indicates that isoxazolidines 4 and 5 are
The mixture of epimeric isoxazolidines 4 and 5 was
then reacted with N,O-bis(trimethylsilyl)acetamide
(BSA) and uracil 6a, or thymine 6b, in acetonitrile in
the presence of TMSOTf or with 5-fluorouracil 6c in
CH2Cl2 at 0°C, in the presence of one equivalent of
SnCl4, to afford, with moderate stereoselectivity and
good yields, the expected a- and b-nucleosides 7a–c and
8a–c, respectively (ratio 2.2:1), in enantiomerically pure
form.
The structures of the obtained compounds were
assessed on the basis of analytical and spectroscopic
data (see Section 3). The 1H NMR spectra of com-
pounds 7a–c showed the diagnostic resonances of H5% as
dd, in the range 6.23–6.24 ppm, while H3% protons
appear as dd, at 4.16–4.17 ppm; the methylene group at
C4% resonate as ddd at 2.40–2.41 and 2.99–2.99. For
compounds 8a–c, H5% protons resonate as dd at 5.94–
6.43, while H3% appear as dd at 4.05–4.12 ppm. Note-
worthy, in 8a–c H5% protons show a long-range coupling
with H3%, thus indicating a cis topological arrangement.
The stereochemical assignments have been performed
on the basis of NOE and T-Roesy measurements. Irra-
diation of the H5% signal in 8a–c (cis) induces a positive
NOE effect on the upfield resonance of methylene
protons at C4%; in turn, irradiation of this proton gives
rise to enhancement of the H3% resonance, thus indicat-
ing that these protons are in a cis arrangement. As
confirmation, T-Roesy experiments reveal an intense
NOE effect between H5%, H4%b and H3%.
Conversely, nucleosides 7a–c (trans) shows a NOE
correlation between H5% and the upfield resonance at
C4%, but only a negligible NOE effect between this last
resonance and H3%.
The reduction of the ester function was performed by
treatment with NaBH4 in dioxane/H2O 1:1 to give
3%-hydroxymethyl derivatives 9a–c and 10a–c. Finally,
the synthetic scheme was completed by removal of the
sugar moiety, which was easily achieved by treatment
with 1.5% aqueous HCl, to afford the target
nucleosides 11 (a) and 12 (b), in enantiomerically pure
form, with a satisfactory global yield starting from
nitrone 3. However, all the attempts to obtain uracil
derivatives 11a and 12a failed.
Scheme 1. Reagents and conditions: (i) Ethyl glyoxylate; (ii)
vinyl acetate, 70°C; (iii) BSA, nucleobases, Me3SiOTf in
refluxed MeCN for 1 h, or SnCl4, at 0°C for 2 h, and then
overnight at rt; (iv) NaBH4, dioxane:water 1:1, rt, 5 h; (v)
1.5% HCl in EtOH, rt, 3 h.

U. Chiacchio et al. / Tetrahedron: Asymmetry 14 (2003) 2717–2723
2719
A valuable improvement in the synthetic strategy has
been exploited through the use of vinylated nucleo-
bases, as dipolarophiles, to afford modified isoxazo-
lidinyl nucleosides 7 and 8 in one step.
200 or 500 MHz (1H) and at 50 or 125 MHz (13C) using
deuteriochloroform or deuterated methanol as solvent;
chemical shifts are given in ppm from TMS as internal
standard. Thin-layer chromatographic separations were
performed on Merck silica gel 60-F254 precoated alu-
minium plates. Preparative separations were made by
flash column chromatography using Merck silica gel
0.063–0.200 mm and 0.035–0.070 mm, respectively,
with chloroform-methanol mixtures as eluent. HPLC
purifications were made with a preparative column
Thus, ribosyl oxyme 2 was reacted with ethyl glyoxylate
and vinyl bases 13a–c in CHCl3 at 60°C for 12 h to
afford nucleosides 7 and 8 in a 1:1.4 ratio (global yield
48%). In this case the reaction pathway appears to be
different from the one presented in the above proce-
dure, based on the Vorbru¨ggen nucleosidation; in fact,
b-nucleosides 8a,c are the major adducts. No attack of
dipole to the double bond of nucleobases has been
observed (Scheme 2).
,
(Microsorb Dynamax 100A, 21.4×250 mm). The purity
of all homochiral compounds has been tested with a
Nucleosil Chiral-2, 4×250 mm column with mixtures of
n-hexane-2-propanol as eluent.
The identification of samples from different experi-
ments was secured by mixed mps and superimposable
IR spectra.
3.1. Starting materials
Ethyl glyoxylate, thymine, uracil, fluorouracil, and
D-
ribose were purchased from Aldrich Co. Isoxazolidines
4 and 5,10 and vinyl bases 1313 were prepared as already
reported. All solvents were dried according to standard
procedures.
Scheme 2. Reagents and conditions: (i) Ethyl glyoxylate, vinyl
bases 13a–c, 60°C, CHCl3, 12 h.
3.2. Method A. General procedure for reactions
between bases 6a,b and isoxazolidines 4 and 5
The cycloaddition reaction shows, besides a complete
diastereofacial selectivity,
a
moderate cis/trans
diastereoselectivity, which can be rationalized by
assuming that the E-endo attack of the dipolarophile on
the re-face of the nitrone is the preferred reaction
pathway, because of secondary orbital interactions
exerted by the pyrimidine ring of nucleobases.
A suspension of bases 6a–c (0.618 mmol) in dry aceto-
nitrile (3 mL) was treated with N,O-bis(trimethylsi-
lyl)acetamide (2.54 mmol) and refluxed for 15 min; to
the clear solution obtained was added a solution of
isoxazolidine 4 and 5 (0.517 mmol) in dry acetonitrile (3
mL) and then trimethylsilyltriflate (0.78 mmol) drop-
wise; the reaction mixture was refluxed for 1 h. After
being cooled to 0°C, the solution was neutralized by
careful addition of aqueous 5% sodium bicarbonate,
and then it was concentrated in vacuo. To the crude
was added dichloromethane (8 mL), and the organic
phase was separated, washed with water (2×10 mL),
dried over sodium sulfate, filtered, and evaporated to
dryness. The residue was purified by radial chromatog-
raphy (cyclohexane/ethyl acetate 3:2) and then by
HPLC with a linear gradient of 2-propanol (6–10%,
0–10 min, flow 3.5 mL/min) in n-hexane.
In conclusion, the enantioselective synthesis of a- and
b-3%-hydroxymethyl-N,O-nucleosides
has
been
described. Two different approaches have been evalu-
ated: the two-step procedure, based on the 1,3-dipolar
cycloaddition of the chiral nitrone 3 with vinyl acetate,
followed by Vorbru¨ggen nucleosidation, leads to better
yields with respect to the one-step approach based on
the cycloaddition reaction, performed with vinyl nucleo-
base. In this latter case, however, the procedure shows
an improved stereoselectivity towards the formation of
b adducts.
The designed methodologies appear versatile and
extendable to the synthesis of all N,O-nucleosides con-
taining different purine and pyrimidine bases. Tests on
the biological activity of the synthesized compounds are
in progress.
3.2.1. 1-[(3R,5R)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl)-3-ethoxycarbonyl-1,2-
isoxazolidin-5-yl]-1H-pyrimidine-2,4-dione 7a. Yield
20%; HPLC: tR 20.5 min. Oil; [h]2D5=+15.3 (c 2.01,
CHCl3). 1H NMR (CDCl3, 500 MHz) l: 1.06 (s,
9H), 1.19 (t, 3H, J=7.5 Hz), 1.34 (s, 3H), 1.52 (s,
3H), 2. 40 (ddd, 1H, J=6.5, 7.4, 14.0 Hz, H4%a),
2.99 (ddd, 1H, J=2.0, 7.0, 13.0 Hz, H4%b), 3.74 (dd,
1H, J=6.0, 11.0 Hz, H5¦a), 3.76 (dd, 1H, J=5.0,
11.5 Hz, H5¦b), 4.09 (dq, 1H, J=7.5, 15.5 Hz), 4.10
(dq, 1H, J=7.5, 15.5 Hz), 4.16 (dd, 1H, J=2.0, 8.0
Hz, H3%), 4.22 (ddd, 1H, J=2.5, 5.0, 6 Hz, H4¦),
4.65 (dd, 1H, J=3,0 e 6,5 Hz, H2¦), 4.71 (dd, 1H,
J=2.5, 6.5 Hz, H3¦), 4.98 (d, 1H, J=3.0 Hz, H1¦), 5.66
3. Experimental
Melting points were determined with a Kofler appara-
tus and are uncorrected. Elemental analyses were per-
formed with a Perkin–Elmer elemental analyzer. IR
spectra were recorded on a Perkin–Elmer Paragon 500
FT-IR Spectrometer using potassium bromide discs.
NMR spectra were recorded on a Varian instrument at

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U. Chiacchio et al. / Tetrahedron: Asymmetry 14 (2003) 2717–2723
(d, 1H, J=8.0 Hz, H5), 6.24 (dd, 1H, J=6.5, 7.0 Hz,
H5%), 7.37–7.43 (m, 6H), 7.60–7.43 (m, 5H), 8.93 (bs,
1H, NH). 13C NMR (CDCl3, 125 MHz) l: 13.9, 19.2,
25.3, 26.8, 27.1, 38.5, 61.5, 61.8, 63.7, 80.8, 82.8, 85.4,
98.9, 102.7, 113.6, 127.8, 129.9, 129,9, 132.8, 132.9,
135.5, 135.5, 139.6, 150.1, 163.1, 169.6. Anal. calcd for
C34H43N3O9Si: C, 61.33; H, 6.51; N, 6.31%. Found: C,
61.31; H, 6.50; N, 6.32%.
emulsion was separated by filtration through Celite,
the aqueous layer was extracted further with ethyl
acetate (3×10 mL), and the combined organic layers
were dried over Na2SO4 and evaporated under reduced
pressure. The residue was purified by radial chro-
matography (cyclohexane/ethyl acetate 3:2) and then
by HPLC with a linear gradient of 2-propanol (6–10%,
0–10 min, flow 3.5 mL/min) in n-hexane.
3.3.1. 5-Fluoro-1-[(3R,5R)-2-(5-O-tert-butyldiphenylsi-
3.2.2. 1-[(3R,5S)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-
lyl-2,3-O-isopropyliden-b-D-ribofuranosyl)-3-ethoxycar-
isopropylidene-b-D-ribofuranosyl)-3-ethoxycarbonyl-1,2-
bonyl-1,2-isoxazolidin-5-yl]-1H-pyrimidine-2,4-dione 7c.
Yield 38.2%; HPLC: tR 16.8 min. White solid: mp
52–56°C from EtOAc; [h]2D5=−31.2 (c 0.08; CHCl3).
1H NMR (CDCl3, 500 MHz) l: 1.00 (s, 9H), 1.13 (t,
3H, J=7.1 Hz), 1.28 (s, 3H), 1.46 (s, 3H), 2.30 (ddd,
1H, J=6.7, 7.0 and 13.6 Hz, H4%a), 2.90 (ddd, 1H,
J=1.8, 7.1 and 13.6 Hz, H4%b), 3.70 (dd, 1H, J=4.4
and 11.3 Hz, H5¦a), 3.74 (dd, 1H, J=5.4 and 11.3 Hz,
isoxazolidin-5-yl]-1H-pyrimidine-2,4-dione 8a. Yield
44%; HPLC: tR 18.4 min. Amorphous solid; [h]2D5=−
1
55.0 (c 1.50, CHCl3). H NMR (CDCl3, 500 MHz) l:
1.07 (s, 9H), 1.27 (t, 3H, J=7.1 Hz), 1.33 (s, 3H), 1.53
(s, 3H), 2.53 (ddd, 1H, J=3.1, 6.2, 13.9 Hz, H4%a), 2.87
(ddd, 1H, J=7.7, 9.7, 13.9 Hz, H4%b), 3.72 (dd, 1H,
J=6.0, 13.0 Hz, H5¦a), 3.74 (dd, 1H, J=6.0, 13.0 Hz,
H5¦b), 4.05 (dd, 1H, J=6.2, 9.7 Hz, H3%), 4.19 (dq, 2H,
J=7.1, 10.5 Hz), 4.24 (dq, 1H, J=3.5 and 6.0 Hz,
H4¦), 4.51 (dd, 1H, J=3.5, 6.2 Hz, H3¦), 4.77 (dd, 1H,
J=2.0, 6.2 Hz, H2¦), 5.02 (dd, 1H, J=1.1, 2.0 Hz,
H1¦), 5.71 (d, 1H, J=8.1 Hz, H5), 5.94 (ddd, 1H,
J=1.1, 3.1, 7.7 Hz, H5%), 7.37–7.45 (m, 6H), 7.69–7.70
(m, 4H), 7.80 (d, 1H, J=8.1 Hz, H6), 8.45 (bs, 1H,
NH). 13C NMR (CDCl3, 125 MHz) l: 14.1, 19.3, 25.4,
26.8, 27.2, 39.8, 60.4, 62.1, 64.4, 81.0, 82.7, 83.7, 86.6,
97.6, 102.2, 113.4, 127.7, 129.8, 129.9, 133.2, 135.6,
135.6, 140.4, 150.1, 162.9 169.3. Anal. calcd for
C34H43N3O9Si: C, 61.33; H, 6.51; N, 6.31%. Found: C,
61.35; H, 6.52; N, 6.33%.
H5¦b), 4.05 (dq, 1H, J=7.1 and 14.8 Hz), 4.07 (dq,
1H, J=7.1 and 14.8 Hz), 4.11 (dd, 1H, J=1.8 and 7.0
Hz, H3%), 4.16 (ddd, 1H, J=2.6, 4.4 and 5.4 Hz, H4¦),
4.56 (dd, 1H, J=3.3 and 6.2 Hz, H2¦), 4.64 (dd, 1H,
J=2.6 and 6.2 Hz, H3¦), 4.95 (d, 1H, J=3.3 Hz, H1¦),
6.19 (dd, 1H, J=6.7 and 7.1 Hz, H5%), 7.30–7.56 (m,
10H), 7.76 (d, 1H, J=6.2 Hz, H6), 8.78 (bs, 1H, NH).
13C NMR (CDCl3, 125 MHz) l: 13.9, 19.2, 25.3, 26.9,
27.1, 38.4, 61.2, 61.9, 63.7, 80.5, 82.7, 85.2, 85.9, 99.1,
113.9, 124.0 (d, J=33.8 Hz), 127.8, 127.8, 129.9,
130.0, 132.8, 132.9, 135.5, 135.6, 140.6 (d, J=232.7
Hz), 155.9 (d, J=27.5 Hz), 169.5. Anal. calcd for
C34H42FN3O9Si: C, 59.72; H, 6.19; N, 6.15%. Found:
C, 59.91; H, 6.17; N, 6.14%.
3.2.3. 1-[(3R,5R)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl)-3-ethoxycarbonyl-1,2-
3.3.2. 5-Fluoro-1-[(3R,5S)-2-(5-O-tert-butyldiphenylsi-
isoxazolidin-5-yl]-5-methyl-1H-pyrimidine-2,4(1H,3H)-
dione 7b. Yield 58%; HPLC: tR 13.5 min. White solid:
mp 53–56°C from EtOAc; [h]2D5=−36.2 (c 1.08;
CHCl3). Anal. calcd for C35H45N3O9Si: C, 61.84; H,
6.67; N, 6.18%. Found: C, 61.81; H, 6.69; N, 6.14%.
All spectroscopic data are identical to the reported
ones.10
lyl-2,3-O-isopropyliden-b-D-ribofuranosyl)-3-ethoxycar-
bonyl-1,2-isoxazolidin-5-yl]-1H-pyrimidine-2,4-dione 8c.
Yield 31.8%; HPLC: tR 19.6 min. White solid: mp
1
51–55°C from EtOAc; [h]2D5=−6.8 (c 0.22; CHCl3). H
NMR (CDCl3, 500 MHz) l: 0.99 (s, 9H), 1.04 (t, 3H,
J=7.2 Hz), 1.28 (s, 3H), 1.45 (s, 3H), 2.52 (ddd, 1H,
J=3.3, 3.4, 14.0 Hz, H4%a), 2.82 (ddd, 1H, J=7.7, 9.9,
14.0 Hz, H4%b), 3.65 (dd, 1H, J=4.0, 11.2 Hz, H5¦a),
3.73 (dd, 1H, J=6.4, 11.2 Hz, H5¦b), 3.90 (dq, 1H,
J=7.2, 10.8 Hz), 3.97 (dq, 1H, J=7.2, 10.8 Hz), 4.04
(ddd, 1H, J=1.5, 3.3, 9.9 Hz, H3%), 4.16 (ddd, 1H,
J=2.3, 4.0, 6.4 Hz, H4¦), 4.61 (dd, 1H, J=2.9, 6.4 Hz,
H2¦), 4.69 (d, 1H, J=2.9 Hz, H1¦), 4.70 (dd, 1H,
J=2.3, 6.4 Hz, H3¦), 6.29 (dd, 1H, J=1.5, 3.4, 7.7 Hz,
H5%), 7.30–7.63 (m, 10H), 7.91 (d, 1H, J=6.2 Hz, H6),
9.30 (bs, 1H, NH). 13C NMR (CDCl3, 125 MHz) l:
13.9, 19.2, 25.2, 26.8, 38.1, 60.6, 62.0, 63.7, 81.0, 82.6,
85.2, 85.6, 100.3, 113.5, 124.9 (d, J=35.1 Hz), 127.9,
127.9, 130.0, 132.8, 132.9, 135.4, 135.5, 140.3 (d, J=
239.7 Hz), 156.7 (d, J=27.1 Hz), 170.8. Anal. calcd
for C34H42FN3O9Si: C, 59.72; H, 6.19; N, 6.15%.
Found: C, 59.63; H, 6.21; N, 6.13%.
3.2.4. 1-[(3R,5S)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl)-3-ethoxycarbonyl-1,2-
isoxazolidin-5-yl]-5-methyl-1H-pyrimidine-2,4(1H,3H)-
dione 8b. Yield 23%; HPLC: tR 11.5 min. White solid:
mp 51–55°C from EtOAc; [h]2D5=+5.6 (c 1.22; CHCl3).
Anal. calcd for C35H45N3O9Si: C, 61.84; H, 6.67; N,
6.18%. Found: C, 61.89; H, 6.65; N, 6.21%. All spec-
troscopic data are identical to the reported ones.10
3.3. Method B. General procedure for reactions
between base 6c and isoxazolidines 4 and 5
To a stirred mixture of 5-fluorouracil 6c (1.5 mmol),
and isoxazolidines 4 and 5 as epimeric mixtures in
anhydrous CH2Cl2 was added N,O-bis(trimethylsi-
lyl)acetamide (3.5 mmol). After 2 h of stirring at room
temperature, the clear solution was cooled at 0°C and
SnCl4 was added. The mixture was warmed to room
temperature, left to stir overnight and, finally, poured
slowly into a mixture of cold saturated aqueous
NaHCO3 (5 mL) and CHCl3 (10 mL). The resulting
3.4. General procedure for reactions between vinyl-bases
13a–c and Vasella-type nitrone 3
A suspension containing one of the vinyl bases 13a–c
(1 equiv.), ribosyl hydroxylamine 2 (1 equiv.) and
ethyl glyoxylate (1 equiv.) in chloroform (ca. 10 mL)

U. Chiacchio et al. / Tetrahedron: Asymmetry 14 (2003) 2717–2723
2721
was heated in a sealed vessel at 60°C under stirring,
until the ribosyl hydroxylamine was consumed (8 h);
after this time, to the reaction mixture were added 0.5
equiv. of the ribosyl hydroxylamine and of formalde-
hyde and was left to react for additional 4 h. Removal
of the solvent in vacuo affords a crude material which
was purified by flash chromatography to give a mixture
of homochiral isoxazolidines 7a–c and 8a–c (1.5:1, 40%
global yield), which was purified by radial chromatog-
raphy (cyclohexane/ethyl acetate 3:2) and then by
HPLC with a linear gradient of 2-propanol (6–10%,
0–10 min, flow 3.5 mL/min) in n-hexane, shows physi-
cal and spectral data listed above.
H3¦), 4.70 (dd, 1H, J=2.7, 6.4 Hz, H2¦), 4.95 (d, 1H,
J=2.7 Hz, H1¦), 5.86 (d, 1H, J=8.0 Hz, H5), 6.42 (dd,
1H, J=5.6, 8.1 Hz, H5%), 7.33–7.41 (m, 6H), 7.50 (d,
1H, J=8.0 Hz, H6), 7.58–7.68 (m, 4H), 9.04 (bs, 1H,
NH). 13C NMR (CDCl3, 125 MHz) l: 12.5, 19.3, 25.4,
26.6, 27.3, 38.2, 62.6, 63.9, 63.9, 80.7, 83.3, 84.4, 85.5,
98.1, 101.2, 113.6, 127.77, 127.84, 131.1, 131.8, 132.8,
133.0, 135.5, 135.6, 150.2, 163.4. Anal. calcd for
C32H41N3O8Si: C, 61.62; H, 6.63; N, 6.74%. Found: C,
61.69; H, 6.62; N, 6.77%.
3.5.3. 1-[(3R,5R)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl)-3-hydroxymethyl-1,2-
isoxazolidin-5-yl]-5-methyl-1H-pyrimidine-2,4-dione 9b.
Yield 93%; white foam; [h]2D5=−42.9 (c 0.35; CHCl3).
1H NMR (CDCl3, 500 MHz) l: 1.07 (s, 9H), 1.33 (s,
3H), 1.53 (s, 3H), 1.90 (d, 3H, J=1.1 Hz), 2.41 (ddd,
1H, J=5.8, 8.0, 13.6 Hz, H4%a), 2.56 (ddd, 1H, J=2.9,
7.7, 13.6 Hz, H4%b), 3.24 (bs, 1H, OH), 3.57 (dd, 1H,
J=6.9, 12.1 Hz, H3%a), 3.62 (dd, 1H, J=3.3, 12.1 Hz,
3.5. General procedure for reduction of nucleosides 7, 8
To a stirred solution of 7a–c, 8a–c (1.0 mmol) in a 1:1
methanol/dioxane mixture (50 mL), was added at 0°C
NaBH4 (6 mmol) and the obtained mixture was stirred
for 5 h. At the end of this time the solvent was removed
and the residue was extracted with ethyl acetate (3×5
mL); the collected organic phases, dried over sodium
sulphate, gave after evaporation of the solvent at
reduced pressure a yellow oil, which was purified by
flash chromatography (chloroform/methanol 85:15).
H3%b), 3.68 (dddd, 1H, J=2.9, 3.3, 6.9, 8.0 Hz, H3%), 3.75
(dd, 1H, J=4.7, 11.3 Hz, H5¦a), 3.81 (dd, 1H, J=6.2,
11.3 Hz, H5¦b), 4.25 (ddd, 1H, J=2.5, 4.7, 6.2 Hz, H4¦),
4.55 (dd, 1H, J=2.5, 6.2 Hz, H3¦), 4.71 (dd, 1H, J=2.9,
6.2 Hz, H2¦), 5.05 (d, 1H, J=2.9 Hz, H1¦), 6.23 (dd, 1H,
J=5.8, 7.7 Hz, H5%), 7.36–7.46 (m, 6H), 7.54 (q, 1H,
J=1.1 Hz, H6), 7.63–7.66 (m, 4H), 9.04 (bs, 1H, NH).
13C NMR (CDCl3, 125 MHz) l: 12.6, 19.2, 25.2, 26.8,
27.1, 38.1, 62.7, 63.0, 64.1, 80.5, 83.1, 83.9, 85.7, 98.5,
111.2, 113.5, 127.8, 127.8, 129.9, 130.0, 132.7, 132.9,
135.3, 135.5, 135.6, 150.4, 163.6. Anal. calcd for
C34H45N3O7Si: C, 64.23; H, 7.13; N, 6.61%. Found: C,
64.47; H, 7.16; N, 6.59%.
3.5.1. 1-[(3R,5R)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl)-3-hydroxymethyl-1,2-
isoxazolidin-5-yl]-1H-pyrimidine-2,4-dione 9a. Yield
86%; amorphous solid; [h]2D5=−59.6 (c 0.86; CHCl3). 1H
NMR (CDCl3, 500 MHz) l: 1.01 (s, 9H), 1.24 (s, 3H),
1.43 (s, 3H), 2.21 (ddd, 1H, J=5.6, 7.8, 13.4 Hz, H4%a),
2.65 (ddd, 1H, J=3.1, 7.6, 13.4 Hz, H4%b), 3.56 (bs, 1H,
OH), 3.59 (dd, 1H, J=6.7, 12.4 Hz, H3%a), 3.61 (dd, 1H,
J=3.4, 12.4 Hz, H3%b), 3.64 (dddd, 1H, J=3.1, 3.4, 6.7,
7.8 Hz, H3%), 3.81 (dd, 1H, J=4.5, 10.9 Hz, H5¦a), 3.84
(dd, 1H, J=5.9, 10.9 Hz, H5¦b), 4.45 (ddd, 1H, J=2.7,
4.5, 5.9 Hz, H4¦), 4.51 (dd, 1H, J=2.7, 5.9 Hz, H3¦),
4.68 (dd, 1H, J=3.1, 5.9 Hz, H2¦), 5.25 (d, 1H, J=3.4
Hz, H1¦), 5.89 (d, 1H, J=8.2 Hz, H5), 6.33 (dd, 1H,
J=5.6, 7.6 Hz, H5%), 7.32–7.51 (m, 6H), 7.54 (d, 1H,
J=8.2 Hz, H6), 7.63–7.66 (m, 4H), 9.04 (bs, 1H, NH).
13C NMR (CDCl3, 125 MHz) l: 12.6, 19.4, 25.0, 27.0,
27.2, 38.5, 62.7, 63.1, 64.1, 80.1, 83.4, 84.1, 85.5, 98.5,
103.5, 113.9, 127.8, 127.6, 130.0, 130.2, 132.7, 132.8,
135.5, 135.6, 135.7, 150.2, 164.0. Anal. calcd for
C32H41N3O8Si: C, 61.62; H, 6.63; N, 6.74%. Found: C,
61.67; H, 6.61; N, 6.79%.
3.5.4. 1-[(3R,5S)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl)-3-hydroxymethyl-1,2-
isoxazolidin-5-yl]-5-methyl-1H-pyrimidine-2,4-dione 10b.
Yield 72%; white solid: mp 54–58°C; [h]2D5=+5.1 (c
1
0.31; CHCl3). H NMR (CDCl3, 500 MHz) l: 1.09 (s,
9H), 1.31 (s, 3H), 1.51 (s, 3H), 1.69 (bs, 1H, OH), 1.87
(d, 3H, J=1.3 Hz), 2.19 (ddd, 1H, J=5.3, 6.9, 13.7 Hz,
H4%a), 2.86 (ddd, 1H, J=7.9, 8.8, 13.7 Hz, H4%b), 3.49
(dddd, 1H, J=6.2, 6.9, 8.1, 8.8 Hz, H3%), 3.56 (dd, 1H,
J=5.3, 12.0 Hz, H5¦a), 3.79 (dd, 1H, J=6.2, 11.3 Hz,
H3%a), 3.80 (dd, 1H, J=8.1, 11.3 Hz, H3%b), 3.81 (dd, 1H,
J=2.9, 12.0 Hz, H5¦b), 4.25 (ddd, 1H, J=2.1, 2.9, 5.3
Hz, H4¦), 4.58 (dd, 1H, J=2.1, 6.4 Hz, H3¦), 4.74 (dd,
1H, J=2.9, 6.4 Hz, H2¦), 4.80 (d, 1H, J=2.9 Hz, H1¦),
6.37 (dd, 1H, J=5.3, 7.9 Hz, H5%), 7.39–7.46 (m, 6H),
7.60 (q, 1H, J=1.3 Hz, H6), 7.64–7.66 (m, 4H), 8.60
(bs, 1H, NH). 13C NMR (CDCl3, 125 MHz) l: 12.7,
19.2, 25.2, 26.8, 26.9, 29.6, 38.2, 62.9, 63.8, 64.5, 80.8,
82.7, 83.5, 85.9, 101.4, 111.1, 113.5, 127.9, 128.0, 130.0,
130.1, 132.6, 132.9, 135.5, 135.6, 150.3, 163.4. Anal.
calcd for C34H45N3O7Si: C, 64.23; H, 7.13; N, 6.61%.
Found: C, 64.37; H, 7.12; N, 6.58%.
3.5.2. 1-[(3R,5S)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl)-3-hydroxymethyl-1,2-
isoxazolidin-5-yl]-1H-pyrimidine-2,4-dione 10a. Yield
75%; amorphous solid; [h]2D5=+12.8 (c 1.08; CHCl3). 1H
NMR (CDCl3, 500 MHz) l: 0.99 (s, 9H), 1.21 (s, 3H),
1.41 (s, 3H), 2.11 (ddd, 1H, J=5.6, 7.4, 13.5 Hz, H4%a),
2.79 (ddd, 1H, J=5.9, 8.1, 13.5 Hz, H4%b), 3.44 (dddd,
1H, J=6.3, 7.1, 8.1, 8.7 Hz, H3%), 3.52 (dd, 1H, J=8.7,
11.9 Hz, H3%b), 3.57 (dd, 1H, J=5.1, 11.1 Hz, H5¦a),
3.62 (bs, 1H, OH), 3.74 (dd, 1H, J=6.4, 11.9 Hz, H3%a),
3.80 (dd, 1H, J=2.7, 11.1 Hz, H5¦b), 4.27 (ddd, 1H,
J=2.0, 2.7, 6.4 Hz, H4¦), 4.57 (dd, 1H, J=2.0, 6.4 Hz,
3.5.5. 5-Fluoro-1-[(3R,5R)-2-(5-O-tert-butyldiphenilsilyl-
2,3-O-isopropylidene-b-D-ribofuranosyl)-3-hydroxy-
methyl-1,2-isoxazolidin-5-yl]pyrimidine-2,4(1H,3H)-
dione 9c. Yield 81%; white solid: mp 53–55°C from
EtOAc; [h]2D5=−40.8 (c 0.30; CHCl3). 1H NMR (CDCl3,

2722
U. Chiacchio et al. / Tetrahedron: Asymmetry 14 (2003) 2717–2723
500 MHz) l: 0.99 (s, 9H), 1.26 (s, 3H), 1.47 (s, 3H),
2.34 (ddd, 1H, J=5.8, 7.9, 13.8 Hz, H4%a), 2.53 (ddd,
1H, J=2.5, 7.5, 13.8 Hz, H4%b), 3.05 (bs, 1H, OH), 3.47
(dd, 1H, J=6.8, 12.2 Hz, H3%a), 3.57 (dd, 1H, J=3.1,
12.2 Hz, H3%b), 3.63 (dddd, 1H, J=2.5, 3.1, 5.8, 6.8 Hz,
H3%), 3.70 (dd, 1H, J=4.2, 11.1 Hz, H5¦a), 3.74 (dd, 1H,
J=5.9, 11.1 Hz, H5¦b), 4.18 (ddd, 1H, J=2.7, 4.2, 5.9
Hz, H4¦), 4.46 (dd, 1H, J=2.7, 6.4 Hz, H3¦), 4.58 (dd,
1H, J=3.3, 6.4 Hz, H2¦), 5.04 (d, 1H, J=3.3 Hz, H1¦),
6.14 (dd, 1H, J=7.5, 7.9 Hz, H5%), 7.32–7.61 (m, 10H),
7.80 (d, 1H, J=6.2 Hz, H6), 8.76 (bs, 1H, NH). 13C
NMR (CDCl3, 125 MHz) l: 25.3, 26.8, 27.2, 29.7, 38.5,
62.4, 62.8, 64.0, 80.1, 84.3, 85.4, 98.3, 113.8, 124.1 (d,
J=34.2 Hz), 127.8, 127.9, 129.9, 130.0, 132.7, 133.0,
135.5, 135.6, 141.1 (d, J=237.4 Hz), 150.3, 157.0 (d,
J=27.9 Hz). Anal. calcd for C32H40FN3O8Si: C, 59.89;
H, 6.28; N, 6.55%. Found: C, 60.08; H, 6.25; N, 6.58%.
H3%), 6.13 (dd, 1H, J=3.6, 7.9 Hz, H5%), 7.55 (q, 1H,
J=0.9 Hz, H6). 13C NMR (D2O, 125 MHz) l: 11.5,
36.5, 60.6, 61.5, 81.3, 111.0, 138.9, 151.9, 166.8. Anal.
calcd for C9H13N3O4: C, 47.57; H, 5.76; N, 18.49%.
Found: C, 47.42; H, 5.74; N, 18.56%.
3.6.2. 1-[(3R,5S)-3-(Hydroxymethyl)isoxazolidin-5-yl]-5-
methylpyrimidine-2,4(1H,3H)-dione 12b. Yield 77%;
HPLC: tR 22.2 min. colourless oil; [h]2D5=+108.3 (c
1
0.06; H2O). H NMR (D2O, 500 MHz) l: 1.92 (d, 3H,
J=1.3 Hz), 2.35 (ddd, 1H, J=6.2, 8.2, 13.7 Hz, H4%a),
2.87 (ddd, 1H, J=7.7, 7.8, 13.7 Hz, H4%b), 3.72 (dddd,
1H, J=4.4, 6.1, 7.7, 8.2 Hz, H3%), 3.78 (dd, 1H, J=6.1,
11.9 Hz, H3¦a), 3.84 (dd, 1H, J=4.4, 11.9 Hz, H3¦b),
6.12 (dd, 1H, J=6.2, 7.8 Hz, H5%), 7.63 (q, 1H, J=1.3
Hz, H6). 13C NMR (D2O, 125 MHz) l: 13.9, 38.3, 62.5,
63.9, 86.1, 113.5, 141.1, 150.7, 162.2. Anal. calcd for
C9H13N3O4: C, 47.57; H, 5.76; N, 18.49%. Found: C,
47.44; H, 5.79; N, 18.44%.
3.5.6. 5-Fluoro-1-[(3R,5S)-2-(5-O-tert-butyldiphenilsilyl-
2,3-O-isopropylidene-b-D-ribofuranosyl)-3-hydroxy-
methyl-1,2-isoxazolidin-5-yl]pyrimidine-2,4(1H,3H)-
3.6.3.
5-Fluoro-1-[(3R,5R)-3-(hydroxymethyl)isoxazo-
dione 10c. Yield 56%; amorphous solid; [h]2D5=+15.0 (c
lidin-5-yl]pyrimidine-2,4(1H,3H)-dione 11c. Yield 75%;
colourless oil; [h]2D5=−89.7 (c 0.15; H2O). 1H NMR
(D2O, 500 MHz) l: 2.61 (ddd, 1H, J=5.3, 7.4, 14.3 Hz,
H4%a), 2.71 (ddd, 1H, J=3.4, 7.6, 14.3 Hz, H4%b), 3.66 (d,
2H, J=5.9 Hz, H3¦), 3.83 (ddt, 1H, J=5.3, 5.9, 7.6 Hz,
H3%), 6.14 (dd, 1H, J=3.4, 7.4 Hz, H5%), 7.95 (d, 1H,
J=6.4 Hz, H6). 13C NMR (D2O, 125 MHz) l: 39.2,
62.6, 63.6, 91.9, 129.34 (d, J=34.0 Hz), 142.9 (d, J=
231.9 Hz), 152.7, 158.3 (d, J=26.7 Hz). Anal. calcd for
C8H10FN3O4: C, 41.56; H, 4.36; N, 18.18%. Found: C,
41.51; H, 4.34; N, 18.19%.
1
0.27; CHCl3). H NMR (CDCl3, 500 MHz): l 1.01 (s,
9H), 1.24 (s, 3H), 1.44 (s, 3H), 2.19 (ddd, 1H, J=4.2,
7.3, 14.0 Hz, H4%a), 2.85 (ddd, 1H, J=7.7, 8.0, 14.0 Hz,
H4%b), 2.97 (bs, 1H, OH), 3.28 (dddd, 1H, J=2.6, 4.6,
7.3, 8.0 Hz, H3%), 3.49 (dd, 1H, J=4.6, 12.0 Hz, H3%a),
3.68 (dd, 1H, J=4.9, 11.3 Hz, H5¦a), 3.70 (dd, 1H,
J=6.2, 11.3 Hz, H5¦b), 3.79 (dd, 1H, J=2.6, 12.0 Hz,
H3%b), 4.19 (ddd, 1H, J=1.8, 4.9, 6.2 Hz, H4¦), 4.49 (dd,
1H, J=1.8, 5.3 Hz, H3¦), 4.67 (d, 1H, J=1.8 Hz, H1¦),
4.68 (dd, 1H, J=1.8, 5.3 Hz, H2¦), 6.22 (dd, 1H, J=4.2,
7.7 Hz, H5%), 7.31–7.59 (m, 10H), 7.93 (d, 1H, J=6.1
Hz, H6), 9.22 (d, 1H, J=4.4 Hz, NH). 13C NMR
(CDCl3, 125 MHz) l: 19.2, 25.1, 26.81, 26.85, 29.7,
38.6, 62.1, 64.5, 64.6, 80.9, 82.8, 83.4, 86.2, 101.7, 113.5,
124.7 (d, J=34.7 Hz), 127.87, 127.95, 130.09, 130.11,
132.5, 132.7, 135.4, 135.5, 140.0 (d, J=236.2 Hz),
149.0, 156.8 (d, J=26.9 Hz). Anal. calcd for
C32H40FN3O8Si: C, 59.89; H, 6.28; N, 6.55%. Found:
C, 60.13; H, 6.26; N, 6.53%.
3.6.4.
5-Fluoro-1-[(3R,5S)-3-(hydroxymethyl)isoxazo-
lidin-5-yl]pyrimidine-2,4(1H,3H)-dione 12c. Yield 78%;
white solid: mp 133–134°C from EtOH; [h]2D5=+57.9 (c
0.16; H2O). H NMR (D2O, 500 MHz) l: 2.33 (dd, 1H,
1
J=6.0, 14.1 Hz, H4%a), 2.91 (ddd, 1H, J=7.2, 7.5, 14.1
Hz, H4%b), 3.66–3.83 (m, 3H, H3% and H3¦), 6.11 (dd, 1H,
J=6.0, 7.2 Hz, H5%), 8.02 (d, 1H, J=6.4 Hz, H6). 13C
NMR (D2O, 125 MHz) l: 36.5, 61.3, 63.9, 89.8, 127.4
(d, J=34.1 Hz), 141.1 (d, J=230.6 Hz), 150.5, 158.6 (d,
J=27.1 Hz). Anal. calcd for C8H10FN3O4: C, 41.56; H,
4.36; N, 18.18%. Found: C, 41.43; H, 4.35; N, 18.19%.
3.6. General procedure for hydrolysis of homochiral
isoxazolidines 9b,c and 10b,c
Isoxazolidines 9b,c and 10b,c were dissolved in a 1.5%
HCl solution in EtOH (ca. 2.5 mL), and the reaction
mixture was stirred at room temperature for 3 h. The
solution was brought to pH 10 by adding aqueous 10%
sodium carbonate and extracted with dichloromethane
(2×10 mL). The organic phase, dried over sodium sul-
fate, was filtered and evaporated to dryness. The
residue was purified by radial chromatography (chloro-
form/methanol 9:1) to furnish homochiral N,O-
nucleosides 11b,c and 12b,c.
Acknowledgements
We thank MIUR and CNR for their financial support.
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