Enantioselective synthesis of homocarbocyclic-2′-oxo-3′- azanucleosides

Article abstract of DOI:10.1016/j.tet.2005.10.075

The enantioselective synthesis of homocarbocyclic-2′oxo-3′- azanucleosides has been performed by cycloaddition reaction of the N-glycosyl nitrones with allyl nucleobases. The use of nitrones originated from two different carbohydrates, the N-ribosyl nitro

Full text of DOI:10.1016/j.tet.2005.10.075

Tetrahedron 62 (2006) 1171–1181
Enantioselective synthesis of homocarbocyclic-20-
oxo-30-azanucleosides
a
a
b
a
Ugo Chiacchio,a, Maria Grazia Saita, Lia Crispino, Giuseppe Gumina, Sergio Mangiafico,
*
Venerando Pistara, Giovanni Romeo, Anna Piperno and Erik De Clercq
a
c,
c
d
*
`
a
`
Dipartimento di Scienze Chimiche, Universita di Catania, Viale Andrea Doria 6, 95125 Catania, Italy
bDepartment of Pharmaceutical Science, Medical University of S. Carolina, 280 Calhoun Street, Charleston, SC 29425, USA
c
`
Dipartimento Farmaco-Chimico, Universita di Messina, Viale SS. Annunziata, 98168 Messina, Italy
dRega Institute for Medical Research, Katholieke Universiteit Leuven, B-300 Leuven, Belgium
Received 30 June 2005; revised 11 October 2005; accepted 27 October 2005
Available online 18 November 2005
Abstract—The enantioselective synthesis of homocarbocyclic-20oxo-30-azanucleosides has been performed by cycloaddition reaction of the
N-glycosyl nitrones with allyl nucleobases. The use of nitrones originated from two different carbohydrates, the N-ribosyl nitrone and the N-
mannosyl nitrone, proceeded in a stereocontrolled and predictable manner with a good degree of enantioselectivity, so allowing an easy entry
to both enantiomers.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
evaluation as antiviral or antiproliferative agents have
been reported in the literature.6 In these compounds, besides
an increased resistance to hydrolytic or enzymatic cleavage,
compared to the relatively reactive aminal linkage of
common nucleosides, more conformational flexibility and
rotation freedom has been introduced.
There has been substantial interest in the synthesis and
applications of various modified nucleic acids.1 In this
context, many nucleoside analogues have been synthesized
with the modification of the base, sugar, and phosphate
region.2 In particular, nucleoside analogues, in which the
furanose ring has been replaced by different carbo- or
heterocyclic systems, have attracted special interest by
virtue of their biological action as antiviral and/or anti-
cancer agents.3 Among them, isoxazolidine nucleosides
(carbocyclic-20oxo-30-azanucleosides) are emerging as an
interesting class of dideoxynucleoside analogues with
potential pharmacological activity.4
Homo-N-nucleosides with a guanine or adenine base moiety
exhibit a good antiviral activity against herpes simplex
virus7 (HSV-1 and HSV-2); the analogous uracil homo-N-
nucleosides have been described as selective inhibitors of
viral uracil-DNA glycosylases (UDGs), while having little
effect on the human enzyme.8 Moreover, also the 10-C-
azanucleosides have proved very valuable as sequence-
specific glycosidase inhibitors and thus as potentially
effective anti-HIV drugs.9
In these last years, with the increasing number of crystal
structures of various enzyme–substrate complexes, it has
become apparent that many binding sites are more flexible
than previously thought and can therefore adjust to fit a wide
range of substrates. Recent reports have shown that flexible
inhibitors can overcome drug resistance mutations in HIV.5
Accordingly, different synthetic approaches towards
10-homo-C- and N-nucleoside, in which a methylene
group has been inserted between the base and the
carbohydrate moiety, and their relative biological
Recently, we have reported the synthesis of a new class of
homo-N-nucleoside analogues as racemic mixtures, in
which the ribofuranose moiety was replaced with an
isoxazolidine ring.10 However, the consideration that both
enantiomeric purity and absolute configuration are key
factors in determining the physiological activity of these
molecules, has prompted us to synthesize homocarbocyclic-
20-oxo-30-aza nucleosides in an enantiomerically pure form,
in order to investigate their biological features.
Keywords: Nucleosides; 1,3-Dipolar cycloaddition; N-Glycosyl nitrones.
*
Corresponding authors. Tel.: C39 095 738 5014; fax: C39 06 233 208
980 (U.C.) tel.: C39 090356230; fax: C39 0906766562; e-mail
addresses: uchiacchio@unict.it; gromeo@unime.it
In this paper, we report the enantioselective synthesis of this
class of compounds: the use of two different N-glycosyl
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.075

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U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181
0
0
nitrones has allowed us to obtain valuable asymmetric
induction towards the single enantiomers. Preliminary data
on the biological activity of the obtained compounds are
also reported.
(H3 ), dZ3.65 and dZ3.85 (H6 a,b), dZ2.16 and dZ2.46
0
(H4 a,b), and dZ7.06 (H6). As regards the trans adducts 6a
0
and 7a, compound 6a shows the H5 resonance at dZ4.21 as
dddds, while H3 resonates at dZ4.00 as dds, H6 a,b at dZ
0
0
0
2.97 and dZ3.85 as dds, H4 a,b at dZ1.91 and dZ2.49 as
ddds, and H6 at dZ6.56 as d. In compound 7a, the same
0
0
resonances appear at dZ3.99 (H5 ), dZ4.24 (H3 ), dZ3.51
2. Results and discussion
0
0
and dZ4.16 (H6 a,b), dZ2.10 and dZ2.63 (H4 a,b), dZ7.23
(H6).
D-Ribosyl nitrone 2, generated in situ by condensation of
D-ribosyl oxime 1 with ethyl glyoxylate,11 has been reacted
with allyl thymine 3a in refluxing toluene for 12 h. The
reaction afforded a mixture of four compounds, two cis (4a
and 5a) and two trans (6a and 7a), in 86% total yield
(Scheme 1).
The assignment of cis/trans configurations to the individual
diastereoisomers was established on the basis of (1H–1H)
NOEDS experiments. In particular, for cis epimers 4a and 5a,
0
irradiation of upfield methylene proton at C4 (H4 a) induced a
0
0
positive NOE effect on H4 b; conversely, irradiation of H4 b
0
gave rise to NOE enhancements for H4 a, H3 , and H5 .
0
0
0
Moreover, when H5 was irradiated, a positive NOE effect was
0
observed on H4 b. These data unambiguously support a cis
0
0
0
.
relationship between H5 , H3 , and H4 b
0
For the trans adducts 6a and 7a, irradiation of H4 a proton
0
produced a strong enhancement for H4 b, and H3 , while
0
0
irradiation of H4 b gave rise to a strong positive NOE effect
0
for H4 a and H5 . These results are clearly indicative of a
0
0
trans relationship between H5 and H3 .
0
The reduction with LiAlH4 of the main cycloadducts 4a, 5a,
and 7a followed by the selective cleavage of the sugar
moiety, performed with 1.2 mmol of p-TosOH in methanol,
generated the target homocarbocyclic-20-oxo-30-aza thymi-
dines 12a, 13a and 15a in enantiomerically pure forms
(Scheme 2).
Scheme 1.
which have been separated by HPLC.
Scheme 2.
The structure of the obtained adducts has been confirmed by
1H NMR experiments. Thus, 5a, the main compound, shows
0
the H5 resonance as doublet of doublet of doublet of
The results obtained indicate that the asymmetric cyclo-
addition reaction proceeded with an high control of the cis/
trans diastereoselectivity (4aC5a:6aC7a ratioZ86.0:14.0)
and a good level of Si/Re diastereofacial selectivity (4aC
6a:5aC7a ratioZ13.8:86.2).
0
doublets (dddds) at dZ4.55, while proton H3 appears as a
0
doublet of doublets (dds) at dZ4.13. Protons H4 give rise to
two doublet of doublet of doublets (ddds) centered at
dZ2.54 and dZ2.25; moreover, the protons of the
0
0
methylene bridge at C5 (H6 ) resonate as two dds at
dZ4.11, and dZ3.62, respectively, while the thymine
proton at C6 resonates as doublet (d) at dZ7.06. The
The facial selectivity observed in the cycloaddition reaction
can be interpreted, by analogy to eralier reports,12 in terms of a
‘O-endo’ transition model (A), as shown in Figure 1. Then, the
0
analogous resonances in 4a appear at dZ4.21 (H5 ), dZ4.02

U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181
1173
00
Then, the distances of interest for the NOEs comparison, H1 –
0
00
0
H3 and H1 –H5 , have been averaged over all retained
conformations, weighted by Boltzmann factors: their values
are reported in Table 1.
Table 1. MMC calculated and averaged distances of NOE interested
protons for compounds 4a–7a
H1 –H3 distancea
H1 –H5 distancea
00
0
00
0
Compound
4a (3R,5S)
5a (3S,5R)
6a (3S,5S)
7a (3R,5R)
2.40
2.68
2.92
2.84
3.99
4.51
4.47
4.76
Figure 1.
majoradductofthereaction, thecisderivative5a, witha3S,5R
configuration in the isoxazolidine, should arise from the
approach of the Z-nitrone 2 to the Re face of the prochiral
olefin 3, through a Z-Re-exo transition state.
a All distances are in angstroms.
On the basis of the reported distances, we must expect noNOE
0
effect between H1 and H5 protons for all the compounds,
00
00
0
whereas a more intense NOE between H1 and H3 protons
could be predictable. Low temperature NOE measurements
To support the above assumption, we tried to assign the
1
absolute stereochemistry of 5a by H NMR experiments:
00
confirm these assumptions: a NOE enhancement between H1
with this aim, compound 13a, according to the 9-anthryl-
methoxyacetic acid shift correlation method,13 was con-
verted into the corresponding esters 16a and 17a
(Scheme 3). Unfortunately, the 1H NMR of these
compounds does not show any diagnostic resonance,
which could be utilized for the assignment of the absolute
configuration.
0
and H3 protons was observed for all compounds, as
computationally foreseen. In particular, compound 4a gives
risetoaNOEof3.60%,whereasfor5atheNOEwasof2.54%;
on these basis, for the major compound 5a, the 3S,5R absolute
configuration, suggested by the transition state approach, was
assigned. Consequently the 3R,5S configuration was assigned
to compound 4a. Unfortunately, for compounds 6a and 7a, the
˚
00
0
difference between H1 –H3 distances is very small (0.08 A) to
be usefully used.
Due to the above demonstrated capacity of the D-ribosyl
auxiliary to create the chiral centers with good selectivity, the
opposite enantiomeric chiral induction by the asymmetric
nitrone cycloaddition was then exploited. With this aim, we
performed the reaction of D-mannosyl nitrone 19, generated
from the oxime 18, with allyl thymine 3a, in order to obtain as
major cycloadduct the compound 20a, derived from a
transition state enantiomeric to that illustrated in Figure 112
Thus, the reaction of 19 with 3a gave rise to three
cycloadducts, two cis (20a, 21a) and one trans (22a), in a
88% yield (Scheme 4)
The reduction with LiAlH4 of the corresponding cyclo-
adducts 20a–23a, led to compounds 24a–26a, respectively,
while the selective cleavage of the sugar moiety, performe0d
with p-TosOH, generated the homocarbocyclic-20-oxo-3 -
azathymidines 12a–14a enantiomerically pure (Scheme 5).
Scheme 3.
Then, we decided to tackle this problem by the exploitation
of semiempirical calculations at PM3 level, for all of the
involved transition states.14 Although not conclusive, these
calculations foresee the isoxazolidine 5a as major product
with a 3S,5R configuration.
Noteworthy, the main product 20a afforded the compound
12a, which is the enantiomer of 13a obtained as major adduct
from the cycloaddition of D-ribosyl nitrone 2. (Scheme 2).
As a further support we tried to assign the absolute
configuration of compounds 4a–7a on the basis of low
temperature NOE enhancements and conformational analysis
calculations. Because of the large number of possible
conformations adopted by these compounds and the poor
geometry prediction by semiempirical calculations on the
sugar portion,12 we performed a conformational analysis
utilizing the Monte Carlo molecular dynamic and MMFF
molecular mechanics force field. We have exploited 1089
possible conformers, for each compound, retaining all that
whoseenergywasuntil3 kcal/molabovetheglobalminimum.
Semiempirical PM3 calculations of all the involved
transition states,14 confirm that isoxazolidine 20a has the
3R,5S configuration.
With respect to nitrone 2, the cycloaddition reaction of
nitrone 19 (Scheme 4) shows a similar control of the cis/
trans diastereoselectivity (20aC21a:22a ratioZ92:8) and a
minor level of Si/Re diastereofacial selectivity (20aC
22a:21a ratioZ62.3: 37.7).

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U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181
3. Antiviral activity
Compounds 12a, 13a, and 24a–26a, were evaluated for
antiviral activity against a wide variety of viruses, including
HIV-1 (strain IIIB) and HIV-2 (strain Rob) in MT-4 cell
cultures, herpes simplex virus type 1 (strain KOS), herpes
simplex virus type 2 (strain G), vaccinia virus, a thymidine
kinase-deficient HSV-1 strain (KOS, ACVR) and vesicular
stomatitis virus (VSV) in HEL cell cultures; respiratory
syncytial virus, Coxsackie virus B4 and vesicular stomatitis
virus in HeLa cell cultures; and type 3 parainfluenza virus,
reovirus type 1, Sindbis virus, Coxsackie virus B4 and Punta
Toro virus in Vero cell cultures. None of these compounds
showed inhibitory activity against any of the viruses tested at
concentrations up to 400 mg/mL.
4. Conclusions
In conclusion, the enantioselective synthesis of 12–15 has
been performed. The cycloaddition reactions of nitrones
originated from two different carbohydrates, that is, the
N-ribosyl nitrone 2 and the N-mannosyl nitrone 19, proceeded
in a stereocontrolled and predictable manner with a good
degree of enantioselectivity, so allo0wing an easy entry to both
enantiomers of homocarbocyclic-2 -oxo-30-azanucleosides.
5. Experimental
5.1. General information
Melting points were measured on a Koffler apparatus
and are uncorrected. 1H NMR spectra were measured
on a 500 MHz Varian Unity Inova instrument in CDCl3
as solvent. Chemical shifts are in ppm (d) from TMS
as internal standard. NOE difference spectra were
obtained by subtracting alternatively right-off-resonance
free induction decays (FIDS) from right-on-resonance-
induced FIDS. IR spectra were recorded using an
FTIR-8300 (Shimadzu) spectrophotometer. MS spectra
were measured with a JEOL JMS-D 300 spectrometer.
Elemental analyses were performed on a Perkin-Elmer
240B microanalyzer. Merck silica gel 60H was used
for preparative short-column chromatography. Allyl
Scheme 4.
nucleobases
literature.10
3 were prepared as reported in the
Scheme 5.
5.2. General procedure for reactions between allyl bases
3a,b and Vasella-type nitrone 2
The generality of the reported cycloaddition processes was
tested with the use of allyl 5-fluoruracil 3b as dipolarophile.
The 1H NMR spectrum of the crude reaction mixture
showed the formation, with nitrone 2, of four adducts,
4b–7b in a relative ratio 5.3:94.4:0.1:0.2 (Scheme 1), while
nitrone 19 afforded three cycloadducts 20b, 21b and
22b in a relative ratio 49.4:37.7:12.9 (Scheme 4). All
the cycloadducts have been separated by HPLC (see
Section 5). The obtained results are in agreement with the
trend observed for allyl thymine 3a. The reduction of 5b,
20b–22b with LiAlH4 followed by cleavage of the sugar
moiety with p-TsOH, generated the corresponding nucleo-
sides 12b–14b (see Schemes 2 and 5).
A suspension containing one of the allyl bases 3a,b
(1 equiv), ribosyl hydroxylamine11 1 (1 equiv) and ethyl
glyoxylate (1 equiv) in toluene (10 mL ca.) was heated in
a sealed vessel at 80 8C under stirring, until the ribosyl
hydroxylamine was consumed (12 h). Removal of the
solvent in vacuo affords a crude material, which was
purified by flash chromatography to give a mixture of
homochiral isoxazolidines 4a,b–7a,b (86–89.6% global
yield), which was purified by radial chromatography
(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.

U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181
1175
0
5.2.1. Ethyl-(3R,5S)-2-[5-O-tert-butyldiphenylsilyl-
2,3-O-isopropylidene-b-D-ribofuranosyl]-5-[(5-methyl-
2,4-dioxo-3,4-dihydropyrimidin-1(2H)-y1)methyl]-
isoxazolidine-3-carboxylate 4a. Yield 9.3%; HPLC: tR
8.3 min. White solid mp 56–59 8C; [a]2D5 K103.6 (c 0.22,
CHCl3). H NMR (CDCl3, 500 MHz) d 1.12 (s, 9H, CH3),
1.21 (t, 3H, JZ7.0 Hz, CH3), 1.46 (s, 3H, CH3), 1.88 (d, 3H,
JZ1.2 Hz, CH3), 2.08 (s, 3H, CH3), 2.17 (ddd, 1H, JZ4.2,
1H, JZ8.0, 14.5 Hz, H6 a), 3.69 (dd, 1H, JZ5.0, 11.0 Hz,
00
00
H5 a), 3.79 (dd, 1H, JZ7.0, 11.0 Hz, H5 b), 3.93 (dq, 1H,
JZ7.0, 14.0 Hz, CH2O), 4.04 (dq, 1H, JZ7.0, 14.0 Hz,
CH2O), 4.13 (dd, 1H, JZ7.0, 14.5 Hz, H6 b), 4.15 (dd, 1H,
JZ4.5, 9.0 Hz, H3 ), 4.19 (ddd, 1H, JZ2.5, 5.0, 7.0 Hz,
H4 ), 4.54 (dddd, 1H, JZ3.0, 7.0, 8.0, 9.0 Hz, H5 ), 4.60 (d,
0
0
1
00
0
00
00
1H, JZ2 Hz, H1 ), 4.68 (dd, 1H, JZ2.5, 6.0 Hz, H3 ), 4.72
(dd, 1H, JZ2.0, 6.0 Hz, H2 ), 7.06 (d, 1H, JZ1.3 Hz, H6),
00
0
0
5.1, 12.7 Hz, H4 a), 2.55 (ddd, 1H, JZ8.3, 9.9, 12.7 Hz, H4 b),
7.35–7.43 (m, 6H, aromatic protons), 7.62–7.64 (m, 4H,
aromatic protons), 9.39 (br s, 1H, NH). 13C NMR (CDCl3,
125 MHz) d 12.13, 13.88, 19.09, 25.1, 25.23, 26.75, 33.87,
50.30, 61.21, 61.42, 63.91, 77.34, 81.22, 83.30, 86.15,
98.86, 110.08, 113.06, 127.70, 129.79, 133.10, 135.42,
141.66, 151.18, 164.44, 171.31. IR (KBr): 2935.5, 2859.2,
1678.4, 1465.1, 1428.3, 1296.6, 1199.3, 1109.5, 795.6,
703.0 cmK1. Anal. Calcd for C36H47N3O9Si: C, 62.32; H,
6.83; N, 6.06%. Found: C, 62.40; H, 6.86; N, 6.27%. Exact
mass calculated for C36H47N3O9Si: 693.8587. Found:
693.8582.
0
3.64 (dd, 1H, JZ5.8, 14.3 Hz, H6 a), 3.68 (dd, 1H, JZ5.8,
10.8 Hz, H5 a), 3.74 (dd, 1H, JZ5.3, 10.8 Hz, H5 b), 3.83
(dd, 1H, JZ3.1, 14.3 Hz, H6 b), 4.03 (dd, 1H, JZ5.1, 9.9 Hz,
H3 ), 4.16 (ddd, 1H, JZ3.2, 5.3, 5.8 Hz, H4 ), 4.18 (dq, 1H,
JZ7.0, 14.0 Hz, CH2O), 4.19 (dq, 1H, JZ7.0, 14.0 Hz,
00
00
0
0
00
0
CH2O), 4.21 (dddd, 1H, JZ3.1, 4.2, 8.3, 8.4 Hz, H5 ), 4.48
(dd, 1H, JZ3.4, 6.2 Hz, H3 ), 4.73 (dd, 1H, JZ2.7, 6.2 Hz,
00
00
00
H2 ), 4.95 (d, 1H, JZ2.7 Hz, H1 ), 7.05 (d, 1H, JZ1.2 Hz,
H6), 7.35–7.44 (m, 6H, aromatic protons), 7.64–7.66 (m, 4H,
aromatic protons), 9.07 (br s, 1H, NH). 13C NMR (CDCl3,
125 MHz) d 12.02, 14.06, 19.18, 25.21, 26.73, 27.20, 35.25,
49.52, 60.88, 61.63, 64.30, 76.16, 80.85, 82.21, 85.59, 97.69,
109.77, 113.38, 127.64, 129.78, 133.26, 135.52, 142.05,
150.93, 164.31, 170.43. IR (KBr): 3192.0, 2934.4, 2859.2,
1677.7, 1465.3, 1428.2, 1319.6, 1267.2, 1079.7, 703.1,
612.4 cmK1. Anal. Calcd for C36H47N3O9Si: C, 62.32; H,
6.83; N, 6.06%. Found: C, 62.27; H, 6.88; N, 6.12%. Exact
mass calculated for C36H47N3O9Si: 693.8587. Found:
693.8591.
5.2.4. Ethyl-(3R,5R)-2-[5-O-tert-butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl]-5-[(5-methyl-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3-
carboxylate 7a. Yield 9.6%; HPLC: tR 12.8 min. White
solid mp 56–58 8C; [a]2D5 K51.0 (c 0.21, CHCl3). 1H MNR
(CDCl3, 500 MHz) d 1.03 (t, 3H, JZ7.1 Hz, CH3), 1.04 (s,
9H, CH3), 1.35 (s, 3H, CH3), 1.51 (s, 3H, CH3), 1.88 (d, 3H,
JZ1.0 Hz, CH3), 2.11 (ddd, 1H, JZ8.0, 9.5, 12.5 Hz, H4 a),
2.63 (ddd, 1H, JZ7.0, 7.5, 12.5 Hz, H4 b), 3.51 (dd, 1H, JZ
8.0, 14.5 Hz, H6 a), 3.71 (dd, 1H, JZ5.5, 11.0 Hz, H5 a),
3.77 (dd, 1H, JZ7.5, 11.0 Hz, H5 b), 3.91 (dq, 1H, JZ7.1,
11.0 Hz, CH2O), 4.01 (dq, 1H, JZ7.1, 11.0 Hz, CH2O),
4.16 (d, 1H, JZ7.5, 8.0 Hz, H3 ), 4.24 (dd, 1H, JZ5.5, 6.0,
7.5 Hz, H4 ), 4.25 (dd, 1H, JZ2.5, 14.5 Hz, H6 b), 4.45
(dddd, 1H, JZ2.5, 7.0, 8.0, 9.5 Hz, H5 ), 4.49 (d, 1H, JZ
3.5 Hz, H1 ), 4.77 (dd, 1H, JZ1.5, 6.0 Hz, H3 ), 4.79 (dd,
1H, JZ1.5, 3.5 Hz, H2 ), 7.24 (d, 1H, JZ1.0 Hz, H6), 7.40–
7.43 (m, 6H, aromatic protons), 7.62–7.64 (m, 4H, aromatic
protons), 9.14 (br s, 1H, NH). 13C MNR (CDCl3, 125 MHz)
d 12.08, 13.92, 19.19, 19.49, 25.14, 26.80, 26.83, 33.43,
61.40, 62.18, 63.80, 77.85, 81.98, 83.69, 86.76, 99.67,
110.27, 113.04, 118.00, 127.76, 129.81, 135.54, 141.64,
150.91, 157.80, 170.44. IR (KBr): 3445.9, 2933.1, 1692.0,
1462.2, 1380.2, 1206.8, 1109.5, 704.1, 610.7 cmK1. Anal.
Calcd for C36H47N3O9Si: C, 62.32; H, 6.83; N, 6.06%.
Found: C, 62.49; H, 6.79; N, 6.11%. Exact mass calculated
for C36H47N3O9Si: 693.8587. Found: 693.8592.
0
0
0
00
5.2.2. Ethyl-(3S,5S)-2-[5-O-tert-butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl]-5-[(5-methyl-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3-
carboxylate 6a. Yield 2.4%; HPLC: tR 8.9 min. White solid
mp 60–62 8C; [a]D25 C37.0 (c 0.03, CHCl3). 1H NMR
(CDCl3, 500 MHz) d 1.07 (s, 9H), 1.26 (t, 3H, JZ7.1 Hz),
1.32 (s, 3H), 1.54 (s, 3H), 1.75 (d, 3H, JZ1.2 Hz), 1.91 (dt,
00
0
00
0
0
00
00
0
00
1H, JZ9.2, 12.4 Hz, H4 a), 2.49 (ddd, 1H, JZ4.0, 6.8,
0
0
12.4 Hz, H4 b), 2.96 (dd, 1H, JZ8.3, 14.4 Hz, H6 a), 3.79
00
(dd, 1H, JZ6.4, 10.6 Hz, H5 a), 3.83 (dd, 1H, JZ5.6,
00
0
10.6 Hz, H5 b), 3.86 (dd, 1H, JZ3.1, 14.4 Hz, H6 b), 4.01
0
(dd, 1H, JZ4.0, 9.2 Hz, H3 ), 4.18 (q, 2H, JZ7.1 Hz), 4.20
(dddd, 1H, JZ3.1, 6.8, 8.3, 9.2 Hz, H5 ), 4.24 (ddd, 1H, JZ
3.9, 5.6, 6.4 Hz, H4 ), 4.45 (dd, 1H, JZ3.9, 6.3 Hz, H3 ),
4.74 (dd, 1H, JZ2.1, 6.3 Hz, H2 ), 4.96 (d, 1H, JZ2.1 Hz,
0
00
00
00
00
H1 ), 6.57 (q, 1H, JZ1.2 Hz, H6), 7.34–7.71 (m, 10H,
aromatic protons), 8.21 (br s, 1H, NH). 13C NMR (CDCl3,
125 MHz) d 12.19, 14.10, 19.26, 25.23, 26.83, 27.15, 35.73,
49.58, 61.11, 61.60, 64.93, 76.33, 81.02, 82.80, 86.28,
110.19, 113.51, 127.80, 129.92, 133.18, 133.27, 135.55,
135.62, 140.47, 150.47, 163.80, 169.87. (Anal. Calcd for
C36H47N3O9Si: C, 62.32; H, 6.83; N, 6.06%. Found: C,
62.39; H, 6.76; N, 6.01%. Exact mass calculated for
C36H47N3O9Si: 693.8587. Found: 693.8595.
5.2.5. Ethyl-(3R,5S)-2-[5-O-tert-butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl]-5-[(5-fluoro-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3-
carboxylate 4b. Yield 4.75%; HPLC: tR 12.7 min. White
solid mp 62–63 8C; [a]2D5 K9.1 (c 0.75, CH2Cl2). 1H NMR
(CDCl3, 500 MHz) d 0.98 (s, 9H, CH3), 1.20 (t, 3H, JZ
7.5 Hz, CH3), 1.26 (s, 3H, CH3), 1.46 (s, 3H, CH3), 2.13
(ddd, 1H, JZ3.5, 4.5, 13.0 Hz, H4 a), 2.39 (ddd, 1H, JZ7.5,
10.0, 13.0 Hz, H4 b), 3.60 (dd, 1H, JZ8.0, 14.5 Hz, H6 a),
3.64 (dd, 1H, JZ5.0, 11.0 Hz, H5 a), 3.65 (dd, 1H, JZ7.0,
11.0 Hz, H5 b), 3.70 (dd, 1H, JZ4.5, 14.5 Hz, H6 b), 3.95
5.2.3. Ethyl-(3S,5R)-2-[5-O-tert-butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl]-5-[(5-methyl-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3-
carboxylate 5a. Yield 64.7%; HPLC: tR 10.4 min. White
solid mp 65–68 8C; [a]2D5 C22.7 (c 0.22, CHCl3). 1H NMR
(CDCl3, 500 MHz) d 1.04 (s, 9H, CH3), 1.07 (t, 3H, JZ
7.0 Hz, CH3), 1.32 (s, 3H, CH3), 1.48 (s, 3H, CH3), 1.87 (d,
3H, JZ1.3 Hz, CH3), 2.27 (ddd, 1H, JZ3.0, 9.0, 13.0 Hz,
0
0
0
00
00
0
0
(dd, 1H, JZ4.5, 10.0 Hz, H3 ), 4.06 (ddd, 1H, JZ4.0, 5.0,
7.0 Hz, H4 ), 4.09 (dq, 1H, JZ7.5, 11.0 Hz, CH2O), 4.11
(dq, 1H, JZ7.5, 11.0 Hz, CH2O), 4.18 (dddd, 1H, JZ3.5,
4.5, 7.5, 8.0 Hz, H5 ), 4.42 (dd, 1H, JZ4.0, 6.5 Hz, H3 ),
00
0
0
0
00
H4 a), 2.55 (ddd, 1H, JZ4.5, 9.0, 13.0 Hz, H4 b), 3.63 (dd,

1176
U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181
00
4.67 (dd, 1H, JZ2.5, 6.5 Hz, H2 ), 4.84 (d, 1H, JZ2.5 Hz,
6.02%. Found: C, 60.18; H, 6.40; N, 6.08%. Exact mass
calculated for C35H44FN3O9Si: 697.8225. Found: 697.8238.
00
H1 ), 7.26 (d, 1H, JZ5.5 Hz, H6), 7.28–7.38 (m, 6H,
aromatic protons), 7.56–7.60 (m, 4H, aromatic protons), 8.9
(br s, 1H, NH). 13C NMR (CDCl3, 125 MHz) d 14.03, 19.2,
25.11, 26.73, 27.16, 34.8, 49.5, 61.59, 61.77, 64.15, 76.88,
80.4, 82.13, 85.44, 98.23, 113.6, 128.4 (d, JZ131.2 Hz),
133.12, 135.36 (d, JZ895.6 Hz), 135.49, 142.3, 149.7,
157.62 (d, JZ104.6 Hz), 170.58, 189.01. IR (KBr) 3834.7,
3746.0, 3678.4, 3564.4, 2933.6, 2361.0, 1471.6, 1429.1,
1378.2, 1243.7, 1209.3, 1079.7, 704.3, 506.8 cmK1. Anal.
Calcd for C35H44FN3O9Si: C, 60.24; H, 6.36; F, 2.72; N,
6.02%. Found: C, 60.20; H, 6.33; N, 6.06%. Exact mass
calculated for C35H44FN3O9Si: 697.8225. Found: 697.8236.
5.2.8. Ethyl-(3R,5R)-2-[5-O-tert-butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl]-5-[(5-fluoro-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3-
carboxylate7b.Yield0.18%;HPLC:tR 26.3 min.Whitesolid
mp 59–61 8C; [a]D25 K52.2 (c 0.718, CH2Cl2). H NMR
1
(CDCl3, 500 MHz)d0.98(s, 9H, CH3), 1.00(t, 3H, JZ7.2 Hz,
CH3), 1.28 (s, 3H, CH3), 1.44 (s, 3H, CH3), 2.04 (ddd, 1H, JZ
0
2.6, 8.6, 12.6 Hz, H4 a), 2.58 (ddd, 1H, JZ7.1, 9.6, 12.6 Hz,
0
0
H4 b), 3.43 (dd, 1H, JZ8.2, 14.5 Hz, H6 a), 3.64 (dd, 1H, JZ
00
00
5.1, 10.9 Hz, H5 a), 3.70 (dd, 1H, JZ7.5, 10.9 Hz, H5 b), 3.86
(dq, 1H, JZ7.2, 14.0 Hz, CH2O), 3.95 (dq, 1H, JZ7.2,
14.0 Hz, CH2O), 4.10 (dd, 1H, JZ7.1, 8.6 Hz, H3 ), 4.17 (ddd,
0
5.2.6. Ethyl (3S,5S)-2-[5-O-tert-butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl]-5-[(5-fluoro-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3-
carboxylate 6b. Yield 0.1%; HPLC: tR 19.4 min. White solid
mp 62–64 8C; [a]D25 C6.2 (c 0.72, CH2Cl2). 1H NMR (CDCl3,
500 MHz) d 0.95 (s, 9H, CH3), 0.99 (t, 3H, JZ7.2 Hz, CH3),
1.27 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.98 (ddd, 1H, JZ2.4,
00
1H, JZ1.6, 5.1, 7.5 Hz, H4 ), 4.19 (dd, 1H, JZ6.0, 14.5 Hz,
0
0
H6 b), 4.38 (dddd, 1H, JZ2.6, 6.0, 8.2, 9.6 Hz, H5 ), 4.44 (m,
00
00
00
1H, H3 ), 4.68 (m, 2H, H1 and H2 ), 7.30–7.37 (m, 6H,
aromatic protons), 7.50 (d, 1H, JZ5.6 Hz, H6), 7.55–7.57 (m,
4H, aromatic protons), 8.60 (br s, 1H, NH). 13C NMR (CDCl3,
125 MHz) d 13.91, 19.15, 24.75, 26.66, 26.78, 29.65, 33.37,
52.01, 61.52, 62.01, 63.64, 77.56, 81.66, 83.37, 86.47, 99.57,
113.33, 128.7 (d, JZ128.9 Hz), 133.10, 135.49 (d, JZ
940.1 Hz), 142.55, 149.55, 156.48 (d, JZ216 Hz), 170.37,
191.4. IR (KBr) 3745.9, 3648.9, 2361.0, 1518.9, 1472.1,
1380.7, 1243.5, 1109.6, 702.6 cmK1. Anal. Calcd for C35H47
FN3O9Si: C, 60.24; H, 6.36; F, 2.72; N, 6.02%. Found: C,
60.27; H, 6.33; N, 6.01%. Exact mass calculated for
C35H44FN3O9Si: 697.8225. Found: 697.8234.
0
0
8.8, 12.5 Hz, H4 a), 2.76 (ddd, 1H, JZ7.0, 9.3, 12.5 Hz, H4 b),
0
3.56–3.73 (m, 2H, H6 ), 3.99–4.14 (m, 5H, H3 , H5 , CH2O),
0
00
00
0
00
4.43–4.46(m, 2H, H4 , H5 ), 4.66(d, 1H, JZ6.5 Hz, H3 ), 4.74
00
00
(dd, 1H, JZ3.5, 6.5 Hz, H2 ), 5.45 (d, 1H, JZ3.5 Hz, H1 ),
7.28–7.36 (m, 6H, aromatic protons), 7.46 (d, 1H, JZ5.5 Hz,
H6), 7.52–7.58 (m, 4H, aromatic protons), 8.64 (br s, 1H, NH).
13C NMR (CDCl3, 125 MHz) d 14.05, 18.95, 25.1, 26.79,
29.66, 37.6, 49.6, 60.54, 61.61; 63.83, 76.36, 81.37, 83.31,
86.24, 98.87, 112.68, 129.88(d, JZ131.6 Hz), 132.94, 135.40
(d, JZ895.0 Hz); 135.48, 142.32, 149.76, 151.18 (d, JZ
104.9 Hz), 175.12, 184.87. IR (KBr): 3745.6, 3648.4, 3564.3,
2932.2, 2361.0, 1471.1, 1377.1, 1243.3, 1207.0, 1110.9,
704.2, 505.2 cmK1.Anal. CalcdforC35H44FN3O9Si: C, 60.24;
H, 6.36; F, 2.72; N, 6.02%. Found: C60.24; H, 6.38; N, 6.07%.
Exact mass calculated for C35H44FN3O9Si: 697.8225. Found:
697.8230.
5.3. General procedure for reactions between allyl bases
3a,b and mannosyl nitrone 19
A suspension containing one of the allyl bases 3a,b (1 equiv),
2,3:5,6-di-O-cyclohexylidene-D-mannose oxime12 18
(1 equiv) and ethyl glyoxylate (1 equiv) in toluene (10 mL
ca.) was heated in a sealed vessel at 80 8C under stirring, until
the mannose oxime was consumed (12 h). Removal of the
solvent in vacuo affords a crude material, which was purified
by flash chromatography to give a mixture of homochiral
isoxazolidines 20a,b–22a,b (88–87% global yield), which
was purified by radial chromatography (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) inn-hexane.
5.2.7. Ethyl-(3S,5R)-2-[5-O-tert-butyldiphenylsilyl-2,3-O-
isopropylidene-b-D-ribofuranosyl]-5-[(5-fluoro-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3-
carboxylate5b. Yield84.6%;HPLC:tR 20.8 min. Whitesolid
mp 69–70 8C; [a]D25 C25.2 (c 0.63, CH2Cl2). 1H NMR
(CDCl3, 500 MHz)d1.00(s, 9H, CH3),1.18(t, 3H, JZ7.5 Hz,
CH3), 1.27 (s, 3H, CH3), 1.56 (s, 3H, CH3), 2.24 (ddd, 1H, JZ
0
2.8, 5.5, 13.0 Hz, H4 a), 2.47 (ddd, 1H, JZ8.0, 9.0, 13.0 Hz,
5.3.1. Ethyl-(3S,5R)-2-[2,3:5,6-di-O-cyclohexylidene-a-
D-mannofuranosyl]-5-[(5-methyl-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-y1)methyl]isoxazolidine-3-carboxylate
21a. Yield 38.5%; HPLC: tR 18.0 min. White solid mp
65.1–66.9 8C; [a]D25 C125.8 (c 0.59, CHCl3); 1H NMR
(CDCl3, 500 MHz) d 1.31 (t, 3H, JZ7.2 Hz), 1.51–1.68 (m,
20H), 1.92 (d, 3H, JZ1.2 Hz), 2.23 (ddd, 1H, JZ3.9, 6.0,
0
00
H4 b), 364 (dd, 1H, JZ4, 5, 11.0 Hz, H5 a), 3.69 (dd, 1H, JZ
0
00
7.3, 14.5 Hz, H6 a), 3.72 (dd, 1H, JZ7.0, 11.0 Hz, H5 b), 3.82
(dq, 1H, JZ7.5, 11.0 Hz, CH2O), 3.95 (dq, 1H, JZ7.5,
11.0 Hz, CH2O), 4.01 (dd, 1H, JZ2.5, 14.5 Hz, H6 b), 4.07
(dd, 1H, JZ2.8, 9.0 Hz, H3 ), 4.15 (ddd, 1H, JZ1.5, 4.5,
7.0 Hz, H4 ), 4.47 (dddd, 1H, JZ2.5, 5.5, 7.3, 8.0 Hz, H5 ),
0
0
00
0
00
0
0
4.51 (d, 1H, JZ2.3 Hz, H1 ), 4.61 (dd, 1H, JZ2.3, 6.5 Hz,
12.9 Hz, H4 a), 2.70 (ddd, 1H, JZ7.9, 9.9, 12.9 Hz, H4 b),
00
00
0
H2 ), 4.67 (dd, 1H, JZ1.5, 6.5 Hz, H3 ), 7.28 (d, 1H, JZ
5.5 Hz, H6), 7.30–7.38 (m, 6H, aromatic protons), 7.56–7.59
(m, 4H, aromatic protons), 8.88 (br s, 1H, NH). 13C NMR
(CDCl3, 125 MHz) d 13.93, 19.15, 25.11, 26.81, 33.24, 39.99,
50.28, 61.34, 61.63, 63.86, 66.21, 77.25, 81.39, 83.33, 86.27,
98.87, 113.12, 130.23 (d, JZ130.5 Hz), 133.09, 137.91
(d, JZ943.2 Hz), 149.67, 152.04, 158.0 (d, JZ104.9 Hz),
171.35, 191.30. IR (KBr) 3746.1, 3649.1, 1519.0, 1471.9,
1379.7, 1243.8, 1206.2, 1110.0, 872.5, 703.0 cmK1. Anal.
Calcd for C35H47 FN3O9Si: C, 60.24; H, 6.36; F, 2.72; N,
3.63 (dd, 1H, JZ9.3, 14.2 Hz, H6 a), 4.02 (dd, 1H, JZ5.7,
8.6 Hz, H5 a), 4.03 (dd, 1H, JZ2.5, 14.2 Hz, H6 b), 4.04
(dd, 1H, JZ6.4, 8.6 Hz, H5 b), 4.10 (dd, 1H, JZ6.0, 9.9 Hz,
H3 ), 4.20 (dd, 1H, JZ3.9, 6.0 Hz, H4 ), 4.21 (dq, 1H,
JZ7.2, 10.8 Hz, CH2O), 4.24 (dq, 1H, JZ7.2, 10.8 Hz,
CH2O), 4.31 (ddd, 1H, JZ5.7, 6.0, 6.4 Hz, H4 ), 4.42
(dddd, 1H, JZ3.0, 3.9, 7.9, 9.3 Hz, H5 ), 4.71 (dd, 1H,
JZ3.9, 6.0 Hz, H3 ), 4.87 (dd, 1H, JZ1.1, 6.0 Hz, H2 ),
000
0
000
0
00
000
0
00
00
00
4.92 (d, 1H, JZ1.1 Hz, H1 ), 7.15 (q, 1H, JZ1.2 Hz, H6),
9.1 (br s, 1H, NH). 13C NMR (CDCl3, 125 MHz) d 12.0,

U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181
1177
23.8, 23.9, 25.1, 25.3, 29.6, 31.5, 33.6, 34.5, 35.8, 36.1,
50.1, 60.1, 61.7, 64.2, 65.7, 73.4, 75.3, 79.9, 83.6, 84.8,
97.2, 109.3, 109.8, 113.4, 142.0, 150.9, 164.4, 170.4. IR
(KBr): 3207.8, 2936.9, 1458.7, 1370.6, 1205.3, 1163.6,
1101.9, 940.3, 846.8 cmK1. Anal. Calcd for C30H43N3O10:
C, 59.49; H, 7.16; N, 6.94%. Found: C, 59.35; H, 7.14; N,
6.96%. Exact mass calculated for C30H43N3O10: 605.2948.
Found: 605.2945.
5.3.4. Ethyl-(3S,5R)-2-[2,3:5,6-di-O-cyclohexylidene-a-D-
mannofuranosyl]-5-[(5-fluoro-2,4-dioxo-3,4-dihydropyri-
midin-1(2H)-yl)methyl]isoxazolidine-3-carboxylate 21b.
Yield 32.8%; HPLC: tR 17.7 min. White solid mp
86–87 8C; [a]2D5 C125.6 (c 0.60, CHCl3); 1H NMR
(CDCl3, 500 MHz) d 1.31 (t, 3H, JZ7.5 Hz), 1.32–1.68
0
(m, 20H), 2.26 (ddd, 1H, JZ4.0, 5.5, 12.8 Hz, H4 a), 2.70
0
(ddd, 1H, JZ8.0, 10.0, 12.8 Hz, H4 b), 3.63 (dd, 1H, JZ9.0,
0
0
14.5 Hz, H6 a), 4.01 (dd, 1H, JZ3.5, 14.5 Hz, H6 b), 4.02
000
(dd, 1H, JZ5.6, 8.7 Hz, H5 a), 4.03 (dd, 1H, JZ6.5, 8.7 Hz,
H5 b), 4.11 (dd, 1H, JZ5.5, 10 Hz, H3 ), 4.20 (dq, 1H, JZ
7.5, 10.5 Hz, CH2O), 4.21 (dd, 1H, JZ4.1, 6.1 Hz, H4 ),
5.3.2. Ethyl-(3R,5S)-2-[2,3:5,6-di-O-cyclohexylidene-a-
D-mannofuranosyl]-5-[(5-methyl-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-y1)methyl]isoxazolidine-3-carboxylate
20a. Yield 42.4%; HPLC: tR 20 min. White solid mp
77–79 8C; [a]2D5 K50.2 (c 0.61, CHCl3). 1H NMR
(CDCl3, 500 MHz) d 1.31 (t, 3H, JZ7.5 Hz), 1.52–1.67
(m, 20H), 1.92 (d, 3H, JZ1.2 Hz), 2.31 (ddd, 1H, JZ
000
0
00
4.23 (dq, 1H, JZ7.5, 10.5 Hz, CH2O), 4.33 (ddd, 1H, JZ
000
5.6, 6.1, 6.5 Hz, H4 ), 4.43 (dddd, 1H, JZ3.5, 4.0, 8.0,
0
00
9 Hz, H5 ), 4.73 (dd, 1H, JZ4.1, 5.7 Hz, H3 ), 4.88 (dd, 1H,
00
00
JZ1.2, 5.7 Hz, H2 ), 4.89 (d, 1H, JZ1.2 Hz, H1 ), 7.43
(q, 1H, JZ6.0 Hz, H6), 8.8 (br s, 1H, NH). 13C NMR
(CDCl3, 125 MHz) d 14.1, 23.5 23.8, 23.9, 24.0, 25.0, 25.1,
33.7, 34.5, 35.5, 35.8, 36.2, 50.5, 60.7, 61.8, 65.6, 73.5,
75.8, 79.9, 83.7, 84.8, 97.9, 109.3, 113.6, 130.2 (d, JZ
130.6 Hz), 140.0 (d, JZ943.4 Hz), 149.4, 157.1 (d, JZ
104.8 Hz), 170.5. Anal. Calcd for C29H40FN3O10: C, 57.13;
H, 6.61; F, 3.12; N, 6.89%. Found: C, 57.18; H, 6.58; F,
3.09; N, 6.92%. Exact mass calculated for C29H40FN3O10:
609.6404. Found: 609.6408.
0
4.5, 5.5, 13.5 Hz, H4 a), 2.66 (ddd, 1H, JZ8.0, 9.0,
0
0
13.5 Hz, H4 b), 3.74 (dd, 1H, JZ8.5, 14.5 Hz, H6 a), 3.96
000
(dd, 1H, JZ5.5, 8.5 Hz, H5 a), 4.02 (dd, 1H, JZ4.5,
9.0 Hz, H3 ), 4.03 (dd, 1H, JZ6.0, 8.5 Hz, H5 b), 4.12
(dd, 1H, JZ2.5, 14.5 Hz, H6 b), 4.20 (dd, 1H, JZ3.5,
6.5 Hz, H4 ), 4.21 (dq, 1H, JZ7.5, 10.8 Hz, CH2O), 4.24
0
000
0
00
(dq, 1H, JZ7.5, 10.8 Hz, CH2O), 4.39 (ddd, 1H, JZ5.5,
000
00
6.0, 6.5 Hz, H4 ), 4.40 (d, 1H, JZ1.2 Hz, H1 ), 4.59
0
(dddd, 1H, JZ2.5, 5.5, 8.0, 8.5 Hz, H5 ), 4.82 (dd, 1H,
00
00
JZ3.5, 6.0 Hz, H3 ), 4.85 (dd, 1H, JZ1.2, 6.0 Hz, H2 ),
7.01 (q, 1H, JZ1.2 Hz, H6), 9.3 (br s, 1H, NH). 13C
NMR (CDCl3, 125 MHz) d 12.1, 23.5, 23.7, 23.8, 25.0,
29.5, 33.7, 34.1, 34.6, 35.6, 36.3, 50.4, 61.7, 63.0, 65.9,
72.6, 76.3, 79.7, 82.6, 83.3, 97.1, 109.1, 109.5, 110.1,
113.3, 141.6, 151.2, 164.5, 171.1. IR (KBr): 3211.2,
2936.5, 2859.9, 1459.3, 1370.0, 1251.6, 1200.6, 1164.6,
1102.9, 940.4 cmK1. Anal. Calcd for C30H43N3O10: C,
59.49; H, 7.16; N, 6.94%. Found: C, 59.40; H, 7.19; N,
6.98%. Exact mass calculated for C30H43N3O10:
605.2948. Found: 605.2951.
5.3.5. Ethyl-(3R,5S)-2-[2,3:5,6-di-O-cyclohexylidene-a-
D-mannofuranosyl]-5-[(5-fluoro-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)methyl]isoxazolidine-3-carboxylate
20b. Yield 43.0%; HPLC: tR 20.2 min. White solid mp 78–
81 8C; [a]2D5 K7.8 (c 0.61, CHCl3). 1H NMR (CDCl3,
500 MHz) d 1.30 (t, 3H, JZ7.5 Hz), 1.54–1.67 (m, 20H),
0
2.36 (ddd, 1H, JZ3.5, 3.8, 13.5 Hz, H4 a), 2.63 (ddd, 1H,
0
JZ7.5, 9.7, 13.5 Hz, H4 b), 3.82 (dd, 1H, JZ7.7, 14.4 Hz,
0
000
H6 a), 3.97 (dd, 1H, JZ5.1, 8.6 Hz, H5 a), 4.05 (dd, 1H, JZ
000
0
3.0, 8.6 Hz, H5 b), 4.07 (dd, 1H, JZ3.5, 7.5 Hz, H3 ), 4.09
(dd, 1H, JZ2.9, 14.4 Hz, H6 b), 4.16 (ddd, 1H, JZ3.0, 5.1,
6.5 Hz, H4 ), 4.20 (dq, 1H, JZ7.5, 11.0 Hz), 4.21 (dq, 1H,
JZ7.5, 11.0 Hz), 4.38 (d, 1H, JZ1.3 Hz, H1 ), 4.39 (dd,
1H, JZ3.5, 6.5 Hz, H4 ), 4.60 (dddd, 1H, JZ2.9, 3.8, 7.7,
9.7 Hz, H5 ), 4.82 (dd, 1H, JZ3.5, 6.0 Hz, H3 ), 4.85 (dd,
1H, JZ1.3, 6.0 Hz, H2 ), 7.37 (q, 1H, JZ6.0 Hz, H6), 8.9
0
000
00
5.3.3. Ethyl-(3S,5S)-2-[2,3:5,6-di-O-cyclohexylidene-a-D-
mannofuranosyl]-5-[(5-methyl-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-y1)methyl]isoxazolidine-3-carboxylate
22a. Yield 7.0%; HPLC: tR 28 min. White solid mp 81–
00
0
00
00
(br s, 1H, NH). 13C NMR (CDCl3, 125 MHz,) d 14.0, 23.6,
23.9, 24.0, 25.0, 25.1, 25.3, 33.2, 34.1, 34.7, 35.7, 36.3,
50.5, 61.9, 62.9, 66.0, 72.6, 76.3, 79.7, 82.7, 83.3, 97.0,
109.6, 113.5, 130.1 (d, JZ131.4 Hz), 140.1 (d, JZ
943.0 Hz), 149.7, 157.1 (d, JZ105.6 Hz), 171.1. Anal.
Calcd for C29H40FN3O10: C, 57.13; H, 6.61; F, 3.12; N,
6.89%. Found: C, 57.08; H, 6.57; F, 3.10; N, 6.94%. Exact
mass calculated for C29H40FN3O10: 609.6404. Found:
609.6400.
83 8C; [a]2D5 C25.8 (c 0.50, CHCl3); H NMR (CDCl3,
1
500 MHz) d 1.29 (t, 3H, JZ7.0 Hz), 1.56–1.69 (m, 20H),
1.92 (d, 3H, JZ1.2 Hz), 2.15 (ddd, 1H, JZ8.4, 8.7,
0
0
12.9 Hz, H4 a), 2.63 (ddd, 1H, JZ3.3, 7.0, 12.9 Hz, H4 b),
0
3.66 (dd, 1H, JZ7.1, 14.6 Hz, H6 a), 3.94 (dd, 1H, JZ3.3,
8.4 Hz, H3 ), 3.94 (dd, 1H, JZ5.8, 8.7 Hz, H5 a), 4.02 (dd,
1H, JZ6.4, 8.7 Hz, H5 b), 4.17 (dd, 1H, JZ3.5, 4.3 Hz,
H4 ), 4.19 (dd, 1H, JZ6.5, 14.6 Hz, H6 b), 4.21 (m, 2H),
4.36 (s, 1H, H1 ), 4.37 (ddd, 1H, JZ4.3, 5.8, 6.4 Hz, H4 ),
4.47 (dddd, 1H, JZ6.5, 7.0, 7.1, 8.7 Hz, H5 ), 4.80 (dd, 1H,
JZ3.5, 5.9 Hz, H3 ), 4.93 (d, 1H, JZ5.9 Hz, H2 ), 7.19 (q,
1H, JZ1.2 Hz, H6), 9.4 (br s, 1H, NH). 13C NMR (CDCl3,
125 MHz) d 12.1, 14.0, 23.7, 23.9, 25.3, 29.6, 33.7, 34.3,
34.7, 35.8, 36.3, 50.3, 61.6, 63.5, 65.9, 72.6, 77.3, 79.9,
82.8, 83.5, 99.0, 109.5, 110.5, 113.5, 141.2, 151.1, 164.2,
170.4. IR (KBr): 2932.5, 2858.1, 1452.1, 1367.8, 1288.5,
1202.5, 1102.5, 939.8 cmK1. Anal. Calcd for C30H43N3O10:
C, 59.49; H, 7.16; N, 6.94%. Found: C, 59.37; H, 7.15; N,
6.95%. Exact mass calculated for: C30H43N3O10: 605.2948.
Found: 605.2946.
0
000
000
00
0
00
000
0
5.3.6. Ethyl-(3S,5S)-2-[2,3:5,6-di-O-cyclohexylidene-a-D-
mannofuranosyl]-5-[(5-fluoro-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)methyl]isoxazolidine-3-carboxylate
22b. Yield 11.2%; HPLC: tR 29.2 min. White solid mp
00
00
76–78 8C; [a]2D5 C39.9 (c 0.50, CHCl3); H NMR (CDCl3,
1
500 MHz) d 1.29 (t, 3H, JZ7.5 Hz), 1.52–1.67 (m, 20H),
0
2.16 (ddd, 1H, JZ6.5, 8.5, 12.9 Hz, H4 a), 2.66 (ddd, 1H,
0
JZ5.0, 10.0, 12.9 Hz, H4 b), 3.58 (dd, 1H, JZ8.0, 14.5 Hz,
0
0
H6 a), 3.96 (dd, 1H, JZ5.0, 8.5 Hz, H3 ), 4.0 (dd, 1H,
000
000
JZ5.0, 8.5 Hz, H5 a), 4.03 (dd, 1H, JZ6.5, 8.5 Hz, H5 b),
4.19 (dd, 1H, JZ3.5, 6.6 Hz, H4 ), 4.20 (dq, 1H, JZ7.5,
00

1178
U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181
00
00
10.8 Hz), 4.23 (dq, 1H, JZ7.5, 10.8 Hz), 4.25 (dd, 1H,
JZ4.8, 11.2 Hz, H5 a), 3.78 (dd, 1H, JZ4.9, 11.2 Hz, H5 b),
0
00
0
JZ2.5, 14.5 Hz, H6 b), 4.36 (s, 1H, H1 ), 4.38 (ddd, 1H,
4.14 (dd, 1H, JZ2.5, 14.5 Hz, H6 b), 4.16 (ddd, 1H, JZ2.2,
4.8, 4.9 Hz, H4 ), 4.47 (ddd, 1H, JZ2.5, 4.6, 6.6, 8.8 Hz, H5 ),
4.58 (dd, 1H, JZ3.3, 6.4 Hz, H2 ), 4.60 (dd, 1H, JZ2.2,
000
00
0
JZ5.0, 6.5, 6.6 Hz, H4 ), 4.50 (dddd, 1H, JZ2.5, 6.5, 8.01,
0
00
00
10.0 Hz, H5 ), 4.82 (dd, 1H, JZ3.5, 6.0 Hz, H3 ), 4.92 (d,
00
00
00
1H, JZ2.0, 6.0 Hz, H2 ), 7.51 (dd, 1H, JZ5.5 Hz, H6), 8.9
6.4 Hz, H3 ), 4.77 (d, 1H, JZ3.3 Hz, H1 ), 7.06 (d, 1H, JZ
1.3 Hz, H6), 7.38–7.46 (m, 6H, aromatic protons), 7.64–7.66
(m, 4H, aromatic protons), 8.17 (s, 1H, NH). 13C NMR
(CDCl3, 125 MHz) d 12.26, 19.20, 25.25, 26.86, 27.07, 34.49,
50.06, 61.36, 64.13, 64.30, 77.85, 80.48, 82.85, 85.01, 100.36,
110.30, 113.63, 127.83, 129.96, 132.96, 135.60, 141.38,
150.79, 163.89. Anal. Calcd for C34H45N3O8Si: C, 62.65; H,
6.96; N, 6.45%. Found: C, 62.77; H, 6.99; N, 6.73%. Exact
mass calculated for C34H45N3O8Si: 651.8220. Found:
651.8229.
(br s, 1H, NH). 13C NMR (CDCl3, 125 MHz) d 14.0, 23.5,
23.8, 23.9, 24.9, 25.0, 29.6, 33.6, 34.1, 34.6, 35.7, 36.3,
51.3, 61.7, 63.4, 65.9, 72.6, 77.1, 79.9, 82.8, 83.4, 99.0,
109.5, 113.7, 129.5 (d, JZ131.4 Hz), 140.3 (d,
JZ951.4 Hz), 149.7, 157.1 (d, JZ104.6 Hz), 170.3. Anal.
Calcd for C29H40FN3O10: C, 57.13; H, 6.61; F, 3.12; N,
6.89%. Found: C, 57.16; H, 6.58; F, 3.17; N, 6.83%. Exact
mass calculated for C29H40FN3O10: 609.6404. Found:
609.6401.
5.4. General procedure for reduction of nucleosides 4, 5,
7, and 20–22
5.4.3. 1-[(3R,5R)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-iso-
propylidene-b-D-ribofuranosyl)-3-hydroxymethyl-1,2-iso-
xazolidin-5-yl]methyl]-5-methylpyrimidine-2,4(1H,3H)-
dione 11a. Yield 79.38%; white solid mp 72–74 8C; [a]D25
K95.5 (c 0.29, CHCl3). H NMR (CDCl3, 500 MHz) d 1.07 (s,
9H, CH3), 1.34 (s, 3H, CH3), 1.53 (s, 3H, CH3), 1.9 (d, 3H, JZ
A suspension of 1.0 mmol of nucleosides and 1.5 mmol
(60 mg) of LiAlH4 in a 20 mL of anhydrous THF was stirred
at 0 8C under N2 for 1 h. The solution was washed with
saturated NH4Cl solution, extracted with ethyl acetate (3!
5 mL) dried over sodium sulphate, and evaporated at
reduced pressure. The crude product was purified by flash
chromatography eluting ethyl acetate to afford the corres-
ponding 3-hydroxymethyl derivatives 8, 9, 11 and 24–26.
0
1.0 Hz, CH3), 2.09 (ddd, 1H, JZ2.5, 8.0, 13.0 Hz, H4 a), 2.17
0
(ddd, 1H, JZ7.0, 7.5, 13.0 Hz, H4 b), 2.30 (m, 1H, OH), 3.39
0
0
(m, 1H, H7 a), 3.40 (m, 1H, H7 b), 3.46 (dd, 1H, JZ8.5,
0
0
14.0 Hz, H6 a), 3.59 (m, 1H, H3 ), 3.71 (dd, 1H, JZ5.5,
00
00
11.0 Hz, H5 a), 3.72 (dd, 1H, JZ7.5, 11.0 Hz, H5 b), 4.19 (dd,
0
1H, JZ2.5, 14.0 Hz, H6 b), 4.24 (ddd, 1H, JZ2.5, 5.5, 7.5 Hz,
H4 ), 4.33 (dddd, 1H, JZ2.5, 7.0, 8.0, 8.5 Hz, H5 ), 4.63 (d,
1H, JZ1.5 Hz, H1 ), 4.65 (dd, 1H, JZ2.5, 6.0 Hz, H3 ), 4.73
(dd, 1H, JZ1.5, 6.0 Hz, H2 ), 7.25 (d, 1H, JZ1.0 Hz, H6),
00
0
5.4.1. 1-[[(3R,5S)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-iso-
propylidene-b-D-ribofuranosyl)-3-hydroxymethyl-1,2-iso-
xazolidin-5-yl]methyl]-5-methylpyrimidine-2,4(1H,3H)-
dione 8a. Yield 62.64%; white solid mp 57–58 8C; [a]D25
K34.9 (cZ0.9, CHCl3). 1H NMR (CDCl3, 500 MHz) d 1.01
(s, 9H, CH3), 1.33 (s, 3H, CH3), 1.53 (s, 3H, CH3), 1.70 (ddd,
00
00
00
7.37–7.44 (m, 6H, aromatic protons), 7.63–7.65 (m, 4H,
aromatic protons), 8.21 (s, 1H, NH). 13C NMR (CDCl3,
125 MHz) d 12.07, 19.15, 25.16, 26.8, 26.93, 33.56, 52.26,
62.63, 63.16, 64.18, 77.43, 80.5, 83.41, 85.89, 99.91, 110.1,
113.27, 127.77, 129.9, 132.98, 135.52, 141.75, 151.06,
164.34. IR (KBr): 3749.0, 3649.9, 3445.6, 2932.1, 1460.3,
1382.1, 1110.3, 822.8, 704.4, 505.3 cmK1. Anal. Calcd for
C34H45N3O8Si: C, 62.65; H, 6.96; N, 6.45%. Found: C, 62.75;
H, 6.90; N, 6.53%. Exact mass calculated for C34H45N3O8Si:
651.8220. Found: 651.8232.
0
1H, JZ5.5, 6.0, 12.5 Hz, H4 a), 1.85 (d, 3H, JZ1.4 Hz, CH3),
0
2.33 (m, 1H, OH), 2.40 (ddd, 1H, JZ8.5, 9.0, 12.5 Hz, H4 b),
0
3.38 (dd, 1H, JZ4.5, 10.5 Hz, H7 a), 3.41 (dd, 1H, JZ4.5,
0
0
10.5 Hz, H7 b), 3.56 (dddd, 1H, JZ4.5, 4.5, 6.0, 9.0 Hz, H3 ),
0
3.63 (dd, 1H, JZ7.0, 14.5 Hz, H6 a), 3.69 (dd, 1H, JZ3.0,
0
00
14.5 Hz, H6 b), 3.75 (dd, 1H, JZ5.5, 10.9 Hz, H5 a), 3.78 (dd,
00
1H, JZ5.0, 10.9 Hz, H5 b), 4.1 (ddd, 1H, JZ3.5, 5.0, 5.5 Hz,
H4 ), 4.28 (dddd, 1H, JZ3.0, 5.5, 7.0, 8.5 Hz, H5 ), 4.53 (dd,
1H, JZ3.5, 6.5 Hz, H3 ), 4.76 (dd, 1H, JZ3.5, 6.5 Hz, H2 ),
4.78 (d, 1H, JZ3.5 Hz, H1 ), 6.97 (d, 1H, JZ1.4 Hz, H6),
00
0
00
00
5.4.4. 5-Fluoro-1-[[(3S,5R)-2-(5-O-tert-Butyldiphenylsilyl-
2,3-O-isopropylidene-b-D-ribofuranosyl)-3-hydroxymethyl-
1,2-isoxazolidin-5-yl]methyl]pyrimidine-2,4(1H,3H)-dione
9b. Yield 64.52%; white solid mp 74.7–76.4 8C; [a]2D5 K9.2
(c 0.65, CH2Cl2). 1H NMR (CDCl3, 500 MHz) d 1.00 (s, 9H,
CH3), 1.47 (s, 3H, CH3), 1.49 (ddd, 1H, JZ4.2, 5.5,
00
7.36–7.44 (m, 6H, aromatic protons), 7.64–7.66 (m, 4H,
aromatic protons), 9.04 (s, 1H, NH). 13C NMR (CDCl3,
125 MHz) d 12.1, 19.2, 25.3, 26.8, 29.6, 35.9, 49.3, 62.3, 64.0,
65.3, 77.7, 80.4, 81.8, 84.5, 98.9, 110.1, 113.8, 127.7, 129.8,
133.2, 135.5, 141.6, 151.0, 164.9.Anal. Calcd for
C34H45N3O8Si: C, 62.65; H, 6.96; N, 6.45%. Found: C,
62.59; H, 6.91; N, 6.61%. Exact mass calculated for
C34H45N3O8Si: 651.8220. Found: 651.8233.
0
12.6 Hz, H4 a), 1.57 (s, 3H, CH3), 2.29 (m, 1H, OH), 2.42
0
(ddd, 1H, JZ8.6, 9.7, 12.6 Hz, H4 b), 3.25 (dd, 1H, JZ3.4,
0
0
11.2 Hz, H7 a), 3.34 (dd, 1H, JZ4.3, 11.2 Hz, H7 b), 3.46
0
(dd, 1H, JZ8.0, 14.4 Hz, H6 a), 3.54 (dddd, 1H, JZ3.4, 4.2,
4.3, 8.6 Hz, H3 ), 3.67 (dd, 1H, JZ5.0 Hz, 11.0, H5 a), 3.61
(dd, 1H, JZ4.8, 11.0 Hz, H5 b), 4.07 (dd, 1H, JZ2.3,
14.4 Hz, H6 b), 4.10 (ddd, 1H, JZ2.0, 4.8, 5.0 Hz, H4 ), 4.40
(dddd, 1H, JZ2.3, 5.5, 8.0, 9.7 Hz, H5 ), 4.51 (dd, 1H, JZ
3.3, 6.5 Hz, H2 ), 4.53 (dd, 1H, JZ2.0, 6.5 Hz, H3 ), 4.69 (d,
1H, JZ3.3 Hz, H1 ), 7.29 (d, 1H, JZ5.5 Hz, H6), 7.31–7.39
0
00
00
5.4.2. 1-[[(3S,5R)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-iso-
propylidene-b-D-ribofuranosyl)-3-hydroxymethyl-1,2-iso-
xazolidin-5-yl]methyl]-5-methylpyrimidine-2,4(1H,3H)-
dione 9a. Yield 60%; white solid mp 73–75; [a]2D5 K10.5 (c
0.2, CHCl3). 1H NMR (CDCl3, 500 MHz) d 1.07 (s, 9H, CH3),
1.32 (s, 3H, CH3), 1.51 (s, 3H, CH3), 1.54 (ddd, 1H, JZ4.6,
0
00
0
00
00
00
(m, 6H, aromatic protons), 7.56–7.59 (m, 4H, aromatic
protons), 8.8 (s, 1H, NH). 13C NMR (CDCl3, 125 MHz) d
19.42, 25.26, 26.89, 27.07, 34.52, 50.30, 61.58, 64.16,
64.37, 77.57, 80.63, 82.90, 85.23, 100.37, 113.70, 127.84,
127.87, 129.37 (d, JZ412.9 Hz), 130.01, 132.89, 133.12,
135.56, 135.62, 140.15 (d, JZ895.3 Hz), 149.49, 158.02 (d,
0
7.5, 12.6 Hz, H4 a), 1.9 (s, 3H, JZ1.3 Hz, CH3), 2.28 (dd, 1H,
0
JZ5, 7.9 Hz, OH), 2.49 (ddd, 1H, JZ8.4, 8.8, 12.6 Hz, H4 b),
0
3.31 (ddd, 1H, JZ5.0, 7.5, 11.5 Hz, H7 a), 3.41 (ddd, 1H, JZ
0
0
4.5, 7.9, 11.5 Hz, H7 b), 3.52 (dd, 1H, JZ7.7, 14.5 Hz, H6 a),
0
3.62 (dddd, 1H, JZ4.5, 7.5, 7.5, 8.0 Hz, H3 ), 3.74 (dd, 1H,

U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181
1179
0
0
JZ105.2 Hz). IR (KBr): 3884.7, 3672.1, 3564.5, 1697.9,
1650.4, 1541.4, 1519.0, 1457.6, 1382.9, 671.9 cmK1. Anal.
Calcd for C33H42FN3O8Si: C, 60.44; H, 6.46; F, 2.90; N,
6.41. Found: C, 60.40; H, 6.50; F, 2.92; N, 6.38. Exact mass
calculated for C33H42FN3O8Si: 655.786. Found: 655.781.
3.54 (m, 1H, H3 ), 3.56 (m, 1H, H7 b), 4.01 (dd, 1H, JZ6.0,
000
000
8.5 Hz, H5 a), 4.07 (dd, 1H, JZ2.0, 8.5 Hz, H5 b), 4.22 (dd,
1H, JZ2.5, 14.5 Hz, H6 b), 4.25 (dd, 1H, JZ3.5, 5.5 Hz,
H4 ), 4.36 (ddd, 1H, JZ2.0, 5.5, 6.0 Hz, H5 ), 4.38 (dddd,
1H, JZ2.5, 7.5, 8.0, 8.5 Hz, H5 ), 4.57 (d, 1H, JZ2.5 Hz,
H1 ), 4.77 (dd, 1H, JZ3.5, 6.0 Hz, H3 ), 4.93 (dd, 1H, JZ
2.5, 6.0 Hz, H2 ), 7.23 (d, 1H, JZ1 Hz, H6), 8.45 (br s, 1H,
0
00
00
0
00
00
00
5.4.5. 1-([(3R,5S)-2-(2,3:5,6-Di-O-cyclohexylidene-a-D-
mannofuranosyl)-3-hydroxymethyl-1,2-isoxazolidin-5-
yl]methyl(-5-methylpyrimidine-2,4(1H,3H)-dione 24a.
Yield 51.8%; white solid mp 128–132 8C; [a]2D5 K19.2
OH). 13C MNR (CDCl3, 125 MHz) d 12.5, 23.7, 23.8, 23.9,
24.9, 25.0, 25.1, 33.6, 34.3, 34.7, 35.9, 36.1, 52.2, 63.3,
64.1, 65.6, 73.1, 76.8, 79.8, 82.6, 83.3, 98.9, 109.3, 110.3,
113.8, 141.4, 150.7, 163.9. IR (KBr): 3456.0, 2935.1,
2858.3, 1452.4, 1367.4, 1164.4, 1104.9, 943.8 cmK1. Anal.
Calcd for C28H41N3O9: C, 59.67; H, 7.33; N, 7.46%. Found:
C, 59.86; H, 7.54; N, 7.64%. Exact mass calculated for
C28H41N3O9: 563.2843. Found: 563.2847.
1
(c 0.6, CHCl3). H NMR (CDCl3, 500 MHz) d 1.52–1.67
0
(m, 20H), 1.73 (ddd, 1H, JZ5.5, 7.0, 12.5 Hz, H4 a), 1.92 (d,
0
3H, JZ1.2 Hz), 2.54 (dt, 1H, JZ8.0, 12.5 Hz, H4 b), 3.49
0
(m, 3H, H3 , H7 a ed OH), 3.59 (m, 1H, H7 b), 3.68 (dd, 1H,
0
0
0
000
JZ7.5, 14.5 Hz, H6 a), 4.01 (dd, 1H, JZ6.0, 8.5 Hz, H5 a),
000
4.05 (dd, 1H, JZ6.6, 8.5 Hz, H5 b), 4.07 (dd, 1H, JZ2.8,
14.5 Hz, H6 b), 4.24 (dd, 1H, JZ3.6, 5.2 Hz, H4 ), 4.39
(ddd, 1H, JZ5.2, 6.0, 6.6 Hz, H4 ), 4.46 (dt, 1H, JZ2.9,
7.4 Hz, H5 ), 4.56 (s, 1H, H1 ), 4.76 (dd, 1H, JZ3.6, 6.1 Hz,
H3 ), 4.86 (d, 1H, JZ6.1 Hz, H2 ), 7.10 (q, 1H, JZ1.2 Hz,
H6), 9.01 (br s, 1H, NH). 13C NMR (CDCl3, 125 MHz) d
12.3, 23.6, 23.8, 23.9, 24.0, 25.0, 25.1, 34.0, 34.1, 34.7,
35.7, 36.1, 50.1, 63.7, 63.9, 65.6, 73.1, 76.2, 79.6, 82.5,
83.3, 97.7, 109.3, 110.4, 113.6, 141.4, 151.1, 164.1. IR
(KBR): 3472.5, 2926.3, 1436.6, 1372.2, 1248.1, 1169.9,
111.8, 928.3 cmK1. Anal. Calcd for C28H41N3O9: C, 59.67;
H, 7.33; N, 7.46%. Found: C, 59.72; H, 7.28; N, 7.41%.
Exact mass calculated for C28H41N3O9: 563.2843. Found:
563.2846.
0
00
5.4.8. 5-Fluoro-1-([(3R,5S)-2-(2,3:5,6-di-O-cyclo-
hexylidene-a-D-mannofuranosyl)-3-hydroxymethyl-1,2-
isoxazolidin-5-yl]methyl(pyrimidine-2,4(1H,3H)-dione
24b. Yield 43.0%; white solid mp 96.98 8C; [a]2D5 C179.2
000
0
00
00
00
1
(c 0.2, CHCl3); H NMR (CDCl3, 500 MHz) d 1.42–1.69
0
(m, 20H), 1.89 (ddd, 1H, JZ5.1, 6.5, 12.5 Hz, H4 a), 2.0
0
(m, OH), 2.54 (ddd, 1H, JZ7.5, 8.0, 12.5 Hz, H4 b), 3.54
(ddd, 1H, JZ6.5, 13.5 Hz, H7 a), 3.62 (ddd, 1H, JZ8.5,
14.5 Hz, H6 a), 3.64 (dddd, 1H, JZ4.5, 5.1, 6.5, 8.0 Hz, H3 ),
3.67 (dd, 1H, JZ4.5, 13.5 Hz, H7 b), 4.0 (dd, 1H, JZ5.5,
8.5 Hz, H5 a), 4.04 (dd, 1H, JZ6.5, 8.5 Hz, H5 b), 4.07 (dd,
1H, JZ3.3, 14.5 Hz, H6 b), 4.14 (dd, 1H, JZ3.5, 5.5 Hz, H4 ),
4.32 (ddd, 1H, JZ3.5, 5.5, 6.5 Hz, H4 ), 4.33 (dddd, 1H,
JZ3.3, 6.5, 7.5, 8.5 Hz, H5 ), 4.73 (s, 1H, H1 ), 4.76 (dd, 1H,
JZ3.6,6.1 Hz, H3 ),4.89(d, 1H, JZ4.0 Hz, H2 ), 7.39(d, 1H,
JZ5.5 Hz, H6), 8.41 (br s, 1H, NH). 13C NMR (CDCl3,
125 MHz) d 23.6, 23.7, 23.9, 25.0, 29.6, 33.7, 34.2, 34.4, 35.8,
36.1, 50.4, 60.8, 61.5, 65.6, 73.4, 76.1, 79.8, 83.8, 84.4, 97.8,
109.2, 113.6, 130.0 (JZ130.6 Hz), 140.0 (JZ943.4 Hz),
149.4, 157.1 (JZ104.8 Hz), 170.5. IR (KBr) 3235.6, 2845.5,
1473.2, 1371.8, 1235.5, 1248.2, 1077.3 cmK1. Anal. Calcd for
C27H38FN3O9: C, 57.13; H, 6.75; F, 3.35; N, 7.40%. Found: C,
57.19; H, 6.70; F, 3.32; N, 7.44%. Exact mass calculated for
C27H38FN3O9: 567.6037. Found: 567.6039.
0
0
0
0
000
000
0
00
000
0
00
00
00
5.4.6. 1-([(3R,5S)-2-(2,3:5,6-Di-O-cyclohexylidene-a-D-
mannofuranosyl)-3-hydroxymethyl-1,2-isoxazolidin-5-
yl]methyl(-5-methylpyrimidine-2,4(1H,3H)-dione 25a.
Yield 60.6%; white solid mp 140–14 28C; [a]2D5 C88.8
(c 0.6, CHCl3); 1H NMR (CDCl3, 500 MHz) d 1.42–1.67 (m,
0
20H), 1.89 (ddd, 1H, JZ6.5, 7.0, 12.5 Hz, H4 a), 1.92 (d, 3H,
0
JZ1.2 Hz), 2.53 (ddd, 1H, JZ7.5, 8.0, 12.5 Hz, H4 b), 3.56
0
(ddd, 1H, JZ5.5, 11.5 Hz, H7 a), 3.58 (dd, 1H, JZ8.5,
0
0
14.5 Hz, H6 a), 3.62 (dddd, 1H, JZ3.5, 5.5, 6.5, 8.0 Hz, H3 ),
0
3.68 (ddd, 1H, JZ3.5, 11.5 Hz, H7 a), 4.00 (dd, 1H, JZ5.5,
8.5 Hz, H5 a), 4.02 (dd, 1H, JZ6.5, 8.5 Hz, H5 b), 4.03 (dd,
1H, JZ3.5, 14.5 Hz, H6 b), 4.15 (dd, 1H, JZ4.0, 6.0 Hz, H4 ),
4.32 (dddd, 1H, JZ4.0, 5.5, 6.0, 6.5 Hz, H4 ), 4.33 (dddd, 1H,
JZ3.5, 7.0, 7.5, 8.5 Hz, H5 ), 4.71 (dd, 1H, JZ4.0, 6.1 Hz,
H3 ), 4.82 (d, 1H, JZ1.5 Hz, H1 ), 4.90 (dd, 1H, JZ1.5,
6.1 Hz, H2 ), 7.10 (q, 1H, JZ1.2 Hz, H6), 8.90 (br s, 1H, NH).
000
000
0
00
5.4.9. 5-Fluoro-1-([(3S,5R)-2-(2,3:5,6-di-O-cyclohexy-
lidene-a-D-mannofuranosyl)-3-hydroxymethyl-1,2-iso-
xazolidin-5-yl]methyl(pyrimidine-2,4(1H,3H)-dione 25b.
Yield 62.0%; white solid mp 92–95 8C; [a]2D5 K25.5 (c 0.35,
CHCl3). 1H NMR (CDCl3, 500 MHz) d 1.52–1.65 (m, 20H),
000
0
00
00
00
13C NMR (CDCl3, 125 MHz) d 12.1, 23.4, 23.6, 23.8, 24.0,
25.0, 25.1, 33.8, 34.4, 34.8, 35.5, 35.8, 36.2, 50.3, 61.1, 61.8,
65.7, 73.4, 76.3, 79.6, 83.9, 84.5, 97.8, 110.3, 113.6, 141.5,
150.9, 164.1. IR (KBr): 3471.6, 2936.0, 1456.7, 1369.3,
1247.9, 1163.2, 1101.9, 939.0 cmK1. Anal. Calcd for
C28H41N3O9: C, 59.67; H, 7.33; N, 7.46%. Found: C, 59.61;
H, 7.43; N, 7.42%. Exact mass calculated for C28H41N3O9:
563.2843. Found: 563.2840.
0
1.79 (ddd, 1H, JZ5.4, 7.1, 12.6 Hz, H4 a), 2.53 (ddd, 1H, JZ
0
8.1, 8.2, 12.6 Hz, H4 b), 3.47 (dddd, 1H, JZ5.4, 6.0, 7.7,
8.2 Hz, H3 ), 3.49(ddd, 1H, JZ6.0, 9.5 Hz, H7 a), 2.60(m, 1H,
OH), 3.58 (dd, 1H, JZ7.7, 9.5 Hz, H7 b), 3.69 (ddd, 1H, JZ
7.4, 14.5 Hz, H6 a), 3.99 (dd, 1H, JZ5.8, 8.5 Hz, H5 a), 4.03
0
0
0
0
000
000
(dd, 1H, JZ6.4, 8.5 Hz, H5 b), 4.05 (dd, 1H, JZ2.8, 14.5 Hz,
0
00
H6 b), 4.21 (dd, 1H, JZ3.4, 5.1 Hz, H4 ), 4.37 (ddd, 1H, JZ
000
5.1, 5.8, 6.4 Hz, H4 ), 4.44 (dddd, 1H, JZ2.8, 7.1, 7.4, 8.1 Hz,
H5 ), 4.53(s, 1H, H1 ), 4.75 (dd, 1H, JZ3.4, 6.0 Hz, H3 ), 4.84
0
00
00
00
5.4.7. 1-([(3R,5S)-2-(2,3:5,6-Di-O-cyclohexylidene-a-D-
mannofuranosyl)-3-hydroxymethyl-1,2-isoxazolidin-5-
yl]methyl(-5-methylpyrimidine-2,4(1H,3H)-dione 26a.
Yield 48%; white solid mp 70–74 8C; [a]2D5 C81.8 (c
0.34, CHCl3). 1H MNR (CDCl3, 500 MHz) d 1.54–1.69 (m,
20H, CH2), 1.92 (d, 3H, JZ1.0 Hz), 2.09 (ddd, 1H, JZ8.0,
(d, 1H, JZ6.0 Hz, H2 ), 7.36 (d, 1H, JZ5.5 Hz, H6), 8.9 (br s,
1H, NH). 13C NMR (CDCl3, 125 MHz) d 23.6, 23.7, 23.9,
25.1, 29.7, 34.0, 34.3, 34.6, 35.7, 36.0, 50.2, 63.7, 64.0, 65.5,
73.0, 75.9, 79.5, 82.5, 83.2, 97.9, 109.3, 113.6, 129.8 (d, JZ
131.2 Hz), 142.1 (d, JZ942.9 Hz), 149.6, 156.8 (d, JZ
942.9 Hz), 170.3. IR (KBr) 3300.3, 2891.6, 1743.5, 1733.4,
1651.3, 1560.2, 1432.3, 1412.4, 1111.4 cmK1. Anal. Calcd for
C27H38FN3O9: C, 57.13; H, 6.75; F, 3.35; N, 7.40%. Found: C,
0
8.0, 13.0 Hz, H4 a), 2.24 (ddd, 1H, JZ2.5, 7.5, 13.0 Hz,
0
0
0
H4 b), 3.44 (dd, 1H, JZ8.5, 14 Hz, H6 a), 3.52 (m, 1H, H7 a),

1180
U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181
57.11; H, 6.79; F, 3.33; N, 7.37%. Exact mass calculated for
C27H38FN3O9: 567.6037. Found: 567.6033.
5.5.2. Reaction of 9a or 25a with p-TosOH. 10-
[(10R,40S)-5-(Methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)methyl]20oxa-30azacyclopent-40yl-methanol
13a. Yield 70% (reaction of 9a); yield 97.6% (reaction
of 25a); white solid mp 163–165 8C; [a]2D5 C56.7 (c
0.31, H2O). Physical and spectroscopic data are identical
to compound 12a.
5.4.10. 5-Fluoro-1-([(3S*,5S*)-2-(2,3:5,6-di-O-cyclo-
hexylidene-a-D-mannofuranosyl)-3-hydroxymethyl-1,2-
isoxazolidin-5-yl]methyl(pyrimidine-2,4(1H,3H)-dione
26b. Yield 54%; white solid mp 95–978C; [a]2D5 C81.8 (c
1
0.34, CHCl3). H MNR (CDCl3, 500 MHz) d 1.20–1.63
0
5.5.3. Reaction of 26a with p-TosOH. 10-[(10S,40S)-5-
(Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)methyl]20oxa-30azacyclopent-40yl-methanol 14a. Yield
67.3%; white solid mp 147–148 8C; [a]2D5 C118.9 (c 0.2,
H2O).1H MNR (D2O, 200 MHz) d 1.92 (d, 1H, JZ1 Hz,
(m, 20H), 2.02 (dt, 1H, JZ7.7, 13 Hz, H4 a), 2.22 (ddd,
0
1H, JZ1.9, 7.5, 13 Hz, H4 b), 2.63 (m, 1H, OH), 3.31
0
(dd, 1H, JZ8.8, 14.4 Hz, H6 a), 3.32 (ddd, 1H, JZ5.5,
000
5.8, 6.6 Hz, H4 ) 3.45–3.54 (m, 3H, H3 CH7 aCH7 b),
0
0
0
000
3.93 (dd, 1H, JZ5.8, 8.6 Hz, H5 a), 3.99 (dd, 1H, JZ
0
0
CH3), 2.26 (m, 1H, H5 a), 2.46 (m, 1H, H5 b), 3.66 (m, 1H,
000
00
6.6, 8.6 Hz, H5 b), 4.19 (dd, 1H, JZ3.4, 5.5 Hz, H4 ),
0
H6 a), 3.77 (m, 1H, H4 a), 4.86 (m, 1H, H4 ), 4.08 (m, 1H,
00
0
0
4.23 (dd, 1H, JZ2.6, 14.4 Hz, H6 b), 4.34 (dddd, 1H, JZ
0
2.6, 7.5, 7.7, 8.8 Hz, H5 ), 4.50 (s, 1H, H1 ), 4.72 (dd,
00
0
0
H4 b), 4.12 (m, 1H, H6 b), 4.31 (m, 1H, H1 ), 7.51 (d, 1H,
JZ1.0 Hz, H6). 13C MNR (CDCl3, 125 MHz) d 11.38,
34.23, 49.87, 59.22, 79.91, 82.0, 110.81, 143.45, 152.56,
167.11. IR (KBr): 3421.8, 1748.9, 1487.6, 1218.3, 1071.9,
940.7 cmK1. Anal. Calcd for C10H15N3O4: C, 49.79; H,
6.27; N, 17.42%. Found: C, 49.52; H, 6.25; N, 17.45%.
Exact mass calculated for C10H15N3O4: 241.1063. Found:
241.1059.
00
00
00
1H, JZ3.4, 5.9 Hz, H3 ), 4.86 (d, 1H, JZ5.9 Hz, H2 ),
7.53 (d, 1H, JZ5.6 Hz, H6), 8.7 (br s, 1H, NH). 13C
MNR (CDCl3, 125 MHz) d 23.4, 23.7, 23.8, 25.0, 29.8,
33.1, 33.9, 34.5, 35.7, 36.0, 53.1, 63.0, 63.5, 65.5, 72.9,
76.3, 79.7, 82.6, 83.3, 98.9, 109.3, 113.9, 129.8 (d, JZ
130.0 Hz), 140.2 (d, JZ943.0 Hz), 149.7, 157.5 (d, JZ
104.4 Hz), 170.8. IR (KBr) 3400.0, 2950.3, 1723.5,
1446.3, 1397.1, 1227.1, 1106.8, 1285.4 cmK1. Anal.
Calcd for C27H38FN3O9: C, 57.13; H, 6.75; F, 3.35; N,
7.40%. Found: C, 57.17; H, 6.71; F, 3.37; N, 7.42%.
Exact mass calculated for C27H38FN3O9: 567.6037.
Found: 567.6041.
5.5.4. Reaction of 11a with p-TosOH. 10-[(10R,40R)-5-
(Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)methyl]20oxa-30azacyclopent-40yl-methanol 15a. Yield
65.2%; white solid mp 141–143 8C; [a]2D5 K123.4 (c 0.32,
H2O). Physical and spectroscopic data are identical to
compound 14a.
5.5. General procedure for preparation of nucleosides
12–15
5.5.5. Reaction of 24b with p-TosOH. 10-[(10S,40R)-5-
(Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)methyl]20oxa-30azacyclopent-40yl-methanol 12b.
Yield 52% (reaction of 24b); white solid mp 192–195 8C;
To a solution of 8–11 and 24–26 (1.0 mmol) in methanol
(50 mL) was added p-TosOH (258 mg, 1.5 mmol) and the
resulting solution was heated at 40 8C for 4 h. The reaction
mixture was cooled at room temperature and neutralized
with Amberlite IRA-400. The mixture was filtered and the
filtrate evaporated under reduced pressure. The residue was
purified by flash chromatography using water as eluent with
a Lichroprep RP-18, 40–63 mm colomn (12!75 mm), to
afford the corresponding homonucleosides 12–15.
1
[a]2D5 K48.9 (c 0.23, H2O).1. H NMR (D2O, 500 MHz) d
0
1.54 (ddd, 1H, JZ5.2, 6.5, 12.5 Hz, H5 a), 2.41 (ddd, 1H,
0
JZ7.5, 8.2, 12.5 Hz, H5 b), 3.38 (dd, 1H, JZ7.0, 13.5 Hz,
00
00
H4 a), 3.44 (dd, 1H, JZ3.8, 13.5 Hz, H4 b), 3.48 (dddd, 1H,
0
JZ3.8, 5.2, 7.0, 7.5 Hz H4 ), 3.73 (dd, 1H, JZ8.0, 14.5 Hz,
0
0
H6 a), 3.95 (dd, 1H, JZ3.2, 14.5 Hz, H6 b), 4.20 (dddd, 1H,
0
JZ3.2, 6.5, 8.0, 8.2 Hz, H1 ), 7.1 (d, 1H, JZ5.5 Hz, H6).
13C NMR (D2O, 125 MHz) d 34.4, 50.3, 51.4, 62.6, 68.3,
131.5, 142.8, 151.1, 157.1. IR (KBr) 3745.9, 3672.5.
5.5.1. Reaction of 8a or 24a with p-TosOH. 10-
[(10S,40R)-5-(Methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)methyl]20oxa-30azacyclopent-40yl-methanol
12a. Yield 62.64% (reaction of 8a); yield 70.2%
(reaction of 24a); white solid mp 164–167 8C; [a]D25
3649.5, 1697.8, 1650.5, 1558.1, 1541.0, 1519.2 cmK1
.
Anal. Calcd for C9H12FN3O4: C, 44.08; H, 4.93; F, 7.75;
N, 17.14%. Found: C, 44.04; H, 4.97; F, 7.73; N, 17.17%.
Exact mass calculated for C9H12FN3O4: 245.2076. Found:
245.2071.
1
K51.8 (c 0.23, H2O). H NMR (D2O, 500 MHz) d 1.77
0
5.5.6. Reaction of 9b or 25b with p-TosOH. 10-
[(10R,40S)-5-(Fluoro-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)methyl]20oxa-30azacyclopent-40yl-methanol
13b. Yield 74% (reaction of 9b); yield 75% (reaction of
25b); white solid mp 195–197 8C; [a]2D5 C51.7 (c 0.23,
H2O). Physical and spectroscopic data are identical to
compound 12b.
(ddd, 1H, JZ6.6, 8.1, 13 Hz, H5 a), 1.92 (d, 3H, JZ
0
1.2 Hz, CH3), 2.62 (ddd, 1H, JZ8.4, 7.8, 13 Hz, H5 b),
00
3.42 (dd, 1H, JZ7.9, 12.3 Hz, H4 a), 3.65 (dd, 1H, JZ
00
3.1, 12.3 Hz, H4 b), 3.72 (dddd, 1H, JZ3.1, 6.6, 8.4,
0
0
7.9 Hz H4 ), 3.95 (dd, 1H, JZ7.8, 15 Hz, H6 a), 4.12 (dd,
0
1H, JZ3.1, 15 Hz, H6 b), 4.44 (ddd, 1H, JZ3.1, 7.8,
8.1 Hz, H1 ), 7.51 (d, 1H, JZ1.2 Hz, H6). 13C NMR
0
(D2O, 125 MHz) d 11.9, 37.1, 51.1, 51.8, 63.4, 71.5,
82.6, 113.2, 131.8, 145.7. IR (KBr): 3424.9, 1677.6,
1493.7, 1384.9, 1238.4, 1059.5, 760.4 cmK1. Anal. Calcd
for C10H15N3O4: C, 49.79; H, 6.27; N, 17.42%. Found:
C, 49.75; H, 6.35; N, 17.54%. Exact mass calculated for
C10H15N3O4: 241.1063. Found: 241.1060.
5.5.7. Reaction 26b with p-TosOH. 10-[(10S,40S)-5-
(Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)
methyl]20oxa-30azacyclopent-40yl-methanol 14b. Yield
61.3%; white solid mp 123–125 8C; [a]2D5 C65.1 (c 0.3,
H2O).1H MNR (D2O, 500 MHz) d 1.84 (ddd, 1H, JZ6.5,

U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181
1181
0
8.0, 12.5 Hz, H5 a), 2.19 (ddd, 1H, JZ6.0, 9.0, 12.5 Hz,
Acknowledgements
0
0
H5 b), 3.18 (dd, 1H, JZ9.1, 13.0 Hz, H6 a), 3.33 (dd, 1H, JZ
6.5, 8.5 Hz, H4 a), 3.62 (dd, 1H, JZ2.5, 13.0 Hz, H6 b), 3.71
(dddd, 1H, JZ2.5, 6.0, 6.5, 8.0 Hz, H4 ), 3.73 (dd, 1H,
JZ2.5, 8.5 Hz, H4 b), 4.60 (dddd, 1H, JZ2.5, 6.5, 9.0,
00
0
This work was partially supported by M.I.U.R. (progetto
P.R.I.N. 2004 and F.I.R.B.). We also thank for financial
support the Boush and Lomb Oftal.
0
00
0
9.1 Hz, H1 ), 7.6 (d, 1H, JZ5.5 Hz, H6). IR (KBr) 3745.9,
3672.5, 3625.2, 3564.8, 1697.8, 1681.7, 1650.6, 1558.1,
1541.0. 1519.1, 1457.2 cmK1
.
Anal. Calcd for
C9H12FN3O4: C, 44.08; H, 4.93; F, 7.75; N, 17.14%.
Found: C, 44.14; H, 4.97; F, 7.71; N, 17.09%. Exact mass
calculated for C9H12FN3O4: 245.2076. Found: 245.2081.
References and notes
1. Ishiyama, K.; Smyth, G. E.; Ueda, T.; Masutomi, Y.; Ohgi, T.;
Yano, J. J. Am. Chem. Soc. 2004, 126, 7476–7485.
2. (a) Eschenmoser, A.; Loewenthal, E. Chem. Soc. Rev. 1992, 21,
1–16. (b) De Mesmaeker, A.; Altmannn, K. H.; Waldner, A.;
Wendeborn, S. Curr. Opin. Struct. Biol. 1995, 5, 343–355. (c)
Matteucci, M. Perspect. Drug Discov. Des. 1996, 4, 1–16.
(d) Schoning, K. U.; Scholz, P.; Guntha, S.; Wu, X.;
Krisnamurthy, R.; Eschenmoser, A. Science 2000, 290,
1347–1351.
5.5.8. Reaction of 11b with p-TosOH. 10-[(10R,40R)-5-
(Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)methyl]20oxa-30azacyclopent-40yl-methanol 15b. Yield
67.5%; white solid mp 122–125 8C; [a]2D5 K72.3 (c 0.3,
H2O). Physical and spectroscopic data are identical to
compound 14b.
3. Merino, P. Curr. Med. Chem. Anti-Infective Agents 2002, 1,
389–411.
4. (a) Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.;
5.6. General procedure for preparation of ester 16–17
To a solution of (R)- or (S)-9-AMA (40 mg, 0.16 mmol) in
dichloromethane at 0 8C were added 43.5 mg (0.16 mmol)
of 13a, 39.6 mg (0.19 mmol) of DCC, and 3.0 mg
(0.1 mmol) of DMPA. After 2 h the reaction mixture was
evaporated under reduced pressure, and the residue was
purified by flash chromatography on silica gel eluting with
hexane–ethyl acetate (80/20).
`
Pistara, V.; Rescifina, A.; Romeo, R.; Valveri, V.;
Mastino, A.; Romeo, G. J. Med. Chem. 2003, 46,
3696–3702. (b) Chiacchio, U.; Balestrieri, E.; Macchi,
B.; Iannazzo, D.; Piperno, A.; Rescifina, A.; Romeo, R.;
Saglimbeni, M.; Sciortino, M. T.; Valveri, V.; Mastino,
A.; Romeo, G. J. Med. Chem. 2005, 48, 1389–1394.
5. De Clercq, E. J. Med. Chem. 2005, 48, 1–17.
6. (a) Hossain, N.; Hendrix, C.; Lescrinier, E.; Van Aerschot, A.;
Busson, R.; De Clercq, E.; Herdewijn, P. Bioorg. Med. Chem.
Lett. 1996, 6, 1465–1468. (b) Saladino, R.; Ciambecchini, U.;
Hanessian, S. Eur. J. Org. Chem. 2003, 4401–4405.
7. (a) De Clercq, E.; Descamps, J.; Verhelst, G.; Walker, R. T.;
Jones, A. S.; Torrence, P. F.; Shugar, D. J. Infect. Dis. 1980,
141, 563–574. (b) De Clercq, E.; Hols, A.; Rosenberg, I.;
Sakuma, T.; Balzarini, J.; Maudgal, P. C. A. Nature 1986, 323,
464–467.
5.6.1. {(3S,5R)-5-[(5-Methyl-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)methyl]isoxazolidin-3-yl}methyl-
(2R)-9-anthryl(hydroxy)acetate 16. Yield 81%; sticky
1
yellow oil; H MNR (CDCl3, 500 MHz) d 1.19 (m, 2H,
0
0
H5 a), 1.94 (m, 1H, H5 b), 1.98 (d, 3H, JZ1.2 Hz, CH3), 2.60
0
(m, 1H, H6 a), 2.80 (m, 1H, H6 b), 3.48 (m, 3H, OCH3), 3.50
0
0
(m, 1H, H4 ), 4.14 (m, 1H, H1 b), 4.19 (m, 2H, H4 a), 4.21
0
00
00
(m, 1H, H4 b), 6.26 (s, 1H), 7.06 (d, 1H, JZ1.2 Hz, H6),
8. Sekino, Y.; Bruner, S. D.; Verdine, G. L. J. Biol. Chem. 2000,
275, 36506–36508.
7.54 (m, 2H, aromatic protons), 7.63 (m, 2H, aromatic
protons), 8.03 (d, 2H, JZ8.0 Hz, aromatic protons), 8.49 (s,
1H, aromatic protons), 8.55 (d, 2H, JZ8.0 Hz, aromatic
protons). Anal. Calcd for C26H25N3O6: C, 65.67; H, 5.30; N,
8.84%. Found: C, 65.54; H, 5.31; N, 8.86%.
9. (a) Deng, L.; Scharer, O. D.; Verdine, G. L. J. Am. Chem. Soc.
1997, 119, 7865–7866. (b) Wong, C. H.; Provencher, L.;
Porco, J. A.; Jung, S.-H.; Wang, J.-F.; Chen, L.; Wang, R.;
Steensma, D. H. J. Org. Chem. 1995, 60, 1492–1501.
10. Chiacchio, U.; Genevose, F.; Iannazzo, D.; Librando, V.;
Merino, P.; Rescifina, A.; Romeo, R.; Procopio, A.; Romeo, G.
Tetrahedron 2004, 60, 441–448.
5.6.2. {(3S,5R)-5-[(5-Methyl-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)methyl]isoxazolidin-3-yl}-
methyl(2S)-9-anthryl(hydroxy)acetate 17. Yield
80%; sticky yellow oil; 1H MNR (CDCl3, 500 MHz) d 1.17
11. Chiacchio, U.; Corsaro, A.; Gumina, G.; Rescifina, A.;
Iannazzo, D.; Piperno, A.; Romeo, G.; Romeo, R. J. Org.
Chem. 1999, 64, 9321–9327.
0
0
(m, 1H, H5 a), 1.95 (m, 1H, H5 b), 1.98 (d, 3H, JZ1.2 Hz,
0
CH3), 2.62 (m, 1H, H6 a), 2.83 (m, 1H, H6 b), 3.48 (m, 4H,
0
12. Kasahara, K.; Iida, H.; Kibayashi, C. J. Org. Chem. 1988, 54,
2225–2233.
0
0
00
00
OCH3, H4 ), 4.01 (m, 1H, H1 b), 4.08 (m, 2H, H4 a, H4 b),
6.44 (s, 1H), 7.06 (d, 1H, JZ1.2 Hz, H6), 7.48 (m, 2H,
aromatic protons), 7.54 (m, 2H, aromatic protons), 8.01 (d,
2H, JZ8.5 Hz, aromatic protons), 8.47 (m, 3H, aromatic
protons). Anal. Calcd for C26H25N3O6: C, 65.67; H, 5.30; N,
8.84%. Found: C, 65.82; H, 5.29; N, 8.83%.
13. Ciminiello, P.; Dell’Aversano, C.; Fattorusso, C.; Fattorusso, E.;
Forino, M.; Magno, S. Tetrahedron 2001, 57, 8189–8192.
14. Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.;
Procopio, A.; Rescifina, A.; Romeo, G.; Romeo, R. Eur.
J. Org. Chem. 2001, 1893–1898.