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Tetrahedron 62 (2006) 1171–1181

Enantioselective synthesis of homocarbocyclic-2 0-


oxo-3 0-azanucleosides
Ugo Chiacchio,a,* Maria Grazia Saita,a Lia Crispino,a Giuseppe Gumina,b Sergio Mangiafico,a
Venerando Pistarà,a Giovanni Romeo,c,* Anna Pipernoc and Erik De Clercqd
a
Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125 Catania, Italy
b
Department of Pharmaceutical Science, Medical University of S. Carolina, 280 Calhoun Street, Charleston, SC 29425, USA
c
Dipartimento Farmaco-Chimico, Università di Messina, Viale SS. Annunziata, 98168 Messina, Italy
d
Rega 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-2 0 oxo-3 0 -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
There has been substantial interest in the synthesis and an increased resistance to hydrolytic or enzymatic cleavage,
applications of various modified nucleic acids.1 In this compared to the relatively reactive aminal linkage of
context, many nucleoside analogues have been synthesized common nucleosides, more conformational flexibility and
with the modification of the base, sugar, and phosphate rotation freedom has been introduced.
region.2 In particular, nucleoside analogues, in which the
furanose ring has been replaced by different carbo- or Homo-N-nucleosides with a guanine or adenine base moiety
heterocyclic systems, have attracted special interest by exhibit a good antiviral activity against herpes simplex
virtue of their biological action as antiviral and/or anti- virus7 (HSV-1 and HSV-2); the analogous uracil homo-N-
cancer agents.3 Among them, isoxazolidine nucleosides nucleosides have been described as selective inhibitors of
(carbocyclic-2 0 oxo-3 0 -azanucleosides) are emerging as an viral uracil-DNA glycosylases (UDGs), while having little
interesting class of dideoxynucleoside analogues with effect on the human enzyme.8 Moreover, also the 1 0 -C-
potential pharmacological activity.4 azanucleosides have proved very valuable as sequence-
specific glycosidase inhibitors and thus as potentially
In these last years, with the increasing number of crystal effective anti-HIV drugs.9
structures of various enzyme–substrate complexes, it has
become apparent that many binding sites are more flexible Recently, we have reported the synthesis of a new class of
than previously thought and can therefore adjust to fit a wide homo-N-nucleoside analogues as racemic mixtures, in
range of substrates. Recent reports have shown that flexible which the ribofuranose moiety was replaced with an
inhibitors can overcome drug resistance mutations in HIV.5 isoxazolidine ring.10 However, the consideration that both
Accordingly, different synthetic approaches towards enantiomeric purity and absolute configuration are key
1 0 -homo-C- and N-nucleoside, in which a methylene factors in determining the physiological activity of these
group has been inserted between the base and the molecules, has prompted us to synthesize homocarbocyclic-
carbohydrate moiety, and their relative biological 2 0 -oxo-3 0 -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 In this paper, we report the enantioselective synthesis of this
addresses: uchiacchio@unict.it; gromeo@unime.it 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
1172 U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181

nitrones has allowed us to obtain valuable asymmetric (H3 0 ), dZ3.65 and dZ3.85 (H6 0 a,b), dZ2.16 and dZ2.46
induction towards the single enantiomers. Preliminary data (H4 0 a,b), and dZ7.06 (H6). As regards the trans adducts 6a
on the biological activity of the obtained compounds are and 7a, compound 6a shows the H5 0 resonance at dZ4.21 as
also reported. dddds, while H3 0 resonates at dZ4.00 as dds, H6 0 a,b at dZ
2.97 and dZ3.85 as dds, H4 0 a,b at dZ1.91 and dZ2.49 as
ddds, and H6 at dZ6.56 as d. In compound 7a, the same
resonances appear at dZ3.99 (H5 0 ), dZ4.24 (H3 0 ), dZ3.51
2. Results and discussion and dZ4.16 (H6 0 a,b), dZ2.10 and dZ2.63 (H4 0 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 The assignment of cis/trans configurations to the individual
with allyl thymine 3a in refluxing toluene for 12 h. The
diastereoisomers was established on the basis of (1H–1H)
reaction afforded a mixture of four compounds, two cis (4a
NOEDS experiments. In particular, for cis epimers 4a and 5a,
and 5a) and two trans (6a and 7a), in 86% total yield
irradiation of upfield methylene proton at C4 (H40 a) induced a
(Scheme 1).
positive NOE effect on H4 0 b; conversely, irradiation of H40 b
gave rise to NOE enhancements for H40 a, H3 0 , and H50 .
Moreover, when H5 0 was irradiated, a positive NOE effect was
observed on H4 0 b. These data unambiguously support a cis
relationship between H5 0 , H3 0 , and H4 0 b.

For the trans adducts 6a and 7a, irradiation of H4 0 a proton


produced a strong enhancement for H4 0 b, and H3 0 , while
irradiation of H4 0 b gave rise to a strong positive NOE effect
for H4 0 a and H5 0 . These results are clearly indicative of a
trans relationship between H5 0 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-2 0 -oxo-3 0 -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
1
H NMR experiments. Thus, 5a, the main compound, shows
the H5 0 resonance as doublet of doublet of doublet of The results obtained indicate that the asymmetric cyclo-
doublets (dddds) at dZ4.55, while proton H3 0 appears as a addition reaction proceeded with an high control of the cis/
doublet of doublets (dds) at dZ4.13. Protons H4 0 give rise to trans diastereoselectivity (4aC5a:6aC7a ratioZ86.0:14.0)
two doublet of doublet of doublets (ddds) centered at and a good level of Si/Re diastereofacial selectivity (4aC
dZ2.54 and dZ2.25; moreover, the protons of the 6a:5aC7a ratioZ13.8:86.2).
methylene bridge at C5 0 (H6 0 ) resonate as two dds at
dZ4.11, and dZ3.62, respectively, while the thymine The facial selectivity observed in the cycloaddition reaction
proton at C6 resonates as doublet (d) at dZ7.06. The can be interpreted, by analogy to eralier reports,12 in terms of a
analogous resonances in 4a appear at dZ4.21 (H5 0 ), dZ4.02 ‘O-endo’ transition model (A), as shown in Figure 1. Then, the
U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181 1173

Then, the distances of interest for the NOEs comparison, H1 00 –


H3 0 and H1 00 –H50 , 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
Compound H1 00 –H3 0 distancea H1 00 –H5 0 distancea
4a (3R,5S) 2.40 3.99
5a (3S,5R) 2.68 4.51
Figure 1.
6a (3S,5S) 2.92 4.47
7a (3R,5R) 2.84 4.76
major adduct of the reaction, the cis derivative 5a, with a 3S,5R
a
configuration in the isoxazolidine, should arise from the All distances are in angstroms.
approach of the Z-nitrone 2 to the Re face of the prochiral
olefin 3, through a Z-Re-exo transition state. On the basis of the reported distances, we must expect no NOE
effect between H100 and H50 protons for all the compounds,
To support the above assumption, we tried to assign the whereas a more intense NOE between H100 and H3 0 protons
absolute stereochemistry of 5a by 1H NMR experiments: could be predictable. Low temperature NOE measurements
with this aim, compound 13a, according to the 9-anthryl- confirm these assumptions: a NOE enhancement between H1 00
methoxyacetic acid shift correlation method,13 was con- and H3 0 protons was observed for all compounds, as
computationally foreseen. In particular, compound 4a gives
verted into the corresponding esters 16a and 17a
rise to a NOE of 3.60%, whereas for 5a the NOE was of 2.54%;
(Scheme 3). Unfortunately, the 1H NMR of these
on these basis, for the major compound 5a, the 3S,5R absolute
compounds does not show any diagnostic resonance,
configuration, suggested by the transition state approach, was
which could be utilized for the assignment of the absolute assigned. Consequently the 3R,5S configuration was assigned
configuration. to compound 4a. Unfortunately, for compounds 6a and 7a, the
difference between H1 00 –H30 distances is very small (0.08 Å) 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)

Scheme 3. The reduction with LiAlH4 of the corresponding cyclo-


adducts 20a–23a, led to compounds 24a–26a, respectively,
Then, we decided to tackle this problem by the exploitation while the selective cleavage of the sugar moiety, performed
of semiempirical calculations at PM3 level, for all of the with p-TosOH, generated the homocarbocyclic-2 0 -oxo-3 0 -
involved transition states.14 Although not conclusive, these azathymidines 12a–14a enantiomerically pure (Scheme 5).
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
As a further support we tried to assign the absolute from the cycloaddition of D-ribosyl nitrone 2. (Scheme 2).
configuration of compounds 4a–7a on the basis of low
temperature NOE enhancements and conformational analysis Semiempirical PM3 calculations of all the involved
calculations. Because of the large number of possible transition states,14 confirm that isoxazolidine 20a has the
conformations adopted by these compounds and the poor 3R,5S configuration.
geometry prediction by semiempirical calculations on the
sugar portion,12 we performed a conformational analysis With respect to nitrone 2, the cycloaddition reaction of
utilizing the Monte Carlo molecular dynamic and MMFF nitrone 19 (Scheme 4) shows a similar control of the cis/
molecular mechanics force field. We have exploited 1089 trans diastereoselectivity (20aC21a:22a ratioZ92:8) and a
possible conformers, for each compound, retaining all that minor level of Si/Re diastereofacial selectivity (20aC
whose energy was until 3 kcal/mol above the global minimum. 22a:21a ratioZ62.3: 37.7).
1174 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 allowing an easy entry to both
enantiomers of homocarbocyclic-2 0 -oxo-3 0 -azanucleosides.

5. Experimental

5.1. General information

Scheme 4.
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
nucleobases 3 were prepared as reported in the
literature.10

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.
A suspension containing one of the allyl bases 3a,b
The 1H NMR spectrum of the crude reaction mixture (1 equiv), ribosyl hydroxylamine11 1 (1 equiv) and ethyl
showed the formation, with nitrone 2, of four adducts, glyoxylate (1 equiv) in toluene (10 mL ca.) was heated in
4b–7b in a relative ratio 5.3:94.4:0.1:0.2 (Scheme 1), while a sealed vessel at 80 8C under stirring, until the ribosyl
nitrone 19 afforded three cycloadducts 20b, 21b and hydroxylamine was consumed (12 h). Removal of the
22b in a relative ratio 49.4:37.7:12.9 (Scheme 4). All solvent in vacuo affords a crude material, which was
the cycloadducts have been separated by HPLC (see purified by flash chromatography to give a mixture of
Section 5). The obtained results are in agreement with the homochiral isoxazolidines 4a,b–7a,b (86–89.6% global
trend observed for allyl thymine 3a. The reduction of 5b, yield), which was purified by radial chromatography
20b–22b with LiAlH4 followed by cleavage of the sugar (cyclohexane/ethyl acetate 3:2) and then by HPLC with a
moiety with p-TsOH, generated the corresponding nucleo- linear gradient of 2-propanol (6–10%, 0–10 min, flow
sides 12b–14b (see Schemes 2 and 5). 3.5 mL/min) in n-hexane.
U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181 1175

5.2.1. Ethyl-(3R,5S)-2-[5-O-tert-butyldiphenylsilyl- 1H, JZ8.0, 14.5 Hz, H6 0 a), 3.69 (dd, 1H, JZ5.0, 11.0 Hz,
2,3-O-isopropylidene-b-D-ribofuranosyl]-5-[(5-methyl- H5 00 a), 3.79 (dd, 1H, JZ7.0, 11.0 Hz, H5 00 b), 3.93 (dq, 1H,
2,4-dioxo-3,4-dihydropyrimidin-1(2H)-y1)methyl]- JZ7.0, 14.0 Hz, CH2O), 4.04 (dq, 1H, JZ7.0, 14.0 Hz,
isoxazolidine-3-carboxylate 4a. Yield 9.3%; HPLC: tR CH2O), 4.13 (dd, 1H, JZ7.0, 14.5 Hz, H6 0 b), 4.15 (dd, 1H,
8.3 min. White solid mp 56–59 8C; [a]25 D K103.6 (c 0.22, JZ4.5, 9.0 Hz, H3 0 ), 4.19 (ddd, 1H, JZ2.5, 5.0, 7.0 Hz,
CHCl3). 1H NMR (CDCl3, 500 MHz) d 1.12 (s, 9H, CH3), H4 00 ), 4.54 (dddd, 1H, JZ3.0, 7.0, 8.0, 9.0 Hz, H5 0 ), 4.60 (d,
1.21 (t, 3H, JZ7.0 Hz, CH3), 1.46 (s, 3H, CH3), 1.88 (d, 3H, 1H, JZ2 Hz, H1 00 ), 4.68 (dd, 1H, JZ2.5, 6.0 Hz, H3 00 ), 4.72
JZ1.2 Hz, CH3), 2.08 (s, 3H, CH3), 2.17 (ddd, 1H, JZ4.2, (dd, 1H, JZ2.0, 6.0 Hz, H2 00 ), 7.06 (d, 1H, JZ1.3 Hz, H6),
5.1, 12.7 Hz, H4 0 a), 2.55 (ddd, 1H, JZ8.3, 9.9, 12.7 Hz, H4 0 b), 7.35–7.43 (m, 6H, aromatic protons), 7.62–7.64 (m, 4H,
3.64 (dd, 1H, JZ5.8, 14.3 Hz, H6 0 a), 3.68 (dd, 1H, JZ5.8, aromatic protons), 9.39 (br s, 1H, NH). 13C NMR (CDCl3,
10.8 Hz, H5 00 a), 3.74 (dd, 1H, JZ5.3, 10.8 Hz, H5 00 b), 3.83 125 MHz) d 12.13, 13.88, 19.09, 25.1, 25.23, 26.75, 33.87,
(dd, 1H, JZ3.1, 14.3 Hz, H6 0 b), 4.03 (dd, 1H, JZ5.1, 9.9 Hz, 50.30, 61.21, 61.42, 63.91, 77.34, 81.22, 83.30, 86.15,
H3 0 ), 4.16 (ddd, 1H, JZ3.2, 5.3, 5.8 Hz, H4 00 ), 4.18 (dq, 1H, 98.86, 110.08, 113.06, 127.70, 129.79, 133.10, 135.42,
JZ7.0, 14.0 Hz, CH2O), 4.19 (dq, 1H, JZ7.0, 14.0 Hz, 141.66, 151.18, 164.44, 171.31. IR (KBr): 2935.5, 2859.2,
CH2O), 4.21 (dddd, 1H, JZ3.1, 4.2, 8.3, 8.4 Hz, H5 0 ), 4.48 1678.4, 1465.1, 1428.3, 1296.6, 1199.3, 1109.5, 795.6,
(dd, 1H, JZ3.4, 6.2 Hz, H3 00 ), 4.73 (dd, 1H, JZ2.7, 6.2 Hz, 703.0 cmK1. Anal. Calcd for C36H47N3O9Si: C, 62.32; H,
H2 00 ), 4.95 (d, 1H, JZ2.7 Hz, H1 00 ), 7.05 (d, 1H, JZ1.2 Hz, 6.83; N, 6.06%. Found: C, 62.40; H, 6.86; N, 6.27%. Exact
H6), 7.35–7.44 (m, 6H, aromatic protons), 7.64–7.66 (m, 4H, mass calculated for C36H47N3O9Si: 693.8587. Found:
aromatic protons), 9.07 (br s, 1H, NH). 13C NMR (CDCl3, 693.8582.
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, 5.2.4. Ethyl-(3R,5R)-2-[5-O-tert-butyldiphenylsilyl-2,3-O-
109.77, 113.38, 127.64, 129.78, 133.26, 135.52, 142.05, isopropylidene-b-D-ribofuranosyl]-5-[(5-methyl-2,4-dioxo-
150.93, 164.31, 170.43. IR (KBr): 3192.0, 2934.4, 2859.2, 3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3-
1677.7, 1465.3, 1428.2, 1319.6, 1267.2, 1079.7, 703.1, carboxylate 7a. Yield 9.6%; HPLC: tR 12.8 min. White
612.4 cmK1. Anal. Calcd for C36H47N3O9Si: C, 62.32; H, solid mp 56–58 8C; [a]25 1
D K51.0 (c 0.21, CHCl3). H MNR
6.83; N, 6.06%. Found: C, 62.27; H, 6.88; N, 6.12%. Exact (CDCl3, 500 MHz) d 1.03 (t, 3H, JZ7.1 Hz, CH3), 1.04 (s,
mass calculated for C36H47N3O9Si: 693.8587. Found: 9H, CH3), 1.35 (s, 3H, CH3), 1.51 (s, 3H, CH3), 1.88 (d, 3H,
693.8591. JZ1.0 Hz, CH3), 2.11 (ddd, 1H, JZ8.0, 9.5, 12.5 Hz, H4 0 a),
2.63 (ddd, 1H, JZ7.0, 7.5, 12.5 Hz, H4 0 b), 3.51 (dd, 1H, JZ
5.2.2. Ethyl-(3S,5S)-2-[5-O-tert-butyldiphenylsilyl-2,3-O- 8.0, 14.5 Hz, H6 0 a), 3.71 (dd, 1H, JZ5.5, 11.0 Hz, H5 00 a),
isopropylidene-b-D-ribofuranosyl]-5-[(5-methyl-2,4-dioxo- 3.77 (dd, 1H, JZ7.5, 11.0 Hz, H5 00 b), 3.91 (dq, 1H, JZ7.1,
3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3- 11.0 Hz, CH2O), 4.01 (dq, 1H, JZ7.1, 11.0 Hz, CH2O),
carboxylate 6a. Yield 2.4%; HPLC: tR 8.9 min. White solid 4.16 (d, 1H, JZ7.5, 8.0 Hz, H3 0 ), 4.24 (dd, 1H, JZ5.5, 6.0,
mp 60–62 8C; [a]25 D C37.0 (c 0.03, CHCl3). H NMR
1
7.5 Hz, H4 00 ), 4.25 (dd, 1H, JZ2.5, 14.5 Hz, H6 0 b), 4.45
(CDCl3, 500 MHz) d 1.07 (s, 9H), 1.26 (t, 3H, JZ7.1 Hz), (dddd, 1H, JZ2.5, 7.0, 8.0, 9.5 Hz, H5 0 ), 4.49 (d, 1H, JZ
1.32 (s, 3H), 1.54 (s, 3H), 1.75 (d, 3H, JZ1.2 Hz), 1.91 (dt, 3.5 Hz, H1 00 ), 4.77 (dd, 1H, JZ1.5, 6.0 Hz, H3 00 ), 4.79 (dd,
1H, JZ9.2, 12.4 Hz, H4 0 a), 2.49 (ddd, 1H, JZ4.0, 6.8, 1H, JZ1.5, 3.5 Hz, H2 00 ), 7.24 (d, 1H, JZ1.0 Hz, H6), 7.40–
12.4 Hz, H4 0 b), 2.96 (dd, 1H, JZ8.3, 14.4 Hz, H6 0 a), 3.79 7.43 (m, 6H, aromatic protons), 7.62–7.64 (m, 4H, aromatic
(dd, 1H, JZ6.4, 10.6 Hz, H5 00 a), 3.83 (dd, 1H, JZ5.6, protons), 9.14 (br s, 1H, NH). 13C MNR (CDCl3, 125 MHz)
10.6 Hz, H5 00 b), 3.86 (dd, 1H, JZ3.1, 14.4 Hz, H6 0 b), 4.01 d 12.08, 13.92, 19.19, 19.49, 25.14, 26.80, 26.83, 33.43,
(dd, 1H, JZ4.0, 9.2 Hz, H3 0 ), 4.18 (q, 2H, JZ7.1 Hz), 4.20 61.40, 62.18, 63.80, 77.85, 81.98, 83.69, 86.76, 99.67,
(dddd, 1H, JZ3.1, 6.8, 8.3, 9.2 Hz, H5 0 ), 4.24 (ddd, 1H, JZ 110.27, 113.04, 118.00, 127.76, 129.81, 135.54, 141.64,
3.9, 5.6, 6.4 Hz, H4 00 ), 4.45 (dd, 1H, JZ3.9, 6.3 Hz, H3 00 ), 150.91, 157.80, 170.44. IR (KBr): 3445.9, 2933.1, 1692.0,
4.74 (dd, 1H, JZ2.1, 6.3 Hz, H2 00 ), 4.96 (d, 1H, JZ2.1 Hz, 1462.2, 1380.2, 1206.8, 1109.5, 704.1, 610.7 cmK1. Anal.
H1 00 ), 6.57 (q, 1H, JZ1.2 Hz, H6), 7.34–7.71 (m, 10H, Calcd for C36H47N3O9Si: C, 62.32; H, 6.83; N, 6.06%.
aromatic protons), 8.21 (br s, 1H, NH). 13C NMR (CDCl3, Found: C, 62.49; H, 6.79; N, 6.11%. Exact mass calculated
125 MHz) d 12.19, 14.10, 19.26, 25.23, 26.83, 27.15, 35.73, for C36H47N3O9Si: 693.8587. Found: 693.8592.
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, 5.2.5. Ethyl-(3R,5S)-2-[5-O-tert-butyldiphenylsilyl-2,3-O-
135.62, 140.47, 150.47, 163.80, 169.87. (Anal. Calcd for isopropylidene-b-D-ribofuranosyl]-5-[(5-fluoro-2,4-dioxo-
C36H47N3O9Si: C, 62.32; H, 6.83; N, 6.06%. Found: C, 3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3-
62.39; H, 6.76; N, 6.01%. Exact mass calculated for carboxylate 4b. Yield 4.75%; HPLC: tR 12.7 min. White
C36H47N3O9Si: 693.8587. Found: 693.8595. solid mp 62–63 8C; [a]25 1
D K9.1 (c 0.75, CH2Cl2). H NMR
(CDCl3, 500 MHz) d 0.98 (s, 9H, CH3), 1.20 (t, 3H, JZ
5.2.3. Ethyl-(3S,5R)-2-[5-O-tert-butyldiphenylsilyl-2,3-O- 7.5 Hz, CH3), 1.26 (s, 3H, CH3), 1.46 (s, 3H, CH3), 2.13
isopropylidene-b-D-ribofuranosyl]-5-[(5-methyl-2,4-dioxo- (ddd, 1H, JZ3.5, 4.5, 13.0 Hz, H4 0 a), 2.39 (ddd, 1H, JZ7.5,
3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3- 10.0, 13.0 Hz, H4 0 b), 3.60 (dd, 1H, JZ8.0, 14.5 Hz, H6 0 a),
carboxylate 5a. Yield 64.7%; HPLC: tR 10.4 min. White 3.64 (dd, 1H, JZ5.0, 11.0 Hz, H5 00 a), 3.65 (dd, 1H, JZ7.0,
solid mp 65–68 8C; [a]25 1
D C22.7 (c 0.22, CHCl3). H NMR 11.0 Hz, H5 00 b), 3.70 (dd, 1H, JZ4.5, 14.5 Hz, H6 0 b), 3.95
(CDCl3, 500 MHz) d 1.04 (s, 9H, CH3), 1.07 (t, 3H, JZ (dd, 1H, JZ4.5, 10.0 Hz, H3 0 ), 4.06 (ddd, 1H, JZ4.0, 5.0,
7.0 Hz, CH3), 1.32 (s, 3H, CH3), 1.48 (s, 3H, CH3), 1.87 (d, 7.0 Hz, H4 00 ), 4.09 (dq, 1H, JZ7.5, 11.0 Hz, CH2O), 4.11
3H, JZ1.3 Hz, CH3), 2.27 (ddd, 1H, JZ3.0, 9.0, 13.0 Hz, (dq, 1H, JZ7.5, 11.0 Hz, CH2O), 4.18 (dddd, 1H, JZ3.5,
H4 0 a), 2.55 (ddd, 1H, JZ4.5, 9.0, 13.0 Hz, H4 0 b), 3.63 (dd, 4.5, 7.5, 8.0 Hz, H5 0 ), 4.42 (dd, 1H, JZ4.0, 6.5 Hz, H3 00 ),
1176 U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181

4.67 (dd, 1H, JZ2.5, 6.5 Hz, H2 00 ), 4.84 (d, 1H, JZ2.5 Hz, 6.02%. Found: C, 60.18; H, 6.40; N, 6.08%. Exact mass
H1 00 ), 7.26 (d, 1H, JZ5.5 Hz, H6), 7.28–7.38 (m, 6H, calculated for C35H44FN3O9Si: 697.8225. Found: 697.8238.
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, 5.2.8. Ethyl-(3R,5R)-2-[5-O-tert-butyldiphenylsilyl-2,3-O-
25.11, 26.73, 27.16, 34.8, 49.5, 61.59, 61.77, 64.15, 76.88, isopropylidene-b-D-ribofuranosyl]-5-[(5-fluoro-2,4-dioxo-
80.4, 82.13, 85.44, 98.23, 113.6, 128.4 (d, JZ131.2 Hz), 3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3-
133.12, 135.36 (d, JZ895.6 Hz), 135.49, 142.3, 149.7, carboxylate 7b. Yield 0.18%; HPLC: tR 26.3 min. White solid
157.62 (d, JZ104.6 Hz), 170.58, 189.01. IR (KBr) 3834.7, mp 59–61 8C; [a]25 D K52.2 (c 0.718, CH2Cl2). H NMR
1

3746.0, 3678.4, 3564.4, 2933.6, 2361.0, 1471.6, 1429.1, (CDCl3, 500 MHz) d 0.98 (s, 9H, CH3), 1.00 (t, 3H, JZ7.2 Hz,
1378.2, 1243.7, 1209.3, 1079.7, 704.3, 506.8 cmK1. Anal. CH3), 1.28 (s, 3H, CH3), 1.44 (s, 3H, CH3), 2.04 (ddd, 1H, JZ
Calcd for C35H44FN3O9Si: C, 60.24; H, 6.36; F, 2.72; N, 2.6, 8.6, 12.6 Hz, H4 0 a), 2.58 (ddd, 1H, JZ7.1, 9.6, 12.6 Hz,
6.02%. Found: C, 60.20; H, 6.33; N, 6.06%. Exact mass H4 0 b), 3.43 (dd, 1H, JZ8.2, 14.5 Hz, H60 a), 3.64 (dd, 1H, JZ
calculated for C35H44FN3O9Si: 697.8225. Found: 697.8236. 5.1, 10.9 Hz, H5 00 a), 3.70 (dd, 1H, JZ7.5, 10.9 Hz, H5 00 b), 3.86
(dq, 1H, JZ7.2, 14.0 Hz, CH2O), 3.95 (dq, 1H, JZ7.2,
5.2.6. Ethyl (3S,5S)-2-[5-O-tert-butyldiphenylsilyl-2,3-O- 14.0 Hz, CH2O), 4.10 (dd, 1H, JZ7.1, 8.6 Hz, H3 0 ), 4.17 (ddd,
isopropylidene-b-D-ribofuranosyl]-5-[(5-fluoro-2,4-dioxo- 1H, JZ1.6, 5.1, 7.5 Hz, H4 00 ), 4.19 (dd, 1H, JZ6.0, 14.5 Hz,
3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3- H6 0 b), 4.38 (dddd, 1H, JZ2.6, 6.0, 8.2, 9.6 Hz, H50 ), 4.44 (m,
carboxylate 6b. Yield 0.1%; HPLC: tR 19.4 min. White solid 1H, H300 ), 4.68 (m, 2H, H100 and H200 ), 7.30–7.37 (m, 6H,
mp 62–64 8C; [a]25 1
D C6.2 (c 0.72, CH2Cl2). H NMR (CDCl3, aromatic protons), 7.50 (d, 1H, JZ5.6 Hz, H6), 7.55–7.57 (m,
500 MHz) d 0.95 (s, 9H, CH3), 0.99 (t, 3H, JZ7.2 Hz, CH3), 4H, aromatic protons), 8.60 (br s, 1H, NH). 13C NMR (CDCl3,
1.27 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.98 (ddd, 1H, JZ2.4, 125 MHz) d 13.91, 19.15, 24.75, 26.66, 26.78, 29.65, 33.37,
8.8, 12.5 Hz, H4 0 a), 2.76 (ddd, 1H, JZ7.0, 9.3, 12.5 Hz, H4 0 b), 52.01, 61.52, 62.01, 63.64, 77.56, 81.66, 83.37, 86.47, 99.57,
3.56–3.73 (m, 2H, H6 0 ), 3.99–4.14 (m, 5H, H30 , H500 , CH2O), 113.33, 128.7 (d, JZ128.9 Hz), 133.10, 135.49 (d, JZ
4.43–4.46 (m, 2H, H400 , H5 0 ), 4.66 (d, 1H, JZ6.5 Hz, H3 00 ), 4.74 940.1 Hz), 142.55, 149.55, 156.48 (d, JZ216 Hz), 170.37,
(dd, 1H, JZ3.5, 6.5 Hz, H2 00 ), 5.45 (d, 1H, JZ3.5 Hz, H1 00 ), 191.4. IR (KBr) 3745.9, 3648.9, 2361.0, 1518.9, 1472.1,
7.28–7.36 (m, 6H, aromatic protons), 7.46 (d, 1H, JZ5.5 Hz, 1380.7, 1243.5, 1109.6, 702.6 cmK1. Anal. Calcd for C35H47
H6), 7.52–7.58 (m, 4H, aromatic protons), 8.64 (br s, 1H, NH). FN3O9Si: C, 60.24; H, 6.36; F, 2.72; N, 6.02%. Found: C,
13
C NMR (CDCl3, 125 MHz) d 14.05, 18.95, 25.1, 26.79, 60.27; H, 6.33; N, 6.01%. Exact mass calculated for
29.66, 37.6, 49.6, 60.54, 61.61; 63.83, 76.36, 81.37, 83.31, C35H44FN3O9Si: 697.8225. Found: 697.8234.
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 5.3. General procedure for reactions between allyl bases
104.9 Hz), 175.12, 184.87. IR (KBr): 3745.6, 3648.4, 3564.3, 3a,b and mannosyl nitrone 19
2932.2, 2361.0, 1471.1, 1377.1, 1243.3, 1207.0, 1110.9,
704.2, 505.2 cmK1.Anal. Calcd for C35H44FN3O9Si: C, 60.24; A suspension containing one of the allyl bases 3a,b (1 equiv),
H, 6.36; F, 2.72; N, 6.02%. Found: C60.24; H, 6.38; N, 6.07%. 2,3:5,6-di-O-cyclohexylidene-D-mannose oxime12 18
Exact mass calculated for C35H44FN3O9Si: 697.8225. Found: (1 equiv) and ethyl glyoxylate (1 equiv) in toluene (10 mL
697.8230. ca.) was heated in a sealed vessel at 80 8C under stirring, until
the mannose oxime was consumed (12 h). Removal of the
5.2.7. Ethyl-(3S,5R)-2-[5-O-tert-butyldiphenylsilyl-2,3-O- solvent in vacuo affords a crude material, which was purified
isopropylidene-b-D-ribofuranosyl]-5-[(5-fluoro-2,4-dioxo- by flash chromatography to give a mixture of homochiral
3,4-dihydropyrimidin-1(2H)-y1)methyl]isoxazolidine-3- isoxazolidines 20a,b–22a,b (88–87% global yield), which
carboxylate 5b. Yield 84.6%; HPLC: tR 20.8 min. White solid was purified by radial chromatography (cyclohexane/ethyl
mp 69–70 8C; [a]25 D C25.2 (c 0.63, CH2Cl2). H NMR
1
acetate 3:2) and then by HPLC with a linear gradient of
(CDCl3, 500 MHz) d 1.00 (s, 9H, CH3), 1.18 (t, 3H, JZ7.5 Hz, 2-propanol (6–10%, 0–10 min, flow 3.5 mL/min) in n-hexane.
CH3), 1.27 (s, 3H, CH3), 1.56 (s, 3H, CH3), 2.24 (ddd, 1H, JZ
2.8, 5.5, 13.0 Hz, H4 0 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-
H4 0 b), 364 (dd, 1H, JZ4, 5, 11.0 Hz, H5 00 a), 3.69 (dd, 1H, JZ D-mannofuranosyl]-5-[(5-methyl-2,4-dioxo-3,4-dihydro-
7.3, 14.5 Hz, H60 a), 3.72 (dd, 1H, JZ7.0, 11.0 Hz, H5 00 b), 3.82 pyrimidin-1(2H)-y1)methyl]isoxazolidine-3-carboxylate
(dq, 1H, JZ7.5, 11.0 Hz, CH2O), 3.95 (dq, 1H, JZ7.5, 21a. Yield 38.5%; HPLC: tR 18.0 min. White solid mp
11.0 Hz, CH2O), 4.01 (dd, 1H, JZ2.5, 14.5 Hz, H60 b), 4.07 65.1–66.9 8C; [a]25 D C125.8 (c 0.59, CHCl3); H NMR
1

(dd, 1H, JZ2.8, 9.0 Hz, H3 0 ), 4.15 (ddd, 1H, JZ1.5, 4.5, (CDCl3, 500 MHz) d 1.31 (t, 3H, JZ7.2 Hz), 1.51–1.68 (m,
7.0 Hz, H4 00 ), 4.47 (dddd, 1H, JZ2.5, 5.5, 7.3, 8.0 Hz, H5 0 ), 20H), 1.92 (d, 3H, JZ1.2 Hz), 2.23 (ddd, 1H, JZ3.9, 6.0,
4.51 (d, 1H, JZ2.3 Hz, H1 00 ), 4.61 (dd, 1H, JZ2.3, 6.5 Hz, 12.9 Hz, H4 0 a), 2.70 (ddd, 1H, JZ7.9, 9.9, 12.9 Hz, H4 0 b),
H2 00 ), 4.67 (dd, 1H, JZ1.5, 6.5 Hz, H3 00 ), 7.28 (d, 1H, JZ 3.63 (dd, 1H, JZ9.3, 14.2 Hz, H6 0 a), 4.02 (dd, 1H, JZ5.7,
5.5 Hz, H6), 7.30–7.38 (m, 6H, aromatic protons), 7.56–7.59 8.6 Hz, H5 000 a), 4.03 (dd, 1H, JZ2.5, 14.2 Hz, H6 0 b), 4.04
(m, 4H, aromatic protons), 8.88 (br s, 1H, NH). 13C NMR (dd, 1H, JZ6.4, 8.6 Hz, H5 000 b), 4.10 (dd, 1H, JZ6.0, 9.9 Hz,
(CDCl3, 125 MHz) d 13.93, 19.15, 25.11, 26.81, 33.24, 39.99, H3 0 ), 4.20 (dd, 1H, JZ3.9, 6.0 Hz, H4 00 ), 4.21 (dq, 1H,
50.28, 61.34, 61.63, 63.86, 66.21, 77.25, 81.39, 83.33, 86.27, JZ7.2, 10.8 Hz, CH2O), 4.24 (dq, 1H, JZ7.2, 10.8 Hz,
98.87, 113.12, 130.23 (d, JZ130.5 Hz), 133.09, 137.91 CH2O), 4.31 (ddd, 1H, JZ5.7, 6.0, 6.4 Hz, H4 000 ), 4.42
(d, JZ943.2 Hz), 149.67, 152.04, 158.0 (d, JZ104.9 Hz), (dddd, 1H, JZ3.0, 3.9, 7.9, 9.3 Hz, H5 0 ), 4.71 (dd, 1H,
171.35, 191.30. IR (KBr) 3746.1, 3649.1, 1519.0, 1471.9, JZ3.9, 6.0 Hz, H3 00 ), 4.87 (dd, 1H, JZ1.1, 6.0 Hz, H2 00 ),
1379.7, 1243.8, 1206.2, 1110.0, 872.5, 703.0 cmK1. Anal. 4.92 (d, 1H, JZ1.1 Hz, H1 00 ), 7.15 (q, 1H, JZ1.2 Hz, H6),
Calcd for C35H47 FN3O9Si: C, 60.24; H, 6.36; F, 2.72; N, 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, 5.3.4. Ethyl-(3S,5R)-2-[2,3:5,6-di-O-cyclohexylidene-a-D-
50.1, 60.1, 61.7, 64.2, 65.7, 73.4, 75.3, 79.9, 83.6, 84.8, mannofuranosyl]-5-[(5-fluoro-2,4-dioxo-3,4-dihydropyri-
97.2, 109.3, 109.8, 113.4, 142.0, 150.9, 164.4, 170.4. IR midin-1(2H)-yl)methyl]isoxazolidine-3-carboxylate 21b.
(KBr): 3207.8, 2936.9, 1458.7, 1370.6, 1205.3, 1163.6, Yield 32.8%; HPLC: t R 17.7 min. White solid mp
1101.9, 940.3, 846.8 cmK1. Anal. Calcd for C30H43N3O10: 86–87 8C; [a]25 D C125.6 (c 0.60, CHCl3);
1
H NMR
C, 59.49; H, 7.16; N, 6.94%. Found: C, 59.35; H, 7.14; N, (CDCl3, 500 MHz) d 1.31 (t, 3H, JZ7.5 Hz), 1.32–1.68
6.96%. Exact mass calculated for C30H43N3O10: 605.2948. (m, 20H), 2.26 (ddd, 1H, JZ4.0, 5.5, 12.8 Hz, H4 0 a), 2.70
Found: 605.2945. (ddd, 1H, JZ8.0, 10.0, 12.8 Hz, H4 0 b), 3.63 (dd, 1H, JZ9.0,
14.5 Hz, H6 0 a), 4.01 (dd, 1H, JZ3.5, 14.5 Hz, H6 0 b), 4.02
(dd, 1H, JZ5.6, 8.7 Hz, H5 000 a), 4.03 (dd, 1H, JZ6.5, 8.7 Hz,
5.3.2. Ethyl-(3R,5S)-2-[2,3:5,6-di-O-cyclohexylidene-a- H5 000 b), 4.11 (dd, 1H, JZ5.5, 10 Hz, H3 0 ), 4.20 (dq, 1H, JZ
D-mannofuranosyl]-5-[(5-methyl-2,4-dioxo-3,4-dihydro- 7.5, 10.5 Hz, CH2O), 4.21 (dd, 1H, JZ4.1, 6.1 Hz, H4 00 ),
pyrimidin-1(2H)-y1)methyl]isoxazolidine-3-carboxylate 4.23 (dq, 1H, JZ7.5, 10.5 Hz, CH2O), 4.33 (ddd, 1H, JZ
20a. Yield 42.4%; HPLC: tR 20 min. White solid mp 5.6, 6.1, 6.5 Hz, H4 000 ), 4.43 (dddd, 1H, JZ3.5, 4.0, 8.0,
77–79 8C; [a]25 D K50.2 (c 0.61, CHCl3). 1H NMR 9 Hz, H5 0 ), 4.73 (dd, 1H, JZ4.1, 5.7 Hz, H3 00 ), 4.88 (dd, 1H,
(CDCl3, 500 MHz) d 1.31 (t, 3H, JZ7.5 Hz), 1.52–1.67 JZ1.2, 5.7 Hz, H2 00 ), 4.89 (d, 1H, JZ1.2 Hz, H1 00 ), 7.43
(m, 20H), 1.92 (d, 3H, JZ1.2 Hz), 2.31 (ddd, 1H, JZ (q, 1H, JZ6.0 Hz, H6), 8.8 (br s, 1H, NH). 13C NMR
4.5, 5.5, 13.5 Hz, H4 0 a), 2.66 (ddd, 1H, JZ8.0, 9.0, (CDCl3, 125 MHz) d 14.1, 23.5 23.8, 23.9, 24.0, 25.0, 25.1,
13.5 Hz, H4 0 b), 3.74 (dd, 1H, JZ8.5, 14.5 Hz, H6 0 a), 3.96 33.7, 34.5, 35.5, 35.8, 36.2, 50.5, 60.7, 61.8, 65.6, 73.5,
(dd, 1H, JZ5.5, 8.5 Hz, H5 000 a), 4.02 (dd, 1H, JZ4.5, 75.8, 79.9, 83.7, 84.8, 97.9, 109.3, 113.6, 130.2 (d, JZ
9.0 Hz, H3 0 ), 4.03 (dd, 1H, JZ6.0, 8.5 Hz, H5 000 b), 4.12 130.6 Hz), 140.0 (d, JZ943.4 Hz), 149.4, 157.1 (d, JZ
(dd, 1H, JZ2.5, 14.5 Hz, H6 0 b), 4.20 (dd, 1H, JZ3.5, 104.8 Hz), 170.5. Anal. Calcd for C29H40FN3O10: C, 57.13;
6.5 Hz, H4 00 ), 4.21 (dq, 1H, JZ7.5, 10.8 Hz, CH2O), 4.24 H, 6.61; F, 3.12; N, 6.89%. Found: C, 57.18; H, 6.58; F,
(dq, 1H, JZ7.5, 10.8 Hz, CH2O), 4.39 (ddd, 1H, JZ5.5, 3.09; N, 6.92%. Exact mass calculated for C29H40FN3O10:
6.0, 6.5 Hz, H4 000 ), 4.40 (d, 1H, JZ1.2 Hz, H1 00 ), 4.59 609.6404. Found: 609.6408.
(dddd, 1H, JZ2.5, 5.5, 8.0, 8.5 Hz, H5 0 ), 4.82 (dd, 1H,
JZ3.5, 6.0 Hz, H3 00 ), 4.85 (dd, 1H, JZ1.2, 6.0 Hz, H2 00 ), 5.3.5. Ethyl-(3R,5S)-2-[2,3:5,6-di-O-cyclohexylidene-a-
7.01 (q, 1H, JZ1.2 Hz, H6), 9.3 (br s, 1H, NH). 13C D-mannofuranosyl]-5-[(5-fluoro-2,4-dioxo-3,4-dihydro-
NMR (CDCl3, 125 MHz) d 12.1, 23.5, 23.7, 23.8, 25.0, pyrimidin-1(2H)-yl)methyl]isoxazolidine-3-carboxylate
29.5, 33.7, 34.1, 34.6, 35.6, 36.3, 50.4, 61.7, 63.0, 65.9, 20b. Yield 43.0%; HPLC: tR 20.2 min. White solid mp 78–
72.6, 76.3, 79.7, 82.6, 83.3, 97.1, 109.1, 109.5, 110.1, 81 8C; [a]25 1
D K7.8 (c 0.61, CHCl3). H NMR (CDCl3,
113.3, 141.6, 151.2, 164.5, 171.1. IR (KBr): 3211.2, 500 MHz) d 1.30 (t, 3H, JZ7.5 Hz), 1.54–1.67 (m, 20H),
2936.5, 2859.9, 1459.3, 1370.0, 1251.6, 1200.6, 1164.6, 2.36 (ddd, 1H, JZ3.5, 3.8, 13.5 Hz, H4 0 a), 2.63 (ddd, 1H,
1102.9, 940.4 cmK1. Anal. Calcd for C30H43N3O10: C, JZ7.5, 9.7, 13.5 Hz, H4 0 b), 3.82 (dd, 1H, JZ7.7, 14.4 Hz,
59.49; H, 7.16; N, 6.94%. Found: C, 59.40; H, 7.19; N, H6 0 a), 3.97 (dd, 1H, JZ5.1, 8.6 Hz, H5 000 a), 4.05 (dd, 1H, JZ
6.98%. Exact mass calculated for C 30H 43 N3 O10: 3.0, 8.6 Hz, H5 000 b), 4.07 (dd, 1H, JZ3.5, 7.5 Hz, H3 0 ), 4.09
605.2948. Found: 605.2951. (dd, 1H, JZ2.9, 14.4 Hz, H6 0 b), 4.16 (ddd, 1H, JZ3.0, 5.1,
6.5 Hz, H4 000 ), 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 00 ), 4.39 (dd,
5.3.3. Ethyl-(3S,5S)-2-[2,3:5,6-di-O-cyclohexylidene-a-D- 1H, JZ3.5, 6.5 Hz, H4 00 ), 4.60 (dddd, 1H, JZ2.9, 3.8, 7.7,
mannofuranosyl]-5-[(5-methyl-2,4-dioxo-3,4-dihydro- 9.7 Hz, H5 0 ), 4.82 (dd, 1H, JZ3.5, 6.0 Hz, H3 00 ), 4.85 (dd,
pyrimidin-1(2H)-y1)methyl]isoxazolidine-3-carboxylate 1H, JZ1.3, 6.0 Hz, H2 00 ), 7.37 (q, 1H, JZ6.0 Hz, H6), 8.9
22a. Yield 7.0%; HPLC: tR 28 min. White solid mp 81– (br s, 1H, NH). 13C NMR (CDCl3, 125 MHz,) d 14.0, 23.6,
83 8C; [a]25 1
D C25.8 (c 0.50, CHCl3); H NMR (CDCl3, 23.9, 24.0, 25.0, 25.1, 25.3, 33.2, 34.1, 34.7, 35.7, 36.3,
500 MHz) d 1.29 (t, 3H, JZ7.0 Hz), 1.56–1.69 (m, 20H), 50.5, 61.9, 62.9, 66.0, 72.6, 76.3, 79.7, 82.7, 83.3, 97.0,
1.92 (d, 3H, JZ1.2 Hz), 2.15 (ddd, 1H, JZ8.4, 8.7, 109.6, 113.5, 130.1 (d, JZ131.4 Hz), 140.1 (d, JZ
12.9 Hz, H4 0 a), 2.63 (ddd, 1H, JZ3.3, 7.0, 12.9 Hz, H4 0 b), 943.0 Hz), 149.7, 157.1 (d, JZ105.6 Hz), 171.1. Anal.
3.66 (dd, 1H, JZ7.1, 14.6 Hz, H6 0 a), 3.94 (dd, 1H, JZ3.3, Calcd for C29H40FN3O10: C, 57.13; H, 6.61; F, 3.12; N,
8.4 Hz, H3 0 ), 3.94 (dd, 1H, JZ5.8, 8.7 Hz, H5 000 a), 4.02 (dd, 6.89%. Found: C, 57.08; H, 6.57; F, 3.10; N, 6.94%. Exact
1H, JZ6.4, 8.7 Hz, H5 000 b), 4.17 (dd, 1H, JZ3.5, 4.3 Hz, mass calculated for C29H40FN3O10: 609.6404. Found:
H4 00 ), 4.19 (dd, 1H, JZ6.5, 14.6 Hz, H6 0 b), 4.21 (m, 2H), 609.6400.
4.36 (s, 1H, H1 00 ), 4.37 (ddd, 1H, JZ4.3, 5.8, 6.4 Hz, H4 000 ),
4.47 (dddd, 1H, JZ6.5, 7.0, 7.1, 8.7 Hz, H5 0 ), 4.80 (dd, 1H, 5.3.6. Ethyl-(3S,5S)-2-[2,3:5,6-di-O-cyclohexylidene-a-D-
JZ3.5, 5.9 Hz, H3 00 ), 4.93 (d, 1H, JZ5.9 Hz, H2 00 ), 7.19 (q, mannofuranosyl]-5-[(5-fluoro-2,4-dioxo-3,4-dihydro-
1H, JZ1.2 Hz, H6), 9.4 (br s, 1H, NH). 13C NMR (CDCl3, pyrimidin-1(2H)-yl)methyl]isoxazolidine-3-carboxylate
125 MHz) d 12.1, 14.0, 23.7, 23.9, 25.3, 29.6, 33.7, 34.3, 22b. Yield 11.2%; HPLC: tR 29.2 min. White solid mp
34.7, 35.8, 36.3, 50.3, 61.6, 63.5, 65.9, 72.6, 77.3, 79.9, 76–78 8C; [a]25 1
D C39.9 (c 0.50, CHCl3); H NMR (CDCl3,
82.8, 83.5, 99.0, 109.5, 110.5, 113.5, 141.2, 151.1, 164.2, 500 MHz) d 1.29 (t, 3H, JZ7.5 Hz), 1.52–1.67 (m, 20H),
170.4. IR (KBr): 2932.5, 2858.1, 1452.1, 1367.8, 1288.5, 2.16 (ddd, 1H, JZ6.5, 8.5, 12.9 Hz, H4 0 a), 2.66 (ddd, 1H,
1202.5, 1102.5, 939.8 cmK1. Anal. Calcd for C30H43N3O10: JZ5.0, 10.0, 12.9 Hz, H4 0 b), 3.58 (dd, 1H, JZ8.0, 14.5 Hz,
C, 59.49; H, 7.16; N, 6.94%. Found: C, 59.37; H, 7.15; N, H6 0 a), 3.96 (dd, 1H, JZ5.0, 8.5 Hz, H3 0 ), 4.0 (dd, 1H,
6.95%. Exact mass calculated for: C30H43N3O10: 605.2948. JZ5.0, 8.5 Hz, H5 000 a), 4.03 (dd, 1H, JZ6.5, 8.5 Hz, H5 000 b),
Found: 605.2946. 4.19 (dd, 1H, JZ3.5, 6.6 Hz, H4 00 ), 4.20 (dq, 1H, JZ7.5,
1178 U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181

10.8 Hz), 4.23 (dq, 1H, JZ7.5, 10.8 Hz), 4.25 (dd, 1H, JZ4.8, 11.2 Hz, H500 a), 3.78 (dd, 1H, JZ4.9, 11.2 Hz, H5 00 b),
JZ2.5, 14.5 Hz, H6 0 b), 4.36 (s, 1H, H1 00 ), 4.38 (ddd, 1H, 4.14 (dd, 1H, JZ2.5, 14.5 Hz, H60 b), 4.16 (ddd, 1H, JZ2.2,
JZ5.0, 6.5, 6.6 Hz, H4 000 ), 4.50 (dddd, 1H, JZ2.5, 6.5, 8.01, 4.8, 4.9 Hz, H400 ), 4.47 (ddd, 1H, JZ2.5, 4.6, 6.6, 8.8 Hz, H50 ),
10.0 Hz, H5 0 ), 4.82 (dd, 1H, JZ3.5, 6.0 Hz, H3 00 ), 4.92 (d, 4.58 (dd, 1H, JZ3.3, 6.4 Hz, H200 ), 4.60 (dd, 1H, JZ2.2,
1H, JZ2.0, 6.0 Hz, H2 00 ), 7.51 (dd, 1H, JZ5.5 Hz, H6), 8.9 6.4 Hz, H3 00 ), 4.77 (d, 1H, JZ3.3 Hz, H1 00 ), 7.06 (d, 1H, JZ
(br s, 1H, NH). 13C NMR (CDCl3, 125 MHz) d 14.0, 23.5, 1.3 Hz, H6), 7.38–7.46 (m, 6H, aromatic protons), 7.64–7.66
23.8, 23.9, 24.9, 25.0, 29.6, 33.6, 34.1, 34.6, 35.7, 36.3, (m, 4H, aromatic protons), 8.17 (s, 1H, NH). 13C NMR
51.3, 61.7, 63.4, 65.9, 72.6, 77.1, 79.9, 82.8, 83.4, 99.0, (CDCl3, 125 MHz) d 12.26, 19.20, 25.25, 26.86, 27.07, 34.49,
109.5, 113.7, 129.5 (d, JZ131.4 Hz), 140.3 (d, 50.06, 61.36, 64.13, 64.30, 77.85, 80.48, 82.85, 85.01, 100.36,
JZ951.4 Hz), 149.7, 157.1 (d, JZ104.6 Hz), 170.3. Anal. 110.30, 113.63, 127.83, 129.96, 132.96, 135.60, 141.38,
Calcd for C29H40FN3O10: C, 57.13; H, 6.61; F, 3.12; N, 150.79, 163.89. Anal. Calcd for C34H45N3O8Si: C, 62.65; H,
6.89%. Found: C, 57.16; H, 6.58; F, 3.17; N, 6.83%. Exact 6.96; N, 6.45%. Found: C, 62.77; H, 6.99; N, 6.73%. Exact
mass calculated for C29H40FN3O10: 609.6404. Found: mass calculated for C34H45N3O8Si: 651.8220. Found:
609.6401. 651.8229.

5.4. General procedure for reduction of nucleosides 4, 5, 5.4.3. 1-[(3R,5R)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-iso-


7, and 20–22 propylidene-b-D-ribofuranosyl)-3-hydroxymethyl-1,2-iso-
xazolidin-5-yl]methyl]-5-methylpyrimidine-2,4(1H,3H)-
A suspension of 1.0 mmol of nucleosides and 1.5 mmol dione 11a. Yield 79.38%; white solid mp 72–74 8C; [a]25 D
(60 mg) of LiAlH4 in a 20 mL of anhydrous THF was stirred K95.5 (c 0.29, CHCl3). H NMR (CDCl3, 500 MHz) d 1.07 (s,
at 0 8C under N2 for 1 h. The solution was washed with 9H, CH3), 1.34 (s, 3H, CH3), 1.53 (s, 3H, CH3), 1.9 (d, 3H, JZ
saturated NH4Cl solution, extracted with ethyl acetate (3! 1.0 Hz, CH3), 2.09 (ddd, 1H, JZ2.5, 8.0, 13.0 Hz, H40 a), 2.17
5 mL) dried over sodium sulphate, and evaporated at (ddd, 1H, JZ7.0, 7.5, 13.0 Hz, H4 0 b), 2.30 (m, 1H, OH), 3.39
reduced pressure. The crude product was purified by flash (m, 1H, H7 0 a), 3.40 (m, 1H, H7 0 b), 3.46 (dd, 1H, JZ8.5,
chromatography eluting ethyl acetate to afford the corres- 14.0 Hz, H60 a), 3.59 (m, 1H, H30 ), 3.71 (dd, 1H, JZ5.5,
ponding 3-hydroxymethyl derivatives 8, 9, 11 and 24–26. 11.0 Hz, H5 00 a), 3.72 (dd, 1H, JZ7.5, 11.0 Hz, H5 00 b), 4.19 (dd,
1H, JZ2.5, 14.0 Hz, H6 0 b), 4.24 (ddd, 1H, JZ2.5, 5.5, 7.5 Hz,
5.4.1. 1-[[(3R,5S)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-iso- H4 00 ), 4.33 (dddd, 1H, JZ2.5, 7.0, 8.0, 8.5 Hz, H5 0 ), 4.63 (d,
propylidene-b-D-ribofuranosyl)-3-hydroxymethyl-1,2-iso- 1H, JZ1.5 Hz, H100 ), 4.65 (dd, 1H, JZ2.5, 6.0 Hz, H3 00 ), 4.73
xazolidin-5-yl]methyl]-5-methylpyrimidine-2,4(1H,3H)- (dd, 1H, JZ1.5, 6.0 Hz, H2 00 ), 7.25 (d, 1H, JZ1.0 Hz, H6),
dione 8a. Yield 62.64%; white solid mp 57–58 8C; [a]25 D 7.37–7.44 (m, 6H, aromatic protons), 7.63–7.65 (m, 4H,
K34.9 (cZ0.9, CHCl3). 1H NMR (CDCl3, 500 MHz) d 1.01 aromatic protons), 8.21 (s, 1H, NH). 13C NMR (CDCl3,
(s, 9H, CH3), 1.33 (s, 3H, CH3), 1.53 (s, 3H, CH3), 1.70 (ddd, 125 MHz) d 12.07, 19.15, 25.16, 26.8, 26.93, 33.56, 52.26,
1H, JZ5.5, 6.0, 12.5 Hz, H40 a), 1.85 (d, 3H, JZ1.4 Hz, CH3), 62.63, 63.16, 64.18, 77.43, 80.5, 83.41, 85.89, 99.91, 110.1,
2.33 (m, 1H, OH), 2.40 (ddd, 1H, JZ8.5, 9.0, 12.5 Hz, H4 0 b), 113.27, 127.77, 129.9, 132.98, 135.52, 141.75, 151.06,
3.38 (dd, 1H, JZ4.5, 10.5 Hz, H7 0 a), 3.41 (dd, 1H, JZ4.5, 164.34. IR (KBr): 3749.0, 3649.9, 3445.6, 2932.1, 1460.3,
10.5 Hz, H7 0 b), 3.56 (dddd, 1H, JZ4.5, 4.5, 6.0, 9.0 Hz, H3 0 ), 1382.1, 1110.3, 822.8, 704.4, 505.3 cmK1. Anal. Calcd for
3.63 (dd, 1H, JZ7.0, 14.5 Hz, H6 0 a), 3.69 (dd, 1H, JZ3.0, C34H45N3O8Si: C, 62.65; H, 6.96; N, 6.45%. Found: C, 62.75;
14.5 Hz, H6 0 b), 3.75 (dd, 1H, JZ5.5, 10.9 Hz, H500 a), 3.78 (dd, H, 6.90; N, 6.53%. Exact mass calculated for C34H45N3O8Si:
1H, JZ5.0, 10.9 Hz, H5 00 b), 4.1 (ddd, 1H, JZ3.5, 5.0, 5.5 Hz, 651.8220. Found: 651.8232.
H4 00 ), 4.28 (dddd, 1H, JZ3.0, 5.5, 7.0, 8.5 Hz, H50 ), 4.53 (dd,
1H, JZ3.5, 6.5 Hz, H300 ), 4.76 (dd, 1H, JZ3.5, 6.5 Hz, H2 00 ), 5.4.4. 5-Fluoro-1-[[(3S,5R)-2-(5-O-tert-Butyldiphenylsilyl-
4.78 (d, 1H, JZ3.5 Hz, H100 ), 6.97 (d, 1H, JZ1.4 Hz, H6), 2,3-O-isopropylidene-b-D-ribofuranosyl)-3-hydroxymethyl-
7.36–7.44 (m, 6H, aromatic protons), 7.64–7.66 (m, 4H, 1,2-isoxazolidin-5-yl]methyl]pyrimidine-2,4(1H,3H)-dione
aromatic protons), 9.04 (s, 1H, NH). 13C NMR (CDCl3, 9b. Yield 64.52%; white solid mp 74.7–76.4 8C; [a]25 D K9.2
125 MHz) d 12.1, 19.2, 25.3, 26.8, 29.6, 35.9, 49.3, 62.3, 64.0, (c 0.65, CH2Cl2). 1H NMR (CDCl3, 500 MHz) d 1.00 (s, 9H,
65.3, 77.7, 80.4, 81.8, 84.5, 98.9, 110.1, 113.8, 127.7, 129.8, CH3), 1.47 (s, 3H, CH3), 1.49 (ddd, 1H, JZ4.2, 5.5,
133.2, 135.5, 141.6, 151.0, 164.9.Anal. Calcd for 12.6 Hz, H4 0 a), 1.57 (s, 3H, CH3), 2.29 (m, 1H, OH), 2.42
C34H45N3O8Si: C, 62.65; H, 6.96; N, 6.45%. Found: C, (ddd, 1H, JZ8.6, 9.7, 12.6 Hz, H4 0 b), 3.25 (dd, 1H, JZ3.4,
62.59; H, 6.91; N, 6.61%. Exact mass calculated for 11.2 Hz, H7 0 a), 3.34 (dd, 1H, JZ4.3, 11.2 Hz, H7 0 b), 3.46
C34H45N3O8Si: 651.8220. Found: 651.8233. (dd, 1H, JZ8.0, 14.4 Hz, H6 0 a), 3.54 (dddd, 1H, JZ3.4, 4.2,
4.3, 8.6 Hz, H3 0 ), 3.67 (dd, 1H, JZ5.0 Hz, 11.0, H5 00 a), 3.61
5.4.2. 1-[[(3S,5R)-2-(5-O-tert-Butyldiphenylsilyl-2,3-O-iso- (dd, 1H, JZ4.8, 11.0 Hz, H5 00 b), 4.07 (dd, 1H, JZ2.3,
propylidene-b-D-ribofuranosyl)-3-hydroxymethyl-1,2-iso- 14.4 Hz, H6 0 b), 4.10 (ddd, 1H, JZ2.0, 4.8, 5.0 Hz, H4 00 ), 4.40
xazolidin-5-yl]methyl]-5-methylpyrimidine-2,4(1H,3H)- (dddd, 1H, JZ2.3, 5.5, 8.0, 9.7 Hz, H5 0 ), 4.51 (dd, 1H, JZ
dione 9a. Yield 60%; white solid mp 73–75; [a]25 D K10.5 (c 3.3, 6.5 Hz, H2 00 ), 4.53 (dd, 1H, JZ2.0, 6.5 Hz, H3 00 ), 4.69 (d,
0.2, CHCl3). 1H NMR (CDCl3, 500 MHz) d 1.07 (s, 9H, CH3), 1H, JZ3.3 Hz, H1 00 ), 7.29 (d, 1H, JZ5.5 Hz, H6), 7.31–7.39
1.32 (s, 3H, CH3), 1.51 (s, 3H, CH3), 1.54 (ddd, 1H, JZ4.6, (m, 6H, aromatic protons), 7.56–7.59 (m, 4H, aromatic
7.5, 12.6 Hz, H40 a), 1.9 (s, 3H, JZ1.3 Hz, CH3), 2.28 (dd, 1H, protons), 8.8 (s, 1H, NH). 13C NMR (CDCl3, 125 MHz) d
JZ5, 7.9 Hz, OH), 2.49 (ddd, 1H, JZ8.4, 8.8, 12.6 Hz, H4 0 b), 19.42, 25.26, 26.89, 27.07, 34.52, 50.30, 61.58, 64.16,
3.31 (ddd, 1H, JZ5.0, 7.5, 11.5 Hz, H70 a), 3.41 (ddd, 1H, JZ 64.37, 77.57, 80.63, 82.90, 85.23, 100.37, 113.70, 127.84,
4.5, 7.9, 11.5 Hz, H7 0 b), 3.52 (dd, 1H, JZ7.7, 14.5 Hz, H60 a), 127.87, 129.37 (d, JZ412.9 Hz), 130.01, 132.89, 133.12,
3.62 (dddd, 1H, JZ4.5, 7.5, 7.5, 8.0 Hz, H3 0 ), 3.74 (dd, 1H, 135.56, 135.62, 140.15 (d, JZ895.3 Hz), 149.49, 158.02 (d,
U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181 1179

JZ105.2 Hz). IR (KBr): 3884.7, 3672.1, 3564.5, 1697.9, 3.54 (m, 1H, H3 0 ), 3.56 (m, 1H, H7 0 b), 4.01 (dd, 1H, JZ6.0,
1650.4, 1541.4, 1519.0, 1457.6, 1382.9, 671.9 cmK1. Anal. 8.5 Hz, H5 000 a), 4.07 (dd, 1H, JZ2.0, 8.5 Hz, H5 000 b), 4.22 (dd,
Calcd for C33H42FN3O8Si: C, 60.44; H, 6.46; F, 2.90; N, 1H, JZ2.5, 14.5 Hz, H6 0 b), 4.25 (dd, 1H, JZ3.5, 5.5 Hz,
6.41. Found: C, 60.40; H, 6.50; F, 2.92; N, 6.38. Exact mass H4 00 ), 4.36 (ddd, 1H, JZ2.0, 5.5, 6.0 Hz, H5 00 ), 4.38 (dddd,
calculated for C33H42FN3O8Si: 655.786. Found: 655.781. 1H, JZ2.5, 7.5, 8.0, 8.5 Hz, H5 0 ), 4.57 (d, 1H, JZ2.5 Hz,
H1 00 ), 4.77 (dd, 1H, JZ3.5, 6.0 Hz, H3 00 ), 4.93 (dd, 1H, JZ
5.4.5. 1-([(3R,5S)-2-(2,3:5,6-Di-O-cyclohexylidene-a-D- 2.5, 6.0 Hz, H2 00 ), 7.23 (d, 1H, JZ1 Hz, H6), 8.45 (br s, 1H,
mannofuranosyl)-3-hydroxymethyl-1,2-isoxazolidin-5- OH). 13C MNR (CDCl3, 125 MHz) d 12.5, 23.7, 23.8, 23.9,
yl]methyl(-5-methylpyrimidine-2,4(1H,3H)-dione 24a. 24.9, 25.0, 25.1, 33.6, 34.3, 34.7, 35.9, 36.1, 52.2, 63.3,
Yield 51.8%; white solid mp 128–132 8C; [a]25 D K19.2 64.1, 65.6, 73.1, 76.8, 79.8, 82.6, 83.3, 98.9, 109.3, 110.3,
(c 0.6, CHCl3). 1H NMR (CDCl3, 500 MHz) d 1.52–1.67 113.8, 141.4, 150.7, 163.9. IR (KBr): 3456.0, 2935.1,
(m, 20H), 1.73 (ddd, 1H, JZ5.5, 7.0, 12.5 Hz, H4 0 a), 1.92 (d, 2858.3, 1452.4, 1367.4, 1164.4, 1104.9, 943.8 cmK1. Anal.
3H, JZ1.2 Hz), 2.54 (dt, 1H, JZ8.0, 12.5 Hz, H4 0 b), 3.49 Calcd for C28H41N3O9: C, 59.67; H, 7.33; N, 7.46%. Found:
(m, 3H, H3 0 , H7 0 a ed OH), 3.59 (m, 1H, H7 0 b), 3.68 (dd, 1H, C, 59.86; H, 7.54; N, 7.64%. Exact mass calculated for
JZ7.5, 14.5 Hz, H6 0 a), 4.01 (dd, 1H, JZ6.0, 8.5 Hz, H5 000 a), C28H41N3O9: 563.2843. Found: 563.2847.
4.05 (dd, 1H, JZ6.6, 8.5 Hz, H5 000 b), 4.07 (dd, 1H, JZ2.8,
14.5 Hz, H6 0 b), 4.24 (dd, 1H, JZ3.6, 5.2 Hz, H4 00 ), 4.39 5.4.8. 5-Fluoro-1-([(3R,5S)-2-(2,3:5,6-di-O-cyclo-
(ddd, 1H, JZ5.2, 6.0, 6.6 Hz, H4 000 ), 4.46 (dt, 1H, JZ2.9, hexylidene-a-D-mannofuranosyl)-3-hydroxymethyl-1,2-
7.4 Hz, H5 0 ), 4.56 (s, 1H, H1 00 ), 4.76 (dd, 1H, JZ3.6, 6.1 Hz, isoxazolidin-5-yl]methyl(pyrimidine-2,4(1H,3H)-dione
H3 00 ), 4.86 (d, 1H, JZ6.1 Hz, H2 00 ), 7.10 (q, 1H, JZ1.2 Hz, 24b. Yield 43.0%; white solid mp 96.98 8C; [a]25 D C179.2
H6), 9.01 (br s, 1H, NH). 13C NMR (CDCl3, 125 MHz) d (c 0.2, CHCl3); 1H NMR (CDCl3, 500 MHz) d 1.42–1.69
12.3, 23.6, 23.8, 23.9, 24.0, 25.0, 25.1, 34.0, 34.1, 34.7, (m, 20H), 1.89 (ddd, 1H, JZ5.1, 6.5, 12.5 Hz, H4 0 a), 2.0
35.7, 36.1, 50.1, 63.7, 63.9, 65.6, 73.1, 76.2, 79.6, 82.5, (m, OH), 2.54 (ddd, 1H, JZ7.5, 8.0, 12.5 Hz, H4 0 b), 3.54
83.3, 97.7, 109.3, 110.4, 113.6, 141.4, 151.1, 164.1. IR (ddd, 1H, JZ6.5, 13.5 Hz, H7 0 a), 3.62 (ddd, 1H, JZ8.5,
(KBR): 3472.5, 2926.3, 1436.6, 1372.2, 1248.1, 1169.9, 14.5 Hz, H60 a), 3.64 (dddd, 1H, JZ4.5, 5.1, 6.5, 8.0 Hz, H3 0 ),
111.8, 928.3 cmK1. Anal. Calcd for C28H41N3O9: C, 59.67; 3.67 (dd, 1H, JZ4.5, 13.5 Hz, H70 b), 4.0 (dd, 1H, JZ5.5,
H, 7.33; N, 7.46%. Found: C, 59.72; H, 7.28; N, 7.41%. 8.5 Hz, H5000 a), 4.04 (dd, 1H, JZ6.5, 8.5 Hz, H5 000 b), 4.07 (dd,
Exact mass calculated for C28H41N3O9: 563.2843. Found: 1H, JZ3.3, 14.5 Hz, H6 0 b), 4.14 (dd, 1H, JZ3.5, 5.5 Hz, H4 00 ),
563.2846. 4.32 (ddd, 1H, JZ3.5, 5.5, 6.5 Hz, H4000 ), 4.33 (dddd, 1H,
JZ3.3, 6.5, 7.5, 8.5 Hz, H5 0 ), 4.73 (s, 1H, H1 00 ), 4.76 (dd, 1H,
5.4.6. 1-([(3R,5S)-2-(2,3:5,6-Di-O-cyclohexylidene-a-D- JZ3.6, 6.1 Hz, H3 00 ), 4.89 (d, 1H, JZ4.0 Hz, H2 00 ), 7.39 (d, 1H,
mannofuranosyl)-3-hydroxymethyl-1,2-isoxazolidin-5- JZ5.5 Hz, H6), 8.41 (br s, 1H, NH). 13C NMR (CDCl3,
yl]methyl(-5-methylpyrimidine-2,4(1H,3H)-dione 25a. 125 MHz) d 23.6, 23.7, 23.9, 25.0, 29.6, 33.7, 34.2, 34.4, 35.8,
Yield 60.6%; white solid mp 140–14 28C; [a]25 D C88.8 36.1, 50.4, 60.8, 61.5, 65.6, 73.4, 76.1, 79.8, 83.8, 84.4, 97.8,
(c 0.6, CHCl3); 1H NMR (CDCl3, 500 MHz) d 1.42–1.67 (m, 109.2, 113.6, 130.0 (JZ130.6 Hz), 140.0 (JZ943.4 Hz),
20H), 1.89 (ddd, 1H, JZ6.5, 7.0, 12.5 Hz, H4 0 a), 1.92 (d, 3H, 149.4, 157.1 (JZ104.8 Hz), 170.5. IR (KBr) 3235.6, 2845.5,
JZ1.2 Hz), 2.53 (ddd, 1H, JZ7.5, 8.0, 12.5 Hz, H4 0 b), 3.56 1473.2, 1371.8, 1235.5, 1248.2, 1077.3 cmK1. Anal. Calcd for
(ddd, 1H, JZ5.5, 11.5 Hz, H7 0 a), 3.58 (dd, 1H, JZ8.5, C27H38FN3O9: C, 57.13; H, 6.75; F, 3.35; N, 7.40%. Found: C,
14.5 Hz, H60 a), 3.62 (dddd, 1H, JZ3.5, 5.5, 6.5, 8.0 Hz, H3 0 ), 57.19; H, 6.70; F, 3.32; N, 7.44%. Exact mass calculated for
3.68 (ddd, 1H, JZ3.5, 11.5 Hz, H70 a), 4.00 (dd, 1H, JZ5.5, C27H38FN3O9: 567.6037. Found: 567.6039.
8.5 Hz, H5000 a), 4.02 (dd, 1H, JZ6.5, 8.5 Hz, H5 000 b), 4.03 (dd,
1H, JZ3.5, 14.5 Hz, H60 b), 4.15 (dd, 1H, JZ4.0, 6.0 Hz, H4 00 ), 5.4.9. 5-Fluoro-1-([(3S,5R)-2-(2,3:5,6-di-O-cyclohexy-
4.32 (dddd, 1H, JZ4.0, 5.5, 6.0, 6.5 Hz, H4000 ), 4.33 (dddd, 1H, lidene-a-D-mannofuranosyl)-3-hydroxymethyl-1,2-iso-
JZ3.5, 7.0, 7.5, 8.5 Hz, H5 0 ), 4.71 (dd, 1H, JZ4.0, 6.1 Hz, xazolidin-5-yl]methyl(pyrimidine-2,4(1H,3H)-dione 25b.
H300 ), 4.82 (d, 1H, JZ1.5 Hz, H100 ), 4.90 (dd, 1H, JZ1.5, Yield 62.0%; white solid mp 92–95 8C; [a]25 D K25.5 (c 0.35,
6.1 Hz, H2 00 ), 7.10 (q, 1H, JZ1.2 Hz, H6), 8.90 (br s, 1H, NH). CHCl3). 1H NMR (CDCl3, 500 MHz) d 1.52–1.65 (m, 20H),
13
C NMR (CDCl3, 125 MHz) d 12.1, 23.4, 23.6, 23.8, 24.0, 1.79 (ddd, 1H, JZ5.4, 7.1, 12.6 Hz, H40 a), 2.53 (ddd, 1H, JZ
25.0, 25.1, 33.8, 34.4, 34.8, 35.5, 35.8, 36.2, 50.3, 61.1, 61.8, 8.1, 8.2, 12.6 Hz, H40 b), 3.47 (dddd, 1H, JZ5.4, 6.0, 7.7,
65.7, 73.4, 76.3, 79.6, 83.9, 84.5, 97.8, 110.3, 113.6, 141.5, 8.2 Hz, H30 ), 3.49 (ddd, 1H, JZ6.0, 9.5 Hz, H70 a), 2.60 (m, 1H,
150.9, 164.1. IR (KBr): 3471.6, 2936.0, 1456.7, 1369.3, OH), 3.58 (dd, 1H, JZ7.7, 9.5 Hz, H7 0 b), 3.69 (ddd, 1H, JZ
1247.9, 1163.2, 1101.9, 939.0 cmK1. Anal. Calcd for 7.4, 14.5 Hz, H6 0 a), 3.99 (dd, 1H, JZ5.8, 8.5 Hz, H5 000 a), 4.03
C28H41N3O9: C, 59.67; H, 7.33; N, 7.46%. Found: C, 59.61; (dd, 1H, JZ6.4, 8.5 Hz, H5 000 b), 4.05 (dd, 1H, JZ2.8, 14.5 Hz,
H, 7.43; N, 7.42%. Exact mass calculated for C28H41N3O9: H6 0 b), 4.21 (dd, 1H, JZ3.4, 5.1 Hz, H4 00 ), 4.37 (ddd, 1H, JZ
563.2843. Found: 563.2840. 5.1, 5.8, 6.4 Hz, H4 000 ), 4.44 (dddd, 1H, JZ2.8, 7.1, 7.4, 8.1 Hz,
H5 0 ), 4.53 (s, 1H, H100 ), 4.75 (dd, 1H, JZ3.4, 6.0 Hz, H300 ), 4.84
5.4.7. 1-([(3R,5S)-2-(2,3:5,6-Di-O-cyclohexylidene-a-D- (d, 1H, JZ6.0 Hz, H200 ), 7.36 (d, 1H, JZ5.5 Hz, H6), 8.9 (br s,
mannofuranosyl)-3-hydroxymethyl-1,2-isoxazolidin-5- 1H, NH). 13C NMR (CDCl3, 125 MHz) d 23.6, 23.7, 23.9,
yl]methyl(-5-methylpyrimidine-2,4(1H,3H)-dione 26a. 25.1, 29.7, 34.0, 34.3, 34.6, 35.7, 36.0, 50.2, 63.7, 64.0, 65.5,
Yield 48%; white solid mp 70–74 8C; [a]25 D C81.8 (c 73.0, 75.9, 79.5, 82.5, 83.2, 97.9, 109.3, 113.6, 129.8 (d, JZ
0.34, CHCl3). 1H MNR (CDCl3, 500 MHz) d 1.54–1.69 (m, 131.2 Hz), 142.1 (d, JZ942.9 Hz), 149.6, 156.8 (d, JZ
20H, CH2), 1.92 (d, 3H, JZ1.0 Hz), 2.09 (ddd, 1H, JZ8.0, 942.9 Hz), 170.3. IR (KBr) 3300.3, 2891.6, 1743.5, 1733.4,
8.0, 13.0 Hz, H4 0 a), 2.24 (ddd, 1H, JZ2.5, 7.5, 13.0 Hz, 1651.3, 1560.2, 1432.3, 1412.4, 1111.4 cmK1. Anal. Calcd for
H4 0 b), 3.44 (dd, 1H, JZ8.5, 14 Hz, H6 0 a), 3.52 (m, 1H, H7 0 a), C27H38FN3O9: C, 57.13; H, 6.75; F, 3.35; N, 7.40%. Found: C,
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 5.5.2. Reaction of 9a or 25a with p-TosOH. 1 0 -
C27H38FN3O9: 567.6037. Found: 567.6033. [(1 0 R,4 0 S)-5-(Methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)methyl]2 0 oxa-3 0 azacyclopent-4 0 yl-methanol
13a. Yield 70% (reaction of 9a); yield 97.6% (reaction
5.4.10. 5-Fluoro-1-([(3S*,5S*)-2-(2,3:5,6-di-O-cyclo- of 25a); white solid mp 163–165 8C; [a]25 D C56.7 (c
hexylidene-a-D-mannofuranosyl)-3-hydroxymethyl-1,2- 0.31, H2O). Physical and spectroscopic data are identical
isoxazolidin-5-yl]methyl(pyrimidine-2,4(1H,3H)-dione to compound 12a.
26b. Yield 54%; white solid mp 95–978C; [a]25 D C81.8 (c
0.34, CHCl3). 1H MNR (CDCl3, 500 MHz) d 1.20–1.63 5.5.3. Reaction of 26a with p-TosOH. 1 0 -[(1 0 S,4 0 S)-5-
(m, 20H), 2.02 (dt, 1H, JZ7.7, 13 Hz, H4 0 a), 2.22 (ddd, (Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
1H, JZ1.9, 7.5, 13 Hz, H4 0 b), 2.63 (m, 1H, OH), 3.31 yl)methyl]2 0 oxa-3 0 azacyclopent-4 0 yl-methanol 14a. Yield
(dd, 1H, JZ8.8, 14.4 Hz, H6 0 a), 3.32 (ddd, 1H, JZ5.5, 67.3%; white solid mp 147–148 8C; [a]25 D C118.9 (c 0.2,
5.8, 6.6 Hz, H4 000 ) 3.45–3.54 (m, 3H, H3 0 CH7 0 aCH7 0 b), H2O).1H MNR (D2O, 200 MHz) d 1.92 (d, 1H, JZ1 Hz,
3.93 (dd, 1H, JZ5.8, 8.6 Hz, H5 000 a), 3.99 (dd, 1H, JZ CH3), 2.26 (m, 1H, H5 0 a), 2.46 (m, 1H, H5 0 b), 3.66 (m, 1H,
6.6, 8.6 Hz, H5 000 b), 4.19 (dd, 1H, JZ3.4, 5.5 Hz, H4 00 ), H6 0 a), 3.77 (m, 1H, H4 00 a), 4.86 (m, 1H, H4 0 ), 4.08 (m, 1H,
4.23 (dd, 1H, JZ2.6, 14.4 Hz, H6 0 b), 4.34 (dddd, 1H, JZ H4 00 b), 4.12 (m, 1H, H6 0 b), 4.31 (m, 1H, H1 0 ), 7.51 (d, 1H,
2.6, 7.5, 7.7, 8.8 Hz, H5 0 ), 4.50 (s, 1H, H1 00 ), 4.72 (dd, JZ1.0 Hz, H6). 13C MNR (CDCl3, 125 MHz) d 11.38,
1H, JZ3.4, 5.9 Hz, H3 00 ), 4.86 (d, 1H, JZ5.9 Hz, H2 00 ), 34.23, 49.87, 59.22, 79.91, 82.0, 110.81, 143.45, 152.56,
7.53 (d, 1H, JZ5.6 Hz, H6), 8.7 (br s, 1H, NH). 13C 167.11. IR (KBr): 3421.8, 1748.9, 1487.6, 1218.3, 1071.9,
MNR (CDCl3, 125 MHz) d 23.4, 23.7, 23.8, 25.0, 29.8, 940.7 cmK1. Anal. Calcd for C10H15N3O4: C, 49.79; H,
33.1, 33.9, 34.5, 35.7, 36.0, 53.1, 63.0, 63.5, 65.5, 72.9, 6.27; N, 17.42%. Found: C, 49.52; H, 6.25; N, 17.45%.
76.3, 79.7, 82.6, 83.3, 98.9, 109.3, 113.9, 129.8 (d, JZ Exact mass calculated for C10H15N3O4: 241.1063. Found:
130.0 Hz), 140.2 (d, JZ943.0 Hz), 149.7, 157.5 (d, JZ 241.1059.
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. 5.5.4. Reaction of 11a with p-TosOH. 1 0 -[(1 0 R,4 0 R)-5-
Calcd for C27H38FN3O9: C, 57.13; H, 6.75; F, 3.35; N, (Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
7.40%. Found: C, 57.17; H, 6.71; F, 3.37; N, 7.42%. yl)methyl]2 0 oxa-3 0 azacyclopent-4 0 yl-methanol 15a. Yield
Exact mass calculated for C27H38FN3O9: 567.6037. 65.2%; white solid mp 141–143 8C; [a]25 D K123.4 (c 0.32,
Found: 567.6041. 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. 1 0 -[(1 0 S,4 0 R)-5-
(Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
To a solution of 8–11 and 24–26 (1.0 mmol) in methanol yl)methyl]2 0 oxa-3 0 azacyclopent-4 0 yl-methanol 12b.
(50 mL) was added p-TosOH (258 mg, 1.5 mmol) and the Yield 52% (reaction of 24b); white solid mp 192–195 8C;
resulting solution was heated at 40 8C for 4 h. The reaction [a]25 1 1
D K48.9 (c 0.23, H2O). . H NMR (D2O, 500 MHz) d
mixture was cooled at room temperature and neutralized 1.54 (ddd, 1H, JZ5.2, 6.5, 12.5 Hz, H5 0 a), 2.41 (ddd, 1H,
with Amberlite IRA-400. The mixture was filtered and the JZ7.5, 8.2, 12.5 Hz, H5 0 b), 3.38 (dd, 1H, JZ7.0, 13.5 Hz,
filtrate evaporated under reduced pressure. The residue was H4 00 a), 3.44 (dd, 1H, JZ3.8, 13.5 Hz, H4 00 b), 3.48 (dddd, 1H,
purified by flash chromatography using water as eluent with JZ3.8, 5.2, 7.0, 7.5 Hz H4 0 ), 3.73 (dd, 1H, JZ8.0, 14.5 Hz,
a Lichroprep RP-18, 40–63 mm colomn (12!75 mm), to H6 0 a), 3.95 (dd, 1H, JZ3.2, 14.5 Hz, H6 0 b), 4.20 (dddd, 1H,
afford the corresponding homonucleosides 12–15. JZ3.2, 6.5, 8.0, 8.2 Hz, H1 0 ), 7.1 (d, 1H, JZ5.5 Hz, H6).
13
C 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. 1 0 - 3649.5, 1697.8, 1650.5, 1558.1, 1541.0, 1519.2 cmK1.
[(1 0 S,4 0 R)-5-(Methyl-2,4-dioxo-3,4-dihydropyrimidin- Anal. Calcd for C9H12FN3O4: C, 44.08; H, 4.93; F, 7.75;
1(2H)-yl)methyl]2 0 oxa-3 0 azacyclopent-4 0 yl-methanol N, 17.14%. Found: C, 44.04; H, 4.97; F, 7.73; N, 17.17%.
12a. Yield 62.64% (reaction of 8a); yield 70.2% Exact mass calculated for C9H12FN3O4: 245.2076. Found:
(reaction of 24a); white solid mp 164–167 8C; [a]25 D 245.2071.
K51.8 (c 0.23, H2O). 1H NMR (D2O, 500 MHz) d 1.77
(ddd, 1H, JZ6.6, 8.1, 13 Hz, H5 0 a), 1.92 (d, 3H, JZ 5.5.6. Reaction of 9b or 25b with p-TosOH. 1 0 -
1.2 Hz, CH3), 2.62 (ddd, 1H, JZ8.4, 7.8, 13 Hz, H5 0 b), [(1 0 R,4 0 S)-5-(Fluoro-2,4-dioxo-3,4-dihydropyrimidin-
3.42 (dd, 1H, JZ7.9, 12.3 Hz, H4 00 a), 3.65 (dd, 1H, JZ 1(2H)-yl)methyl]2 0 oxa-3 0 azacyclopent-4 0 yl-methanol
3.1, 12.3 Hz, H4 00 b), 3.72 (dddd, 1H, JZ3.1, 6.6, 8.4, 13b. Yield 74% (reaction of 9b); yield 75% (reaction of
7.9 Hz H4 0 ), 3.95 (dd, 1H, JZ7.8, 15 Hz, H6 0 a), 4.12 (dd, 25b); white solid mp 195–197 8C; [a]25 D C51.7 (c 0.23,
1H, JZ3.1, 15 Hz, H6 0 b), 4.44 (ddd, 1H, JZ3.1, 7.8, H2O). Physical and spectroscopic data are identical to
8.1 Hz, H1 0 ), 7.51 (d, 1H, JZ1.2 Hz, H6). 13C NMR compound 12b.
(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, 5.5.7. Reaction 26b with p-TosOH. 1 0 -[(1 0 S,4 0 S)-5-
1493.7, 1384.9, 1238.4, 1059.5, 760.4 cmK1. Anal. Calcd (Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)
for C10H15N3O4: C, 49.79; H, 6.27; N, 17.42%. Found: methyl]2 0 oxa-3 0 azacyclopent-4 0 yl-methanol 14b. Yield
C, 49.75; H, 6.35; N, 17.54%. Exact mass calculated for 61.3%; white solid mp 123–125 8C; [a]25 D C65.1 (c 0.3,
C10H15N3O4: 241.1063. Found: 241.1060. H2O).1H MNR (D2O, 500 MHz) d 1.84 (ddd, 1H, JZ6.5,
U. Chiacchio et al. / Tetrahedron 62 (2006) 1171–1181 1181

8.0, 12.5 Hz, H5 0 a), 2.19 (ddd, 1H, JZ6.0, 9.0, 12.5 Hz, Acknowledgements
H5 0 b), 3.18 (dd, 1H, JZ9.1, 13.0 Hz, H6 0 a), 3.33 (dd, 1H, JZ
6.5, 8.5 Hz, H4 00 a), 3.62 (dd, 1H, JZ2.5, 13.0 Hz, H6 0 b), 3.71 This work was partially supported by M.I.U.R. (progetto
(dddd, 1H, JZ2.5, 6.0, 6.5, 8.0 Hz, H4 0 ), 3.73 (dd, 1H, P.R.I.N. 2004 and F.I.R.B.). We also thank for financial
JZ2.5, 8.5 Hz, H4 00 b), 4.60 (dddd, 1H, JZ2.5, 6.5, 9.0, support the Boush and Lomb Oftal.
9.1 Hz, H1 0 ), 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 cm K1. Anal. Calcd for
C9H12FN3O4: C, 44.08; H, 4.93; F, 7.75; N, 17.14%. References and notes
Found: C, 44.14; H, 4.97; F, 7.71; N, 17.09%. Exact mass
calculated for C9H12FN3O4: 245.2076. Found: 245.2081. 1. Ishiyama, K.; Smyth, G. E.; Ueda, T.; Masutomi, Y.; Ohgi, T.;
Yano, J. J. Am. Chem. Soc. 2004, 126, 7476–7485.
5.5.8. Reaction of 11b with p-TosOH. 1 0 -[(1 0 R,4 0 R)-5- 2. (a) Eschenmoser, A.; Loewenthal, E. Chem. Soc. Rev. 1992, 21,
(Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- 1–16. (b) De Mesmaeker, A.; Altmannn, K. H.; Waldner, A.;
yl)methyl]2 0 oxa-3 0 azacyclopent-4 0 yl-methanol 15b. Yield Wendeborn, S. Curr. Opin. Struct. Biol. 1995, 5, 343–355. (c)
67.5%; white solid mp 122–125 8C; [a]25 D K72.3 (c 0.3,
Matteucci, M. Perspect. Drug Discov. Des. 1996, 4, 1–16.
H2O). Physical and spectroscopic data are identical to (d) Schoning, K. U.; Scholz, P.; Guntha, S.; Wu, X.;
compound 14b. Krisnamurthy, R.; Eschenmoser, A. Science 2000, 290,
1347–1351.
3. Merino, P. Curr. Med. Chem. Anti-Infective Agents 2002, 1,
5.6. General procedure for preparation of ester 16–17 389–411.
4. (a) Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.;
To a solution of (R)- or (S)-9-AMA (40 mg, 0.16 mmol) in Pistarà, V.; Rescifina, A.; Romeo, R.; Valveri, V.;
dichloromethane at 0 8C were added 43.5 mg (0.16 mmol) Mastino, A.; Romeo, G. J. Med. Chem. 2003, 46,
of 13a, 39.6 mg (0.19 mmol) of DCC, and 3.0 mg 3696–3702. (b) Chiacchio, U.; Balestrieri, E.; Macchi,
(0.1 mmol) of DMPA. After 2 h the reaction mixture was B.; Iannazzo, D.; Piperno, A.; Rescifina, A.; Romeo, R.;
evaporated under reduced pressure, and the residue was Saglimbeni, M.; Sciortino, M. T.; Valveri, V.; Mastino,
purified by flash chromatography on silica gel eluting with A.; Romeo, G. J. Med. Chem. 2005, 48, 1389–1394.
hexane–ethyl acetate (80/20). 5. De Clercq, E. J. Med. Chem. 2005, 48, 1–17.
6. (a) Hossain, N.; Hendrix, C.; Lescrinier, E.; Van Aerschot, A.;
5.6.1. {(3S,5R)-5-[(5-Methyl-2,4-dioxo-3,4-dihydro- Busson, R.; De Clercq, E.; Herdewijn, P. Bioorg. Med. Chem.
pyrimidin-1(2H)-yl)methyl]isoxazolidin-3-yl}methyl- Lett. 1996, 6, 1465–1468. (b) Saladino, R.; Ciambecchini, U.;
(2R)-9-anthryl(hydroxy)acetate 16. Yield 81%; sticky Hanessian, S. Eur. J. Org. Chem. 2003, 4401–4405.
yellow oil; 1H MNR (CDCl3, 500 MHz) d 1.19 (m, 2H, 7. (a) De Clercq, E.; Descamps, J.; Verhelst, G.; Walker, R. T.;
H5 0 a), 1.94 (m, 1H, H5 0 b), 1.98 (d, 3H, JZ1.2 Hz, CH3), 2.60 Jones, A. S.; Torrence, P. F.; Shugar, D. J. Infect. Dis. 1980,
(m, 1H, H6 0 a), 2.80 (m, 1H, H6 0 b), 3.48 (m, 3H, OCH3), 3.50 141, 563–574. (b) De Clercq, E.; Hols, A.; Rosenberg, I.;
(m, 1H, H4 0 ), 4.14 (m, 1H, H1 0 b), 4.19 (m, 2H, H4 00 a), 4.21 Sakuma, T.; Balzarini, J.; Maudgal, P. C. A. Nature 1986, 323,
(m, 1H, H4 00 b), 6.26 (s, 1H), 7.06 (d, 1H, JZ1.2 Hz, H6), 464–467.
7.54 (m, 2H, aromatic protons), 7.63 (m, 2H, aromatic 8. Sekino, Y.; Bruner, S. D.; Verdine, G. L. J. Biol. Chem. 2000,
protons), 8.03 (d, 2H, JZ8.0 Hz, aromatic protons), 8.49 (s, 275, 36506–36508.
1H, aromatic protons), 8.55 (d, 2H, JZ8.0 Hz, aromatic 9. (a) Deng, L.; Scharer, O. D.; Verdine, G. L. J. Am. Chem. Soc.
protons). Anal. Calcd for C26H25N3O6: C, 65.67; H, 5.30; N, 1997, 119, 7865–7866. (b) Wong, C. H.; Provencher, L.;
Porco, J. A.; Jung, S.-H.; Wang, J.-F.; Chen, L.; Wang, R.;
8.84%. Found: C, 65.54; H, 5.31; N, 8.86%.
Steensma, D. H. J. Org. Chem. 1995, 60, 1492–1501.
10. Chiacchio, U.; Genevose, F.; Iannazzo, D.; Librando, V.;
5.6.2. {(3S,5R)-5-[(5-Methyl-2,4-dioxo-3,4-dihydro- Merino, P.; Rescifina, A.; Romeo, R.; Procopio, A.; Romeo, G.
p y r i m i d i n - 1 ( 2H ) - y l ) m e t h y l ] i s o x a z ol i d i n - 3 - y l } - Tetrahedron 2004, 60, 441–448.
methyl(2S)-9-anthryl(hydroxy)acetate 17. Yield 11. Chiacchio, U.; Corsaro, A.; Gumina, G.; Rescifina, A.;
80%; sticky yellow oil; 1H MNR (CDCl3, 500 MHz) d 1.17 Iannazzo, D.; Piperno, A.; Romeo, G.; Romeo, R. J. Org.
(m, 1H, H5 0 a), 1.95 (m, 1H, H5 0 b), 1.98 (d, 3H, JZ1.2 Hz, Chem. 1999, 64, 9321–9327.
CH3), 2.62 (m, 1H, H6 0 a), 2.83 (m, 1H, H6 0 b), 3.48 (m, 4H, 12. Kasahara, K.; Iida, H.; Kibayashi, C. J. Org. Chem. 1988, 54,
OCH3, H4 0 ), 4.01 (m, 1H, H1 0 b), 4.08 (m, 2H, H4 00 a, H4 00 b), 2225–2233.
6.44 (s, 1H), 7.06 (d, 1H, JZ1.2 Hz, H6), 7.48 (m, 2H, 13. Ciminiello, P.; Dell’Aversano, C.; Fattorusso, C.; Fattorusso, E.;
aromatic protons), 7.54 (m, 2H, aromatic protons), 8.01 (d, Forino, M.; Magno, S. Tetrahedron 2001, 57, 8189–8192.
2H, JZ8.5 Hz, aromatic protons), 8.47 (m, 3H, aromatic 14. Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.;
protons). Anal. Calcd for C26H25N3O6: C, 65.67; H, 5.30; N, Procopio, A.; Rescifina, A.; Romeo, G.; Romeo, R. Eur.
8.84%. Found: C, 65.82; H, 5.29; N, 8.83%. J. Org. Chem. 2001, 1893–1898.