Diastereoselective synthesis of d-xylo-isoxazolidinyl nucleosides

Article abstract of DOI:10.1016/j.tet.2008.01.133

The condensation of the acetoxyisoxazolidines with silylated uracil, thymine, cytosine, N-acetylcytosine, and guanine proceeded in good yields and with moderate to good stereoselectivity to give isoxazolidinyl β- and α-nucleosides. The stereoselectivity o

Full text of DOI:10.1016/j.tet.2008.01.133

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Tetrahedron 64 (2008) 3111e3118
www.elsevier.com/locate/tet
Diastereoselective synthesis of D-xylo-isoxazolidinyl nucleosides
a
a,
b
b
ˇ ´ a
ˇ
*
´
´
Eva Hyrosova , Michal Medvecky , Lubor Fisera , Christian Hametner , Johannes Frohlich ,
¨
Martina Marchetti c, Gunter Allmaier c
¨
a Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovak Republic
b Institute of Applied Synthetic Chemistry, University of Technology, A-1060 Vienna, Austria
c Institute of Chemical Technologies and Analytics, University of Technology, A-1060 Vienna, Austria
Received 18 October 2007; received in revised form 16 January 2008; accepted 31 January 2008
Available online 6 February 2008
Abstract
The condensation of the acetoxyisoxazolidines with silylated uracil, thymine, cytosine, N-acetylcytosine, and guanine proceeded in good
yields and with moderate to good stereoselectivity to give isoxazolidinyl b- and a-nucleosides. The stereoselectivity of the addition is dependent
on the structure of the substituent at C-3 originating from the starting chiral nitrone. The Vorbruggen nucleosidation of isoxazolidine 8 at 70 ꢀC
¨
afforded b-anomers as the exclusive nucleosides together with the isoxazoline 11. It was found that the nucleosidation proceeded also in
methylene chloride at room temperature.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Nucleosides; 1,3-Dipolar cycloaddition; C-Glycosyl nitrones
1. Introduction
Vorbruggen nucleosidation of 5-acetoxyisoxazolidines.3e12
¨
Recently, with the aim to prepare some novel azanucleosides
by the transformation of modified isoxazolidinyl nucleosides
2 we have prepared the appropriate sugar-derived nitrones
4a,b possessing structures suitable for the building of pyrrol-
idine.9 Cycloadditions of chiral nitrones 4a and 4b easily pre-
pared from D-xylose to vinylated nucleobases derived from
uracil and adenine proceeded regioselectively and led to the
Nucleosides are generally defined as DNA or RNA subunits
and consist of both a base moiety such as adenine, thymine,
guanine, cytosine, and uracil, and a sugar moiety such as
D-ribose or D-deoxyribose.1 Many nucleoside analogues have
been synthesized with modification of the base, sugar, and phos-
phane region. In particular, nucleoside analogues in which the
furanose ring has been replaced by different carbon or heterocy-
clic systems have attracted special interest by virtue of their
biological action as antiviral and/or anticancer agents.2 Among
them, uracil, thymine, cytosine, and adenine nucleosides 1
possessing an isoxazolidinyl moiety (carbocyclic-20-oxo-30-
azanucleosides) are emerging as an interesting class of dideoxy-
nucleoside analogues with potential pharmacological activity.2
For the synthesis of modified isoxazolidinyl nucleosides 1e3
two strategies can be used. In particular a one-step approach
based on the 1,3-dipolar cycloaddition of nitrones with vinyl
nucleobases and a two-step methodology based on the
OMe
O
OR1 OR3
O
OR4
B
B
R
B
O N
OR2
O N
O N
O
Bn
Bn
Bn
3
2
1
OR2
Bn
R4O
N
O
OR3 OR1
4
a R1, R2=R3, R4=CMe2
b R1, R2=CMe2, R3=Bz, R4=TBDPS
c R1, R2=CMe2, R3=Bn, R4=TBDPS
* Corresponding author. Tel./fax: þ421 2529 68560.
ˇ
E-mail address: lubor.fisera@stuba.sk (L. Fisera).
Figure 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.133

3112
E. Hy´rosˇova´ et al. / Tetrahedron 64 (2008) 3111e3118
isoxazolidines 2 as a mixture of four diastereoisomers in all
cases.9 With our continuing efforts to utilize chiral 1,3-dipolar
cycloadditions,9e15 we are now extending the 1,3-dipolar cy-
cloaddition approach to synthesize novel 40-aza-20,30-dideoxy-
furanosyl nucleosides 2 by reaction of readily available chiral
sugar-derived D-xylosyl nitrones 4 to vinyl acetate with the sub-
sequent transformation of the formed 5-acetoxyisoxazolidines
(Fig. 1).
the 1,3-dipolar cycloaddition of nitrone 4b with vinyl ace-
tate,19 the Vorbruggen nucleosidations with silylated nucleo-
¨
bases proceeded at 70 ꢀC with the excellent stereoselectivity
and the corresponding b-anomers 9a,b,d are now the exclusive
nucleosides for all of the used nucleobases (Scheme 2). That
9a,b,d has the same configuration as 6a whose structure was
elucidated by X-ray analysis is inferred from the diagnostic
signals and NOEDS results.
The research groups of Merino, Chiacchio, and Romeo
have reported that the anomeric distribution obtained by the
2. Results and discussion
Vorbruggen nucleosidation with chiral 5-acetoxyisoxazol-
¨
The anti, trans-isoxazolidine 5 prepared by the 1,3-dipolar
cycloaddition of nitrone 2a with vinyl acetate19 was coupled
with silylated nucleobases according to the Vorbruggen meth-
¨
idines depends on the attacking nucleobase.21e24 The attack
on the intermediate oxonium from either the a- or b-side is
possible, and hence the product distribution is sensitive to
structural changes of the reactants. Evidently, in our case the
stereoselectivity of the addition of the silylated nucleobase is
more dependent on the structure of the substituent at C-3 orig-
inating from the starting chiral nitrone. Moreover, in this case
the product of elimination, the corresponding isoxazoline de-
rivative 11, was also isolated (Scheme 2). It is noteworthy
that in the case of silylated 5-fluorouracil, the isoxazoline 11
is formed as the major product (9a/11 ratio 58:42, 9b/11 ratio
81:19, 9c/11 ratio 90:10, 9f/11 ratio 9:91). The unexpected
side-product 11 was analyzed by 2D NMR spectroscopy and
mass spectrometry. Using homonuclear (COSY) and one-
bond (HSQC) as well as long-range (HMBC) heteronuclear
correlation spectra the structure could be elucidated and the
signals were assigned. The existence of a double bond within
the isoxazoline ring is supported by good agreement of the
chemical shifts with similar structural elements, e.g., 2-benz-
yl-3-isopropyl-4-isoxazoline (6.45 and 4.88 ppm for 1H,
141.5 and 97.5 ppm for 13C).25 The remarkably small coupling
constant of 2.2 Hz between the olefinic protons is also charac-
teristic for cyclic enol ethers. Furthermore, the shifts of the
side chain are well comparable to those of similar compounds
within this work. Thus the structure of the product in question
is confirmed both by the correlation pattern within the 2D
NMR spectra as well as the chemical shift analysis. The sug-
gested structure of 11 was also confirmed by HRMS as well by
MALDI and electrospray mass spectrometry.
odology.20 The condensation of 5 with silylated uracil, thy-
mine, cytosine, and N-acetylcytosine at 70 ꢀC in the presence
of trimethylsilyltriflate as catalyst, proceeded with low (uracil,
thymine) to good (cytosine and N-acetylcytosine) yields and
moderate stereoselectivity with formation of the expected isox-
azolidinyl b- and a-nucleosides (6a/7a ratio 63:37, 6b/7b
ratio 63:37, 6c/7c ratio 55:45, 6d/7d ratio 66:34, Scheme 1).
The ratio of anomeric nucleosides was determined from quan-
titative 13C NMR spectra, by integration of the peaks from C-4
and C-5 of the isoxazolidines. The b-anomers 6aed predomi-
nate, but a significant amount of a-anomers 7aed were also ob-
tained. These results are fully in accord with the data obtained
for the related Vorbruggen nucleosidations. Purification by
¨
flash chromatography allowed the isolation of pure nucleosides
6a and 7a; their assigned stereochemistry is supported by NMR
analysis. In fact, NOE measurements performed on b-anomers
6aed show a positive NOE effect for protons H-3 when irradi-
ating H-5 thus indicating a cis relationship between these
protons. The major diastereomer 6a has been already prepared
by us by the 1,3-dipolar cycloaddition of nitrone 2a with vinyl
uracil and its structure was subsequently confirmed by X-ray
crystallographic analysis.9 It should be noted that the
chromatographic separation of 6bed and 7bed was not
possible.
A surprising and unexpected fact is that in the case of the
anti, trans-5-acetoxysubstituted isoxazolidine 8 prepared by
OR1
O
4
3
2'
O
5
B
1'
3'
4'
-anti-cis
1
2
OR1
O
O
N
OR2
6
O
Bn
AcO
BSA, nucleobase
Me3SiOTf, MeCN
70 °C
O
N
OR2
Bn
OR1
O
O
B
1'
-anti-trans
anti-trans
OR2
7
O
N
5
R1=R2=CMe2
Bn
O
O
NH2
NHAc
HN
HN
N
N
O
N
H
O
N
H
O
N
H
O
N
H
a
b
c
d
Scheme 1.

E. Hy´rosˇova´ et al. / Tetrahedron 64 (2008) 3111e3118
3113
OR1 OBz
4
2'
4'
5
3
OTBDPS
B
B
3'
1'
-anti-cis
9
1
2
OR2
O
N
Bn
OR1 OBz
OR2
OR1 OBz
OR2
OTBDPS
AcO
OTBDPS
OTBDPS
BSA, nucleobase
Me3SiOTf, MeCN
-anti-cis
10
O
N
O
N
Bn
Bn
anti-trans
OR1 OBz
8
OR2
O
N
R1=R2=CMe2
Bn
11
O
O
O
NHAc
N
O
F
N
HN
HN
HN
HN
AcHN
N
H
O
N
H
O
N
H
O
N
H
O
N
H
N
a
b
d
e
f
Scheme 2.
To the best of our knowledge, such a formation of 2,3-dihy-
droisoxazoles by the Vorbruggen nucleosidation has not been
¨
nitrone 4c (Scheme 3). The synthesis of 4c was performed ac-
cording to the procedure previously reported by us for 4b.19
Thus, benzoylation of silylated dithioacetal 129 with benzyl
bromide afforded the protected dithioacetal 13. Deprotection
of the thiol group (HgCl2/HgO) and condensation of aldehyde
14 with N-benzylhydroxylamine according to the method of
Dondoni28 gave nitrone 4c.
Nitrone 4c reacted smoothly in vinyl acetate at reflux over
24 h to give an 83:10:7 mixture of diastereoisomeric isoxazol-
idines 15, 16, and 17 in 85% yield (Scheme 4). The cycload-
dition proceeded with very good diastereoselectivity for the
anti, trans-isoxazolidine 15 and is completely regioselective
with only the sterically favored 5-substituted isoxazolidines
being detected. Purification by flash chromatography allowed
the isolation of pure endo-adduct 15, with the C-3/C-5 trans
relative configuration identified by spectroscopic analysis, par-
ticularly NOE difference experiments. Based on our previous
results from 1,3-dipolar cycloadditions of sugar nitrones bear-
ing a protected hydroxy group in the a-position,9e19 as well as
the fact that the 1,3-dipolar cycloaddition of electron-rich al-
kenes to chiral a-alkoxy nitrones gave preferentially anti ad-
ducts,4 we assigned to isomer 15 a C-10/C-3 anti relationship
as a result of dipolarophile attack from the less sterically hin-
dered si diastereotopic face of nitrone 4c.
observed. 2,3-Dihydroisoxazoles represent a class of heterocy-
cles that may be employed as useful building blocks for
synthesis.26 Recently, Carreira et al. have reported a conceptu-
ally simple and attractive synthesis toward 2,3,5-trisubstituted
2,3-dihydroisoxazoles via 5-endo-dig CeO bond formation of
propargylic N-hydroxylamines catalyzed by Zn(II) salts.27 The
obtained chiral 2,3-disubstituted 2,3-dihydroisoxazole 11 rep-
resents a very rare/unusual compound of this class.
We suppose that the isoxazoline 11 is formed by the elimi-
nation of the corresponding a-anomers 10a,b and 10d. There-
fore, we next studied the Vorbruggen nucleosidation in
¨
methylene chloride at room temperature. Indeed, the product
of elimination 11 was not detected and both b- and a-anomeric
isoxazolidinyl nucleosides 9 and 10 were formed with high
stereoselectivities in favor of the b-anomers 9 (9a/10a ratio
95:5, 9b/10b ratio 80:20, 9d/10d ratio 83:17, 9e/10e ratio
70:30, Scheme 3). Also, the first successful isoxazolidinyl nu-
cleosides 9e and 10e derived from N-acetylguanine were
obtained.
As has been already mentioned, the best stereoselectivity in
the nucleosidation was achieved in the case of benzoylsubsti-
tuted isoxazolidine 8. To exclude or to support the possibility
of the participation of the neighboring benzoyl group, we have
prepared the corresponding D-xylose derived benzylsubstituted
The subsequent Vorbruggen nucleosidation of anti, trans-
¨
benzyloxysubstituted isoxazolidine 15 with silylated uracil,
OR2
OR2 S-i-Pr
OR2 S-i-Pr
OR2
1
5
2
4
Bn
(a)
(b)
(c)
TBDPSO
N
O
3
TBDPSO
S-i-Pr
TBDPSO
S-i-Pr
TBDPSO
OR1
O
BnO
OR1
OR1
OH
OR1
BnO
BnO
12
13
14
4c
R1=R2=CMe2
Scheme 3. (a) BnBr, NaH, THF, rt, 21 h, 61%; (b) HgCl2/HgO, acetone, H2O, 56 ꢀC, 2 h; (c) BnNHOH, CH2Cl2, MgSO4, rt, 12 h, 93%.

3114
E. Hy´rosˇova´ et al. / Tetrahedron 64 (2008) 3111e3118
OR2
OR1
4c
case of the anti, trans-5-acetoxysubstituted isoxazolidine 8,
the Vorbruggen nucleosidation with silylated nucleobases is
¨
O
TBDPSO
N
O
O
CH3
also dependent on the reaction temperature, at 70 ꢀC the cor-
responding b-anomers 9aec are the exclusive nucleosides
for all of the used nucleobases, along with the product of elim-
ination; the corresponding isoxazoline derivative 11 was also
isolated. It was found that the nucleosidation also proceeded
in methylene chloride at room temperature. The cycloaddition
of the chiral nitrone 4c with vinyl acetate proceeded with very
good diastereoselectivity for the anti, trans-isoxazolidine 15.
BnO
OR1 OBn
OR1 OBn
OR2
4
3
2'
4'
5
OTBDPS
OTBDPS
OTBDPS
OTBDPS
AcO
AcO
AcO
AcO
1'
3'
1
2
OR2
O
O
N
O
O
N
Bn
Bn
15
16
4. Experimental
OR1 OBn
OR2
OR1 OBn
OR2
4.1. General information
N
N
Bn
Bn
All commercially available starting materials and reagents
(Fluka, Merck, Across or Aldrich) were used without further
purification. Solvents were dried before use. Thin layer chro-
matography (TLC, ALUGRAM Sil G/UV254 Macherey-Na-
gel) was used for the monitoring of reaction courses; eluents
are given in the text. For column chromatography the flash
chromatography technique was employed using silica 60
17
18
R1=R2=CMe2
Scheme 4.
thymine, N-acetylcytosine, and guanine at room temperature
in methylene chloride in the presence of trimethylsilyltriflate
as catalyst, afforded the b-anomeric nucleosides 19 with the
best diastereoselectivities in this series, i.e., uracil and acetyl-
ated cytosine reacted with 90% diastereomeric excess (19a/
20a ratio 95:5, 19b/20b ratio 80:20, 19d/20d ratio 94:6, 19e/
20e ratio 63:37, Scheme 5).
1
(0.040e0.063 mm, Merck). The H and 13C NMR spectra of
deuterochloroform solutions were obtained using Varian IN-
OVA-600 (600 MHz) and VXR-300 (300 MHz) instruments,
tetramethylsilane (TMS) being the internal reference. Specific
rotations [a] were measured on an IBZ Messtechnik Polar-
LmP polarimeter at the sodium D line (589 nm) using a 1 dm
cell. Elemental analyses were conducted using the Fisons EA
1108 Analyser. MS and HRMS analyses were performed on Var-
ian Ionspec QFT-7 (ESI-FT ICRMS), Bruker, Esquire 3000plus
(ESI-IT-MS) and Shimadzu, AXIMA TOF (MALDI-TOF/
RTOF-MS).
3. Conclusion
In conclusion, the synthesis of isoxazolidinyl nucleosides
as potential antiviral agents is reported. The condensation of
the acetoxyisoxazolidines 5, 8, and 15 with silylated uracil,
thymine, cytosine, N-acetylcytosine, and guanine proceeded
with good yields and from moderate to good stereoselectivity
in the formation of the expected isoxazolidinyl b- and a-nucleo-
sides. Thestereoselectivityoftheadditionofthesilylatednucleo-
base is dependent on the structure of the substituent at C-3
originating from the starting chiral nitrone. Moreover, in the
4.2. Method A: general procedure for reactions between
nucleobases and isoxazolidines 5 and 8
A suspension of the nucleobase (0.58 mmol) in dry aceto-
nitrile (2 mL) was treated with bis(trimethylsilyl)acetamide
(2.32 mmol) and heated at 70 ꢀC for 15 min under stirring.
OR1 OBn
4
3
4'
2'
5
-anti-cis
OTBDPS
B
1'
3'
1
OR1 OBn
2
19
OR2
O
N
OTBDPS
AcO
Bn
BSA, nucleobase
Me3SiOTf, CH2Cl2
r.t.
OR2
O
N
Bn
OR1 OBn
OR2
anti-trans
-anti-cis
OTBDPS
B
15
20
O
N
R1=R2=CMe2
Bn
O
O
NHAc
N
O
N
HN
HN
HN
AcHN
N
H
O
N
H
O
N
H
O
N
H
N
a
b
d
e
Scheme 5.

E. Hy´rosˇova´ et al. / Tetrahedron 64 (2008) 3111e3118
3115
Isoxazolidine 519 or 819 (0.48 mmol) in dry acetonitrile (2 mL)
and TMSOTf (0.72 mmol) were added to the obtained clear so-
lution. The reaction mixture was stirred at 70 ꢀC for 2 h. After
cooling at 0 ꢀC, the solution was neutralized byaddition of aque-
ous 5% sodium bicarbonate and then concentrated in vacuo. Af-
ter addition of methylene chloride (8 mL), the organicphasewas
separated, washed with water, dried over sodium sulfate, fil-
tered, and evaporated to dryness. The residue was purified by
column chromatography using ethyl acetate/hexanes (60:40).
H-arom), 7.96 (1H, d, J¼8.1 Hz, H-600), 8.54 (1H, br s, NH);
13C NMR: d 19.07 (OSiC(CH3)3), 26.63 (C(CH3)2), 26.65
(OSiC(CH3)3), 26.87 (C(CH3)2), 37.04 (C-4), 61.39 (NCH2Ph),
62.78 (C-40), 65.21 (C-3), 71.63 (C-30), 73.98 (C-10), 77.33
(C-20), 82.78 (C-5), 101.49 (C-500), 109.89 (C(CH3)2),
127.69e135.86 (C-arom), 141.48 (C-600), 150.46 (CO), 163.17
(CO), 165.98 (CO); IR (KBr): 3194, 3069, 2932, 2858, 1711,
1688, 1270, 1112, 708 cmꢁ1. Anal. Calcd for C44H49N3O8Si
(775.96): C, 68.11; H, 6.36; N, 5.42. Found: C, 68.37; H, 6.41;
N, 5.65.
4.2.1. 1-[(3S,5R)-2-Benzyl-3-(1,2:3,4-di-O-isopropylidene-
D-xylo)isoxazolidine-5-yl]-1H-pyrimidine-2,4-dione 6a9
Yield 34%, colorless crystals; mp 187e189 ꢀC; Rf (hexanes/
EtOAc, 60:40) 0.29; [a]D ꢁ52.7 (c 0.12, MeOH); H NMR:
4.2.4. 1-[(3S,5R)-2-Benzyl-3-(1,2-O-isopropylidene-3-O-
benzoyl-4-O-tert-butyldiphenylsilyl-D-xylo)isoxazolidine-
5-yl]-5-methyl-1H-pyrimidine-2,4(1H,3H)-dione 9b
Yield 42%, colorless solid; mp 75e76 ꢀC; Rf (hexanes/
1
d 1.32, 1.34, 1.36, 1.39 (4ꢂ3H, s, CH3), 2.57 (1H, ddd,
J¼10.6, 3.2, 7.3 Hz, H-4a), 2.89 (1H, m, H-4b), 3.24 (1H, m,
H-3), 3.66 (2H, m, H-20, H-4a0), 4.02 (1H, d, J¼14.1 Hz,
NCH2Ph), 4.10 (3H, m, H-4b0, H-10, H-30), 4.24 (1H, d,
J¼14.1 Hz, NCH2Ph), 5.68 (1H, dd, J¼8.2, 1.8 Hz, H-500),
6.25 (1H, dd, J¼2.9, 7.6 Hz, H-5), 7.35 (5H, m, H-arom), 7.95
(1H, d, J¼8.2 Hz, H-600), 8.65 (1H, br s, NH); 13C NMR:
d 23.37, 25.44, 26.02, 26.79 (C(CH3)2), 36.76 (C-4), 61.01
(NCH2Ph), 64.74 (C-3), 65.50 (C-40), 74.23, 74.52 (C-10,
C-30), 78.07 (C-20), 82.75 (C-5), 101.68 (C-500), 109.73
(C(CH3)2), 127.88e135.42 (C-arom), 141.30 (C-600), 150.66
(CO), 163.60 (CO). Anal. Calcd for C24H31N3O7 (473.52): C,
60.88; H, 6.60; N, 8.87. Found: C, 61.22; H, 6.39; N, 8.56.
1
EtOAc, 50:50) 0.35; [a]D ꢁ53.8 (c 0.08, CH2Cl2); H NMR:
d 1.00 (9H, s, OSiC(CH3)3), 1.31, 1.36 (2ꢂ3H, s, C(CH3)3),
1.84 (3H, s, CH3), 2.57 (1H, ddd, J¼13.9, 3.1, 7.5 Hz,
H-4a), 2.87 (1H, m, H-4b), 3.23 (1H, m, H-3), 3.86 (1H, dd,
J¼8.8, 2.2 Hz, H-10), 3.92 (2H, m, H-40), 3.99 (1H, m,
H-20), 4.06 (1H, d, J¼13.2 Hz, NCH2Ph), 4.07 (1H, d, J¼
14.3 Hz, NCH2Ph), 5.31 (1H, m, H-30), 6.25 (1H, dd, J¼3.1,
7.4 Hz, H-5), 7.20e8.06 (20H, m, H-arom), 7.83 (1H, d,
J¼1.1 Hz, H-600), 8.64 (1H, br s, NH); 13C NMR: d 12.38
(CH3), 19.07 (OSiC(CH3)3), 26.66 (OSiC(CH3)3), 26.66
(C(CH3)2), 26.91 (C(CH3)2), 37.00 (C-4), 60.97 (NCH2Ph),
62.79 (C-40), 65.21 (C-3), 71.60 (C-30), 74.02 (C-10), 77.33
(C-20), 82.24 (C-5), 109.75 (C-500), 109.86 (C(CH3)2),
127.74e136.14 (C-arom), 137.53 (C-600), 150.58 (CO),
163.84 (CO), 165.98 (CO); IR (KBr): 3411, 3192, 3070,
2931, 2857, 1690, 1270, 1112, 703 cmꢁ1. Anal. Calcd for
C45H51N3O8Si (789.99): C, 68.42; H, 6.51; N, 5.32. Found:
C, 68.27; H, 6.86; N, 5.30.
4.2.2. 1-[(3S,5S)-2-Benzyl-3-(1,2:3,4-di-O-isopropylidene-
D-xylo)isoxazolidine-5-yl]-1H-pyrimidine-2,4-dione 7a
Yield 8%, colorless semisolid; Rf (CH2Cl2/MeOH, 97:3)
0.17; 1H NMR: d 1.26, 1.31, 1.35, 1.38 (4ꢂ3H, s, CH3),
2.56 (1H, ddd, J¼9.4, 2.9, 6.4 Hz, H-4a), 2.94 (1H, m,
H-4b), 3.24 (1H, m, H-3), 3.66 (2H, m, H-20, H-4a0), 4.01
(1H, d, J¼14.1 Hz, NCH2Ph), 4.14 (3H, m, H-4b0, H-10, H-
30), 4.22 (1H, d, J¼13.5 Hz, NCH2Ph), 5.68 (1H, d,
J¼8.2 Hz, H-500), 6.22 (1H, dd, J¼2.9, 7.6 Hz, H-5), 7.35
(5H, m, H-arom), 7.85 (1H, d, J¼8.2 Hz, H-600), 9.27 (1H,
br s, NH); 13C NMR: d 26.78, 26.99 (C(CH3)2), 37.21 (C-4),
61.55 (NCH2Ph), 64.34 (C-40), 64.70 (C-3), 69.70, 74.91 (C-
10, C-30), 80.06 (C-20), 83.37 (C-5), 101.71 (C-500), 109.88
(C(CH3)2), 128.02e135.51 (C-arom), 141.01 (C-600), 150.50
(CO), 163.36 (CO). Anal. Calcd for C24H31N3O7 (473.52):
C, 60.88; H, 6.60; N, 8.87. Found: C, 61.17; H, 6.31; N, 9.23.
4.2.5. 1-[(3S,5R)-2-Benzyl-3-(1,2-O-isopropylidene-3-O-
benzoyl-4-O-tert-butyldiphenylsilyl-D-xylo)isoxazolidine-
5-yl]-4-acetylaminopyrimidine-2-one 9d
Yield 63%, colorless solid; mp 93e94 ꢀC; Rf (hexanes/
1
EtOAc, 30:70) 0.17; [a]D ꢁ4.4 (c 0.16, CH2Cl2); H NMR:
d 1.00 (9H, s, OSiC(CH3)3), 1.24, 1.26 (2ꢂ3H, s, C(CH3)3),
2.22 (3H, s, OCOCH3), 2.60 (1H, ddd, J¼13.5, 2.3, 6.5 Hz,
H-4a), 2.99 (1H, m, H-4b), 3.27 (1H, m, H-3), 3.77 (1H, dd,
J¼8.5, 2.6 Hz, H-10), 3.90 (2H, m, H-40), 3.94 (1H, dd,
J¼8.8, 2.3 Hz, H-20), 3.99 (1H, d, J¼14.1 Hz, NCH2Ph), 4.10
(1H, d, J¼14.1 Hz, NCH2Ph), 5.33 (1H, m, H-30), 6.16 (1H,
dd, J¼1.8, 7.6 Hz, H-5), 7.20e8.05 (20H, m, H-arom), 7.28
(1H, d, J¼7.6 Hz, H-500), 8.14 (1H, d, J¼7.6 Hz, H-600), 9.85
(1H, br s, NH); 13C NMR: d 19.10 (OSiC(CH3)3), 24.86
(OCOCH3), 26.69 (OSiC(CH3)3), 26.87 (C(CH3)2), 37.94
(C-4), 61.84 (NCH2Ph), 62.91 (C-40), 65.36 (C-3), 71.75
(C-30), 74.28 (C-10), 77.40 (C-20), 85.12 (C-5), 95.70 (C-500),
109.84 (C(CH3)2), 127.72e136.08 (C-arom), 146.14 (C-600),
162.49 (CO), 166.05 (CO), 170.68 (CO); IR (KBr): 3233,
3071, 2959, 2932, 2858, 1721, 1664, 1492, 1271, 1112,
703 cmꢁ1. Anal. Calcd for C46H52N4O8Si (817.01): C, 67.62;
H, 6.42; N, 6.86. Found: C, 67.30; H, 6.66; N, 6.60.
4.2.3. 1-[(3S,5R)-2-Benzyl-3-(1,2-O-isopropylidene-3-O-
benzoyl-4-O-tert-butyldiphenylsilyl-D-xylo)isoxazolidine-
5-yl]-1H-pyrimidine-2,4-dione 9a
Yield 48%, colorless solid; mp 62e63 ꢀC; Rf (hexanes/
1
EtOAc, 50:50) 0.35; [a]D ꢁ45.0 (c 0.1, CH2Cl2); H NMR:
d 1.00 (9H, s, OSiC(CH3)3), 1.29, 1.34 (2ꢂ3H, s, C(CH3)3),
2.58 (1H, ddd, J¼13.9, 2.9, 7.0 Hz, H-4a), 2.87 (1H, m,
H-4b), 3.24 (1H, m, H-3), 3.81 (1H, dd, J¼8.8, 2.6 Hz, H-10),
3.91 (2H, m, H-40), 3.97 (1H, dd, J¼8.8, 2.6 Hz, H-20), 3.98
(1H, d, J¼13.9 Hz, NCH2Ph), 4.07 (1H, d, J¼14.3 Hz,
NCH2Ph), 5.31 (1H, m, H-30), 5.59 (1H, dd, J¼1.1, 8.1 Hz,
H-500), 6.24 (1H, dd, J¼2.9, 7.7 Hz, H-5), 7.20e8.06 (20H, m,

3116
E. Hy´rosˇova´ et al. / Tetrahedron 64 (2008) 3111e3118
4.2.6. 1-[(3S,5R)-2-Benzyl-3-(1,2-O-isopropylidene-3-O-
benzoyl-4-O-tert-butyldiphenylsilyl-D-xylo)isoxazolidine-
5-yl]-2-acetylguanine 9e
4.3. Preparation of nitrone 4c
4.3.1. (2,3-O-Isopropylidene-4-O-benzyl-5-O-tert-butyl-
diphenylsilyl-D-xylo)-diisopropyldithioacetal 13
Yield 22%, colorless solid; mp 102e103 ꢀC; Rf (hexanes/
1
EtOAc, 20:80) 0.17; H NMR: d 1.00 (9H, s, OSiC(CH3)3),
A solution of dithioacetal 1219 (7.78 g, 15.21 mmol) in THF
(32 mL) was added dropwise to a stirred solution of sodium hy-
dride in paraffin (0.61 g, 15.21 mmol) and THF (5 mL) at 0 ꢀC.
The mixture was stirred for 1 h and benzyl bromide (2.86 g,
2 mL, 16.6 mmol) was added at 0 ꢀC. Next the mixture was
stirred for 12 h at room temperature. Then water was added,
the organic layer was separated and extracted with ethyl acetate,
and dried over sodium sulfate. The solvent was evaporated and
the product was isolated by column chromatography (silica gel,
hexanes/EtOAc, 96:4). Compound 13 was obtained in 61%
yield as colorless oil; Rf (hexanes/EtOAc, 80:20) 0.53; [a]D
ꢁ34.8 (c 2.4, CH2Cl2); 1H NMR: d 1.07 (9H, s, OSiC(CH3)3),
1.22e1.28 (12H, m, SCH(CH3)2), 1.37, 1.43 (2ꢂ3H, s,
C(CH3)2), 3.09e3.24 (2H, m, SCH(CH3)2), 3.76e3.82 (1H,
m, H-3), 3.89e3.95 (3H, m, H-5a, H-5b, H-1), 4.34e4.40
(2H, m, H-2, H-4), 4.51 (1H, d, J¼11.6 Hz, OCH2Ph), 4.75
(1H, d, J¼11.6 Hz, OCH2Ph), 7.24e7.73 (15H, m, H-arom);
13C NMR: d 19.2 (OSiC(CH3)3), 23.2, 23.3, 23.4 (SCH(CH3)2),
26.9, 27.0, 27.3 (OSiC(CH3)3, C(CH3)2), 35.1, 35.4
(SCH(CH3)2), 50.8 (C-1), 63.8 (C-5), 73.4 (OCH2Ph), 78.5
(C-2), 78.6 (C-4), 79.6 (C-3), 109.6 (C(CH3)2), 127.4e138.5
(OSiPh2, OCH2Ph). Anal. Calcd for C37H52O4S2Si (653.02):
C, 68.05; H, 8.03. Found: C, 68.42; H, 8.31.
1.25, 1.28 (2ꢂ3H, s, C(CH3)3), 2.36 (3H, s, OCOCH3), 2.81
(1H, ddd, J¼13.9, 2.2, 7.0 Hz, H-4a), 3.02 (1H, m, H-4b),
3.27 (1H, m, H-3), 3.77 (1H, dd, J¼8.8, 2.2 Hz, H-10), 3.91
(2H, m, H-40), 3.96 (1H, dd, J¼8.8, 2.2 Hz, H-20), 4.08 (2H,
m, NCH2Ph), 5.29 (1H, m, H-30), 6.85 (1H, dd, J¼2.2,
8.1 Hz, H-5), 7.11e8.06 (20H, m, H-arom), 8.57 (1H, s,
H-800), 11.31 (1H, br s, NHAc), 12.32 (1H, br s, CONH);
13C NMR: d 19.06 (OSiC(CH3)3), 24.57 (OCOCH3), 26.53
(C(CH3)2), 26.66 (OSiC(CH3)3), 26.83 (C(CH3)2), 37.79
(C-4), 60.73 (NCH2Ph), 62.80 (C-40), 65.28 (C-3), 71.61
(C-30), 73.60 (C-10), 77.29 (C-20), 82.84 (C-5), 109.89
(C(CH3)2), 111.29 (C-500), 127.41e136.09 (C-arom), 143.01
(C-800), 147.98, 153.21, 156.24 (C-200, C-400, C-600), 165.98
(CO), 173.27 (CO); IR (KBr): 3133, 3070, 2932, 2857,
1718, 1686, 1269, 1252, 1112, 708 cmꢁ1. Anal. Calcd for
C47H52N6O8Si (857.04): C, 65.87; H, 6.12; N, 9.81. Found:
C, 65.59; H, 6.31; N, 10.12.
4.2.7. 1-[(3S,5R)-2-Benzyl-3-(1,2-O-isopropylidene-3-O-
benzoyl-4-O-tert-butyldiphenylsilyl-D-xylo)isoxazolidine-
5-yl]-5-fluoro-1H-pyrimidine-2,4(1H,3H)-dione 9f
Yield 6%, sticky yellow oil; 1H NMR: d 1.00 (9H, s,
OSiC(CH3)3), 1.29, 1.37 (2ꢂ3H, s, C(CH3)3), 2.57 (1H, ddd,
J¼13.9, 2.6, 7.3 Hz, H-4a), 2.87 (1H, m, H-4b), 3.23 (1H, m,
H-3), 3.82 (1H, dd, J¼8.8, 2.2 Hz, H-10), 3.93 (3H, m, H-40,
H-20), 4.01 (1H, d, J¼13.2 Hz, NCH2Ph), 4.05 (1H, d,
J¼13.9 Hz, NCH2Ph), 5.27 (1H, m, H-30), 6.24 (1H, m, H-5),
7.19e8.06 (20H, m, H-arom), 8.24 (1H, d, J¼7.3 Hz, H-600),
8.91 (1H, br s, NH); 13C NMR: d 19.08 (OSiC(CH3)3), 26.54
(C(CH3)2), 26.66 (OSiC(CH3)3), 26.78 (C(CH3)2), 36.56 (C-
4), 61.11 (NCH2Ph), 62.74 (C-40), 65.02 (C-3), 71.56 (C-30),
73.69 (C-10), 77.27 (C-20), 82.62 (C-5), 110.00 (C(CH3)2),
127.70e135.75 (C-arom), 141.49 (C-600), 149.14 (C-500),
156.76 (CO), 157.10 (CO), 166.04 (CO). Anal. Calcd for
C44H48FN3O8Si (793.95): C, 66.56; H, 6.09; N, 5.29. Found:
C, 66.92; H, 6.40; N, 5.42.
4.3.2. 2,3-O-Isopropylidene-4-O-benzyl-5-O-tert-butyl-
diphenylsilyl-aldehydo-D-xylose 14
To a vigorously stirred solution of dithioacetal 13 (0.340 g,
0.52 mmol) in acetone/water (10 mL, 9:1), mercury(II) oxide
(0.220 g, 1.03 mmol) and mercury(II) chloride (0.280 g,
1.03 mmol) were added. The contents of the flask were stirred
for 2 h under reflux. The resulting mixture was filtered through
CeliteÒ, washed with acetone and the solvent was removed on
a rotary evaporator. Chloroform (10 mL) was added, the pre-
cipitate was collected by filtration and filtrate was extracted
with 1 M aqueous potassium iodide (2ꢂ10 mL) followed by
water (10 mL). The organic layer was dried with sodium sul-
fate and solvent was evaporated under reduced pressure to give
the crude aldehyde as a pale-yellow oil (0.27 g), which was
used in the next reaction without further purification.
4.2.8. 2-Benzyl-3-(1,2-O-isopropylidene-3-O-benzyl-4-O-
tert-butyldiphenylsilyl-D-xylo-1-yl)-2,3-dihydroisoxazole 11
1
Sticky yellow oil; H NMR: d 1.00 (9H, s, OSiC(CH3)3),
4.3.3. (Z)-N-(1-Deoxy-2,3-O-isopropylidene-4-O-benzyl-5-
O-tert-butyldiphenylsilyl-D-xylo-1-ylidene)-benzylamine-
N-oxide 4c
1.43, 1.45 (2ꢂ3H, s, 2ꢂC(CH3)3), 3.87 (1H, dd, J¼8.1,
4.4 Hz, H-10), 3.90 (1H, m, H-4a0), 3.95 (1H, d, J¼13.9 Hz,
NCH2Ph), 3.99 (1H, m, H-4b0), 4.18 (1H, d, J¼13.2 Hz,
NCH2Ph), 4.23 (1H, m, H-3), 4.32 (1H, dd, J¼8.1,
2.2 Hz, H-20), 4.98 (1H, dd, J¼2.2 Hz, H-4), 5.53 (1H, m,
H-30), 6.50 (1H, dd, J¼2.2 Hz, H-5), 7.26e8.14 (20H, m, H-
arom); 13C NMR: d 19.06 (OSiC(CH3)3), 26.58 (OSiC(CH3)3),
27.03 (C(CH3)2), 27.26 (C(CH3)2), 63.37 (C-40), 63.96
(NCH2Ph), 69.99 (C-3), 73.13 (C-30), 76.08 (C-20), 78.01
(C-10), 95.57 (C-4), 109.41 (C(CH3)2), 127.44e136.56
(C-arom), 143.50 (C-5), 165.96 (CO). Exact mass calculated
for C40H45NO6Si: 663.3016. Found: 663.3012.
To a well-stirred solution of crude aldehyde 14 (4.09 g,
7.89 mmol) in methylene chloride (170 mL), anhydrous magne-
sium sulfate (4.37 g, 36.3 mmol) and N-benzylhydroxylamine
(972 mg, 7.89 mmol) were added. The reaction mixture was
stirred for 15 h at room temperature and the progress of the re-
action was monitored by TLC (hexanes/EtOAc, 70:30). After
the removal of magnesium sulfate by filtration, the solvent
was evaporated under reduced pressure. The nitrone 4c was iso-
lated in 93% yield as a colorless oil by column chromatography
(silica gel, hexanes/EtOAc, 80:20); Rf (hexanes/EtOAc, 70:30)

E. Hy´rosˇova´ et al. / Tetrahedron 64 (2008) 3111e3118
3117
1
0.23; [a]D þ9.6 (c 1.57, CH2Cl2); H NMR: d 1.03 (9H, s,
OSiC(CH3)3), 1.35, 1.39 (2ꢂ3H, s, C(CH3)2), 3.82 (2H, d,
J¼6.2 Hz, H-5), 3.91e3.97 (1H, ddd, J¼6.3, 2.2 Hz, H-4),
4.22 (1H, dd, J¼2.2, 7.5 Hz, H-3), 4.73 (1H, d, J¼11.7 Hz,
OCH2Ph), 4.79 (1H, d, J¼11.7 Hz, OCH2Ph), 4.88 (2H, s,
NCH2Ph), 5.35 (1H, t, J¼5.9 Hz, H-2), 6.81 (1H, d, J¼
5.7 Hz, H-1), 7.14e7.70 (20H, m, H-arom); 13C NMR: d 19.1
(OSiC(CH3)3), 26.5, 26.6 (C(CH3)2), 26.8 (OSiC(CH3)3), 63.8
(C-5), 69.5 (NCH2Ph), 72.1 (C-2), 73.8 (OCH2Ph), 78.7
(C-4), 79.7 (C-3), 110.4 (C(CH3)2), 127.2e133.4, 135.5,
135.6 (OSiPh2, NCH2Ph, OCH2Ph), 137.7 (C-1). Anal. Calcd
for C38H45NO5Si (623.85): C, 73.16; H, 7.27; N, 2.25. Found:
C, 73.53; H, 7.07; N, 2.64.
4.5.1. 1-[(3S,5R)-2-Benzyl-3-(1,2-O-isopropylidene-3-O-
benzyl-4-O-tert-butyldiphenylsilyl-D-xylo)isoxazolidine-
5-yl]-1H-pyrimidine-2,4-dione 19a
Yield 61%, sticky yellow oil; Rf (hexanes/EtOAc, 50:50)
1
0.37; [a]D ꢁ60.2 (c 1.95, CH2Cl2); H NMR: d 1.08 (9H, s,
OSiC(CH3)3), 1.31, 1.34 (2ꢂ3H, s, C(CH3)2), 2.47 (1H, ddd,
J¼3.1, 7.4, 13.4 Hz, H-4a), 2.79 (1H, m, H-4b), 3.04 (1H, m,
H-3), 3.48 (1H, m, H-30), 3.71 (1H, d, J¼14.0 Hz, NCH2Ph),
3.86 (4H, m, H-20, H-40, NCH2Ph), 4.01 (1H, m, H-10), 4.42
(1H, d, J¼12.0 Hz, OCH2Ph), 4.73 (1H, d, J¼12.0 Hz,
OCH2Ph), 5.59 (1H, d, J¼8.1 Hz, H-500), 6.26 (1H, dd, J¼2.9,
7.7 Hz, H-5), 7.21e7.45 (20H, m, H-arom), 7.91 (1H, d,
J¼8.2 Hz, H-600), 9.96 (1H, br s, NH); 13C NMR: d 19.0
(OSiC(CH3)3), 26.6 (OSiC(CH3)3), 26.7 (C(CH3)2), 26.8
(C(CH3)2), 36.6 (C-4), 61.0 (NCH2Ph), 63.0 (C-40), 65.6
(C-3), 72.6 (OCH2Ph), 73.9 (C-10), 77.3 (C-30), 78.1 (C-20),
82.3 (C-5), 101.6 (C-500), 109.4 (C(CH3)2), 127.5e137.8
(C-arom), 141.3 (C-600), 150.7 (CO), 163.7 (CO); IR (KBr):
3193, 3067, 2931, 2857, 1687, 1270, 1112, 701 cmꢁ1. Anal.
Calcd for C44H51N3O7Si (761.98): C, 69.36; H, 6.75; N, 5.51.
Found: C, 68.98; H, 7.09; N, 5.33.
4.4. 1,3-Dipolar cycloaddition of nitrone 4c with vinyl acetate
A mixture of nitrone 4c (4.347 g, 6.97 mmol) and vinyl
acetate (25 mL) was stirred for 24 h under reflux. When the
starting nitrone had been consumed (TLC), the solvent was
evaporated under vacuum and the mixture of diastereoisomers
in the ratio 83:10:7 in 85% yield was separated by column
chromatography (silica gel, hexanes/CH2Cl2, 90:10).
4.5.2. 1-[(3S,5R)-2-Benzyl-3-(1,2-O-isopropylidene-3-O-
benzyl-4-O-tert-butyldiphenylsilyl-D-xylo)isoxazolidine-
5-yl]-5-methyl-1H-pyrimidine-2,4(1H,3H)-dione 19b
Yield 64%, colorless solid; mp 46e48 ꢀC; Rf (hexanes/
4.4.1. (3S,5S)-5-Acetoxy-2-benzyl-3-(1,2-O-isopropylidene-
3-O-benzyl-4-O-tert-butyldiphenylsilyl-D-xylo-1-yl)-
isoxazolidine 15
Yield 74%, colorless oil; 1H NMR: d 1.07 (9H, s,
OSiC(CH3)3), 1.31, 1.38 (2ꢂ3H, s, C(CH3)2), 1.78 (3H, s,
OCOCH3), 2.51 (2H, m, H-4), 3.23 (1H, m, H-3), 3.70 (1H,
dd, J¼1.5, 7.9 Hz, H-20), 3.79 (1H, m, H-30), 3.88 (3H, m,
H-4, NCH2Ph), 4.00 (1H, d, J¼13.3 Hz, NCH2Ph), 4.30 (1H,
dd, J¼7.8 Hz, H-10), 4.70 (1H, d, J¼11.8 Hz, OCH2Ph), 4.89
(1H, d, J¼11.8 Hz, OCH2Ph), 6.44 (1H, dd, J¼3.3 Hz, H-5),
7.16e7.41, 7.66e7.73 (20H, m, H-arom); 13C NMR: d 19.1
(OSiC(CH3)3), 20.9 (OCOCH3), 26.6, 27.1 (C(CH3)2), 26.7
(OSiC(CH3)3), 36.8 (C-4), 62.7 (NCH2Ph), 64.5 (C-40), 65.0
(C-3), 73.6 (OCH2Ph), 74.8 (C-10), 78.3 (C-30), 79.8 (C-20),
96.4 (C-5), 108.9 (C(CH3)2), 127.2e133.3 (OSiPh2, NCH2Ph),
135.5e140.1 (OCH2Ph), 170.1 (CH3CO); IR (KBr): 2976,
2858, 2930, 1752, 1231, 1115, 701 cmꢁ1. Anal. Calcd for
C42H51NO7Si (709.94): C, 71.05; H, 7.24; N, 1.97. Found: C,
70.68; H, 7.03; N, 2.35.
EtOAc, 50:50) 0.37; [a]D ꢁ66.3 (c 0.75, CH2Cl2); H NMR:
1
d 1.07 (9H, s, OSiC(CH3)3), 1.32, 1.34 (2ꢂ3H, s, C(CH3)2),
1.83 (3H, s, CH3), 2.50 (1H, ddd, J¼3.5, 7.6, 13.6 Hz, H-4a),
2.77 (1H, m, H-4b), 3.02 (1H, m, H-3), 3.47 (1H, m, H-30),
3.70 (1H, d, J¼14.0 Hz, NCH2Ph), 3.85 (4H, m, H-20, H-40,
NCH2Ph), 4.04 (1H, dd, J¼2.1, 8.7 Hz, H-10), 4.41 (1H, d,
J¼12.0 Hz, OCH2Ph), 4.72 (1H, d, J¼12.0 Hz, OCH2Ph),
6.24 (1H, dd, J¼3.4, 7.9 Hz, H-5), 7.13e7.68 (20H, m,
H-arom), 7.78 (1H, d, J¼1.8 Hz, H-600), 9.02 (1H, br s, NH);
13C NMR:
d 12.3 (CH3), 19.1 (OSiC(CH3)3), 26.7
(OSiC(CH3)3), 26.8 (C(CH3)2), 27.0 (C(CH3)2), 36.4 (C-4),
60.8 (NCH2Ph), 63.2 (C-40), 65.6 (C-3), 72.9 (OCH2Ph), 74.1
(C-10), 77.1 (C-30), 78.3 (C-20), 82.2 (C-5), 109.5 (C-500), 109.9
(C(CH3)2), 127.6e137.4 (C-arom), 138.0 (C-600), 150.7 (CO),
164.3 (CO); IR (KBr): 3193, 3069, 2931, 2857, 1690, 1268,
1113, 701 cmꢁ1. Anal. Calcd for C45H53N3O7Si (776.00): C,
69.65; H, 6.88; N, 5.41. Found: C, 69.34; H, 7.22; N, 5.22.
4.5. Method B: general procedure for reactions between
nucleobases and isoxazolidines 8 and 15
4.5.3. 1-[(3S,5S)-2-Benzyl-3-(1,2-O-isopropylidene-3-O-
benzyl-4-O-tert-butyldiphenylsilyl-D-xylo)isoxazolidine-
5-yl]-5-methyl-1H-pyrimidine-2,4(1H,3H)-dione 20b
Yield 16%, sticky yellow oil; Rf (hexanes/EtOAc, 50:50)
A suspension of the nucleobase (0.58 mmol) in dry methyl-
ene chloride (3 mL) was treated with bis(trimethylsilyl)acet-
amide (2.32 mmol) and stirred for 20 min at reflux.
Isoxazolidine 8 or 15 (0.48 mmol) in dry methylene chloride
(3 mL) and TMSOTf (0.72 mmol) were added to the obtained
clear solution. The reaction mixture was stirred at room temper-
ature for 2 h. The solution was neutralized by the addition of
aqueous 5% sodium bicarbonate. The organic phase was sepa-
rated, washed with water, dried over sodium sulfate, filtered,
and evaporated to dryness. The residue was purified by column
chromatography using ethyl acetate/hexanes (60:40).
1
0.33; [a]D ꢁ38.4 (c 0.55, CH2Cl2); H NMR: d 1.06 (9H, s,
OSiC(CH3)3), 1.37, 1.40 (2ꢂ3H, s, C(CH3)2), 1.77 (3H, s,
CH3), 2.35 (1H, m, H-4a), 3.01 (1H, ddd, J¼3.8, 7.4, 13.4 Hz,
H-4b), 3.41 (1H, m, H-3), 3.60 (1H, m, H-30), 3.88 (4H, m,
H-20, H-40, NCH2Ph), 4.00 (1H, d, J¼13.8 Hz, NCH2Ph), 4.19
(1H, m, H-10), 4.47 (1H, d, J¼11.8 Hz, OCH2Ph), 4.75 (1H, d,
J¼11.9 Hz, OCH2Ph), 5.94 (1H, dd, J¼5.4, 6.9 Hz, H-5), 7.05
(1H, m, C-600), 7.23e7.69 (20H, m, H-arom), 9.01 (1H, s,
NH); 13C NMR: d 12.4 (CH3), 19.2 (OSiC(CH3)3), 26.7

3118
E. Hy´rosˇova´ et al. / Tetrahedron 64 (2008) 3111e3118
(OSiC(CH3)3), 26.8 (C(CH3)2), 27.2 (C(CH3)2), 36.6 (C-4),
60.7 (NCH2Ph), 63.5 (C-40), 64.4 (C-3), 73.1 (OCH2Ph), 74.0
(C-10), 77.7 (C-30), 78.5 (C-20), 85.1 (C-5), 109.8 (C-500), 110.1
(C(CH3)2), 127.7e136.1 (C-arom), 138.1 (C-600), 150.1 (CO),
164.0 (CO); IR (KBr): 3191, 3069, 2931, 2857, 1693, 1266,
1112, 701 cmꢁ1. Anal. Calcd for C45H53N3O7Si (776.00): C,
69.65; H, 6.88; N, 5.41. Found: C, 69.42; H, 7.11; N, 5.52.
part was facilitated by the support of Slovak National
Research (No. 2003SP200280203).
References and notes
1. Yokoyama, M.; Momotake, A. Synthesis 1999, 1541e1554.
2. Merino, P. Curr. Med. Chem. Anti-Infective Agents 2002, 1, 389e411.
3. Chiacchio, U.; Corsaro, A.; Gumina, G.; Rescifina, A.; Iannazzo, D.;
Piperno, A.; Romeo, G.; Romeo, R. J. Org. Chem. 1999, 64, 9321e9327.
4. Merino, P.; Del Alamo, E. M.; Santiago, F.; Merchan, F. L.; Simon, A.;
Tejero, T. Tetrahedron: Asymmetry 2000, 11, 1543e1554.
4.5.4. 1-[(3S,5R)-2-Benzyl-3-(1,2-O-isopropylidene-3-O-
benzyl-4-O-tert-butyldiphenylsilyl-D-xylo)isoxazolidine-
5-yl]-4-acetylaminopyrimidine-2-one 19d
Yield 69%, sticky yellow oil; 1H NMR: d 1.00 (9H, s,
OSiC(CH3)3), 1.16, 1.20 (2ꢂ3H, s, C(CH3)2), 2.15 (3H, s,
OCOCH3), 2.44 (1H, ddd, J¼13.4, 2.4, 6.9 Hz, H-4a), 2.84
(1H, m, H-4b), 3.00 (1H, m, H-3), 3.39 (1H, m, H-30), 3.63
(1H, d, J¼13.9 Hz, NCH2Ph), 3.77 (4H, m, H-20, H-40,
NCH2Ph), 3.89 (1H, m, H-10), 4.34 (1H, d, J¼12.0 Hz,
OCH2Ph), 4.65 (1H, d, J¼12.0 Hz, OCH2Ph), 6.07 (1H, dd,
J¼2.3, 7.2 Hz, H-5), 7.16e7.62 (21H, m, H-arom, H-500), 8.00
(1H, d, J¼7.5 Hz, H-600), 10.24 (1H, br s, NH); 13C NMR:
d 19.1 (OSiC(CH3)3), 24.7 (OCOCH3), 26.6, 26.8, 26.9
(OSiC(CH3)3, C(CH3)2), 37.8 (C-4), 61.5 (NCH2Ph), 63.0 (C-
40), 65.8 (C-3), 72.7 (OCH2Ph), 74.1 (C-10), 77.2 (C-30), 78.0
(C-20), 84.6 (C-5), 95.9 (C-500), 109.4 (C(CH3)2), 127.6e138.6
(C-arom), 145.7 (C-600), 155.4 (CO), 162.7 (C-400), 171.1
(CO); IR (KBr): 3069, 2958, 2931, 2857, 1717, 1240, 1112,
701 cmꢁ1. Anal. Calcd for C46H54N4O7Si (803.03): C, 68.80;
H, 6.78; N, 6.98. Found: C, 68.59; H, 6.99; N, 7.25.
5. Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Pieperno, A.; Procopio, A.;
Rescifina, A.; Romeo, G.; Romeo, R. Eur. J. Org. Chem. 2001, 1893e1898.
6. Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.; Pistara, V.;
Procopio, A.; Rescifina, A.; Romeo, G.; Romeo, R.; Siciliano, M. C. R.;
Valveri, E. ARKIVOC 2002, xi, 159e167.
7. Colacino, E.; Converso, A.; Ligueri, A.; Napoli, A.; Siciliano, C.;
Sindona, G. Tetrahedron 2001, 57, 8551e8557.
8. Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.; Pistara, V.;
Rescifina, A.; Romeo, R.; Valveri, V.; Mastino, A.; Romeo, G. J. Med.
Chem. 2003, 46, 3696e3702.
´
ˇ
´
´
9. Fischer, R.; Druckova, A.; Fisera, L.; Rybar, A.; Hametner, C.; Cyranski,
M. K. Synlett 2002, 1113e1117.
´
ˇ
´
´
ˇ
10. Fischer, R.; Hyrosova, E.; Druckova, A.; Fisera, L.; Hametner, C.;
´
Cyranski, M. K. Synlett 2003, 2364e2368.
´
ˇ
´
ˇ
´
11. Hyrosova, E.; Fisera, L.; Jame, R. M.-A.; Pronayova, N.; Medvecky, M.;
´
´
´ˇ
Koos, M. Chem. Heterocycl. Comp. 2007, 43, 10e17.
ˇ
12. Fisera, L. Heterocycles from Carbohydrate Precursors; El Ashry, E. S. H.,
Ed.; Springer: Berlin, Heidelberg, 2007; pp 287e324.
´
´
´
ˇ
ˇ
´
13. Kuban, J.; Blanarikova, I.; Fisera, L.; Jaroskova, L.; Fengler-Veith, M.;
´ˇ
´
Jager, V.; Kozısek, J.; Humpa, O.; Pronayova, N.; Langer, V. Tetrahedron
´
ꢀ
¨
1999, 55, 9501e9514.
´
ꢀ
ˇ
´
´
14. Kuban, J.; Kolarovic, A.; Fisera, L.; Jager, V.; Humpa, O.; Pronayova, N.;
¨
4.5.5. 1-[(3S,5R)-2-Benzyl-3-(1,2-O-isopropylidene-3-O-
benzyl-4-O-tert-butyldiphenylsilyl-D-xylo)isoxazolidine-
5-yl]-2-acetylguanine 19e
Ertl, P. Synlett 2001, 1862e1865.
´
ꢀ
ˇ
´
´
15. Kuban, J.; Kolarovic, A.; Fisera, L.; Jager, V.; Humpa, O.; Pronayova, N.
¨
Synlett 2001, 1866e1868.
´
´
´
ꢀ´
´
ˇ
´
16. Blanarikova-Hlobilova, I.; Kopanicakova, Z.; Fisera, L.; Cyranski, M. K.;
Yield15%, stickyyellow oil; Rf (EtOAc) 0.33;[a]D ꢁ107.6(c
0.23, CH2Cl2); 1H NMR: d 1.07 (9H, s, OSiC(CH3)3), 1.22 (6H,
s, C(CH3)2), 2.34 (3H, s, OCOCH3), 2.75 (1H, ddd, J¼1.8, 7.0,
13.5 Hz, H-4a), 2.93 (1H, m, H-4b), 3.04 (1H, m, H-3), 3.46 (1H,
m, H-30), 3.75 (1H, d, J¼14.2 Hz, NCH2Ph), 3.85 (4H, m, H-20,
H-40, NCH2Ph), 3.99 (1H, dd, J¼1.1, 8.6 Hz, H-10), 4.42 (1H, d,
J¼12.0 Hz, OCH2Ph), 4.72 (1H, d, J¼12.0 Hz, OCH2Ph), 6.81
(1H, dd, J¼1.6, 7.8 Hz, H-5), 7.20e7.69 (20H, m, H-arom), 8.55
(1H, s, H-800), 11.14 (1H, br s, NH), 12.28 (1H, br s, NHCO); 13C
NMR: d 19.1 (OSiC(CH3)3), 24.5 (OCOCH3), 26.7, 26.8, 26.9
(OSiC(CH3)3, C(CH3)2), 37.7 (C-4), 60.5 (NCH2Ph), 63.1
(C-40), 65.7 (C-3), 72.8 (OCH2Ph), 73.7 (C-10), 77.2 (C-30),
78.3 (C-20), 82.8 (C-5), 109.7 (C(CH3)2), 111.3 (C-500),
127.5e136.2 (C-arom), 143.1 (C-800), 147.8, 153.2, 156.2
(C-200, C-400, C-600), 173.1 (CO); IR (KBr): 3133, 3069, 2932,
2857, 1684, 1615, 1370, 1252, 1113, 701 cmꢁ1. Anal. Calcd
for C47H54N6O7Si (843.05): C, 66.96; H, 6.46; N, 9.97. Found:
C, 66.59; H, 6.73; N, 9.59.
´
Salanski, P.; Jurczak, J.; Pronayova, N. Tetrahedron 2003, 59, 3333e
´
3339.
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´
ꢀ
Heterocycles 2005, 65, 591e605.
ꢀ
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18. Dugovic, B.; Fisera, L.; Cyranski, M. K.; Hametner, C.; Pronayova, N.;
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Obranec, M. Helv. Chim. Acta 2005, 88, 1432e1443.
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ˇ
19. Fischer, R.; Druckova, A.; Fisera, L.; Hametner, C. ARKIVOC 2002, viii,
80e90.
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R. Tetrahedron: Asymmetry 2000, 11, 2045e2048.
23. Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.; Pistara, V.;
Rescifina, A.; Romeo, R.; Sindona, G.; Romeo, G. Tetrahedron: Asymmetry
2003, 14, 2717e2723.
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Rescifina, A.; Saglimbeni, M. Bioorg. Med. Chem. 2006, 14, 955e959.
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Acknowledgements
27. Aschwanden, P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000, 2, 2331e
2333.
The authors are grateful to the Slovak Grant Agency (No.
13549/06) and APVV (No. 20/000305). NMR experimental
28. Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F. L.; Merino, P.; Tejero,
T. Synth. Commun. 1994, 23, 2537e2550.