Diastereoselective synthesis of D-erythro- and D-threo-isoxazolidinyl nucleosides

Article abstract of DOI:10.1055/s-2008-1042942

The synthesis of isoxazolidinyl nucleosides based on the Vorbrueggen nucleosidation of 5-acetoxyisoxazolidines 5 and 9 is reported. The 1,3-dipolar cycloaddition of D-erythro-nitrone 4 with vinyl acetate proceeded with respectable anti-facial (84:16) and

Full text of DOI:10.1055/s-2008-1042942

PAPER
1233
Diastereoselective Synthesis of D-erythro- and D-threo-Isoxazolidinyl
Nucleosides
D
iastereoselecti
v
ve Synthesis
a
of Isoxazolidinyl
H
N
ucleosides ýrošová,a Lubor Fišera,*a Jozef Kožíšek,b Marek Froncb
a
Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovak
Republic
Fax +421(2)52968560; E-mail: lubor.fisera@stuba.sk
Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovak
Republic
b
Received 14 November 2007; revised 17 January 2008
Dedicated to Professor Volker Jäger on the occasion of his 65th birthday
have prepared the appropriate sugar-derived nitrone pos-
sessing structures suitable for building the pyrrolidine.4
The condensation of the acetoxyisoxazolidines prepared
from D-xylose and D-lyxose with silylated uracil, thym-
Abstract: The synthesis of isoxazolidinyl nucleosides based on the
Vorbrüggen nucleosidation of 5-acetoxyisoxazolidines 5 and 9 is
reported. The 1,3-dipolar cycloaddition of D-erythro-nitrone 4 with
vinyl acetate proceeded with respectable anti-facial (84:16) and
endo-facial (72:28) diastereoselectivity to give the diastereomeric ine, cytosine, N-acetylcytosine, and acetylguanine pro-
isoxazolidines 5–7. The reaction of D-threo-nitrone 8 with vinyl
acetate is more selective and proceeds with excellent anti-facial
preference producing only two diastereomers 9 and 10, although
four diastereomers are possible. The condensation of the acetoxy-
isoxazolidines 5 and 9 with silylated uracil, thymine, N-acetylcy-
tosine, N2-acetylguanine, and purines proceeded with moderate to
excellent stereoselectivity with formation of the expected isoxazo-
lidinyl b- and a-nucleosides. The stereoselectivity of the addition of
silylated nucleobase is depended on the structure of the substituent
at C3 originating from the starting chiral nitrone and on the attack-
ing nucleobase.
ceeded with good yields and moderate to good
stereoselectivity with formation of the isoxazolidinyl b-
and a-nucleosides.4c–e The stereoselectivity of the addi-
tion was depended on the structure of the substituent at C3
in the starting chiral nitrone. We have also found that the
cycloaddition of methyl acrylate with D-erythro-nitrones
4 and D-threo-nitrones 8 possessing the sterically de-
manding O-tert-butyldimethylsilyl group prepared from
D-glucose and D-galactose, respectively, proceeds with
excellent anti- and endo-facial selectivity.5b Continuing in
our efforts to utilize chiral 1,3-dipolar cycloadditions,4,5
we have now extended the 1,3-dipolar cycloaddition ap-
proach to the synthesis of novel 4¢-aza-2¢,3¢-dideoxyfura-
nosyl nucleosides 11–14 by reaction of readily available
chiral sugar D-erythrose and D-threose derived nitrones 4
and 8 to vinyl acetate with subsequent transformation of
the thus formed 5-acetoxyisoxazolidines (Figure 1).
Key words: nucleosides, isoxazolidines, cycloadditions, C-glyco-
syl nitrones, stereoselective synthesis
Nucleosides are generally defined as DNA or RNA sub-
units 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 modifications of
the base, sugar, and phosphane region. In particular, nu-
cleoside analogues in which the furanose ring has been re-
placed by different carbon or heterocyclic systems have
attracted special interest by virtue of their biological ac-
tion as antiviral and/or anticancer agents.2 Among them,
nucleosides 1 (B = uracil, thymine, cytosine, adenine)
possessing an isoxazolidinyl moiety (carbocyclic-2¢-oxo-
3¢-azanucleosides) are emerging as an interesting class of
dideoxynucleoside analogues with potential pharmaco-
logical activity.2 For the synthesis of modified isoxazolid-
inyl nucleosides 1, two strategies can be used. In
particular a one-step approach based on the 1,3-dipolar
cycloaddition of nitrones to vinyl nucleobases and a two-
step methodology based on the Vorbrüggen nucleosida-
tion of 5-acetoxyisoxazolidines.3 Recently, with the aim
of preparing some novel azanucleosides by the transfor-
mation of modified isoxazolidinyl nucleosides 2 and 3, we
OR1 OR3
OMe
O
OR4
B
R
B
B
O
O
N
O
N
O
N
OR2
O
Bn
Bn
Bn
1
2
3
a R1–R2 = R3–R4 = CMe2
b R1–R2 = CMe2,
R
3 = Bz, R4 = TBDPS
c R1–R2 = CMe2,
3 = Bn, R4 = TBDPS
R
Figure 1 Isoxazolidinyl nucleosides
D-erythro-Nitrone 4 reacted smoothly in refluxing vinyl
acetate over 20 hours to give a 56:28:16 mixture of dia-
stereomeric isoxazolidines 5–7 in 78% yield (Scheme 1).
The cycloaddition proceeded with very good anti-facial
(84:16) and endo-facial (72:28) diastereoselectivity and is
completely regioselective with only the sterically favored
5-substituted isoxazolidines being detected. It is worthy of
note that in this case the reaction, probably for steric rea-
SYNTHESIS 2008, No. 8, pp 1233–1240
x
x
.
x
x
.2
0
0
8
Advanced online publication: 18.03.2008
DOI: 10.1055/s-2008-1042942; Art ID: T17507SS
© Georg Thieme Verlag Stuttgart · New York

1234
E. Hýrošová et al.
PAPER
sons, proceeded with reversed diastereoselectivity as ex-
pected for an inverse demand cycloaddition reaction
where the corresponding 3,5-cis-adducts are the major
products.3,4 Purification by HPLC provided a first fraction
containing pure 6 and a second fraction containing a 93:7
mixture of isoxazolidines 5 and 6. The major compound 5
could be isolated by crystallization from hexane. The
trans-anti structure of 5 was established unambiguously
by X-ray diffraction studies (Figure 2).6 This allowed us
to propose the structures shown in Scheme 1 for diaste-
reomeric isoxazolidines 6 and 7. The 3,5-cis relative con-
figuration of 6 was confirmed by the observation of the
O
O
AcO
O
N
OTBDMS
OTBDMS
O
Bn
Bn
OAc
N
O
9
O
68% (9/10 = 84:16)
O
O
8
AcO
O
N
1
OTBDMS
NOEs in the 2D-NOESY H NMR spectra of this com-
Bn
pound. Such NOEs were not observed for 7, therefore, the
isolated isoxazolidine 7 possessed the trans-syn configu-
ration.
10
Scheme 2 Cycloaddition of D-threo-nitrone 8 with vinyl acetate
OTBDMS
O
O
were separated by preparative HPLC and completely
characterized. The relative configuration of the cycload-
ducts obtained was ascertained by conventional NMR
techniques including 2D NOESY, COSY, and HMBC ex-
periments. The structure of the minor trans-anti-isoxazo-
lidine 10 was established unambiguously by X-ray
diffraction studies (Figure 3).6 Based on our previous re-
sults from the 1,3-dipolar cycloaddition of sugar nitrones
bearing a protected hydroxy group in the a-position4,5 as
well as the fact that 1,3-dipolar cycloaddition of electron-
rich alkenes to chiral a-alkoxynitrones gave preferentially
anti-adducts3 and by comparison with the aforementioned
results of the cycloaddition of nitrone 4 with vinyl acetate,
we assigned a C1¢/C3 anti-relationship to major isomer 9,
resulting from dipolarophile attack from the less sterically
hindered si diastereotopic face of nitrone 8. Thus, the ob-
served excellent facial diastereoselectivity for the D-ga-
lactose-derived nitrone 8 is in contrast to the previously
results obtained for nitrone cycloaddition to vinyl ace-
tate.3,4
Bn
AcO
OAc
N
O
O
O
O
N
OTBDMS
78% (5/6/7 = 56:28:16)
Bn
5
4
O
O
O
O
AcO
AcO
O
N
OTBDMS
O
N
OTBDMS
Bn
Bn
6
7
Scheme 1 Cycloaddition of D-erythro-nitrone 4 with vinyl acetate
Next the major isoxazolidines 5 and 9 were coupled with
silylated nucleobases according to the Vorbrüggen meth-
od.8 Following extensive screening, the best reaction con-
ditions for the Vorbrüggen nucleosidation of acetoxy-
Figure 2 The molecular structure of 5, with the numbering scheme7
of the asymmetric unit; displacement ellipsoids are drawn at the 30%
probability level
On the other hand, the reaction of D-threo-nitrone 8 with
vinyl acetate proceeded diastereoselectively and gave
only two diastereomers 9 and 10 in a 84:16 ratio with 9,
which has the anti-cis structure, predominating although
four diastereomers are possible, showing now a prefer-
ence for exo-attack as expected for an inverse demand cy-
cloaddition reaction (Scheme 2).3,4 Moreover, in this case
excellent anti-diastereofacial induction was observed; the
corresponding syn-adducts were not detected in the reac-
tion mixture. Thus, the corresponding adducts 9 and 10
Figure 3 The molecular structure of 10, with the numbering
scheme7 of the asymmetric unit (one molecule from two indepen-
dent); displacement ellipsoids are drawn at the 30% probability level
Synthesis 2008, No. 8, 1233–1240 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of Isoxazolidinyl Nucleosides
1235
substituted isoxazolidines prepared from sugar-derived cytosine, the b-anomers 13 clearly predominate, while in
nitrones were found by us to be at room temperature in the case of N2-acetylguanine and purines a significant
dichloromethane. The nucleosidation of anti-trans-isox- amount of a-anomer 14 was obtained. This lower diaste-
azolidine 5 with silylated uracil, thymine, and N-acetylcy- reoselectivity is in contrast with the excellent diastereose-
tosine at room temperature in dichloromethane in the lectivity observed for 5, but these results are fully in
presence of trimethylsilyl triflate as catalyst, afforded the accord with the data obtained for the related Vorbrüggen
b-anomeric nucleosides 11a–c in moderate yields (65– nucleosidations.3,4,9 Purification by flash chromatography
66%), but with excellent diastereoselectivities (ratio 11a/ allowed the isolation not only of all b-nucleosides 13a–f,
12a = 92:8, 11b/12b = 90:10, 11c/12c = 94:6; Scheme 3), but also the three a-nucleosides 14b,e,f were obtained.
whereas the reaction with N2-acetylguanine gave a lower The assigned configuration is supported by NMR analy-
yield (36%) and the diastereoselectivity was only moder- sis.
ate (11d/12d = 69:31). The ratio of anomeric nucleosides
was determined from quantitative 13C NMR spectra, by
O
O
integration of the peaks from C4 and C5 of the isoxazo-
lidines. Purification by flash chromatography allowed the
isolation of pure nucleosides 11a–d; their assigned stereo-
chemistry is supported by NMR analysis. In fact, NOE
measurements performed on b-anomers 11a–d show a
positive NOE effect for protons H3 when irradiating H5
thus indicating a cis relationship between these protons.
B
O
N
OTBDMS
O
O
BSA, nucleobase,
TMSOTf, CH2Cl2, r.t.
Bn
13
AcO
O
N
OTBDMS
Bn
9
O
O
B
O
N
N
OTBDMS
O
O
Bn
14
B
4
3
5
O
NHAc
O
O
N
OTBDMS
BSA,
Bn
nucleobase,
TMSOTf,
O
O
HN
HN
11
CH2Cl2, r.t.
AcO
O
N
H
O
N
H
O
N
H
O
N
OTBDMS
a
b
c
Bn
91:9
73:27
87:13
O
O
5
Br
N
Cl
N
O
N
B
N
N
N
O
N
N
OTBDMS
N
HN
Bn
N
H
N
H
N
H
AcHN
12
d
f
e
52:48
66:34
70:30
O
N
O
NHAc
O
Scheme 4 Nucleosidation of anti-cis-isoxazolidine 9
N
HN
HN
N
HN
In conclusion, the synthesis of isoxazolidinyl nucleosides,
as potential antiviral agents, based on the Vorbrüggen nu-
cleosidation of the 5-acetoxyisoxazolidines 5 and 9 is re-
ported. The 1,3-dipolar cycloaddition of D-erythro-
nitrone 4 with vinyl acetate proceeded with respectable
anti-facial (84:16) and endo-facial (72:28) diastereoselec-
tivity to give the diastereomeric isoxazolidines 5–7. The
reaction of D-threo-nitrone 8 to vinyl acetate is more se-
lective and proceeds with an excellent anti-facial prefer-
ence producing only two diastereomers 9 and 10, although
four diastereomers are possible. The condensation of the
acetoxyisoxazolidines 5 and 9 with silylated uracil, thym-
ine, N-acetylcytosine, N2-acetylguanine, and purines pro-
ceeded with moderate to excellent stereoselectivity with
formation of the expected isoxazolidinyl b- and a-nucleo-
sides. The stereoselectivity of the addition of silylated nu-
cleobase, is depended on the structure of the substituent at
C3 originated from the starting chiral nitrone and on the
attacking nucleobase.
N
H
AcHN
O
N
H
O
N
O
N
H
H
a
92:8
b
c
94:6
d
90:10
69:31
Scheme 3 Nucleosidation of anti-trans-isoxazolidine 5
The Vorbrüggen nucleosidation of anti-cis-isoxazolidine
9 with silylated uracil, thymine, N-acetylcytosine, N2-
acetylguanine, and 6-chloro- and 6-bromopurine at room
temperature in dichloromethane in the presence of tri-
methylsilyl triflate as catalyst, proceeded with low (pu-
rines) to good (uracil, thymine, and N-acetylcytosine)
yields and from moderate to good stereoselectivity with
formation of the expected isoxazolidinyl b- and a-nucleo-
sides 13 and 14 (ratio 13a/14a = 91:9, 13b/14b = 73:27,
13c/14c = 87:13, 13d/14d = 52:48, 13e/14e = 70:30,
13f/14f = 66:34, Scheme 4). For uracil and N-acetyl-
Synthesis 2008, No. 8, 1233–1240 © Thieme Stuttgart · New York

1236
E. Hýrošová et al.
PAPER
(3R,5R)-5-Acetoxy-2-benzyl-3-[(2R,4S,5R)-5-(tert-butyldimeth-
ylsiloxy)-2-methyl-1,3-dioxan-4-yl]isoxazolidine (7)
Colorless solid; yield: 227 mg (18%); mp 77–79 °C.
All commercially available starting materials and reagents (Fluka,
Merck, Across or Aldrich) were used without further purification.
Solvents were dried before use. TLC (Alugram Sil G/UV254 Mach-
erey-Nagel) was used for monitoring of reaction courses; eluents
are given in the text. For column chromatography the flash chroma-
tography technique was employed using silica 60 (0.040–0.063
mm, Merck). The 1H and 13C NMR spectra of CDCl3 solns were ob-
tained using Varian Inova-600 (600 MHz), VXR-300 (300 MHz)
and Bruker AC 500 (500 MHz) instruments; TMS was the internal
reference. Specific rotations [a] were measured on an IBZ
Messtechnik Polar-LmP polarimeter at the Na D line (589 nm) using
a 1 dm cell. HPLC analyses were performed on preparative column
(diameter 32, length 237 mm) with nucleosil 50-5. Elemental anal-
yses were conducted using the Fisons EA 1108 Analysator. Ni-
trones 4 and 8 were prepared from the corresponding aldehydes by
the reaction with N-benzylhydroxylamine according to the proce-
dure already described.5a,b
1H NMR (600 MHz, CDCl3): d = 7.40–7.25 (m, 5 H, C6H5), 6.28
(dd, J = 2.5, 6.6 Hz, 1 H, H5), 4.62 (q, J = 4.9 Hz, 1 H, H2¢), 4.23
(d, J = 14.3 Hz, 1 H, NCH2C6H5), 4.00 (m, 1 H, H4b¢), 3.98 (d,
J = 14.3 Hz, 1 H, NCH2C6H5), 3.41 (m, 2 H, H6¢, H5¢), 3.29 (m, 1
H, H4a¢), 3.24 (m, 1 H, H3), 2.72 (ddd, J = 2.6, 8.8, 13.2 Hz, 1 H,
H4b), 2.52 (ddd, J = 6.8, 9.1, 13.5 Hz, 1 H, H4a), 2.07 (s, 3 H,
COCH3), 1.36 (d, J = 4.9 Hz, 3 H, CH3,), 0.87 [s, 9 H, OSiC(CH3)3],
0.05, 0.03 [2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 170.8 (CO), 135.7, 129.8,
128.1, 127.4 (C6H5), 98.8 (C2¢), 95.3 (C5), 77.9 (C6¢), 71.3 (C4¢),
64.5 (C5¢), 63.9 (C3), 60.7 (NCH2C6H5), 36.1 (C4), 25.6 [OS-
iC(CH3)3], 21.3 (COCH3), 20.4 (CHCH3), 17.8 [OSiC(CH3)3], –4.2,
–4.8 [OSi(CH3)2].
Anal. Calcd for C23H37NO6Si (451.6): C, 61.17; H, 8.26; N, 3.10.
Found: C, 61.20; H, 8.26; N 2.86.
1,3-Dipolar Cycloaddition of D-erythro-Nitrone 4 with Vinyl
Acetate; General Procedure
A mixture of the nitrone 4 (1.040 g, 2.85 mmol) and vinyl acetate
(25 mL) was stirred for 24 h under reflux. When starting nitrone had
been consumed (TLC), solvent was evaporated under vacuum to
give a 56:28:16 mixture of diastereomeric isoxazolidines 5–7 in
78% yield. The mixture of diastereomers was separated by prepar-
ative HPLC (hexane–EtOAc, 85:15).
1,3-Dipolar Cycloaddition of D-threo-Nitrone 8 with Vinyl Ace-
tate
A mixture of the nitrone 8 (1.706 g, 4.67 mmol) and vinyl acetate
(25 mL) was stirred for 24 h under reflux. When starting nitrone had
been consumed (TLC), solvent was evaporated under vacuum to
give 84:16 mixture of diastereomeric isoxazolidines 9 and 10 in
68% yield. The mixture of diastereomers was separated by prepar-
ative HPLC (hexane–EtOAc, 88:12).
(3S,5S)-5-Acetoxy-2-benzyl-3-[(2R,4S,5R)-5-(tert-butyldimeth-
ylsiloxy)-2-methyl-1,3-dioxan-4-yl]isoxazolidine (5)
Colorless solid; yield: 525 mg (41%); mp 91–93 °C.
(3R,5S)-5-Acetoxy-2-benzyl-3-[(2S,4R,5R)-5-(tert-butyldimeth-
ylsiloxy)-2-methyl-1,3-dioxan-4-yl]isoxazolidine (9)
Colorless oil; yield: 1.254g (59%).
1H NMR (600 MHz, CDCl3): d = 7.38–7.25 (m, 5 H, C6H5), 6.35 (d,
J = 4.9 Hz, 1 H, H5), 4.63 (q, J = 4.9 Hz, 1 H, H2¢), 4.27 (d, J = 12.9
Hz, 1 H, NCH2C6H5), 4.09 (d, J = 13.2 Hz, 1 H, NCH2C6H5), 3.96
(dd, J = 4.4, 10.7 Hz, 1 H, H4b¢), 3.64 (dd, J = 7.7 Hz, 1 H, H3),
3.39 (m, 2 H, H6¢, H5¢), 3.27 (m, 1 H, H4a¢), 2.84 (ddd, J = 5.2, 8.2,
13.4 Hz, 1 H, H4b), 2.32 (ddd, J = 1.4, 7.1, 12.9 Hz, 1 H, H4a), 2.05
(s, 3 H, COCH3), 1.32 (d, J = 4.9 Hz, 3 H, CH3), 0.82 [s, 9 H,
OSiC(CH3)3], 0.03, 0.02 [2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 169.9 (CO), 136.6, 129.4,
128.3, 127.5 (C6H5), 98.8 (C2¢), 98.3 (C5), 80.6 (C6¢), 71.1 (C4¢),
64.3 (NCH2Ph), 64.2 (C5¢), 62.4 (C3), 35.4 (C4), 25.8
[OSiC(CH3)3], 21.3 (COCH3), 20.4 (CHCH3), 17.7 [OSiC(CH3)3],
–4.3, –5.0 [OSi(CH3)2].
[a]D +81.3 (c 0.16, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 7.36–7.26 (m, 5 H, C6H5), 6.41 (d,
J = 5.8 Hz, 1 H, H5), 4.72 (q, J = 5.1 Hz, 1 H, H2¢), 4.11 (m, 1 H,
H4b¢), 4.08 (d, J = 14.1 Hz, 1 H, NCH2C6H5), 3.94 (m, 1 H, H5¢),
3.90 (d, J = 14.1 Hz, 1 H, NCH2C6H5), 3.76 (m, 1 H, H4a¢), 3.71 (m,
1 H, H6¢), 3.63 (m, 1 H, H3), 2.54 (dd, J = 1.3, 14.1 Hz, 1 H, H4b),
2.25 (ddd, J = 6.1, 8.1, 14.1 Hz, 1 H, H4a), 2.01 (s, 3 H, COCH3),
1.36 (d, J = 4.5 Hz, 3 H, CH3), 0.96 [s, 9 H, OSiC(CH3)3], 0.17, 0.11
[2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 169.8 (CO), 136.5, 129.3,
128.4, 127.6 (C6H5), 99.1 (C2¢), 97.2 (C5), 78.7 (C6¢), 71.3 (C4¢),
64.6 (C5¢), 63.1 (NCH2C6H5), 62.2 (C3), 35.8 (C4), 26.0 [OS-
iC(CH3)3], 21.3 (COCH3), 21.0 (CHCH3), 18.4 [OSiC(CH3)3], –3.8,
–3.9 [OSi(CH3)2].
Anal. Calcd for C23H37NO6Si (451.6): C, 61.17; H, 8.26; N, 3.10.
Found: C, 61.62; H, 8.27; N, 2.95.
(3S,5R)-5-Acetoxy-2-benzyl-3-[(2R,4S,5R)-5-(tert-butyldimeth-
ylsiloxy)-2-methyl-1,3-dioxan-4-yl]isoxazolidine (6)
Colorless solid; yield: 249 mg (19%); mp 112–114 °C.
Anal. Calcd for C23H37NO6Si (451.6): C, 61.17; H, 8.26; N, 3.10.
Found: C, 61.70; H, 8.27; N 3.02.
[a]D –21.3 (c 0.15, CH2Cl2).
(3R,5R)-5-Acetoxy-2-benzyl-3-[(2S,4R,5R)-5-(tert-butyldimeth-
ylsiloxy)-2-methyl-1,3-dioxan-4-yl]isoxazolidine (10)
Colorless solid; yield: 189 mg (9%); mp 59–60 °C.
1H NMR (600 MHz, CDCl3): d = 7.37–7.23 (m, 5 H, C6H5), 6.28 (d,
J = 4.1 Hz, 1 H, H5), 4.68 (q, J = 5.1 Hz, 1 H, H2¢), 4.27 (d, J = 13.7
Hz, 1 H, NCH2C6H5), 4.10 (d, J = 13.7 Hz, 1 H, NCH2C6H5), 4.07
(dd, J = 5.2, 11.0 Hz, 1 H, H4b¢), 3.78 (ddd, J = 5.1, 8.5, 9.8 Hz, 1
H, H5¢), 3.47 (m, 2 H, H6¢, H3), 3.37 (dd, J = 10.4 Hz, 1 H, H4a¢),
2.52 (m, 2 H, H4a,b), 2.05 (s, 3 H, COCH3), 1.34 (d, J = 4.9 Hz, 3
H, CH3,), 0.88 [s, 9 H, OSiC(CH3)3], 0.10, 0.09 [2 × s, 2 × 3 H,
OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 169.9 (CO), 137.7, 129.4,
128.2, 127.2 (C6H5), 98.8 (C2¢), 97.6 (C5), 84.0 (C6¢), 71.1 (C4¢),
65.7 (NCH2C6H5), 65.3 (C5¢), 64.0 (C3), 39.8 (C4), 25.8
[OSiC(CH3)3], 21.4 (COCH3), 20.4 (CHCH3), 17.9 [OSiC(CH3)3],
–3.7, –4.5 [OSi(CH3)2].
[a]D –23 (c 0.10, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 7.38–7.26 (m, 5 H, C6H5), 6.40
(dd, J = 2.6, 6.4 Hz, 1 H, H5), 4.70 (q, J = 5.1 Hz, 1 H, H2¢), 4.30
(d, J = 13.5 Hz, 1 H, NCH2C6H5), 4.06 (dd, J = 1.8, 12.3 Hz, 1 H,
H4b¢), 3.99 (d, J = 13.5 Hz, 1 H, NCH2C6H5), 3.87 (m, 1 H, H5¢),
3.75 (m, 1 H, H3), 3.72 (dd, J = 1.2, 12.3 Hz, 1 H, H4a¢), 3.41 (dd,
J = 1.3, 9.0 Hz, 1 H, H6¢), 2.87 (ddd, J = 3.9, 6.4, 10.3 Hz, 1 H,
H4b), 2.62 (ddd, J = 2.6, 7.7, 10.3 Hz, 1 H, H4a), 2.08 (s, 3 H,
COCH3), 1.35 (d, J = 5.1 Hz, 3 H, CH3,), 0.93 [s, 9 H, OSiC(CH3)3],
0.15, 0.08 [2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 169.7 (CO), 137.3, 128.6,
128.2, 127.2 (C6H5), 99.1 (C2¢), 98.9 (C5), 79.5 (C6¢), 71.1 (C4¢),
Anal. Calcd for C23H37NO6Si (451.6): C, 61.17; H, 8.26; N 3.10.
Found: C, 61.46; H, 8.24; N 3.00.
Synthesis 2008, No. 8, 1233–1240 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of Isoxazolidinyl Nucleosides
1237
64.6 (C5¢), 63.7 (C3), 63.3 (NCH2C6H5), 37.2 (C4), 25.8 [OS-
iC(CH3)3], 21.2 (COCH3), 20.8 (CHCH3), 18.2 [OSiC(CH3)3], –4.0,
–4.2 [OSi(CH3)2].
Anal. Calcd for C26H39N3O6Si (517.7): C, 60.32; H, 7.59; N, 8.12.
Found: C, 60.02; H, 7.66; N, 7.72.
4-(Acetylamino)-1-{(3S,5R)-2-benzyl-3-[(2R,4S,5R)-5-(tert-
butyldimethylsiloxy)-2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-
yl}pyrimidin-2(1H)-one (11c)
Anal. Calcd for C23H37NO6Si (451.6): C, 61.17; H, 8.26; N, 3.10.
Found: C, 61.44 H, 8.22; N 2.97.
According to the general procedure, the mixture from isoxazolidine
5 (0.22 mmol) and N-acetylcytosine (0.27 mmol) was purified by
column chromatography (silica gel, hexanes–EtOAc, 15:85) to give
11c (0.080 g, 66%) as a colorless solid; mp 49–50 °C.
Nucleosidation of Acetoxyisoxazolidines; General Procedure
A suspension of the corresponding nucleobase (0.58 mmol) in an-
hyd CH2Cl2 (3 mL) was treated with N,O-bis(trimethylsilyl)acet-
amide (2.32 mmol) and stirred for 20 min at reflux. Isoxazolidine 5
or 9 (0.48 mmol) in anhyd CH2Cl2 (3 mL) and TMSOTf (0.72
mmol) were added to the obtained clear soln. The mixture was
stirred at r.t. for 2 h. The soln was neutralized by addition of 5% aq
NaHCO3. The organic phase was separated, washed with H2O, dried
(Na2SO4), filtered, and evaporated to dryness. The residue was pu-
rified by column chromatography (silica gel).
[a]D –28.75 (c 0.08, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 10.12 (br s, 1 H, NH), 8.21 (d,
J = 7.3 Hz, 1 H, H6¢¢), 7.37–7.28 (m, 5 H, C6H5), 7.32 (d, J = 7.3
Hz, 1 H, H5¢¢), 6.16 (dd, J = 2.2, 7.3 Hz, 1 H, H5), 4.57 (q, J = 4.9
Hz, 1 H, H2¢), 4.19 (d, J = 13.2 Hz, 1 H, NCH2C6H5), 3.99 (d,
J = 13.9 Hz, 1 H, NCH2C6H5), 3.96 (dd, J = 4.8, 9.9 Hz, 1 H, H4a¢),
3.37 (m, 3 H, H5¢, H6¢, H3), 3.26 (m, 1 H, H4b¢), 2.89 (ddd, J = 7.3,
9.9, 13.6 Hz, 1 H, H4a), 2.72 (ddd, J = 2.2, 6.6, 13.6 Hz, 1 H, H4b),
2.25 (s, 3 H, COCH3), 1.13 (d, J = 5.1 Hz, 3 H, CH3,), 0.87 [s, 9 H,
OSiC(CH3)3], 0.06, 0.04 [2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 171.0 (CO), 162.5 (C4¢¢), 155.4
(CO), 146.6 (C6¢¢), 136.2–127.8 (C6H5), 98.5 (C2¢), 95.5 (C5¢¢),
85.1 (C5), 78.7 (C6¢), 71.1 (C4¢), 64.2 (C5¢), 64.1 (C3), 61.6
(NCH2C6H5), 36.8 (C4), 25.6 [OSiC(CH3)3], 24.8 (COCH3), 20.1
(CHCH3), 17.7 [OSiC(CH3)3], –4.2, –5.0 [OSi(CH3)2].
1-{(3S,5R)-2-Benzyl-3-[(2R,4S,5R)-5-(tert-butyldimethylsiloxy)-
2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-yl}pyrimidine-
2,4(1H,3H)-dione (11a)
According to the general procedure, the mixture from isoxazolidine
5 (0.34 mmol) and uracil (0.41 mmol) was purified by column chro-
matography (silica gel, hexanes–EtOAc, 50:50) to give 11a (0.112
g, 65%) as a colorless solid; mp 71–73 °C.
[a]D –107 (c 0.1, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 9.05 (br s, 1 H, NH), 8.10 (d,
J = 8.2 Hz, 1 H, H6¢¢), 7.34–7.28 (m, 5 H, C6H5), 6.27 (dd, J = 2.6,
7.9 Hz, 1 H, H5), 5.60 (dd, J = 1.8, 8.2 Hz, 1 H, H5¢¢), 4.62 (q,
J = 5.0 Hz, 1 H, H2¢), 4.16 (d, J = 13.5 Hz, 1 H, NCH2C6H5), 3.99
(m, 1 H, H4a¢), 3.98 (d, J = 14.1 Hz, 1 H, NCH2C6H5), 3.37 (m, 3
H, H5¢, H6¢, H3), 3.28 (m, 1 H, H4b¢), 2.80 (ddd, J = 7.6, 10.0, 13.5
Hz, 1 H, H4a), 2.70 (ddd, J = 2.9, 7.2, 13.5 Hz, 1 H, H4b), 1.26 (d,
J = 4.7 Hz, 3 H, CH3), 0.87 [s, 9 H, OSiC(CH3)3], 0.06, 0.05 [2 × s,
2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 163.6 (CO), 150.7 (CO), 142.3
(C6¢¢), 136.1–127.7 (C6H5), 101.0 (C5¢¢), 98.5 (C2¢), 82.8 (C5), 78.7
(C6¢), 71.1 (C4¢), 64.2 (C3), 64.1 (C5¢), 61.2 (NCH2C6H5), 36.0
(C4), 25.6 [OSiC(CH3)3], 20.2 (CHCH3), 17.7 [OSiC(CH3)3], –4.2,
–5.0 [OSi(CH3)2].
Anal. Calcd for C27H40N4O6Si (544.7): C, 59.53; H, 7.40; N, 10.29.
Found: C, 59.49; H, 7.74; N, 9.98.
N2-(Acetylamino)-1-{(3S,5R)-2-benzyl-3-[(2R,4S,5R)-5-(tert-
butyldimethylsiloxy)-2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-
yl}guanine (11d)
According to the general procedure, the mixture from isoxazolidine
5 (0.18 mmol) and N2-acetylguanine (0.22 mmol) was purified by
column chromatography (silica gel, CH2Cl2–MeOH, 97:3) to give
11d (0.032 g, 30%) as a colorless solid; mp 173–175 °C.
1H NMR (600 MHz, CDCl3): d = 12.31 (br s, 1 H, CONH), 11.22
(br s, 1 H, NHAc), 8.57 (s, 1 H, H8¢¢), 7.40–7.26 (m, 5 H, C6H5),
6.83 (dd, J = 2.9, 6.6 Hz, 1 H, H5), 4.60 (q, J = 4.8 Hz, 1 H, H2¢),
4.22 (d, J = 14.7 Hz, 1 H, NCH2C6H5), 4.02 (d, J = 13.9 Hz, 1 H,
NCH2C6H5), 3.98 (m, 1 H, H4a¢), 3.33 (m, 4 H, H5¢, H6¢, H3, H4b¢),
2.94 (m, 2 H, H4a,b), 2.37 (s, 3 H, COCH3), 1.23 (d, J = 5.1 Hz, 3
H, CH3), 0.89 [s, 9 H, OSiC(CH3)3], 0.08, 0.05 [2 × s, 2 × 3 H,
OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 173.1 (CO), 156.2, 153.3,
147.8, 143.3 (Cadenine), 136.3–127.5 (C6H5), 111.2 (Cadenine), 98.6
(C2¢), 83.1 (C5), 78.5 (C6¢), 71.2 (C4¢), 64.5 (C3), 64.2 (C5¢), 60.7
(NCH2C6H5), 37.3 (C4), 25.6 [OSiC(CH3)3], 24.6 (COCH3), 20.2
(CHCH3), 17.8 [OSiC(CH3)3], –4.1, –4.9 [OSi(CH3)2].
Anal. Calcd for C25H37N3O6Si (503.7): C, 59.62; H, 7.40; N, 8.34.
Found: C, 59.34; H, 7.62; N, 7.97.
1-{(3S,5R)-2-Benzyl-3-[(2R,4S,5R)-5-(tert-butyldimethylsiloxy)-
2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-yl}-5-methylpyrimi-
dine-2,4(1H,3H)-dione (11b)
According to the general procedure, the mixture from isoxazolidine
5 (0.40 mmol) and thymine (0.48 mmol) was purified by column
chromatography (silica gel, hexanes–EtOAc, 50:50) to give 11b
(0.145 g, 51%) as a colorless solid; mp 188–189 °C.
Anal. Calcd for C28H40N6O6Si (584.7): C, 57.51; H, 6.89; N, 14.37.
Found: C, 57.47; H, 7.28; N, 14.10.
[a]D –93.6 (c 0.11, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 9.03 (br s, 1 H, NH), 7.90 (s, 1 H,
H6¢¢), 7.35–7.28 (m, 5 H, C6H5), 6.28 (dd, J = 3.2, 7.9 Hz, 1 H, H5),
4.64 (q, J = 5.0 Hz, 1 H, H2¢), 4.18 (d, J = 14.1 Hz, 1 H,
NCH2C6H5), 4.01 (dd, J = 4.1, 11.1 Hz, 1 H, H4a¢), 3.97 (d, J = 14.1
Hz, 1 H, NCH2C6H5), 3.41 (m, 2 H, H5¢, H6¢), 3.35 (m, 1 H, H3),
3.30 (m, 1 H, H4b¢), 2.79 (ddd, J = 7.6, 9.4, 13.5 Hz, 1 H, H4a), 2.70
(ddd, J = 3.5, 7.6, 13.5 Hz, 1 H, H4b), 1.88 (s, 3 H, CH3), 1.29 (d,
J = 4.7 Hz, 3 H, CH3,), 0.87 [s, 9 H, OSiC(CH3)3], 0.06, 0.05 [2 × s,
2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 164.0 (CO), 150.7 (CO), 137.9
(C6¢¢), 136.3–127.6 (C6H5), 109.5 (C5¢¢), 98.6 (C2¢), 82.4 (C5), 78.8
(C6¢), 71.2 (C4¢), 64.3 (C3), 64.2 (C5¢), 60.9 (NCH2C6H5), 35.9
(C4), 25.6 [OSiC(CH3)3], 20.4 (CHCH3), 17.7 [OSiC(CH3)3], 12.4
(CH3), –4.1, –5.0 [OSi(CH3)2].
1-{(3R,5S)-2-Benzyl-3-[(2S,4R,5R)-5-(tert-butyldimethylsiloxy)-
2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-yl}pyrimidine-
2,4(1H,3H)-dione (13a)
According to the general procedure, the mixture from isoxazolidine
9 (0.55 mmol) and uracil (0.67 mmol) was purified by column chro-
matography (silica gel, hexanes–EtOAc, 50:50) to give 13a (0.187
g, 67%) as a colorless solid; mp 44–45 °C.
[a]D +84 (c 0.1, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 10.03 (br s, 1 H, NH), 8.06 (d,
J = 8.2 Hz, 1 H, H6¢¢), 7.33–7.31 (m, 5 H, C6H5), 6.31 (dd, J = 3.5,
7.0 Hz, 1 H, H5), 5.63 (d, J = 8.2 Hz, 1 H, H5¢¢), 4.68 (q, J = 5.0 Hz,
1 H, H2¢), 4.13 (d, J = 14.1 Hz, 1 H, NCH2C6H5), 4.01 (d, J = 14.1
Hz, 1 H, NCH2C6H5), 3.98 (dd, J = 1.2, 12.3 Hz, 1 H, H4a¢), 3.72
Synthesis 2008, No. 8, 1233–1240 © Thieme Stuttgart · New York

1238
E. Hýrošová et al.
PAPER
4-(Acetylamino)-1-{(3R,5S)-2-benzyl-3-[(2S,4R,5R)-5-(tert-
(dd, J = 1.2, 12.3 Hz, 1 H, H4b¢), 3.60 (m, 1 H, H5¢), 3.52 (m, 1 H,
H6¢), 3.11 (m, 1 H, H3), 2.94–2.80 (m, 2 H, H4a,b), 1.30 (d, J = 4.7
Hz, 3 H, CH3), 0.92 [s, 9 H, OSiC(CH3)3], 0.10, 0.08 [2 × s, 2 × 3
H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 163.9 (CO), 150.8 (CO), 141.9
(C6¢¢), 136.2, 128.5, 128.3, 127.5 (C6H5), 101.0 (C5¢¢), 98.6 (C2¢),
82.8 (C5), 77.6 (C6¢), 71.3 (C4¢), 66.6 (C3), 65.8 (C5¢), 61.6
(NCH2C6H5), 37.1 (C4), 25.7 [OSiC(CH3)3], 20.6 (CHCH3), 18.0
[OSiC(CH3)3], –4.4, –4.6 [OSi(CH3)2].
butyldimethylsiloxy)-2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-
yl}pyrimidin-2-one (13c) and 4-(Acetylamino)-1-{(3R,5R)-2-
benzyl-3-[(2S,4R,5R)-5-(tert-butyldimethylsiloxy)-2-methyl-
1,3-dioxan-4-yl]isoxazolidin-5-yl}pyrimidin-2-one (14c)
According to the general procedure, the mixture from isoxazolidine
9 (0.43 mmol) and N-acetylcytosine (0.53 mmol) was purified by
column chromatography (silica gel, hexanes–EtOAc, 20:80) to give
13c (0.150 g, 50%) as a colorless solid; mp 79–80 °C and 14c (0.028
g, 9%) as a colorless solid; mp 219–220 °C.
Anal. Calcd for C25H37N3O6Si (503.7): C, 59.62; H, 7.40; N, 8.34.
Found: C, 59.40; H, 7.71; N 7.89.
13c
[a]D +18 (c 0.1, CH2Cl2).
1-{(3R,5S)-2-Benzyl-3-[(2S,4R,5R)-5-(tert-butyldimethylsiloxy)-
2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-yl}-5-methylpyrimi-
dine-2,4(1H,3H)-dione (13b) and 1-{(3R,5R)-2-Benzyl-3-
[(2S,4R,5R)-5-(tert-butyldimethylsiloxy)-2-methyl-1,3-dioxan-
4-yl]isoxazolidin-5-yl}-5-methylpyrimidine-2,4(1H,3H)-dione
(14b)
According to the general procedure, the mixture from isoxazolidine
9 (0.55 mmol) and thymine (0.067 mmol) was purified by column
chromatography (silica gel, hexanes–EtOAc, 50:50) to give 13b
(0.145 g, 51%) as a colorless solid; mp 62–63 °C and 14b (0.066 g,
23%) as a colorless solid; mp 152–153 °C.
1H NMR (600 MHz, CDCl3): d = 10.25 (br s, 1 H, NH), 8.14 (d,
J = 7.0 Hz, 1 H, H6¢¢), 7.37–7.29 (m, 5 H, C6H5), 7.32 (d, J = 7.0
Hz, 1 H, H5¢¢), 6.18 (dd, J = 1.8, 7.0 Hz, 1 H, H5), 4.61 (q, J = 4.9
Hz, 1 H, H2¢), 4.17 (d, J = 14.1 Hz, 1 H, NCH2C6H5), 4.04 (d,
J = 13.5 Hz, 1 H, NCH2C6H5), 3.98 (dd, J = 1.2, 12.6 Hz, 1 H,
H4a¢), 3.69 (dd, J = 1.2, 12.3 Hz, 1 H, H4a¢), 3.53 (m, 1 H, H5¢),
3.42 (dd, J = 1.2, 4.1 Hz, 1 H, H6¢), 3.22 (m, 1 H, H3), 2.99 (ddd,
J = 7.6, 10.0, 14.7 Hz, 1 H, H4a), 2.82 (ddd, J = 1.8, 5.3, 14.7 Hz, 1
H, H4b), 2.25 (s, 3 H, COCH3), 1.20 (d, J = 5.3 Hz, 3 H, CH3), 0.92
[s, 9 H, OSiC(CH3)3], 0.11, 0.08 [2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 171.1 (CO), 162.8 (C4¢¢), 155.2
(CO), 146.0 (C6¢¢), 136.5, 128.7, 128.6, 127.8 (C6H5), 98.9 (C2¢),
95.5 (C5¢¢), 85.4 (C5), 78.7 (C6¢), 71.3 (C4¢), 65.9 (C5¢), 65.7 (C3),
62.5 (NCH2C6H5), 38.8 (C4), 25.9 [OSiC(CH3)3], 24.8 (COCH3),
20.6 (CHCH3), 18.2 [OSiC(CH3)3], –4.2 [OSi(CH3)2].
13b
[a]D +85 (c 0.1, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 9.75 (br s, 1 H, NH), 7.76 (d,
J = 1.2 Hz, 1 H, H6¢¢), 7.34–7.28 (m, 5 H, C6H5), 6.32 (dd, J = 3.5,
7.6 Hz, 1 H, H5), 4.70 (q, J = 5.0 Hz, 1 H, H2¢), 4.13 (d, J = 14.1
Hz, 1 H, NCH2C6H5), 4.00 (d, J = 14.1 Hz, 1 H, NCH2C6H5), 3.98
(m, 1 H, H4a¢), 3.75 (m, 1 H, H4b¢), 3.63 (m, 1 H, H5¢), 3.56 (m, 1
H, H6¢), 3.14 (ddd, J = 3.5, 6.7, 9.4 Hz, 1 H, H3), 2.94–2.75 (m, 2
H, H4a,b), 1.89 (d, J = 1.2 Hz, 3 H, CH3), 1.34 (d, J = 5.3 Hz, 3 H,
CH3), 0.93 [s, 9 H, OSiC(CH3)3], 0.11, 0.08 [2 × s, 2 × 3 H,
OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 164.2 (CO), 150.9 (CO), 137.3
(C6¢¢), 136.5, 128.5, 128.3, 127.5 (C6H5), 109.6 (C5¢¢), 98.8 (C2¢),
82.5 (C5), 77.9 (C6¢), 71.4 (C4¢), 66.5 (C3), 65.8 (C5¢), 61.3
(NCH2C6H5), 37.0 (C4), 25.8 [OSiC(CH3)3], 20.8 (CHCH3), 18.0
[OSiC(CH3)3], 12.4 (CH3), –4.3, –4.4 [OSi(CH3)2].
Anal. Calcd for C27H40N4O6Si (544.7): C, 59.53; H, 7.40; N, 10.29.
Found: C, 59.10; H, 7.79; N, 9.83.
14c
1H NMR (600 MHz, CDCl3): d = 10.00 (br s, 1 H, NH), 7.68 (d,
J = 7.6 Hz, 1 H, H6¢¢), 7.42–7.31 (m, 5 H, C6H5), 7.26 (d, J = 7.6
Hz, 1 H, H5¢¢), 5.94 (dd, J = 6.3, 6.4 Hz, 1 H, H5), 4.76 (q, J = 5.1
Hz, 1 H, H2¢), 4.13 (d, J = 14.1 Hz, 1 H, NCH2C6H5), 4.03 (m, 2 H,
NCH2C6H5, H4a¢), 3.90 (m, 1 H, H5¢), 3.80 (m, 1 H, H4a¢), 3.71 (m,
1 H, H6¢, H3), 3.56 (ddd, J = 1.8, 7.0, 14.4 Hz, 1 H, H4a), 2.50 (m,
1 H, H4b), 2.26 (s, 3 H, COCH3), 1.37 (d, J = 4.7 Hz, 3 H, CH3),
0.90 [s, 9 H, OSiC(CH3)3], 0.13, 0.02 [2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 171.0 (CO), 162.9 (C4¢¢), 155.1
(CO), 144.1 (C6¢¢), 136.4, 128.7, 128.0, 127.9 (C6H5), 99.2 (C2¢),
95.9 (C5¢¢), 89.0 (C5), 77.6 (C6¢), 71.3 (C4¢), 64.8 (C5¢), 64.6 (C3),
61.7 (NCH2C6H5), 37.7 (C4), 25.8 [OSiC(CH3)3], 24.8 (COCH3),
20.9 (CHCH3), 18.2 [OSiC(CH3)3], –4.1, –4.3 [OSi(CH3)2].
Anal. Calcd for C26H39N3O6Si (517.7): C, 60.32; H, 7.59; N, 8.12.
Found: C, 59.85; H, 7.59; N, 7.79.
14b
[a]D +34.5 (c 0.1, CH2Cl2).
Anal. Calcd for C27H40N4O6Si (544.7): C, 59.53; H, 7.40; N, 10.29.
Found: C, 59.22; H, 7.66; N, 10.57.
1H NMR (600 MHz, CDCl3): d = 9.37 (br s, 1 H, NH), 7.40–7.30
(m, 5 H, C6H5), 7.06 (d, J = 1.2 Hz, 1 H, H6¢¢), 5.98 (dd, J = 6.8, 6.7
Hz, 1 H, H5), 4.77 (q, J = 5.0 Hz, 1 H, H2¢), 4.16 (d, J = 14.6 Hz, 1
H, NCH2C6H5), 4.08 (dd, J = 1.6, 12.1 Hz, 1 H, H4a¢), 4.07 (d,
J = 14.6 Hz, 1 H, NCH2C6H5), 3.85 (m, 1 H, H5¢), 3.80 (dd, J = 1.2,
12.4 Hz, 1 H, H4b¢), 3.70 (m, 2 H, H6¢, H3), 3.28 (ddd, J = 2.4, 7.1,
14.0 Hz, 1 H, H4a), 2.47 (m, 1 H, H4b), 1.76 (d, J = 1.0 Hz, 3 H,
CH3), 1.38 (d, J = 5.0 Hz, 3 H, CH3), 0.92 [s, 9 H, OSiC(CH3)3],
0.14, 0.05 [2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 164.0 (CO), 150.3 (CO), 136.4
(C6¢¢), 135.6, 128.6, 128.3, 127.7 (C6H5), 110.1 (C5¢¢), 99.1 (C2¢),
86.5 (C5), 77.5 (C6¢), 71.3 (C4¢), 64.9 (C5¢), 64.8 (C3), 61.4
(NCH2C6H5), 36.6 (C4), 25.8 [OSiC(CH3)3], 20.8 (CHCH3), 18.2
[OSiC(CH3)3], 12.3 (CH3), –4.1, –4.3 [OSi(CH3)2].
N2-Acetyl-1-{(3R,5S)-2-benzyl-3-[(2S,4R,5R)-5-(tert-butyldi-
methylsiloxy)-2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-yl}gua-
nine (13d)
According to the general procedure, the mixture from isoxazolidine
9 (0.66 mmol) and N2-acetylguanine (0.80 mmol) was purified by
column chromatography (silica gel, CH2Cl2–MeOH, 97:3) to give
13d (0.118 g, 31%) as a colorless solid; mp 117–118 °C.
[a]D +106.2 (c 0.08, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 12.36 (br s, 1 H, CONH), 11.56
(br s, 1 H, NHAc), 8.53 (s, 1 H, H8¢¢), 7.31–7.25 (m, 5 H, C6H5),
6.83 (dd, J = 1.2, 8.2 Hz, 1 H, H5), 4.65 (q, J = 5.0 Hz, 1 H, H2¢),
4.15 (d, J = 14.7 Hz, 1 H, NCH2C6H5), 4.08 (d, J = 14.1 Hz, 1 H,
NCH2C6H5), 3.98 (d, J = 12.3 Hz, 1 H, H4a¢), 3.71 (d, J = 12.3 Hz,
1 H, H4b¢), 3.59 (m, 1 H, H5¢), 3.55 (m, 1 H, H6¢), 3.16 (m, 1 H,
H3), 3.09 (ddd, J = 1.5, 5.6, 13.2 Hz, 1 H, H4a), 3.01 (m, 1 H, H4b),
2.17 (d, J = 1.2 Hz, 3 H, COCH3), 1.30 (d, J = 5.3 Hz, 3 H, CH3),
0.92 [s, 9 H, OSiC(CH3)3], 0.11, 0.09 [2 × s, 2 × 3 H, OSi(CH3)2].
Anal. Calcd for C26H39N3O6Si (517.7): C, 60.32; H, 7.59; N, 8.12.
Found: C, 59.99; H, 7.75; N, 8.31.
Synthesis 2008, No. 8, 1233–1240 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of Isoxazolidinyl Nucleosides
1239
13C NMR (125.5 MHz, CDCl3): d = 173.2 (CO), 156.4, 153.2,
147.9, 142.8 (Cadenine), 136.4–127.6 (C6H5), 111.4 (Cadenine), 98.8
(C2¢), 83.5 (C5), 77.7 (C6¢), 71.5 (C4¢), 66.8 (C3), 65.9 (C5¢), 61.3
(NCH2C6H5), 38.3 (C4), 25.8 [OSiC(CH3)3], 24.5 (COCH3), 20.7
(CHCH3), 18.1 [OSiC(CH3)3], –4.3, –4.4 [OSi(CH3)2].
umn chromatography (silica gel, hexanes–EtOAc, 50:50) to give
13f (0.118 g, 30%) as a colorless oil and 14f (0.063 g, 16%) as a col-
orless oil.
13f
[a]D +95 (c 0.1, CH2Cl2).
Anal. Calcd for C28H40N6O6Si (584.7): C, 57.51; H, 6.89; N, 14.37.
Found: C, 57.61; H, 7.12; N, 14.04.
1H NMR (600 MHz, CDCl3): d = 8.98 (s, 1 H, H2¢¢), 8.66 (s, 1 H,
H8¢¢), 7.30–7.25 (m, 5 H, C6H5), 6.56 (dd, J = 2.1, 8.0 Hz, 1 H, H5),
4.67 (q, J = 5.1 Hz, 1 H, H2¢), 4.19 (d, J = 14.1 Hz, 1 H,
NCH2C6H5), 4.09 (d, J = 14.1 Hz, 1 H, NCH2C6H5), 3.97 (dd,
J = 1.2, 12.3 Hz, 1 H, H4a¢), 3.72 (dd, J = 1.2, 12.3 Hz, 1 H, H4b¢),
3.69 (m, 1 H, H5¢), 3.53 (m, 1 H, H6¢), 3.23 (ddd, J = 1.8, 5.6, 7.3
Hz, 1 H, H3), 3.11 (ddd, J = 1.8, 9.4, 14.7 Hz, 1 H, H4a), 3.02 (m,
1 H, H4b), 1.32 (d, J = 5.3 Hz, 3 H, CH3), 0.92 [s, 9 H,
OSiC(CH3)3], 0.11, 0.10 [2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 151.5, 150.2 (C4¢¢, C6¢¢), 145.3
(C2¢¢), 142.4 (C8¢¢), 136.1, 128.4, 128.3, 127.5 (C6H5, C5¢¢), 98.7
(C2¢), 80.7 (C5), 76.7 (C6¢), 71.5 (C4¢), 67.4 (C3), 66.1 (C5¢), 60.9
(NCH2C6H5), 37.4 (C4), 25.7 [OSiC(CH3)3], 20.6 (CHCH3), 18.0
[OSiC(CH3)3], –4.3, –4.6 [OSi(CH3)2].
1-{(3R,5S)-2-Benzyl-3-[(2S,4R,5R)-5-(tert-butyldimethylsiloxy)-
2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-yl}-4-chloropurine
(13e) and 1-{(3R,5R)-2-Benzyl-3-[(2S,4R,5R)-5-(tert-butyldi-
methylsiloxy)-2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-yl}-4-
chloropurine (14e)
According to the general procedure, the mixture from isoxazolidine
9 (0.66 mmol) and 6-chloropurine (0.18 mmol) was purified by col-
umn chromatography (silica gel, hexanes–EtOAc, 50:50) to give
13e (0.100 g, 28%) as a colorless oil and 14e (0.046 g, 13%) as a
colorless oil.
13e
[a]D +103 (c 0.1, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 8.97 (s, 1 H, H2¢¢), 8.71 (s, 1 H,
H8¢¢), 7.30–7.25 (m, 5 H, C6H5), 6.57 (dd, J = 1.8, 7.6 Hz, 1 H, H5),
4.68 (q, J = 5.1 Hz, 1 H, H2¢), 4.19 (d, J = 14.1 Hz, 1 H,
NCH2C6H5), 4.09 (d, J = 14.1 Hz, 1 H, NCH2C6H5), 3.98 (dd,
J = 1.8, 12.3 Hz, 1 H, H4a¢), 3.72 (dd, J = 1.2, 12.3 Hz, 1 H, H4b¢),
3.69 (m, 1 H, H5¢), 3.53 (m, 1 H, H6¢), 3.24 (ddd, J = 2.1, 5.6, 7.6
Hz, 1 H, H3), 3.11 (ddd, J = 1.8, 9.7, 14.1 Hz, 1 H, H4a), 3.00 (m,
1 H, H4b), 1.33 (d, J = 5.3 Hz, 3 H, CH3), 0.92 [s, 9 H,
OSiC(CH3)3], 0.11, 0.10 [2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 151.8, 151.7 (C4¢¢, C6¢¢), 150.6
(C2¢¢), 145.7 (C8¢¢), 136.4, 128.6, 128.5, 127.8 (C6H5, C5¢¢), 99.0
(C2¢), 80.9 (C5), 77.7 (C6¢), 71.8 (C4¢), 67.7 (C3), 66.4 (C5¢), 61.2
(NCH2C6H5), 37.7 (C4), 26.0 [OSiC(CH3)3], 20.9 (CHCH3), 18.3
[OSiC(CH3)3], –4.1, –4.3 [OSi(CH3)2].
14f
[a]D +20 (c 0.1, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 8.73 (s, 1 H, H2¢¢), 8.17 (s, 1 H,
H8¢¢), 7.30–7.20 (m, 5 H, C6H5), 6.31 (dd, J = 6.6, 6.7 Hz, 1 H, H5),
4.80 (q, J = 5.1 Hz, 1 H, H2¢), 4.23 (d, J = 14.1 Hz, 1 H,
NCH2C6H5), 4.12 (d, J = 13.5 Hz, 1 H, NCH2C6H5), 4.09 (dd,
J = 1.2, 12.3 Hz, 1 H, H4a¢), 3.93 (m, 1 H, H3), 3.84 (m, 1 H, H5¢),
3.80 (dd, J = 1.8, 12.3 Hz, 1 H, H4b¢), 3.70 (d, J = 1.2, 7.0 Hz, 1 H,
H6¢), 3.37 (m, 2 H, H4a,b), 1.40 (d, J = 4.7 Hz, 3 H, CH3), 0.91 [s,
9 H, OSiC(CH3)3], 0.15, 0.05 [2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 151.8, 149.7 (C4¢¢, C6¢¢), 144.0
(C2¢¢), 143.3 (C8¢¢), 136.4, 128.5, 128.4, 127.7 (C6H5, C5¢¢), 99.2
(C2¢), 86.2 (C5), 78.5 (C6¢), 71.3 (C4¢), 65.2 (C3), 64.8 (C5¢), 62.4
(NCH2C6H5), 35.1 (C4), 25.8 [OSiC(CH3)3], 20.9 (CHCH3), 18.2
[OSiC(CH3)3], –4.1, –4.3 [OSi(CH3)2].
Anal. Calcd for C26H36ClN5O4Si (546.1): C, 57.18; H 6.64; N,
12.82; Found: C, 57.44; H, 7.06; N, 12.61.
Acknowledgment
14e
[a]D +24 (c 0.1, CH2Cl2).
The authors are grateful to the Slovak Grant Agency (No. 13549/06)
and APVV (No. 20/000305). NMR experimental part was facilita-
ted by the support of Slovak National Research (No
2003SP200280203). Research (No 2003SP200280203) as well as
the Structural Funds IIIA for the financial support in purchasing the
diffractometer. We are also grateful to Ms. C. Groneberg from FU
Berlin for her help with preparative HPLC.
1H NMR (600 MHz, CDCl3): d = 8.78 (s, 1 H, H2¢¢), 8.16 (s, 1 H,
H8¢¢), 7.30–7.21 (m, 5 H, C6H5), 6.32 (dd, J = 6.6, 6.7 Hz, 1 H, H5),
4.80 (q, J = 5.1 Hz, 1 H, H2¢), 4.23 (d, J = 14.1 Hz, 1 H,
NCH2C6H5,), 4.11 (d, J = 14.1 Hz, 1 H, NCH2C6H5), 4.10 (dd,
J = 1.2, 12.3 Hz, 1 H, H4a¢), 3.93 (m, 1 H, H3), 3.84 (m, 1 H, H5¢),
3.80 (m, 1 H, H4b¢), 3.70 (m, 1 H, H6¢), 3.38 (m, 2 H, H4a,b), 1.41
(d, J = 4.7 Hz, 3 H, CH3), 0.92 [s, 9 H, OSiC(CH3)3], 0.15, 0.06
[2 × s, 2 × 3 H, OSi(CH3)2].
13C NMR (125.5 MHz, CDCl3): d = 151.9, 151.3 (C4¢¢. C6¢¢), 151.0
(C2¢¢), 146.4 (C8¢¢), 132.4, 128.5, 128.4, 127.7 (C6H5, C5¢¢), 99.2
(C2¢), 86.2 (C5), 78.5 (C6¢), 71.3 (C4¢), 65.3 (C3), 64.9 (C5¢), 62.4
(NCH2C6H5), 35.1 (C4), 25.8 [OSiC(CH3)3], 20.9 (CHCH3), 18.2
[OSiC(CH3)3], –4.1, –4.3 [OSi(CH3)2].
References
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(3) (a) Chiacchio, U.; Corsaro, A.; Gumina, G.; Rescifina, A.;
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Anal. Calcd for C26H36ClN5O4Si (546.1): C, 57.18; H 6.64; N,
12.82; Found: C, 57.29; H, 6.87; N, 12.72.
1-{(3R,5S)-2-Benzyl-3-[(2S,4R,5R)-5-(tert-butyldimethylsiloxy)-
2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-yl}-4-bromopurine
(13f) and 1-{(3R,5R)-2-Benzyl-3-[(2S,4R,5R)-5-(tert-butyldi-
methylsiloxy)-2-methyl-1,3-dioxan-4-yl]isoxazolidin-5-yl}-4-
bromopurine (14f)
According to the general procedure, the mixture from isoxazolidine
9 (0.66 mmol) and 6-bromopurine (0.80 mmol) was purified by col-
Synthesis 2008, No. 8, 1233–1240 © Thieme Stuttgart · New York

1240
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PAPER
G.; Romeo, R.; Siciliano, M. C. R.; Valveri, E. ARKIVOC
2002, (xi), 159. (e) Colacino, E.; Converso, A.; Liguori, A.;
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(qmax = 29.58°) were performed on a Gemini R
diffractometer10 at 198 (1) K. Structure solution was done
busing direct methods11 and refinements were achieved by
full-matrix least-squares method11 on F**2. Further details
of the crystal structure investigation can be obtained from
the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK (CCDC deposition no.
667909).
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Crystal data of compound 10: C23H37NO6Si, M = 451.63,
orthorhombic, P212121, a = 11.724 (1)Å, 20.530 (2) Å,
20.887 (1) Å, V = 5027.5 (2) Å3, Z = 8, Dx = 1.193 mg m–3,
m (Mo-Ka) = 0.1246 mm–1, F(000) = 1952, colorless block,
0.186 × 0.237 × 0.723 mm–3, 120826 diffractions measured
(Rint = 0.043), 10249 unique, wR2 = 0.0904, conventional
R = 0.0360 on I values of 7674 diffractions with I > 2.0s(I),
(D/s)max = 0.001), S = 1.043 for all data and 561 parameters.
Unit cell determination and intensity data collection
(qmax = 26.37°) were performed on a Gemini R
diffractometer10 at 100 (1) K. Structure solution was done
busing direct methods11 and refinements were achieved by
full-matrix least-squares method11 on F**2. Further details
of the crystal structure investigation can be obtained from
the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK (CCDC deposition no.
667908).
(7) Brandenburg, K. DIAMOND, Visual Information System for
Crystal Structures, Bonn, Germany.
(8) Vorbrüggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber.
1981, 114, 1234.
(9) (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. J. Org.
Chem. 2000, 65, 5575. (b) Chiacchio, U.; Rescifina, A.;
Corsaro, A.; Pistará, V.; Romeo, G.; Romeo, R.
Tetrahedron: Asymmetry 2000, 11, 2045. (c) Chiacchio, U.;
Corsaro, A.; Iannazzo, D.; Piperno, A.; Pistará, V.;
Rescifina, A.; Romeo, R.; Sindona, G.; Romeo, G.
Tetrahedron: Asymmetry 2003, 14, 2717. (d)Chiacchio, U.;
Iannazzo, D.; Piperno, A.; Romeo, R.; Romeo, G.; Rescifina,
A.; Saglimbeni, M. Bioorg. Med. Chem. 2006, 14, 955.
(10) Oxford Diffraction (2007), CrysAlis CCD and CrysAlis
RED, Oxford Diffraction Ltd, Abingdon, Oxfordshire,
England.
(6) Crystal data of compound 5: C23H37NO6Si, M = 451.63,
orthorhombic, P212121, a = 9.764 (1) Å, 10.393 (1) Å,
25.479 (2) Å, V = 2585.6 (4) Å3, Z = 4, Dx = 1.160 mg m–3,
m (Mo-Ka) = 0.126 mm–1, F(000) = 976, colorless block,
0.104 × 0.146 × 0.782 mm–3, 65565 diffractions measured
(Rint = 0.067), 6751 unique, wR2 = 0.1545, conventional
R = 0.0483 on I values of 2882 diffractions with I > 2.0s(I),
(D/s)max = 0.001), S = 0.902 for all data and 280 parameters.
Unit cell determination and intensity data collection
(11) Sheldrick, G. M. SHELXS97 and SHEXL97, University of
Göttingen, Germany, 1997.
Synthesis 2008, No. 8, 1233–1240 © Thieme Stuttgart · New York