2′,3′-dideoxy- and 3′-azido-2′,3′-dideoxynucleosides of 5-phenyl-2(1H)-pyrimidinone. Preparation of 2′,3′-dideoxypentofuranoses

Article abstract of DOI:10.1135/cccc19960478

The synthesis of methyl 3-azido-5-benzoyl-2,3-dideoxy-β-D-ribofuranoside (10) from methyl 2-deoxy-D-ribofuranoside (1) and its use for the preparation of 3′-azido-2′,3′-dideoxy-β-D-ribofuranosides is described. Reaction of methylglucoside 1 with benzoyl c

Full text of DOI:10.1135/cccc19960478

478
Krecmerova, Hrebabecky, Masojidkova, Holy:
2′,3′-DIDEOXY- AND 3′-AZIDO-2′,3′-DIDEOXYNUCLEOSIDES
OF 5-PHENYL-2(1H)-PYRIMIDINONE. PREPARATION
OF 2′,3′-DIDEOXYPENTOFURANOSES
Marcela KRECMEROVA, Hubert HREBABECKY, Milena MASOJIDKOVA and Antonin HOLY
Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic
Received October 11, 1995
Accepted November 18, 1995
The synthesis of methyl 3-azido-5-benzoyl-2,3-dideoxy-β-D-ribofuranoside (10) from methyl 2-deoxy-D-ribo-
furanoside (1) and its use for the preparation of 3′-azido-2′,3′-dideoxy-β-D-ribofuranosides is de-
scribed. Reaction of methylglucoside 1 with benzoyl chloride in pyridine afforded 5-O-benzoyl
derivative 2, which on oxidation with complex of chromium trioxide, pyridine and acetic anhydride
afforded 3-keto derivative 3. This was reduced with sodium borohydride in ethanol to give a mixture
of methyl 2-deoxyglycosides of α-D-ribo- (4) and β-D-xylo- (5) configuration. Their mesyl derivatives 6
and 7 were chromatographically separated. Compound 7 reacted with sodium azide in hot dimethylform-
amide to afford methyl 3-azido-5-O-benzoyl-2,3-dideoxy-β-D-ribofuranoside (10). 5-Phenyl-2(1H)-
pyrimidinone was converted into silyl derivative 11 by treatment with hexamethyldisilazane.
Reaction of compound 11 with the azido sugar 10, catalyzed by trimethylsilyl trifluoromethanesulfo-
nate, and subsequent methanolysis, furnished a mixture of anomeric 3′-azido-2′,3′-dideoxynucleosides
14 and 15. Methyl 5-O-benzoyl-2,3-dideoxy-α-D-ribofuranoside (17) was prepared from methyl-α-
glycoside 4 by reaction with thionyl chloride and subsequent reduction of the obtained 3-chloro deri-
vative 16 with tributylstannane. Silyl derivative 11 reacted with 2,3-dideoxy sugar 17 under catalysis
with trimethylsilyl triflate to give mainly 1-(5-O-benzoyl-2,3-dideoxy-α-D-glycero-pentofuranosyl)-5-
phenyl-2(1H)-pyrimidinone (19) and minor amount of the β-anomer 18. Their methanolysis afforded
dideoxynucleosides 20 and 21.
Key words: Nucleosides; Pyrimidine; Sugar-modified; AZT analogs; Dideoxynucleosides; 5-Phenyl-
2(1H)-pyrimidinone.
This work represents a continuation of our preceding paper1 concerning the preparation
of nucleoside analogs derived from 5-phenyl-2(1H)-pyrimidinone. The reason for the
study of this system is its relation with the uracil and cytosine systems in which sub-
stitution with an aromatic group often leads to marked biological effects, especially
inhibition of uridine phosphorylase and thymidine phosphorylase.
In connection with the quest for compounds active against retroviruses, several
5-substituted pyrimidinone nucleosides containing 3′-azido-2′,3′-dideoxyribofuranose
sugar component have been described: derivatives with a halogen atom (bromine or
iodine) in position 5 (ref.2) and also the 5-methyl-2(1H)-pyrimidinone analog of AZT.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Preparation of 2’,3’-Dideoxypentofuranoses
479
The latter exhibited a very strong anti-HIV activity3, similar to that of the parent AZT.
The analog was synthesized from protected AZT by deoxygenation in position 4 via the
4-triazolyl and the 4-hydrazino derivative, which was then converted into the pyrimidi-
none analog by heating with silver oxide3,4
.
The paper on 5-halogeno substituted nucleosides with 3′-azido group2 describes their
synthesis by the nucleosidation reaction of the corresponding base with methyl 5-O-
acetyl-3-azido-2,3-dideoxy-D-ribofuranoside. This azido sugar was prepared in seven
steps from D-xylose according to the described procedures5–7. Apart from the low total
yield (8%), this synthesis has a drawback in that the sugar is obtained as a mixture of
anomers of the pyranose and furanose forms that are difficult to separate2.
In order to avoid such complications, we first worked out a relatively simple prepara-
tion of protected methyl 3-azido-2,3-dideoxy-β-D-ribofuranoside from methyl 2-deoxy-
D-ribofuranoside8 (1) (Scheme 1).
The starting methyl glycoside 1 was first quantitatively and selectively benzoylated
in position 5 with benzoyl chloride in pyridine. The obtained 5-O-benzoyl derivative 2
was oxidized with the chromium trioxide–pyridine–acetic anhydride complex to give
3-keto derivative 3 which was reduced with sodium borohydride in ethanol to a mixture
of methyl glycosides 4 a 5, the β-anomer 5 having the 2-deoxyxylo- and the α-anomer 4 the
2-deoxyribo-configuration. Although compounds 4 and 5 could not be separated by
chromatography, their respective mesyl derivatives 6 and 7 were separable. The indi-
vidual steps of the pathway 1–7 give high yields and, on a larger scale, the intermedi-
ates can be used without purification, the only one chromatography involved in the
preparation being used in the separation of compounds 6 and 7.
When performing this reaction sequence, we have repeatedly observed that the ratio
of the obtained 3-O-mesyl-2-deoxyribo to the 3-O-mesyl-2-deoxyxylo derivative (6 : 7), as
well as the ratio of the 2-deoxyribo to the 2-deoxyxylo derivative (4 : 5), determined by
NMR spectroscopy, corresponded to the α : β anomer ratio in the starting methyl 2-deoxy-
riboside 1. It follows that in the described oxidation–reduction reaction of the anomeric
benzoyl derivative 2 the configuration in position 3 is changed only in the β-anomer,
analogously to the same oxidation–reduction reaction of β-2′-deoxynucleosides9,
whereas the α-anomer of originally 2-deoxyribo-configuration gave again the α-2-
deoxyriboside. We have confirmed this assumption by carrying out the whole reaction
sequence starting from the anomerically pure methyl 5-O-benzoyl-2-deoxy-β-D-ribo-
furanoside (9) (Scheme 1). Since it was difficult to separate anomers of the starting
methylglycoside 1, we used its 3,5-bis(O-p-toluoyl) derivative 8 (ref.8), an easily ac-
cessible starting sugar for the synthesis of 2′-deoxynucleosides whose both anomers
can be well separated by chromatography. The protecting groups were removed by
methanolysis and the obtained methyl 2-deoxy-β-D-ribofuranoside was benzoylated
under the same conditions as the anomer mixture 1. Oxidation with chromium trioxide–
pyridine–acetic anhydride complex and subsequent reduction with sodium borohydride
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

480
Krecmerova, Hrebabecky, Masojidkova, Holy:
actually afforded methyl 5-O-benzoyl-2-deoxy-β-D-xylofuranoside (5) in high yield
(85%). Compound 5 was further mesylated to afford the above-mentioned 2-deoxy-3-
O-mesyl-β-D-xylo derivative 7. This on heating with sodium azide furnished the
desired methyl 3-azido-5-O-benzoyl-2,3-dideoxy-β-D-ribofuranoside (10) as the start-
ing sugar for the preparation of 3′-azido-3′-deoxynucleosides.
OCH
HO
BzO
BzO
TolO
BzO
BzO
3
O
O
OCH
3
OH
OTol
1
8
OCH
3
O
O
OCH
3
OH
OH
OH
2
9
OCH
BzO
+
3
O
O
4
O
OCH
3
OCH
3
OH
O
3
5
OCH
OCH
BzO
BzO
BzO
3
3
O
10
O
6
O
7
OMs
OCH
3
OMs
N
3
Bz, benzoyl
Ms, methanesulfonyl
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Preparation of 2’,3’-Dideoxypentofuranoses
481
For nucleosidation reactions with this synthon we have used 5-phenyl-2(1H)-pyri-
midinone which was silylated with hexamethyldisilazane in the presence of ammonium
sulfate. Reaction of the silylated base 11 with the azido sugar 10, catalyzed with tri-
methylsilyl trifluoromethanesulfonate in acetonitrile, gave in high yield a mixture of
anomeric 3′-azidonucleosides 12 and 13. Finally, removal of the benzoyl protecting
groups by treatment with methanolic ammonia gave free 3′-azido-2′,3′-dideoxy nucleo-
sides 14 and 15. It was advantageous to separate the anomers at the stage of free
nucleosides. Whereas the protected derivatives 12 and 13 were chromatographically
almost unseparable, the difference in chromatographic mobilities of the free β- and
α-anomers 14 and 15 was sufficient for the separation.
RO
O
N
O
N
N
O
RO
N3
O
N
N3
R
R
12 Bz
14
13 Bz
H
15
H
The deblocking of compounds 12 and 13 with methanolic ammonia was not accom-
panied with intramolecular cyclization to O2,5′-cyclo derivatives described for the pyri-
midone nucleosides, e.g. for the synthesis of 3′-azidonucleosides of 5-halogeno-2-pyrimi-
dones2 which were obtained not in the individual form but only as equilibrium mixtures
of the free nucleoside and its cyclic form.
As for 2′,3′-dideoxynucleosides, sugar synthons for the preparation of 2,3-dideoxy
sugars have been recently synthesized from L-glutamic acid10–13. In the present com-
munication we describe new synthesis of the starting sugar synthon from methyl 5-O-
benzoyl-2,3-dideoxy-D-ribofuranoside (17) that makes use of the above-described
5′-benzoylated methyl glycoside 4. This derivative was subjected to reaction with thio-
nyl chloride and the obtained 3-chloro derivative 16 was reduced with tributylstannane
to give dideoxy derivative 17 (Scheme 2). The compound 17 was pure α-anomer, how-
ever, for the described reaction sequence, as well as for the subsequent nucleosidation,
the configuration at the anomeric center was not substantial.
The nucleosidation reaction of silyl derivative 11 with the 2,3-dideoxy sugar 17 was
performed at 0 °C in acetonitrile under catalysis with trimethylsilyl triflate. In our case,
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

482
Krecmerova, Hrebabecky, Masojidkova, Holy:
the β-anomer 18 was obtained only in a low yield, the α-anomer 19 being the major
product. The anomers were separated on silica gel and deblocked with methanolic am-
monia to give dideoxynucleosides 21 and 20.
BzO
BzO
O
O
Cl
OCH3
OCH3
OH
N
16
4
BzO
O
OCH3
Me3SiO
N
11
17
SCHEME 2
1
The configuration and anomeric purity of the compounds was verified by H NMR
(decoupled) and 13C NMR spectra. The individual carbon atoms were assigned on the
basis of J-modulated spectra (APT), which permit discrimination of C, CH, CH2 and CH3
carbon atoms. The observed chemical shifts and coupling constants are given in the
Experimental and agree (allowing for the substitution effects) with the data publish-
ed14,15 for the anomeric pairs of 2-deoxyfuranosyl and 2,3-dideoxyfuranosyl derivatives.
RO
O
N
O
N
N
O
RO
O
N
R
R
18 Bz
20
19 Bz
H
21
H
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Preparation of 2’,3’-Dideoxypentofuranoses
483
None of the free 2′,3′-dideoxy and 3′-azido-2′,3′-dideoxynucleosides exhibited any cy-
tostatic effects16 on cell cultures L1210, HeLa and L929.
EXPERIMENTAL
Unless stated otherwise, the solutions were evaporated at 40 °C/2 kPa and the compounds were dried
over phosphorus pentoxide at 13 Pa. Thin-layer chromatography was performed on Silufol UV 254
foils (Kavalier, Czech Republic) in the systems S1, toluene–ethyl acetate 10 : 1; S2, toluene–ethyl
acetate 8 : 1; S3, toluene–ethyl acetate 3 : 2; S4, toluene–ethyl acetate 1 : 1; S5, ethyl acetate; S6,
ethyl acetate–acetone–ethanol–water 36 : 6 : 1 : 1. Spots were detected by UV light at 254 nm.
Preparative column chromatography was carried out on silica gel (30–60 µm, Service Laboratory of
the Institute). NMR spectra (δ, ppm; J, Hz) were measured on Varian UNITY 200 (1H at 200 MHz
and 13C at 50.3 MHz) or Varian UNITY 500 (1H at 500 MHz and 13C at 125.7 MHz) spectrometers
in hexadeuteriodimethyl sulfoxide. The chemical shifts of protons were referenced to tetramethyl-
silane as internal standard whereas those of the carbon atoms to the solvent signal (δ(CD3SOCD3) =
39.7 ppm). Mass spectra were obtained with a ZAB-EQ spectrometer (VG Analytical) using the FAB
method (Xe, 8 kV, glycerol (G) or thioglycerol (TG) as matrices).
Methyl 5-O-Benzoyl-2-deoxy-D-ribofuranoside (2)
Prior to the reaction, methyl 2-deoxy-D-ribofuranoside (1; 9.6 g, 65 mmol) was codistilled with py-
ridine (150 ml) and the residue was dissolved in dry pyridine (390 ml). A solution of benzoyl
chloride (8.3 ml, 71 mmol) in pyridine (390 ml) was added dropwise during 8 h with stirring and
cooling with ice. After addition of all the benzoyl chloride, the reaction mixture was stirred for an-
other 30 min at 0 °C, quenched with methanol (30 ml) and the solution was set aside at room tem-
perature overnight. The solvent was evaporated, the residue was codistilled with toluene and
partitioned between water and ethyl acetate (500 ml each). The organic phase was washed success-
ively with 1% hydrochloric acid to slightly acid reaction, water and saturated sodium hydrogen car-
bonate, dried over magnesium sulfate, and the solvent was evaporated. Yield 15.1 g (92%) of
yellowish sirup. The obtained chromatographically homogeneous benzoyl derivative 2 (RF 0.38, S4)
was used without purification in the next step.
Methyl 5-O-Benzoyl-2-deoxy-3-O-methanesulfonyl-α-D-ribofuranoside (6) and
Methyl 5-O-Benzoyl-2-deoxy-3-O- methanesulfonyl-β-D-xylofuranoside (7)
Chromium trioxide (14 g, 140 mmol) was added in portions to dry pyridine (110 ml) so as to keep the
reaction mixture only slightly warm. A solution of compound 2 (7.6 g, 30.1 mmol) in pyridine (20 ml)
was added to the resulting yellow-brown solution, the mixture was cooled with ice and acetic anhy-
dride (10.5 ml) was added dropwise. The reaction mixture was stirred at 0 °C for 10 min and at room
temperature for 10 min, diluted with ethyl acetate (1 l) and filtered through a layer (1 cm) of silica
gel. The filtrate was taken down, the residue codistilled with toluene and then with absolute ethanol.
The obtained crude 3-keto derivative 3 was dissolved in absolute ethanol (300 ml) cooled with ice
and sodium borohydride (3.70 g, 98 mmol) was added. After stirring for 20 min at 0 °C, the reaction
was quenched with saturated ammonium chloride (600 ml) and several drops of dilute (1 : 1) hydro-
chloric acid. The solution was concentrated to one half, the aqueous phase was extracted with ethyl
acetate (2 × 500 ml), the combined extracts were dried over magnesium sulfate and the solvent was
evaporated. Yield 5 g (66%) of a sirupy mixture of 2-deoxyribofuranosyl (4) and 2-deoxyxylofurano-
syl (5) derivative.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

484
Krecmerova, Hrebabecky, Masojidkova, Holy:
The mixture was codistilled with pyridine (40 ml), the residue was dissolved in pyridine (60 ml)
and methanesulfonyl chloride (7.8 ml, 100 mmol) was added at 0 °C. The mixture was stirred at 0 °C
for 15 min and at room temperature for 5 h. After cooling to 0 °C, methanol (25 ml) was added and
the solvent was evaporated. The residue was mixed with ethyl acetate (300 ml) and washed with 1%
hydrochloric acid to slightly acid reaction. The organic layer was further washed with water and satu-
rated solution of sodium hydrogen carbonate, dried over magnesium sulfate and the solvent was
evaporated. The residue was chromatographed on silica gel in system S3. First fractions afforded (RF 0.38)
the amorphous methyl 5-O-benzoyl-2-deoxy-3-O-methanesulfonyl-α-D-ribofuranoside (6): 2.6 g
(40%). For C14H18O7S (330.4) calculated: 50.90% C, 5.49% H, 9.71% S; found: 50.77% C, 5.46% H,
1
9.89% S. H NMR spectrum: 2.12 br, dt, 1 H, J(2a,1) = J(2a,3) = 1.0, J(gem) = 14.8 (H-2a); 2.49 ddd,
1 H, J(2b,3) = 7.8, J(2b,1) = 5.3 (H-2b); 3.26 s, 3 H (CH3, mesyl); 3.29 s, 3 H (OCH3); 4.37 dd, 1 H,
J(5a,4) = 5.7, J(gem) = 12.8 (H-5a); 4.45 dd, 1 H, J(5b,4) = 4.0 (H-5b); 4.45 m, 1 H (H-4); 5.15 br d,
1 H (H-1); 5.24 ddd, 1 H, J(3,2b) = 7.8, J(3,2a) = 1.5, J(3,4) = 2.7 (H-3); 7.54 t, 2 H, 7.68 t, 1 H
and 7.99 d, 2 H (H arom.). 13C NMR spectrum: 37.65 (CH3); 39.06 (C-2); 54.71 (OCH3); 63.91
(C-5); 80.38 (C-3); 81.01 (C-4); 104.73 (C-1); 128.98, 2 C and 129.48 2 C and 129.52 and 133.69
(C arom.); 165.67 (C=O).
Further elution afforded amorphous methyl 5-O-benzoyl-2-deoxy-3-O-methanesulfonyl-β-D-xylo-
furanoside (7) (RF 0.28, S3): 0.70 g (11%). For C14H18O7S (330.4) calculated: 50.90% C, 5.49% H,
9.71% S; found: 51.00% C, 5.48% H, 9.58% S. 1H NMR spectrum: 2.21 dt, 1 H, J(2a,1) = J(2a,3) = 1.3,
J(gem) = 14.8 (H-2a); 2.48 ddd, 1 H, J(2b,1) = 5.7, J(2b,3) = 6.2 (H-2b); 3.22 s, 3 H (OCH3); 3.26 s, 3 H
(CH3, mesyl); 4.43 dd, 1 H, J(5a,4) = 7.1, J(gem) = 11.4 (H-5a); 4.45 dd, 1 H, J(5b,4) = 4.9 (H-5b);
4.52 dt, 1 H (H-4); 5.08 dd, 1 H (H-1); 5.38 ddd, 1 H, J(3,2b) = 6.6, J(3,2a) = 1.5, J(3,4) = 5.1 (H-3);
7.53 t, 2 H, 7.67 t, 1 H and 8.00 d, 2 H (H arom.). 13C NMR spectrum: 37.77 (CH3); 39.43 (C-2);
54.81 (OCH3); 63.79 (C-5); 78.32 (C-3); 79.47 (C-4); 104.37 (C-1); 128.92, 2 C and 129.48 2 C and
129.66 and 133.63 (C arom.); 165.68 (C=O).
Methyl 5-O-Benzoyl-2-deoxy-β-D-xylofuranoside (5)
The β-anomer 9 (195 mg, 0.765 mmol) was oxidized with a mixture of chromium trioxide (360 mg,
3.6 mmol), pyridine (2 ml), and acetic anhydride (0.27 ml) as described for the anomeric mixture 2.
The obtained 3-keto derivative was reduced with sodium borohydride (100 mg, 2.64 mmol) in abso-
lute ethanol (10 ml), reaction time 20 min. The reaction mixture was worked up as described for
compound 2. The crude product was chromatographically homogeneous and was purified on a column
of silica gel (25 ml), elution with system S4 (RF 0.39). Yield 116 mg (59%) of a sirupy residue,
containing at least 85% of pure β-anomer of xylo-configuration 5. 1H NMR spectrum: 1.83 ddd, 1 H, J(2a,1) = 2.0,
J(2a,3) = 3.3, J(gem) = 13.7 (H-2a); 2.28 ddd, 1 H, J(2b,1) = 5.9, J(2b,3) = 7.1 (H-2b); 3.24 s, 3 H
(OCH3); 4.22 ddd, 1 H, J(4,3) = 5.5, J(4,5a) = 8.1, J(4,5b) = 4.0 (H-4); 4.36 dd, 1 H, J(gem) = 11.5
(H-5a); 4.37 m, 1 H (H-3); 4.49 dd, 1 H (H-5b); 4.92 d, 1 H, J(OH,3) = 5.1 (3-OH); 4.96 dd, 1 H
(H-1); 7.53 t, 2 H, 7.66 t, 1 H and 8.00 d, 2 H (H arom.). 13C NMR spectrum: 41.17 (C-2); 54.66
(OCH3); 65.53 (C-5); 69.65 (C-3); 79.75 (C-4); 104.70 (C-1); 129.00, 2 C and 129.44, 2 C and
130.08 and 133.57 (C arom.); 166.07 (C=O).
Methyl 3-Azido-5-O-benzoyl-2,3-dideoxy-β-D-ribofuranoside (10)
Finely ground sodium azide (1.29 g, 19.84 mmol) was added to a solution of mesyl derivative 7
(1.33 g, 4.03 mmol) in dimethylformamide (15 ml) and the mixture was stirred at 100 °C for 5 h
under argon. The solid was filtered off, washed with a mixture of ethyl acetate and toluene, and the
combined filtrates were concentrated. The residue was codistilled with toluene and partitioned be-
tween water and ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Preparation of 2’,3’-Dideoxypentofuranoses
485
evaporated and the residue was chromatographed on silica gel (180 ml) in system S1 (RF 0.34) to
give 1.04 g (93%) of compound 10 as colorless oil. For C13H15N3O4 (277.3) calculated: 56.31% C,
5.45% H, 15.15% N; found: 56.49% C, 5.43% H, 14.95% N. IR spectrum (CCl4): 2 103 cm–1 (N3).
1H NMR spectrum: 2.10 ddd, 1 H, J(2a,1) = 5.3, J(2a,3) = 7.1 J(gem) = 13.4 (H-2a); 2.32 ddd, 1 H,
J(2b,1) = 1.8, J(2b,3) = 7.3 (H-2b); 3.20 s, 3 H (OCH3); 4.19 q, 1 H (H-4); 4.31 dd, 1 H, J(5a,4) = 5.6,
J(gem) = 11.5 (H-5a); 4.40 dd, 1 H, J(5b,4) = 5.1 (H-5b); 4.40 td, 1 H, J(3,4) = 5.3 (H-3); 5.08 dd, 1 H
(H-1); 7.53 t, 2 H, 7.65 t, 1 H and 8.05 d, 2 H (H arom.). 13C NMR spectrum: 38.39 (C-2); 54.56
(OCH3); 61.11 (C-3); 65.06 (C-5); 81.10 (C-4); 104.67 (C-1); 128.89, 2 C and 129.44 2 C and
129.65 and 133.62 (C arom.); 165.66 (C=O).
Methyl 5-O-Benzoyl-3-chloro-2,3-dideoxy-α-D-xylofuranoside (16)
Thionyl chloride (0.7 ml, 9.6 mmol) was added at 0 °C to a solution of methyl 5-O-benzoyl-2-deoxy-
α-D-ribofuranoside (4; 1.602 g, 6.35 mmol) in hexamethylphosphoric triamide (12 ml). After stirring
at 0 °C for 10 min and then at room temperature for 6 h, the mixture was poured into saturated
sodium hydrogen carbonate solution, the organic layer was dried over magnesium sulfate and the
solvent was evaporated. Chromatography of the residue on silica gel in system S2 (RF 0.53) afforded
1.31 g (76%) of compound 16 as colorless sirup. 1H NMR spectrum: 2.40 ddd, 1 H, J(2a,1) = 3.9,
J(2a,3) = 6.1, J(gem) = 14.9 (H-2a); 2.51 ddd, 1 H, J(2b,1) = 5.6, J(2b,3) = 2.0 (H-2b); 3.20 s, 3 H
(OCH3); 4.45 m, 3 H (H-4 and H-5); 4.89 ddd, 1 H, J(3,2a) = 6.1, J(3,2b) = 2.0, J(3,4) = 3.2 (H-3);
5.27 dd, 1 H (H-1); 7.55 t, 2 H, 7.68 t, 1 H and 7.99 d, 2 H (H arom.). 13C NMR spectrum: 43.63 (C-2);
55.28 (OCH3); 60.42 (C-3); 64.19 (C-5); 77.20 (C-4); 104.12 (C-1); 129.00, 2 C and 129.39, 2 C and
129.50 and 133.70 (C arom.); 165.58 (C=O).
Methyl 5-O-Benzoyl-2,3-dideoxy-α-D-ribofuranoside (17)
Tributylstannane in toluene (1 M, 5.3 ml) and azo-bis(isobutyronitrile) (175 mg) were added to a solution
of 3-chloro derivative 16 (1.11 g, 4.10 mmol) in toluene (8 ml) at 120 °C. The reaction mixture was
stirred at 120 °C for 1 h, cooled and the solvent was evaporated. Chromatography on silica gel (200 ml)
in system S1 (RF 0.30) gave 919 mg (95%) of dideoxy sugar 17 as colorless liquid. Mass spectrum (FAB;
1
G + CHCl3): 235.2 (M + H). H NMR spectrum: 1.71 m, 1 H (H-3a); 1.77 m, 1 H (H-2a); 2.00 m, 1 H,
J(2b,1) = 5.0, J(2b,3a) = J(2b,3b) = 9.0, J(gem) = 12.7 (H-2b); 2.05 m, 1 H (H-3b); 3.22 s, 3 H
(OCH3); 4.24 dd, 1 H, J(5a,4) = 6.8, J(gem) = 12.5 (H-5a); 4.31–4.35 m, 2 H (H-4 and H-5b); 5.03 dd,
1 H, J = 1.0 and 5.0 (H-1); 7.54 t, 2 H, 7.65 t, 1 H and 7.97 d, 2 H (H arom.). 13C NMR spectrum:
25.52 (C-3); 31.63 (C-2); 54.21 (OCH3); 66.52 (C-5); 75.40 (C-4); 105.04 (C-1); 128.99, 2 C and
129.36 2 C and 129.77 and 133.58 (C arom.); 165.81 (C=O).
1-(3-Azido-2,3-dideoxy-β-D-ribofuranosyl)-5-phenyl-2(1H)-pyrimidinone (14) and
1-(3-Azido-2,3-dideoxy-α-D-ribofuranosyl)-5-phenyl-2(1H)-pyrimidinone (15)
A suspension of 5-phenyl-2(1H)-pyrimidinone (800 mg, 4.65 mmol) and a catalytic amount of ammonium
sulfate in hexamethyldisilazane (20 ml) was heated at 150 °C until it dissolved, and then for addi-
tional 2 h. The solvent was evaporated and the residue was codistilled with xylene (30 ml), leaving
the silyl derivative 11. A solution of the azido sugar 9 (970 mg, 3.50 mmol) in acetonitrile (25 ml)
was added, the reaction mixture was cooled to 0 °C and trimethylsilyl trifluoromethanesulfonate
(1.16 ml, 6.4 mmol) was added. The mixture was stirred at 0 °C for 40 min and the reaction was
quenched with saturated solution of sodium hydrogen carbonate (100 ml). After stirring at room tem-
perature for 15 min, the product was taken up in ethyl acetate (150 ml). The organic layer was dried
over magnesium sulfate, the solvent was evaporated and the residue was chromatographed on silica
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Krecmerova, Hrebabecky, Masojidkova, Holy:
gel (250 ml) in ethyl acetate to give 1.2 g (82%) of chromatographically homogeneous mixture of anomers 12
and 13 as a white foam, RF 0.50 (S5). Mass spectrum (FAB; G + dimethylformamide): 418.4 (M + H).
The obtained mixture of anomers in methanolic ammonia (about 100 ml) was allowed to stand in
a refrigerator at 4 °C for 20 h. The solution was concentrated and the residue was chromatographed
on silica gel (250 ml) in ethyl acetate. The β-anomer 14 (RF 0.31, S5) was eluted first, yield 389 mg
(47%) of white foam, collected after standing overnight with ethyl acetate–ether in a refrigerator. For
C15H15N5O3 (313.3) calculated: 57.50% C, 4.83% H, 22.35% N; found: 57.38% C, 4.83% H, 22.32% N.
IR spectrum (CHCl3): 2 107 cm–1 (N3). 1H NMR spectrum: 2.55 m, 2 H (H-2′); 3.67 ddd, 1 H, J(5′a,4′) = 2.6,
J(5′a,OH) = 4.7, J(gem) = 12.4 (H-5′a); 3.84 ddd, 1 H, J(5′b,4′) = 2.9, J(5′b,OH) = 4.7 (H-5′b); 3.98 m,
1 H (H-4′); 4.44 br q, 1 H, J(3′,4′) = 6.6 (H-3′); 5.58 t, 1 H (5′-OH); 6.09 br t, 1 H, J = 5.2 and 5.7
(H-1′); 7.30–7.55 m, 3 H and 7.65 m, 2 H (H arom.); 8.98 s, 1 H and 9.00 s, 1 H (H-4 and H-6). 13C
NMR spectrum: 38.11 (C-2′); 57.92 (C-3′); 59.62 (C-5′); 85.33 (C-1′); 86.72 (C-4′); 116.63 (C-5);
125.52, 2 C and 127.56 and 129.26, 2 C and 133.67 (C arom.); 141.30 (C-6); 154.24 (C-2); 164.63
(C-4).
Further elution with system S6 afforded the α-anomer 15 (RF 0.26). Yield 420 mg (51%) of color-
less amorphous compound. For C15H15N5O3 (313.3) calculated: 57.50% C, 4.83% H, 22.35% N;
1
found: 57.78% C, 4.86% H, 22.11% N. IR spectrum (CHCl3): 2 107 cm–1 (N3). H NMR spectrum:
2.27 dt, 1 H, J(2′a,1′) = J(2′a,3′) = 2.6, J(gem) = 14.5 (H-2′a); 2.87 dt, 1 H, J(2′b,1′) = J(2′b,3′) =
6.7 (H-2′b); 3.55 t, 2 H (H-5′); 4.43 dt, 1 H (H-3′); 4.59 td, 1 H, J(4′,3′) = 2.6, J(4′,5′) = 4.5 (H-4′);
5.11 t, 1 H, J(OH,5′) = 5.7 (5′-OH); 6.07 dd, 1 H (H-1′); 7.37 t, 1 H, 7.47 t, 2 H and 7.63 d, 2 H (H
arom.); 8.36 d, 1 H (H-6); 8.99 d, 1 H, J(4,6) = 3.4 (H-4). 13C NMR spectrum: 37.58 (C-2′); 61.13
(C-3′); 61.68 (C-5′); 87.33 (C-1′); 88.81 (C-4′); 116.74 (C-5); 125.83, 2 C and 127.70 and 129.30, 2 C
and 133.61 (C arom.); 140.68 (C-6); 154.36 (C-2); 164.95 (C-4).
1-(5-O-Benzoyl-2,3-dideoxy-β-D-glycero-pentofuranosyl)-5-phenyl-2(1H)-pyrimidinone (18) and
1-(5-O-Benzoyl-2,3-dideoxy-α-D-glycero-pentofuranosyl)-5-phenyl-2(1H)-pyrimidinone (19)
5-Phenyl-2(1H)-pyrimidinone (800 mg, 4.65 mmol) was converted into the silyl derivative 11 as de-
scribed for compounds 14 and 15. The residue was mixed with a solution of the deoxy sugar 17 (850 mg,
3.6 mmol) in acetonitrile (30 ml), the solution was cooled to 0 °C and trimethylsilyl trifluorometha-
nesulfonate (1.16 ml, 6.4 mmol) was added. After stirring at 0 °C for 75 min, saturated solution of
sodium hydrogen carbonate was added and the product was extracted with ethyl acetate. The organic
phase was dried over magnesium sulfate, the solvent was evaporated and the residue was chromato-
graphed on silica gel (400 ml) in ethyl acetate. The α-anomer 19 (RF 0.21, S5), was eluted first, yield
515 mg (38%) of amorphous compound. For C22H20N2O4 (376.4) calculated: 70.20% C, 5.36% H,
1
7.44% N; found: 69.12% C, 5.50% H, 7.00% N. H NMR spectrum: 1.95 m, 1 H (H-3′a); 2.15 m, 1 H
(H-3′b); 2.20 m, 1 H, J(2′a,1′) = 3.3 (H-2′a); 2.60 m, 1 H, J(2′b,1′) = 6.4 (H-2′b); 4.36 dd, 1 H,
J(5′a,4′) = 5.8, J(gem) = 11.7 (H-5′a); 4.44 dd, 1 H, J(5′b,4′) = 3.7 (H-5′b); 5.00 m, 1 H (H-4′); 6.10 dd,
1 H (H-1′); 7.36 t, 1 H, 7.45 t, 2 H, 7.55 t, 2 H, 7.64 d, 2 H, 7.68 t, 1 H and 8.00 d, 2 H (H arom.);
8.29 d, 1 H (H-6); 9.00 d, 1 H, J(4,6) = 3.3 (H-4). 13C NMR spectrum: 25.67 (C-3′); 32.15 (C-2′);
66.37 (C-5′); 79.26 (C-4′); 89.63 (C-1′); 116.90 (C-5); 125.96, 127.62, 129.02, 129.06, 129.12,
129.16, 129.39, 2 C, 129.66, 133.62 and 133.68 (C arom.); 140.77 (C-6); 154.33 (C-2); 164.88 (C-4);
165.79 (C=O).
Further elution furnished the β-anomer 18, yield 131 mg (10%) upon crystallization from ethyl
acetate, m.p. 151.5–154.5 °C, RF 0.14 (S5). For C22H20N2O4 (376.4) calculated: 70.20% C, 5.36% H,
1
7.44% N; found: 70.14% C, 5.40% H, 7.30% N. H NMR spectrum: 1.94 dq, 1 H, J(3′a,2′a) = 8.2,
J(3′a,2′b) = J(3′a,4′) = 8.6 (H-3′a); 2.11 ddd, 1 H, J(3′b,2′b) = 7.9, J(3′b,2′a) = 4.4, J(3′b,4′) = 6.2,
J(gem) = 12.7 (H-3′b); 2.18 d pent, 1 H, J(2′a,1′) = 4.0, J(gem) = 13.7 (H-2′a); 2.58 ddd, 1 H, J(2′b,1′)
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Preparation of 2’,3’-Dideoxypentofuranoses
487
= 6.8 (H-2′b); 4.55 dtd, 1 H, J(4′,5′a) = 2.9, J(4′,5′b) = 6.0 (H-4′); 4.59 dd, 1 H, J(gem) = 12.2 (H-5′a);
4.63 dd, 1 H (H-5′b); 6.00 dd, 1 H (H-1′); 7.29 m, 3 H, 7.37 t, 2 H, 7.50 d, 2 H, 7.58 t, 1 H and
7.87 d, 2 H (H arom.); 8.36 d, 1 H (H-6); 8.95 d, 1 H, J(4,6) = 3.3 (H-4). 13C NMR spectrum: 25.21
(C-3′); 32.34 (C-2′); 65.75 (C-5′); 79.68 (C-4′); 88.67 (C-1′); 116.79 (C-5); 125.63, 2 C and 127.53,
and 128.85, 2 C and 129.11, 2 C and 129.27, 2 C and 129.34, 133.51, 133.62 (C arom.); 140.23
(C-6); 154.32 (C-2); 164.83 (C-4); 165.86 (C=O).
1-(2,3-Dideoxy-β-D-glycero-pentofuranosyl)-5-phenyl-2(1H)-pyrimidinone (20)
A mixture of 5′-O-benzoyl derivative 18 (100 mg, 0.266 mmol) and methanolic ammonia (10 ml)
was stirred at room temperature for 48 h. After evaporation of the solvent, the residue was crystal-
lized from ethyl acetate and ethanol, collected and washed with ethyl acetate and ether. Yield 60 mg
(83%) of compound 20, m.p. 174–177 °C, RF 0.22 (S6). Mass spectrum (FAB; G + dimethyl sulfoxide):
1
273.3 (M + H). H NMR spectrum: 1.82 dddd, 1 H, J(3′a,2′a) = 2.0, J(3′a,4′) = 5.5, J(3′a,2′b) = 7.9
(H-3′a); 1.91 dddd, 1 H, J(3′b,2′a) = 7.3, J(3′b,4′) = 10.2, J(3′b,2′b) = 11.9, J(gem) = 12.6 (H-3′b);
2.10 ddt, 1 H, J(2′a,1′) = 1.7, J(gem) = 13.6 (H-2′a); 2.47 ddt, 1 H (H-2′b); 3.63 ddd, 1 H, J(5′a,4′) = 2.5,
J(5′a,OH) = 4.4, J(gem) = 12.3 (H-5′a); 3.91 ddd, 1 H, J(5′b,4′) = 2.5, J(5′b,OH) = 5.3 (H-5′b); 4.20 ddt,
1 H (H-4′); 5.45 br t, 1 H (5′-OH); 5.98 dd, 1 H, J(1′,2′a) = 1.7, J(1′,2′b) = 6.8 (H-1′); 7.34 t, 1 H,
7.43 t, 2 H and 7.63 d, 2 H (H arom.); 8.98 d, 1 H (H-6); 9.20 d, 1 H, J(4,6) = 3.5 (H-4). 13C NMR
spectrum: 23.01 (C-3′); 33.42 (C-2′); 60.78 (C-5′); 83.57 (C-4′); 87.81 (C-1′); 125.41, 2 C and 127.42
and 129.26, 2 C and 133.81 (C arom.); 141.62 (C-6); 154.38 (C-2); 164.14 (C-4).
1-(2,3-Dideoxy-α-D-glycero-pentofuranosyl)-5-phenyl-2(1H)-pyrimidinone (21)
A solution of compound 19 (485 mg, 1.29 mmol) in methanolic ammonia (40 ml) was allowed to
stand at room temperature for 48 h. After evaporation of the solvent, the residue was chromato-
graphed on silica gel (200 ml) in system S6 (RF 0.16) to give 220 mg (63%) of amorphous com-
pound 19. According to NMR spectrum, the product contained small amount of the β-anomer, which
had been formed in the debenzoylation. Mass spectrum (FAB; G + dimethyl sulfoxide): 273.1 (M + H).
1H NMR spectrum: 1.80–2.50 m, 4 H, overlapped with signals of [D6]-DMSO and the β-anomer (H-2′
and H-3′); 3.44 dd, 1 H, J(5′a,4′) = 4.8, J(gem) = 11.7 (H-5′a); 3.50 dd, 1 H, J(5′b,4′) = 4.4 (H-5′b);
4.62 m, 1 H, J(4′,3′) = 7.0 (H-4′); 6.02 dd, 1 H, J(1′,2′a) = 6.4, J(1′,2′b) = 3.5 (H-1′); 7.34–7.63 m,
5 H (H arom.); 8.23 d, 1 H (H-6); 8.96 d, 1 H, J(4,6) = 3.3 (H-4). 13C NMR spectrum: 25.25 (C-3′);
32.32 (C-2′); 63.50 (C-5′); 82.70 (C-4′); 89.43 (C-1′); 116.86 (C-5); 140.49 (C-6); 156.32 (C-2);
164.72 (C-4). The aromatic carbon atom signals overlapped with those of the β-anomer.
The authors are indebted to the staff of the Analytical Laboratory of this Institute (Dr V. Pechanec,
Head) for the elemental analyses, to Dr J. Kohoutova for measurement of the mass spectra and to Dr I.
Votruba for the cytostatic activity assays. The technical assistance of Dr A. Sterecova is gratefully
acknowledged. This work was supported by a Rhone-Poulenc Rorer (France) research grant.
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