3-Substituted pyrazinone nucleosidesA new family of D4T analogues

Article abstract of DOI:10.1080/15257770903169999

The synthesis of a new family of D4T analogues is described to study the influence of pyrazinone base on antiretroviral power. Substitution of 3H by methyl or n-decyl increases the lipophilic character and may facilitate diffusion across cell membranes. T

Full text of DOI:10.1080/15257770903169999

Nucleosides, Nucleotides and Nucleic Acids, 28:866–873, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770903169999
3-SUBSTITUTED PYRAZINONE NUCLEOSIDES—A NEW FAMILY OF
D4T ANALOGUES
Nathalie Batoux, Robert Granet, Rachida Zerrouki, and Pierre Krausz
Universite´ de Limoges, Laboratoire de Chimie des Substances Naturelles, Faculte´ des Sciences
et Techniques, Limoges, France
The synthesis of a new family of D4T analogues is described to study the influence of pyrazinone
2
base on antiretroviral power. Substitution of 3H by methyl or n-decyl increases the lipophilic character
and may facilitate diffusion across cell membranes. The compounds were characterized by 1H NMR
and infrared spectroscopy. Antiviral (HIV-1) properties of these compounds were examined.
Keywords Pyrazinone; d4t; nucleosides; HIV
The nucleoside analogue 2ꢁ,3ꢁ-didehydro-2ꢁ,3ꢁ-dideoxythymidine (d4T)
is used in combination with other drugs to treat human immunodeficiency
virus (HIV) infection. As part of our program to search for new anti-HIV
nucleosides, we were interested in the preparation of a new family of d4t
analogues 5a,b,c and to study the influence of the pyrazinone base on their
antiretroviral power. Substitution of H-3 by methyl or n-decyl increases the
lipophilic character and may facilitate diffusion across cellular membranes.
The strategy of synthesis of d4t analogues 5a,b,c is presented in Scheme 1.
RESULTS AND DISCUSSION
Pyrazinone nucleosides (1a,b,c) were synthesized according to a method
described in a previous article;[1] the preparation of 2ꢁ,3ꢁ-unprotected
compounds 2a,b,c[2] was eased because secondary hydroxyl groups can be
efficiently and selectively deprotected by methanolic NH3, provided that
the amount of NH3 be 25 equivalents per protecting benzoyl group. In
each case, the reaction was checked by thin layer chromatography (TLC)
Received 1 July 2009; accepted 7 July 2009.
Address correspondence to Rachinda Zerrouki, Universite´ de Limoges, Laboratoire de Chimie
des Substances Naturelles, EA1069, Faculte´ des Sciences et Techniques, 123, Av. Albert Thomas, 87060,
Limoges, France. E-mail: Rachida.zerrouki@unilim.fr
866

3-Substituted Pyrazinone Nucleosides
867
SCHEME 1 Strategy of synthesis of d4t analogues.
and was stopped as soon as the trihydroxyl derivatives appeared. A reaction
time of 6 hours at room temperature led to the unprotected products. After
evaporation and purification, deprotected compounds 2a,b,c were obtained
in reasonable yields (60%, 64%, and 65%). Infrared (IR) spectra display a
hydroxyl band at 3410 cm−1 and 1H NMR indicates the presence of only one
benzoyl group.
Many methods have been described for obtaining double bonds from
diols. We used the Barton’s method[3] in order to synthesize unsaturated
compounds 4a,b,c. The reaction proceeds in two steps The first step is in the
formation of a bisxanthate intermediate by reaction of the diol with carbon
disulfide, sodium hydride, and methyl iodide in anhydrous tetrahydrofuran
(THF). In these conditions, reaction of 2a gives two products. Structural
elucidation of these compounds indicated that one was the expected bisx-
antate product 3a obtained in low yield (31%) and the second (53%) was
a cyclic thionocarbonate. After numerous attempts, the reaction was finally
conducted in anhydrous N,N-dimethylformamide (DMF), and compound
2a led to the desired bisxantate 3a in 82% yield along with 15% of cyclic
thionocarbonate. Compounds 3b and 3c were obtained in 65% and 70%
yields, respectively, with 15% of cyclic thionocarbonate.
The second step, which allows the formation of the double bond, is
a radical reaction that takes place in anhydrous dioxane in the presence
of tributylphosphine-borane and 2,2-azobisisobutyronitrile as initiator. The
olefin compound 4c was obtained in good yield (95%), compound 4b
in acceptable yield (60%), and compound 4a in low yield 36%. We have

868
N. Batoux et al.
tried several methods[4] for obtaining 4a in acceptable yield but without
improvement.
Deprotection of the primary hydroxyl group was achieved using 7 M
ammonia in methanol. The expected compounds were obtained in good
yields.
The biological properties of compounds 5a,b,c were evaluated on CEM-
SS cells infected by HIV-1 LAI virus and on MT4 cells infected by HIV-1 IIIB
according to standardized protocols.[5] These compounds do not show any
activity against these viruses and were found non-cytotoxic.
EXPERIMENTAL
All the solvents and chemicals were commercially available and, unless
otherwise stated, were used as received. Reactions were monitored by TLC
on precoated 0.2 mm silica gel 60 F254 (Merck, Germany) plates and
visualized in several ways: with an ultraviolet light source at 254 nm, by
spraying with sulfuric acid (6N), and heating to 200◦C. Silica gel (Merck
1
Kieselgel 60, 15–40 µm) was used for flash chromatography. H NMR
spectra were recorded at 400.13 MHz with a Bruker (Germany) DPX spec-
trometer. Chemical shifts (δ) are expressed in ppm with Me4Si as internal
standard (δ = 0). Data are reported as follows: chemical shift, multiplicity
(s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet and
br, broad), coupling constants (Hz), and assignment. Melting points (m.p.)
were determined with a Kofler block and are uncorrected. IR spectra were
recorded on a Perkin Elmer (France) 1310 grating spectrophotometer and
are reported in wave number (cm−1).
1-(5ꢁ-O-benzoyl-β-D-ribofuranosyl)pyrazin-2-one (2a). 1-(2ꢁ,3ꢁ,5ꢁ-O-benzoyl-β-
D-ribo furanosyl)pyrazin-2-one 1a (1.62 g, 3 mmol) was stirred with
methanolic ammonia (7 N) (50 equiv.) in methanol (21.50 mL) at room
temperature during 6 hours. The solvent was removed under reduced
pressure and the crude residue was purified by recrystallization in ethyl
acetate to yield compound 2a as crystal in 60% (600 mg). Rf = 0.46
(CHCl3/EtOH, 9/1, v/v); Tf = 155–158◦C; IR: 3400–3250 (OH), 3050–2860
1
=
=
=
(CH), 1720 (C O benzoyl), 1651 (C O),ꢁ 1585 (C C). H NMR (400.13
ꢁ
ꢁ
−
MHz, CDCl3 CD3OD): δ 4.18 (m, 2H, H-2 , H-3 ); 4.48 (m, 1H, H-4 ); 4.67
(dd, 1H, J = 12.7, 3.0 Hz, H-5ꢁa); 4.81 (dd, 1H, J = 12.7, 2.2 Hz, H-5ꢁb);
5.92 (brs, 1H, H-1ꢁ); 7.24 (d, 1H, J = 3.9 Hz, H-5); 8.10 (brs, 1H, H-3),
7.49–8.01 (m, Har, H-6). 13C NMR:δ 63.26 (C-5ꢁ); 69.43 (C-3ꢁ); 75.13 (C-2ꢁ);
82.20 (C-4ꢁ); 91.84 (C-1ꢁ); 123.38 (C-5); 124.65 (C-6); 128.83, 129.51, 129.68,
−
=
133.85 (C Ar); 148.60 (C-3); 156.15 (C-2), 166.61 (C O). SM (DCI/NH3):
m/z 333 (M+H)+; m/z 350 (M+ NH4)+.
1-(5ꢁ-O-benzoyl-β-D-ribofuranosyl)-3-methylpyrazin-2-one (2b). Compound
2b was prepared according to the procedure described for 2a starting from

3-Substituted Pyrazinone Nucleosides
869
1-(2ꢁ,3ꢁ,5ꢁ-O-benzoyl-β-D-ribo furanosyl)-3-methylpyrazin-2-one 1b (1.11 g, 2
mmol) and stirred with methanolic ammonia (7 N) (50 equiv.). Yield: 64%
(444 mg). Rf = 0.50 (CHCl3/EtOH, 9/1, v/v); IR: 3390 (OH), 3000–2860
1
=
=
=
(CH), 1720 (C O benzoyl), 1645 (C O), 1580 (C C). H NMR (400.13
MHz, CDCl3): δ 2.45 (s, 3H, CH3); 4.20 (m, 2H, H-2ꢁ, H-3ꢁ); 4.48 (m, 1H,
H--4ꢁ); 4.67 (dt, 1H, J = 12.7, 3.0 Hz, H-5ꢁa); 4.81 (dt, 1H, J = 12.7, 2.2
Hz, H-5ꢁb); 5.93 (d, 1H, J = 3.2 Hz, H-1ꢁ); 7.24 (d, 1H, J = 3.9 Hz, H-5);
7.50–8.01 (m, Har, H-6). 13C NMR:δ 20.38 (CH3); 63.67 (C-5ꢁ); 71.16 (C-3ꢁ);
76.43 (C-2ꢁ); 83.99 (C-4ꢁ); 93.01 (C-1ꢁ); 121.04 (C-5); 124.07 (C-6); 128.66,
−
=
128.79, 129.67, 130.30 (C Ar); 156.62 (C-3); 157.38 (C-2), 166.29 (C O).
SM (DCI/NH3): m/z 347 (M+H)+; m/z 364 (M+ NH4)+.
1-(5ꢁ-O-benzoyl-β-D-ribofuranosyl)-3-decylpyrazin-2-one (2c). Compound 2c
was prepared according to the procedure described for 2a starting from
1-(2ꢁ,3ꢁ,5ꢁ-O-benzoyl-β-D-ribo furanosyl)-3-decylpyrazin-2-one 1c (1.36 g, 2
mmol) and stirred with methanolic ammonia (7 N) (50 equiv.). Yield:
65% (615 mg). Rf = 0.39 (CHCl3/EtOH, 95/5, v/v); IR: 3400 (OH),
1
=
=
=
3000–2850 (CH), 1719 (C O benzoyl), 1650 (C O), 1585 (C C). H
NMR (400.13 MHz, CDCl3): δ 0.88 (t, 3H, J = 6.7 Hz, CH3); 1.25 (brs,
14H, (CH2)7); 1.68 (quint, 2H, J = 7.5 Hz, CH2); 2.80 (brq, 2H, J =
7.3 Hz, CH2); 4.26 (dd, 1H, J = 5.2, 4.2 Hz, H-2ꢁ); 4.33 (dd, 1H, J = 3.7,
5.2 Hz, H-3ꢁ); 4.55 (dd, 1H, J = 12.4, 3.5 Hz, H-5ꢁa); 4.64 (ddt, 1H, J = 3.5,
2.9 Hz, H-4ꢁ); 4.72 (dd, 1H, J = 12.4, 2.9 Hz, H-5ꢁb);5.91 (d, 1H, J = 4.2
Hz, H-1ꢁ), 7.28 (d, 1H, J = 4.6 Hz, H-5); 7.52 (d, 1H, J = 4.6, H-6); 7.40–
7.88 (m, Har). 13C NMR: δ 14.11 (CH3); 22.68, 26.58, 29.33, 29.47, 29.52,
29.56, 29.61(C-alkyl); 63.72 (C-5ꢁ); 71.73 (C-3ꢁ); 76.84 (C-2ꢁ); 84.56 (C-4ꢁ);
93.26 (C-1ꢁ); 120.34 (C-5); 124.08 (C-6); 128.47, 128.61, 129.46, 130.17,
−
=
133.59, 133.62 (C Ar); 156.47 (C-3); 160.31 (C-2), 166.04 (C O). SM
(DCI/NH3): m/z 473 (M+H)+.
1-(5-O-benzoyl-2,3-bis-O-((methylthio)thiocarbonyl)-β-D-ribofuranosyl)pyra-
zin-2-one (3a). Compound 2a (300 mg, 0.903 mmol) was solubilized in 7.5
mL of anhydrous DMF with 0.183 mL (3.24 mmol, 3.35 equiv.) of CS2 and
120 mg (3.24 mmol) of sodium hydride. This solution was placed under
argon; iodomethane was then added (126 µL, 2.031 mmol). The mixture
was stirred until completion of reaction as monitored by TLC (30 minutes)
and stopped with the addition of ethanol. After work up, the crude residue
purified by thin layer preparative chromatography on silica gel
(CHCl3/EtOH, 93/7) yielded compound 3a in 82% (381 mg). Rf =
=
0.49 (CHCl3/EtOH, 95/5, v/v); IR: 2900 (CH), 1722 (C O benzoyl), 1652
1
=
=
=
(C O), 1600 (C C), 1020 (C S). H NMR (400.13 MHz, CDCl3): δ 2.58
(s, 3H, S-CH3); 2.60 (s, 3H, S-CH3); 4.67 (dd, 1H, J = 4.6, 13.0 Hz, H--5ꢁa);
4.80 (dd, 1H, J = 2.8, 13.0 Hz, H-5ꢁb); 4.82 (m, 2H, H-4ꢁ); 6.25 (t, 1H, J =
4.7 Hz, H-2ꢁ); 6.40 (dd, 1H, J = 4.9, 5.7 Hz, H-3ꢁ); 6.49 (t, 1H, J = 5.5 Hz,
H-1ꢁ), 7.17–7.61 (m, Har, H-5, H-6); 8.09 (d, 1H, J = 1.2, H-3). 13C NMR: δ

870
N. Batoux et al.
19.39 (S-CH3); 19.59 (S-CH3); 63.59 (C-5ꢁ); 77.35 (C-4ꢁ); 80.02 (C-3ꢁ); 80.80
(C-2ꢁ); 89.28 (C-1ꢁ); 123.90 (C-5); 128.68, 128.85, 129.17, 129.77, 133.65,
−
=
(C Ar, C-6); 150.47 (C-3); 155.15 (C-2), 166.00 (C O). SM (DCI/NH3):
m/z 513 (M+H)+, 530 (M+NH4)+.
1-(5-O-benzoyl-2,3-bis-O-((methylthio)thiocarbonyl)-β-D-ribofuranosyl)-3-
methylpyrazin-2-one (3b). Compound 3b was prepared according to the
procedure described for 3a starting from 2b (350 mg, 1.01 mmol). Yield:
65% (342 mg). Rf = 0.57 (CHCl3/EtOH, 95/5, v/v); IR: 2850 (CH), 1720
1
=
=
=
=
(C O benzoyl), 1650 (C O), 1605 (C C), 1020 (C S). H NMR (400.13
MHz, CDCl3): δ 2.44 (s, 3H, CH3); 2.58 (s, 3H, S-CH3); 2.59 (s, 3H, S-CH3);
4.65 (dd, 1H, J = 3.2, 11.9 Hz, H--5ꢁa); 4.80 (m, 2H, H-4ꢁ, H-5ꢁb); 6.20 (t,
1H, J = 4.4 Hz, H-3ꢁ); 6.40 (dd, 1H, J = 4.4, 5.8 Hz, H-2ꢁ); 6.49 (t, 1H, J
= 5.8 Hz, H-1ꢁ), 7.07–8.10 (m, Har, H-5, H-6).13C NMR: δ 19.42 (S-CH3);
19.57 (S-CH3); 20.52 (CH3); 64.02 (C-5ꢁ); 81.02 (C-3ꢁ); 81.43 (C-2ꢁ); 87.99
(C-4ꢁ); 92.00 (C-1ꢁ); 120.84 (C-5); 124.15; 128.62, 129.00, 129.65, 130.80
−
=
(C Ar, C-6); 155.62 (C-3); 157.88 (C-2), 166.00 (C O). SM (DCI/NH3):
m/z 527 (M+H)+, 544 (M+NH4)+.
1-(5-O-benzoyl-2,3-bis-O-((methylthio)thiocarbonyl)-β-D-ribofuranosyl)-3-
decylpyrazin-2-one (3c). Compound 3c was prepared according to the
procedure described for 3a starting from 2c (200 mg, 0.42 mmol). Yield:
70% (185 mg). Rf = 0.60 (CHCl3/EtOH, 98/2, v/v); IR: 2900 (CH), 1725
1
=
=
=
=
(C O benzoyl), 1665 (C O), 1610 (C C), 1022 (C S). H NMR (400.13
MHz, CDCl3): δ 0.90 (t, 3H, J = 7.0 Hz, CH3); 1.28 (brs, 14H, (CH2)7);
1.66 (quint, 2H, J = 7.5 Hz, CH2); 2.59 (s, 3H, S-CH3); 2.60 (s, 3H, S-CH3);
2.84 (brq, 2H, J = 7.0 Hz, CH2); 6.35 (dd, 1H, J = 5.2, 6.0 Hz, H--2ꢁ); 6.15
(dd, 1H, J = 3.7, 5.2 Hz, H-3ꢁ); 4.62 (dd, 1H, J = 12.0, 3.8 Hz, H-5ꢁa); 4.82
(m, 2H, H-4ꢁ, H-5ꢁb); 6.48 (d, 1H, J = 6.0 Hz, H-1ꢁ), 7.20 (d, 1H, J = 4.6
Hz, H-5); 7.17–8.07 (m, Har, H-6).13C NMR: δ 14.16 (CH3); 19.40 (S-CH3);
19.55 (S-CH3); 22.66, 26.08, 29.00, 29.32, 29.44, 29.56, 29.71(C-alkyl); 64.12
(C-5ꢁ); 84.51 (C-3ꢁ); 81.73 (C-2ꢁ); 87.00 (C-4ꢁ); 92.12 (C-1ꢁ); 122.80 (C-5);
−
127.11 (C-6); 128.70, 129.20, 129.86, 132.73, 133.21, 133.52 (C Ar); 154.12
+
=
(C-3); 157.43 (C-2), 166.11 (C O). SM (DCI/NH3): m/z 653 (M+H) ,
670 (M+NH4)+.
1-(5-benzoyl-2,3-dideoxy-β-D-glyceropent-2-enofuranosyl) pyrazin-2-one (4a).
An amount of 254 mg (0.494 mmol) of compound 3a were dissolved in
anhydrous dioxane (6 mL) and tributylphosphine borane (0.40 mL, 1.486
mmol). This system was stirred under argon and immersed in an oil bath at
105◦C. A solution of AIBN (0.6 equiv.) in dioxane was added dropwise and
let to react during 5 houra. The reaction was evaporated and the crude
product was purified using preparative TLC (CHCl3/EtOH, 95/5, v/v).
Pure 4a (54 mg) was recovered in 36% yield. Rf = 0.30 (CHCl3/EtOH,
=
=
=
95/5, v/v); IR: 2900 (CH), 1720 (C O benzoyl), 1650 (C O), 1610 (C C).
1H NMR (400.13 MHz, CDCl3): δ 4.57 (dd, 1H, J = 2.7, 12.5 Hz, H-5ꢁa);

3-Substituted Pyrazinone Nucleosides
871
4.73 (dd, 1H, J = 3.7, 12.5 Hz, H-5ꢁb); 5.28 (m, 1H, H-4ꢁ); 6.10 (brt,
1H, J = 5.8 Hz, H-3ꢁ); 6.34 (dt, 1H, J = 1.3, 6.0 Hz, H-2ꢁ); 7.06 (m, 1H,
H-1ꢁ); 7.08 (d, 1H, J = 4.6 Hz, H-6); 7.41 (brd, 1H, J = 4.5 Hz, H-5); 8.09
(brs, 1H, H-3); 7.44–7.97 (m, Har). 13C NMR: δ 64.75 (C-5ꢁ); 85.58 (C-4ꢁ);
90.81 (C-1ꢁ); 121.46 (C-5); 122.35 (C-6); 155.64 (C-3); 158.10 (C-2); 127.74,
ꢁ
ꢁ
−
128.62, 129.40, 129.73, 132.34, 133.71 (C Ar, C-2 , C-3 ); 166.28 (C-6). SM
(DCI/NH3): m/z 299 (M+H)+, 316 (M+NH4)+.
1-(5-benzoyl-2,3-dideoxy-β-D-glyceropent-2-enofuranosyl)-3-methylpyrazin-2-
one (4b). Compound 4b was prepared according to the procedure described
for 4a starting from 3b (240 mg, 0.456 mmol). Yield: 65% (93 mg); Rf =
=
0.40 (CHCl3/EtOH, 95/5, v/v); IR: 3090 (CH), 1720 (C O benzoyl), 1654
1
=
=
(C O), 1600 (C C). H NMR (400.13 MHz, CDCl3): δ 2.45 (s, 3H, CH3);
4.55 (dd, 1H, J = 2.9, 12.5 Hz, H-5ꢁa); 4.75 (dd, 1H, J = 3.9, 12.5 Hz, H-5ꢁb);
5.27 (m, 1H, H-4ꢁ); 6.07 (dt, 1H, J = 5.8, 1.4 Hz, H-3ꢁ); 6.34 (dt, 1H, J = 1.5,
6.0 Hz, H-2ꢁ); 6.97 (d, 1H, J = 4.7 Hz, H-6); 7.11 (m, 1H, H-1ꢁ); 7.28 (d,
1H, J = 4.7 Hz, H-5); 7.45–7.97 (m, Har). 13C NMR: δ 20.70 (CH3); 64.85
(C-5ꢁ); 85.52 (C-4ꢁ); 90.61 (C-1ꢁ); 121.42 (C-5); 122.18 (C-6); 155.67 (C-3);
ꢁ
−
158.19 (C-2); 127.73, 128.56, 129.40, 129.68, 132.22, 133.55 (C Ar, C-2 ,
C-3ꢁ); 166.16 (C-6). SM (DCI/NH3): m/z 313 (M+H)+, 330 (M+NH4)+.
1-(5-benzoyl-2,3-dideoxy-β-D-glyceropent-2-enofuranosyl)-3-decylpyrazin-2-
one (4c). Compound 4c was prepared according to the procedure described
for 4a starting from 3c (150 mg, 0.228 mmol). Yield: 95% (96 mg); Rf =
=
0.57 (CHCl3/EtOH, 98/2, v/v); IR: 2920 (CH), 1720 (C O benzoyl), 1650
1
=
=
(C O), 1595 (C C). H NMR (400.13 MHz, CDCl3): δ 0.87 (t, 3H, J = 6.7
Hz, CH3); 1.25 (brs, 14H, CH2); 1.68 (quint, 2H, J = 7.5 Hz, CH2); 2.78 (dt,
2H, J = 1.9, 7.1 Hz, CH2) 4.57 (dd, 1H, J = 2.9, 12.5 Hz, H-5ꢁa); 4.71 (dd,
1H, J = 4.8, 12.5 Hz, H-5ꢁb); 5.28 (m, 1H, H-4ꢁ); 6.07 (dt, 1H, J = 5.9, 1.7
Hz, H-3ꢁ); 6.36 (dt, 1H, J = 1.5, 6.0 Hz, H-2ꢁ); 6.99 (d, 1H, J = 4.6 Hz, H-6);
7.10 (m, 1H, H-1ꢁ); 7.31 (d, 1H, J = 4.7 Hz, H-5); 7.45–7.97 (m, Har). 13C
NMR: δ 14.14 (CH3); 22.75, 26.68, 29.40, 29.54, 29.60, 29.63, 29.67, 31.99,
33.45 (CH2); 64.98 (C-5ꢁ); 85.64 (C-4ꢁ); 90.78 (C-1ꢁ); 121.52 (C-5); 122.71
(C-6); 155.60 (C-3); 161.31 (C-2); 127.73, 128.68, 129.41, 129.73, 132.4+4,
ꢁ
ꢁ
−
133.72 (C Ar, C-2 , C-3 ); 166.45 (C-6). SM (DCI/NH3): m/z 453 (M+H) ,
471 (M+NH4)+.
1-(2,3-dideoxy-β-D-glyceropent-2-enofuranosyl)pyrazin-2-one (5a). Compo-
und 4a (71 mg, 0.235 mmol) was dissolved in methanolic ammonia (7
N) (10 mL) and stirred during 3 days at room temperature. Solvent was
removed under reduced pressure and the crude residue was purified by thin
layer preparative chromatography on silica gel (CHCl3/ EtOH, 9/1, v/v) to
yield compound 5a in 95% (44 mg). Rf = 0.40 (CHCl3/EtOH, 9/1, v/v);
1
=
=
IR: 3400 (OH), 2900 (CH), 1650 (C O), 1600 (C C). H NMR (400.13
MHz, CD3OD): δ 3.76 (dd, 1H, J = 3.5, 12.4 Hz, H-5ꢁa); 3.81 (dd, 1H, J =
3.2, 12.4 Hz, H-5ꢁb); 4.99 (m, 1H, H-4ꢁ); 6.02 (ddd, 1H, J = 1.5, 1.8, 6.1 Hz,

872
N. Batoux et al.
H-3ꢁ); 6.41 (dt, 1H, J = 1.6, 6.1 Hz, H-2ꢁ); 7.06 (m, 1H, H-1ꢁ); 7.39 (d, 1H, J
= 4.6 Hz, H-6); 7.95 (dd, 1H, J = 1.0, 4.6 Hz, H-5); 8.02 (brs, 1H, H-3). SM
(DCI/NH3): m/z 195 (M+H)+, 212 (M+NH4)+.
1-(2,3-dideoxy-β-D-glyceropent-2-enofuranosyl)-3-methylpyrazin-2-one (5b). 5b
was prepared according to the procedure described for 5a starting from 4b
(50 mg, 0.16 mmol). Yield: 96% (32 mg); Rf = 0.43 (CHCl3/EtOH, 9/1,
1
=
=
v/v); IR: 3395 (OH), 2915 (CH), 1651 (C O), 1591 (C C), 1020. H NMR
(400.13 MHz, CD3OD): δ 2.39 (brs, 3H, CH3); 3.74 (dd, 1H, J = 3.7, 12.4
Hz, H-5ꢁa); 3.80 (dd, 1H, J = 3.2, 12.4 Hz, H-5ꢁb); 4.98 (m, 1H, H-4ꢁ); 6.00
(ddd, 1H, J = 1.5, 1.8, 6.0 Hz, H-3ꢁ); 6.39 (dt, 1H, J = 1.6, 6.0 Hz, H-2ꢁ); 7.08
(m, 1H, H-1ꢁ); 7.21 (d, 1H, J = 4.6, H-6); 7.79 (d, 1H, J = 4.6 Hz, H-5). SM
(ESI): m/z 230.97 (M+Na)+.
1-(2,3-dideoxy-β-D-glyceropent-2-enofuranosyl)-3-methylpyrazin-2-one
(5c).
Compound 5c was prepared according to the procedure described for
5a starting from 4c (50 mg, 0.115 mmol). Yield: 99% (39 mg); Rf = 0.32
=
(CHCl3/EtOH, 95/5, v/v); IR: 3360 (OH), 2900 (CH), 1650 (C O), 1591
1
=
(C C). H NMR (400.13 MHz, CD3OD): δ 0.89 (brt, 3H, J = 6.8 Hz, CH3);
1.29 (brs, 14H, CH2); 1.68 (br quint, 2H, J = 7.4 Hz, CH2); 2.76 (dd, 2H, J
= 6.6, 8.5 Hz, CH2); 3.74 (dd, 1H, J = 3.7, 12.3 Hz, H-5ꢁa); 3.80 (dd, 1H, J
= 3.2, 12.3 Hz, H-5ꢁb); 4.98 (m, 1H, H-4ꢁ); 6.00 (ddd, 1H, J = 1.5, 1.9, 6.0
Hz, H-3ꢁ); 6.39 (dt, 1H, J = 1.6, 6.0 Hz, H-2ꢁ); 7.08 (m, 1H, H-1ꢁ); 7.25 (d,
1H, J = 4.6 Hz, H-6); 7.78 (d, 1H, J = 4.6 Hz, H-5). SM (ESI): m/z 357.20
(M+Na)+.
REFERENCES
1. Davis, J.; Benhaddou, R.; Granet, R.; Krausz, P.; De Monte, M.; Aubertin, A. M. Synthesis and antiviral
evaluation of pyrazinones substituted with acyclic chains. Nucleosides Nucleotides 1998, 17, 875–
893.
2. Zerrouki, R.; Roy, V.; Hadj-Bouazza, A.; Krausz, P. Selective deprotection of fully benzoylated
nucleoside derivatives. J. Carbohydr. Chem. 2004, 23, 299–303.
3. a) Barton, D.H.R.; McCombie, S.W. A new method for the deoxygenation of secondary alco-
hols. Perkin Trans I 1975, 16, 1574–1585. b) Barett, A.G.M.; Barton, D.H.R.; Bielski, R. Re-
actions of relevance to the chemistry of aminoglycoside antibiotics. Part 11. Preparation of
olefins from vicinal diols. Perkin Trans I 1979, 2378–2381. c) Barton, D.H.R.; Ok Jang, D.;
Jaszberenyi, J.Cs. On the mechanism of deoxygenation of secondary alcohols by tin hydride
reduction of methyl xanthates and other thiocarbonyl derivatives. Tetrahedron Lett. 1990, 31, 3991–
3994.
4. a) Eastwood, F.W.; Harrington, K.J.; Josan, J.S.; Pura, J.L. Conversion of 2-dimethylamino-1,3-
dioxolanes into alkenes. Tetrahedron Lett. 1970, 60, 5223–5224. b) Hanessian, S.; Moralioglu,
E. Preparative and explorative carbohydrate chemistry. Chemistry and synthetic utility of a -
(dimethylamino)benzylidene and 1-(dimethylamino)ethylidene acetals. Can. J. Chem. 1972, 50,
233–245. c) Samuelsson, B.; Garreg, P.J. One-step conversion of vicinal diols into olefins, using a
novel reagent system. Synthesis 1979, 469–470. d) Liu, Z.; Classon, B.; Samuelson, B. A novel route
to olefins from vicinal diols. J. Org. Chem. 1990, 55, 4273–4275. e) Corey, E.J.; Carey, F.A.; Winter,
R.A.E. Stereospecific syntheses of olefins from 1,2-thionocarbonates and 1,2-trithiocarbonates. trans-
cycloheptene. J. Am. Chem. Soc. 1965, 87, 934–935. f) Corey, E.J.; Winter, R.A.E. New stereospecific

3-Substituted Pyrazinone Nucleosides
873
olefin synthesis from 1,2-diols. J. Am. Chem. Soc. 1963, 85, 2677–2678. g) Corey, E.J.; Hopkins,
P.B. A mild procedure for the conversion of 1,2-diols to olefins. Tetrahedron Lett. 1982, 23, 1979–
1982.
5. Moog, C.; Wick, A.; Le Ber, P.; Kirn, A.; Aubertin, A.M. Bicyclic imidazo derivatives, a new class
of highly selective inhibitors for the human immunodeficiency virus type 1. Antivir. Res. 1994, 24,
275–288.