Synthesis and anti-HIV activity of L-β-3′-C-cyano-2′,3′-unsaturated nucleosides and L-3′-C-cyano-3′-deoxyribonucleosides

Article abstract of DOI:10.1016/S0040-4020(03)01074-3

An efficient synthetic method was developed for L-β-3′-C-cyano-2′,3′-unsaturated nucleosides and L-3′-C-cyano-3′-deoxyribonucleosides. The key intermediate 11 was obtained from L-xylose, from which a series of pyrimidine and purine nucleosides were prepared in high yield by the coupling of 11 and various silyl-protected bases in the presence of TMSOTf. These nucleosides were eliminated, followed by deprotecting to give L-β-3′-C-cyano-2′,3′-unsaturated nucleosides. When selectively deprotected by hydrazine hydrate in buffered acetic acid-pyridine followed by treatment with potassium carbonate in methanol, L-3′-C-cyano-3′-deoxyribonucleosides were obtained. The synthesized nucleosides were tested for anti-HIV activity.

Full text of DOI:10.1016/S0040-4020(03)01074-3

Tetrahedron 59 (2003) 6423–6431
Synthesis and anti-HIV activity of
L-b-30-C-cyano-20,30-unsaturated nucleosides and
L-30-C-cyano-30-deoxyribonucleosides
Wei Zhu,a Giuseppe Gumina,a Raymond F. Schinazib and Chung K. Chua
,
*
aDepartment of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, GA 30602-2352, USA
bEmory University School of Medicine/Veterans Affairs Medical Center, Decatur, GA 30033, USA
Received 27 May 2003; revised 9 July 2003; accepted 9 July 2003
Abstract—An efficient synthetic method was developed for L-b-30-C-cyano-20,30-unsaturated nucleosides and L-30-C-cyano-30-
deoxyribonucleosides. The key intermediate 11 was obtained from L-xylose, from which a series of pyrimidine and purine nucleosides
were prepared in high yield by the coupling of 11 and various silyl-protected bases in the presence of TMSOTf. These nucleosides were
eliminated, followed by deprotecting to give L-b-30-C-cyano-20,30-unsaturated nucleosides. When selectively deprotected by hydrazine
hydrate in buffered acetic acid–pyridine followed by treatment with potassium carbonate in methanol, L-30-C-cyano-30-deoxyribonucleo-
sides were obtained. The synthesized nucleosides were tested for anti-HIV activity.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
common key intermediate can be coupled to different
heterocyclic moieties to obtain a series of L-30-C-cyano-
d4Ns. Our scheme also afford0ed another interesting class of
nucleosides: L-30-C-cyano-3 -deoxyribonucleosides from
the key intermediates. Both types of nucleosides were
evaluated for anti-HIV activity.
Nucleoside analogs are used extensively as chemo-
therapeutic agents targeting human immunodeficiency
virus (HIV), the virus responsible for acquired immuno-
deficiency syndrome (AIDS). The pas0t decade has
witnessed the discovery of a class of 2 ,30-unsaturated
nucleosides such as d4T,1 L-d4C,2 L-d4FC2 and abacavir3 as
interesting therapeutic agents against HIV. As part of our
efforts to develop novel antiviral agents, we recently
reported the synthesis and anti-HIV activity of L-b-20(0or
30)-fluor0o-20,30-unsaturated nucleosides4 and L-b-20(or 3 )-
fluoro-2 ,30-unsaturated 40-thionucleosides.5 These nucleo-
sides were designed to take advantage of the characteristics
of L-nucleosides, particularly the lower toxicity that they
showed in many instances compared to their D-counter-
parts.4–6 In view of the interesting biological activity of
these compounds, we decided to extend our studies to L-30-
C-cyano-20,30-didehydro-30-dideoxynucleosides (L-30-C-
cyano-d4Ns), in which an electronegative cyano grou0p
replaces the fluorine atom. Previously, the synthesis of D-3 -
C-cyano-d4Ns via elimination reaction started from indi-
vidual D-nucleosides.7 Such a linear approach involves the
repetition of the same scheme for each nucleoside. Besides,
the synthesis of L-isomers is complicated by the unavail-
ability of L-nucleosides as starting materials. For these
reasons, we developed an efficient synthetic route in which a
2. Results and discussion
2.1. Chemistry
Compound 11 was the key intermediate in our synthesis. As
earlier described for the synthesis of the D-enantiomer,7,8
Protected L-xylose 19 was converted to 3-C-cyano-3-deoxy-
1,2-O-isopropylidene-a-L-ribo-pentofura-nose 8 in 63%
overall yield (Scheme 1). Benzoylation of the 5-hydroxyl
group gave compound 9, which was deprotected to a lactol
10 by using 90% trifluoroacetic acid.
Acetylation of 10 afforded the key intermediate 11 as an
epimeric mixture. Condensation of 11 with various silylated
pyrimidines gave the corresponding pyrimidine analogs
12–14 in 80–86% yield (Scheme 2). The condensation
reaction gave the b-anomer by virtue of the neighbor group
participating effect of the 2-acetyl group. With the aid of the
acidic 30-a proton10 accompanied by a good leaving group
(OAc) at the 20 position, compounds 12–14 were quanti-
tatively converted to 20,30-unsaturated compounds 18–20 by
treatment with DBU (0.2 equiv.)/DMAP (6 equiv.) in
dichloromethane. Compounds 18 and 19 could be directly
Keywords: unsaturated L-nucleoside; HIV; antiviral; cyano.
*
Corresponding author. Tel.: þ1-706-542-5379; fax: þ1-706-542-5381;
e-mail: dchu@rx.uga.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01074-3

6424
W. Zhu et al. / Tetrahedron 59 (2003) 6423–6431
˚
Scheme 1. (a) (i) H2SO4, CuSO4, acetone, rt; (ii) 0.2% HCl solution, rt; (b) TBDMSCl, imidazole, CH2Cl2, rt; (c) PCC, Ac2O, 4 A M. S., CH2Cl2, rt; (d) NaCN,
NaHCO3, H2O, Et2O, rt; (e) PhOC(S)Cl, DMAP, CH2Cl2, rt; (f) AIBN, Bu3SnH, toluene, 80–908C; (g) 0.1N HCl, MeOH; (h) BzCl, Py/CH2Cl2; (i) TFA, H2O;
(j) Ac2O, Py.
deprotected by careful treatment with a catalytic amount of
potassium carbonate in methanol in 20 min to give the
desired L-b-30-C-cyano-20,30-unsaturated uracil derivative
33 and L-b-30-C-cyano-20,30-unsaturated thymine derivative
34 in ca. 70% yield. Compound 20 could not be converted to
the desired compound 35 when using the same procedure
described for 18 and 19. Our understanding is that longer
time required for the deprotection of the benzamidic
functionality in compound 20 allows the competitive
deprotonation of H-40, with elimination of the base and
formation of a furan-type product. As further evidence of
this mechanism, when 18 and 19 were treated with
potassium carbonate in methanol for more than 1 h, the
yields for 33 and 34 were very low, about 8–10%, and a
similar decomposition pattern was observed. When com-
pounds 18–20 were tested for acid–base stability, their
half-life at pH 11.0 was found to be only 2 h, whereas the
compounds were stable at pH 2.0 and 7.0. Because of the
lability of these nucleosides under basic conditions, the
deprotection reaction for 20 was run in two steps. First,
selective N 4-debenzoylation was accomplished using
hydrazine hydrate in buffered acetic acid–pyridine11 to
give 21. Compound 21 was then treated with potassium
carbonate in methanol under carefully controlled conditions
to afford compound 35. The total yield for the two steps was
about 60%. This two-step deprotection strategy was also
applied for the formation of L-b-30-C-cyano-30-deoxy–
ribonucleosides 36–38 (Scheme 2). Because of the acidit0y
of 30-H and the presence of a leaving group at the 2 -
position, attempts to deprotect 12–14 by potassium
carbonate in methanol or NH3/MeOH did not produce the
desired products. Instead, complex mixtures were obtained,
containing also b-elimination products. Removal of the 20-
acetyl group by treatment with hydrazine hydrate i0n
buffered acetic acid–pyridine to selectively deprotect 2 -
OAc to 20-OH allowed us to remove the leaving group,
thereby avoiding the elimination reaction under the
subsequent basic conditions. As a result, compounds 22–
24 could be deprotected by treatment with potassium
carbonate in methanol to produce the desired products
36–38 in good yields. For the synthesis of purine analogs,
the key intermediate 11 was condensed with silylated N 6-
benzoyladenine and N 2-acetyl-6-O-diphenylcarbamoylgua-
nine derivatives to give the corresponding nucleosides 15
and 16 in 75 and 62% yields, respectively (Scheme 2). In
both cases, only N-9 glycosylation products were obtained.
However, when 11 was condensed with silylated hypox-
anthine, besides the N-9 isomer 17, also the N-7 isomer was
obtained, with a N-9/N-7 ratio of 5:1 in 73% total yield. The
pure compound 17 was isolated from the mixture by
recrystallization from methanol/acetone/hexane. The
unsaturated purines 25–27 were obtained by using the
same elimination procedure as described for the pyrimidines
12–14 with DBU/DMAP. Nucleosides 25 and 26 were
deprotected by treatment with hydrazine hydrate in buffered
acetic acid–pyridine to give 28 and 29, respectively. In the
latter compound, the N 2-acetate could not be deprotected
under the reaction conditions. This caused the final
deprotection step to 40 to proceed in lower yield (35%)
than for the deprotection of 27 to 41 (65%) and 28 to 39
(71%). By using the same procedure employed for
pyrimidines 36–38, purines 15–17 were first selectively
deprotected by hydrazine hydrate in buffered acetic acid–
pyridine, then further deprotected by tre0atment wit0h
potassium carbonate in methanol to give L-3 -C-cyano-3 -
deoxyribonucleosides 42–44.
2.2. Anti-HIV activity
The synthesized L-b-30-C-cyano-20,30-unsaturated nucleo-
sides (33–35, 39–41) and L-30-C-cyano-30-deoxyribo-
nucleosides (36–38, 42–44) were evaluated against HIV-
1 in human PBM cells in vitro and the results are
summarized in Tables 1 and 2. Among the tested nucleo-
sides, only compounds 33 (EC50 21.7 mM), 34 (EC50
38.0 mM), 39 (EC50 67.4 mM), 40 (EC50 28.0 mM) and 42

W. Zhu et al. / Tetrahedron 59 (2003) 6423–6431
6425
Scheme 2. (a) BSA, pyrimidines or purines, TMSOTf, CH3CN; (b) DMAP, DBU, CH2Cl2; (c) N2H4·H2O, AcOH, Py; (d) K2CO3, MeOH.
(EC50 74.8 mM) showed modest anti-HIV activity. Only the
guanosine analog showed some cytotoxicity (IC50
46.7 mM).
previously reported for the synthesis of D-isomers.7 The
newly synthesized compounds were evaluated for anti-HIV
activity and four of them showed modest antiviral activity.
3. Conclusion
4. Experimental
4.1. General
We described an efficient and convenient route for the
synthesis of L-b-30-C-cyano-20,30-didehydro-2030-dideoxy-
nucleosides and L-b-30-C-cyano-30-deoxyribonucleosides.
Our scheme features a convergent approach in which the
common key intermediate can be coupled to an array of
heterocycles to synthesize a series of modified nucleosides,
thus overcoming the limitation of linear approaches
Melting points were determined on a Mel-temp II apparatus
and are uncorrected. Nuclear magnetic resonance spectra
were recorded on a Bruker 400 AMX spectrometer at
1
400 MHz for H NMR and 100 MHz for 13C NMR with
tetramethylsilane as the internal standard. Chemical shifts

6426
W. Zhu et al. / Tetrahedron 59 (2003) 6423–6431
Table 1. Anti-HIV activity and cytotoxicity of L-30-C-cyano-20,30-
unsaturated nucleosides
as a white solid: Rf 0.58 (hexane/ethyl acetate, 2:1); mp 95–
1
978C; [a]2D5¼296.8 (c 2.9, CH2Cl2); H NMR (CDCl3) d
8.07–7.43 (m, 5H), 5.93 (d, J¼3.5 Hz, 1H), 4.89 (t,
J¼4.1 Hz, 1H), 4.63–4.54 (m, 3H), 2.99 (dd, J¼9.4,
4.5 Hz, 1H), 1.61 (s, 3H), 1.37 (s, 3H); MS (ESI) m/z 304
(MHþ). Anal. calcd for C16H17NO5: C, 63.36; H, 5.65; N,
4.62. Found: C, 63.32; H, 5.54; N, 4.57.
Compd (B)
HIV (EC50, mM)
Toxicity (IC50, mM)
PBM
PBM
CEM
VERO
4.1.2. 1,2-Di-O-acetyl-5-O-benzoyl-3-C-cyano-3-deoxy-
L-ribofuranose (11). A solution of 9 (28 g, 92.0 mmol) in
trifluoroacetic acid/water (30 mL, 9:1 v/v) was stirred for
6 h. The mixture was concentrated in vacuum to crude 10.
This was diluted with dry pyridine (40 mL). After cooling to
08C, acetic anhydride (23 mL, 240 mmol) was added
dropwise with stirring at 0–88C, and stirring was continued
for 12 h at rt. The mixture was concentrated in vacuum,
diluted with dichloromethane (200 mL), washed with
aqueous 5% sodium bicarbonate (100 mL) and water
(100 mL), dried over sodium sulfate, filtered and concen-
trated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate, 10:1–3:1) to give
the pure anomeric mixture 11 (32 g, 90% yield) as a white
solid: Rf 0.50 (hexane/ethyl acetate, 2:1); 1H NMR (CDCl3)
d 8.08–7.45 (m, 5H), 6.49 and 6.20 (d and s, J¼4.1 Hz, 1H),
5.47 and 5.30 (d and dd, J¼4.6 Hz; 8.8, 4.2 Hz, 1H), 4.85–
4.46 (m, 3H), 3.66–3.54 (m, 1H), 2.22 and 2.20 (2£s, 3H),
1.90 (s, 3H); MS (ESI) m/z 348 (MHþ). Anal. calcd for
C17H17NO7: C, 58.79; H, 4.93; N, 4.03. Found: C, 58.60; H,
4.97; N, 4.03.
33 (Uracil)
21.7
38.0
.100
67.4
28.0
.100
.100
.100
.100
.100
.100
.100
.100
82.9
.100
.100
46.7
.100
.100
.100
.100
.100
.100
29.0
34 (Thymine)
35 (Cytosine)
39 (Adenine)
40 (Guanine)
41 (Hypoxanthine)
AZT
50.0
0.004
.100
14.3
Table 2. Anti-HIV activity and cytotoxicity of L-30-C-cyano-20,30-
unsaturated nucleosides
Compd (B)
HIV (EC50, mM)
Toxicity (IC50, mM)
PBM
PBM
CEM
VERO
36 (Uracil)
.100
.100
.100
74.8
.100
.100
0.004
.100
.100
.100
.100
.100
.100
.100
.100
.100
.100
.100
.100
.100
14.3
.100
.100
.100
.100
.100
.100
29.0
37 (Thymine)
38 (Cytosine)
42 (Adenine)
43 (Guanine)
44 (Hypoxanthine)
AZT
4.1.3. 1-(20-O-Acetyl-50-O-benzoyl-30-C-cyano-30-deoxy-
L-ribofuranosyl)uracil (12). N,O-Bis(trimethylsilyl)aceta-
mide (BSA, 4.4 mL, 18 mmol) was added at rt to a mixture
of compound 11 (2.10 g, 6.0 mmol) and uracil (800 mg,
7.2 mmol) in anhydrous acetonitrile (40 mL), then stirred
under argon for 2 h at 50–608C to form a clear solution.
After being cooled to rt, trimethylsilyl trifluoromethane-
sulfonate (TMSOTf, 1.2 mL, 6.6 mmol) was added, and the
resulting mixture was refluxed for 10 h under argon. The
reaction mixture was cooled to rt, then quenched with
saturated aqueous sodium bicarbonate solution (20 mL) and
stirred until the evolution of CO2 ceased. The resulting
mixture was diluted with ethyl acetate (150 mL), washed
with brine (2£100 mL), dried over sodium sulfate, filtered
and concentrated. The residue was purified by silica gel
column chromatography (dichloromethane/methanol, 50:1)
to give compound 12 (2.0 g, 84% yield) as a white foam: Rf
0.63 (CH2Cl2/MeOH, 10:1); [a]2D5¼23.8 (c 0.35, CH2Cl2);
1H NMR (CDCl3) d 8.78 (br, 1H), 8.08–7.45 (m, 5H), 7.14
(d, J¼8.1 Hz, 1H), 5.73 (dd, J¼6.4, 1.5 Hz, 1H), 5.68 (d,
J¼8.1 Hz, 1H), 5.34 (d, J¼1.5 Hz, 1H), 4.72 (dd, J¼11.8,
3.7 Hz, 1H), 4.66 (dt, J¼10.0, 3.9 Hz, 1H), 4.59 (dd,
J¼11.8, 4.0 Hz, 1H), 4.08 (dd, J¼10.0, 6.4 Hz, 1H), 2.25 (s,
3H); MS (ESI) m/z 400 (MHþ). Anal. calcd for
C19H17N3O7·0.2H2O: C, 56.63; H, 4.35; N, 10.43. Found:
C, 56.60; H, 4.38; N, 10.27.
(d) are reported in parts per million (ppm), and signals are
reported as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), or br (broad singlet). UV spectra were recorded
on a Beckman DU-650 spectrophotometer. Optical rotations
were measured on a Jasco DIP-370 digital polarimeter.
Mass spectra were recorded on a Micromass Autospec high-
resolution mass spectrometer. TLC was performed on
Uniplates (silica gel) purchased from Analtech Co. Column
chromatograph was performed using silica gel G (TLC
grade, .440 mesh) for vacuum flash column chromato-
graph. Elemental analyses were performed by Atlantic
Microlab Inc., Norcross, GA.
4.1.1. 5-O-Benzoyl-3-C-cyano-3-deoxy-1,2-O-isopropyl-
idene-a-L-ribofuranose (9). To a solution of 3-C-cyano-
3-deoxy-1,2-O-isopropylidene-a-L-ribofuranose
(8)7–9
(20 g, 0.1 mol) and pyridine (16 mL, 0.2 mol) in dry
dichloromethane (300 mL), benzoyl chloride (14 mL,
0.12 mol) was added dropwise at 08C with stirring. The
mixture was stirred for 1 h at rt with the exclusion of
moisture. Water (100 mL) was added, and stirred for 10 min
more. After separation, the organic phase was subsequently
washed with 1% HCl (100 mL), saturated sodium
bicarbonate (100 mL) and brine (100 mL), dried over
sodium sulfate, filtered and concentrated. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate, 10:1–3:1) to give compound 9 (28.8 g, 95% yield)
4.1.4. 1-(20-O-Acetyl-50-O-benzoyl-30-C-cyano-30-deoxy-
L-ribofuranosyl)thymine (13). Using the same procedure
as described for 12, compound 11 (2.10 g, 6.0 mmol) was
condensed with thymine (900 mg, 7.2 mmol) for 10 h to
produce compound 13 (2.13 g, 86% yield) as a white foam:
Rf 0.68 (CH2Cl2/MeOH, 10:1); [a]2D4¼þ11.1 (c 0.6,

W. Zhu et al. / Tetrahedron 59 (2003) 6423–6431
6427
CH2Cl2); 1H NMR (CDCl3) d 8.49 (br, 1H), 8.08–7.44 (m,
5H), 6.93 (s, 1H), 5.73 (dd, J¼6.4, 1.4 Hz, 1H), 5.34 (d,
J¼1.4 Hz, 1H), 4.73 (dd, J¼12.0, 3.7 Hz, 1H), 4.64 (dt,
J¼10.0, 3.9 Hz, 1H), 4.57 (dd, J¼12.0, 3.9 Hz, 1H), 4.12
(dd, J¼10.0, 6.4 Hz, 1H), 2.25 (s, 3H), 1.83 (s, 3H); MS
(ESI) m/z 414 (MHþ). Anal. calcd for C20H19N3O7·0.3H2O:
C, 57.36; H, 4.72; N, 10.03. Found: C, 57.32; H, 4.67; N,
9.80.
(MHþ), 446 (MþNa). Anal. calcd for C20H17N5O6: C,
56.74; H, 4.05; N, 16.54. Found: C, 56.79; H, 4.06; N, 16.48.
4.1.9. 1-(50-O-Benzoyl-30-C-cyano-20,30-didehydro-20,30-
dideoxy-L-furanosyl)uridine (18). To a solution of com-
pound 12 (800 mg, 2.0 mmol) in dichloromethane (15 mL),
DMAP (1.46 g, 12.0 mmol) and DBU (60 mL, 0.4 mmol)
were added at rt. The reaction was completed after stirring
for 1 h. After removal of the solvent, the residue was
purified by silica gel column chromatography (dichloro-
methane/methanol, 50:1) to give compound 18 (0.66 g, 97%
yield) as a white solid: Rf 0.54 (CH2Cl2/MeOH, 10:1); mp
184–1868C; [a]D24¼þ66.8 (c 0.32, CH2Cl2); 1H NMR
(CDCl3) d 8.31 (br, 1H), 8.01–7.48 (m, 5H), 7.24 (d,
J¼7.8 Hz, 1H), 7.12 (d, J¼4.3 Hz, 1H), 6.78 (s, 1H), 5.28
(m, 1H), 5.19 (d, J¼7.8 Hz, 1H), 4.88 (dd, J¼12.9, 3.1 Hz,
1H), 4.63 (dd, J¼12.9, 2.7 Hz, 1H); MS (ESI) m/z 362
(MþNa). Anal. calcd for C17H13N3O5: C, 60.18; H, 3.86; N,
12.38. Found: C, 60.20; H, 3.93; N, 12.27.
4.1.5. 1-(20-O-Acetyl-50-O-benzoyl-30-C-cyano-30-deoxy-
L-ribofuranosyl)-N 4-benzoylcytosine (14). Using the
same procedure as described for 12, compound 11 (2.10 g,
6.0 mmol) was condensed with N 4-benzoyl cytosine
(1.55 g, 7.2 mmol) for 10 h to produce compound 14
(2.41 g, 80% yield) as a white foam: Rf 0.62 (CH2Cl2/
MeOH, 20:1); [a]D23¼220.0 (c 1.2, CHCl3); 1H NMR
(CDCl3) d 9.05 (br, 1H), 8.09–7.45 (m, 12H), 5.96 (d,
J¼6.0 Hz, 1H), 5.59 (s, 1H), 4.78–4.66 (m, 3H), 4.12 (dd,
J¼10.4, 6.0 Hz, 1H), 2.20 (s, 3H); MS (ESI) m/z 503
(MHþ). Anal. calcd for C26H22N4O7: C, 62.15; H, 4.41; N,
11.15. Found: C, 61.85; H, 4.27; N, 11.13.
4.1.10. 1-(50-O-Benzoyl-30-C-cyano-20,30-didehydro-30-
deoxy-L-furanosyl)thymidine (19). Using the same pro-
cedure as described for 18, compound 13 (1.00 g, 2.4 mmol)
was reacted with DMAP (1.46 g, 12.0 mmol) and DBU
(60 mL, 0.4 mmol) in dichloromethane (15 mL) to give
compound 19 (820 mg, 96% yield) as a white solid: Rf 0.59
(CH2Cl2/MeOH, 10:1); mp 206–2078C; [a]2D5¼þ69.3 (c
0.55, CH2Cl2); 1H NMR (CDCl3) d 8.28 (br, 1H), 8.02–7.46
(m, 5H), 7.11 (dd, J¼4.4, 1.2 Hz, 1H), 6.96 (s, 1H), 6.81 (s,
1H), 5.28 (m, 1H), 4.87 (dd, J¼12.9, 2.8 Hz, 1H), 4.58 (dd,
J¼12.9, 3.1 Hz, 1H), 1.37 (s, 3H); MS (ESI) m/z 354
(MHþ), 376 (MþNa). Anal. calcd for C18H15N3O5·0.4H2O:
C, 59.96; H, 4.42; N, 11.65. Found: C, 59.97; H, 4.23; N,
11.54.
4.1.6. N 6-Benzoyl-9-(20-O-acetyl-50-O-benzoyl-30-C-
cyano-30-deoxy-L-ribofuranosyl)adenine (15). Using the
same procedure as described for 12, compound 11 (2.10 g,
6.0 mmol) was condensed with N 6-benzoyl adenine (1.72 g,
7.2 mmol) for 24 h to produce compound 15 (2.40 g, 75%
yield) as a white foam: Rf 0.72 (CH2Cl2/MeOH, 10:1);
1
[a]2D2¼þ8.5 (c 1, CH2Cl2); H NMR (CDCl3) d 8.95 (br,
1H), 8.60 (s, 1H), 8.02 (s, 1H), 8.00–7.39 (m, 10H), 6.09 (d,
J¼4.5 Hz, 1H), 6.02 (s, 1H), 4.83–4.76 (m, 3H), 4.63 (m,
1H), 2.28 (s, 3H); MS (ESI) m/z 527 (MHþ). Anal. calcd for
C27H22N6O6·0.4MeOH: C, 61.02; H, 4.41; N, 15.58. Found:
C, 61.21; H, 4.57; N, 15.32.
4.1.7. N 2-Acetyl-6-O-diphenylcarbamoyl-9-(20-O-acetyl-
50-O-benzoyl-30-C-cyano-30-deoxy-L-ribofuranosyl)-
guanine (16). Using the same procedure as described for 12,
compound 11 (4 g, 11.5 mmol) was condensed with
4.1.11. 1-(50-O-Benzoyl-30-C-cyano-20,30-didehydro-20,30-
dideoxy-L-furanosyl)-N 4-benzoylcytidine (20). Using the
same procedure as described for 18, compound 14 (1.2 g,
2.4 mmol) was reacted with DMAP (1.46 g, 12.0 mmol) and
DBU (60 mL, 0.4 mmol) in dichloromethane (15 mL) to
give compound 20 (1.0 g, 95% yield) as a white solid: Rf
0.38 (hexanes/ethyl acetate, 1:2); mp 181–1838C;
N 2-acetyl-6-O-diphenylcarbamoyl
guanine12
(5.36 g,
13.8 mmol) for 24 h to produce compound 16 (4.82 g,
62% yield) as a white foam: Rf 0.3 (hexane/ethyl acetate,
1
1
1:1); [a]2D5¼27.6 (c 0.68, CH2Cl2); H NMR (CDCl3) d
[a]2D7¼261.5 (c 0.27, CHCl3); H NMR (CDCl3) d 8.68
8.23 (br, 1H), 7.91–7.32 (m, 16H), 5.90 (s, 1H), 5.88
(d, J¼5.9 Hz, 1H), 5.69 (m, 1H), 4.80 (dt, J¼10.3, 4.9 Hz,
1H), 4.68 (dd, J¼12.0, 4.3 Hz, 1H), 4.63 (dd, J¼12.0,
5.3 Hz, 1H), 2.22 (s, 3H), 2.12 (s, 3H); MS (ESI) m/z 676
(MHþ), 698 (MþNa). Anal. calcd for C35H29N7O8:
C, 62.22; H, 4.33; N, 14.51. Found: C, 62.57; H, 4.18; N,
14.37.
(br, 1H), 7.95–7.43 (m, 12H), 7.05 (m, 2H), 5.39 (m, 1H),
4.79 (dd, J¼12.9, 2.8 Hz, 1H), 4.71 (dd, J¼12.9, 3.1 Hz,
1H); MS (ESI) m/z 443 (MHþ). Anal. calcd for
C24H18N4O5: C, 65.15; H, 4.10; N, 12.66. Found: C,
65.17; H, 4.09; N, 12.55.
4.1.12. 1-(50-O-Benzoyl-30-C-cyano-20,30-didehydro-20,30-
dideoxy-L-furanosyl)cytidine (21). To a solution of
compound 20 (900 mg, 2.0 mmol) in AcOH–Py (10 mL,
1:4 v/v), 85% hydrazine hydrate (0.7 mL, 12.0 mmol) was
added at rt. After continually stirring for 24 h, acetone
(5 mL) was added, and stirred for 30 min more. After
removal of the solvent, the residue was purified by silica gel
4.1.8. 9-(20-O-acetyl-50-O-benzoyl-30-C-cyano-30-deoxy-L-
ribofuranosyl)hypoxanthine (17). Using the same pro-
cedure as described for 12, compound 11 (3 g, 8.6 mmol)
was condensed with hypoxanthine (1.76 g, 13 mmol) for
36 h to produce compound 17 (2.22 g, 61% yield)
accompanied with its N-7 isomer (0.44 g, 12% yield). The
pure N-9 isomer was recrystallized from the mixture in
methanol/acetone/hexanes: Rf 0.45 (CH2Cl2/MeOH, 10:1);
mp 248–2508C; 1H NMR (DMSO-d6) d 12.43 (br, 1H), 8.22
(s, 1H), 7.92 (s, 1H), 7.91–7.47 (m, 5H), 6.29 (d, J¼1.6 Hz,
1H), 5.94 (dd, J¼5.9, 1.6 Hz, 1H), 4.77 (dt, J¼10.2, 3.9 Hz,
1H), 4.66–4.53 (m, 3H), 2.17 (s, 3H); MS (ESI) m/z 424
column
chromatography
(dichloromethane/methanol,
50:1–30:1) to give compound 21 (616 mg, 91% yield) as
a white solid: Rf 0.27 (CH2Cl2/MeOH, 10:1); mp 184–
1878C; [a]2D4¼þ62.2 (c 0.29, MeOH); 1H NMR (CD3OD) d
8.01–7.49 (m, 5H), 7.44 (d, J¼7.5 Hz, 1H), 7.06 (m, 2H),
5.46 (d, J¼7.5 Hz, 1H), 5.34 (m, 1H), 4.75 (dd, J¼12.7,
3.3 Hz, 1H), 4.62 (dd, J¼12.7, 3.3 Hz, 1H); MS (ESI) m/z

6428
W. Zhu et al. / Tetrahedron 59 (2003) 6423–6431
339 (MHþ). Anal. calcd for C17H14N4O4: C, 60.35; H, 4.17;
N, 16.56. Found: C, 60.58; H, 3.96; N, 16.58.
26 (2.0 g, 93% yield) as a white solid: Rf 0.38 (hexanes/
ethyl acetate, 1:2); mp 206–2088C; [a]2D4¼þ11.8 (c 0.55,
1
CH2Cl2); H NMR (CDCl3) d 8.09 (br, 1H), 7.93 (s, 1H),
4.1.13. 1-(50-O-Benzoyl-30-C-cyano-30-deoxy-L-ribofura-
nosyl)uracil (22). Using the same procedure as described
for 21, compound 12 (1.00 g, 2.5 mmol) was selectively
deprotected by 85% hydrazine hydrate (0.9 mL, 15 mmol)
in AcOH–Py (10 mL, 1:4 v/v) to give compound 22
(805 mg, 90% yield), as a white foam: Rf 0.43 (CH2Cl2/
MeOH, 10:1); [a]2D5¼216.4 (c 0.35, MeOH); 1H NMR
(CDCl3) d 8.03–7.46 (m, 6H), 5.71 (s, 1H), 5.51 (d,
J¼7.0 Hz, 1H), 4.89–4.66 (m, 4H), 3.36 (dd, J¼10.5,
5.4 Hz, 1H); MS (ESI) m/z 358 (MHþ). Anal. calcd for
C17H15N3O6: C, 57.14; H, 4.23; N, 11.76. Found: C, 57.34;
H, 4.54; N, 11.75.
7.89–7.24 (m, 15H), 7.06 (m, 1H), 7.01 (s, 1H), 5.35 (m,
1H), 4.75 (dd, J¼12.4, 4.3 Hz, 1H), 4.62 (dd, J¼12.4,
4.1 Hz, 1H), 2.45 (s, 3H); MS (ESI) m/z 616 (MHþ), 638
(MþNa). Anal. calcd for C33H25N7O6: C, 64.39; H, 4.09; N,
15.93. Found: C, 64.42; H, 4.14; N, 15.83.
4.1.18. 9-(50-O-Benzoyl-30-C-cyano-20,30-didehydro-20,30-
dideoxy-L-furanosyl)inosine (27). Using the same pro-
cedure as described for 18, compound 17 (1.10 g, 2.6 mmol)
was reacted with DMAP (1.46 g, 12.0 mmol) and DBU
(60 mL, 0.4 mmol) in dichloromethane (15 mL) to give
compound 27 (897 mg, 95% yield) as a white solid: Rf 0.40
(CH2Cl2/MeOH, 10:1); mp 214–2168C; [a]2D2¼þ31.6 (c
4.1.14. 1-(50-O-Benzoyl-30-C-cyano-30-deoxy-L-ribofura-
nosyl)thymine (23). Using the same procedure as described
for 21, compound 13 (1.00 g, 2.4 mmol) was selectively
deprotected by 85% hydrazine hydrate (0.9 mL, 15 mmol)
in AcOH–Py (10 mL, 1:4 v/v) to give compound 23
(817 mg, 91% yield) as a white solid: Rf 0.44 (CH2Cl2/
MeOH, 10:1); mp 124–1268C, [a]2D3¼þ12.4 (c 0.52,
0.36, MeOH); H NMR (CD3OD) d 7.81–7.28 (m, 7H),
1
6.98 (m, 2H), 5.26 (m, 1H), 4.59–4.51 (m, 2H); MS (ESI)
m/z 364 (MHþ). Anal. calcd for C18H13N5O4·0.4H2O: C,
58.35; H, 3.75; N, 18.90. Found: C, 58.53; H, 3.66; N, 18.68.
4.1.19. 9-(50-O-Benzoyl-30-C-cyano-20,30-didehydro-20,30-
dideoxy-L-furanosyl)adenosine (28). Using the same
procedure as described for 21, compound 25 (900 mg,
1.9 mmol) was selectively deprotected by 85% hydrazine
hydrate (0.7 mL, 12.0 mmol) in AcOH–Py (10 mL, 1:4 v/v)
to give compound 28 (615 mg, 88% yield) as a white solid:
Rf 0.35 (CH2Cl2/MeOH, 10:1); mp 236–2388C (dec.);
1
MeOH); H NMR (CD3OD) d 8.10–7.38 (m, 5H), 7.37 (s,
1H), 5.69 (d, J¼1.6 Hz, 1H), 4.77 (dd, J¼12.2, 3.5 Hz, 1H),
4.73–4.67 (m, 2H), 4.59 (dd, J¼12.2, 3.8 Hz, 1H), 3.76 (dd,
J¼10.1, 5.7 Hz, 1H), 1.65 (s, 3H); MS (ESI) m/z 372
(MHþ). Anal. calcd for C18H17N3O6: C, 58.22; H, 4.61; N,
11.32. Found: C, 58.34; H, 4.88; N, 10.97.
1
[a]2D6¼þ69.27 (c 0.19, MeOH); H NMR (CD3OD) d 8.19
(s, 1H), 8.02 (s, 1H), 7.91–7.43 (m, 5H), 7.34 (m, H), 7.19
(m, 1H), 5.47 (m, 1H), 4.73 (dd, J¼12.4, 4.0 Hz, 1H), 4.65
(dd, J¼12.4, 4.0 Hz, 1H), MS (ESI) m/z 363 (MHþ). Anal.
calcd for C18H14N6O3: C, 59.67; H, 3.89; N, 23.19. Found:
C, 59.48; H, 4.01; N, 22.98.
4.1.15. 1-(50-O-Benzoyl-30-C-cyano-30-deoxy-L-ribofura-
nosyl)cytosine (24). Using the same procedure as described
for 21, compound 14 (1.00 g, 2.0 mmol) was selectively
deprotected by 85% hydrazine hydrate (0.7 mL, 12.0 mmol)
in AcOH–Py (10 mL, 1:4 v/v) to give compound 24
(631 mg, 89% yield) as a white solid: Rf 0.1 (CH2Cl2/
MeOH, 10:1); mp 234–2368C (dec.); [a]2D4¼258.2 (c 0.11,
MeOH); 1H NMR (CD3OD) d 8.10–7.50 (m, 6H), 5.70 (d,
J¼7.3 Hz, 1H), 5.69 (s, 1H), 4.75–4.63 (m, 4H), 3.61 (dd,
J¼10.1, 5.1 Hz, 1H); MS (ESI) m/z 357 (MHþ). Anal. calcd
for C17H16N4O5: C, 57.30; H, 4.53; N, 15.72. Found: C,
57.09; H, 4.61; N, 15.83.
4.1.20. N 2-Acetyl-9-(50-O-benzoyl-30-C-cyano-20,30-dide-
hydro-20,30-dideoxy-L-furanosyl)guanosine (29). Using
the same procedure as described for 21, compound 26
(1.85 g, 3 mmol) was selectively deprotected by 85%
hydrazine hydrate (1 mL, 17 mmol) in AcOH–Py (10 mL,
1:4 v/v) to give compound 29 (1.07 g, 85% yield) as a white
foam: Rf 0.5 (CH2Cl2/MeOH, 10:1); [a]2D2¼þ70.0 (c 0.28,
CH2Cl2); 1H NMR (CDCl3) d 12.00 (br, 1H), 9.95 (br, 1H),
8.01–7.45 (m, 6H), 6.90–6.88 (m, 2H), 5.55 (dd, J¼11.6,
7.6 Hz, 1H), 5.36 (m, 1H), 4.40 (dd, J¼11.6, 4.8 Hz, 1H),
2.36 (s, 3H); MS (ESI) m/z 421 (MHþ). Anal. calcd for
C20H16N6O5: C, 57.14; H, 3.84; N, 19.99. Found: C, 57.02;
H, 3.92; N, 20.03.
4.1.16. N 6-Benzoyl-9-(50-O-benzoyl-30-C-cyano-20,30-
didehydro-20,30-dideoxy-L-furanosyl)adenosine
(25).
Using the same procedure as described for 18, compound
15 (1.2 g, 2.3 mmol) was reacted with DMAP (1.46 g,
12.0 mmol) and DBU (60 mL, 0.4 mmol) in dichloro-
methane (15 mL) to give compound 25 (1.0 g, 94% yield)
as
a
white foam: Rf 0.67 (CH2Cl2/MeOH, 10:1);
4.1.21. 9-(50-O-Benzoyl-30-C-cyano-30-deoxy-L-ribofura-
nosyl)adenine (30). Using the same procedure as described
for 21, compound 15 (1.00 g, 1.9 mmol) was selectively
deprotected by 85% hydrazine hydrate (0.7 mL, 12.0 mmol)
in AcOH–Py (10 mL, 1:4 v/v) to give compound 30
(636 mg, 88% yield) as a white solid: Rf 0.34 (CH2Cl2/
MeOH, 10:1); mp 125–1278C; [a]2D5¼þ14.9 (c 0.29,
1
[a]2D2¼þ13.6 (c 1, CH2Cl2); H NMR (CDCl3) d 9.07 (br,
1H), 8.74 (s, 1H), 8.05 (s, 1H), 7.99–7.37 (m, 10H), 7.20 (d,
J¼3.1 Hz, 1H), 7.17 (s, 1H), 5.41 (m, 1H), 4.75 (dd, J¼12.4,
4.0 Hz, 1H), 4.66 (dd, J¼12.4, 4.2 Hz, 1H); MS (ESI) m/z
467 (MHþ). Anal. calcd for C25H18N6O4: C, 64.37; H, 3.89;
N, 18.02. Found: C, 64.18; H, 4.01; N, 17.98.
1
MeOH); H NMR (CD3OD) d 8.18 (s, 1H), 8.03 (s, 1H),
4.1.17. N 2-Acetyl-6-O-diphenylcarbamoyl-9-(50-O-
benzoyl-30-C-cyano-20,30-didehydro-20,30-dideoxy-L-fura-
nosyl)guanosine (26). Using the same procedure as
described for 18, compound 16 (2.4 g, 3.6 mmol) was
reacted with DMAP (1.46 g, 12.0 mmol) and DBU (60 mL,
0.4 mmol) in dichloromethane (15 mL) to give compound
7.90–7.40 (m, 5H), 6.06 (d, J¼1.2 Hz, 1H), 5.14 (d,
J¼4.5 Hz, 1H), 4.79 (dt, J¼10.2, 3.6 Hz, 1H), 4.72 (dd,
J¼12.4, 3.7 Hz, 1H), 4.62 (dd, J¼12.4, 3.5 Hz, 1H), 4.42
(dd, J¼10.2, 5.3 Hz, 1H); MS (ESI) m/z 381 (MHþ). Anal.
calcd for C18H16N6O4: C, 56.84; H, 4.24; N, 22.10. Found:
C, 57.11; H, 4.24; N, 21.97.

W. Zhu et al. / Tetrahedron 59 (2003) 6423–6431
6429
4.1.22. N2-Acetyl-9-(50-O-benzoyl-30-C-cyano-30-deoxy-
L-ribofuranosyl)guanine (31). Using the same procedure
as described for 21, compound 16 (2 g, 3 mmol) was
selectively deprotected by 85% hydrazine hydrate (1.2 mL,
20 mmol) in AcOH–Py (15 mL, 1:4 v/v) to give compound
31 (1.04 g, 80% yield) as a white solid: Rf 0.37 (CH2Cl2/
MeOH, 10:1); mp 219–2208C; [a]2D4¼252.8 (c 0.61,
treated with potassium carbonate (50 mg, 0.36 mmol) in
methanol (15 mL) to give compound 35 (232 mg, 67%
yield) as a white solid: Rf 0.43 (CH2Cl2/MeOH, 4:1); mp
250–2528C (dec.); [a]D24¼2116.4 (c 0.079, MeOH); UV
(MeOH) lmax 267.5 nm (1 8853); 1H NMR (CD3OD) d 7.92
(d, J¼7.5 Hz, 1H), 7.12 (dd, J¼3.9, 1.6 Hz, 1H), 6.90 (t,
J¼1.8 Hz, 1H), 5.88 (d, J¼7.5 Hz, 1H), 5.02 (m, 1H), 3.87
(m, 2H); 13C NMR (CD3OD) d 166.6, 156.9, 142.4, 142.2,
118.4, 112.5, 95.4, 90.8, 87.1, 61.0; MS (ESI) m/z 235
(MHþ). Anal. calcd for C10H10N4O3: C, 51.28; H, 4.30; N,
23.92. Found: C, 51.35; H, 4.28; N, 23.79.
1
acetone); H NMR (CD3OD) d 7.99 (s, 1H), 7.85–7.35
(m, 5H), 5.96 (s, 1H), 5.03 (d, J¼5.1 Hz, 1H), 4.77 (m, 1H),
4.74 (m, 1H), 4.47 (dd, J¼10.2, 5.1 Hz, 1H), 2.12 (s, 3H);
MS (ESI) m/z 439 (MHþ). Anal. calcd for C20H18N6O6: C,
54.79; H, 4.14; N, 19.17. Found: C, 54.41; H, 4.28; N, 19.38.
4.1.27. 1-(30-C-Cyano-30-deoxy-L-ribofuranosyl)uracil
(36). Using the same procedure as described for 33,
compound 22 (700 mg, 2.0 mmol) was treated with
potassium carbonate (70 mg, 0.5 mmol) in methanol
(15 mL) to give compound 36 (411 mg, 83% yield) as a
white foam: Rf 0.3 (CH2Cl2/MeOH, 9:1); [a]2D5¼244.8 (c
0.3, MeOH); UV (MeOH) lmax 260 nm (1 9279); 1H NMR
(CD3OD) d 8.01 (d, J¼8.0 Hz, 1H), 5.75 (s, 1H), 5.64 (d,
J¼8.0 Hz, 1H), 4.56 (d, J¼5.1 Hz, 1H), 4.44 (dt, J¼10.2,
2.3 Hz, 1H), 4.02 (dd, J¼12.9, 2.4 Hz, 1H), 3.76 (dd,
J¼12.9, 2.7 Hz, 1H), 3.49 (dd, J¼10.2, 5.1 Hz, 1H); 13C
NMR (CD3OD) d 165.1, 150.8, 141.2, 115.9, 101.0, 93.4,
82.8, 75.4, 59.5, 34.6; MS (ESI) m/z 276 (MþNa). Anal.
calcd for C10H11N3O5: C, 47.43; H, 4.38; N, 16.59. Found:
C, 47.20; H, 4.27; N, 16.55.
4.1.23. 9-(50-O-Benzoyl-30-C-cyano-30-deoxy-L-ribofura-
nosyl)hypoxanthine (32). Using the same procedure as
described for 21, compound 17 (1.00 g, 2.4 mmol) was
selectively deprotected by 85% hydrazine hydrate (0.9 mL,
15 mmol) in AcOH–Py (10 mL, 1:4 v/v) to give compound
32 (783 mg, 87% yield) as a white solid: Rf 0.2 (CH2Cl2/
MeOH, 10:1); mp 174–1768C; [a]2D6¼þ18.5 (c 0.72,
1
acetone); H NMR (CD3OD) d 8.16 (s, 1H), 7.93–7.43
(m, 6H), 6.07 (s, 1H), 5.07 (d, J¼5.5 Hz, 1H), 4.79–4.64
(m, 3H), 4.30 (dd, J¼10.2, 5.1 Hz, 1H); MS (ESI) m/z 382
(MHþ). Anal. calcd for C18H15N5O5: C, 56.69; H, 3.96; N,
18.37. Found: C, 56.34; H, 4.07; N, 18.06.
4.1.24. 1-(30-C-Cyano-20,30-didehydro-20,30-dideoxy-L-
furanosyl)uridine (33). To a solution of compound 18
(550 mg, 1.6 mmol) in methanol (15 mL) was added
potassium carbonate (56 mg, 0.4 mmol) at 08C. After
stirring at rt for 20 min more, the reaction was quenched
with acetic acid (50 mL). After removal of the solvent, the
residue was purified by silica gel column chromatography
(dichloromethane/methanol, 50:1–25:1) to give compound
33 (270 mg, 71% yield) as a white solid: Rf 0.35 (CH2Cl2/
MeOH, 10:1); mp 138–1418C; [a]2D2¼260.7 (c 0.18,
4.1.28. 1-(30-C-Cyano-30-deoxy-L-ribofuranosyl)thymine
(37). Using the same procedure as described for 33,
compound 23 (700 mg, 1.9 mmol) was treated with
potassium carbonate (70 mg, 0.5 mmol) in methanol
(15 mL) to give compound 37 (423 mg, 84% yield) as a
white solid: Rf 0.29 (CH2Cl2/MeOH, 10:1); mp 108–1108C;
[a]2D4¼220.5 (c 0.37, MeOH); UV (MeOH) lmax 264.5 nm
1
(1 9717); H NMR (CD3OD) d 7.85 (s, 1H), 5.76 (s, 1H),
1
MeOH); UV (MeOH) lmax 257.5 nm (1 11004); H NMR
4.54 (d, J¼5.3 Hz, 1H), 4.42 (dt, J¼10.0, 2.4 Hz, 1H), 4.02
(dd, J¼12.8, 2.3 Hz, 1H), 3.76 (dd, J¼12.8, 2.6 Hz, 1H),
3.52 (dd, J¼10.0, 5.3 Hz, 1H), 1.84 (s, 3H); 13C NMR
(CD3OD) d 164.5, 151.0, 136.8, 117.7, 109.7, 92.0, 82.1,
74.8, 60.3, 35.6, 12.9; MS (ESI) m/z 268 (MHþ). Anal. calcd
for C11H13N3O5: C, 49.44; H, 4.90; N, 15.72. Found: C,
49.25; H, 4.94; N, 15.58.
(CD3OD) d 7.89 (d, J¼8.1 Hz, 1H), 7.08 (m, 1H), 6.90 (t,
J¼1.8 Hz, 1H), 5.67 (d, J¼8.1 Hz, 1H), 5.01 (m, 1H), 3.86
(s, 2H); 13C NMR (CD3OD) d 164.9, 151.1, 141.8, 141.0,
119.2, 112.0, 101.8, 89.7, 87.2, 60.8; MS (ESI) m/z 258
(MþNa). Anal. calcd for C10H9N3O4·0.5H2O: C, 49.18; H,
4.13; N, 17.21. Found: C, 49.32; H, 4.08; N, 16.90.
4.1.25. 1-(30-C-Cyano-20,30-didehydro-30-deoxy-L-fura-
nosyl)thymidine (34). Using the same procedure as
described for 33, compound 19 (650 mg, 1.8 mmol) was
treated with potassium carbonate (60 mg, 0.43 mmol) in
methanol (15 mL) to give compound 34 (312 mg, 68%
yield) as a white solid: Rf 0.37 (CH2Cl2/MeOH, 10:1); mp
200–2028C; [a]2D6¼217.1 (c 0.5, MeOH) (the optical
rotation for the D-isomer7a has not been reported); UV
(MeOH) lmax 263 nm (1 13400); 1H NMR (CD3OD) d 7.75
(s, 1H), 7.09 (dd, J¼3.9, 1.5 Hz, 1H), 6.90 (t, J¼1.5 Hz,
1H), 5.00 (m, 1H), 3.88 (s, 2H), 1.84 (s, 3H); 13C NMR
(CD3OD) d 166.4, 152.5, 142.6, 138.6, 120.3, 113.3, 111.8,
90.7, 88.3, 62.0, 12.4; MS (ESI) m/z 250 (MHþ). Anal. calcd
for C11H11N3O4: C, 53.01; H, 4.45; N, 16.86. Found: C,
52.97; H, 4.51; N, 16.53.
4.1.29. 1-(30-C-Cyano-30-deoxy-L-ribofuranosyl)cytosine
(38). Using the same procedure as described for 33,
compound 24 (500 mg, 1.4 mmol) was treated with
potassium carbonate (70 mg, 0.5 mmol) in methanol
(15 mL) to give compound 38 (287 mg, 81% yield) as a
white solid: Rf 0.25 (CH2Cl2/MeOH, 3:1); mp 126–1298C;
[a]2D3¼248.9 (c 1.8, MeOH); UV (MeOH) lmax 270.5 nm
(1 6705); 1H NMR (CD3OD) d 8.05 (d, J¼7.5 Hz, 1H), 5.85
(d, J¼7.5 Hz, 1H), 5.75 (s, 1H), 4.51 (d, J¼4.9 Hz, 1H),
4.46 (dt, J¼10.4, 2.4 Hz, 1H), 4.04 (dd, J¼12.8, 2.2 Hz,
1H), 3.78 (dd, J¼12.8, 2.5 Hz, 1H), 3.42 (dd, J¼10.4,
4.9 Hz, 1H); 13C NMR (CD3OD) d 166.6, 156.9, 141.5,
116.0, 94.4, 94.1, 82.8, 75.8, 59.4, 34.4; MS (ESI) m/z 253
(MHþ). Anal. calcd for C10H12N4O4: C, 47.62; H, 4.80; N,
22.21. Found: C, 47.49; H, 4.94; N, 22.09.
4.1.26. 1-(30-C-Cyano-20,30-didehydro-20,30-dideoxy-L-
furanosyl)cytidine (35). Using the same procedure as
described for 33, compound 21 (500 mg, 1.5 mmol) was
4.1.30. 9-(30-C-Cyano-20,30-didehydro-20,30-dideoxy-L-
furanosyl)adenosine (39). Using the same procedure as
described for 33, compound 28 (500 mg, 1.4 mmol) was

6430
W. Zhu et al. / Tetrahedron 59 (2003) 6423–6431
treated with potassium carbonate (50 mg, 0.36 mmol) in
methanol (15 mL) to give compound 39 (253 mg, 71%
yield) as a white solid: Rf 0.45 (CH2Cl2/MeOH, 8:1); mp
223–2258C (dec.); [a]2D3¼241.4 (c 0.13, MeOH); UV
(MeOH) lmax 259 nm (1 14703); 1H NMR (CD3OD) d 8.30
(s, 1H), 8.20 (s, 1H), 7.18 (dd, J¼3.5, 1.6 Hz, 1H), 7.08 (t,
J¼1.8 Hz, 1H), 5.16 (m, 1H), 3.88 (m, 2H); 13C NMR
(CD3OD) d 156.8, 153.5, 149.6, 142.4, 140.0, 119.2, 118.2,
113.8, 88.5, 87.7, 61.9; MS (ESI) m/z 259 (MHþ). Anal.
calcd for C11H10N6O2: C, 51.16; H, 3.90; N, 32.54. Found:
C, 51.09; H, 3.93; N, 32.35.
MeOH–H2O (1:1)); UV (MeOH) lmax 251.5 nm (1 15513);
1H NMR (D2OþDMSO-d6) d 7.88 (s, 1H), 5.77 (s, 1H),
4.71 (d, J¼5.7 Hz, 1H), 4.31 (m, 1H), 3.93–3.67 (m, 2H),
3.60 (m, 1H); 13C NMR (D2OþDMSO-d6) d 157.4, 154.4,
151.4, 136.3, 118.0, 117.4, 90.7, 82.4, 75.1, 61.4, 36.9; MS
(ESI) m/z 293 (MHþ). Anal. calcd for C11H12N6O4: C,
45.21; H, 4.14; N, 28.76. Found: C, 45.17; H, 4.26; N, 28.48.
4.1.35. 9-(30-C-Cyano-30-deoxy-L-ribofuranosyl)hypox-
anthine (44). Using the same procedure as described for
33, compound 32 (650 mg, 1.7 mmol) was treated with
potassium carbonate (70 mg, 0.5 mmol) in methanol
(15 mL) to give compound 44 (368 mg, 78% yield) as a
white solid: mp 148–1508C; [a]2D3¼þ42.1 (c 0.6, MeOH);
UV (MeOH) lmax 245.5 nm (1 11590); 1H NMR (CD3OD)
d 8.36 (s, 1H), 8.07 (s, 1H), 6.10 (d, J¼1.5 Hz, 1H), 4.91
(dd, J¼5.4, 1.9 Hz, 1H), 4.55 (dt, J¼9.8, 2.7 Hz, 1H), 4.01
(dd, J¼12.7, 2.9 Hz, 1H), 3.93 (dd, J¼9.8, 5.4 Hz, 1H), 3.79
(dd, J¼12.7, 2.9 Hz, 1H); 13C NMR (CD3OD) d 157.6,
148.1, 145.7, 139.4, 124.7, 116.1, 92.2, 83.0, 75.6, 60.1,
35.3; MS (ESI) m/z 278 (MHþ). Anal. calcd for
C11H11N5O4·0.5H2O: C, 46.16; H, 4.23; N, 24.47. Found:
C, 46.20; H, 4.19; N, 24.40.
4.1.31. 9-(30-C-Cyano-20,30-didehydro-20,30-dideoxy-L-
furanosyl)guanosine (40). Using the same procedure as
described for 33, compound 29 (900 mg, 2.1 mmol) was
treated with potassium carbonate (70 mg, 0.5 mmol) in
methanol (15 mL) to give compound 40 (205 mg, 35%
yield) as a white foam: Rf 0.45 (CH2Cl2/MeOH, 8:1);
[a]2D6¼231.8 (c 0.1, MeOH); UV (MeOH) lmax 251 nm (1
1
15014);); H NMR (D2OþDMSO-d6) d 7.94 (s, 1H), 7.04
(s, 1H), 6.91 (s, 1H), 5.10 (m, 1H), 3.86 (m, 2H). 13C NMR
(D2OþDMSO-d6) d 157.4, 154.7, 151.4, 142.3, 136.2,
118.2, 116.8, 113.8, 87.8, 87.6, 61.8. MS (ESI) m/z 275
(MHþ). Anal. calcd for C11H9N5O3: C, 48.18; H, 3.68; N,
30.65. Found: C, 48.23; H, 3.75; N, 30.56.
Acknowledgements
4.1.32. 9-(30-C-Cyano-20,30-didehydro-20,30-dideoxy-L-
furanosyl)inosine (41). Using the same procedure as
described for 33, compound 27 (700 mg, 1.9 mmol) was
treated with potassium carbonate (60 mg, 0.43 mmol) in
methanol (15 mL) to give compound 41 (325 mg, 65%
yield) as a white solid: Rf 0.26 (CH2Cl2/MeOH, 8:1); mp
150–1528C; [a]2D2¼237.4 (c 0.4, MeOH); UV (MeOH)
This research was supported by the US Public Health
Service grant AI 32351 from the National Institute of
Allergy and Infectious Diseases, NIH.
l
max 244 nm (1 12378); 1H NMR (CD3OD) d 8.30 (s, 1H),
References
8.07 (s, 1H), 7.20 (dd, J¼3.3, 1.9 Hz, 1H), 7.09 (t,
J¼1.9 Hz, 1H), 5.15 (m, 1H), 3.87 (m, 2H); 13C NMR
(CD3OD) d 157.7, 148.6, 146.0, 140.0, 139.6, 124.0, 119.1,
112.0, 88.8, 88.1, 61.0; MS (ESI) m/z 260 (MHþ). Anal.
calcd for C11H9N5O3·0.9H2O: C, 47.97; H, 3.95; N, 25.43.
Found: C, 48.15; H, 4.00; N, 25.14.
1. (a) Hamamoto, Y.; Yamamoto, N.; Matsui, T.; Matsuda, A.;
Ueda, T. Antimicrob. Agents Chemother. 1987, 31, 907–910.
(b) Lin, T.-S.; Schinazi, R. F.; Prusoff, W. H. Biochem.
Pharmacol. 1987, 36, 2713–2718.
2. (a) Gosselin, G.; Schinazi, R. F.; Sommadossi, J.-P.; Mathe,
C.; Bergogne, M. C.; Aubertin, A.-M.; Kirn, A.; Imbach, J.-L.
Antimicrob. Agents Chemother. 1994, 38, 1292–1297. (b) Lin,
T.-S.; Luo, M. Z.; Liu, M. C.; Zhu, Y. L.; Gullen, E.;
Dutchman, G. E.; Cheng, Y.-C. J. Med. Chem. 1996, 39,
1757–1759.
4.1.33. 9-(30-C-Cyano-30-deoxy-L-ribofuranosyl)adenine
(42). Using the same procedure as described for 33,
compound 30 (500 mg, 1.3 mmol) was treated with
potassium carbonate (70 mg, 0.5 mmol) in methanol
(15 mL) to give compound 42 (276 mg, 76% yield) as a
white solid: Rf 0.14 (CH2Cl2/MeOH, 10:1); mp 236–2388C
(dec.); [a]2D3¼þ45.3 (c 0.11, MeOH); UV (MeOH) lmax
258.5 nm (1 14894); 1H NMR (D2OþDMSO-d6) d 8.34 (s,
1H), 8.15 (s, 1H), 5.99 (d, J¼2.0 Hz, 1H), 4.84 (dd, J¼5.6,
2.0 Hz, 1H), 4.40 (m, 1H), 3.90 (dd, J¼9.1, 5.6 Hz, 1H),
3.76–3.51 (m, 2H); 13C NMR (D2OþDMSO-d6) d 156.8,
153.3, 149.4, 139.9, 119.7, 117.9, 91.2, 82.6, 74.9, 61.1,
36.4; MS (ESI) m/z 277 (MHþ). Anal. calcd for
C11H12N6O3: C, 47.83; H, 4.38; N, 30.42. Found: C,
47.47; H, 4.46; N, 30.27.
3. Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.; St.
Clair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.; Reardon,
J. E.; Dornsife, R. E.; Averet, D. R.; Krenitsky, T. A.
Antimicrob. Agents Chemother. 1997, 41, 1082–1093.
4. (a) Lee, K.; Choi, Y. S.; Gullen, E.; Schlueter-Wirtz, S.;
Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1999,
42, 1320–1328. (b) Chong, Y. H.; Gumina, G.; Schinazi, R. F.;
Chu, C. K. J. Med. Chem. 2003. in press.
5. (a) Choo, H.; Chong, Y. H.; Choi, Y. S.; Mathew, J.; Schinazi,
R. F.; Chu, C. K. J. Med. Chem. 2003, 46, 389–398. (b) Zhu,
W.; Choo, H.; Chong, Y.; Mathews, J.; Schinazi, R. F.; Chu,
C. K. J. Med. Chem. 2003 submitted.
4.1.34. 9-(30-C-Cyano-30-deoxy-L-ribofuranosyl)guanine
(43). Using the same procedure as described for 33,
compound 31 (800 mg, 1.9 mmol) was treated with
potassium carbonate (70 mg, 0.5 mmol) in methanol
(15 mL) to give compound 43 (350 mg, 63% yield) as a
white solid: mp 235–2378C (dec.); [a]2D5¼þ22.0 (c 0.08,
6. (a) Gumina, G.; Song, G.-Y.; Chu, C. K. FEMS Microbiol.
Lett. 2001, 202, 9–15. (b) Schinazi, R. F.; Chu, C. K.; Peck,
A.; McMillan, A.; Mathis, R.; Cannon, D.; Jeong, L.-S.;
Beach, J. W.; Choi, W.-B.; Yeola, S.; Liotta, D. C. Antimicrob.
Agents Chemother. 1992, 36, 672–676. (c) Schinazi, R. F.;
McMillan, A.; Cannon, D.; Mathis, R.; Lloyd, R. M.; Peck, A.;

W. Zhu et al. / Tetrahedron 59 (2003) 6423–6431
6431
Sommadossi, J.-P.; St. Clair, M.; Wilson, J.; Furman, P. A.;
Painter, G.; Choi, W.-B.; Liotta, D. C. Antimicrob. Agents
Chemother. 1992, 36, 2423–2431. (d) Furman, P. A.; Davis,
M.; Liotta, D. C.; Paff, M.; Frick, L. W.; Nelson, D. J.;
Dornsife, R. E.; Wurster, J. A.; Wilson, L. J.; Fyfe, J. A.;
Tuttle, J. V.; Miller, W. H.; Condreay, L.; Averett, D. R.;
Schinazi, R. F.; Painter, G. R. Antimicrob. Agents Chemother.
1992, 36, 2686–2692. (e) Beach, J. W.; Jeong, L. S.; Alves,
A. J.; Pohl, D.; Kim, H. O.; Chang, C.-N.; Doong, S.-L.;
Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K. J. Org. Chem. 1992,
57, 2217–2219.
8. (a) Calvo-Mateo, A.; Camarasa, M.-J.; Diaz-Ortiz, A.; De las
Heras, F. G. J. Chem. Soc. Chem. Commun. 1988, 1114–1115.
(b) Filichev, V. V.; Brandt, M.; Pedersen, E. B. Carbohydr.
Res. 2001, 333, 115–122. (c) Lu, Y.; Just, G. Tetrahedron
2001, 57, 1677–1687.
9. (a) Ma, T.; Pai, S. B.; Zhu, Y. L.; Lin, J. S.; Shanmuganathan,
K.; Du, J.; Wang, C.; Kim, H.; Newton, M. G.; Cheng, Y.-C.;
Chu, C. K. J. Med. Chem. 1996, 39, 2835–2843.
(b) Cooperwood, J. S.; Boyd, V.; Gumina, G.; Chu, C. K.
Nucleosides Nucleotides 2000, 19, 219–236.
10. (a) Matsuda, A.; Azuma, A. Nucleosides Nucleotides 1995, 14,
461–471. (b) Azuma, A.; Nakajima, Y.; Nishizono, N.;
Minakawa, N.; Suzuki, M.; Hanaoka, K.; Kobayashi, T.;
Tanaka, M.; Sasaki, T.; Matsuda, A. J. Med. Chem. 1993, 36,
4183–4189.
´
´
7. (a) Calvo-Mateo, A.; Camarasa, M.-J.; Dıaz-Ortız, A.; De las
Heras, F. G.; Alemany, A. Tetrahedron 1988, 44, 4895–4903.
(b) Faul, M. M.; Huff, B. E.; Dunlap, S. E.; Frank, S. A.; Fritz,
J. E.; Kaldor, S. W.; Le Tourneau, M. E.; Staszak, M. A.;
Ward, J. A.; Kaldor, S. W.; Le Tourneau, M. E.; Staszak,
M. A.; Ward, J. A.; Werner, J. A.; Winneroski, L. L.
Tetrahedron 1997, 53, 8085–8104.
11. Ishido, Y.; Nakazaki, N.; Sakairi, N. J. Chem. Soc., Perkin
Trans. 1 1979, 2088–2098.
12. Zou, R.; Robins, M. J. Can. J. Chem. 1987, 65, 1436–1437.