Syntheses of 4'-C-ethynyl-beta-D-arabino- and 4'-C-ethynyl-2'-deoxy-beta-D-ribo-pentofuranosylpyrimidines and -purines and evaluation of their anti-HIV activity.

Article abstract of DOI:10.1021/jm000209n

4'-C-Ethynyl-beta-D-arabino- and 4'-C-ethynyl-2'-deoxy-beta-D-ribo-pentofuranosylpyrimidine and -purine nucleosides were synthesized and evaluated for their in vitro anti-HIV activity. The key intermediate, 4-C-ethynyl- or 4-C-triethylsilylethynyl-D-ribo-

Full text of DOI:10.1021/jm000209n

4516
J . Med. Chem. 2000, 43, 4516-4525
Syn th eses of 4′-C-Eth yn yl-â-D-a r a bin o- a n d
4′-C-Eth yn yl-2′-d eoxy-â-D-r ibo-p en tofu r a n osylp yr im id in es a n d -p u r in es a n d
Eva lu a tion of Th eir An ti-HIV Activity
Hiroshi Ohrui,*,† Satoru Kohgo,† Kenji Kitano,§ Shinji Sakata,§ Eiichi Kodama,‡ Kazuhisa Yoshimura,#
Masao Matsuoka,‡ Shiro Shigeta,| and Hiroaki Mitsuya#,
Division of Life Science, Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi,
Aoba-ku, Sendai 981-8555, J apan, Biochemicals Division, Yamasa Corporation, Chiba 288-0056, J apan, Laboratory of Virus
Immunology, Research Center for AIDS, Institute for Virus Research, Kyoto University, Kyoto 606-8507, J apan, Department of
Microbiology, Fukushima Medical University, Fukushima 960-1295, J apan, Department of Internal Medicine II, Kumamoto
University, School of Medicine, Kumamoto 860, J apan, and Experimental Retrovirology Section, Medicine Branch, Division of
Clinical Sciences, National Cancer Institute, Bethesda, Maryland 20892
Received May 16, 2000
4′-C-Ethynyl-â-D-arabino- and 4′-C-ethynyl-2′-deoxy-â-D-ribo-pentofuranosylpyrimidine and
-purine nucleosides were synthesized and evaluated for their in vitro anti-HIV activity. The
key intermediate, 4-C-ethynyl- or 4-C-triethylsilylethynyl-D-ribo-pentofuranose, was prepared
from D-glucose and glycosidated with various pyrimidine or purine bases. The arabino
pyrimidine derivatives were prepared from the corresponding ribo derivatives via O2,2′-anhydro
nucleosides. The 2′-deoxy-ribo derivatives were synthesized by radical reduction of 2′-bromo
or 2′- phenoxythiocarbonyloxy nucleosides. Among these 4′-C-ethynyl nucleosides, seven
analogues proved to be potent against HIV-1 in vitro with EC50 values ranging from 0.0003 to
0.03 µM. These compounds also exerted activity against clinical and multi-dideoxy-nucleoside-
resistant HIV-1 strains with comparable EC50 values. Three such 4′-C-ethynyl-2′-deoxypurine
analogues including 4′-C-ethynyl-2′-deoxyadenosine and 4′-C-ethynyl-2,6-diamino-2′-deoxy-
purine were less cytotoxic [selectivity indices (SIs): 975-2733] than three 4′-C-ethynyl-2′-
deoxycytidine analogues (SIs: 63-363). 4′-C-Ethynyl-5-fluoro-2′-deoxycytidine was least toxic
(SI: >3333) and potent against all HIV strains tested.
In tr od u ction
positions of the sugar moiety of natural nucleosides, and
these modifications can be easily attained by the
chemistry of their hydroxy groups.6 However, few
examples of nucleosides modified at the 4′-position of
the sugar moiety have been reported: for example, 4′-
cyano-,7 4′-azido-,8 and 4′-ethynylthymidine (30)9 and
4′-ethynyl-2′-deoxycytidine (58)10 which reportedly have
potent anti-HIV activity. This may be due to their
difficult chemistry. It is proposed that the conformation
of the furanose ring of 4′-C-azidothymidine is extremely
unnatural with a 3′-C-endo,8 and its unnatural confor-
mation is closely related to its biological activities.
We have previously described synthetic methods of
4′-C-alkyl-substituted nucleosides from 4-C-hydroxy-
methyl ribose derivatives and reported that most of
their 2′-deoxy derivatives exhibited various biological
activities.11-17 For example, 4′-C-methyl-2′-deoxycyti-
dine (1)12 exhibits remarkable anti-HIV and antileuke-
mia activities.13 We also have reported the synthesis of
4′-C-ethynyl-ribo nucleosides (2-4) as a new series of
4′-C-substituted nucleosides.16,17 However, they exerted
no significant antiviral activity.16 In this report, we
describe novel methods for the synthesis of 4′-C-ethynyl-
D-arabino-pentofuranosyl (5) and 4′-C-ethynyl-2′-deoxy-
D-ribo-pentofuranosyl (6) nucleosides which proved to
act as inhibitors of the HIV reverse transcriptase similar
to 4′-azido-2′-deoxy nucleosides and 1.
The human immunodeficiency virus (HIV), the caus-
ative agent of aquired immune deficiency syndrome
(AIDS), has spread all over the world to become a
serious life-threatening disease. In the treatment of
AIDS, six nucleoside reverse trascriptase inhibitors, 3′-
azido-3′-deoxythymidine (AZT),1 2′,3′-dideoxyinosine
(ddI),2 2′,3′-dideoxycytidine (ddC),2 2′,3′-dehydro-2′,3′-
dideoxythymidine (d4T),3 L-1,3-oxathiolanylcytosine
(3TC),4 and abacavir (ABC),5 all of which function as
viral DNA chain terminators, have currently been used
as chemotherapeutic agents for AIDS treatment, and
the development of new anti-HIV nucleoside derivatives
has been enthusiastically studied. However, the emer-
gence of mutants which resist these drugs has been a
critical problem in using these chemotherapeutic agents,
and there are cases in which these mutants show high
levels of cross-resistance. Consequently, the develop-
ment of structurally new nucleoside derivatives which
are active against HIV variants resistant to the existing
2′,3′-dideoxy nucleosides is urgently needed.
All of the six existing therapeutic nucleoside reverse
transcriptase inhibitors are modified at the 2′- and 3′-
* To whom correspondence should be addressed. Tel: +81-22-717-
8803. Fax: +81-22-717-8806. E-mail: ohrui@biochem.tohoku.ac.jp.
† Tohoku University.
§ Yamasa Corp.
‡ Kyoto University.
Ch em istr y
| Fukushima Medical University.
Although 4′-C-ethynyl nucleosides can be prepared
#
Kumamoto University, School of Medicine.
National Cancer Institute.
from the corresponding natural nucleosides, we used
10.1021/jm000209n CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/14/2000

arabino/ ribo-Pyrimidines and -Purines
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4517
Sch em e 2a
4-C-hydroxymethyl-3,5-di-O-benzyl-1,2-O-isopropylidene-
R-D-ribo-pentofuranose (7)11 as starting material for the
synthesis of D-arabino and 2′-deoxy-D-ribo analogues of
4′-C-ethynyl nucleosides. Synthesis of the ribose unit
bearing an ethynyl group at the 4-C-position is outlined
in Scheme 1. The 4-C-hydroxymethyl group in 7 was
oxidized to a formyl group by Swern oxidation in
quantitative yield. Conversion of the aldehyde 8 into an
ethynyl group was performed by Corey’s protocol.18
Treatment of 8 with carbon tetrabromide and triphen-
ylphosphine in dichloromethane afforded 4-C-dibro-
movinyl derivative 9 in 95% yield, and the dibromovinyl
group was converted to an ethynyl group in 90% yield
by treatment of 9 with n-butyllithium in tetrahydro-
furan. Hydrolysis of the acetonide of 10 in 70% acetic
acid containing 10% trifluoroacetic acid followed by
acetylation of the resulting hydroxy groups gave 11 as
an anomeric mixture in 81% yield (Scheme 1).
a
Reagents: (a) silylated base, TMSOTf, 1,2-DCE; (b) NaOH(aq),
MeOH; (c) MsCI, pyridine; (d) NaOH(aq), THF; (e) BBr3, CH2Cl2;
(f) Ac2O, pyridine; (g) MeONa, MeOH; (h) 1,2,4-triazole, Cl2P(dO)-
OC6H4Cl, pyridine; (i) NH4OH, dioxane.
Synthetic routes of 4-C-ethynyl-â-D-arabino-pento-
furanosylthymine (17) and -cytosine (22) are shown in
Sch em e 1a
Scheme 2. Condensation of 11 with silylated thymine
and uracil in 1,2-dichloroethane in the presence of
trimethylsilyl trifluoromethanesulfonate as a catalyst
afforded thymine and uracil derivatives 14 and 18 in
96% and 87% yields, respectively. After deacetylation
of 14 and 18 in 0.1 N sodium hydroxide in water-
methanol, the resulting 2′-R-hydroxy group was meth-
anesulfonylated and inverted to the 2′-â-orientation by
treatment with 0.6 N sodium hydroxide in water-
tetrahydrofuran through O2,2′-anhydro nucleoside to
give 15 and 19 in 91% and 73% yields, respectively.
Deprotection of the 3′- and 5′-O-benzyl groups in 15 and
19 with boron tribromide in dichloromethane and
subsequent acetylation of the resulting hydroxy groups
afforded 16 and 20 in 91% and 94% yields, respectively.
4′-C-Ethynyl-arabino-furanosylthymine 17 was obtained
by deacylation of 16 with sodium methoxide in methanol
in an 80% yield. On the other hand, 4′-C-ethynyl-
arabino-furanosylcytosine 22 was obtained in a 75%
yield from 20 by Reese’s method19 through 4-triazolo-
uridine derivative 21.
a
Reagents: (a) (COCl)2, DMSO, Et3N, CH2Cl2; (b) CBr4, PPh3,
In deoxygenation of the 2′-hydroxyl group of a ribo
nucleoside, a radical reduction of the 2′-halo or thiocar-
CH2Cl2; (c) n-BuLi, THF; (d) n-BuLi, THF, then Et3SiCl; (e) 1. 70%
AcOH, TFA, 2. Ac2O, pyridine.

4518 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23
Ohrui et al.
Sch em e 3a
which were obtained by treatment of 27, 33, and 39 with
acetyl bromide in acetonitrile,23 to give 29, 35, and 41
in 66%, 55%, and 81% yields, respectively. 4′-C-Eth-
ynylthymidine 30,9 4′-C-ethynyl-5-ethyl-2′-deoxyuridine
36, and 4′-C-ethynyl-2′-deoxyuridine 42 were obtained
in 92%, 88%, and 97% yields by deprotection of 29, 35,
and 41. 4′-C-Ethynyl-2′-deoxy-5-methylcytidine 56 and
4′-C-ethynyl-2′-deoxycytidine 5810 were obtained from
29 and 41 in 49% and 72% yields, respectively, by the
similar method described for 22 (Scheme 6).
We also synthesized 2′-deoxy-5-halouridines and cy-
tidines bearing an ethynyl group at the 4′-C-position.
5-Fluoro-2′-deoxyuridine derivative 48 was synthesized
from 4′-C-triethylsilylethynyl-2′-O-acetyl-3′,5′-di-O-ben-
zyl-5-fluorouridine (43) obtained by glycosylation of
5-fluorouracil with 13. 43 was derived to 4′-C-triethyl-
silylethynyl-3′,5′-di-O-acetyl-2′-deoxy-5-fluorouridine (47)
in 57% yield by the method used for synthesizing 29.
47 was deprotected under alkaline conditions to give 4′-
C-ethynyl-2′-deoxy-5-fluorouridine (48) in 88% yield
(Scheme 4). 5-Chloro-, bromo-, and iodo-2′-deoxyuridine
derivatives 50, 52, and 54 were synthesized by haloge-
nation of 2′-deoxyuridine derivative 41. 41 was haloge-
nated with lithium chloride, lithium bromide, or iodine
in the presence of ammonium cerium nitrate in aceto-
nitrile or acetonitrile-acetic acid24 to give 5-halouracil
derivatives 49, 51, and 53 in over 90% yields, respec-
tively (Scheme 5). These were deacetylated under
alkaline conditions to give 50, 52, and 54 in 94%, 96%,
and 97% yields, respectively. 4′-C-Ethynyl-2′-deoxy-5-
halocytidines 60, 62, 64, and 66 were synthesized in
60%, 58%, 68%, and 44% yields, respectively, by the
method used for preparing 22 (Scheme 6).
a
Reagents: (a) silylated thymine, TMSOTf, 1,2-DCE; (b) Et3N,
MeOH; (c) ClC(dS)OPh, DMAP, MeCN; (d) n-Bu3SnH, AIBN,
toluene.
bonate of the ribo nucleoside with tri-n-butyltin hydride
has generally been utilized.20 Since it is known that the
hydrostannylation of terminal alkyne21,22 could be avoided
by protection of the ethynyl group with a bulky group,22
we planned to protect the ethynyl group in 10 with a
triethylsilyl group to prevent hydrostannylation. Treat-
ment of 10 with n-butyllithium in tetrahydrofuran and
then with chlorotriethylsilane afforded ribose derivative
12 bearing a triethylsilylated ethynyl group in 98%
yield. 12 was converted to 13 by the similar procedure
to that described for 11 in 80% yield (Scheme 1).
First, we attempted to synthesize 2′-deoxy derivatives
using the thymine derivative as a model compound by
reduction of the 2′-hydroxy group of 4′-C-triethylsilyl-
ethynyl-3′,5′-di-O-benzyl derivative 24 and subsequent
deprotection (Scheme 3). The thymine nucleoside 23 was
obtained in 87% yield by condensation of 13 with
silylated thymine. This was deacetylated in methanol
containing 5% triethylamine to afford 24 in 90% yield.
The 2′-hydroxyl group in 24 was phenoxythiocarbony-
lated with phenyl chlorothionoformate in acetonitrile in
the presence of 4-(dimethylamino)pyridine to give 25,
which was reduced to the 2′-deoxy derivative 26 by
radical reduction using tri-n-butyltin hydride in toluene
in the presence of 2,2′-azobis(isobutyronitrile) without
the addition of tributyltin radical to the terminal alkyne
in 94% yield. However, attempts of debenzylation of 26
by treatment with boron tribromide, boron trichloride,
or iodotrimethylsilane were not successful because of
the acid lability of the 2′-deoxy nucleoside. Therefore,
we then tried another route for the synthesis of 2′-deoxy
nucleosides (Scheme 4). 13 was condensed with silylated
5-ethyluracil and uracil, and the corresponding nucleo-
sides 31 and 37 were obtained in 76% and 78% yields,
respectively. Deacetylation of 31 and 37 with triethyl-
amine in methanol gave deacetylation products 32 and
38 in 92% and 93%, respectively, and 24, 32, and 38
were debenzylated to give free ribo nucleosides 27, 33,
and 39 in 98%, 84%, and 93% yields, respectively. The
2′-hydroxyl groups of these ribo nucleosides 27, 33, and
39 were deoxygenated by radical reduction with tri-n-
butyltin hydride in toluene via 3′,5′-di-O-acetyl-2′-
bromo-2′-deoxypyrimidine nucleosides 28, 34, and 40,
In addition to the syntheses of 4′-C-ethynylpyrimidine
nucleosides, we attempted to synthesize adenine, 2,6-
diaminopurine, hypoxanthine, and guanine nucleosides
bearing an ethynyl group at the 4′-C-position. The
glycosidation of 13 with pertrimethylsilylated adenine,
under the conditions described for the synthesis of 23,
gave 67 in 55% yield. In this reaction, no 7-glycosylated
product was detected in the reaction mixture by TLC
analyses. Deacetylation of 67 with triethylamine in
methanol (86% yield) was followed by treatment with
phenyl chlorothionoformate and 4-(dimethylamino)-
pyridine in acetonitrile. After short silica gel column
purification of the thioformate 69, radical reduction of
69 with tri-n-butyltin hydride in the presence of azobis-
(isobutyronitrile) was carried out to produce 70 in 68%
yield. Desilylation of 70 with tetrabutylammonium
fluoride in tetrahydrofuran was followed by debenzyla-
tion under the Birch reduction conditions. Together with
the target compound 72, the purine derivative 73
formed by reduction of the C6-double bond of 72 was
produced. Separation using ODS reversed-phase column
chromatography gave 72 and 73 in yields of 53% and
8%, respectively. When 8 mol equiv of sodium metal was
used, 72 and 73 were produced in the ratio of ca. 1:4.5.
2,6-Diamino-9-(2-deoxy-4-C-ethynyl-â-D-ribo-pentofura-
nosyl)purine (80) was prepared from 13 by a procedure
similar to that described for the preparation of 72. In
the final step of debenzylation, only a trace amount of
the deaminated product was formed. Treatment of 72
and 80 with adenosine deaminase, followed by purifica-
tion of the products with ODS reversed-phase column

arabino/ ribo-Pyrimidines and -Purines
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4519
Sch em e 4a
a
Reagents: (a) silylated base, TMSOTf, 1,2-DCE; (b) Et3N, MeOH; (c) BCl3, CH2Cl2; (d) AcBr, MeCN; (e) n-Bu3SnH, AIBN, toluene; (f)
NaOH(aq), MeOH.
Sch em e 5a
Sch em e 6a
a
Reagents: (a) LiCl, CAN, AcOH-MeCN; (b) LiBr, CAN, MeCN;
(c) I2, CAN, MeCN; (d) NaOH(aq), MeOH.
chromatography, gave 4′-C-ethynyl-2′-deoxyinosine 74
and 4′-C-ethynyl-2′-deoxyguanosine 81 in yields of 72%
and 50%, respectively (Scheme 7).
In Vitr o An tivir a l Activity of 4′-Su bstitu ted
Nu cleosid es
a
Reagents: (a) 1,2,4-triazole, Cl2P(dO)OC6H4Cl, pyridine; (b)
Among 19 4′-substituted nucleoside analogues exam-
ined for antiviral activity against a wild-type laboratory
strain HIV-1LAI, 7 4′-C-ethynyl nucleoside analogues
(compounds 22, 56, 58, 60, 72, 80, and 81) were potent
against HIV-1 in vitro (Table 1). These compounds also
exerted potent antiviral activity against a wild-type
clinical HIV-1 strain (HIV-1104pre) and a multi-dideoxy-
nucleoside-resistant infectious molecular clone (HIV-
1MDR). It was noted, however, that three 4′-C-ethynyl-
cytidine analogues (compounds 22, 56, and 58) were
relatively more cytotoxic than the three 4′-C-ethynyl-
purine analogues (compounds 72, 80, and 81). Selective
indices (CC50/EC50) of the formers ranged from 63 to
363, while those of the latter ranged from 975 to 2733.
1. NH4OH, dioxane, 2. NaOH(aq), MeOH.
Interestingly, the substitution of a hydrogen atom at
position 5 of cytosine of 4′-C-ethynyl-2′-deoxycytidine
(compound 58) with fluorine, generating 4′-C-ethynyl-
2′-deoxy-5-fluorocytidine (compound 60), substantially
decreased the cytotoxicity of compound 58. The selective
index of compound 60 was greater than 3333 (Table 1).
However, the substitution of the same with other
halogen atoms (chlorine, bromine, and iodine) converted
compound 58 to inert compounds 62, 64, and 66,
respectively.
It is of note that although HIV-1MDR carrying five
amino acid substitutions (Ala62Val, Val75Leu, Phe77Leu,

4520 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23
Ohrui et al.
Sch em e 7a
a
Reagents: (a) silylated base, TMSOTf, 1,2-DCE; (b) Et3N, MeOH; (c) CIC(dS)OPh, DMAP, MeCN; (d) n-Bu3SnH, AIBN, toluene; (e)
TBAF, THF; (f) Na, NH3(liq), THF; (g) adenosine deaminase, Tris-HCl buffer.
Ta ble 1. In Vitro Antiviral Activity of 4′-C-Ethynyl
form. However, despite the presence of the 3′-OH, they
might be able to act as chain terminators as well as
Nucleosidesa
MTT assay
MAGI assay
reverse transcriptase inhibitors because of the sharply
diminished reactivity of the 3′-OH due to the neopentyl
alcohol character of the 3′-OH and the severe steric
hindrance to it by the vicinal cis 4′-substituent.
Although both 74 and 81 were prepared from 72 and
80, respectively, by treatment with adenosine deami-
nase, the different biological activities between 72 and
74, and between 80 and 81, indicated that both 72 and
80 were not deaminated so easily by adenosine deami-
nase under the physiological conditions used for the
antviral activity test. These results may be ascribed to
the conformational change of the furanose ring of
4-substituted nucleosides.8
EC50 (µM)
CC50
(µM)
EC50 (µM) EC50 (µM)
HIV-1104pre HIV-IMDR
compd HIV-ILAI
SI
17
22
30
36
42
48
50
52
54
56
58
60
62
64
66
72
73
74
80
81
AZT
>350
0.0048
0.61
>350
ND
363
>623
ND
ND
ND
13.6
>44
>765
63
NE
NE
1.74
0.0048
0.4
0.0078
0.24
NE
>380
>360
>100
>360
>100
>10
NE
NE
NE
NE
NE
NE
NE
NE
3.4
81.7
>100
>260
0.70
0.92
>100
6.0
2.3
0.34
NE
0.36
0.0057
0.00096
0.002
NE
0.62
0.0045
0.0015
0.009
NE
0.011
0.0048
0.030
192
>3333
>100
>100
>100
0.012
117
0.15
>100
>100
>100
11.7
>380
216
ND
ND
ND
975
NE
NE
NE
NE
Exp er im en ta l Section
Gen er a l. Melting point data were obtained with a Shibata
melting apparatus and are uncorrected. 1H NMR spectra were
recorded with a J EOL J NMEX-400 spectrometer, using tet-
ramethylsilane as an internal standard. Mass spectra were
recorded with a Hitachi M-80B spectrometer at 70 eV. Specific
rotation was measured with a J asco DIP-360 at 589 nm. Merck
silica gel art. #9385 was used for column chromatography and
Merck silica gel art. #5554 for analytical thin-layer chroma-
tography.
3,5-Di-O-b en zyl-4-C-for m yl-1,2-O-isop r op ylid en e-r-D-
r ibo-p en tofu r a n ose (8). To a solution of oxalyl chloride (3.38
mL, 38.7 mmol) in dichloromethane (80.0 mL) was dropwised
dimethyl sulfoxide (5.50 mL, 77.5 mmol) at -60 °C. The
mixture was stirred for 15 min at the same temperature, and
then a solution of 711 (10.3 g, 25.7 mmol) in dichloromethane
(100 mL) was added dropwise. After stirring of mixture at -60
°C for 30 min, triethylamine (10.9 mL, 78.2 mmol) was added
and the mixture was stirred for 30 min at room temperature.
The reaction mixture was partitioned with water and the
organic layer was dried over magnesium sulfate. After evapo-
ration of the solvent, the residue was purified by silica gel
column chromatography (2:1 n-hexane/ethyl acetate) to give
8 as a colorless oil (9.68 g, 24.3 mmol, 94.6%): [R]D +24.5° (c
) 1.03, CHCl3).
0.0068
0.0054
>3.2 132
14.4
2733
1071
>2632
145
0.83
0.65
0.0003
0.0014
0.038
0.82
1.5
>100
0.0019
0.0071
0.002
0.0013
0.0054
24.9
a
MT-4 cells and HIV-1LAI were employed in the MTT assay
(except for compounds 42, 48, 50, and 52), while HeLa-CD4-LTR-
â-gal cells and HIV-1MDR were used in the MAGI assay as target
cells and infectious virions, respectively. For testing compounds
42, 48, 50, and 52, MT-2 cells and HIV-1LAI were employed in the
MTT assay. EC50, compound concentration that suppresses the
replication of HIV-1 by 50%; SI, selectivity index (CC50/EC50); ND,
not determined; NE, not examined.
Phe116Tyr, and Gln151Met) showed a high level of
resistance against all the currently available nucleoside
reverse transcriptase inhibitors,25,26 which have a 2′,3′-
dideoxy configuration, the 4′-C-ethynyl-2′-deoxy nucleo-
side analogues potent against HIV-lLAI were also highly
active against HIV-1MDR (Table 1).
From the results of anti-HIV activities of 4′-ethynlyl-
2′-deoxy nucleosides and the previous result13 that 4′-
C-methyl-2′-deoxycytidine triphosphate was both a strong
inhibitor of polymerase R and a chain terminator for
DNA polymerase R-catalyzed chain elongation of DNA
strands, it may be concluded that some 4′-C-substituted-
2′-deoxy (and arabino) nucleosides may have strong
affinity for deoxy nucleoside kinases at the nucleoside
level due to the presence of the 3′-down hydroxy group
and also for reverse transcriptases in their triphosphate
3,5-Di-O-ben zyl-4-C-(2,2-d ibr om oeth en yl)-1,2-O-isop r o-
p ylid en e-r-D-r ibo-p en tofu r a n ose (9). To a solution of 8
(9.50 g, 23.8 mmol) in dichloromethane (200 mL) were added
carbon tetrabromide (15.8 g, 47.6 mmol) and triphenylphos-
phine (25.0 g, 95.3 mmol) at 0 °C and the mixture was stirred
for 1 h. Triethylmine (20.0 mL, 142 mmol) was added and the
mixture was poured into n-hexane (1000 mL). After filtration
of insoluble precipitate, the filtrate was evaporated. The
residue was purified by silica gel column chromatography (3:1

arabino/ ribo-Pyrimidines and -Purines
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4521
n-hexane/ethyl acetate) to give 9 as a colorless oil (12.6 g, 22.7
mmol, 95.4%): [R]D +6.20° (c ) 1.00, CHCl3).
rated. The residue was coevaporated with pyridine and dis-
solved in pyridine (50 mL). To the solution was added
methanesulfonyl chloride (0.45 mL, 5.77 mmol) at 0 °C and
the mixture was stirred for 1 h at room temperature. The
mixture was evaporated and the residue was dissolved in ethyl
acetate. The organic layer was washed with water and dried
over magnesium sulfate. The solvent was removed under
reduced pressure. The residue was coevaporated with toluene
and dissolved in tetrahydrofuran (30 mL). To the solution was
added 1 N sodium hydroxide solution (50 mL) and the resulting
mixture was refluxed for 1 h. The mixture was neutralized
and evaporated. The residue was partitioned between ethyl
acetate and water. The organic layer was dried over magne-
sium sulfate and evaporated. The residue was purified by silica
gel column chromatography (1:2 n-hexane/ethyl acetate) to give
15 as a white powder (1.67 g, 3.61 mmol, 91.2%): [R]D +30.6°
(c ) 1.00, CHCl3).
1-(2,3,5-Tr i-O-a cet yl-4-C-et h yn yl-â-D-a r a bin o-p en t o-
fu r a n osyl)th ym in e (16). To a solution of 15 (1.50 g, 3.24
mmol) in dichloromethane (40.0 mL) was added boron tribro-
mide (1.0 M in dichloromethane, 16.2 mL, 16.2 mmol) at -78
°C under an argon atmosphere and the mixture was stirred
for 2 h at the same temperature. To the solution was added a
mixture of pyridine (7.00 mL) and methanol (10.0 mL) and
the mixture was stirred for 10 min at -78 °C and evaporated.
The residue was coevaporated with pyridine and dissolved in
pyridine (50 mL). The solution was added acetic anhydride
(4.59 mL, 48.7 mmol) and stirred for 12 h at room temperature.
The reaction mixture was evaporated and the residue was
partitioned between ethyl acetate and water. The organic layer
was dried over magnesium sulfate and evaporated. The residue
was purified by silica gel column chromatography (1:2 n-
hexane/ethyl acetate) to give 16 as a white powder (1.20 g,
2.94 mmol, 90.7%): [R]D +7.20° (c ) 1.00, CHCl3).
1-(4-C-E t h yn yl-â-D-a r a bin o-p en t ofu r a n osyl)t h ym in e
(17). To a solution of 16 (1.00 g, 2.45 mmol) in methanol (50.0
mL) was added sodium methoxide (0.20 g, 3.70 mmol) and the
resulting mixture was stirred for 1 h at room temperature.
The reaction mixture was neutralized with cation exchanger
resin (Dowex 50W×8, 200-400 mesh, H+ form) and evapo-
rated. The residue was purified by silica gel column chroma-
tography (9:1-4:1 chloroform/methanol) and the desired frac-
tion was crystalized from methanol-ether to give 17 (0.55 g,
1.95 mmol, 79.6%): [R]D +49.86° (c ) 1.035, CH3OH).
1-(2-Di-O-a cet yl-3,5-d i-O-b en zyl-4-C-et h yn yl-â-D-r ibo-
p en tofu r a n osyl)u r a cil (18). Under the conditions analogous
to those used for the preparation of 14, 11 (2.50 g, 5.70 mmol)
gave 18 as a colorless gum (2.44 g, 4.97 mmol, 87.2%): [R]D
+29.0° (c ) 1.00, CHCl3).
1-(3,5-Di-O-ben zyl-4-C-eth yn yl-â-D-a r a bin o-p en tofu r a -
n osyl)u r a cil (19). Under the conditions analogous to those
used for the preparation of 15, 18 (2.30 g, 4.69 mmol) gave 19
as a white powder (1.54 g, 3.43 mmol, 73.1%): [R]D +40.7° (c
) 1.00, CHCl3).
1-(4-C-Eth yn yl-2,3,5-tr i-O-acetyl-â-D-a r a bin o-pen tofu r a-
n osyl)u r a cil (20). Under the conditions analogous to those
used for the preparation of 16, 19 (1.40 g, 3.12 mmol) gave 20
as a white powder (1.15 g, 2.92 mmol, 93.6%): [R]D +18.2° (c
) 1.00, CHCl3).
1-(4-C-E t h yn yl-â-D-a r a bin o-p en t ofu r a n osyl)cyt osin e
(22). To a solution of 20 (1.00 g, 2.54 mmol) in pyridine (50.0
mL) was added 4-chlorophenyl phosphorodichloridate (1.05
mL, 6.38 mmol) at 0 °C and the resulting mixture was stirred
for 5 min at the same temperature. 1,2,4-Triazole (1.75 g, 25.3
mmol) was added to the solution and the mixture was stirred
for 7 days at room temperature. The reaction mixture was
evaporated and the residue was partitioned between ethyl
acetate and water. The organic layer was dried over magne-
sium sulfate and evaporated. The residue was coevaporated
with toluene and purified by silica gel column chromatography
(1:3 n-hexane/ethyl acetate) to give 21. To a solution of 21 in
dioxane (60.0 mL) was added 25% ammonium hydroxide (20.0
mL) and stirred for 24 h at room temperature. The reaction
mixture was evaporated and the residue was purified by
3,5-Di-O-b en zyl-4-C-et h yn yl-1,2-O-isop r op ylid en e-D-
r ibo-p en tofu r a n ose (10). To a solution of 9 (12.4 g, 22.4
mmol) in dry tetrahydrofuran (160 mL) was added n-butyl-
lithium (1.6 M solution in n-hexane, 30.7 mL, 49.1 mmol) at
-78 °C under an argon atmosphere and the mixture was
stirred for 30 min at the same temperature. After addition of
water, ethyl acetate was added and the organic layer was
washed with water. The organic layer was dried over magne-
sium sulfate and evaporated. The residue was purified by silica
gel column chromatography (3:1 n-hexane/ethyl acetate) to give
10 as a colorless oil (7.95 g, 20.2 mmol, 90.2%): [R]D +22.6° (c
) 1.00, CHCl3).
1,2-Di-O-acetyl-3,5-di-O-ben zyl-4-C-eth yn yl-D-r ibo-pen to-
fu r a n ose (11). To a solution of 10 (6.00 g, 15.2 mmol) in 70%
acetic acid (100 mL) was added trifluoroacetic acid (10.0 mL)
and the solution was stirred for 4 h at 40 °C. The mixture was
evaporated and the residue was coevaporated with toluene.
To the solution of the residue in pyridine (50.0 mL) was added
acetic anhydride (14.3 mL, 0.15 mol), and the mixture was
stirred for 12 h at room temperature. The mixture was
evaporated and the residue was coevaporated with toluene.
The residue was dissolved in ethyl acetate and the organic
layer was washed with water. The solvent was dried over
magnesium sulfate and evaporated. The residue was purified
by silica gel column chromatography (3:1 n-hexane/ethyl
acetate) to give 11 as a colorless oil (5.40 g, 12.3 mmol,
80.9%): for R-anomer (second eluting), [R]D -7.980° (c ) 1.015,
CHCl3); for â-anomer (first eluting), [R]D -22.54° (c ) 1.065,
CHCl3).
3,5-Di-O-ben zyl-1,2-O-isop r op ylid en e-4-C-tr ieth ylsilyl-
eth yn yl-r-D-r ibo-p en tofu r a n ose (12). To a solution of 10
(5.00 g, 12.7 mmol) in dry tetrahydrofuran (100 mL) was added
n-butyllithium (1.6 M solution in n-hexane, 9.50 mL, 15.2
mmol) at -78 °C under an argon atmosphere and the mixture
was stirred for 5 min at the same temperature. After stirring,
chlorotriethylsilane (2.55 mL, 15.2 mmol) was added at -78
°C under an argon atmosphere and stirred for 30 min at same
temperature. After addition of water, ethyl acetate was added
and the organic layer was washed with water. The organic
layer was dried over magnesium sulfate and evaporated. The
residue was purified by silica gel column chromatography (3:1
n-hexane/ethyl acetate) to give 12 as a colorless oil (6.32 g,
12.4 mmol, 97.6%): [R]D -27.27° (c ) 1.045, CHCl3).
1,2-Di-O-acetyl-3,5-di-O-ben zyl-4-C-tr ieth ylsilyleth yn yl-
D-r ibo-p en tofu r a n ose (13). Under the conditions analogous
to those used for the preparation of 11, compound 12 (5.55 g,
10.9 mmol) gave 13 as an anomeric mixture (R:â ) 1:6.6) as a
colorless oil (4.80 g, 8.68 mmol, 79.6%): for R-anomer (second
eluting), [R]D -21.8° (c ) 1.00, CHCl3); for â-anomer (first
eluting), [R]D -58.0° (c ) 1.00, CHCl3).
1-(2-O-Acetyl-3,5-di-O-ben zyl-4-C-eth yn yl-â-D-r ibo-pen to-
fu r a n osyl)th ym in e (14). A mixture of 11 (2.00 g, 4.56 mmol),
N,O-bis(trimethylsilyl)acetamide (6.76 mL, 27.4 mmol) and
thymine (l.15 g, 9.12 mmol) in 1,2-dichloroethane (50.0 mL)
was refluxed for 1 h. After cooling to room temperature, to
the reaction mixture was added trimethylsilyl trifluoromethane-
sulfonate (1.65 mL, 6.05 mmol) and the resulting mixture was
refluxed for 12 h. To the reaction mixture was added saturated
aqueous sodium hydrogen carbonate and the mixture was
stirred. Insoluble precipitate was removed by filtration. The
organic layer was dried over magnesium sulfate and evapo-
rated. The residue was purified by silica gel column chroma-
tography (2:3 n-hexane/ethyl acetate) to give 14 as a colorless
gum (2.21 g, 4.38 mmol, 96.1%): [R]D +10.0° (c ) 1.04, CHCl3).
1-(3,5-Di-O-ben zyl-4-C-eth yn yl-â-D-a r a bin o-p en tofu r a -
n osyl)th ym in e (15). To a solution of 14 (2.00 g, 3.96 mmol)
in methanol (90 mL) was added 1 N sodium hydroxide solution
(10 mL) and the mixture was stirred for 1 h at room temper-
ature. After neutralization of the reaction mixture by addition
of acetic acid, the solvent was removed by evaporation. The
residue was partitioned between ethyl acetate and water. The
organic layer was dried over magnesium sulfate and evapo-

4522 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23
Ohrui et al.
reverse phase column chromatography (Wakosil 40C18, 3%
acetonitrile in water) and the desired fraction was crystalized
from methanol-ether to give 22 (0.51 g, 1.91 mmol, 75.2%):
[R]D +95.7° (c ) 1.00, CH3OH).
1-(2-O-Acetyl-3,5-d i-O-ben zyl-4-C-tr ieth ylsilyleth yn yl-
â-D-r ibo- p en tofu r a n osyl)th ym in e (23). Under the condi-
tions analogous to those used for the preparation of 14, 13 (4.50
g, 8.14 mmol) gave 23 as a colorless gum (4.40 g, 7.11 mmol,
87.4%): [R]D -22.3° (c ) 1.00, CHCl3).
1-(3,5-Di-O-b en zyl-4-C-t r iet h ylsilylet h yn yl-â-D-r ibo-
p en tofu r a n osyl)th ym in e (24). A solution of 23 (4.00 g, 6.46
mmol) in methanol (100 mL) containing 5% triethylamine was
stirred for 12 h at room temperature. The mixture was
evaporated and the residue was purified by silica gel column
chromatography (1:1 n-hexane/ethyl acetate) to give 24 as a
white powder (3.35 g, 5.81 mmol, 89.9%): [R]D -18.2° (c ) 0.99,
CHCl3).
fraction was crystalized from methanol-ether to give 30 (0.19
g, 0.71 mmol, 92.2%): [R]D +40.2° (c ) 1.00, CH3OH).
1-(2-O-Acetyl-3,5-d i-O-ben zyl-4-C-tr ieth ylsilyleth yn yl-
â-D-r ibo-p en tofu r a n osyl)-5-eth ylu r a cil (31). Under the
conditions analogous to those used for the preparation of 14,
13 (1.80 g, 3.26 mmol) gave 31 as a colorless gum (1.60 g, 2.53
mmol, 77.6%): [R]D -21.7° (c ) 1.15, CHCl3).
1-(3,5-Di-O-b en zyl-4-C-t r iet h ylsilylet h yn yl-â-D-r ibo-
p en tofu r a n osyl)-5-eth ylu r a cil (32). Under the conditions
analogous to those used for the preparation of 24, 31 (1.50 g,
2.37 mmol) gave 32 as a white foam (1.29 g, 2.18 mmol,
92.0%): [R]D -12.1° (c ) 1.20, CHCl3).
1-(4-C-Tr ieth ylsilyleth yn yl-â-D-r ibo-p en tofu r a n osyl)-5-
eth ylu r a cil (33). Under the conditions analogous to those
used for the preparation of 27, 32 (1.25 g, 2.12 mmol) gave 33
as a white powder (0.73 g, 1.78 mmol, 84.0%): [R]D +5.100 (c
) 1.00, CH3OH).
1-(3,5-Di-O-a cetyl-2-d eoxy-4-C-tr ieth ylsilyleth yn yl-â-D-
r ibo-p en tofu r a n osyl)-5-eth ylu r a cil (35). Under the condi-
tions analogous to those used for the preparation of 29,
compound 33 (0.63 g, 1.53 mmol) gave 35 as a white powder
(0.40 g, 0.84 mmol, 54.9%): [R]D -10.0° (c ) 1.00, CHCl3).
1-(2-Deoxy-4-C-eth yn yl-â-D-r ibo-p en tofu r a n osyl)-5-eth -
ylu r a cil (36). Under the conditions analogous to those used
for the preparation of 30, 35 (0.33 g, 0.69 mmol) gave 36 as a
white foam (0.17 g, 0.61 mmol, 88.4%): [R]D +37.9° (c ) 1.00,
CH3OH).
1-(2-Acetyl-3,5-d i-O-ben zyl-4-C-tr ieth ylsilyleth yn yl-â-
D-r ibo-p en tofu r a n osyl)u r a cil (37). Under the conditions
analogous to those used for the preparation of 14, 13 (3.00 g,
5.43 mmol) gave 37 as a colorless gum (2.50 g, 4.13 mmol,
76.1%): [R]D -21.97° (c ) 1.015, CHCl3).
1-(3,5-d i-O-b e n zyl-4-C-t r ie t h ylsilyle t h yn yl-â-D-r ibo-
p en tofu r a n osyl)u r a cil (38). Under the conditions analogous
to those used for the preparation of 24, 13 (2.00 g, 3.31 mmol)
gave 38 as a white powder (1.72 g, 3.06 mmol, 92.5%): [R]D
-21.56° (c ) 1.025, CHCl3).
1-(4-C-Tr iet h ylsilylet h yn yl-â-D-r ibo-p en t ofu r a n osyl)-
u r a cil (39). Under the conditions analogous to those used for
the preparation of 27, 38 (1.50 g, 2.67 mmol) gave 39 as a white
powder (0.95 g, 2.48 mmol, 92.9%): [R]D -4.50° (c ) 1.00, CH3-
OH).
1-(3,5-Di-O-ben zyl-2-d eoxy-4-C-tr ieth ylsilyleth yn yl-â-
D-r ibo-p en t ofu r a n osyl)t h ym in e (26). To a solution of 24
(1.00 g, 1.73 mmol) in acetonitrile (20.0 mL) were added
4-(dimethylamino)pyridine (0.63 g, 5.16 mmol) and phenyl
chlorothionoformate (0.29 mL, 2.09 mmol) and the mixture was
stirred for 1 h at room temperature. After evaporation of the
solvent, the residue was dissolved in ethyl acetate and the
organic layer was washed with 5% citric acid solution and
water. The solution was dried over magnesium sulfate and
evaporated to give crude 25 as a yellowish gum. To the solution
of crude 25 in toluene (20.0 mL) were added tri-n-butyltin
hydride (2.79 mL, 10.4 mmol) and a small amount of azobis-
(isobutyronitrile) at 85 °C and the mixture was stirred for 1 h
at the same temperature. The reaction mixture was evaporated
and the residue was purified by silica gel column chromatog-
raphy (3:1 toluene/ethyl acetate) to give 26 as a colorless gum
(0.92 g, 1.64 mmol, 94.8%): [R]D -3.21° (c ) 1.09, CHCl3).
1-(4-C-Tr iet h ylsilylet h yn yl-â-D-r ibo-p en t ofu r a n osyl)-
th ym in e (27). To a solution of 24 (1.00 g, 1.73 mmol) in
dichloromethane (50.0 mL) was added boron trichloride (1.0
M in dichloromethane, 17.3 mL, 17.3 mmol) at -78 °C under
an argon atmosphere and the mixture was stirred for 2 h at
the same temperature. To the mixture was added a mixture
of pyridine (10.0 mL) and methanol (20.0 mL), and the mixture
was stirred for 10 min at -78 °C and evaporated. The residue
was partitioned between ethyl acetate and water. The organic
layer was dried over magnesium sulfate and evaporated. The
residue was purified by silica gel column chromatography (9:1
chloroform/methanol) to give 27 as a white powder (0.67 g,
1.69 mmol, 97.7%): [R]D - 1.86° (c ) 1.02, CH3OH).
1-(3,5-Di-O-a cetyl-2-d eoxy-4-C-tr ieth ylsilyleth yn yl-â-D-
r ibo-pen tofu r an osyl)u r acil (41). Under the conditions analo-
gous to those used for the preparation of 29, 39 (0.77 g, 2.01
mmol) gave 41 as a colorless gum (0.73 g, 1.62 mmol, 80.6%);
[R]D -11.7° (c ) 1.04, CHCl3).
1-(3,5-Di-O-a cetyl-2-d eoxy-4-C-tr ieth ylsilyleth yn yl-â-D-
r ibo-p en tofu r a n osyl)th ym in e (29). To a suspension of 27
(0.67 g, 1.69 mmol) in acetonitrile (25.0 mL) was added
dropwise acetyl bromide (1.50 mL, 20.3 mmol) in acetonitrile
(20.0 mL) over 30 min at 85 °C and the resulting mixture was
refluxed for 2 h. The reaction mixture was evaporated and the
residue was dissolved in ethyl acetate. After washing of the
organic layer with saturated aqueous sodium hydrogen car-
bonate solution and saturated aqueous sodium chloride solu-
tion, the organic layer was dried over magnesium sulfate and
evapolated to give crude bromide 28 as a brownish foam. The
residue was coevaporated with toluene and dissolved in
toluene (50 mL). To the solution were added tri-n-butyltin
hydride (0.86 mL, 3.33 mmol) and a small amount of azobis-
(isobutyronitrile) at 85 °C and the mixture stirred for 1 h at
the same temperature. The reaction mixture was evaporated
and the residue was purified by silica gel column chromatog-
raphy (1:1 toluene/ethyl acetate) to give 29 as a colorless gum
(0.52 g, 1.12 mmol, 66.3%): [R]D -11.40° (c ) 1.035, CHCl3).
1-(2-D e o x y -4-C-e t h y n y l-â-D -r i b o-p e n t o fu r a n o s y l)-
u r a cil (42). Under the conditions analogous to those used for
the preparation of 30, 41 (0.30 g, 0.67 mmol) gave 42 as a white
foam (165 mg, 0.65 mmol, 97.0%): [R]D +37.8° (c ) 0.51, CH3-
OH).
1-(2-O-Acetyl-3,5-d i-O-ben zyl-4-C-tr ieth ylsilyleth yn yl-
â-D-r ibo-p en tofu r a n osyl)-5-flu or ou r a cil (43). A mixture of
13 (2.00 g, 3.62 mmol), N,O-bis(trimethylsilyl)acetamide (5.37
mL, 21.7 mmol) and 5-fluorouracil (0.71 g, 5.46 mmol) in 1,2-
dichloroethane (60.0 mL) was refluxed for 1 h. To the reaction
mixture was added trimethylsilyl trifluoromethanesulfonate
(0.85 ml, 4.70 mmol) at room temperature and the mixture
was stirred at 50 °C for 24 h. To the reaction mixture was
added saturated aqueous sodium hydrogen carbonate and the
mixture was stirred. The organic layer was dried over mag-
nesium sulfate and evaporated. The residue was purified by
silica gel column chromatography (2:1 n-hexane/ethyl acetate)
to give 43 as a colorless gum (0.80 g, 1.28 mmol, 35.4%): [R]D
-23.3° (c ) 0.18, CHCl3).
1-(2-Deoxy-4-C-et h yn yl-â-D-r ibo-p en t ofu r a n osyl)t h y-
m in e (30). To a solution of 29 (0.36 g, 0.77 mmol) in methanol
(24.0 mL) was added 1 N aqueous sodium hydroxide solution
(6.00 mL) and the mixture was stirred overnight at room
temperature. The reaction mixture was neutralized with cation
exchanger resin (Dowex 50W×8, 200-400 mesh, H+ form) and
evaporated. The residue was purified by silica gel column
chromatography (9:1 chloroform/methanol) and the desired
1-(3,5-Di-O-b en zyl-4-C-t r iet h ylsilylet h yn yl-â-D-r ibo-
p en tofu r a n osyl)-5-flu or ou r a cil (44). A solution of 43 (0.77
g, 1.24 mmol) in methanol containing 10% triethylamine (50.0
mL) was stirred for 48 h at 30 °C. The mixture was coevapo-
rated with tetrahydrofuran and the residue was purified by
silica gel column chromatography (2:1 n-hexane/ethyl acetate)
to give 44 as a white powder (0.68 g, 1.17 mmol, 94.4%): [R]D
-16.3° (c ) 1.05, CHCl3).

arabino/ ribo-Pyrimidines and -Purines
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4523
1-(4-C-Tr ieth ylsilyleth yn yl-â-D-r ibo-p en tofu r a n osyl)-5-
flu or ou r a cil (45). Under the conditions analogous to those
used for the preparation of 27, compound 44 (1.00 g, 1.73
mmol) gave 45 as a white powder (0.64 g, 1.60 mmol, 93.0%):
[R]D -2.30° (c ) 1.00, CH3OH).
1-(3,5-Di-O-a cetyl-2-d eoxy-4-C-tr ieth ylsilyleth yn yl-â-D-
r ibo-p en tofu r a n osyl)-5-flu or ou r a cil (47). Under the condi-
tions analogous to those used for the preparation of 29,
compound 45 (0.54 g, 1.35 mmol) gave 47 as a white powder
(0.41 g, 0.88 mmol, 65.2%): [R]D -12.9° (c ) 1.00, CHCl3).
1-(2-Deoxy-4-C-eth yn yl-â-D-r ibo-p en tofu r a n osyl)-5-flu -
or ou r a cil (48). Under the conditions analogous to those used
for the preparation of 30, compound 47 (0.20 g, 0.43 mmol)
gave 48 as a white powder (103 mg, 0.38 mmol, 88.4%): [R]D
+45.2° (c ) 1.02, CH3OH).
1-(3,5-Di-O-a cetyl-2-d eoxy-4-C-tr ieth ylsilyleth yn yl-â-D-
r ibo-p en tofu r a n osyl)-5-ch lor ou r a cil (49). To a solution of
41 (0.30 g, 0.67 mmol) in a mixture of acetonitrile (5.50 mL)
and acetic acid (5.50 mL) were added lithium chloride (34.0
mg, 0.80 mmol) and ammonium cerium nitrate (0.73 g, 1.34
mmol) and the mixture was refluxed for 6 h. The reaction
mixture was diluted with ethyl acetate and then washed with
saturated aqueous sodium hydrogen carbonate and dried over
magnesium sulfate. After evaporation of the solvent, the
residue was purified by silica gel column chromatography (1:1
n-hexane/ethyl acetate) to give 49 as a white powder (0.30 g,
0.62 mmol, 92.5%): [R]D - 12.7° (c ) 1.00, CHCl3).
1-(2-De oxy-4-C-â-D -r ibo-p e n t ofu r a n osyl)-5-c h lor o-
u r a cil (50). Under the conditions analogous to those used for
the preparation of 30, 49 (0.25 g, 0.52 mmol) gave 50 as a white
foam (0.14 g, 0.49 mmol, 94.2%): [R]D +43.8° (c ) 1.00, CH3-
OH).
1-(3,5-Di-O-a cetyl-2-d eoxy-4-C-tr ieth ylsilyleth yn yl-â-D-
r ibo-p en tofu r a n osyl)-5-br om ou r a cil (51). To a solution of
41 (0.30 g, 0.67 mmol) in acetonitrile (11.0 mL) were added
lithium bromide monohydrate (84.0 mg, 0.80 mmol) and
ammonium cerium nitrate (0.73 g, 1.34 mmol) and the mixture
was refluxed for 2 h. The reaction mixture was diluted with
ethyl acetate and then washed with saturated aqueous sodium
chloride and dried over magnesium sulfate. After evaporation
of the solvent, the residue was purified by silica gel column
chromatography (1:1 n-hexane/ethyl acetate) to give 51 as a
white powder (0.33 g, 0.62 mmol, 92.5%): [R]D -14.8° (c ) 1.00,
CHCl3).
1-(2-Deoxy-4-C-eth yn yl-â-D-r ibo-p en tofu r a n osyl)-5-br o-
m ou r a cil (52). Under the conditions analogous to those used
for the preparation of 30, 51 (0.25 g, 0.47 mmol) gave 52 as a
white foam (0.15 g, 0.45 mmol, 95.7%): [R]D +36.1° (c ) 1.00,
CH3OH).
between ethyl acetate and water. The organic layer was dried
over magnesium sulfate and evaporated. The residue was
coevaporated with toluene and purified by silica gel column
chromatography (1:3 n-hexane/ethyl acetate) to give 55. To a
solution of 55 in dioxane (60.0 mL) was added 25% aqueous
ammonium hydroxide solution (20.0 mL) and the mixture was
stirred for 24 h at room temperature. The reaction mixture
was evaporated. The residue was dissolved in methanol (45.0
mL). To the solution was added 1 N aqueous sodium hydroxide
solution (5.00 mL). After being stirred for 2 h, the reaction
mixture was neutralized with acetic acid (0.29 mL, 5.00 mmol)
and evaporated under reduced pressure to give a syrup. The
syrup was purified by reverse phase gel column chromatog-
raphy (Wakosil 40C18, 5% acetonitrile in water) and the
desired fraction was crystalized from methanol-ether to give
56 (0.21 g, 0.79 mmol, 49.1%): [R]D +58.93° (c ) 1.061, CH3-
OH).
1-(2-D e o x y -4-C-e t h y n y l-â-D -r i b o-p e n t o fu r a n o s y l)-
cytosin e (58). Under the conditions analogous to those used
for the preparation of 56, compound 41 (0.30 g, 0.67 mmol)
gave 58 as a white powder (0.12 g, 0.48 mmol, 71.6%): [R]D
+75.0° (c ) 1.00, CH3OH).
1-(2-Deoxy-4-C-eth yn yl-â-D-r ibo-p en tofu r a n osyl)-5-flu -
or ocytosin e (60). To a solution of 47 (0.35 g, 0.75 mmol) in
pyridine (5.00 mL) was added 4-chlorophenyl phosphoro-
dichloridate (0.62 mL, 3.77 mmol) at 0 °C and the mixture was
stirred for 5 min at the same temperature. To the mixture was
added 1,2,4-triazole (0.78 g, 11.3 mmol) and the mixture was
stirred for 24 h at 30 °C. The reaction mixture was evaporated
and the residue was partitioned between ethyl acetate and
water. The organic layer was dried over magnesium sulfate
and evaporated. The residue was coevaporated with toluene
and purified by silica gel column chromatography (ethyl
acetate) to give 59. To a solution of 59 in dioxane (15.0 mL)
was added 25% aqueous ammonium hydroxide solution (5.00
mL) and the mixture was stirred for 24 h at room temperature.
The reaction mixture was evaporated. The residue was dis-
solved in methanol (45.0 mL) and added 1 N aqueous sodium
hydroxide (5.00 mL). After being stirred for 2 h, the reaction
mixture was neutralized with acetic acid (0.29 mL, 5.00 mmol).
The mixture was evaporated and the residue was purified by
silica gel column chromatography (4:1 chloroform/ethanol) and
the desired fraction was crystallized from methanol-ether to
give 60 (120 mg, 0.45 mmol, 60.0%): [R]D +77.9° (c ) 1.00,
CH3OH).
1-(2-Deoxy-4-C-eth yn yl-â-D-r ibo-pen tofu r an osyl)-5-ch lo-
r ocytosin e (62). Under the conditions analogous to those used
for the preparation of 60, 49 (0.35 g, 0.72 mmol) gave 62 (121
mg, 0.42 mmol, 58.3%): [R]D +58.6° (c ) 0.49, CH3OH).
1-(3,5-Di-O-a cetyl-2-d eoxy-4-C-tr ieth ylsilyleth yn yl-â-D-
r ibo-p en tofu r a n osyl)-5-iod ou r a cil (53). To a solution of 41
(0.95 g, 2.11 mmol) in acetonitrile (35.0 mL) were added iodine
(0.32 g, 11.3 mmol) and ammonium cerium nitrate (0.56 g, 1.02
mmol) and the mixture was refluxed for 2 h. The reaction
mixture was evaporated and the residue was coevaporated
with toluene. The residue was partitioned between ethyl
acetate and water and the organic layer was dried over
magnesium sulfate. After evaporation of the solvent, the
residue was purified by silica gel column chromatography (1:1
n-hexane/ethyl acetate) to give 53 as a white powder (1.11 g,
1.93 mmol, 91.5%): [R]D -10.73° (c ) 1.025, CHCl3).
1-(2-De oxy-4-C-e t h yn yl-â-D-r ibo-p e n t ofu r a n osyl)-5-
iod ou r a cil (54). Under the conditions analogous to those used
for the preparation of 30, compound 53 (0.20 g, 0.35 mmol)
gave 54 as a white foam (0.13 g, 0.34 mmol, 97.1%): [R]D
+32.8° (c ) 1.00, CH3OH).
1-(2-De oxy-4-C-e t h yn yl-â-D-r ibo-p e n t ofu r a n osyl)-5-
m eth ylcytosin e (56). To a solution of 29 (0.75 g, 1.61
mmol) in pyridine (50.0 mL) was added 4-chlorophenyl phos-
phorodichloridate (1.31 mL, 7.96 mmol) at 0 °C and the
mixture was stirred for 5 min at the same temperature. To
the mixture was added 1,2,4-triazole (1.67 g, 24.2 mmol) and
the mixture was stirred for 7 days at room temperature. The
mixture was evaporated and the residue was partitioned
1-(2-Deoxy-4-C-eth yn yl-â-D-r ibo-p en tofu r a n osyl)-5-br o-
m ocytosin e (64). Under the conditions analogous to those
used for the preparation of 60, compound 51 (0.30 g, 0.57
mmol) gave 64 (128 mg, 0.39 mmol, 68.4%): [R]D +50.0° (c )
1.05, CH3OH).
1-(2-De oxy-4-C-e t h yn yl-â-D-r ibo-p e n t ofu r a n osyl)-5-
iod ocytosin e (66). Under the conditions analogous to those
used for the preparation of 60, 53 (0.36 g, 0.62 mmol) gave 66
(103 mg, 0.27 mmol, 43.5%): [R]D +41.2° (c ) 0.99, CH3OH).
9-(2-O-Acetyl-3,5-d i-O-ben zyl-4-C-tr ieth ylsilyleth yn yl-
â-D-r ibo-p en tofu r a n osyl)a d en in e (67). A mixture of 13
(1.10 g, 2.0 mmol), adenine (405 mg, 3.0 mmol) and N,O-bis-
(trimethylsilyl)acetamide (2.70 mL, 11.0 mmol) in 1,2-dichlo-
roethane (17.0 mL) was stirred at reflux for 1.5 h. To the
mixture was added dropwise trimethylsilyl trifluoromethane-
sulfonate (0.77 mL, 4.0 mmol) at 0 °C under an argon
atmosphere. The mixture was stirred at room temperature for
15 min and then at reflux for 24 h. The mixture was quenched
with saturated aqueous sodium hydrogen carbonate at room
temperature and filtered through a pad of Celite. The filtrate
was extracted with chloroform and the organic phase was
washed with saturated aqueous sodium chloride and dried over
sodium sulfate. The filtrate was concentrated under reduced
pressure and the residue was purified by column chromatog-

4524 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23
Ohrui et al.
raphy over silica gel (AcOEt-hexanes-EtOH, 20:20:1) to give
67 (690 mg, 55%) as an oil.
gel (AcOEt-hexanes-EtOH, 30:10:1), 76 (740 mg, 93%) was
obtained as a foam.
9-(3,5-Di-O-b en zyl-4-C-t r iet h ylsilylet h yn yl-â-D-r ibo-
p en tofu r a n osyl)a d en in e (68). To a solution of 67 (354 mg,
0.565 mmol) in methanol (14.0 mL) was added triethylamine
(3.3 mL) and the mixture was stirred at room temperature
for 24 h. The solvent was removed under reduced pressure
and the residue was purified by column chromatography over
silica gel (AcOEt-hexanes-EtOH, 20:10:1) to give 68 (283 mg,
86%) as colorless prisms.
9-(3,5-Di-O-ben zyl-2-d eoxy-4-C-tr ieth ylsilyleth yn yl-â-
D-r ibo-p en tofu r a n osyl)a d en in e (70). To a acetonitrile solu-
tion (7.00 mL) of 68 (112 mg, 0.191 mmol) and 4-(dimethyl-
amino)pyridine (70.5 mg, 0.573 mmol) was added phenyl
chlorothionoformate (40.0 µL, 0.287 mmol) at room tempera-
ture under an argon atmosphere, and the mixture was stirred
at the same temperature for 1 h. After the solvent was removed
under reduced pressure, the residue was partitioned between
ethyl acetate and water. The organic phase was washed with
water and brine and dried over sodium sulfate. The filtrate
was concentrated under reduced pressure, and the residue was
passed through a short silica gel column to give an oily 69. To
a toluene solution (6.00 mL) of 69 were added 2,2′-azobis-
(isobutyronitrile) (7.9 mg, 0.048 mmol) and tri-n-butyltin
hydride (0.26 mL, 1.15 mmol), and the mixture was stirred at
85 °C under an argon atmosphere for 1 h. The mixture was
evaporated under reduced pressure. The residue was purified
by column chromatography over silica gel (AcOEt-hexanes-
EtOH, 20:10:1) to give 70 (74.0 mg, 68%) as a paste.
9-(2-Deoxy-4-C-et h yn yl-â-D-r ibo-p en t ofu r a n osyl)a d e-
n in e (72) a n d 9-(2-Deoxy-4-C-eth yn yl-â-D-r ibo-p en tofu r a -
n osyl)p u r in e (73). To a solution of 70 (189 mg, 0.332 mmol)
in tetrahydrofuran (8.00 mL) was added a tetrahydrofuran
solution of tetrabutylammonium fluoride (1.0 M, 0.37 mL, 0.37
mmol) at room temperature. After stirring at the same
temperature for 30 min, the solvent was removed under
reduced pressure. The residue was passed through a short
silica gel column to give an oily 71. To a solution of 71 in
tetrahydrofuran (1.5 mL) was introduced ammonia gas dried
with potassium hydroxide at -78 °C. To a solution of the oil
in a mixture of liquid ammonia (ca. 15 mL) and tetrahydro-
furan (15 mL) was added sodium metal (38.0 mg, 1.66 mmol)
in several pieces at -78 °C. The mixture was vigorously stirred
at the same temperature for 10 min. To the reaction mixture
was added ammonium chloride (270 mg), and the mixture was
stirred at room temperature for 2 h. To the resulting mixture
was added ethanol, and the suspension was passed through a
pad of Celite. The pad was washed with ethanol and the
combined filtrates were concentrated under reduced pressure.
The residue was purified by column chromatography over silica
gel (MeOH-CHCl3, 1:10) to give a mixture of 72 and 73. The
mixture was separated by ODS reversed-phase column chro-
matography (5-7.5% ethanol in water) to give 73 (7.0 mg, 8%)
as white powder and 72 (48 mg, 53%) as white powder.
9-(3,5-Di-O-ben zyl-2-d eoxy-4-C-tr ieth ylsilyleth yn yl-â-
D-r ibo-p en t ofu r a n osyl)-2,6-d ia m in op u r in e (78). Com-
pound 76 (470 mg, 0.783 mmol) was treated as described in
the synthesis of 70. After purification by column chromatog-
raphy over silica gel (AcOEt-hexanes-EtOH, 30:10:1), 78 (276
mg, 60%) was obtained as an oil.
9-(2-Deoxy-4-C-et h yn yl-â-D-r ibo-p en t ofu r a n osyl)-2,6-
d ia m in op u r in e (80). Compound 78 (263 mg, 0.45 mmol) was
deprotected as described in the synthesis of 72. After purifica-
tion by column chromatography over silica gel (MeOH-CHCl3,
1:8) and trituration with methanol, 80 (56.0 mg, 43%) was
obtained as amorphous crystals.
9-(2-Deoxy-4-C-et h yn yl-â-D-r ibo-p en t ofu r a n osyl)gu a -
n in e (81). Compound 80 (30.0 mg, 0.103 mmol) was treated
as described in the synthesis of 74. After desalting and
purification by reversed-phase column chromatography over
ODS silica gel (2.5-5% EtOH in H2O), recystallization from
water gave 81 (15.0 mg, 50%) as an amorphous crystals.
An tivir a l Assa y Aga in st HIV-1. A laboratory HIV-1 strain
(HIV-1LAI),27 a wild-type clinical HIV-1 strain (HIV-1104pre),25
and an infectious molecular clone which contains five amino
acid substitutions (Ala62Val, Val75Leu, Phe77Leu, Phe116Tyr,
and Gln115Met) and shows a high level of resistance against
a variety of 2′,3′-dideoxy nucleoside analogues26 were employed
as a source of infectious virions.
Antiviral activity of compounds against HIV-1 was con-
ducted as previously described.28 Briefly, MT-2 or MT-4 cells
(2 × 104/mL) were exposed to 100 TCID50 of the HIV-1LAI in
the presence of various concentrations of drugs in 96-well
microculture plates and incubated at 37 °C for 7 days. After
100 µL of the medium was removed from each well, 10 µL of
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) solution (7.5 mg/mL) in phosphate-buffered saline (PBS)
was added to each well in the plate. The plate was then
incubated at 37 °C for 2 h. After incubation, to dissolve the
formazan crystals, 100 µL of acidified 2-propanol containing
4% (v/v) Triton X-100 was added to each well. The optical
density (wavelength 570 nm) was measured in a microplate
reader (model 3550, Biorad). All assays were performed in
triplicate.
The MAGI assay using HeLa-CD4-LTR-â-gal indicator cells
was conducted as previously described.29 Briefly, HeLa-CD4-
LTR-â-gal cells were seeded (104 cells/well) and cultured in
96-well microculture plates for 24 h and exposed to HIV-1104pre
or HIV-1MDR at a 30 TCID50 dose for 2 h at 37 °C. Various
concentrations of drugs were added to the culture 2 h prior to
or 2 h after viral exposure. The drugs were continuously
present and no cell washing was performed throughout the
culture. In 48 h of culture, the cells were fixed with 1%
formaldehyde and 0.2% glutaraldehyde in PBS and stained
with 5-bromo-4-chloro-3-indolyl-â-D-galactopyranoside (X-Gal).
Infected cells were counted in situ by virtue of their blue color
after incubation with X-Gal under the inverted microscope.
9-(2-Deoxy-4-C-eth yn yl-â-D-r ibo-p en tofu r a n osyl)h yp o-
xa n th in e (74). A mixture of 72 (22.0 mg, 0.08 mmol) and
adenosine deaminase (44.0 µL, 20 units) in Tris-HCl buffer (6
mL, pH 7.5) was stirred at 40 °C for 2 h. The solution was
cooled to room temperature and applied to an ODS silica gel
column. After washing the column with water (500 mL), the
eluate of 2.5% ethanol in water was collected and concentrated
under reduced pressure to give a residue. The residue was
triturated with 2-propanol to give 74 (16.0 mg, 72%) as an
amorphous crystals.
9-(2-O-Acetyl-3,5-d i-O-ben zyl-4-C-tr ieth ylsilyleth yn yl-
â-D-r ibo-p en tofu r a n osyl)-2,6-d ia m in op u r in e (75). Com-
pound 13 (1.10 g, 2.0 mmol) was treated as described in the
synthesis of 67. After purification by column chromatography
over silica gel (AcOEt-hexanes-EtOH, 20:10:1), 75 (850 mg,
66%) was obtained as a foam.
Ack n ow led gm en t. We thank Dr. Kenji Maeda for
technical assistance and helpful discussion. This work
was supported in part by a Sasagawa scientific research
grant from the J apan Science Society, a grant from the
Research for the Future Program of the J apan Society
for the Promotion of Science (J SPS-RFTF 97L00705), a
grant-in-aid for scientific research (priority areas) from
the Ministry of Education (Monbusho) of J apan, and a
grant for the promotion of AIDS research from the
Ministry of Health and Welfare (Koseisho) of J apan.
9-(3,5-Di-O-b en zyl-4-C-t r iet h ylsilylet h yn yl-â-D-r ibo-
p en t ofu r a n osyl)-2,6-d ia m in op u r in e (76). Compound 75
(850 mg, 1.32 mmol) was treated as described in the synthesis
of 68. After purification by column chromatography over silica
Su p p or tin g In for m a tion Ava ila ble: Elemental analysis
or mass and 1H NMR spectral data for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.

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