Synthesis and antiviral activity of novel acyclic nucleosides: Discovery of a cyclopropyl nucleoside with potent inhibitory activity against herpesviruses

Article abstract of DOI:10.1021/jm9705869

A series of acyclic nucleosides with two hydroxymethyl groups mimicking the 3'- and 5'-hydroxyl groups of the 2'-deoxyribose moiety were prepared and evaluated for their antiherpetic activity. Among those, 9-[[cis-1,2'- bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine (3) showed extremely potent antiviral activity against herpes simplex virus type-1 (HSV-1) with good selectivity. Both enantiomers of 3 were synthesized starting from chiral epichlorohydrins, and only one of the enantiomers with 1'S,2'R-configuration (3a) exhibited strong antiherpetic activity (IC₅₀ of 0.020 μg/mL against HSV-1 Tomioka vs 0.81 μg/mL for acyclovir). Enantiomer 3a was also more inhibitory than acyclovir against varicella-zoster virus (VZV) but ineffective against human immunodeficiency virus (HIV). Compound 3a is phosphorylated by HSV-1 thymidine kinase (TK) very efficiently. The relationship between conformation and antiherpetic activity in this series of compounds is discussed.

Full text of DOI:10.1021/jm9705869

1284
J . Med. Chem. 1998, 41, 1284-1298
Syn th esis a n d An tivir a l Activity of Novel Acyclic Nu cleosid es: Discover y of a
Cyclop r op yl Nu cleosid e w ith P oten t In h ibitor y Activity a ga in st Her p esvir u ses
Takaaki Sekiyama, Satoshi Hatsuya, Yasuhiro Tanaka, Mamoru Uchiyama, Nobukazu Ono, Satoshi Iwayama,
Miki Oikawa, Katsuya Suzuki, Masahiko Okunishi, and Takashi Tsuji*
Central Research Laboratories, Ajinomoto Company, Inc., 1-1 Suzuki-cho, Kawasaki 210, J apan
Received September 3, 1997
A series of acyclic nucleosides with two hydroxymethyl groups mimicking the 3′- and 5′-hydroxyl
groups of the 2′-deoxyribose moiety were prepared and evaluated for their antiherpetic activity.
Among those, 9-[[cis-1′,2′-bis(hydroxymethyl)cycloprop-1′-yl]methyl]guanine (3) showed ex-
tremely potent antiviral activity against herpes simplex virus type-1 (HSV-1) with good
selectivity. Both enantiomers of 3 were synthesized starting from chiral epichlorohydrins, and
only one of the enantiomers with 1′S,2′R-configuration (3a ) exhibited strong antiherpetic activity
(IC50 of 0.020 µg/mL against HSV-1 Tomioka vs 0.81 µg/mL for acyclovir). Enantiomer 3a was
also more inhibitory than acyclovir against varicella-zoster virus (VZV) but ineffective against
human immunodeficiency virus (HIV). Compound 3a is phosphorylated by HSV-1 thymidine
kinase (TK) very efficiently. The relationship between conformation and antiherpetic activity
in this series of compounds is discussed.
In tr od u ction
(HSV-1, HSV-2), varicella-zoster virus (VZV), and hu-
man cytomegalovirus (HCMV). The characteristic struc-
tural feature of oxetanocins is the two hydroxymethyl
groups located on a rigid four-membered ring. These
findings have prompted us to design compounds by
introducing conformational restriction on acyclic nucleo-
sides with two hydroxymethyl groups mimicking the 3′-
and 5′-hydroxyl groups of the 2′-deoxyribose moiety.
Nucleosides with olefinic and cyclopropyl C4 alcohols
were reported previously,7 and among them, 9-[[(Z)-2-
(hydroxymethyl)cyclopropan-1-yl]methyl]guanine and
9-[(Z)-4-hydroxy-2-buten-1-yl]guanine showed moderate
activity against HSV-1 and -2. These acyclic nucleosides
are efficiently phosphorylated by viral TK and further
phosphorylated by cellular kinases. These results sug-
gest that the position of the hydroxyl group mimicking
the 5′-hydroxyl group of nucleosides is suitable for
phosphorylation in this series of compounds and that
the introduction of the second hydroxyl group mimicking
the 3′-hydroxyl group of nucleosides in this series of
compounds will lead to a more potent antiherpetic
compound.
Since the discovery of acyclovir (ACV, 1a ) as a potent
antiherpetic agent,1 acyclic nucleosides have attracted
interest of medicinal chemists as well as virologists. The
efforts in search of a new agent with superior activity
over ACV resulted in the finding of ganciclovir2 (GCV,
1b), with broader antiviral activity, and penciclovir3
(PCV, 1c) as new therapeutic agents. As represented
by these two drugs, one of the approaches to improve
antiherpetic activity is to design a compound with two
hydroxyl groups mimicking the 3′- and 5′-hydroxyl
groups of the 2′-deoxyribose moiety of nucleosides. The
recent report on the crystal structure of HSV-1 thymi-
dine kinase (TK), a key enzyme to activate antiherpetic
nucleosides, complexed with GCV indicates the impor-
tance of the two hydroxyl groups of GCV for substrate
recognition.4
In this study, we introduced rotational restriction
between the C2 and C3 positions in a C4 alcohol
attached to a nucleoside base with olefinic, cyclopropyl,
and oxiranic moieties and located the second hydroxy-
methyl group corresponding to the 3′-hydroxyl group of
2′-deoxyribose at the appropriate position. Among the
compounds we synthesized, 9-[[cis-1′,2′-bis(hydroxy-
methyl)cycloprop-1′-yl]methyl]guanine (3) showed ex-
tremely potent antiviral activity against HSV-1 with
good selectivity. The two enantiomers of 3 were pre-
pared starting from chiral epichlorohydrins, and among
the enantiomers the 1′S,2′R-form (3a ) was proved to be
active. Antiviral spectra and mode of antiviral action
of the series of compounds are also presented. The
relationship of the side-chain conformation and flex-
The discovery of oxetanocins5 has led to a related
carbocyclic analogue, cyclobut-G6 (BHCG, 2), as a highly
potent inhibitor of broad spectrum against herpesvi-
ruses including herpes simplex virus type-1 and -2
S0022-2623(97)00586-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/24/1998

Cyclopropyl Nucleosides with Antiherpetic Activity
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1285
Sch em e 1a
a
(a) N2CHCO2Et, Rh2(OAc)4; (b) Red-Al; (c) TsCl, DMAP; (d) 2-amino-6-(benzyloxy)purine, K2CO3, 18-crown-6; (e) HCl/MeOH; (f) LiAlH4.
ibility to antiherpetic activity and phosphorylation by
HSV-1 TK in this series of compounds are also dis-
cussed.
7% yield, respectively. Stereochemistry of 8 and 9 was
confirmed by vicinal coupling constant between protons
on the cyclopropane ring.9 Compound 8 was reduced
to alcohol 10, and its tosylate was coupled with 2-amino-
6-(benzyloxy)purine to give the desired 9-alkyl deriva-
tive 11. Deprotection of 11 afforded 12. In a similar
manner 9 was converted to 15.
Ch em istr y
The synthesis of trans-2,3-bis(hydroxymethyl)cyclo-
propane derivative 7 is shown in Scheme 1. Cycload-
dition of ethyl diazoacetate to the protected trans-1,4-
butenediol in the presence of rhodium acetate gave
1,2,3-trisubstituted cyclopropane 4 which was reduced
to alcohol 5 with sodium bis(2-methoxyethoxy)alumi-
num hydride (Red-Al), and the resultant alcohol was
converted to its tosylate. Without purification the
tosylate was used for coupling with 2-amino-6-(benzyl-
oxy)purine to yield the desired 9-alkyl derivative 6 in
34% yield.8 The 7-isomer was also obtained in 27%
yield. Deprotection of 6 with 0.2 N hydrochloric acid
in methanol gave 7.
Scheme 2 shows the syntheses of 1,2-bis(hydroxy-
methyl)cyclopropane derivatives. 1,1,2-Tris(hydroxy-
methyl)cyclopropane (16a ) was synthesized as described
previously with modification7 and converted to the
disilyl ether 16b with tert-butyldimethylsilyl chloride
(TBDMS-Cl). Oxidation of the double bond of 16b with
osmium tetraoxide, followed by oxidation with sodium
metaperiodate, gave aldehyde 17, which was converted
to alcohol 18a by reduction with NaBH4. Benzoylation
of the resulting hydroxyl group and acid hydrolysis of
the silyl ether gave diol 19. Treatment with an equimo-
lar amount of benzoyl chloride gave two monobenzoates
(20a and 21a .) The regioisomers were separated by
silica gel column chromatography, and their configura-
tion was determined by NOE experiments.10 Tosylation
of 20a and 21a to 20b and 21b followed by treatment
with 2-amino-6-(benzyloxy)purine afforded 9-alkylated
The syntheses of cis-2,3-bis(hydroxymethyl)cyclopro-
pane derivatives are also outlined in Scheme 1. The
silyl-protected cis-1,4-butenediol was treated with ethyl
diazoacetate in the presence of rhodium acetate to give
1,2,3-trisubstituted cyclopropanes 8 and 9 in 8% and

1286 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Sekiyama et al.
Sch em e 2a
a
(a) OsO4, MNO then NaIO4; (b) NaBH4; (c) BzCl, pyridine; (d) aq HCl; (e) TsCl, DMAP; (f) 2-amino-6-(benzyloxy)purine, K2CO3,
18-crown-6; (g) MeONa/MeOH then 1 N HCl.
purine derivatives 22 and 24, both in 61% yield, which
were then deprotected to yield 23 and 3.
amino- and 2-aminopurine derivatives of 3 were pre-
pared by coupling of 21b with 2-amino-6-chloropurine
followed by either amination or catalytic hydrogenation.
The compounds described above were synthesized as
racemates. The enantiomers of the most active com-
pound in the series, 9-[[cis-1′,2′-bis(hydroxymethyl)-
cycloprop-1′-yl]methyl]guanine (3), were synthesized by
the route shown in Scheme 5. Optically active cyclo-
propane lactone 47 was synthesized in the manner
previously described by Pirrung et al.14 with modifica-
tion. Condensation of diethyl malonate and (R)-(-)-
epichlorohydrin in ethanol under reflux gave 47 in 65%
yield with >97% ee. The optical purity of 47 was
established by chiral HPLC. Selective reduction of the
lactone moiety was performed by NaBH4 at room
temperature to give diol ester 48 in 69% yield, which
was converted to an acetonide and then reduced to
alcohol 50a by LiBH4. Compound 50a was converted
to benzyl ether 50b and subsequently hydrolyzed to diol
51a by aqueous HCl. Benzoylation of 51a , followed by
palladium-catalyzed hydrogenation, gave dibenzoate 52
which was converted to 3a in a similar manner as
shown in Scheme 2.15 The other enantiomer, 3b, was
prepared from (S)-(+)-epichlorohydrin in the same way.
The syntheses of olefinic derivatives are described in
Scheme 3. Reaction of triethyl phosphonoacetate with
ketone 25, derived from dihydroxyacetone dimer by the
method of Shibasaki et al.,11 in the presence of sodium
hydride produced bis-TBDMS ether 26 in 88% yield.
Reduction of the ester group of 26 with diisobutylalu-
minun hydride (DIBAL-H) yielded alcohol 27a which
was subsequently converted to diol 28 by benzoylation
followed by acid hydrolysis of the silyl ethers. Treat-
ment of 28 with an equimolar amount of benzoyl
chloride gave dibenzoate 29a , as an E- and Z-mixture,
which was converted to bromide 29b with PBr3 and
coupled with 2-amino-6-(benzyloxy)purine without pu-
rification. Two 9-alkylated purine derivatives, 30 and
31, were obtained, both in 20% yield, after separation
on a silica gel column. The configuration of these
stereoisomers was determined by NOE experiments.12
Deprotection of 30 and 31 gave guanine derivatives 32
and 33, respectively.
The syntheses of epoxides 38 and 39 are shown in
Scheme 3. Oxidation of dibenzoate 29a with m-CPBA
yielded epoxide 34. Tosylation of 34 and coupling of
tosylate 35 with 2-amino-6-(benzyloxy)purine gave 9-alky-
lated purine derivatives 36 and 37 in 23% and 24%
yield, respectively, after separation by reversed-phase
column chromatography.13 Deprotection by catalytic
hydrogenation followed by sodium methoxide treatment
yielded 38 and 39.
Biologica l Stu d ies
Antiherpetic activities of the series of compounds were
measured by a quantitative CPE reduction assay16
against HSV-1 Tomioka strain. Results are sum-
marized in Table 1. Among the compounds tested, 3
showed extremely potent activity against HSV-1 and is
nearly 20 times as potent as ACV (1a ) with better
selectivity. Of the two enantiomers of 3, 1′S,2′R-form
3a is the active form and is about 40 times as potent as
ACV. The weak activity of the other enantiomer 3b is
possibly due to contamination of 3a (<3%). The stere-
oisomer of 3, the trans-cyclopropane 23, is only margin-
ally active. In contrast, the olefin analogues are weakly
active, and both E- and Z-forms are equally active.
Among the epoxide analogues only the E-epoxide 38 is
active, and the Z-form is inactive. However, in this case,
Derivatives of nucleosides bearing bases other than
guanine were prepared as shown in Scheme 4. Tosylate
or bromide 20b, 21b, and 29b were coupled with
adenine, thymine, and cytosine base. After coupling of
29b, the stereoisomers were separated by reversed-
phase column chromatography and the stereochemistry
was determined by NOE experiments.12 Deprotection
of the benzoyl groups gave a series of adenine, thymine,
and cytosine derivatives (40-42). Hypoxanthine de-
rivatives 43a ,b were prepared from adenine derivatives
40a ,b by diazotization with sodium nitrite. 2,6-Di-

Cyclopropyl Nucleosides with Antiherpetic Activity
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1287
Sch em e 3a
a
(a) (EtO)2P(O)CH2CO2Et, NaH; (b) DIBAL-H; (c) BzCl, pyridine; (d) aq HCl; (e) PBr3; (f) 2-amino-6-(benzyloxy)purine, NaH; (g) MeONa/
MeOH then aq HCl; (h) m-CPBA; (i) TsCl, pyridine; (j) H2, Pd/C; (k) MeONa/MeOH.
decomposition of the epoxide ring under assay condi-
tions was observed possibly by an intramolecular attack
of N3 of purine to the epoxide. The 1′,2′,3′-trisubstituted
cyclopropane analogues 7, 12, and 15 are completely
devoid of activity.
Among the compounds with base moieties other than
guanine, 40b with adenine, 45 with 2,6-diaminopurine,
and 46 with 6-aminopurine, all with the cis-1′,2′-bis-
(hydroxymethyl) moiety, are weakly active. The activity
of the latter two compounds may be due to intracellular
conversion to 3.
The compounds were also tested against HIV-1. In
contrast to the strong activity against HSV-1, 3a was
inactive against HIV. Among the compounds tested
41b, a cytosine derivative of 3, was moderately active,
and some thymine, hypoxanthine, and 2,6-diaminopu-
rine derivatives showed weak activity.
Anti-VZV activity of some of the compounds was
evaluated by inhibition of plaque formation. The results
are summarized in Table 2. All the compounds which
are active against HSV-1 showed inhibitory activity
against VZV, and among them, 3a is more than 10 times
as potent as ACV. E-Olefin 32 is more than 10 times
as active as Z-olefin 33 in contrast to their anti-HSV-1
activity in which both isomers show equal activity.
Most of the antiherpetic acyclic nucleosides are phos-
phorylated by viral TK, and this step is critical for
activity and selectivity. To study the phosphorylation
of 3 and other compounds, they were incubated with
an extract of HSV-1-infected BU25 cells lacking cellular
TK17 and amounts of monophosphates were measured
by HPLC analysis.18 Conversion of each nucleoside to
the corresponding monophosphate is summarized in
Table 3. Though the inactive compounds 7, 12, and 15
showed no or slow phosphorylation, the most potent (3a )
is 7-8 times more efficiently phosphorylated than ACV
by the cellular extract. The less active enantiomer, 3b,
is also phosphorylated, more slowly than 3a but faster
than ACV. 23, 32, and 33 are better substrates than
acyclovir for the viral TK despite their weaker anti
HSV-1 activity. The two enantiomers of 23 were
separated by chiral HPLC, and phosphorylation of both
enantiomers were studied. Although the absolute con-
figuration of each enantiomer was not identified, one
of the enantiomers showed highly efficient phosphory-
lation and the other showed no phosphorylation. No

1288 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Sekiyama et al.
Ta ble 1. Anti-HSV-1 Activity (Tomioka in Vero Cells) by
Quantitative CPE Assay and Anti-HIV-1 Activity (RF in CEM
Cells) by Plaque Reduction Assay of the Compounds
Sch em e 4a
HSV-1
HIV-1
e
compda
typeb positionc based IC50
CC50 IC50 CC25
1a (ACV)
AZT
ddC
3
3a
3b
7
12
15
23
0.81
-
-
0.046 530
0.020 240
2.2
820
-
-
-
f
0.003 35.6
-
0.02
-
>100 >100
-
-
-
-
0.49
-
cp
cp
cp
cp
cp
cp
cp
ol
1′,2′-c
1′,2′-c
1′,2′-c
2′,3′-t
2′,3′-c
2′,3′-c
1′,2′-t
2,3-E
2,3-Z
2,3-E
2,3-Z
1′,2′-t
1′,2′-c
2,3-E
2,3-Z
1′,2′-t
1′,2′-c
2,3-E
2,3-Z
1′,2′-t
1′,2′-c
1′,2′-t
1′,2′-c
1′,2′-c
1′,2′-c
G
G
G
G
G
G
G
G
G
G
G
A
A
A
A
T
T
T
T
C
C
HX
HX
>500
-
-
-
-
>500 >500
>500 >500
>500 >500
10
>500 >100 >100
>500 >100 >100
>500 >100 >100
32
33
38
39
4.2
4.2
14
ol
ep
ep
cp
cp
ol
>500
-
-
-
-
>500 >500
>500 260
47
>500 260
>500 260
40a
40b
40c
40d
41a
41b
41c
41d
42a
42b
43a
43b
45
>100 >100
>100 19.8
>100 >100
>100 >100
120
ol
cp
cp
ol
>500 >500 >100 >100
>500 >500 3.2
>100
>500 >500 >100 >100
>500 >500 >100 >100
ol
cp
cp
cp
cp
cp
cp
120
>500 23.7
>100
>500 >500 >100 >100
>500 >500 20.1
>500 >500 25.7
>100
>100
>100
-
DAP 29
2AP 30
>500 32.1
>500
46
-
a
All compounds except AZT, ddC, and 3a ,b are racemates.
b
Type of bonds in the side chains: cp, cyclopropane; ol, olefin; ep,
epoxide. c Positions of the two hydroxymethyl groups in the side
chains. G, guanine; T, thymine; C, cytosine; A, adenine; HX,
d
hypoxanthine; DAP, 2,6-diaminopurine; 2AP, 2-aminopurine.
a
(a) Adenine, NaH; (b) MeONa/MeOH; (c) thymine, Na2CO3;
e Concentrations in µg/mL. f Not measured.
(d) cytosine, NaH; (e) NaNO2/AcOH; (f) 2-amino-6-chloropurine,
K2CO3, 18-crown-6; (g) NH3/MeOH; (h) 10% Pd/C, HCO2NH4.
of the side chain, showed extremely potent antiviral
activity against HSV-1. Concerning the chirality around
the carbon atom bearing the hydroxymethyl group
corresponding to the 3′-hydroxyl of a nucleoside, the 2R-
form of 2HM-HBG is the active form and, in case of 3,
the 1′S-form is the active configuration. Because of the
characteristics of a cyclopropane ring, the direction of
the side chain leading to the hydroxyl group corre-
sponding to the 5′-hydroxyl group of a nucleoside is
different in 3 and 2HM-HBG even with the same
chirality around the 1′- and 2-carbon atoms, respec-
tively, and it is not surprising that the opposite enan-
tiomers are the active forms. Among the other com-
phosphate formation was observed when these com-
pounds were incubated with an extract of uninfected
BU25 cells.
Discu ssion
Rotational restrictions were introduced into flexible
acyclosugar moieties of nucleosides, and their effects on
antiviral activity were examined. Among the com-
pounds synthesized, 3, which is considered to be a 9-[4-
hydroxy-2-(hydroxymethyl)butyl]guanine (2HM-HBG19)
analogue with a cyclopropane ring in the 2,3-position
Sch em e 5a
a
(a) NaBH4; (b) 2,2-dimethoxypropane, cat. TsOH; (c) LiBH4; (d) benzyl bromide, NaH; (e) aq HCl; (f) BzCl, pyridine; (g) H2, Pd/C.

Cyclopropyl Nucleosides with Antiherpetic Activity
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1289
Ta ble 2. Anti-VZV Activity (DM625 in HFF Cells) by Plaque
Reduction Assay of the Compounds
ogy to 2, compounds in which a cyclopropyl moiety is
attached directly to a nucleoside base were also syn-
thesized previously, but these analogues are only weakly
or not at all active against herpesviruses.21 In the
compounds with a cyclopropane ring directly attached
to the nucleoside base, the hydroxyl group to be phos-
phorylated is too close to the base in comparison to 2.
Thus, the compounds with an extra methylene group
were synthesized in this study. However, the relative
positions of the two hydroxyl groups and the base moiety
are proved to be unsuitable in these compounds. In
contrast, ring expansion of 2 has also been tried to find
a unique adenine nucleoside active against HIV.22
b
compda
IC50
MTCc
SId
1a (ACV)
3a
7
23
32
33
40a
40b
2.7
>320
320
320
320
320
>320
320
320
>83
0.20
240
19.4
3.2
52.8
1600
1.3
16
100
>6.1
1.5
220
19.8
16
a
b
All compounds except 3a are racemates. Concentrations in
µg/mL. c Minimum cytotoxic concentration determined by micro-
scopic examination of the drug-treated uninfected cells. Selec-
d
tivity index ) IC50/minimum cytotoxic concentration of drugs.
Cyclopropyl and olefinic derivatives of 9-(4-hydroxy-
butyl)guanine (HBG) and PCV were reported previ-
ously,7,23 and the (Z)-cyclopropyl analogue which lacks
the 1′-hydroxymethyl group of 23 showed moderate
activity. In contrast to our results, the corresponding
(E)-cyclopropyl analogue which lacks the 1′-hydroxy-
methyl group of 3 was inactive against HSV-1 and -2.
Importance of the relative positioning of the two hy-
droxyl groups in the side chain should be noted.
Ta ble 3. Conversion of Nucleosides to Their Monophosphates
compda
conversion (%)b
compda
conversion (%)b
2′-dG
1a (ACV)
3a
3b
7
0
6
46
11
16
0
15
23
23a
23b
32
14
46
0
94
39
32
12
33
a
All compounds except 2′-dG, 3a ,b, and 23a ,b are racemates.
Since exhibition of the antiherpetic activity of these
nucleoside analogues is the sum of several steps of
enzymatic processes including phosphorylation to mono-
phosphates by a viral TK, further phosphorylation to
triphosphates by cellular kinases, and finally inhibition
of viral DNA replication,24 to make detailed discussion
in structure-activity relationships studies on each step
are required. In the present study the first step of
activation was studied, since this step is known to be
critical for the selectivity and activity of antiherpes
acyclic nucleosides. All the compounds tested which are
active against HSV-1 to some extent were phosphory-
lated more efficiently than acyclovir. The most active
compound (3a ) is not the best compound in terms of the
efficacy of phosphorylation. The inactive enantiomer
(3b) is also phosphorylated to some extent. In the case
of PCV the major form of the monophosphate produced
by HSV-TK is the (S)-PCV monophosphate, but the (R)-
monophosphate is also formed.25 Quite surprisingly,
one of the enantiomers of 23 is the best substrate of viral
TK. Enantiomeric selectivity observed in 23 is similar
to that in GCV in which a single enantiomeric mono-
phosphate is formed.26 In case of cyclobut-G, efficiency
of phosphorylation of each enantiomer by HSV-TK does
not correlate with their antiherpesvirus activity.27
Though there is no clear parallel relationship between
efficacy of phosphorylation by viral TK and antiviral
activity, efficient phosphorylation by herpes TK is
apparently one of the reasons for the strong antiherpetic
activity of 3a .
b
Calculated percentage based on phosphorylated and unphospho-
rylated compound after incubation for 24 h at 37 °C.
pounds, 32 and 33 which are the E- and Z-olefinic
analogues of 2HM-HBG are moderately active. Though
in the olefinic version the E- and Z-isomers showed
almost identical antiherpetic activity, 23, which is the
trans-cyclopropyl analogue of 3, showed a dramatic
decrease in antiherpetic activity compared to the cor-
responding cis form. There is only a small difference
in the possible location of the two hydroxyl groups in
the E- and Z-forms of the olefinic and cyclopropyl
derivatives; however, this small change in the side-chain
orientation caused by the different type of restriction
plays a critical role in the antiviral activity. Among the
oxirane analogues only the E-form 38 showed weak
activity. The side-chain orientations of the oxirane
derivatives are almost identical to that of the cyclopropyl
derivatives except for the presence of the oxygen atom.
The low activity of the oxirane derivatives may be due
to the disturbance of interaction with the target en-
zymes by the presence of the oxygen atom. Another
possibility might be the instability of the compounds
under the assay conditions as described in the previous
section.
Although less active against HSV-1 and -2 than ACV,
2HM-HBG shows superior activity over ACV against
VZV.19 Similar to 2HM-HBG, anti-VZV activity of 3a
is more than 10 times as potent as ACV; thus, 3a is
proved to be one of the most potent anti-VZV acyclogua-
nine nucleosides ever known. Unlike PCV and GCV,
the carbon skeleton of the sugar moiety does not trace
that of deoxyribose in 3a and 2HM-HBG and the
position of the 3′-hydroxyl group is closer to the guanine
base. This structural feature will be one of the reasons
for the high activity against VZV.
Recently, crystal structures of the thymidine kinase
of HSV-1 and its complexes with thymidine and GCV
were solved.4 As shown in the crystal structure of the
complexes, the binding modes of thymidine and GCV
are different from each other. Combining the informa-
tion from the crystal structure with the fact that
2′-deoxyguanosine is not a good substrate of the HSV-
TK,28 the resemblance of the acycloguanine nucleoside
to 2′-deoxyguanosine is unfavorable in the step of
phosphorylation. However, in the steps of further
phosphorylation by cellular kinases and the triphos-
phate inhibition of DNA polymerases, structural simi-
The 1′,2′,3′-trisubstituted type compounds are all
inactive. These compounds resemble cyclobut-G 2 but
have an extra methylene between the guanine base and
the ring. Other base analogues of this type of com-
pounds were synthesized by Katagiri et al.,20 and none
of them showed antiviral activity. By the simple anal-

1290 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Sekiyama et al.
indicated only by the elements, were within (0.4% of theoreti-
cal values. Anti-VZV and anti-HIV assays were performed
under contract by Southern Research Institute. All antiviral
titrations were done in either triplicate or quadruplicate.
larity to 2′-deoxyguanosine nucleotides is supposed to
be important. In fact carbocyclic 2′-deoxyguanosine29
and its 2′-fluoro derivative30 which are structurally
closest to 2′-deoxyguanosine show potent antiherpetic
activity. Since these compounds are also active against
HCMV lacking the viral thymidine kinase, they might
be phosphorylated by the cellular guanosine kinases.
Effect of the cyclopropane ring should be the intro-
duction of restriction which arranges the relative ori-
entation of the two hydroxyl groups while maintaining
a certain amount of flexibility. From our preliminary
results on conformational studies using molecular me-
chanics, the two hydroxyl groups of 3a can take posi-
tions close to those of 2′-deoxyguanosine in one of their
stable conformations. At the same time, it was revealed
that the rotational barriers around the bonds between
the cyclopropane ring and the methylene carbon at-
tached to the ring were lowered compared to the normal
single bond, which means the entire molecule is flexible
enough to adopt different conformers suitable for further
phosphorylation and DNA polymerase inhibition after
phosphorylation. The structural requirement for the
highly active compounds is not described with a single
conformation. They should have proper conformations,
both in themselves and in phosphorylated forms, against
several enzymes, viral and cellular kinases, and viral
DNA polymerase, and 3a is one of such compounds, in
terms of conformational rigidity and flexibility, espe-
cially for HSV-1. To introduce conformational rigidity
is one of the approaches to decide the active conforma-
tion, and a cyclopropane ring has also been used
recently to fix sugar ring puckering by introducing it
into carbocyclic 2′-deoxynucleosides.31 In contrast to
such trials to give complete rigidity in the molecule,
rigidity is limited in the present study, and this partial
conformational restriction has led to a highly potent
antiviral compound.
Eth yl c-2,t-3-Bis[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-
r -1-cyclop r op a n eca r boxyla te (4). To an ice-cooled mixture
of ethyl glycinate HCl (5.60 g, 40 mmol) in H2O (10 mL) and
CH2Cl2 (23 mL) was added aqueous NaNO2 (3.28 g, 47.5 mmol,
10 mL), and then 5% aqueous H2SO4 (3.90 mL) was added
dropwise at -20 °C. After stirring for 10 min at -20 °C, the
mixture was extracted with CH2Cl2 and the organic layer was
washed with saturated NaHCO3. The organic layer was
combined and concentrated to 7.5 mL in vacuo. The solution
was added dropwise over 6 h to a solution of (E)-1,4-bis[(tert-
butyldimethylsilyl)oxy]-2-butene (10.38 g, 32.8 mmol) and
rhodium(II) acetate dimer (90 mg, 0.20 mmol) in CH2Cl2 (20
mL) at room temperature. After stirring for 14 h, the solvent
was removed in vacuo and the residue was chromatographed
on silica gel eluting with 4-10% Et2O in hexane to yield 4 as
a colorless oil (4.01 g, 30%): 1H NMR (CDCl3) δ 0.03 (s, 12H),
0.86 (s, 18H), 1.25 (t, J ) 7.2 Hz, 3H), 1.55-1.65 (m, 2H), 1.73
(dd, J ) 5.4, 9.0 Hz, 1H), 3.61 (dd, J ) 4.8, 10.5 Hz, 1H), 3.66
(dd, J ) 4.5, 10.5 Hz, 1H), 3.71 (dd, J ) 7.8, 11.0 Hz, 1H),
3.90 (dd, J ) 5.7, 11.0 Hz, 1H), 4.11(q, J ) 7.2 Hz, 1H), 4.12
(q, J ) 7.2 Hz, 1H); FD MS m/z 402 (M+).
c-2,t-3-Bis[[(ter t-b u t yld im et h ylsilyl)oxy]m et h yl]-r -1-
cyclop r op a n em eth a n ol (5). A solution of 4 (2.24 g, 5.56
mmol) in anhydrous THF (25 mL) was cooled to -5 °C and
treated with a 3.3 M solution of Red-Al in toluene (2.8 mL,
9.24 mmol). After stirring at -5 °C for 20 min, saturated NH4-
Cl was added and the resulting mixture was extracted with
EtOAc. The organic layer was washed with brine and con-
centrated in vacuo. The residue was chromatographed on
silica gel eluting with 15-20% Et2O in hexane to yield 5 as a
colorless oil (1.34 g, 67%): 1H NMR (CDCl3) δ 0.03 (s, 6H),
0.09 (s, 3H), 0.11 (s, 3H), 0.88 (s, 9H), 0.89 (m, 1H), 0.90 (s,
9H), 1.17 (m, 1H), 1.30 (m, 1H), 3.28 (m, 1H), 3.34 (m, 1H),
3.51 (dd, J ) 5.7, 10.8 Hz, 1H), 3.55 (dd, J ) 5.7, 10.8 Hz,
1H), 3.94 (dd, J ) 5.1, 11.3 Hz, 1H), 4.13 (dd, J ) 5.6, 11.3
Hz, 1H); FD MS m/z 361 (MH+).
2-Am in o-6-(b en zyloxy)-9-[[c-2′,t-3′-b is[[(ter t-b u t yld i-
m e t h y ls ily l)o x y ]m e t h y l]c y c lo p r o p -r -1′-y l]m e t h y l]-
p u r in e (6). p-TsCl (3.39 g, 17.8 mmol) was added to a solution
of 5 (2.14 g, 5.93 mmol) and 4-(N,N-dimethylamino)pyridine
(4.35 g, 35.6 mmol) in CH2Cl2 (80 mL) at 0 °C, and the mixture
was stirred at 0-5 °C for 2.5 h. The solution was diluted with
EtOAc-hexane (1:1) and washed with saturated NH4Cl,
saturated NaHCO3, and brine. The organic layer was con-
centrated in vacuo, and the resulting residue was dissolved
in DMF (10 mL). The solution was added to a suspension of
2-amino-6-(benzyloxy)purine (1.43 g, 5.93 mmol), K2CO3 (0.82
g, 5.93 mmol), and 18-crown-6 (1.42 g, 5.93 mmol) in DMF
(40 mL). After stirring at 110 °C for 16 h, the mixture was
cooled to room temperature, diluted with EtOAc-hexane (1:
1, 100 mL), and then washed with brine. The organic layer
was concentrated in vacuo, and the residue was chromato-
graphed on silica gel eluting with 2% MeOH in CH2Cl2 to yield
6 as a white solid (1.19 g, 34%): 1H NMR (CDCl3) δ -0.01 (s,
6H), 0.06 (s, 6H), 0.84 (s, 9H), 0.89 (s, 9H), 1.08 (m, 1H), 1.21
(m, 1H), 1.31 (m, 1H), 3.48 (dd, J ) 6.0, 10.8 Hz, 1H), 3.57-
3.67 (m, 2H), 3.97 (dd, J ) 4.8, 11.4 Hz, 1H), 4.10 (dd, J )
7.2, 14.4 Hz, 1H), 4.30 (dd, J ) 7.2, 14.4 Hz, 1H), 4.92 (bs,
2H), 5.56 (s, 2H), 7.25-7.36 (m, 3H), 7.48-7.52 (m, 2H), 7.91
(s, 1H); FD MS m/z 584 (MH+).
Since 3a exhibits superior activity against a wide
variety of herpesviruses with a good selectivity index
and preliminary in vivo experiments showed a superior
therapeutic potential of this compound,32 it may provide
a new therapeutic tool with better clinical efficacy over
the existing drugs. Further studies such as antiviral
spectrum against various strains of herpesviruses in
different cell lines and in vivo efficacy will be reported
elsewhere.32
Exp er im en ta l Section
Gen er a l. Reagents used were the highest quality available
commercially. (R )- and (S)-epichlorohydrin (>98% ee) were
obtained from Daiso (Osaka, J apan). Unless otherwise noted,
organic extracts were dried over anhydrous MgSO4 or Na2-
SO4, and temperature refers to the temperature of the bath.
Melting points (uncorrected) were determined on a Yanaco MP-
S3 micromelting point apparatus. 1H NMR spectra were
recorded with a Varian XL-300 300-MHz or a J EOL J NM-GX-
400 400-MHz spectrometer, using tetramethylsilane as an
internal standard, and ultraviolet spectra were recorded with
a HITACHI U-3200 spectrophotometer. Mass spectra were
recorded on a J EOL J MS-DX300 spectrophotometer, and
accurate masses were measured on a J EOL J MS-HX110
spectrometer. Thin-layer chromatography was carried out on
silica gel 60F254 precoated plates (Merck art. 5715), and silica
gel column chromatography was conducted on silica gel 60
(70-230 mesh; Merck art. 7734). Preparative reversed-phase
column chromatography was conducted on Merck LiChroprep
RP-18 (40-63 µm). Elemental combustion analyses, where
9-[[c-2′,t-3′-Bis(h yd r oxym eth yl)cyclop r op -r -1′-yl]m eth -
yl]gu a n in e (7). To a solution of 6 (552 mg, 0.945 mmol) in
MeOH (25 mL) was added 1 N HCl (5 mL), and the mixture
was stirred at 50 °C for 2 h. After cooling to room temperature,
the solvent was removed in vacuo and the residue was
dissolved in H2O and washed with EtOAc. The aqueous layer
was concentrated in vacuo, and the residue was recrystallized
from MeOH to yield the HCl salt of 7 as white crystals (53.5
1
mg, 19%): mp 265-267 °C dec; H NMR (DMSO-d6) δ 1.02-
1.20 (m, 2H), 1.26-1.37 (m, 1H), 3.12 (dd, J ) 7.2, 11.4 Hz,

Cyclopropyl Nucleosides with Antiherpetic Activity
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1291
1H), 3.31 (dd, J ) 9.3, 11.7 Hz, 1H), 3.47 (dd, J ) 5.4, 11.4
Hz, 1H), 3.76 (dd, J ) 5.4, 11.7 Hz, 1H), 4.06 (dd, J ) 8.1,
14.4 Hz, 1H), 4.24 (dd, J ) 7.2, 14.4 Hz, 1H), 7.18 (bs, 2H),
9.11 (s, 1H), 11.61 (bs, 1H); FD MS m/z 266 (MH+); HRMS
calcd for C11H16O3N5 (MH+) 266.1253, found 266.1247. Anal.
(C11H16O3N5Cl) C, H, N.
C11H16O3N5 (MH+) 266.1253, found 266.1245. Anal.
(C11H16O3N5Cl‚0.2H2O) C, H, N.
1,1-Bis[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-2-vin yl-
cyclop r op a n e (16b). To a solution of diethyl 2-vinyl-1,1-
cyclopropyldicarboxylate (17.5 g, 82.3 mmol) in anhydrous THF
(82.3 mL) was added dropwise 0.1 M LiAlH4 in anhydrous THF
(90.5 mL, 90.5 mmol) at 0 °C. After stirring at room temper-
ature for 30 min, 33 mL of MeOH was added at 0 °C. MeOH
(300 mL) and H2O (15 mL) were added, and the mixture was
stirred at room temperature overnight. The resulting emul-
sion was filtered over Celite, and the filtrate was concentrated
in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and
filtered, and the filtrate was concentrated in vacuo. The
residue containing 16a (7.0 g, 55 mmol) and imidazole (16.5
g, 242 mmol) were dissolved in DMF (105 mL), and tert-
butyldimethylsilyl chloride (18.2 g, 121 mmol) was added at 0
°C. After stirring overnight at room temperature, the solvent
was removed in vacuo. The residue was dissolved in Et2O and
washed with saturated NaHCO3. The organic layer was
concentrated in vacuo, and the residue was chromatographed
on silica gel eluting with 3% EtOAc in hexane to yield 16b as
a colorless oil (16.5 g, 56%): 1H NMR (CDCl3) δ 0.02 (s, 6H),
0.03 (s, 6H), 0.56 (dd, J ) 4.8, 4.8 Hz, 1H), 0.80 (dd, J ) 4.8,
8.4 Hz, 1H), 0.88 (s, 9H), 0.89 (s, 9H), 1.50 (m, 1H), 3.43 (d, J
) 9.9 Hz, 1H), 3.51 (d, J ) 10.5 Hz, 1H), 3.68 (d, J ) 9.9 Hz,
1H), 3.71 (d, J ) 10.5 Hz, 1H), 4.97 (ddd, J ) 0.6, 2.1, 10.2
Hz, 1H), 5.18 (ddd, J ) 0.9, 2.1, 17.1 Hz, 1H), 5.69 (ddd, J )
8.1, 10.2, 17.1 Hz, 1H).
2,2-Bis[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-1-cyclo-
p r op a n eca r ba ld eh yd e (17). Osmium tetraoxide in acetone
(0.1 M solution, 23.2 mL, 2.32 mmol) was added to a solution
of 16b (16.5 g, 46.4 mmol) and 4-methylmorpholine N-oxide
(10.9 g, 92.8 mmol) in H2O/THF (1:2, 165 mL), and the mixture
was stirred at room temperature for 84 h. The solvent was
removed in vacuo, and the residue was dissolved in CH2Cl2
and washed with saturated NaHCO3. The organic layer was
concentrated in vacuo, and the residue was treated with NaIO4
(11.9 g, 55.7 mmol) in H2O/THF (1:2, 248 mL) at room
temperature overnight. The solvent was removed in vacuo,
and the residue was dissolved in Et2O and washed with
saturated NaHCO3. The organic layer was concentrated in
vacuo, and the residue was chromatographed on a silica gel
column eluting with 7% Et2O in hexane to yield 17 as a
colorless oil (13.5 g, 81%): 1H NMR (CDCl3) δ 0.01 (s, 3H),
0.03 (s, 3H), 0.04 (s, 6H), 0.86 (s, 9H), 0.88 (s, 9H), 1.20 (dd, J
) 5.1, 7.8 Hz, 1H), 1.42 (dd, J ) 5.1, 5.1 Hz, 1H), 1.91 (ddd, J
) 5.1, 5.1, 7.8 Hz, 1H), 3.46 (d, J ) 10.2 Hz, 1H), 3.58 (d, J )
11.1 Hz, 1H), 3.80 (d, J ) 10.2 Hz, 1H), 3.95 (d, J ) 11.1 Hz,
1H), 9.46 (d, J ) 4.5 Hz, 1H); FAB MS m/z 301 (M+ - t-Bu).
2,2-Bis[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-1-cyclo-
p r op a n em eth a n ol (18a ). NaBH4 (3.56 g, 94.0 mmol) was
added in portions to a stirred solution of 17 (13.5 g, 37.6 mmol)
in MeOH (200 mL) at 0 °C. After 30 min, the solvent was
removed in vacuo and the residue was dissolved in CH2Cl2 and
washed with saturated NH4Cl. The organic layer was con-
centrated in vacuo, and the residue was chromatographed on
a silica gel column eluting with 10% Et2O in hexane to yield
18a as a colorless oil (11.8 g, 87%): 1H NMR (CDCl3) δ 0.03
(s, 3H), 0.03 (s, 3H), 0.10 (s, 3H), 0.11 (s, 3H), 0.34 (t, J ) 5.1
Hz, 1H), 0.70 (dd, J ) 5.1, 8.4 Hz, 1H), 0.89 (s, 9H), 0.91 (s,
9H), 1.19 (m, 1H), 2.87 (d, J ) 10.5 Hz, 1H), 3.20-3.32 (m,
3H), 3.94 (m, 1H), 4.11 (d, J ) 10.5 Hz, 1H), 4.27 (dd, J )
10.8 Hz, 1H); FD MS m/z 361 (MH+), 403 (M+ - t-Bu).
[2,2-Bis[[(ter t-bu tyldim eth ylsilyl)oxy]m eth yl]cyclopr op-
1-yl]m eth yl Ben zoa te (18b). BzCl (5.69 mL, 49.1 mmol) was
added to a solution of 18a (11.8 g, 32.7 mmol) in pyridine (177
mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min.
Then, ice-water was added at 0 °C, and the mixture was
stirred for 15 min. The solvent was removed in vacuo, and
the residue was dissolved in Et2O and washed with saturated
NaHCO3. The organic layer was concentrated in vacuo and
the residue was chromatographed on a silica gel column with
3% Et2O in hexane to yield 18b as a colorless oil (14.7 g,
97%): 1H NMR (CDCl3) δ 0.02 (s, 3H), 0.03 (s, 6H), 0.04 (s,
Eth yl 2,3-Bis[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-1-
cyclop r op a n eca r boxyla te (8 a n d 9). (Z)-1,4-Bis[(tert-bu-
tyldimethylsilyl)oxy]-2-butene (10.00 g, 31.6 mmol) was treated
in the same manner as described in preparation of 4. After
chromatography, 1.06 g of 8 (8.3%) and 0.93 g of 9 (7.3%) were
obtained as a colorless oil along with 5.73 g (57%) of starting
material. Ethyl c-2,c-3-bis[[(tert-butyldimethylsilyl)oxy]methyl]-
r-1-cyclopropanecarboxylate 8: 1H NMR (CDCl3) δ 0.04 (s, 6H,
CH3Si), 0.05 (s, 6H, CH3Si), 0.88 (s, 18H, t-Bu), 1.25 (t, J )
7.2 Hz, 3H, CH2CH3), 1.67 (m, 2H, C2H, C3H), 1.83 (dd, J )
8.1, 9.3 Hz, 1H, C1H), 3.94 (m, 2H, CH2O), 4.02 (m, 2H, CH2O),
4.09 (q, J ) 7.2 Hz, 2H, CH2CH3). Ethyl t-2,t-3-bis[[(tert-
butyldimethylsilyl)oxy]methyl]-r-1-cyclopropanecarboxylate,
9: 1H NMR (CDCl3) δ 0.04 (s, 6H, CH3Si), 0.05 (s, 6H, CH3Si),
0.89 (s, 18H, t-Bu), 1.25 (t, J ) 7.2 Hz, 3H, CH2CH3), 1.57 (m,
1H, C1H), 1.77 (m, 2H, C2H, C3H), 3.73 (m, 4H, CH2O), 4.12
(q, J ) 7.2 Hz, 2H, CH2CH3).
c-2,c-3-Bis[[(ter t-b u t yld im et h ylsilyl)oxy]m et h yl]-r -1-
cyclop r op a n em eth a n ol (10). Treatment of 8 (2.17 g, 5.39
mmol) as described in preparation of 5 gave 10 as a colorless
oil (0.530 g, 27%): 1H NMR (CDCl3) δ 0.08 (s, 12H), 0.90 (s,
18H), 1.31-1.51 (m, 3H), 3.11 (t, J ) 6.6 Hz, 1H), 3.64-3.76
(m, 4H), 3.86-3.92 (m, 2H).
2-Am in o-6-(b en zyloxy)-9-[[c-2′,c-3′-b is[[(ter t-b u t yld i-
m e t h y ls ily l)o x y ]m e t h y l]c y c lo p r o p -r -1′-y l]m e t h y l]-
p u r in e (11). Compound 10 (530 mg, 1.47 mmol) was treated
as described in preparation of 6 to give 11 as a white solid
(137 mg, 16%): 1H NMR (CDCl3) δ 0.07 (s, 12H), 0.90 (s, 18H),
1.36-1.54 (m, 3H), 3.75-3.81 (m, 2H), 3.90-3.96 (m, 2H), 4.23
(d, J ) 6.9 Hz, 2H), 4.90 (bs, 2H), 5.57 (s, 2H), 7.28-7.37 (m,
3H), 7.48-7.52 (m, 2H), 7.98 (s, 1H).
9-[[c-2′,c-3′-Bis(h yd r oxym eth yl)cyclop r op -r -1′-yl]m eth -
yl]gu a n in e (12). Treatment of 137 mg of 11 (0.235 mmol) as
described in preparation of 7 afforded the HCl salt of 12 as
1
white crystals (30.7 mg, 43%): mp 235-237 °C dec; H NMR
(DMSO-d6) δ 1.23-1.36 (m, 2H), 1.48-1.62 (m, 1H), 3.50 (dd,
J ) 8.7, 11.7 Hz, 2H), 3.69 (dd, J ) 5.4, 11.7 Hz, 2H), 4.26 (d,
J ) 7.8 Hz, 2H), 7.10 (bs, 2H), 8.91 (s, 1H), 11.49 (bs, 1H);
FAB MS m/z 266 (MH+); HRMS calcd for C11H16O3N5 (MH+)
266.1253, found 266.1241. Anal. (C11H16O3N5Cl) C, H, N.
t-2,t-3-Bis[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-r -1-cy-
clop r op a n em eth a n ol (13). A solution of 9 (1.09 g, 2.71
mmol) in anhydrous THF (10 mL) was treated with 1.0 M
LiAlH4 in THF (10 mL, 10 mmol) at 0 °C. After stirring at 0
°C for 30 min, saturated NH4Cl was added and the resulting
mixture was extracted with EtOAc. The organic layer was
washed with brine and concentrated in vacuo. The residue
was chromatographed on silica gel eluting with 15-20% Et2O
in hexane to yield 13 as a colorless oil (0.769 g, 79%): 1H NMR
(CDCl3) δ 0.06 (s, 12H), 0.90 (s, 18H), 1.03-1.12 (m, 3H), 1.45
(bs, 1H), 3.48 (d, J ) 6.6 Hz, 2H), 3.60-3.66 (m, 2H), 3.71-
3.76 (m, 2H).
2-Am in o-6-(b en zyloxy)-9-[[t-2′,t-3′-b is[[(ter t-b u t yld i-
m e t h y ls ily l)o x y ]m e t h y l]c y c lo p r o p -r -1′-y l]m e t h y l]-
p u r in e (14). Compound 13 (667 mg, 1.85 mmol) was treated
as described in preparation of 6 to yield 14 as a pale-yellow
solid (319 mg, 30%): 1H NMR (CDCl3) δ 0.07 (s, 12H), 0.88 (s,
18H), 1.20-1.35 (m, 3H), 3.6-3.7 (m, 2H), 3.7-3.8 (m, 2H),
3.96 (d, J ) 6.9 Hz, 2H), 4.78 (bs, 2H), 5.57 (s, 2H), 7.28-7.37
(m, 3H), 7.48-7.52 (m, 2H), 7.95 (s, 1H).
9-[[t-2′,t-3′-Bis(h yd r oxym et h yl)cyclop r op a n -r -1′-yl]-
m eth yl]gu a n in e (15). Treatment of 14 (319 mg, 0.546 mmol)
as described in preparation of 7 gave the HCl salt of 15 as
1
white crystals (121 mg, 73%): mp 295-298 °C dec; H NMR
(DMSO-d6) δ 1.12-1.21 (m, 1H, H1), 1.22-1.32 (m, 3H), 3.37-
3.48 (m, 4H), 3.99 (d, J ) 7.2 Hz, 2H), 7.22 (bs, 2H), 9.11 (s,
1H), 11.5 (bs, 1H); FAB MS m/z 266 (MH+); HRMS calcd for

1292 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Sekiyama et al.
3H), 0.55 (dd, J ) 5.1, 5.1 Hz, 1H), 0.76 (dd, J ) 5.1, 8.4 Hz,
1H), 0.87 (s, 18H), 1.29 (m, 1H), 3.44 (d, J ) 10.2 Hz, 1H),
3.63 (d, J ) 10.2 Hz, 1H), 3.63 (d, J ) 11.1 Hz, 1H), 3.86 (d,
J ) 11.1 Hz, 1H), 4.34 (dd, J ) 7.8, 11.7 Hz, 1H), 4.43 (dd, J
) 7.8, 11.7 Hz, 1H), 7.43 (m, 2H), 7.55 (m, 1H), 8.06 (m, 2H);
FD MS m/z 464 (M+), 407 (M+ - t-Bu).
[2,2-Bis(h ydoxym eth yl)cyclopr op-1-yl]m eth yl Ben zoate
(19). To a solution of 18b (21.2 g, 45.5 mmol), in MeOH (683
mL) was added 1 N HCl (137 mL, 137 mmol), and the mixture
was stirred at room temperature for 40 min. The solvent was
removed in vacuo, and the residue was chromatographed on
a silica gel column with 4% MeOH in CH2Cl2 to yield 19 as a
colorless oil (10.9 g, 100%): 1H NMR (CDCl3) δ 0.52 (dd, J )
5.4, 5.4 Hz, 1H), 0.82 (dd, J ) 5.1, 8.7 Hz, 1H), 1.41 (m, 1H),
2.95 (bs, 2H), 3.55 (d, J ) 11.4 Hz, 1H), 3.66 (d, J ) 11.4 Hz,
1H), 3.69 (d, J ) 12.0 Hz, 1H), 4.03 (d, J ) 12.0 Hz, 1H), 4.29
(dd, J ) 8.7, 12.0 Hz, 1H), 4.57 (dd, J ) 6.3, 12.0 Hz, 1H),
7.44 (m, 2H), 7.56 (m, 1H), 8.04 (m, 2H); FD MS m/z 236 (M+).
t r a n s-[2-[(Be n zoyloxy)m e t h yl]-1-(h yd r oxym e t h yl)-
cyclop r op -1-yl]m et h yl Ben zoa t e (20a ) a n d cis-[2-
[(Ben zoyloxy)m eth yl]-1-(h yd r oxym eth yl)cyclop r op -1-yl]-
m eth yl Ben zoa te (21a ). A solution of 19 (1.06 g, 4.49 mmol)
in pyridine (16 mL) was cooled to 0 °C and treated with BzCl
(0.52 mL, 4.49 mmol). After stirring at room temperature for
40 min, ice-water was added and the solvent was removed in
vacuo. The residue was dissolved in CH2Cl2 and washed with
saturated NaHCO3. The organic layer was concentrated in
vacuo, and the residue was chromatographed on silica gel
eluting with 1% MeOH in CH2Cl2. The first elute gave 20a
as a colorless oil (455 mg, 30%): 1H NMR (CDCl3) δ 0.68 (dd,
J ) 5.7, 5.7 Hz, 1H, C3HH), 1.04 (dd, J ) 5.7, 9.3 Hz, 1H,
C3HH), 1.57 (dddd, J ) 5.7, 5.7, 9.3, 9.3 Hz, 1H, C2H), 1.78
(bs, 1H, OH), 3.70 (d, J ) 12.6 Hz, 1H, CHHOH), 3.94 (d, J )
12.6 Hz, 1H, CHHOH), 4.18 (dd, J ) 9.3, 12.0 Hz, 1H,
2-CHHOBz), 4.33 (d, J ) 11.4 Hz, 1H, 1-CHHOBz), 4.38 (d, J
) 11.4 Hz, 1H, 1-CHHOBz), 4.74 (dd, J ) 5.7, 12.0 Hz, 1H,
2-CHHOBz), 7.39 (m, 4H, Ar), 7.55 (m, 2H, Ar), 8.01 (m, 4H,
Ar); FD MS m/z 341 (M+ + H). The second elute gave 21a as
a colorless oil (455 mg, 30%): 1H NMR (CDCl3) δ 0.74 (dd, J
) 6.0, 6.0 Hz, 1H, C3HH), 0.98 (dd, J ) 6.0, 9.0 Hz, 1H, C3HH),
1.50 (dddd, J ) 6.0, 6.0, 9.0, 9.0 Hz, 1H, C2H), 1.99 (bs, 1H,
OH), 3.41 (d, J ) 12.0 Hz, 1H, CHHOH), 3.71 (d, J ) 12.0 Hz,
1H, CHHOH), 4.28 (dd, J ) 9.0, 12.3 Hz, 1H, 2-CHHOBz),
4.29 (d, J ) 12.3 Hz, 1H, 1-CHHOBz), 4.64 (dd, J ) 6.0, 12.3
Hz, 1H, 2-CHHOBz), 4.85 (d, J ) 12.3 Hz, 1H, 1-CHHOBz),
7.35 (m, 4H, Ar), 7.52 (m, 2H, Ar), 7.98 (m, 4H, Ar); FD MS
m/z 340 (M+).
cis-[1,2-Bis[(ben zoyloxy)m eth yl]cyclop r op -1-yl]m eth -
yl p-Tolu en esu lfon a te (20b). p-TsCl (3.58 g, 18.8 mmol) was
added to a solution of 20a (2.13 g, 6.26 mmol) and 4-(N,N-
dimethylamino)pyridine (4.59 g, 37.6 mmol) in 32 mL of CH2-
Cl2 at 0 °C, and the mixture was stirred at 0 °C for 1 h. The
solution was diluted with CH2Cl2 and washed with saturated
NaHCO3. The organic layer was concentrated in vacuo, and
the concentrate was chromatographed on a silica gel column
eluting with hexanes-EtOAc (3:1) to yield 20b as a white solid
(2.59 g, 84%): 1H NMR (CDCl3) δ 0.81 (dd, J ) 6.0, 6.0 Hz,
1H), 1.08 (dd, J ) 6.0, 8.7 Hz, 1H), 1.66 (m, 1H), 2.27 (s, 3H),
4.02 (dd, J ) 9.3, 12.3 Hz, 1H), 4.05 (d, J ) 12.0 Hz, 1H), 4.23
(d, J ) 12.0 Hz, 1H), 4.26 (d, J ) 11.1 Hz, 1H), 4.30 (d, J )
11.1 Hz, 1H), 4.64 (dd, J ) 6.0, 12.3 Hz, 1H), 7.18 (m, 2H),
7.27-7.41 (m, 4H), 7.55 (m, 2H), 7.74 (m, 2H), 7.85 (m, 2H),
7.97 (m, 2H); FD MS m/z 494 (M+).
obtained as a white solid (199 mg, 61%): 1H NMR (CDCl3) δ
1.05 (dd, J ) 6.0, 9.3 Hz, 1H), 1.15 (dd, J ) 6.0, 6.0 Hz, 1H),
1.74 (dddd, J ) 6.0, 6.0, 9.3, 9.3 Hz, 1H), 3.95 (d, J ) 12.3 Hz,
1H), 4.22 (d, J ) 15.3 Hz, 1H), 4.33 (dd, J ) 9.3, 12.3 Hz, 1H),
4.35 (d, J ) 12.3 Hz, 1H), 4.57 (d, J ) 15.3 Hz, 1H), 4.90 (bs,
2H), 4.92 (dd, J ) 6.0, 12.3 Hz, 1H), 5.47 (d, J ) 12.3 Hz, 1H),
5.52 (d, J ) 12.3 Hz, 1H), 7.30-7.39 (m, 7H), 7.47-7.57 (m,
4H), 7.83 (s, 1H), 7.92-7.98 (m, 4H); FD MS m/z 563 (M+).
The 7-isomer was obtained as the second elute (82.6 mg, 25%).
9-[[t r a n s-1′,2′-Bis(h yd r oxym e t h yl)cyclop r op -1′-yl]-
m eth yl]gu a n in e (23). NaH (60%, 42.4 mg, 1.06 mmol) in
MeOH (2 mL) was added to a solution of 22 (199 mg, 0.35
mmol) in MeOH (2 mL), and the mixture was stirred at 40 °C
for 30 min. Then 1, N HCl (1.77 mL, 1.77 mmol) was added,
and the mixture was stirred at 50 °C for 0.5 h. After cooling
to room temperature, the solvent was removed in vacuo and
the residue was dissolved in H2O and washed with EtOAc. The
aqueous layer was concentrated in vacuo, and the residue was
purified by reversed-phase chromatography eluting with 0-30%
MeOH in H2O to yield 23 as a white solid (80.5 mg, 86%): mp
273.5-275 °C; 1H NMR (DMSO-d6) δ 0.52-0.59 (m, 2H), 1.12
(dddd, J ) 6.0, 6.0, 8.4, 8.4 Hz, 1H), 3.03 (dd, J ) 4.5, 11.4
Hz, 1H), 3.15 (dd, J ) 4.5, 11.4 Hz, 1H), 3.47 (m, 1H), 3.72
(m, 1H), 3.99 (d, J ) 14.4 Hz, 1H), 4.14 (d, J ) 14.4 Hz, 1H),
4.64 (m, 2H), 6.40 (bs, 2H), 7.75 (s, 1H), 10.56 (bs, 1H); HRMS
calcd for C11H16O3N5 (MH+) 266.1253, found 266.1244. Anal.
(C11H15O3N5) C, H, N.
t r a n s-[1,2-Bis[(b e n zoyloxy)m e t h yl]cyclop r op -1-yl]-
m eth yl p-Tolu en esu lfon a te (21b). Treatment of 11.5 g of
21a (33.8 mmol) as described in the preparation of 20b
afforded 21b as a white solid (15.6 g, 93%): 1H NMR (CDCl3)
δ 0.83 (dd, J ) 6.0, 6.0 Hz, 1H), 1.07 (dd, J ) 6.0, 9.0 Hz),
1.56 (dddd, J ) 6.0, 6.0, 9.0, 9.0 Hz, 1H), 2.28 (s, 3H), 3.93 (d,
J ) 10.5 Hz, 1H), 4.16 (dd, J ) 9.0, 12.0 Hz, 1H), 4.22 (d, J )
12.3 Hz, 1H), 4.23 (d, J ) 10.5 Hz, 1H), 4.54 (d, J ) 12.3 Hz,
1H), 4.63 (dd, J ) 6.0, 12.0 Hz, 1H), 7.20 (m, 2H), 7.31 (m,
4H), 7.52 (m, 2H), 7.76 (m, 2H), 7.85 (m, 2H), 7.91 (m, 2H);
FD MS m/z 494 (M+).
2-Am in o-6-(b en zyloxy)-9-[[cis-1′,2′-b is[(b en zoyloxy)-
m eth yl]cyclop r op -1′-yl]m eth yl]p u r in e (24). Coupling of
92.1 mg of 21b (0.186 mmol) with 2-amino-6-(benzyloxy)purine
as described in preparation of 22 gave 24 as a white solid (64.1
mg, 61%): 1H NMR (CDCl3) δ 0.87 (dd, J ) 6.0, 6.0 Hz, 1H),
1.29 (dd, J ) 5.7, 9.0 Hz, 1H), 2.02 (m, 1H), 4.10 (d, J ) 14.7
Hz, 1H), 4.11 (dd, J ) 9.6, 12.3 Hz, 1H), 4.25 (d, J ) 12.3 Hz,
1 Hz), 4.30 (d, J ) 14.7 Hz, 1H), 4.55 (d, J ) 12.3 Hz, 1H),
4.72 (dd, J ) 6.0, 12.3 Hz, 1H), 4.92 (bs, 2H), 5.47 (s, 2H),
7.26-7.40 (m, 7H), 7.43-7.51 (m, 4H), 7.79-7.87 (m, 5H); FD
MS m/z 563 (M+). The 7-isomer was also obtained as a white
solid (27.8 mg, 27%).
9-[[cis-1′,2′-Bis(h ydr oxym eth yl)cyclopr op-1′-yl]m eth yl]-
gu a n in e (3). Deprotection of 64.1 mg of 24 (0.114 mmol) as
described in the preparation of 23 afforded 3 as a white solid
(24.4 mg, 81%): mp >300 °C; 1H NMR (DMSO-d6) δ 0.40 (t, J
) 5.1 Hz, 1H), 0.88 (dd, J ) 4.8, 8.7 Hz, 1H), 1.23 (m, 1H),
3.24-3.37 (m, 2H), 3.41 (dd, J ) 6.0, 12.0 Hz, 1H), 3.58 (dt, J
) 12.0, 6.0 Hz, 1H), 3.81 (d, J ) 14.1 Hz, 1H), 4.00 (d, J )
14.1 Hz, 1H), 4.49 (m, 1H), 4.64 (m, 1H), 6.38 (bs, 2H), 7.71
(s, 1H), 10.49 (bs, 1H); HRMS calcd for C11H16O3N5 (MH+)
266.1253, found 266.1263. Anal. (C11H15O3N5) C, H, N.
Eth yl 4-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-[[(ter t-bu tyld i-
m eth ylsilyl)oxy]m eth yl]-2-bu ten ate (26). Triethyl phospho-
noacetate (2.07 mL, 10.0 mmol) was added to a suspension of
420 mg of NaH (60%, 10.5 mmol) in benzene (50 mL) at 0 °C;
then 25 (3.15 g, 9.9 mmol) was added dropwise at room
temperature over 0.5 h. The precipitate was dissolved in
EtOH, H2O was added, and the mixture was extracted with
EtOAc. The organic layer was concentrated in vacuo, and the
residue was chromatographed on silica gel eluting with hex-
anes-EtOAc (10:1) to yield 26 as a pale-yellow oil (3.4 g,
88%): 1H NMR (CDCl3) δ 0.06 (s, 6H), 0.09 (s, 6H), 0.89 (s,
9H), 0.93 (s, 9H), 1.28 (t, J ) 7.2 Hz, 3H), 4.15 (q, J ) 7.2 Hz,
2H), 4.43 (m, 2H), 4.86 (m, 2H), 5.97 (t, J ) 2.0 Hz, 1H); FD
MS m/z 389 (MH+), 331 (M+ - t-Bu).
2-Am in o-6-(ben zyloxy)-9-[[tr a n s-1′,2′-bis[(ben zoyloxy)-
m eth yl]cyclop r op a n -1′-yl]m eth yl]p u r in e (22). A solution
of 20b (287 mg, 0.580 mmol) in DMF (7.5 mL) was added to
the mixture of 2-amino-6-(benzyloxy)purine (168 mg, 0.70
mmol), K2CO3 (96 mg, 0.70 mmol), and 18-crown-6 (167 mg,
0.70 mmol) in DMF (4 mL), and the resulting mixture was
stirred at 60 °C for 2 h. After concentration in vacuo, the
residue was dissolved in CH2Cl2 and washed with saturated
NaHCO3. The organic layer was concentrated in vacuo, and
the residue was chromatographed on a silica gel column with
2-7% MeOH in CH2Cl2. Compound 22 was eluted first and

Cyclopropyl Nucleosides with Antiherpetic Activity
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1293
4-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-[[(ter t-bu tyld im eth -
ylsilyl)oxy]m eth yl]-2-bu ten -1-ol (27a ). Compound 26 (3.4
g, 8.8 mmol) in CH2Cl2 (6 mL) was treated with 1.0 M
DIBAL-H in toluene (17.5 mL, 17.5 mmol) at -78 °C. After
stirring at 0 °C for 30 min, H2O and 3 mL of 1 N NaOH were
added to dissolve the precipitate, and the resulting solution
was extracted with CH2Cl2. The organic layer was concen-
trated in vacuo, and the residue was chromatographed on silica
gel eluting with hexanes-EtOAc (10:1) to yield 27a as a
colorless oil (2.28 g, 75%): 1H NMR (CDCl3) δ 0.07-0.1 (m,
12H), 0.90 (s, 9H), 0.92 (s, 9H), 4.15-4.35 (m, 6H), 5.8 (m, 1H);
FD MS m/z 289 (M+ - t-Bu).
4-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-[[(ter t-bu tyld im eth -
ylsilyl)oxy]m eth yl]-2-bu ten -1-yl Ben zoa te (27b). Benzoy-
lation of 27a (2.28 g, 6.6 mmol) as described in the preparation
of 18b gave 27b as a colorless oil (2.97 g, 100%): 1H NMR
(CDCl3) δ 0.09 (s, 12H), 0.90 (s, 9H), 0.92 (s, 9H), 4.24 (s, 2H),
4.31 (s, 2H), 4.96 (d, J ) 7.0 Hz, 2H), 5.81 (t, J ) 7.0 Hz, 1H),
7.4-7.6 (m, 3H), 8.0-8.1 (m, 2H); FD MS m/z 451 (MH+), 393
(M+ - t-Bu).
4-Hyd r oxy-3-(h yd r oxym et h yl)-2-b u t en -1-yl Ben zoa t e
(28). A mixture of 27b (14.25 g, 31.7 mmol) in MeOH (500
mL) and 1 N HCl (95 mL, 95 mmol) was stirred at room
temperature for 1 h. The solvent was removed in vacuo, and
the residue was chromatographed on silica gel eluting with
CH2Cl2-MeOH (10:1) to yield 28 as a colorless oil (5.87 g,
83%): 1H NMR (CDCl3) δ 4.27 (s, 2H), 4.39 (s, 2H), 4.96 (d, J
) 7.2 Hz, 2H), 5.79 (t, J ) 7.2 Hz, 1H), 7.4-7.6 (m, 3H), 8.03
(m, 2H); FD MS m/z 222 (M+).
4-(Ben zoyloxy)-2-(h yd r oxym eth yl)-2-bu ten -1-yl Ben -
zoa te (29a ). Compound 28 (5.55 g, 25 mmol) was benzoylated
as described in the preparation of 18b to give 29a as a pale-
yellow oil of a 1:1 mixture of E and Z-forms (3.81 g, 47%): 1H
NMR (recorded as a sum of two isomers, CDCl3) δ 2.1 (bs, 1H),
2.65 (bs, 1H), 4.28 (d, J ) 6.0 Hz, 2H), 4.39 (d, J ) 6.3 Hz,
2H), 4.96 (s, 2H), 4.99-5.06 (m, 2H, 2H), 5.06 (s, 2H), 5.92 (t,
J ) 6.9 Hz, 1H), 6.04 (t, J ) 7.0 Hz, 1H), 7.38-7.6 (m, 6H,
6H), 8.0-8.7 (m, 4H, 4H); FD MS m/z 327 (MH+).
4-(Ben zoyloxy)-2-(br om om eth yl)-2-bu ten -1-yl Ben zoate
(29b). PBr3 (0.12 mL, 1.26 mmol) was added to 29a (410 mg,
1.26 mmol) in benzene (3 mL) at 0 °C. After stirring at room
temperature for 2 h, ice-water was added and the mixture
was extracted with EtOAc. The organic layer was concen-
trated in vacuo to give 29b (360 mg, 70%): 1H NMR (recorded
as a sum of two isomers, CDCl3) δ 4.18 (s, 2H), 4.20 (s, 2H),
4.98-5.11 (m, 4H, 4H), 6.08 (t, J ) 6.8 Hz, 1H), 6.16 (t, J )
6.8 Hz, 1H), 7.38-7.65 (m, 6H, 6H), 8.03-8.12 (m, 4H, 4H);
FD MS m/z 309 (M+ - Br).
2-Am in o-9-[(E)-4-(ben zoyloxy)-2-[(ben zoyloxy)m eth yl]-
2-bu ten -1-yl]-6-(ben zyloxy)p u r in e (30) a n d 2-Am in o-9-
[(Z)-4-(b en zoyloxy)-2-[(b en zoyloxy)m et h yl]-2-b u t en -1-
yl]-6-(ben zyloxy)p u r in e (31). Compound 29b (360 mg,
0.888 mmol) in DMF (1 mL) was added to a suspension of
2-amino-6-(benzyloxy)purine (241 mg, 1.0 mmol) and K2CO3
(600 mg, 4.34 mmol) in DMF (2 mL), and the resulting mixture
was stirred at room temperature for 2 h. The solvent was
removed in vacuo, and the residue was dissolved in EtOAc and
washed with H2O. The organic layer was concentrated in
vacuo, and the residue was chromatographed on silica gel
eluting with CH2Cl2-MeOH (10:1). The E-isomer 30 was
obtained as the first elute: white solid (145 mg, 30%); 1H NMR
(CDCl3) δ 4.76 (s, 2H, 2-CH2OBz), 4.77 (s, 2H, C1H2), 4.95 (bs,
2H, NH2), 5.26 (d, J ) 6.6 Hz, 2H, C4H2), 5.52 (s, 2H, CH2Ph),
6.16 (t, J ) 6.6 Hz, 1H, C3H), 7.3-7.6 (m, 11H, Ar), 7.74 (s,
1H, C8H), 7.95 (m, 2H, Ar), 8.06 (m, 2H, Ar); FD MS m/z 549
(M+). The Z-isomer 31 was eluted later: pale-yellow foam (142
mg, 29%); 1H NMR (CDCl3) δ 4.71 (s, 2H, 2-CH2OBz), 4.84 (s,
2H, C1H2), 4.97 (bs, 2H, NH2), 5.04 (d, J ) 6.7 Hz, 2H, C4H2),
5.53 (s, 2H, CH2Ph), 5.90 (t, J ) 6.7 Hz, 1H, C3H), 7.3-7.6
(m, 11H, Ar), 7.64 (s, 1H, C8H), 7.95 (m, 2H, Ar), 8.00 (m, 2H,
Ar); FD MS m/z 549 (M+).
phase chromatography eluting with 15% MeOH in H2O af-
forded 32 as a white solid (86.1 mg, 76%): mp 268-268.5 °C;
1H NMR (DMSO-d6) δ 3.77 (d, J ) 5.3 Hz, 2H), 4.17 (dd, J )
6.1, 5.4 Hz, 2H), 4.58 (s, 2H, H1′), 4.76 (t, J ) 5.4 Hz, 1H),
4.91 (t, J ) 5.3 Hz, 1H), 5.78 (t, J ) 6.1 Hz, 1H), 6.40 (bs, 2H),
7.57 (s, 1H), 10.57 (bs, 1H); HRMS calcd for C10H14O3N5 (MH+)
252.1096, found 252.1095. Anal. (C10H13O3N5) C, H, N.
(Z)-9-[4-Hyd r oxy-2-(h yd r oxym eth yl)-2-bu ten -1-yl]gu a -
n in e (33). Treatment of 31 as above yielded 33 in 76% yield
as a white solid: mp 269-271 °C; 1H NMR (DMSO-d6) δ 3.97
(m, 4H), 4.59 (s, 2H), 4.88 (bs, 1H), 5.10 (bs, 1H), 5.78 (t, J )
6.1 Hz, 1H), 6.44 (bs, 2H), 7.58 (s, 1H), 10.6 (bs, 1H); HRMS
calcd for C10H14O3N5 (MH+) 252.1096, found 252.1090. Anal.
(C10H13O3N5) C, H, N.
(E)- a n d (Z)-4-(Ben zoyloxy)-2,3-ep oxy-2-(h yd r oxy-
m eth yl)bu t-1-yl Ben zoa te (34). A solution of 29a (2.0 g, 6.13
mmol) in CH2Cl2 (20 mL) was treated with m-chloroperbenzoic
acid (1.32 g, 6.13 mmol) at 4 °C. After stirring at 4 °C for 4
days, saturated NaHCO3 was added and the mixture was
extracted with CH2Cl2. The organic layer was concentrated
in vacuo, and the residue was chromatographed on silica gel
eluting with 5% MeOH in CH2Cl2 to yield the mixture of 34
as a colorless oil (1.77 g, 84%).
(E)- a n d (Z)-4-(Ben zoyloxy)-2-[(ben zoyloxy)m eth yl]-
2,3-ep oxybu t-1-yl p-Tolu en esu lfon a te (35). A solution of
34 (1.10 g, 3.21 mmol) in CH2Cl2 (30 mL) containing pyridine
(1.04 mL, 16.1 mmol) was treated with p-TsCl (642 mg, 3.37
mmol) at 0 °C. After 15 h, ice-water was added and the
mixture was extracted with CH2Cl2. The organic layer was
concentrated in vacuo, and the residue was chromatographed
on silica gel eluting with 2% MeOH in CH2Cl2 to yield 35 as a
colorless oil (790 mg, 50%).
2-Am in o-9-[(E)-4(b en zoyloxy)-2,3-ep oxy-2-[(b en zoyl-
oxy)m et h yl]b u t -1-yl]-6-(b en zyloxy)p u r in e
(36)
a n d
2-Am in o-9-[(Z)-4-(b e n zoyloxy)-2,3-e p oxy-2-[(b e n zoyl-
oxy)m eth yl]bu t-1-yl]-6-(ben zyloxy)p u r in e (37). 2-Amino-
6-(benzyloxy)purine (300 mg, 1.24 mmol) was added to 50 mg
of NaH (60%, 1.25 mmol) in anhydrous DMF (15 mL). After
stirring at room temperature for 1 h, 35 (500 mg, 1.01 mmol)
in DMF (10 mL) was added and the mixture was stirred at 60
°C for 1.5 h. The mixture was cooled to room temperature,
poured into brine, and extracted with EtOAc. The organic
layer was concentrated in vacuo, and the residue was chro-
matographed on silica gel eluting with 4% MeOH in CH2Cl2
to yield a mixture of 36 and 37. Then the mixture was purified
by reversed-phase chromatography eluting with CH3CN-H2O
(3:2). The first elute was the E-isomer 36 isolated as a
colorless oil (130 mg, 23%): 1H NMR (CDCl3) δ 3.56 (dd, J )
4.8, 6.0 Hz, 1H, C3H), 4.23 (d, J ) 12.6 Hz, 1H, 2-CHHOBz),
4.31 (d, J ) 12.6 Hz, 1H, 2-CHHOBz) 4.41 (d, J ) 15.0 Hz,
1H, C1HH), 4.57 (d, J ) 15.0 Hz, 1H, C1HH), 4.63 (dd, J )
12.6, 6.0 Hz, 1H, C4HH), 4.88 (bs, 2H, NH2), 5.02 (dd, J ) 12.6,
4.8 Hz, 1H, C4HH), 5.49 (s, 2H, CH2Ph), 7.28-7.62 (m, 11H,
Ar), 7.74 (s, 1H, C8H), 7.91-7.79 (m, 4H, Ar). The second elute
was the Z-isomer 37: colorless oil (135 mg, 24%); 1H NMR
(CDCl3) δ 3.49 (dd, J ) 4.5, 6.6 Hz, 1H, C3H), 4.43 (s, 2H,
2-CH2OBz), 4.46 (dd, J ) 6.6, 12.3 Hz, 1H, C4HH), 4.48 (s,
2H, C1H2), 4.71 (dd, J ) 4.5, 12.3 Hz, 1H, C4HH), 4.74 (bs,
2H, NH2), 5.50 (s, 2H, CH2Ph), 7.30-7.60 (m, 12H, Ar), 7.67
(s, 1H, C8H), 7.96-8.02 (m, 3H, Ar).
(E)-9-[2,3-Epoxy-4-h ydr oxy-2-(h ydr oxym eth yl)bu t-1-yl]-
gu a n in e (38). A suspension of 36 (130 mg, 0.23 mmol) in
MeOH (10 mL) was hydrogenated in the presense of 10% Pd/C
(100 mg) at room temperature under atomospheric pressure
for 10 h. After filtration, the filtrate was treated with 28%
MeONa/MeOH (96.5 mg, 0.50 mmol). After 0.5 h, the solution
was neutralized with 2 N HCl and washed with EtOAc. The
aqueous layer was concentrated, and the residue was purified
by reversed-phase chromatography eluting with 10% MeOH/
H2O to yield 38 as a white solid (10 mg, 16%): mp 265-268
1
°C dec; H NMR (DMSO-d6) δ 3.12 (dd, J ) 5.1, 6.3 Hz, 1H),
(E)-9-[4-Hyd r oxy-2-(h yd r oxym eth yl)-2-bu ten -1-yl]gu a -
n in e (32). Deprotection of 30 (250 mg, 0.45 mmol) as
described in the preparation of 23 and purification by reversed-
3.15-3.35 (m, 2H), 3.63 (ddd, J ) 5.7, 6.3, 12.9 Hz, 1H), 3.79
(ddd, J ) 5.1, 5.4, 12.9 Hz, 1H), 4.18 (d, J ) 14.7 Hz, 1H),
4.22 (d, J ) 14.7 Hz, 1H), 5.01 (m, 1H), 5.09 (m, 1H, 6.42 (bs,

1294 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Sekiyama et al.
2H), 7.62 (s, 1H), 10.66 (bs, 1H); HRMS calcd for C10H14O4N5
raphy eluting with 0-15% MeOH/H2O afforded 40c as a white
solid (75%): mp 181-182.5 °C; 1H NMR (DMSO-d6) δ 3.79 (d,
J ) 4.8 Hz, 2H), 4.22 (t, J ) 6.1 Hz, 2H), 4.80 (s, 2H), 4.89
(bs, 1H), 4.94 (bs, 1H), 5.79 (t, J ) 6.1 Hz, 1H), 7.18 (bs, 2H),
8.03 (s, 1H), 8.13 (s, 1H); HRMS calcd for C10H14O2N5 (MH+)
236.1147, found 236.1158. Anal. (C10H13O2N5) C, H, N.
40d : white solid (82%); mp 202-204 °C; 1H NMR (DMSO-d6)
δ 3.80 (d, J ) 4.8 Hz, 2H), 4.23 (t, J ) 6.0 Hz, 2H), 4.81 (s,
2H), 4.89-4.97 (bs, 2H), 5.80 (t, J ) 6.0 Hz, 1H), 7.19 (bs, 2H),
8.05 (s, 1H), 8.14 (s, 1H); HRMS calcd for C10H14O2N5 (MH+)
236.1147, found 236.1137. Anal. (C10H13O2N5) C, H, N.
(MH+) 268.1046, found 268.1042. Anal. (C10H13O4N5) C, H,
N.
(Z)-9-[2,3-Epoxy-4-h ydr oxy-2-(h ydr oxym eth yl)bu t-1-yl]-
gu a n in e (39). Treatment of 37 (135 mg, 0.24 mmol) as above
afforded 39 as a white solid (14 mg, 22%): mp 272-275 °C
dec; 1H NMR (DMSO-d6) δ 2.63 (dd, J ) 3.6, 6.9 Hz, 1H), 3.1-
3.4 (m, 2H), 3.50 (m, 1H), 3.64 (ddd, J ) 3.6, 5.7, 12.6 Hz,
1H), 4.17 (d, J ) 15.0 Hz, 1H), 4.37 (d, J ) 15.0 Hz, 1H), 4.90
(bs, 1H), 5.15 (bs, 1H), 6.52 (bs, 2H), 7.53 (s, 1H), 10.6 (bs,
1H); HRMS calcd for C10H14O4N5 (MH+) 268.1046, found
268.1034. Anal. (C10H13O4N5) C, H, N.
1-[[t r a n s-1′,2′-Bis(h yd r oxym e t h yl)cyclop r op -1′-yl]-
m eth yl]th ym in e (41a ). To a mixture of thymine (215 mg,
1.70 mmol), K2CO3 (236 mg, 1.70 mmol), and 18-crown-6 (409
mg, 1.70 mmol) in DMF (6 mL) was added a solution of 20b
(700 mg, 1.42 mmol) in DMF (10 mL), and the resulting
mixture was stirred at 60 °C for 2 h. The solvent was removed
in vacuo, and the residue was dissolved in CH2Cl2 and washed
with saturated NaHCO3. The organic layer was concentrated
in vacuo, and the residue was chromatographed on silica gel
eluting with 2% MeOH in CH2Cl2 to yield 1-[[trans-1′,2′-bis-
[(benzoyloxy)methyl]cycloprop-1′-yl]methy]thymine as a white
foam (370 mg, 58%). Deprotection by the procedure described
in the preparation of 40a yielded 41a as a white solid (113
9-[[t r a n s-1′,2′-Bis(h yd r oxym e t h yl)cyclop r op -1′-yl]-
m eth yl]a d en in e (40a ). Adenine (386 mg, 2.85 mmol) was
treated with 114 mg of NaH (60%, 2.85 mmol) in anhydrous
DMF (12 mL) at room temperature for 20 min, and 20b (1.18
g, 2.38 mmol) in DMF (6 mL) was added. The mixture was
stirred at 60 °C for 3 h. The solvent was removed in vacuo,
and the residue was dissolved in CH2Cl2 and washed with
saturated NaHCO3. The organic layer was concentrated in
vacuo, and the residue was chromatographed on silica gel
eluting with 4% MeOH in CH2Cl2 to yield 9-[[trans-1′,2′-bis-
[(benzoyloxy)methyl]cycloprop-1′-yl]methyl]adenine as a white
gum (844 mg, 77%). The protected adenine derivative (844
mg, 1.84 mmol) in MeOH (2 mL) was treated with MeONa/
MeOH (5.53 mmol, 7 mL) at 40 °C for 30 min. The solution
was neutralized with 1 N HCl (5.5 mL, 5.5 mmol) and
concentrated in vacuo. The residue was dissolved in H2O and
washed with EtOAc. The aqueous layer was concentrated in
vacuo, and the residue was purified by reversed-phase chro-
matography eluting with 0-30% MeOH/H2O to yield 40a as
a white solid (424 mg, 92%). Recrystallization from MeOH
gave white crystals (389 mg, 85%): mp 211-213 °C; 1H NMR
(DMSO-d6) δ 0.53-0.60 (m, 2H), 1.14 (dt, J ) 6.0, 8.4 Hz, 1H),
3.05 (dd, J ) 5.7, 11.4 Hz, 1H), 3.12 (dd, J ) 5.7, 11.4 Hz,
1H), 3.51 (ddd, J ) 5.1, 8.4, 12.0 Hz, 1H), 3.77 (ddd, J ) 5.1,
6.0, 11.4 Hz, 1H), 4.24 (d, J ) 14.7 Hz, 1H), 4.32 (d, J ) 14.7
Hz, 1H), 4.75 (t, J ) 5.7 Hz, 1H), 4.85 (m, 1H), 7.19 (bs, 2H),
8.13 (s, 1H), 8.18 (s, 1H); HRMS calcd for C11H16O2N5 (MH+)
250.1304, found 250.1295. Anal. (C11H15O2N5) C, H, N.
1
mg, 57%): mp 169.5-171 °C; H NMR (DMSO-d6) δ 0.48 (m,
1H), 0.55 (dd, J ) 4.5, 8.7 Hz, 1H), 1.06 (m, 1H), 1.76 (d, J )
0.9 Hz, 3H), 3.08 (dd, J ) 5.1, 11.7 Hz, 1H), 3.24 (dd, J ) 5.7,
11.7 Hz, 1H), 3.37 (m, 1H), 3.66 (m, 1H), 3.77 (d, J ) 14.4 Hz,
1H), 3.86 (d, J ) 14.4 Hz, 1H), 4.55-4.63 (m, 2H), 7.60 (m,
1H), 11.20 (bs, 1H); HRMS calcd for
C
11H17O4N2 (MH+)
241.1188, found 241.1193. Anal. (C11H16O4N2) C, H, N.
1-[[cis-1′,2′-Bis(h ydr oxym eth yl)cyclopr op-1′-yl]m eth yl]-
th ym in e (41b). Treatment of 21b (321 mg, 0.649 mmol) as
above gave 1-[[cis-1′,2′-bis[(benzoyloxy)methyl]cycloprop-1′-yl]-
methyl]thymine as a white gum (188 mg, 65%). Deprotection
gave 41b as a white solid (83.6 mg, 83%): mp 164-166 °C;
1H NMR (DMSO-d6) δ 0.37 (m, 1H), 0.80 (dd, J ) 4.5, 8.4 Hz,
1H), 1.19 (m, 1H), 1.76 (s, 3H), 3.26-3.40 (m, 2H), 3.46-3.63
(m, 2H), 3.61 (d, J ) 14.1 Hz, 1H), 3.67 (d, J ) 14.1 Hz, 1H),
4.55 (bs, 2H), 7.50 (s, 1H), 11.20 (bs, 1H); HRMS calcd for
C11H17O4N2 (MH+) 241.1188, found 241.1189. Anal.
(C11H16O4N2) C, H, N.
9-[[cis-1′,2′-Bis(h ydr oxym eth yl)cyclopr op-1′-yl]m eth yl]-
a d en in e (40b). Compound 21b (1.50 g, 3.03 mmol) was
treated as above to afford 9-[[cis-1′,2′-bis[(benzoyloxy)methyl]-
cycloprop-1′-yl]methyl]adenine as a white foam (1.12 g, 80%).
Deprotection gave 40b as a white solid (489 mg, 80%).
Recrystallization from MeOH gave white crystals (445 mg,
(E )-1-[4-H yd r oxy-2-(h yd r oxym e t h yl)-2-b u t e n -1-yl]-
th ym in e (41c) a n d (Z)-1-[4-Hyd r oxy-2-(h yd r oxym eth yl)-
2-bu ten -1-yl]th ym in e (41d ). To a mixture of thymine (190
mg, 1.5 mmol)and K2CO3 (320 mg, 2.32 mmol) in DMF (2 mL)
was added a solution of 29 (584 mg, 1.5 mmol) in DMF (3 mL),
and the resulting mixture was stirred at 70 °C for 15 h. The
solvent was removed in vacuo, and the residue was dissolved
in CH2Cl2 and washed with H2O. The organic layer was
concentrated in vacuo, and the residue was chromatographed
on silica gel eluting with CH2Cl2-MeOH (20:1) followed by
preparative TLC with hexanes-EtOAc (1:2) to give (E)-1-[4-
(benzoyloxy)-2-[(benzoyloxy)methyl]-2-buten-1-yl]thymine as a
colorless oil (45 mg): 1H NMR (CDCl3) δ 1.78 (s, 3H, 5-CH3),
4.66 (s, 2H, 2-CH2OBz), 4.81 (s, 2H, C1H2), 5.08 (d, J ) 6.9
Hz, 2H, C4H2), 6.18 (t, J ) 6.6 Hz, 1H, C3H), 7.17 (s, 1H, C6H),
7.39-7.61 (m, 6H, Ar), 7.96-8.14 (m, 4H, Ar), 8.4 (bs, 1H,
N3H). The product having a lower Rf was (Z)-1-[4-(benzoyl-
oxy)-2-[(benzoyloxy)methyl]-2-buten-1-yl]thymine: colorless oil
1
73%): mp 189-190.5 °C; H NMR (DMSO-d6) δ 0.41 (t, J )
5.1 Hz, 1H), 0.93 (dd, J ) 5.1, 8.7 Hz, 1H), 1.32 (m, 1H), 3.23-
3.44 (m, 3H), 3.58 (m, 1H), 4.02 (d, J ) 14.2 Hz, 1H), 4.19 (d,
J ) 14.2 Hz, 1H), 4.56 (t, J ) 5.2 Hz, 1H), 4.74 (t, J ) 5.2 Hz,
1H), 7.20 (bs, 2H), 8.13 (s, 1H), 8.16 (s, 1H); HRMS calcd for
C
11H16O2N5 (MH+) 250.1304, found 250.1310. Anal.
(C11H15O2N5 0.2H2O) C, H, N.
(E )-9-[4-H yd r oxy-2-(h yd r oxym e t h yl)-2-b u t e n -1-yl]-
a d en in e (40c) a n d (Z)-9-[4-Hyd r oxy-2-(h yd r oxym eth yl)-
2-bu ten -1-yl]a d en in e (40d ). Coupling of 29b (834 mg, 2.14
mmol) with adenine in a similar manner as described in the
preparation of 40a afforded (E)-9-[4-(benzoyloxy)-2-[(benzoy-
loxy)methyl]-2-buten-1-yl]adenine and (Z)-9-[4-benzoyloxy)-2-
[(benzoyloxy)methyl]-2-buten-1-yl]adenine which were sepa-
rated by chromatography on silica gel eluting with 4% MeOH
in CH2Cl2. The E-isomer, colorless oil (290 mg, 31%), was
eluted first: 1H NMR (CDCl3) δ 5.00 (s, 4H, 2-CH2OBz, C1H2),
5.06 (d, J ) 6.6 Hz, 2H, C4H2), 5.70 (bs, 2H, NH2), 5.94 (t, J )
6.6 Hz, 1H, C3H), 7.38-7.44 (m, 4H, Ar), 7.53-7.58 (m, 2H,
Ar), 7.85 (s, 1H, C2H or C8H), 7.91-7.93 (m, 2H, Ar), 7.99-
8.22 (m, 2H, Ar), 8.31 (s, 1H, C8H or C2H). The second elute
was the Z-isomer: colorless oil (360 mg, 38%); 1H NMR (CDCl3)
δ 4.77 (s, 2H, 2-CH2OBz), 5.12 (s, 2H, C1H2), 5.21(d, J ) 6.9
Hz, 2H, C4H2), 5.6 (bs, 2H, NH2), 6.2 (t, J ) 6.9 Hz, 1H, C3H),
7.38-7.48 (m, 4H, Ar), 7.52-7.61 (m, 2H, Ar), 7.87-7.91 (m,
2H, Ar), 7.96 (s, 1H, C2H or C8H), 8.04-8.08 (m, 2H, Ar), 8.29
(s, 1H, C8H or C2H). Both products were separately depro-
tected as above. Purification by reversed-phase chromatog-
1
(45 mg); H NMR (CDCl3) δ 1.81 (d, 3H, J ) 0.9 Hz, 5-CH3),
4.51 (s, 2H, 2-CH2OBz), 4.99 (s, 2H, C1H2), 5.09 (d, J ) 6.6
Hz, 2H, C4H2), 5.96 (t, J ) 6.6 Hz, 1H, C3H), 6.98 (q, J ) 0.9
Hz, 1H, C6H), 7.37-7.58 (m, 6H, Ar), 7.96-8.14 (m, 4H, Ar),
8.4 (bs, 1H, N3H). Both products were deprotected separately
as described in the preparation of 41a . Compound 41c was
1
isolated as a white solid (15 mg, 75%): mp 132-134 °C; H
NMR (DMSO-d6) δ 1.75 (s, 3H) 3.80 (s, 2H), 4.12 (d, J ) 6.3
Hz, 2H), 4.31 (s, 2H), 4.70 (bs, 1H), 4.86 (bs, 1H), 5.77 (t, J )
6.3 Hz, 1H), 7.34 (s, 1H), 11.2 (bs, 1H); HRMS calcd for
C10H15O4N2 (MH+) 227.1032, found 227.1015. Anal.
(C10H14O4N2) C, H, N. Compound 41d (16 mg, 80%) was
obtained as a white solid: mp 170.5-172 °C; 1H NMR (DMSO-
d6) δ 1.74 (s, 3H), 3.94 (s, 2H), 4.02 (d, J ) 6.0 Hz, 2H), 4.28

Cyclopropyl Nucleosides with Antiherpetic Activity
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1295
(s, 2H), 4.66 (bs, 1H), 4.8 (bs, 1H), 5.28 (t, J ) 6.0 Hz, 1H),
7.34 (s, 1H), 11.2 (bs, 1H); HRMS calcd for C10H15O4N2 (MH+)
227.1032, found 227.1016. Anal. (C10H14O4N2) C, H, N.
(s, 1H); FD MS m/z 491 (M+). The 7-isomer was eluted
afterward: white crystalline solid (45.2 mg, 11%).
2,6-Dia m in o-9-[[cis-1′,2′-bis(h yd r oxym eth yl)cyclop r op -
1′-yl]m eth yl]p u r in e (45). Compound 44 (550 mg, 1.12 mmol)
was dissolved in saturated NH3/MeOH (56 mL), and the
mixture was stirred at 90 °C for 7 days. The solvent was
removed in vacuo and the residue was taken up in H2O (5 mL)
and washed with EtOAc. The aqueous layer was concentrated
in vacuo, and the residue was purified by reversed-phase
chromatography eluting with 0-20% MeOH/H2O to yield 45
1-[[t r a n s-1′,2′-Bis(h yd r oxym e t h yl)cyclop r op -1′-yl]-
m eth yl]cytosin e (42a ). Compound 20b (104 mg, 0.21 mmol)
was coupled with cytosine (28 mg, 0.25 mmol) followed by
deprotection in a similar manner as described in the prepara-
tion of 40a . Chromatography on silica gel eluting with 5-10%
MeOH in CH2Cl2 yielded 1-[[trans-1′,2′-bis[(benzoyloxy)methyl]-
cycloprop-1′-yl]methyl]cytosine as a white gum (54.2 mg, 60%).
Deprotection gave 42a as a white solid (38.2 mg, 79%): mp
1
as a white solid (150 mg, 51%): mp 186-188.5 °C; H NMR
1
(DMSO-d6) δ 0.38 (t, J ) 5.1 Hz, 1H), 0.90 (dd, J ) 4.8, 8.7
Hz, 1H), 1.24 (m, 1H), 3.16-3.44 (m, 3H), 3.56 (m, 1H), 3.81
(d, J ) 14.4 Hz, 1H), 4.02 (d, J ) 14.4 Hz, 1H), 4.47 (m, 1H),
4.87 (m, 1H), 5.76 (bs, 2H), 6.65 (bs, 2H), 7.73 (s, 1H); HRMS
calcd for C11H17O2N6 (MH+) 265.1427, found 265.1423. Anal.
(C11H16O2N6) C, H, N.
214-216 °C; H NMR (DMSO-d6) δ 0.43 (t, J ) 4.8 Hz, 1H),
0.49 (dd, J ) 4.8, 8.7 Hz, 1H), 1.02 (m, 1H), 3.02 (dd, J ) 6.0,
11.7 Hz, 1H), 3.10 (dd, J ) 6.0, 11.7 Hz, 1H), 3.38 (m, 1H),
3.65 (m, 1H), 3.76 (d, J ) 14.4 Hz, 1H), 3.89 (d, J ) 14.4 Hz,
1H), 4.71 (t, J ) 5.4 Hz, 1H), 4.77 (t, J ) 6.0 Hz, 1H), 5.68 (d,
J ) 7.2 Hz, 1H), 7.04 (bs, 1H), 7.09 (bs, 1H), 7.65 (d, J ) 7.2
Hz, 1H); HRMS calcd for C10H16O3N3 (MH+) 226.1191, found
226.1204. Anal. (C10H15O3N3) C, H, N.
2-Am in o-9-[[cis-1′,2′-bis(h yd r oxym eth yl)cyclop r op -1′-
yl]m eth yl]p u r in e (46). A mixture of 44 (1.41 g, 2.87 mmol),
ammonium formate (724 mg, 11.5 mmol), and 10% Pd/C (86
mg) in MeOH (29 mL) was refluxed at 75 °C for 3 h. After
filtration the solvent was removed in vacuo. The residue was
dissolved in CH2Cl2 and washed with saturated NaHCO3. The
organic layer was concentrated in vacuo, and the residue was
chromatographed on silica gel eluting with 4-10% MeOH in
CH2Cl2 to yield 2-amino-9-[[cis-1′,2′-bis[(benzyloxy)methyl]-
cycloprop-1′-yl]methyl]purine as a white gum (1.10 g, 84%).
The benzoyl group was removed by treating the dibenzoate
(242 mg, 0.529 mmol) in MeONa/MeOH (1.59 mmol, 2 mL) at
40 °C for 30 min. The solution was neutralized with 2 N HCl
(0.79 mL, 1.58 mmol) and concentrated in vacuo. The residue
was dissolved in H2O and washed with EtOAc. The aqueous
layer was concentrated in vacuo, and the residue was purified
by reversed-phase chromatography eluting with 0-20% MeOH/
H2O to yield 46 as a white solid (116 mg, 88%): mp 159-162
°C; 1H NMR (DMSO-d6) δ 0.43 (t, J ) 5.1 Hz, 1H), 0.93 (dd, J
) 5.1, 9.0 Hz, 1H), 1.29 (m, 1H), 3.16 (s, 0.6H, CH3OH), 3.26-
3.38 (m, 2H), 3.42 (dd, J ) 5.4, 12.0 Hz, 1H), 3.60 (m, 1H),
3.96 (d, J ) 14.4 Hz, 1H), 4.01 (s, 0.2H, CH3OH), 4.79 (d, J )
14.4 Hz, 1H), 4.54 (t, J ) 5.4 Hz, 1H), 4.64 (t, J ) 5.4 Hz, 1H),
6.44 (bs, 2H), 8.10 (s, 1H), 8.55 (s, 1H); HRMS calcd for
1-[[cis-1′,2′-Bis(h ydr oxym eth yl)cyclopr op-1′-yl]m eth yl]-
cytosin e (42b). Treatment of 21b (500 mg, 1.01 mmol) as
above gave 1-[[cis-1′,2′-bis[(benzoyloxy)methyl]cycloprop-1′-yl]-
methyl]cytosine as a white gum (284 mg, 65%). Deprotection
gave 42b as a white solid (118 mg, 80%). Recrystallization
from MeOH gave white crystals (107 mg, 73%): mp 207-208
°C; 1H NMR (DMSO-d6) δ 0.32 (t, J ) 5.1 Hz, 1H), 0.82 (dd, J
) 5.1, 9.0 Hz, 1H), 1.15 (m, 1H), 3.16-3.44 (m, 3H), 3.53 (m,
1H), 3.58 (d, J ) 14.1 Hz, 1H), 3.74 (d, J ) 14.1 Hz, 1H), 4.42
(bs, 1H), 4.71 (t, J ) 5.7 Hz, 1H), 5.66 (d, J ) 7.2 Hz, 1H),
7.02 (bs, 2H), 7.57 (d, J ) 7.2 Hz, 1H); HRMS calcd for
C
10H16O3N3 (MH+) 226.1191, found 226.1194. Anal.
(C10H15O3N3) C, H, N.
9-[[t r a n s-1′,2′-Bis(h yd r oxym e t h yl)cyclop r op -1′-yl]-
m eth yl]h yp oxa n th in e (43a ). To a solution of 40a (97.0 mg,
0.389 mmol) in AcOH (11.7 mL) was added a solution of
NaNO2 (805 mg, 11.7 mmol) in H2O (3.9 mL), and the mixture
was stirred at 60 °C for 5 h. After cooling to room temperature,
the pH was adjusted to 7 with 2 N NaOH and the solvent was
removed in vacuo. The residue was purified by reversed-phase
chromatography eluting with 0-15% MeOH in H2O to yield
43a as a white solid (86.0 mg, 88%): mp 238-240 °C; 1H NMR
(DMSO-d6) δ 0.54-0.60 (m, 2H), 1.16 (m, 1H), 3.04 (dd, J )
5.1, 11.4 Hz, 1H), 3.18 (m, 1H), 3.48 (m, 1H), 3.75 (m, 1H),
4.20 (d, J ) 14.7 Hz, 1H), 4.36 (d, J ) 14.7 Hz, 1H), 4.61 (m,
1H), 4.67 (m, 1H), 8.03 (s, 1H), 8.15 (s, 1H), 12.23 (bs, 1H);
HRMS calcd for C11H15O3N4 (MH+) 251.1144, found 251.1149.
Anal. (C11H14O3N4‚0.2H2O) C, H, N.
9-[[cis-1′,2′-Bis(h ydr oxym eth yl)cyclopr op-1′-yl]m eth yl]-
h yp oxa n th in e (43b). Deamination of 40b as above afforded
43b as a white solid (28.2 mg, 63%): mp 234.5-237 °C; 1H
NMR (DMSO-d6) δ 0.43 (t, J ) 5.4 Hz, 1H), 0.90 (dd, J ) 4.8,
8.7 Hz, 1H), 1.32 (m, 1H), 3.25-3.37 (m, 2H), 3.41 (dd, J )
6.0, 12.0 Hz, 1H), 3.60 (dt, J ) 12.0, 6.0 Hz, 1H), 4.05 (d, J )
14.1 Hz, 1H), 4.17 (d, J ) 14.1 Hz, 1H), 4.54 (m, 1H, OH),
4.61 (m, 1H), 8.02 (s, 1H), 8.11 (s, 1H), 12.23 (bs, 1H); HRMS
calcd for C11H15O3N4 (MH+) 251.1144, found 251.1157. Anal.
(C11H14O3N4) C, H, N.
C
11H16O2N5 (MH+) 250.1304, found 250.1316. Anal.
(C11H15O2N5‚0.2MeOH) C, H, N.
Eth yl (3a S,4a R)-3,3a ,4,4a -Tetr a h yd r o-3-oxo-1H-cyclo-
p r op a [c]fu r a n -3a -ca r boxyla te (47). Sodium (2.42 g, 105
mmol) was dissolved in EtOH (195 mL), and diethyl malonate
(16.7 mL, 110 mmol) was added at 0 °C over 5 min to the
solution. (R)-(-)-Epichlorohydrin (7.8 mL, 100 mmol) in EtOH
(5 mL) was added dropwise to the solution at room tempera-
ture over 1 h, and the mixture was stirred at 75 °C for 20 h.
The mixture was filtered, and the filtrate was concentrated
in vacuo. The residue was dissolved in CH2Cl2 and washed
with H2O. The organic layer was concentrated in vacuo, and
the residue was chromatographed on silica gel eluting with
15-50% EtOAc in hexane to yield 47 as a colorless oil (12.0 g,
70%): 1H NMR (CDCl3) δ 1.31 (t, J ) 7.1 Hz, 3H), 1.37 (dd, J
) 4.8, 5.4 Hz, 1H), 2.08 (dd, J ) 4.8, 8.0 Hz, 1H), 2.72 (m,
1H), 4.18 (d, J ) 9.6 Hz, 1H), 4.27 (q, J ) 7.1 Hz, 2H), 4.36
(dd, J ) 4.5, 9.6 Hz, 1H); FAB MS m/z 170 (M+); [R]25
)
2-Am in o-9-[[cis-1′,2′-bis[(ben zoyloxy)m eth yl]cyclopr op-
1′-yl]m eth yl]-6-ch lor op u r in e (44). A solution of 21b (400
mg, 0.809 mmol) in DMF (8 mL) was added to a mixture of
2-amino-6-chloropurine (165 mg, 0.973 mmol), K2CO3 (134 mg,
0.970 mmol) and 18-crown-6 (233 mg, 0.970 mmol), in DMF
(8 mL) and stirred at 60 °C for 1.5 h. After concentration in
vacuo, the residue was dissolved in CH2Cl2 and washed with
saturated NaHCO3. The organic layer was concentrated in
vacuo, and the residue was chromatographed on silica gel
eluting with 2-7% MeOH in CH2Cl2 to give 44 as a white solid
(323 mg, 81%): 1H NMR (CDCl3) δ 0.91 (t, J ) 6.0 Hz, 1H),
1.26 (dd, J ) 6.0, 9.0 Hz, 1H), 2.04 (tt, J ) 6.0, 9.0 Hz, 1H),
4.02 (d, J ) 14.4 Hz, 1H), 4.11 (dd, J ) 9.0, 12.3 Hz, 1H), 4.27
(d, J ) 12.9 Hz, 1H), 4.32 (d, J ) 14.4 Hz, 1H), 4.55 (d, J )
12.9 Hz, 1H), 4.74 (dd, J ) 6.0, 12.3 Hz, 1H), 4.91 (bs, 2H),
7.31-7.37 (m, 4H), 7.49-7.56 (m, 2H), 7.76-7.84 (m, 4H), 7.90
D
-146.58 (c ) 1.22, EtOH). The optical purity of 47 was
analyzed by chiral HPLC using Chiralpak AD (Daicel, Tokyo)
by an isocratic elution using hexanes-EtOAc-Et2NH (75:25:
0.2) at a detection wavelength of 235 nm. The optical purity
of 47 obtained by this procedure was >97% ee. The other
enantiomer derived from (S)-(+)-epichlorohydrin showed [R]25
) +145.48 (c ) 1.22, EtOH).
D
Eth yl (1R,2R)-1,2-Bis(h yd r oxym eth yl)-1-cyclop r op a n -
eca r boxyla te (48). NaBH4 (2.0 g, 53 mmol) was added
portionwise to a solution of 47 (12 g, 70 mmol) in EtOH (200
mL), and the mixture was stirred at room temperature for 2
h. HCl (2 N, 27 mL, 54 mmol) and EtOAc (100 mL) were
added at 0 °C, and the mixture was filtered. After concentra-
tion in vacuo the residue was dissolved in CH2Cl2 and washed
with H2O. The organic layer was concentrated in vacuo, and

1296 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Sekiyama et al.
the residue was chromatographed on silica gel eluting with
4% MeOH in CH2Cl2 to yield 48 as a colorless oil (8.35 g,
69%): 1H NMR (CDCl3) δ 0.76 (dd, J ) 4.8, 6.6 Hz, 1H), 1.27
(t, J ) 7.2 Hz, 3H), 1.49 (dd, J ) 4.8, 9.0 Hz, 1H), 2.05 (m,
1H), 3.06 (bs, 1H), 3.23 (d, J ) 12.8 Hz, 1H), 3.24 (bs, 1H),
3.33 (dd, J ) 11.1, 12.5 Hz, 1H), 4.08 (dd, J ) 5.1, 12.5 Hz,
1H), 4.17 (q, J ) 7.2 Hz, 2H), 4.52 (d, J ) 12.8 Hz, 1H); FD
MS m/z 175 (MH+).
as a colorless oil (5.35 g, 68%): 1H NMR (CDCl3) δ 0.75 (t, J
) 5.5 Hz, 1H), 0.98 (dd, J ) 5.4, 9.0 Hz, 1H), 1.51 (m, 1H),
3.39 (d, J ) 10.1 Hz, 1H), 3.62 (d, J ) 10.1 Hz, 1H), 4.22 (dd,
J ) 9.0, 12.0 Hz, 1H), 4.35 (d, J ) 11.9 Hz, 1H), 4.55 (s, 2H),
4.66 (dd, J ) 6.6, 12.0 Hz, 1H), 4.76 (d, J ) 11.9 Hz, 1H), 7.2-
7.35 (m, 9H), 7.5 (m, 2H), 7.94 (m, 4H); FD MS m/z 430 (M+).
(1S,2R)-[2-[(Ben zoyloxy)m et h yl]-1-(h yd r oxym et h yl)-
cyclop r op -1-yl]m eth yl Ben zoa te (52) ) (1S,2R)-21a .
A
E t h yl (1R,7R)-4,4-Dim et h yl-3,5-d ioxa b icyclo[5.1.0]-
octa n e-1-ca r boxyla te (49). To a solution of 48 (8.35 g, 47.9
mmol) in DMF (100 mL) were added p-TsOH monohydrate (57
mg, 0.3 mmol) and dimethoxypropane (12 mL, 100 mmol), and
solution of 51b (5.35 g, 12.4 mmol) in EtOH (50 mL) containing
AcOH (15 mL) was hydrogenated at room temperature under
atmospheric pressure for 3 days in the presence of 10% Pd/C
(500 mg). After filtration, the filtrate was concentrated in
vacuo. The residue was dissolved in water, neutralized with
2 N NaOH, and then extracted with CH2Cl2. The organic layer
was concentrated in vacuo, and the residue was chromato-
graphed on silica gel eluting with 2% MeOH in CH2Cl2 to yield
52 as a colorless oil (4.20 g, 99%). 1H NMR was identical to
that of 21a .
the mixture was stirred at room temperature for 12 h.
A
mixture of 150 mL each of hexane and EtOAc was added, and
the mixture was washed with H2O. The organic layer was
concentrated in vacuo, and the residue was chromatographed
on silica gel eluting with EtOAc-hexane (1:5) to yield 49 as a
colorless oil (4.99 g, 49%): 1H NMR (CDCl3) δ 1.28 (s, 3H),
1.2-1.3 (m, 4H), 1.37 (s, 3H), 1.41 (dd, J ) 3.8, 9.5 Hz, 1H),
1.80 (m, 1H), 3.75 (d, J ) 13.5 Hz, 1H), 3.76 (dd, J ) 4.2, 13.2
Hz, 1H), 4.05-4.21 (m, 3H), 4.62 (d, J ) 13.5 Hz, 1H); FD MS
m/z 214 (M+).
(1S,7R)-4,4-Dim et h yl-3,5-d ioxa b icyclo[5.1.0]oct a n e-1-
m eth a n ol (50a ). To a solution of 49 (7.92 g, 37.0 mmol) in
anhydrous THF (18.5 mL) was added 2 M LiBH4 in anhydrous
THF (18.5 mL, 37.0 mmol) over 5 min, and the mixture was
refluxed at 72 °C for 12 h. Saturated NH4Cl was added at 0
°C, and the resulting clear solution was extracted with EtOAc.
The organic layer was concentrated in vacuo, and the resulting
colorless oil 50a was used in the next step without further
purification (4.07 g, 64%): 1H NMR (CDCl3) δ 0.67 (dd, J )
4.4, 8.9 Hz, 1H), 0.90 (dd, J ) 4.4, 5.8 Hz, 1H), 1.06 (m, 1H),
1.28 (s, 3H), 1.38 (s, 3H), 1.5-1.7 (bs, 1H), 3.45 (bs, 2H), 3.69
(dd, J ) 4.2, 13.2 Hz, 1H), 3.78 (d, J ) 12.9 Hz, 1H), 4.12 (dd,
J ) 5.7, 13.2 Hz, 1H), 4.17 (d, J ) 12.9 Hz,1H); FD MS m/z
173 (MH+).
(1S ,2R )-1-[(B e n z y lo x y )m e t h y l]-1,4-d i m e t h y l-3,5-
d ioxa bicyclo[5.1.0]octa n e (50b). Crude 50a (4.07 g, 23.6
mmol) was added to a suspension of 1.2 g of NaH (60%, 30
mmol) in anhydrous DMF (80 mL). After stirring for 5 min,
benzyl bromide (3.97 mL, 30 mmol) was added and the mixture
was stirred at room temperature for 14 h. After cooling to 0
°C, the pH was adjusted to 7 with saturated NH4Cl (about 5
mL), and the solution was diluted with hexanes-EtOAc (1:1)
and washed with H2O. The organic layer was concentrated
in vacuo, and the residue was chromatographed on silica gel
eluting with 15% EtOAc in hexane to yield 50b as a colorless
oil (5.56 g, 90%): 1H NMR (CDCl3) δ 0.67 (dd, J ) 4.2, 8.4 Hz,
1H), 0.92 (m, 1H), 1.00 (m, 1H), 1.28 (s, 3H), 1.37 (s, 3H), 3.13
(d, J ) 10.2 Hz, 1H), 3.50 (d, J ) 10.2 Hz, 1H), 3.70 (dd, J )
3.9, 13.2 Hz, 1H), 3.78 (d, J ) 13.1 Hz, 1H), 4.12 (dd, J ) 5.1,
13.2 Hz, 1H), 4.15 (d, J ) 13.1 Hz, 1H), 4.50 (d, J ) 12.0 Hz,
1H), 4.55 (d, J ) 12.0 Hz, 1H), 7.32 (m, 5H); FD MS m/z 262
(M+).
(1R,2R)-1-[(Ben zyloxy)m et h yl]-2-(h yd r oxym et h yl)-1-
cyclop r op a n em et h a n ol (51a ). A solution of 50b (5.56 g,
21.1 mmol) in THF (50 mL) was treated with 1 N HCl (50 mL)
at 0 °C for 30 min and the solvent was removed in vacuo. The
residue was dissolved in CH2Cl2 and washed with H2O. The
organic layer was concentrated in vacuo, and the resulting
colorless oil 51a was used in the next step without further
purification (4.08 g, 86%): 1H NMR (CDCl3) δ 0.41 (t, J ) 5.4
Hz, 1H), 0.66 (dd, J ) 5.4, 8.7 Hz, 1H), 1.32 (m, 1H), 2.0-2.2
(bs, 2H), 3.25-3.40 (m, 3H), 3.60 (d, J ) 9.3 Hz, 1H), 4.06
(dd, J ) 5.4, 12.6 Hz, 1H), 4.22 (d, J ) 12.3 Hz, 1H), 4.56 (s,
2H), 7.34 (m, 5H); FD MS m/z 223 (MH+).
(1′S,2′R)-9-[[1′,2′-Bis(h yd r oxym et h yl)cyclop r op a n -1′-
yl]m et h yl]gu a n in e
(3a ) a n d
(1′R,2′S)-9-[[1′,2′-Bis-
(h yd r oxym eth yl)cyclop r op a n -1′-yl]m eth yl]gu a n in e (3b).
Compounds 3a ,b were synthesized as described in the prepa-
ration of racemate 3 by using 52 or its enatiomer instead of
21a . 1H MNR spectra of 3a ,b were identical to that of 3. 3a :
mp 297-298.5 °C; [R]20 ) -11.18 (c ) 1%, DMSO). Anal.
D
(C11H15O3N5) C, H, N. 3b: mp 296-298 °C; [R]20 ) +11.08
D
(c ) 1%, DMSO). Anal. (C11H15O3N5‚0.2H2O) C, H, N.
Qu a n tita tive CP E Red u ction Assa y (HSV-1). The ac-
tivities of test compounds were determined by neutral red dye
uptake method16 with modification. Dilutions (3-fold) of the
test compounds were prepared in 100-µL volumes of Eagle
minimum essential medium (EMEM) supplemented with 2%
FBS in the wells of 96-well culture plates; 60 µL of Vero cells
(3 × 105 cells/mL, EMEM 10% FBS) were then dispensed into
each well. HSV-1 Tomioka strain was diluted in medium
(EMEM 2% FBS) to approximately 100 TCID50/40 µL, as
determined by prior titration in a similar dye uptake assay,
and 40-µL volumes of viral suspension were added to the
respective wells. Control wells containing no test compound
and no virus (cell control) or no cells (blank control) were
included in each plate. After the plates were incubated for 3
days at 37 °C in an atmosphere of 5% CO2, 50 µL of neutral
red dye (0.15% in saline, pH 5.5) was dispensed into each well,
and the cultures were incubated for a further 45 min at 37 °C
(pH 4.2, equal volumes of 0.1 M Sorensen citrate buffer and
ethanol). The medium was removed, and the well was rinsed
with 150 µL of PBS; 100 µL of citrate-ethanol buffer (pH 4.2,
equal volumes of 0.1 M Sorensen citrate buffer and ethanol)
was added, and absorbance at 550 nm was measured. The
mean OD of the cell control wells was assigned a value of 100%
and that of the control blank wells a value of 0%, and the
concentration of the test compounds producing a 50% OD
reading was determined as IC50
. For determining cytotoxic
activity of the test compounds, the same method without viral
infection was performed to give CC50. All experiments were
performed in quadruplicate.
P la qu e Red u ction Assa ys (VZV). Anti-VZV assay was
performed as described.33 Briefly, subconfluent monolayers
of human foreskin fibroblasts (HFF) cells in 12-well plates
were rinsed with MEM and exposed to 0.5 mL/well of a
suspension of VZV DM625 strain (a clinical isolate from Dr.
Rich Whitley’s laboratory at University of Alabama, Birming-
ham) and diluted in MEM + 2% FBS for 2 h at 37 °C to allow
virus adsorption. The fluids were removed, and the cell layers
were rinsed with MEM + 2% FBS. The test compounds in 1
mL of overlay medium (MEM, 2% FBS in 0.25% agarose) were
added, and the plates were incubated at 37 °C in a humidified
atmosphere of 5% CO2. After 5 days the plaques were counted
and the effect of each drug concentration on plaque formation
was determined by comparing the mean number of plaques
in the drug-treated cultures with the mean plaque counts of
the untreated virus control cultures. The concentration of the
test compounds which conferred 50% inhibition of plaque
formation compared to virus control (untreated control) was
(1S,2R)-[2-[(Ben zoyloxy)m eth yl]-1-[(ben zyloxy)m eth -
yl]cyclop r op -1-yl]m eth yl Ben zoa te (51b). A solution of
51a (4.08 g, 18.2 mmol) in CHCl3 (64 mL) containing pyridine
(11.8 mL, 146 mmol) was treated with BzCl (8.45 mL,72.8
mmol) at 0 °C for 12 h. Saturated NH4Cl was added, and the
mixture was extracted with CH2Cl2. The organic layer was
concentrated in vacuo, and the residue was chromatographed
on silica gel eluting with 15% EtOAc in hexane to yield 51b

Cyclopropyl Nucleosides with Antiherpetic Activity
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1297
F.; Martin, J . C.; Verheyden, J . P. H.; Matthews, T. R. Antiher-
pesvirus Activity of the Acyclic Nucleosides 9-(1,3-Dihydroxy-
2-propoxymethyl)guanine. Antimicrob. Agents Chemother. 1983,
23, 676-682. (c) Field, E. K.; Davies, M. E.; DeWitt, C.; Perry,
H. C.; Liou, R.; Germershausen, J .; Karkas, J . D.; Ashton, W.
T.; J ohnston, D. B.; Tolman, R. L. 9-([2-Hydroxy-1-(hydroxy-
methyl)ethoxy]methyl)guanine: A Selective Inhibitor of Herpes
Group Virus Replication. Proc. Natl. Acad. Sci. U.S.A. 1983, 80,
4139-4143.
interpolated from the dose-response curve and was defined
as IC50. The drug cytotoxicity control cultures were examined
microscopically for gross morphologic changes and then treated
with MTT and 30% SDS for quantitative measurement. Since
all the compounds tested were not toxic to give CC25 at the
highest concentration (320 µg/mL), minimum concentrations
to give morphologic changes were determined microscopically.
All experiments were performed in triplicate.
An ti-HIV Assa y. Anti-HIV assay was performed as de-
scribed.34 Briefly, CEM cells were pregrown as monolayers
in wells of 96-well tissue culture plates containing RPMI 1640
medium supplemented with 10% FCS. Stock viruses (HIV-1
RF strain, from the National Institutes of Health AIDS
Research and Reference Reagent Respository) were pretitered
and diluted in cell culture medium to yield 32-100 CCID50
units/0.1 mL. To each of the cell cultures were added 0.1 mL
of the test compound solution and 0.1 mL of virus suspension.
The plates were incubated at 37 °C in a humidified atmosphere
of 5% CO2 for 7 days, and CPE inhibition (IC50) and cytotoxicity
(CC25) were determined by a dye uptake (MTT) procedure. All
experiments were performed in triplicate.
P h osp h or yla tion by HSV-1 TK. Crude HSV-1 TK frac-
tion was prepared from the HSV-1 (KOS)-infected BU25 cells
by ammonium sulfate precipitation as described.17 Briefly,
monolayer of BU25 (TK-) cells was infected with HSV-1 (KOS)
at a multiplicity of infection of 10 pfu/cell and then was
incubated at 37 °C for 18 h. Cells were harvested with 50 mM
Tris-HCl buffer (pH 8.0) containing 0.9% NaCl and were
washed four times with the same buffer. After centrifugation
the cell pellet was resuspended with 0.1 M Tris-HCl (pH 8.0)
containing 20 mM 2-mercaptoethanol and disrupted by soni-
cation at 4 °C. The sonicated suspension was centrifuged at
600g for 60 min. Ammonium sulfate was added to the
supernatant to give 30% saturation. The mixture was allowed
to stand for 30 min on ice, and then the precipitate was
removed by centrifugation at 900g for 30 min. Additional
ammonium sulfate was added to the supernatant to give 50%
saturation, and then the mixture was allowed to stand for 30
min on ice. The precipitate was collected by centrifugation at
900g for 30 min. The pellet was resuspended in 50 mM Tris-
HCl (pH 8.0) containing 20 mM 2-mercaptoethanol and
dialyzed overnight with the same buffer containing 10%
glycerol. The extract was stored at -80 °C until use.
TK reaction was performed at 37 °C for 24 h using the above
crude HSV-1 TK extract. Test compounds (final concentration
of 400 µM) were incubated in an assay buffer containing 50
mM Tris-HCl (pH 8.0), 5 mM ATP, 5 mM MgCl2, 9 mM KF, 5
mM phosphoenol pyruvate, 10 mM 2-mercaptoethanol, and 15
µg of protein/mL crude HSV-1 TK extract. Monophosphates
were analyzed by HPLC as described previously18 except that
a Partisil 10 SAX was used with 0-1 M KH2PO4 (pH 3.5)
linear gradient at a flow rate of 1.5 mL/min for analysis.
Amounts of monophosphate were determined by absorbance
at 254 nm.
(3) (a) Harnden, M. R.; J arvest, R. L.; Bacon, T. H.; Boyd, M. R.
Synthesis and Antiviral Activity of 9-[4-Hydroxy-3-(hydroxym-
ethyl)but-1-yl]purines. J . Med. Chem. 1987, 30, 1636-1643. (b)
Vere Hodge, R. A.; Perkins, R. M. Mode of Action of 9-(4-
Hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) against
Herpes Simplex Virus in MRC-5 Cells. Antimicrob. Agents
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(4) Brown, D. G.; Visse, R.; Sandhu, G.; Davies, A.; Rizkallah, P.
J .; Melitz, C.; Summers, W. C.; Sanderson, M. R. Crystal
Structures of the Thymidine Kinase from Herpes Simplex Virus
Type-I in Complex with Deoxythymidine and Ganciclovir. Nature
Struct. Biol. 1995, 2, 876-881.
(5) (a) Shimada, N.; Hasegawa, S.; Harada, T.; Tomisawa, T.; Fujii,
A.; Takita, T. Oxetanocin, A Novel Nucleoside from Bacteria. J .
Antibiot. 1986, 39, 1623-1625. (b) Nakamura, H.; Hasegawa,
S.; Shimada, N.; Fujii, A.; Takita, T.; Iitaka, Y. X-ray Structure
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(c) Hoshino, H.; Shimizu, N.; Shimada, N.; Takita, T.; Takeuchi,
T. Inhibition of Infectivity of Human Immunodeficiency Virus
by Oxetanocin. J . Antibiot. 1987, 40, 1077-1078. (d) Nishiyama,
Y.; Yamamoto, N.; Takahashi, K.; Shimada, N. Selective Inhibi-
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30, 6453-6456. (b) Nishiyama, Y.; Yamamoto, N.; Yamada, Y.;
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42, 1854-1859. (c) Norbeck, D. W.; Kern, E.; Hayashi, S.;
Rosenbrook, W.; Sham, H.; Herrin, T.; Plattner, J . J .; Erikson,
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(8) The site of alkylation was verified by the same method in ref 7
by comparing the ultraviolet spectra to those of model com-
pounds. For purine analogues NMR spectra were also used for
assignments; see: Kjellberg, J .; J ohansson, N. G. Characteriza-
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NMR. Tetrahedron 1986, 42, 6541-6544.
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the cyclopropane ring are 8.06 Hz for 8 (all-cis) and 4.64 Hz for
9, respectively.
23 was separated by SUMICHIRAL OA-6100 using 2 mM
CuSO4 and acetonitrile (90:10) into each enantiomer and used
as a substrate in this experiment. Fast eluting enantiomer
was designated 23a , and latter was designated 23b.
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droxymethyl and the methylene protons of 2-(benzoyloxy)methyl.
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Ack n ow led gm en t. The authors thank Noriko Take-
sada, Toshimi Mizukoshi, Uno Tagami, Reiko Yuji, and
Dr. Tomoko Akashi for measurement of NMR and mass
spectra. We are also grateful to Dr. Kohki Ishikawa for
X-ray crystallographic analysis and to Katsutoshi Saka-
ta for efficient technical assistance.
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ylene protons adjacent to the purine ring in Z-olefin 31 and the
protected forms of 40d and 41d .
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compound synthesized from (E)-29a in a separate run.
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with inversion of stereochemistry, the absolute configuration of
the cyclopropane lactone prepared from (R)-(-)-epichlorohydrin
should be that of 47. To confirm the stereochemistry, 4-bro-
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1298 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Sekiyama et al.
mophenacyl ester of 47 was prepared and the absolute structure
was determined by X-ray crystallography. Since there is no
chance of racemization in the preparation of 3a from 47, the
absolute conformation of 3a prepared from (R)-(-)-epichlorohy-
drin is 1′S,2′R.
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