Conformationally locked nucleoside analogues based on the bridgehead substituted 7-oxonorbornane and their antiviral properties

Article abstract of DOI:10.1135/cccc2011152

We report on the preparation of novel 1'-homonucleoside derivatives locked in a West conformation by 1',4'-bridge consisting of annulated benzene or naphthalene ring. The crucial step of the synthesis was Diels-Alder reaction of an appropriate aryne with

Full text of DOI:10.1135/cccc2011152

Conformationally Locked Nucleosides
1549
CONFORMATIONALLY LOCKED NUCLEOSIDE ANALOGUES
BASED ON THE BRIDGEHEAD SUBSTITUTED 7-OXONORBORNANE
AND THEIR ANTIVIRAL PROPERTIES
b1
Milan DEJMEKa1, Hubert HŘEBABECKÝa2, Martin DRAČÍNSKÝa3, Johan NEYTS
,
a4
a5,
Pieter LEYSSENb2, Helena MERTLÍKOVÁ-KAISEROVÁ and Radim NENCKA
*
a
Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6,
1
2
Czech Republic; e-mail: dejmek@uochb.cas.cz, hubert@uochb.cas.cz,
3
4
5
dracinsky@uochb.cas.cz, kaiserova@uochb.cas.cz, nencka@uochb.cas.cz
Rega Institute for Medical Research, Minderbroedersstraat 10, BE-3000 Leuven, Belgium;
b
1
2
e-mail: johan.neyts@rega.kuleuven.be, pieter.leyssen@rega.kuleuven.be
Received July 29, 2011
Accepted August 22, 2011
Published online December 22, 2011
Dedicated to the 75th anniversary of Professor Antonín Holý’s birthday and the 25th anniversary of
the discovery of antiviral nucleoside phosphonates.
We report on the preparation of novel 1′-homonucleoside derivatives locked in a West con-
formation by 1′,4′-bridge consisting of annulated benzene or naphthalene ring. The crucial
step of the synthesis was Diels–Alder reaction of an appropriate aryne with a suitable furane
derivative. Antiviral properties of novel compounds were studied and slight activity against
HCV was detected in several compounds.
Keywords: 1′-Homonucleosides; Diels–Alder reaction; Cycloaddition; Antiviral agents.
For several decades, modified nucleoside analogues have been a synonym
for extremely attractive topic in antiviral drug discovery1. In this context,
conformationally locked nucleosides (CLNs) have attracted considerable at-
tention of researchers especially due to the findings of Marquez and co-
workers2, which were connected to the conformational preference studies
of various enzymes involved in the metabolism and antiviral action of
nucleoside derivatives. Their research resulted also in the discovery of
N-MCT 1 that possesses significant activity against herpes viruses and pro-
vided solid base for further exploration of the CLNs 3.
In parallel, the discovery of locked nucleic acids (LNA) 2 provided the
second important stimulus for the exploration of bicyclic and tricyclic
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1549–1566
© 2011 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2011152

1550
Dejmek et al.:
nucleoside derivatives. The success of LNA has been based on the unique
influence of certain CLN monomers incorporation into structure of
olionucleotides resulting in significant improvement of their hybridization
properties4.
O
O
B
NH
N
O
HO
O
O
O
HO
1
2, B = nucleobase
CHART 1
Both these impulses led to intensive studies of variously locked nucleo-
sides. The research in this field was recently reviewed in detail5.
In our laboratory we have synthesized a broad library of locked nucleo-
side analogues containing compounds with significant activity against the
Coxsackie B3 virus6. After a very recent discovery7 that carbocyclic nucleo-
side analogues with an annulated benzene ring bear a remarkable activity
against the Coxsackie B3 virus, we have decided to synthesize also non-
carbocyclic nucleoside analogues with an annulated benzene ring in order
to investigate their antiviral activity. Furthermore, our detailed SAR in-
vestigation revealed that 6-chloropurine derivates possess the highest anti-
Coxsackie activity8.
Goal of this project was to design and prepare a series of conformational-
ly constrained nucleoside analogues with an aromatic ring employed as the
locking bridge and to test these compounds for antiviral properties.
First of all, we prepared a dideoxyderivative 8 by five-step procedure start-
ing with the Diels–Alder reaction of 5-acetoxymethyl-2-furanaldehyde (4)
as a diene with in situ generated benzyne carried out by a slightly modified
literature procedure9, which furnished compound 5. This unstable adduct
was immediately reduced to an unsaturated derivative 6, which was ob-
tained in 67% yield over two steps. Hydrogenation of this product provided
saturated analogue 7, which was used in the next step without purification.
The nucleobase was introduced by means of Mitsunobu reaction (with
6-chloropurine, triphenylphosphine and diisopropylazodicarboxylate) and
subsequently the hydroxymethyl group was deprotected with potassium
hydrogencarbonate in the same pot (52% yield over three steps). The ob-
tained chloropurine derivative 8 was subjected to antiviral screening. In ad-
dition, we obtained the unsaturated analogue 9 in good yield (59% over
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Conformationally Locked Nucleosides
1551
two steps), by similar nucleobase introducition and deprotection, employ-
ing the intermediate 6 (Scheme 1).
Nucleoside 9 was further transformed to its cis-hydroxy derivative 10 uti-
lizing osmium tetroxide. The chlorine atom at the C-6 position of the nu-
cleobase was subsequently ammonolyzed to form an adenine derivative 11
(see Scheme 1). Although the reaction afforded product in good yields, pu-
AcO
O
O
4
COOH
a
O
NH2
AcO
O
3
5
b
c
OH
OH
O
O
AcO
AcO
7
6
d
e
Cl
N
Cl
N
N
N
N
N
N
N
O
O
HO
HO
8
9
f
NH2
Cl
N
N
N
N
N
N
N
g
N
O
O
HO
HO
HO OH
HO OH
11
10
a) i. isoamyl nitrite, Cl3CCOOH, dioxane; ii. 4, toluene, 60 °C;
b) NaBH4, MeOH, 0 °C, 67% (two steps from 4); c) H2, Pd(OH)2, MeOH;
d) i. 6-chloropurine, Ph3P, DIAD, dioxane; ii. KHCO3, MeOH, 52% (three
steps); e) i. 6-chloropurine, Ph3P, DIAD, dioxane; ii. KHCO3, MeOH, 59%
(two steps); f) OsO4, NMMO, dioxane/H2O, 79%; g) NH3, 90 °C, 75%.
SCHEME 1
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1552
Dejmek et al.:
rification was somewhat tricky due to very low solubility of the compound.
Satisfactorily pure product was obtained by precipitation from hot DMF so-
lution with methanol.
Moreover, nucleoside analogues 12 and 13 with two 6-chloropurine
nucleobases were prepared after deprotection of 6 by double Mitsunobu re-
action and subsequent cis-hydroxylation, respectively (Scheme 2).
OAc
O
HO
6
a
Cl
N
Cl
N
N
N
N
N
N
N
O
12
b
Cl
N
Cl
N
N
N
N
N
N
N
O
HO OH
13
a) i. K2CO3, MeOH; ii. 6-chloropurine, Ph3P, DIAD, THF, 57%
(two steps); b) OsO4, NMMO, dioxane/H2O, 59%.
SCHEME 2
Since a number of C-4′-truncated nucleoside derivatives exerted signifi-
cant anti-Coxsackievirus activities in our previous studies, we decided to
prepare analogues missing hydroxymethyl group derived from this series as
well.
The initial step of their synthesis was also Diels–Alder reaction of
benzyne with furfuryl benzoate 14. Double bond of 15 was hydroborated
with borane-tetrahydrofuran complex to provide alcohol 16, however yield
of this reaction was low since complicated mixtures containing mainly
compounds with disconnected oxygen bridge. Despite this unfortunate
complication the derivative 18 was synthesized in two simple steps, alcohol
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1549–1566

Conformationally Locked Nucleosides
1553
deprotection and introduction of the nucleobase by Mitsunobu reaction
(Scheme 3).
COOH
NH2
OBz
3
O
a
14
b
OBz
OBz
O
O
HO
e
15
16
c
c
OH
OH
OH
O
O
O
HO
17
19
21
d
d
d
Cl
N
Cl
Cl
N
N
N
N
N
N
N
N
N
N
N
O
O
O
HO
18
20
22
a) i. isoamyl nitrite, Cl3CCOOH, dioxane; ii. 14, toluene, 60 °C, 90%;
b) i. BH3.THF, THF; ii. NaBO3.4H2O, H2O, 37%; c) MeONa, MeOH
80% for 17, 91% for 19; d) 6-chloropurine, Ph3P, DIAD,THF, 79% for 18,
72% for 20, 76% for 22; e) i. H2, Pd(OH)2/C, MeOH; ii. MeONa, MeOH,
87% (two steps)
SCHEME 3
Analogues 20 and 22 were synthesized in a very similar manner as the
hydroxymethyl-bearing analogues 8 and 9. After debenzoylation of the in-
termediate 15, the nucleobase was either directly introduced by Mitsunobu
reaction to obtain analogue 20 or the double bond was hydrogenated first
and the 6-chloropurine was put on afterwards to give the saturated counter-
part 22 (see Scheme 3).
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1554
Dejmek et al.:
Cl
N
Cl
N
N
N
N
N
N
N
b
O
O
HO OH
20
24
c
a
Cl
N
NH2
N
N
N
N
N
N
N
O
O
O
HO OH
23
25
a) mCPBA, DCM, 64%; b) OsO4, NMMO, acetone/H2O, 62%;
c) NH3, 63%
SCHEME 4
COOH
NH2
26
a
Cl
N
N
N
b
c
OH
OR
N
O
O
O
31
27 R = Bz
30 R = H
28
d
e
c
Cl
NH2
N
Cl
N
N
N
N
N
N
N
f
N
N
N
N
O
O
O
HO
OH
HO
OH
29
33
32
a) i. isoamyl nitrite, Cl3CCOOH, dioxane; ii. 14, toluene, 60 °C; b) H2,
Pd(OH)2, MeOH, 84%; c) 6-chloropurine, Ph3P, DIAD, THF, 76% for 29,
66% for 31; d) MeONa, MeOH, 92%; e) OsO4, NMMO, dioxane/H2O,
81%; f) NH3, 73%
SCHEME 5
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Conformationally Locked Nucleosides
1555
Furthermore, reaction of 20 with meta-chloroperoxybenzoic acid af-
forded tetracyclic compound 23. The unsaturated derivative 20 was also
utilized in the synthesis of derivatives 24 and 25, which were prepared by
cis-hydroxylation of the double bond by osmium tetroxide. Compound 24
was transformed into 25 by heating the 6-chloropurine derivative with
liquid ammonia in an autoclave (Scheme 4).
Compounds with an annulated naphtalene were prepared similarly to the
above described procedure – naphtyne generated in situ from 3-amino-
2-naphtoic acid (26) was used as a dienophile in the Diels–Alder reaction
and this procedure afforded compound 27. Deprotection followed by
Mitsunobu reaction resulted in the formation of 31, which was further
oxidized to 32, and subsequently transformed into appropriate adenine de-
rivative 33. Also saturated derivative 29, analogous to 22, was prepared em-
ploying hydrogenation procedure into the reaction sequence (Scheme 5).
TABLE I
Anti-HCV activities and cytotoxicity of the synthesized compounds
Entry
Compound
EC50, µM
CC50, µM
1
2
8
66.5
63.9
45.1
>100
44.4
>100
68.7
16.1
21.9
21.4
>100
>100
11.0
8.01
6.31
85.3
89.3
>100
>100
>100
>100
>100
95.2
72.4
72.6
73.8
>100
>100
13.6
11.1
11.6
>100
9
3
10
11
12
13
18
20
22
23
24
25
27
28
29
30
4
5
6
7
8
9
10
11
12
13
14
15
16
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1556
Dejmek et al.:
In conclusion, we prepared a series of novel 1′-homonucleoside ana-
logues with conformation of the sugar ring locked in the West position by
bridge consisting of either benzene or naphthalene ring. Our synthetic ap-
proach presents a concise and robust pathway towards these nucleoside de-
rivatives.
The presented compounds underwent antiviral screening against a num-
ber of RNA viruses. Although none of the presented compounds exerted sig-
nificant anti-Coxsackie virus activity (higher then 50 µM), some of them
possessed modest anti-HCV activity, which unfortunately largely correlated
with cytotoxicity. The results of the anti-HCV screening are summarized in
Table I. The highest selectivity index was observed for compound 20,
which exerts EC50 = 16.1 µM and CC50 = 72.4 µM. Compound 29 signifi-
cantly reduced the growth of CCRF-CEM cells with IC50 = 5.73 µM.
EXPERIMENTAL
Melting points were determined on a Büchi B-540 apparatus. NMR spectra (δ, ppm; J, Hz)
were measured on a Bruker Avance II-600 and/or Bruker Avance II-500 instruments (600.1 or
500.0 MHz for 1H and 150.9 or 125.7 MHz for 13C) in hexadeuterated dimethyl sulfoxide or
CDCl3 and referenced to the solvent signal (DMSO-d6 δ 2.50 and 39.70, respectively) or in-
ternal standard (TMS). Mass spectra were measured on a LTQ Orbitrap XL (Thermo Fisher
Scientific) using electrospray ionization (ESI). Column chromatography was performed on
Silica gel 60 (Fluka) and thin-layer chromatography (TLC) on Silica gel 60 F254 foils (Merck).
Solvents were evaporated at 2 kPa and bath temperature 30–60 °C; the compounds were
dried at 13 Pa and 50 °C. The elemental analyses were obtained on a Perkin–Elmer CHN
Analyzer 2400, Series II Sys (Perkin–Elmer). The elemental compositions for all compounds
agreed to within 0.4% of the calculated values.
[4-(Hydroxymethyl)-1,4-epoxynaphthalen-1(4H)-yl]methyl Acetate (6)
To a solution of anthranilic (1.02 g, 7.4 mmol) and trichloroacetic acids (10 mg, 0.06 mmol)
in dry dioxane (15 ml) at 0 °C, isoamyl nitrite (1.4 g, 11.9 mmol) was added dropwise. This
mixture was stirred at r.t. for 90 min, diazonium salt was filtered off and washed with
dioxane (2 × 5 ml, the salt was never allowed to dry entirely) and added to a solution of
5-acetoxymethyl-2-furaldehyde (1 g, 6 mmol) in dry dioxane (20 ml). Reaction mixture was
heated to 60 °C for 2 h (evolution of N2 and CO2). Evaporation of volatiles afforded brown
slurry of the crude aldehyde, which was without further purification dissolved in methanol
(50 ml), cooled to 0 °C and to this solution solid NaBH4 (140 mg, 3.6 mmol) was added
portionwise. After 1 h of stirring at 0 °C, the solvent was evaporated and chromatography of
the residue on silica (hexanes/ethyl acetate 1:1) afforded 6 (990 mg, 67%) as a white solid.
Analytical sample was crystallized from toluene/cyclohexane mixture (white needles). M.p.
84–85 °C. ESI MS m/z (%): 269.1 (100) [M + Na]. 13C NMR (DMSO): 20.82 (CH3); 58.95
(8-CH2); 61.10 (1-CH2); 90.23 (C-1); 93.22 (C-8); 119.28 (C-3); 119.82 (C-6); 124.73 and
124.93 (C-4, C-5); 143.61 (C-10); 145.11 (C-9); 149.95 (C-2); 150.73 (C-7); 170.53 (COO).
1H NMR (DMSO): 2.06 s, 3 H (CH3); 4.10 dd, 1 H, Jgem = 12.4, J(CH2-OH) = 5.7 and 4.24 dd,
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Conformationally Locked Nucleosides
1557
1 H, Jgem = 12.5, J(CH2-OH) = 6.0 (8-CH2O); 4.78 d, 1 H, Jgem = 12.7 and 4.89 d, 1 H, Jgem
=
12.7 (1-CH2O); 5.23 t, 1 H, J(OH-CH2) = 5.9 (OH); 6.93 d, 1 H, J(10-9) = 5.4 (H-10);
6.94–6.97 m, 2 H (H-4, H-5); 7.01 d, 1 H, J(9-10) = 5.4 (H-9); 7.21 m, 1 H (H-3); 7.27 m, 1 H
(H-6). For C14H14O4 (246.26) calculated: 68.28% C, 5.73% H; found: 68.52% C, 5.46% H.
{(1S*,4R*)-4-[(6-Chloro-9H-purin-9-yl)methyl]-3,4-dihydro-1,4-epoxynaphthalen-1(2H)-yl}-
methanol (8)
To a solution of 6 (200 mg, 0.8 mmol) in dry methanol (10 ml) was added Pd(OH)2/C
(30 mg) and the mixture was hydrogenated (10 atm) overnight. Catalyst was filtered off on
a cellite pad and after evaporation of the solvent (200 mg of hydrogenated product), PPh3
(430 g, 1.6 mmol), 6-chloropurine (190 mg, 1.2 mmol) and dry dioxane (20 ml) were added
and a solution of DIAD (250 µl, 1.2 mmol) in dry dioxane (5 ml) was introduced dropwise
afterwards. Reaction mixture was stirred at r.t. overnight, volatiles were evaporated and
chromatography on silica (hexanes/ethyl acetate 1:1) afforded crude acetylated compound,
which was without further purification dissolved in methanol (50 ml) and stirred with solid
KHCO3 (400 mg, 4 mmol) for 2 h. After the solvent was evaporated, chromatography of the
residue on silica (hexanes/ethyl acetate 1:3) afforded 8 (142 mg, 52%) as a white solid. Ana-
lytical sample was crystallized from toluene (white needles). M.p. 178 °C. ESI MS m/z (%):
343.1 (12) [M + H], 365.1 (100) [M + Na], 707.1 (3) [2M + Na]. 13C NMR (DMSO): 29.95
(C-9′); 31.01 (C-10′); 43.68 (CH2N); 60.32 (CH2O); 86.59 (C-1′); 88.98 (C-8′); 118.01 (C-3′);
118.90 (C-6′); 126.52 (C-4′); 126.96 (C-5′); 130.27 (C-5); 144.63 (C-2′); 146.54 (C-7′); 148.38
(C-8); 149.30 (C-6); 151.96 (C-2); 152.48 (C-4). 1H NMR (DMSO): 1.29 ddd, 1 H, Jgem = 11.5,
J(9′en-10′en) = 8.8, J(9′en-10′ex) = 4.1 (H-9′endo); 1.49 ddd, 1 H, Jgem = 11.6, J(10′en-9′en) =
8.8, J(10′en-9′ex)
= 4.1 (H-10′endo); 1.84 m, 1 H (H-10′exo); 1.99 td, 1 H, Jgem =
J(9′ex-10′ex) = 11.0, J(9′ex-10′en) = 3.9 (H-9′exo); 4.06 dd, 1 H, Jgem = 12.4, J(CH2-OH) = 6.0
and 4.10 dd, 1 H, Jgem = 12.4, J(CH2-OH) = 5.5 (CH2O); 5.05 t, 1 H J(OH-CH2) = 5.8 (OH);
5.09 d, 1 H, Jgem = 15.2 and 5.30 d, 1 H, Jgem = 15.2 (CH2N); 7.09 td, 1 H, J(4′-5′) = J(4′-3′) =
7.4, J(4′-6′) = 1.0 (H-4′); 7.14 td, 1 H, J(5′-4′) = J(5′-6′) = 7.4, J(5′-3′) = 1.0 (H-5′); 7.26 td, 1 H,
J(6′-5′) = 7.2, J(6′-3′) = J(6′-4′) = 1.0 (H-6′); 7.30 td, 1 H, J(3′-4′) = 7.3, J(3′-5′) = J(3′-6′) = 1.0
(H-3′); 8.54 s, 1 H (H-8); 8.89 s, 1 H (H-2). For C17H15ClN4O2 (342.78) calculated: 59.57% C,
4.41% H, 16.34% N, 10.34% Cl; found: 59.62% C, 4.39% H, 16.09% N, 10.59% Cl.
{4-[(6-Chloro-9H-purin-9-yl)methyl]-1,4-epoxynaphthalen-1(4H)-yl}methanol (9)
To a mixture of 6 (645 mg, 2.6 mmol), PPh3 (1.4 g, 5.2 mmol) and 6-chloropurine (605 mg,
4 mmol) in dry dioxane (50 ml), a solution of DIAD (800 µl, 4 mmol) in dry dioxane
(15 ml) was added dropwise. Reaction was refluxed 6 h, volatiles were evaporated and chro-
matography on silica (hexanes/ethyl acetate 2:1) afforded crude acetylated compound,
which was without further purification dissolved in methanol and stirred with solid KHCO3
(1.3 g, 13 mmol) for 30 min. After the solvent was evaporated, chromatography of the resi-
due on silica (hexanes/ethyl acetate 1:4) afforded 9 (523 mg, 59%) as a white solid. Analyti-
cal sample was crystallized trom toluene (white needles). M.p. 180 °C. ESI MS m/z (%): 341.1
(14) [M + H], 363.0 (100) [M + Na]. 13C NMR (DMSO): 42.40 (CH2N); 58.78 (CH2OH); 90.91
(C-1′); 93.30 (C-8′); 119.10 (C-3′); 120.00 (C-6′); 124.88 (C-4′); 125.22 (C-5′); 130.49 (C-5);
143.25 (C-10′); 146.09 (C-9′); 148.26 (C-8); 149.36 (C-6); 149.46 (C-2′); 150.66 (C-7′); 151.99
(C-2); 152.39 (C-4). 1H NMR (DMSO): 4.07 dd, 1 H, Jgem = 12.5, J(CH2-OH) = 5.6 and
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1558
Dejmek et al.:
4.21 dd, 1 H, Jgem = 12.5, J(CH2-OH) = 5.8 (CH2O); 5.18 t, 1 H J(OH-CH2) = 5.7 (OH); 5.22 d,
1 H, Jgem = 15.3 and 5.42 d, 1 H, Jgem = 15.3 (CH2N); 6.93–7.00 m, 4 H (H-4′, H-5, H-9′,
H-10′); 7.26 m, 1 H (H-6′); 7.37 m, 1 H (H-3′); 8.66 s, 1 H (H-8); 8.88 s, 1 H (H-2). For
C
17H13ClN4O2 (340.76) calculated: 59.92% C, 3.85% H, 16.44% N, 10.40% Cl; found:
59.80% C, 3.90% H, 16.15% N, 10.59% Cl.
(1R*,2R*,3S*,4S*)-1-[(6-Chloro-9H-purin-9-yl)methyl]-4-(hydroxymethyl)-
1,2,3,4-tetrahydro-1,4-epoxynaphthalene-2,3-diol (10)
To a solution of 9 (210 mg, 0.6 mmol) in dioxane/water mixture (4:1, 25 ml), NMMO (50%
w/w solution in water, 1.5 ml), a 2% w/w solution of OsO4 in water (40 µl) was added and
the reaction mixture was stirred at r.t. for 48 h. Volatiles were evaporated and chromatogra-
phy on silica (ethyl acetate/ acetone/ethanol/water 20:3:1.2:0.8) and subsequent crystalliza-
tion from methanol afforded 10 (185 mg, 79%) as a white powder. M.p. >230 °C (decomp.).
ESI MS m/z (%): 373.1 (100) [M – H]. 13C NMR (DMSO): 40.98 (CH2N); 58.01 (CH2O); 71.21
(C-9); 71.90 (C-10); 89.15 (C-1); 90.91 (C-8); 119.50 (C-3); 121.28 (C-6); 127.18 (C-4); 127.70
(C-5); 130.22 (C-5′); 142.62 (C-2); 145.10 (C-7); 148.19 (C-8′); 149.18 (C-6′); 151.87 (C-2′);
152.65 (C-4′). 1H NMR (DMSO): 3.74 dd, 1 H, J(9-OH) = 6.5, J(9-10) = 5.7 (H-9); 3.84 dd, 1
H, J(10-OH) = 6.5, J(10-9) = 5.7 (H-10); 4.03 dd, 1 H, Jgem = 12.0, J(CH2Ob-OH) = 4.8
(CH2Ob); 4.19 dd, 1 H, Jgem = 12.0, J(CH2Oa-OH) = 6.5 (CH2Oa); 4.84 dd, 1 H, J(OH-CH2) =
5.8 and 4.8 (CH2O); 5.22 d, 1 H, J(OH-9) = 6.5 (9-OH); 5.24 d, 1 H, J(OH-10) = 6.6 (10-OH);
4.92 and 5.33 d, 2 H, Jgem = 15.4 (CH2N); 7.03 td, 1 H, J(4-5) = J(4-3) = 7.5, J(4-6) = 1.1
(H-4); 7.13 td, 1 H, J(5-4) = J(5-6) = 7.5, J(5-3) = 1.1 (H-5); 7.18 dm, 1 H, J(3-4) = 7.4 (H-3);
7.35 dm, 1 H, J(6-5) = 7.3 (H-6); 8.50 s, 1 H (H-8′); 8.89 s, 1 H (H-2′). For C17H15ClN4O4
(374.78) calculated: 54.48% C, 4.03% H, 14.95% N, 9.46% Cl; found: 54.42% C, 4.05% H,
15.15% N, 9.46% Cl.
(1R*,2R*,3S*,4S*)-1-[(6-Amino-9H-purin-9-yl)methyl]-4-(hydroxymethyl)-
1,2,3,4-tetrahydro-1,4-epoxynaphthalene-2,3-diol (11)
A solution of 10 (120 mg, 0.3 mmol) in liquid ammonia (20 ml) was heated in autoclave at
90 °C overnight. Ammonia was evaporated and the remaining solid was extracted with hot
water (5 × 50 ml) to afford 11 (80 mg, 75%) as a brownish powder. M.p. 166 °C. ESI MS m/z
(%): 356.1 (24) [M + H], 378.1 (100) [M + Na], 733.2 (5) [2M + Na]. 13C NMR (DMSO): 39.95
(CH2N); 58.13 (CH2O); 71.16 (C-9); 72.01 (C-10); 89.45 (C-1); 90.75 (C-8); 118.03 (C-5′);
119.52 (C-3); 121.17 (C-6); 127.09 (C-4); 127.51 (C-5); 141.39 (C-8′); 143.06 (C-2); 145.17
(C-7); 150.21 (C-4′); 152.71 (C-2′); 156.11 (C-6′). 1H NMR (DMSO): 3.74 dd, 1 H, J(9-OH) =
6.5, J(9-10) = 5.7 (H-9); 3.81 dd, 1 H, J(10-OH) = 6.5, J(10-9) = 5.7 (H-10); 4.04 dd, 1 H,
Jgem = 11.9, J(CH2Ob-OH) = 4.9 (CH2Ob); 4.20 dd, 1 H, Jgem = 11.9, J(CH2Oa-OH) = 6.2
(CH2Oa); 4.87 dd, 1 H, J(OH-CH2) = 6.2 and 5.0 (CH2O); 4.71 and 5.14 d, 2 H, Jgem = 15.4
(CH2N); 5.14 d, 1 H, J(OH-9) = 6.5 (9-OH); 5.32 d, 1 H, J(OH-10) = 6.5 (10-OH); 7.00 td, 1 H,
J(4-5) = J(4-3) = 7.5, J(4-6) = 1.1 (H-4); 7.09 dm, 1 H, J(3-4) = 7.4 (H-3); 7.11 td, 1 H, J(5-4) =
J(5-6) = 7.4, J(5-3) = 1.1 (H-5); 7.18 bs, 2 H (NH2); 7.35 dm, 1 H, J(6-5) = 7.3 (H-6); 7.94 s,
1 H (H-8′); 8.25 s, 1 H (H-2′). For C17H17N5O4·1/2H2O (364.36) calculated: 56.04% C, 4.98% H,
19.22% N; found: 55.83% C, 5.03% H, 18.89% N.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1549–1566

Conformationally Locked Nucleosides
1559
9,9′-[(1R*,4S*)-1,4-Epoxynaphthalene-1,4-diyldimethanediyl]bis(6-chloro-9H-purine) (12)
To a solution of 6 (250 mg, 1 mmol) in methanol (20 ml), potassium carbonate (300 mg,
2.2 mmol) was added and this suspension was stirred at r.t. for 15 min. The reaction mix-
ture was diluted with water (50 ml), extracted with ethyl acetate (3 × 50 ml), combined
organic extracts were dried over sodium sulfate and evaporated. To a solution of thus pre-
pared diol, PPh3 (1.05 g, 4 mmol) and 6-chloropurine (462 mg, 3 mmol) in dry THF (30 ml),
a solution of DIAD (600 µl, 3 mmol) in dry THF (5 ml) was added dropwise. Reaction
was stirred at r.t. overnight, volatiles were evaporated and chromatography on silica (ethyl
acetate/hexanes/acetone 14:7:4) and subsequent crystallization from toluene afforded 12
(270 mg, 57%) as white crystals. M.p. 241 °C. ESI MS m/z (%): 477.1 (17) [M + H], 499.1
(100) [M + Na]. 13C NMR (CDCl3): 42.10 (CH2N); 91.69 (C-1′, C-8′); 119.45 (C-3′, C-6′);
126.09 (C-4′, C-5′); 131.10 (C-5); 144.41 (C-9′, C-10′); 145.91 (C-8); 147.40 (C-2′, C-7′);
151.39 (C-6); 151.95 (C-4); 152.14 (C-2). 1H NMR (CDCl3): 5.16 d, 2 H, Jgem = 15.4 and
5.26 d, 2 H, Jgem = 15.2 (CH2N); 6.84 s, 2 H (H-9′, H-10′); 6.97 m, 2 H (H-4′, H-5′); 7.23 m,
2 H (H-3′, H-6′); 8.28 s, 2 H (H-8); 8.83 s, 2 H (H-2). For C22H14Cl2N8O·C6H12 (561.47) calcu-
lated: 59.90% C, 4.67% H, 19.96% N, 12.63% Cl; found: 59.72% C, 4.51% H, 19.85% N,
12.35% Cl.
(1R*,2R*,3S*,4S*)-1,4-Bis[(6-chloro-9H-purin-9-yl)methyl]-
1,2,3,4-tetrahydro-1,4-epoxynaphthalene-2,3-diol (13)
To a solution of 12 (150 mg, 0.3 mmol) in dioxane/water mixture (4:1, 20 ml), NMMO
(50% w/w solution in water, 0.7 ml), a 2% w/w solution of OsO4 in water (30 µl) was added
and the reaction mixture was stirred at r.t. for 48 h. Product, which gradually precipitated
from the reaction mixture, was filtered off and crystalized from DMF/methanol mixture af-
fording 13 (95 mg, 59%) as a grayish powder. M.p. >300 °C (decomp.). ESI MS m/z (%):
511.1 (12) [M + H], 533.1 (100) [M + Na]. 13C NMR (DMSO): 40.85 (CH2N); 72.18 (C-9,
C-10); 89.91 (C-1, C-8); 120.21 (C-4, C-5); 128.03 (C-3, C-6); 130.16 (C-5′); 142.18 (C-2,
C-7); 148.11 (C-8′); 149.23 (C-6′); 151.82 (C-2′); 152.50 (C-4′). 1H NMR (DMSO): 3.92 m, 2 H
(H-9, H-10); 4.98 d, 2 H, Jgem = 15.5 and 5.36 d, 2 H, Jgem = 15.5 (CH2N); 5.55 m, 2 H (OH);
6.99 m, 2 H (H-3, H-6); 7.27 m, 2 H (H-4, H-5); 8.53 s, 2 H (H-8′); 8.86 s, 2 H (H-2′). For
C
22H16Cl2N8O3 (511.32) calculated: 51.68% C, 3.15% H, 21.91% N, 13.87% Cl; found:
51.57% C, 3.13% H, 21.49% N, 14.19% Cl.
1,4-Epoxynaphtalen-1(4H)-ylmethyl Benzoate (15)
To a solution of anthranilic (1.82 g, 13.3 mmol) and trichloroacetic acids (16 mg, 0.1 mmol)
in dry dioxane (30 ml) at 0 °C, isoamyl nitrite (1.82 g, 13.3 mmol) was added dropwise. This
mixture was stirred at r.t. for 90 min, diazonium salt was filtered off and washed with
dioxane (2 × 5 ml, the salt was never allowed to dry entirely) and added to a solution of
furfuryl benzoate (2 g, 10.6 mmol) in dry dioxane (30 ml). Reaction mixture was heated to
60 °C for 1 h (evolution of N2 and CO2). Chromatography of the residue in toluene afforded
product 15 (2.5 g, 90%) as a white solid. NMR spectrum was in agreement with the work of
Chen and Chow9.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1549–1566

1560
Dejmek et al.:
[(1R*,3S*,4R*)-3-Hydroxy-3,4-dihydro-1,4-epoxynaphthalen-1(2H)-yl]methyl Benzoate (16)
To 15 (2.57 g, 9.2 mmol) at 0 °C under Ar atmosphere, borane–THF complex (1 M solution,
5.5 ml) was added dropwise and the resulting solution was stirred at this temperature for 3
h. Excess borane was decomposed by careful addition of water and then NaBO3·4H2O (4.3 g,
27.7 mmol) in water (15 ml) was added and this suspension was stirred at r.t. overnight. Re-
action mixture was then diluted with water (50 ml) and extracted with Et2O (3 × 50 ml).
Chromatography (hexane/ethyl acetate 1:1) yielded product 16 (1 g, 37%) as a colorless oil,
which solidifies on standing. M.p. 107 °C. ESI MS m/z (%): 295.2 (36) [M – H]. 13C NMR
(DMSO): 40.02 (C-10); 62.69 (CH2O); 72.87 (C-9); 85.55 (C-8); 86.59 (C-1); 118.67 (C-3);
120.61 (C-6); 126.89 and 127.09 (C-5, C-4); 129.07 (C-3′); 129.43 (C-2′); 129.60 (C-1′);
133.77 (C-4′); 143.66 (C-7); 145.90 (C-2); 165.69 (COO). 1H NMR (DMSO): 1.67 dd, 1 H,
Jgem = 12.0, J(10ex-9) = 2.3 (H-10exo); 1.88 dd, 1 H, Jgem = 12.0, J(10en-9) = 6.6 (H-10endo);
3.90 ddd, 1 H, J(9-10en) = 6.6, J(9-OH) = 5.0, J(9-10ex) = 2.3 (H-9); 5.00 d and 5.05 d, 2 H,
Jgem = 12.5 (CH2O); 5.09 s, 1 H (H-8); 5.28 d, 1 H, J(OH-9) = 5.0 (OH); 7.16–7.22 m, 2 H
(H-4, H-5); 7.28 m, 1 H (H-3); 7.36 m, 1 H (H-6); 7.52 m, 2 H (H-3′); 7.66 m, 1 H (H-4′);
7.93 m, 2 H (H-2′). For C18H16O4 (296.32) calculated: 72.96% C, 5.44% H; found: 72.82% C,
5.53% H.
(1R*,2S*,4R*)-4-[(6-Chloro-9H-purin-9-yl)methyl]-
1,2,3,4-tetrahydro-1,4-epoxynaphthalen-2-ol (18)
To a solution of 16 (200 mg, 0.7 mmol) in absolute methanol (15 ml), sodium methoxide
(75 mg, 1.4 mmol) was added and the reaction mixture was stirred at r.t. for 3 h. Volatiles
were evaporated and column chromatography of the residue (toluene/ethyl acetate 1:2) af-
forded 17 as a white solid. To a mixture of the intermediate 17 (102 mg, 0.5 mmol), PPh3
(262 mg, 1 mmol) and 6-chloropurine (116 mg, 0.75 mmol) in dry THF (10 ml) and a solu-
tion of DIAD (150 mg, 0.75 mmol) in dry THF (5 ml) were added dropwise. Reaction
mixture was stirred at r.t. overnight, volatiles were evaporated and chromatography on silica
(toluene/ethyl acetate 1:4) and subsequent crystallization from toluene afforded product 18
(136 mg, 79% ) as white crystals. M.p. 191 °C. ESI MS m/z (%): 311.1 (79) [M + H], 333.0
(100) [M + Na]. 13C NMR (DMSO): 40.50 (C-10′); 43.45 (CH2N); 73.20 (C-9′); 85.46 (C-8′);
87.06 (C-1′); 118.46 (C-3′); 120.66 (C-6′); 127.11 and 127.14 (C-4′, C-5′); 130.38 (C-5);
143.63 (C-7′); 145.15 (C-2′); 148.45 (C-8); 149.32 (C-6); 151.97 (C-2); 152.56 (H-4). 1H NMR
(DMSO): 1.39 dd, 1 H, Jgem = 12.1, J(10′a-9′) = 2.3 (H-10′a); 1.92 dd, 1 H, Jgem = 12.2,
J(10′b-9′) = 6.7 (H-10′b); 3.86 ddd, 1 H, J(9′-10′b) = 6.7, J(9′-OH) = 4.2, J(9′-10′a) = 2.3 (H-9′);
5.09 s, 1 H (H-8′); 5.21 bd, 1 H, J(OH-9′) = 4.5 (OH); 5.15 d and 5.24 d, 2 H, Jgem = 15.3
(CH2N); 7.09–7.14 m, 2 H (H-4′, H-5′); 7.30–7.34 m, 2 H (H-3′, H-6′); 8.61 s, 1 H (H-8);
8.88 s, 1 H (H-2). For C16H13ClN4O2 (328.75) calculated: 58.45% C, 3.99% H, 17.04% N,
10.78% Cl; found: 58.05% C, 3.99% H, 17.14% N, 11.04% Cl.
1,4-Epoxynaphtalen-1(4H)-ylmethanol (19)
To a solution of 15 (300 mg, 1.1 mmol) in absolute methanol (20 ml), sodium methoxide
(120 mg, 2.2 mmol) was added and the reaction mixture was stirred at r.t. for 3 h. Volatiles
were evaporated and column chromatography of the residue (hexanes/ethyl acetate 4:1) af-
forded product 19 (173 mg, 91%) as a white solid. NMR spectrum corresponded with ref.10
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1549–1566

Conformationally Locked Nucleosides
1561
6-Chloro-9-(1,4-epoxynaphtalen-1(4H)-ylmethyl)-9H-purine (20)
To a mixture of 19 (200 mg, 1.15 mmol), PPh3 (600 mg, 2.3 mmol) and 6-chloropurine
(260 mg, 1.7 mmol) in dry THF (15 ml), a solution of DIAD (340 mg, 1.7 mmol) in dry THF
(7 ml) was added dropwise. Reaction mixture was stirred at r.t. overnight, volatiles were
evaporated and chromatography on silica (toluene/ethyl acetate 3:1) and subsequent crystal-
lization from water/methanol mixture afforded product 20 (257 mg, 72% ) as white crystals.
M.p. 137 °C. ESI MS m/z (%): 311.1 (79) [M + H], 333.0 (100) [M + Na]. 13C NMR (CDCl3):
42.30 (CH2N); 82.87 (C-8′); 91.35 (C-1′); 118.98 (C-3′); 120.51 (C-6′); 125.27 (C-5′); 125.65
(C-4′); 131.01 (C-5); 141.19 (C-10′); 146.13 (C-9′); 146.54 (C-8); 146.62 (C-2′); 149.87 (C-7′);
151.06 (C-6); 151.98 (C-2); 152.01 (C-4). 1H NMR (CDCl3): 5.13 and 5.31 d, 1 H, Jgem = 15.2
(CH2N); 5.75 d, 1 H, J(8′-9′) = 1.9 (H-8′); 6.75 d, 1 H, J(10′-9′) = 5.5 (H-10′); 6.93–7.00 m, 2 H
(H-4′, H-5′); 7.05 dd, 1 H, J(9′-10′) = 5.5, J(9′-8′) = 1.9 (H-9′); 7.20 m, 1 H (H-3′); 7.25 m, 1 H
(H-6′); 8.36 s, 1 H (H-8); 8.83 s, 1 H (H-2). For C16H11ClN4O (310.74) calculated: 61.84% C,
3.57% H, 18.03% N, 11.41% Cl; found: 61.69% C, 3.60% H, 17.79% N, 11.77% Cl.
3,4-Dihydro-1,4-epoxynaphtalen-1(4H)-ylmethanol (21)
To a solution of 1 (1 g, 3.6 mmol) in dry methanol (40 ml), Pd(OH)2/C (50 mg) was added
and the mixture was hydrogenated (10 atm) overnight. Catalyst was filtered off on a cellite
pad, sodium methoxide (390 mg, 7.1 mmol) dry methanol (40 ml) was added and the reac-
tion mixture was stirred at r.t. for 2 h. Volatiles were evaporated and column chromatogra-
phy of the residue (hexanes/ethyl acetate 4:1) afforded product 21 (551 mg, 87%) as a white
solid). NMR spectrum corresponded with ref.11
6-Chloro-9-(3,4-dihydro-1,4-epoxynaphtalen-1(4H)-ylmethyl)-9H-purine (22)
To a mixture of 21 (200 mg, 1.14 mmol), PPh3 (600 mg, 2.3 mmol) and 6-chloropurine
(260 mg, 1.7 mmol) in dry THF (15 ml), a solution of DIAD (340 mg, 1.7 mmol) in dry THF
(7 ml) was added dropwise. Reaction mixture was stirred at r.t. overnight, volatiles were
evaporated and chromatography on silica (toluene/ethyl acetate 3:1) and subsequent crystal-
lization from water/methanol mixture afforded product 22 (270 mg, 76% ) as white crystals.
M.p. 140 °C. ESI MS m/z (%): 313.1 (27) [M + H], 335.1 (100) [M + Na]. 13C NMR (CDCl3):
28.99 (C-9′); 29.30 (C-10′); 43.74 (CH2N); 78.87 (C-8′); 87.24 (C-1′); 117.55 (C-3′); 119.07
(C-6′); 126.79 (C-4′); 127.29 (C-5′); 130.84 (C-5); 142.75 (C-2′); 145.94 (C-7′); 146.73 (C-8);
150.93 (C-6); 151.92 (C-2); 152.16 (C-4). 1H NMR (CDCl3): 1.47–1.56 m, 2 H (H-9′endo,
H-10′endo); 1.77 m, 1 H (H-10′exo); 2.21 m, 1 H (H-9′exo); 4.92 and 5.32 d, 1 H, Jgem = 15.1
(CH2N); 5.45 d, 1 H, J(8′-9′ex) = 5.0 (H-8′); 7.05 m, 1 H (H-4′); 7.11–7.16 m, 2 H (H-3′, H-5′);
7.22 m, 1 H (H-6′); 8.34 s, 1 H (H-8); 8.84 s, 1 H (H-2). For C16H13ClN4O·1/3H2O (318.76)
calculated: 60.29% C, 4.32% H, 17.58% N, 11.12% Cl; found: 60.17% C, 4.33% H, 17.19% N,
11.45% Cl.
6-Chloro-9-[(1aR*,2R*,7R*,7aR*)-7,7a-dihydro-2,7-epoxynaphtho[2,3-b]oxiren-
2(1aH)-ylmethyl]-9H-purine (23)
To a solution of 20 (310 mg, 1 mmol) in DCM (45 ml), mCPBA (65%, 400 mg, 1.5 mmol)
was added and the reaction mixture was stirred at r.t. overnight. Volatiles were evaporated
and chromatography on silica (toluene/ethyl acetate 3:1) and subsequent crystallization
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1549–1566

1562
Dejmek et al.:
from water/methanol mixture afforded 23 (210 mg, 64%) as white crystals. M.p. >160 °C
(decomp.). ESI MS m/z (%): 327.0 (34) [M + H], 349.9 (100) [M + Na]. 13C NMR (CDCl3):
41.36 (CH2N); 54.83 (C-10′); 55.74 (C-9′); 77.14 (C-8′); 86.03 (C-1′); 120.06 (C-3′); 121.47
(C-6′); 127.37 (C-4′); 127.81 (C-5′); 131.05 (C-5); 143.14 (C-2′); 145.54 (C-7′); 146.56 (C-8);
151.13 (C-6); 151.94 (C-2); 152.03 (H-4). 1H NMR (CDCl3): 3.50 d, 1 H, J(10′-9′) = 3.6
(H-10′); 3.57 d, 1 H, J(9′-10′) = 3.6 (H-9′); 5.11 d and 5.21 d, 2 H, Jgem = 15.3 (CH2N); 5.27 s,
1 H (H-8′); 7.12 m, 1 H (H-4′); 7.18 m, 1 H (H-5′); 7.32–7.34 m, 2 H (H-3′, H-6′); 8.36 s, 1 H
(H-8); 8.83 s, 1 H (H-2). For C16H11ClN4O2 (326.74) calculated: 58.82% C, 3.39% H,
17.15% N, 10.85% Cl; found: 58.89% C, 3.39% H, 16.79% N, 10.67% Cl.
(1R*,2R*,3S*,4R*)-1-[(6-Chloro-9H-purin-9-yl)methyl]-
1,2,3,4-tetrahydro-1,4-epoxynaphthalene-2,3-diol (24)
To a solution of 20 (800 mg, 2.6 mmol) in acetone/water mixture (1:1, 45 ml), NMMO
(50% w/w solution in water, 6 ml), a 2% w/w solution of OsO4 in water (150 µl) was added
and the reaction mixture was stirred at r.t. for 48 h. Product, which gradually precipitated
from the reaction mixture, was filtered off and crystalized from DMF/methanol mixture af-
fording 24 (555 mg, 62%) as a white powder. M.p. >250 °C (decomp.). ESI MS m/z (%):
153.0 (100) [(M + 3K)3+/3], 345.1 (11) [M + H], 689.3 (36) [2 M + H]. 13C NMR (DMSO):
41.00 (CH2N); 70.81 (C-10); 71.03 (C-9); 84.09 (C-8); 90.02 (C-1); 120.13 (C-3); 120.82 (C-6);
127.41 (C-4); 127.88 (C-5); 130.27 (C-5′); 141.84 (C-2); 143.64 (C-7); 148.14 (C-8′); 149.21
(C-6′); 151.87 (C-2′); 152.64 (H-4′). 1H NMR (DMSO): 3.77–3.81 m, 2 H (H-9, H-10); 5.10 d,
1 H, J(OH-10) = 6.4 (10-OH); 5.11 s, 1 H (H-8); 5.00 d and 5.35 d, 2 H, Jgem = 15.4 (CH2N);
5.49 d, 1 H, J(OH-10) = 5.5 (9-OH); 7.06 m, 1 H (H-4); 7.12 m, 1 H (H-5); 7.28 m, 1 H (H-6);
7.34 m, 1 H (H-3); 8.50 s, 1 H (H-8′); 8.87 s, 1 H (H-2′). For C16H13ClN4O3 (344.75) calcu-
lated: 55.74% C, 3.80% H, 16.25% N, 10.28% Cl; found: 55.62% C, 3.86% H, 16.06% N,
10.19% Cl.
(1R*,2R*,3S*,4R*)-1-[(6-amino-9H-purin-9-yl)methyl]-
1,2,3,4-tetrahydro-1,4-epoxynaphthalene-2,3-diol (25)
A solution of 24 (170 mg, 0.5 mmol) in liquid ammonia (20 ml) was heated in autoclave at
90 °C overnight. Ammonia was evaporated and the remaining solid was extracted on a filter
with methanol (100 ml) and crystalized from water/methanol mixture to afford 25 (102 mg,
63%) as a brownish powder. M.p. >270 °C (decomp.). ESI MS m/z (%): 326.1 (100) [M + H],
348.1 (83) [M + Na], 673.2 (32) [2 M + Na]. 13C NMR (DMSO): 39.93 (CH2N); 70.96 and
71.01 (C-9 and C-10); 84.11 (C-8); 90.32 (C-1); 118.07 (C-5′); 120.05 (C-3); 120.69 (C-6);
127.30 (C-4); 127.68 (C-5); 141.39 (C-8′); 142.22 (C-2); 143.65 (C-7); 150.21 (C-4′); 152.72
(C-2′); 156.11 (C-6′). 1H NMR (DMSO): 3.76–3.79 m, 2 H (H-9, H-10); 4.77 and 5.17 d, 2 H,
Jgem = 15.4 (CH2N); 5.12 s, 1 H (H-8); 5.17 m, 1 H (10-OH); 5.40 m, 1 H (9-OH); 7.02 td,
1 H, J(4-5) = J(4-3) = 7.5, J(4-6) = 1.1 (H-4); 7.10 td, 1 H, J(5-4) = J(5-6) = 7.4, J(5-3) = 1.0
(H-5); 7.18 bs, 2 H (NH2); 7.21 dm, 1 H, J(3-4) = 7.4 (H-3); 7.28 dm, 1 H, J(6-5) = 7.3 (H-6);
7.92 s, 1 H (H-8′); 8.24 s, 1 H (H-2′). For C16H15N5O3 (325.32) calculated: 59.07% C,
4.65% H, 21.53% N; found: 58.70% C, 4.67% H, 21.30% N.
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Conformationally Locked Nucleosides
1563
1,4-Epoxyanthracen-1(4H)-ylmethyl Benzoate (27)
To a refluxing solution of furfuryl benzoate (2.5 g, 13.3 mmol) in dioxane (15 ml), solutions
of 3-amino-2-naphthoic acid (80%, 2.5 g, 10.7 mmol) in dioxane (20 ml) and isoamylnitrite
(2.5 g, 21 mmol) in dioxane (10 ml) were simultaneously, but from separate syringes, added.
Reaction mixture was further refluxed for another 90 min, after which volatiles were evapo-
rated and the chromatography on silica (hexanes/ethyl acetate 10:1) afforded 27 as a white
solid. Crystallization from benzene/hexane mixture yielded pure product (1.1 g, 31%) in the
form of white crystals. M.p. 159 °C. ESI MS m/z (%): 351.3 (100) [M + Na]. 13C NMR
(CDCl3): 61.86 (CH2O); 81.84 (C-12); 90.50 (C-1); 188.05 (C-3); 118.71 (C-10); 126.29 and
126.41 (C-6, C-7); 128.07 and 128.26 (C-5 and C-8); 128.43 (C-3′); 129.55 (C-1′); 129.86
(C-2′); 131.68 and 131.80 (C-4 and C-9); 133.26 (C-4′); 140.88 (C-14); 143.34 (C-2); 143.43
(C-13); 144.98 (C-11); 166.47 (COO). 1H NMR (CDCl3): 5.13 dd, 1 H, Jgem = 12.7,
J(CH2a-13) = 0.7; 5.36 d, 1 H, Jgem = 12.7 (CH2O); 5.86 d, 1 H, J(12-13) = 2.0 (H-12); 6.90 d,
1 H, J(14-13) = 5.6 (H-14); 7.09 ddd, 1 H, J(13-14) = 5.6, J(13-12) = 1.9, J(13-CH2a) = 0.6
(H-13); 7.42–7.46 m, 4 H (H-3′, H-6, H-7); 7.57 m, 1 H (H-4′); 7.59 s, 1 H (H-3); 7.60 s, 1 H
(H-10); 7.71–7.74 m, 2 H (H-5, H-8); 8.10 s, 1 H (H-2′). For C22H16O3 (328.26) calculated:
80.47% C, 4.91% H; found: 80.46% C, 4.83% H.
3,4-Dihydro-1,4-epoxyanthracen-1(2H)-ylmethanol (28)
To a solution of 27 (350 mg, 1.06 mmol) in methanol/dioxane mixture (20 ml, 1:1),
Pd(OH)2/C (50 mg) was added and the reaction mixture was subjected to hydrogenation
(10 atm) overnight. Catalyst was filtered off on a cellite pad and sodim methoxide (108 mg,
2.2 mmol) was added to the solution. After stirring at r.t. for 1 h, volatiles were evaporated
and chromatography on silica (hexanes/ethyl acetate 1:4) and subsequent crystallization
from toluene/cyclohexane mixture afforded product 28 (202 mg, 84%) as white crystals.
M.p. 136 °C. ESI MS m/z (%): 249.1 (100) [M + Na]. 13C NMR (DMSO): 28.49 (C-14); 29.16
(C-13); 60.71 (CH2O); 77.61 (C-12); 88.63 (C-1); 116.49 and 116.62 (C-3 and C-10); 125.70
and 125.71 (C-6 and C-7); 128.16 and 128.25 (C-5, C-8); 132.41 and 132.42 (C-4 and C-9);
144.69 (C-2); 145.26 (C-11). 1H NMR (DMSO): 1.36 ddd, 1 H, Jgem = 11.4, J(14en-13en) =
8.9, J(14en-13ex) = 4.0 (H-14endo); 1.46 ddd, 1 H, Jgem = 11.5, J(13en-14en) = 9.0,
J(13en-14ex) = 4.0 (H-13endo); 1.99 td, 1 H, Jgem = J(14ex-13ex) = 11.2, J(14ex-13en) = 4.0
(H-14exo); 2.13 tdd, 1 H, Jgem = J(13ex-14ex) = 11.2, J(13ex-12) = 5.3, J(13ex-14en) = 4.1
(H-13exo); 4.15 dd, 1 H, Jgem = 12.2, J(CH2-OH) = 5.8 and 4.21 dd, 1 H, Jgem = 12.2,
J(CH2-OH) = 5.8 (CH2); 5.13 t, 1 H, J(OH-CH2) = 5.8 (OH); 5.48 d, 1 H, J(12-13ex) = 5.2
(H-12); 7.45–7.47 m, 2 H (H-6, H-7); 7.699 s, 1 H and 7.703 s, 1 H (H-3 and H-10);
7.85–7.88 m, 2 H (H-5, H-8). For C15H14O2 (226.27) calculated: 79.62% C, 6.24% H; found:
79.28% C, 6.24% H.
6-Chloro-9-(3,4-dihydro-1,4-epoxyanthracen-1(2H)-ylmethyl)-9H-purine (29)
To a mixture of 28 (152 mg, 0.67 mmol), PPh3 (350 mg, 1.4 mmol) and 6-chloropurine
(154 mg, 1 mmol) in dry dioxane (15 ml), a solution of DIAD (202 mg, 1 mmol) in dry
dioxane (5 ml) was added dropwise. Reaction mixture was stirred at r.t. overnight, volatiles
were evaporated and chromatography on silica (toluene/ethyl acetate 4:1) and subsequent
crystallization from methanol afforded product 29 (184 mg, 76% ) as white crystals. M.p.
>200 °C (decomp.). ESI MS m/z (%): 363.0 (100) [M + H], 385.0 (52) [M + Na]. 13C NMR
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1549–1566

1564
Dejmek et al.:
(DMSO): 29.37 (C-13′); 29.70 (C-14′); 43.64 (CH2N); 77.96 (C-12′); 86.99 (C-1′); 116.51
(C-3′); 117.02 (C-10′); 125.92 and 126.08 (C-6′ and C-7′); 128.12 and 128.20 (C-5′, C-8′);
130.30 (C-5); 132.10 and 132.47 (C-4′ and C-9′); 142.29 (C-2′); 144.32 (C-11′); 148 24 (C-8);
149.26 (C-6); 151.84 (C-2); 152.51 (C-4). 1H NMR (DMSO): 1.47 ddd, 1 H, Jgem = 11.7,
J(13′en-14′en)
J(14′en-13′en)
=
=
8.9, J(13′en-14′ex)
8.8, J(14′en-13′ex)
=
=
4.1 (H-13′endo); 1.58 ddd,
4.1 (H-14′endo); 1.80 ddd,
1
1
H, Jgem
H, Jgem
=
=
11.7,
11.7,
J(14′ex-13′ex) = 11.0, J(14′ex-13′en) = 4.1 (H-14′exo); 2.14 dddd, 1 H, Jgem = 11.7,
J(13′ex-14′ex) = 11.0, J(13′ex-12′) = 5.3, J(13′ex-14′en) = 4.0 (H-13′exo); 5.25 d, 1 H and
5.39 d, 1 H Jgem = 15.3 (CH2N); 5.58 d, 1 H, J(12′-13′ex) = 5.1 (H-12′); 7.45–7.49 m, 2 H
(H-6′, H-7′); 7.71 s, 1 H (H-10′); 7.81 m, 1 H (H-5′); 7.85 m, 1 H (H-8′); 7.89 s, 1 H (H-3′);
8.61 s, 1 H (H-8); 8.91 s, 1 H (H-2). For C20H15ClN4O (362.81) calculated: 66.21% C,
4.17% H, 15.44% N, 9.77% Cl; found: 66.16% C, 4.26% H, 15.03% N, 9.47% Cl.
1,4-Epoxyanthracen-1(4H)-ylmethanol (30)
To a solution of 27 (150 mg, 0.46 mmol) in absolute methanol (15 ml), sodium methoxide
(54 mg, 1 mmol) was added and the reaction mixture was stirred at r.t. for 1 h. Volatiles
were evaporated and column chromatography of the residue (hexanes/ethyl acetate 1:2) af-
forded product 30 (95 mg, 92%) as a white solid. Crystallization of analytical sample was ac-
complished from toluene/cyclohexane mixture. NMR spectrum was in agreement with the
work of Chen and Chow9.
6-Chloro-9-(1,4-epoxyanthracen-1(4H)-ylmethyl)-9H-purine (31)
To a mixture of 30 (375 mg, 1.7 mmol), PPh3 (880 mg, 3.3 mmol) and 6-chloropurine
(386 mg, 2.5 mmol) in dry dioxane (35 ml), a solution of DIAD (500 mg, 2.5 mmol) in dry
dioxane (10 ml) was added dropwise. Reaction mixture was stirred at r.t. overnight, volatiles
were evaporated and chromatography on silica (toluene/ethyl acetate 4:1) and subsequent
crystallization from methanol afforded product 31 (405 mg, 66%) as white crystals. M.p.
232.5 °C. ESI MS m/z (%): 361.6 (59) [M + H], 383.6 (100) [M + Na]. 13C NMR (DMSO):
42.41 (CH2N); 81.08 (C-12′); 90.90 (C-1′); 117.98 (C-3′); 118.64 (C-10′); 126.54 and 126.65
(C-6′ and C-7′); 128.21 and 128.29 (C-5′ and C-8′); 130.56 (C-5); 131.28 and 131.47 (C-4′
and C-9′); 140.84 (C-14′); 143.61 (C-2′); 144.77 (C-13′); 145.62 (C-11′); 148.23 (C-8); 149.38
(C-6); 152.01 (C-2); 152.47 (C-4). 1H NMR (DMSO): 5.61 dd, 1 H, Jgem = 15.3, J(CH2b-13′) =
0.9 (CH2b); 5.55 d, 1 H, Jgem = 15.3 (CH2a); 5.89 d, 1 H, J(12′-13′) = 2.0 (H-12′); 6.95 d, 1 H,
J(14′-13′) = 5.5 (H-14′); 7.04 ddd, 1 H, J(13′-14′) = 5.5, J(13′-12′) = 2.0, J(13′-CH2b) = 0.8
(H-13′); 7.46–7.49 m, 2 H (H-6′, H-7′); 7.67 s, 1 H (H-10′); 7.76–7.80 m, 2 H (H-5′, H-8′);
7.87 s, 1 H (H-3′); 8.73 s, 1 H (H-8); 8.89 s, 1 H (H-2). For C20H13ClN4O (360.80) calculated:
66.58% C, 3.63% H, 15.53% N, 9.83% Cl; found: 66.45% C, 3.58% H, 14.99% N, 9.50% Cl.
(1R*,2R*,3S*,4R*)-1-[(6-Chloro-9H-purin-9-yl)methyl]-
1,2,3,4-tetrahydro-1,4-epoxyanthracene-2,3-diol (32)
To a solution of 29 (250 mg, 0.7 mmol) in dioxane/water mixture (4:1, 25 ml), NMMO
(50% w/w solution in water, 1.5 ml), a 2% w/w solution of OsO4 in water (40 µl) was added
and the reaction mixture was stirred at r.t. overnight. Volatiles were evaporated and chro-
matography on silica (toluene/ ethyl acetate 1:4) and subsequent crystallization from metha-
nol afforded 30 (225 mg, 81%) as a white powder. M.p. >230 °C (decomp.). ESI MS m/z (%):
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1549–1566

Conformationally Locked Nucleosides
1565
393.1 (30) [M – H], 787.2 (100) [2 M – H]. 13C NMR (DMSO): 41.13 (CH2N); 71.78 (C-14′);
72.00 (C-13′); 84.11 (C-12′); 89.95 (C-1′); 119.02 and 119.04 (C-3′ and C-10′); 126.41 and
126.59 (C-6′ and C-7′); 128.25 and 128.37 (C-5′ and C-8′); 130.28 (C-5); 132.38 (C-4′);
132.77 (C-9′); 139.64 (C-2′); 140.91 (C-11′); 148.25 (C-8); 149.21 (C-6); 151.84 (C-2); 152.71
(C-4). 1H NMR (DMSO): 3.90–3.95 m, 2 H (H-13′, H-14′); 5.19 d, 1 H, J(OH-14′) = 6.6
(14′-OH); 5.25 s, 1 H (H-12′); 5.11 and 5.45 d, 2 H, Jgem = 15.5 (CH2N); 5.57 d, 1 H,
J(OH-13′) = 5.6 (13′-OH); 7.43–7.47 m, 2 H (H-6′, H-7′); 7.72–7.74 m, 2 H (H-8′, H-10′); 7.82
m, 1 H (H-5′); 7.88 bs 1 H (H-3′); 8.57 s, 1 H (H-8); 8.92 s, 1 H (H-2). For C20H15ClN4O3
(394.81) calculated: 60.84% C, 3.83% H, 14.19% N, 8.98% Cl; found: 60.48% C, 3.76% H,
13.99% N, 9.09% Cl.
(1R*,2R*,3S*,4R*)-1-[(6-Amino-9H-purin-9-yl)methyl]-
1,2,3,4-tetrahydro-1,4-epoxyanthracene-2,3-diol (33)
A solution of 32 (150 mg, 0.4 mmol) in liquid ammonia (20 ml) was heated in an autoclave
at 90 °C overnight. Ammonia was evaporated and the remaining solid was extracted with
hot water (5 × 50 ml) to afford 33 (110 mg, 73%) as a brownish powder. M.p. >300°C
(decomp.). ESI MS m/z (%): 376.2 (41) [M + H], 398.2 (100) [M + Na]. 13C NMR (DMSO):
40.04 (CH2N); 71.89 and 71.99 (C-13′ and C-14′); 81.12 (C-12′); 90.28 (C-1′); 118.09 (C-5);
118.85 and 118.95 (C-3′ and C-10′); 126.32 and 126.44 (C-6′ and C-7′); 128.23 (C-5′ and
C-8′); 132.37 (C-4′); 132.71 (C-9′); 139.95 (C-2′); 141.03 (C-11′); 141.39 (C-8); 150.28 (C-4);
152.65 (C-2); 156.08 (C-6). 1H NMR (DMSO): 3.89–3.92 m, 2 H (H-13′, H-14′); 5.25 m, 1 H
(14′-OH); 5.26 s, 1 H (H-12′); 4.87 and 5.27 d, 2 H, Jgem = 15.5 (CH2N); 5.49 m, 1 H
(13′-OH); 7.14 bs, 2 H (NH2); 7.40–7.44 m, 2 H (H-6′, H-7′); 7.63 m, 1 H (H-8′); 7.74 s, 1 H
(H-10′); 7.78 s, 1 H (H-3′); 7.82 m, 1 H (H-5′); 7.96 s, 1 H (H-8); 8.31 s, 1 H (H-2). For
C
20H17N5O3·1/2H2O (384.39) calculated: 62.49% C, 4.72% H, 18.22% N; found: 62.62% C,
4.77% H, 17.72% N.
The authors are indebted to Ms J. Sklenářová for excellent technical assistance and to the staff of
the Analytical Laboratory of the Institute for elemental analyses. This work, a part of the research
project Z4 055 0506, was supported by “Centre for New Antivirals and Antineoplastics” (Ministry of
Education, Youth and Sports of the Czech Republic, 1M0508) and by Gilead Sciences, Inc. (Foster
City, CA, U.S.A.).
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Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 12, pp. 1549–1566

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