Synthesis of novel carbocyclic nucleoside analogues derived from 7-oxabicyclo[2.2.1]heptane-2-methanol

Article abstract of DOI:10.1135/cccc2008204

Hydroboration of [(lR*,2R*,4R*)-7-oxabicyclo[2.2.1]hept- 5-en-2-yl]methyl benzoate (5), which was prepared by Diels-Alder reaction of furan with acrolein and subsequent reduction and benzoylation of the Diels-Alder product, afforded [(lR*,2S*,4S*,6S*)-6-h

Full text of DOI:10.1135/cccc2008204

Novel Carbocyclic Nucleoside Analogues
487
SYNTHESIS OF NOVEL CARBOCYCLIC NUCLEOSIDE ANALOGUES
DERIVED FROM 7-OXABICYCLO[2.2.1]HEPTANE-2-METHANOL
b1
Hubert HŘEBABECKÝa1,*, Martin DRAČÍNSKÝa2, Armando M. De PALMA
,
b2
a3
Johan NEYTS and Antonín HOLÝ
a
Centre for New Antivirals and Antineoplastics, Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic;
1
2
3
e-mail: hubert@uochb.cas.cz, dracinsky@uochb.cas.cz, holy@uochb.cas.cz
Katholieke Universiteit Leuven, Rega Institute for Medical Research,
Minderbroedersstraat 10, BE-3000, Leuven, Belgium;
b
1
2
e-mail: armando.depalma@rega.kuleuven.be, johan.neyts@rega.kuleuven.ac.be
Received Novem ber 5, 2008
Accepted Novem ber 26, 2008
Publish ed on lin e March 13, 2009
Hydroboration of [(1R*,2R*,4R*)-7-oxabicyclo[2.2.1]h ept-5-en -2-yl]m eth yl ben zoate (5),
wh ich was prepared by Diels–Alder reaction of furan with acrolein an d subsequen t reduction
an d ben zoylation of th e Diels–Alder product, afforded [(1R*,2S*,4S*,6S*)-6-h ydroxy-
7-oxabicyclo[2.2.1]h eptan -2-yl]m eth yl ben zoate (6) an d [(1R*,2R*,4R*,5S*)-5-h ydroxy-
7-oxabicyclo[2.2.1]h eptan -2-yl]m eth yl
ben zoate
(7).
Th e
key
in term ediates,
[(1R*,2S*,4S*,6R*)-6-h ydroxy-7-oxabicyclo[2.2.1]h eptan -2-yl]m eth yl ben zoate (10) an d
[(1R*,2R*,4R*,5R*)-5-h ydroxy-7-oxabicyclo[2.2.1]h eptan -2-yl]m eth yl ben zoate (11), were
prepared from 6 an d 7, respectively, by oxidation with pyridin ium dich rom ate an d subse-
quen t reduction of th e th us obtain ed keton es. Th e Mitsun obu reaction of 10 an d 11 with
6-ch loropurin e an d subsequen t reductive deprotection with diisobutylalum in ium h ydride
afforded 6-ch loropurin e derivatives, wh ich were con verted to oth er purin e an alogues.
Th ym in e an alogues were prepared by Mitsun obu reaction of 10 an d 11 with 3-ben zoyl-
5-m eth ylpyrim idin e-2,4(1H,3H)-dion e an d subsequen t m eth an olysis. Th e target com poun ds
were tested for th e activity again st Coxsackie virus.
Keyw ord s: Nucleosides; Carbocyclic n ucleosides; Purin es; Aden in e; Th ym in e; 5-Meth yl-
pyrim idin e-2,4(1H,3H)-dion e; 6-Ch loropurin e; 6-(Dim eth ylam in o)purin e; 6-(Cyclopropyl-
am in o)purin e; Mitsun obu reaction ; Coxsackie virus.
Exten sive m odification s of n aturally occurrin g n ucleosides led to discovery
of a great deal of com poun ds with rem arkable biological activity. Th e m ost
im portan t are th e effects on various severe diseases such as can cer or viral
in fection . A disadvan tage of an alogues of n atural n ucleosides is cleavage of
N-glycosidic bon d by ph osph orylases. On e of m odification s, wh ich were
exam in ed to overcom e th is difficulty, is substitution of th e furan ose rin g of
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 3, pp. 487–502
© 2009 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2008204

488
Hřebabecký, Dračínský, De Palma, Neyts, Holý:
th e sugar m oiety by h ydrocarbon rin g. Man y of such m odified an alogues –
carbocyclic n ucleosides1 – exh ibit in terestin g an tiviral activity. U.S. Food
an d Drug Adm in istration approved abacavir (Ziagen ; 1)2 for th e treatm en t
of HIV-1 in fection s an d en tecavir (Baraclude; 2)3 for th e treatm en t of
ch ron ic h epatitis B virus (HBV) in fection s (Ch art 1).
N
N
CH2
O
NH
NH
N
N
HO
HO
N
N
N
HO
NH2
NH2
2
1
CHART 1
Th e an alogues con tain g bicyclic or tricyclic skeleton were also syn th e-
sized. Jacobson an d co-workers4 described bisph osph ate of th e 2-iodo-
an d 2-ch loro-6-(m eth ylam in o)purin e an alogues con tain in g th e oxabicyclo-
[2.2.1]h eptan e m oiety wh ich are th e m ost poten t kn own an tagon ists of
th e P2Y1 receptor. Recen tly, we reported th e syn th eses of n ovel racem ic
con form ation ally-locked carbocyclic purin e n ucleoside an alogues5 derived
from bicyclo[2.2.1]h eptan e, 4-oxa- an d 4,8-dioxatricyclo[4.2.1.03,7]n on an e,
an d 4-oxatricyclo[4.3.1.03,7]decan e. Som e of th e prepared com poun ds ex-
CH3
CH3
OEt
N
N
O
O
O
N
OEt
HO
O
N
HO
CH3
CH3
O
O
O
O
O
O
N
NH
N
N
NH
HO
HO
HO
O
O
N
N
X
X
N
N
N
HO
N
N
X = Cl, NH , NMe ,
NH
Cl
2
2
N
N
Cl
O
O
N
N
Cl
N
N
Cl
N
N
CHART 2
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 3, pp. 487–502

Novel Carbocyclic Nucleoside Analogues
489
h ibit a weak activity5a,5c,5f in tests for an ti-HIV-1 an d an ti-HIV-2 in h um an
T-lym ph ocyte (CEM) cells an d an activity5g–5i,6 again st th e Coxsackie virus
(CVB3). Th e virus is a sm all cytolytic virus, belon gin g to th e gen us En tero-
virus with in th e fam ily of Picornaviridae. Th e clin ical m an ifestation s as-
sociated with en teroviruses ran ge from m ild illn esses, such as fever, rash ,
h an d-foot-m outh syn drom e, an d h erpan gin a, to serious life-th reaten in g
in fection s, such as m en in gitis, en ceph alitis, m yocarditis, pan creatitis, acute
paralysis, or n eon atal sepsis. Th ere is curren tly n o approved th erapy for
treatm en t of en teroviral in fection s7.
Th is study con cern s syn th esis an d an ti-coxsackievirus assay of n ovel
racem ic n ucleoside an alogues con tan in g 7-oxabicyclo[2.2.1]h eptan e-
2-m eth an ol. Ch art 2 describes th e target com poun ds.
Alcoh ol 3, wh ich was prepared by Diels–Alder reaction between furan
an d acrolein an d subsequen t reduction with lith ium alum in ium h ydride,
was used as th e key startin g m aterial (Sch em e 1). Th e Diels–Alder products
O
O
CHO
(i)
+
O +
HO
3
4
HO
(ii)
O
O
O
(iii)
OH
BzO
BzO
BzO
+
OH
6
5
7
(iv)
(iv)
O
O
O
O
BzO
BzO
BzO
9
8
(v)
(v)
O
O
BzO
OH
OH
11
10
(i) 1. 100 °C, pressure, 2. LiAlH4/THF, 0 °C,16.5% of 3, 8.5% of
4, both based on acrolein; (ii) benzoyl chloride/pyridine, 89%;
.
(iii) 1. BF3 THF, 0 °C, 2. NaBO3, 48% of 6, 46% of 7;
(iv) PDC/CH2Cl2, 75% of 8, 85% of 9; (v) NaBH4/MeOH/THF,
0 °C, 84% of 10, 79% of 11
SCHEME 1
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490
Hřebabecký, Dračínský, De Palma, Neyts, Holý:
were im m ediately reduced with out isolation to preven t th e back reaction
leadin g to startin g m aterials8. Exo-3 (16.5% based on acrolein ) an d endo-4
(8.5% based on acrolein ) were separated by ch rom atograph y on silica gel
an d isom er 3 was ben zoylated. Hydroboration of th e protected n orborn en e
derivative 5 with th e boran e-tetrah ydrofuran com plex afforded a m ixture
of h ydroxy derivatives 6 an d 7 wh ich were separated by ch rom atograph y
on silica gel. Th e desired 2-endo-h ydroxy derivatives 10 an d 11 were pre-
pared by oxidation of 6 an d 7 with pyridin ium dich rom ate an d subsequen t
reduction of th e th us obtain ed keton es 8 or 9 with sodium boroh ydride,
respectively.
Th e reaction of alcoh ols 10 an d 11 with 4-eth oxy-5-m eth ylpyrim idin -
2(1H)-on e was perform ed un der Mitsun obu con dition s9 an d afforded, after
treatm en t with m eth an olic sodium m eth oxide, pyrim idin yloxy derivatives
12 (85%) an d 14 (77%), respectively (Sch em e 2). Th e sam e reaction of 10
an d 11 with 3-ben zoyl-5-m eth ylpyrim idin e-2,4(1H,3H)-dion e gave, after
deprotection , th e expected th ym in e derivative 13 (59%) an d 15 (60%),
respectively.
CH3
CH3
OEt
N
O
O
O
O
N
N
NH
HO
HO
(ii)
O
(i)
12
13
O
BzO
OH
10
CH3
CH3
OEt
N
O
O
O
O
N
N
NH
HO
HO
(ii)
O
(i)
14
15
O
BzO
OH
11
(i) 1. 4-ethoxy-5-methylpyrimidin-2(1H)-one, PPh3, DIAD, THF, 2.
MeONa/MeOH, 85% of 12 based on 10, 77% of 14 based on 11;
(ii) 3-benzoyl-5-methylpyrimidine-2,4(1H,3H)-dione, PPh3, DIAD,
THF, 2. MeONa/MeOH, 59% of 13 based on 10, 60% of 15 based
on 11
SCHEME 2
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 3, pp. 487–502

Novel Carbocyclic Nucleoside Analogues
491
Th e Mitsun obu reaction of 10 an d 11 with 6-ch loro-9H-purin e afforded
6-ch loropurin e derivatives 16 (59%) an d 17 (56%), respectively, wh ich were
deprotected with diisobutylalum inium hydride in dichlorom ethane at –78 °C
(Sch em e 3). Ch loropurin e derivatives 18a an d 19a were con verted to
aden in e derivatives 18b (72%) an d 19b (80%), respectively, by am m on o-
lysis with liquid am m on ia at 75 °C. Treatm en t of 18a an d 19a with
dim eth ylam m on ium dim eth ylcarbam ate led to 6-(dim eth ylam in o)purin e
an alogues 18c (79%) an d 19c (80%), respectively. Am in olysis of 18a an d
19a with cyclopropylam in e afforded 6-(cyclopropylam in o)purin e deriva-
tives 18d (83%) an d 19d (79%), respectively.
O
O
BzO
BzO
OH
OH
11
10
(i)
(i)
N
N
N
N
Cl
Cl
O
O
N
N
BzO
N
N
BzO
16
(ii)
17
(ii)
N
N
N
N
N
X
X
O
O
N
HO
N
N
HO
(iii)
18
19
a, X = Cl
b, X = NH2
c, X = NMe2
d, X = NH
(iv)
(v)
(i) 6-chloro-9H-purine, PPh3, DIAD, THF, 59% of 16, 56% of 17; (ii)
DIBAL-H/CH2Cl2, - 78 °C, 71% of 18a, 88% of 19a; (iii) NH3 (l), 70
°C, 72% of 18b, 80% of 19b; (iv) Me2NCOO-Me2NH2+, r.t., 79% of
18c, 80% of 19c; (v) cyclopropylamine, r.t., 83% of 18d, 79% of
19d
SCHEME 3
Substitution of th e h ydroxym eth yl group for th e ch lorom eth yl group led,
in som e cases, to in creasin g an tiviral activity5i. Th erefore, th e ch lorom eth yl
derivatives 20 an d 21 were prepared by th e treatm en t of 18a or 19a with
th ion yl ch loride in h exam eth ylph osph oram ide (HMPA) at 80 °C in 77 an d
82% yields, respectively (Sch em e 4).
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492
Hřebabecký, Dračínský, De Palma, Neyts, Holý:
N
N
Cl
Cl
O
O
(i)
N
N
HO
HO
Cl
N
N
N
N
18a
20
N
N
Cl
Cl
O
O
N
(i)
N
N
N
N
Cl
N
21
19a
(i) SOCl2/HMPA, 80 °C, 77% of 20, 82% of 21
SCHEME 4
Th e structures of th e prepared com poun ds were con firm ed by NMR spec-
1
troscopy. Com plete assign m en t of all H an d 13C reson an ces was m ade on
th e basis of com bin ation of 1H, 13C APT, H,H-COSY, H,C-HSQC, an d
H,C-HMBC experim en ts.
In con clusion , n ovel racem ic con form ation ally-locked carbocyclic
n ucleoside an alogues of th ym in e, 6-ch loropurin e, aden in e, 6-(dim eth yl-
am in o)purin e, an d 6-(cyclopropylam in o)purin e derived from (1R*,2R*,4S*)-
7-oxabicyclo[2.2.1]h eptan e-2-m eth an ol substituted with a base in th e po-
sition 5-exo or 6-exo were prepared. Th e target com poun ds were tested for
th e activity again st Coxsackie virus (CVB3). Prelim in ary data sh owed th at
th e 6-ch loropurin e an alogues 18a, 19a, 20, an d 21 exh ibit som e activity
(18a: EC50 1.40 µM an d CC50 > 50 µM; 19a: EC50 2.21 µM an d CC50
50 µM; 20: EC50 0.84 µM an d CC50 > 50 µM; 21: EC50 5.08 µM an d CC50
>
>
50 µM). Th e an tiviral activity will be discussed in detail in a separate paper.
EXPERIMENTAL
Meltin g poin ts were determ in ed on a a Büch i B-540 apparatus an d are n ot corrected. NMR
spectra (δ, ppm ; J, Hz) were m easured on a Varian Un ity 500 an d/or Bruker Avan ce-500 in -
strum en ts (500 MHz for 1H an d 125.7 MHz for 13C) in h exadeuterated dim eth yl sulfoxide
an d referen ced to th e solven t sign al (δ 2.50 an d 39.70, respectively). Mass spectra were m ea-
sured on a ZAB-EQ (VG An alytical) spectrom eter usin g th e FAB ion ization (Xe, acceleratin g
voltage 8 kV, th ioglycerol–glycerol 3:1 or bis(2-h ydroxyeth yl) disulfide m atrix) an d LTQ
Orbitrap XL (Th erm o Fisch er Scien tific) usin g th e ESI. Colum n ch rom atograph y was per-
form ed on Silica gel 60 (Fluka) an d th in -layer ch rom atograph y (TLC) on Silufol Silica gel 60
F254 foils (Merck). Solven ts were evaporated at 2 kPa an d bath tem perature 30–60 °C; com -
poun ds were dried at 13 Pa an d 50 °C.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 3, pp. 487–502

Novel Carbocyclic Nucleoside Analogues
493
(1R*,2R*,4R*)-7-Oxabicyclo[2.2.1]h ept-5-en e-2-m eth an ol (3) an d
(1R*,2S*,4R*)-7-Oxabicyclo[2.2.1]h ept-5-en e-2-m eth an ol (4)
A m ixture of furan (50 m l), acrolein (10 m l), an d h ydroquin on e (300 m g) was kept at room
tem perature un der argon for 15 days an d th en evaporated. A solution of th e residue in
tetrah ydrofuran (18 m l) was added dropwise to a stirred 1 M solution of lith ium alum in ium
h ydride in tetrah ydrofuran (20 m l) at 0 °C un der argon . Th e m ixture was stirred at room
tem perature for 3 h an d excess of th e h ydride was decom posed by slow addition of water.
Th en solid CO2 was added to adjust pH of th e m ixture to ~8. Th e th ick suspen sion was fil-
tered with a Celite pad, th e filter was wash ed with tetrah ydrofuran (3 × 30 m l) an d th e com -
bin ed filtrates were evaporated. Ch rom atograph y of th e residue on a silica gel colum n in
eth yl acetate–toluen e (22:3) afforded 4.46 g (16.5%) of 3 an d 2.26 g (8.5%) of 4, both as
a syrup.
Compound 3: For C7H10O2 (126.2) calculated: 66.64% C, 7.99% H; foun d: 66.45% C,
8.10% H. ESI MS, m/z: 149.1 [M + Na]. 1H NMR: 1.05 ddd, 1 H, Jgem = 11.4, J(3ex,4) = 4.6,
J(3ex,2) = 3.5 (H-3ex); 1.23 dd, 1 H, Jgem = 11.3, J(3en ,2) = 8.0 (H-3en ); 1.58 dddd, 1 H,
J(2,3en ) = 7.9, J(2,3ex) = 3.5, J(2,CH2) = 9.5 an d 4.8 (H-2); 3.24 m , 1 H an d 3.41 m , 1 H
(CH2O); 4.68 t, 1 H, J(OH,CH2) = 5.4 (OH); 4.74 m , 1 H (H-1); 4.84 m , 1 H (H-4); 6.30–6.33
m , 2 H (H-5 an d H-6). 13C NMR: 28.37 (C-3); 40.48 (C-2); 64.21 (CH2O); 77.14 (C-4); 78.64
(C-1); 135.08 (C-6); 135.97 (C-5).
Compound 4: For C7H10O2 (126.2) calculated: 66.64% C, 7.99% H; foun d: 66.37% C,
8.13% H. ESI MS, m/z (%): 149 (100) [M + Na], 150 (9) [M + Na + H]. 1H NMR: 0.56 dd, 1 H,
Jgem = 11.1, J(3en ,2) = 4.2 (H-3en ); 1.79 ddd, 1 H, Jgem = 11.1, J(3ex,2) = 9.1, J(3ex,4) = 4.8
(H-3ex); 2.21 m , 1 H (H-2); 2.92 td, 1 H, Jgem = J(CH2,2) = 10.1, J(CH2,OH) = 5.0 an d
3.27 ddd, 1 H, Jgem = 10.5, J(CH2,OH) = 6.1, J(CH2,2) = 4.5 (CH2O); 4.54 t, 1 H, J(OH,CH2) =
5.1 (OH); 4.83 m , 1 H (H-4); 4.85 m , 1 H (H-1); 6.24 d, 1 H, J(6,5) = 5.9, J(6,1) = 1.6 (H-6);
6.37 dd, 1 H, J(5,6) = 5.9, J(5,4) = 1.7 (H-5). 13C NMR: 27.97 (C-3); 40.83 (C-2); 63.74
(CH2O); 77.66 (C-4); 78.98 (C-1); 132.36 (C-6); 136.42 (C-5).
[(1R*,2R*,4R*)-7-Oxabicyclo[2.2.1]h ept-5-en -2-yl]m eth yl Ben zoate (5)
Ben zoyl ch loride (20.9 m l, 18 m m ol) was added at 0 °C to a stirred solution of alcoh ol 3
(18.91 g, 150 m m ol) in pyridin e (200 m l) an d th e m ixture was allowed to stan d at room
tem perature overn igh t. Pyridin e was th en evaporated an d th e residue was partition ed be-
tween eth yl acetate (600 m l) an d water (300 m l). Th e organ ic ph ase was wash ed with water
(300 m l), 5% h ydroch loric acid (to acidic reaction of th e aqueous ph ase), 10% sodium
h ydrogen carbon ate solution (3 × 300 m l), dried over an h ydrous sodium sulfate an d evapo-
rated. Ch rom atograph y of th e residue on silica gel (1 kg) in toluen e–eth yl acetate (22:3)
afforded 30.74 g (89%) of ben zoate 5 as a th ick sirup. For C14H14O3 (230.3) calculated:
73.03% C, 6.13% H; foun d: 72.89% C, 6.10% H. 1H NMR: 1.31 ddd, 1 H, Jgem = 11.5,
J(3ex,4) = 4.6, J(3ex,2) = 3.4 (H-3exo); 1.39 dd, 1 H, Jgem = 11.5, J(3en ,2) = 7.9 (H-3en );
1.95 dddd, 1 H, J(2,CH2O) = 9.4 an d 6.2, J(2,3en ) = 7.9, J(2,3ex) = 3.6 (H-2); 4.12 dd, 1 H,
Jgem = 10.8, J(CH2,2) = 9.4 an d 4.32 dd, 1 H, J(CH2,2) = 6.2 (CH2O); 4.85 m , 1 H (H-1);
4.95 dm , 1 H, J(4,3ex) = 4.5 (H-4); 6.37 dd, 1 H, J(5,6) = 5.8, J(5,4) = 1.7 (H-5); 6.39 dd, 1 H,
J(6,5) = 5.8, J(6,1) = 1.6 (H-6); 7.54 m , 2 H, 7.67 m , 1 H an d 8.01 m , 2 H (arom .). 13C NMR:
28.49 (C-3); 36.95 (C-2); 67.43 (CH2O); 77.38 (C-4); 78.82 (C-1); 128.99, 2 C, 129.45, 2 C,
129.97 an d 133.58 (arom .); 134.79 (C-6); 136.52 (C-5); 165.94 (C=O).
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494
Hřebabecký, Dračínský, De Palma, Neyts, Holý:
[(1R*,2S*,4S*,6S*)-6-Hydroxy-7-oxabicyclo[2.2.1]h eptan -2-yl]m eth yl Ben zoate (6) an d
[(1R*,2R*,4R*,5S*)-5-Hydroxy-7-oxabicyclo[2.2.1]h eptan -2-yl]m eth yl Ben zoate (7)
A 1 M solution of boran e in tetrah ydrofuran (20 m l) was added dropwise un der argon to
a stirred solution of alken e 5 (9.21 g, 40 m m ol) in tetrah ydrofuran (10 m l) cooled to 0 °C.
Th e reaction m ixture was stirred at 0 °C for 3 h . Excess of boran e was decom posed by
addition of water (0.5 m l) an d th en a suspen sion of sodium perborate tetrah ydrate (18.5 g,
120 m m ol) in water (70 m l) was added in on e portion . Th e reaction m ixture was stirred at
room tem perature overn igh t an d th en diluted with eth yl acetate (300 m l). Th e organ ic
ph ase was separated, dried over an h ydrous sodium sulfate, an d evaporated. Th e residue was
ch rom atograph ed on silica gel (1.3 kg) in toluen e–eth yl acetate (1:1).
Compound 6: Yield 4.80 g (48%) of a sirup. For C14H16O4 (248.3) calculated: 67.73% C,
6.50% H; foun d: 67.72% C, 6.64% H. FAB MS, m/z (%): 249 (48) [M + H], 105 (100) [ben zoyl].
1H NMR: 1.13 m , 1 H (H-3ex); 1.36 m , 1 H (H-5ex); 1.49 dd, 1 H, Jgem = 11.9, J(3en ,2) = 8.5
(H-3en ); 1.81 dd, 1 H, Jgem = 12.4, J(5en ,6) = 7.1 (H-5en ); 2.05 m , 1 H (H-2); 3.82 ddd, 1 H,
J(6,5en ) = 7.0, J(6,OH) = 4.7, J(6,5ex) = 2.5 (H-6); 4.00 dd, 1 H, Jgem = 10.7, J(CH2,2) = 9.3
an d 4.06 dd, 1 H, Jgem = 10.7, J(CH2,2) = 6.4 (CH2O); 4.09 bs, 1 H (H-1); 4.50 t, 1 H,
J(4,3ex) = J(4,5ex) = 5.3 (H-4); 4.78 d, 1 H, J(OH,6) = 4.7 (OH); 7.54 m , 2 H (H-3´); 7.67 m ,
1 H (H-4´); 7.98 m , 2 H (H-2´). 13C NMR: 32.76 (C-3); 37.25 (C-2); 41.98 (C-5); 66.52
(CH2O); 72.49 (C-6); 74.67 (C-4); 83.64 (C-1); 129.00 (C-3´); 129.37 (C-2´); 129.93 (C-1´);
133.59 (C-4´); 165.89 (C=O).
Compound 7: Yield 4.57 g (46%) of a sirup. For C14H16O4 (248.3) calculated: 67.73% C,
6.50% H; foun d: 67.56% C, 6.69% H. FAB MS, m/z (%): 249 (41) [M + H], 105 (100) [ben zoyl].
1H NMR: 1.14 bddd, 1 H, Jgem = 12.6, J(3ex,4) = 5.7, J(3ex,2) = 3.6 (H-3ex); 1.40 dddd, 1 H,
Jgem = 12.6, J(6ex,1) = 5.7, J(6ex,5) = 2.4, Jl.r. = 0.9 (H-6ex); 1.47 dd, 1 H, Jgem = 12.6, J(3en ,2) =
8.5 (H-3en ); 1.83 dd, 1 H, Jgem = 12.5, J(6en ,5) = 7.0 (H-6en ); 2.03 m , 1 H (H-2); 3.78 ddd,
1 H, J(5,6en ) = 7.0, J(5,OH) = 4.8, J(5,6ex) = 2.4 (H-5); 3.97 dd, 1 H, Jgem = 10.8, J(CH2,2) =
9.3 an d 4.02 dd, 1 H, Jgem = 10.8, J(CH2,2) = 6.4 (CH2O); 4.20 d, 1 H, J(4,3ex) = 5.7 (H-4);
4.38 d, 1 H, J(1,6ex) = 5.6 (H-1); 4.77 d, 1 H, J(OH,5) = 4.8 (OH); 7.53 m , 2 H (H-3´); 7.66 m ,
1 H (H-4´); 7.97 m , 2 H (H-2´). 13C NMR: 28.52 (C-3); 40.92 (C-2); 41.31 (C-6); 66.74
(CH2O); 72.85 (C-5); 75.94 (C-1); 81.88 (C-4); 128.97 (C-3´); 129.38 (C-2´); 129.93 (C-1´);
133.54 (C-4´); 165.90 (C=O).
[(1R*,2S*,4S*)-6-Oxo-7-oxabicyclo[2.2.1]h eptan -2-yl]m eth yl Ben zoate (8) an d
[(1R*,2R*,4R*)-5-Oxo-7-oxabicyclo[2.2.1]h eptan -2-yl]m eth yl Ben zoate (9)
A solution of alcoh ol 6 or 7 (2.48 g, 10 m m ol) in dich lorom eth an e (20 m l) was added to
a suspen sion of powdered m olecular sieves (5.5 g) an d pyridin ium dich rom ate (5.83 g,
15.5 m m ol) in dich lorom eth an e (60 m l). Th e reaction m ixure was stirred at room tem pera-
ture for 3 days. Solids were filtered off an d wash ed with eth yl acetate. Th e filtrate was evap-
orated, th e residue was dissolved in eth yl acetate (100 m l), filtered an d th e filtrate
evaporated. Th e residue was ch rom atograph ed on silica gel (150 g) in toluen e–eth yl acetate
(4:1) an d crystallized from m eth an ol.
Compound 8: Yield 1.85 g (75%). M.p. 105–106 °C. For C14H14O4 (246.3) calculated:
68.28% C, 5.73% H; foun d: 68.26% C, 5.78% H. 1H NMR: 1.56 dddd, 1 H, Jgem = 12.4,
J(3ex,4) = 5.4, J(3ex,2) = 4.3, J(3ex,5ex) = 2.5 (H-3ex); 1.97 dd, 1 H, Jgem = 12.4, J(3en ,2) =
8.7 (H-3en ); 2.14 d, 1 H, Jgem = 15.5 (H-5en ); 2.37–2.45 m , 2 H (H-2 an d H-5ex); 4.12 dd,
1 H, Jgem = 10.8, J(CH2,2) = 9.1 an d 4.20 dd, 1 H, J(CH2,2) = 6.3 (CH2O); 4.35 bs, 1 H (H-1);
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Novel Carbocyclic Nucleoside Analogues
495
4.93 t, 1 H, J(4,3ex) = J(4,5ex) = 5.6 (H-4); 7.54 m , 2 H, 7.67 m , 1 H an d 7.99 m , 2 H
(arom .). 13C NMR: 31.97 (C-3); 36.93 (C-2); 43.87 (C-5); 65.32 (CH2O); 76.31 (C-4); 80.70
(C-1); 129.03, 2 C, 129.47, 2 C, 129.75 an d 133.70 (arom .); 165.85 (C=O); 211.80 (C-6).
Compound 9: Yield 2.09 (85%). M.p. 103–104 °C. For C14H14O4 (246.3) calculated:
68.28% C, 5.73% H; foun d: 68.33% C, 5.82% H. FAB MS, m/z (%): 247 (8) [M + H], 105
(100) [ben zoyl]. 1H NMR: 1.58 dddm , 1 H, Jgem = 13.4, J(3ex,4) = 6.4, J(3ex,2) = 4.2 (H-3ex);
1.82 dd, 1 H, Jgem = 13.4, J(3en ,2) = 8.6 (H-3en ); 2.17 d, 1 H, Jgem = 17.5 (H-6en ); 2.45 ddm ,
1 H, Jgem = 17.5, J(6ex,1) = 6.1 (H-6ex); 2.52 m , 1 H (H-2); 4.11 dd, 1 H, Jgem = 10.9, J(CH2,2) =
9.1 an d 4.18 dd, 1 H, Jgem = 10.9, J(CH2,2) = 6.3 (CH2O); 4.41 bd, 1 H, J(4,3ex) = 6.3 (H-4);
4.80 bd, 1 H, J(1,6ex) = 6.0 (H-1); 7.54 m , 2 H (H-3´); 7.67 m , 1 H (H-4´); 8.00 m , 2 H (H-2´).
13C NMR: 27.80 (C-3); 40.34 (C-2); 42.90 (C-6); 66.23 (CH2O); 77.55 (C-1); 78.96 (C-4);
128.97 (C-3´); 129.45 (C-2´); 129.83 (C-1´); 133.62 (C-4´); 165.87 (C=O); 211.79 (C-5).
[(1R*,2S*,4S*,6R*)-6-Hydroxy-7-oxabicyclo[2.2.1]h eptan -2-yl]m eth yl Ben zoate (10) an d
[(1R*,2R*,4R*,5R*)-5-Hydroxy-7-oxabicyclo[2.2.1]h eptan -2-yl]m eth yl Ben zoate (11)
Sodium boroh ydride (760 m g, 20 m m ol) was added to a stirred solution of keton e 8 or 9
(4.93 g, 20 m m ol) in m eth an ol (75 m l) an d tetrah ydrofuran (25 m l) at 0 °C. Th e m ixture
was stirred at 0 °C for 30 m in an d th en a saturated aqueous solution of am m on ium ch loride
was slowly added. Th e m ixture was extracted with eth yl acetate (400 m l), th e eth yl acetate
solution was dried over an h ydrous sodium sulfate an d evaporated. Th e residue was
ch rom atograph ed on a silica gel colum n (450 g) in toluen e–eth yl acetate (1:1) an d com -
poun d 10 was th en crystallized from dieth yl eth er–cycloh exan e.
Compound 10: Yield 4.17 g (84%). M.p. 117–118 °C. For C14H16O4 (248.3) calculated:
67.73% C, 6.50% H; foun d: 67.53% C, 6.59% H. FAB MS, m/z (%): 249 (17) [M + H], 105
(100) [ben zoyl]. 1H NMR: 1.04 dd, 1 H, Jgem = 12.2, J(5en ,6) = 3.3 (H-5en ); 1.30 dtd, 1 H,
Jgem = 11.8, J(3ex,2) = J(3ex,4) = 5.0, J(3ex,5ex) = 2.6 (H-3ex); 1.73 dd, 1 H, Jgem = 11.9,
J(3en ,2) = 8.7 (H-3en ); 1.96 dddd, 1 H, Jgem = 12.2, J(5ex,6) = 10.0, J(5ex,4) = 5.7, J(5ex,3ex) =
2.6 (H-5ex); 2.90 tdd, 1 H, J(2,CH2) = J(2,3en ) = 8.9, J(2,CH2) = 6.7, J(2,3ex) = 4.5 (H-2);
4.05 dd, 1 H, Jgem = 10.6, J(CH2,2) = 9.2 an d 4.10 dd, 1 H, Jgem = 10.6, J(CH2,2) = 6.6
(CH2O); 4.10 m , 1 H (H-6); 4.18 d, 1 H, J(1,6) = 5.0 (H-1); 4.42 t, 1 H, J(4,3ex) = J(4,5ex) =
5.4 (H-4); 5.09 d, 1 H, J(OH,6) = 4.0 (OH); 7.53 m , 2 H (H-3´); 7.66 m , 1 H (H-4´); 7.98 m ,
2 H (H-2´). 13C NMR: 33.81 (C-2); 34.26 (C-3); 39.11 (C-5); 66.62 (CH2O); 69.95 (C-6); 77.22
(C-4); 79.91 (C-1); 128.95 (C-3´); 129.38 (C-2´); 130.02 (C-1´); 133.53 (C-4´); 165.94 (C=O).
Compound 11: Yield 3.92 g (79%) as a solid foam . For C14H16O4 (248.3) calculated:
67.73% C, 6.50% H; foun d: 67.57% C, 6.66% H. ESI MS, m/z (%): 271.1 (100) [M + Na], 249
(5) [M + H]. 1H NMR: 1.04 dd, 1 H, Jgem = 12.3, J(6en ,5) = 3.4 (H-6en ); 1.10 m , 1 H (H-3en );
2.01 ddd, 1 H, Jgem = 12.3, J(6ex,5) = 10.0, J(6ex,1) = 6.0 (H-6ex); 2.24 tdd, 1 H, J(2,3en ) =
J(2,CH2) = 8.8, J(2,CH2) = 6.5, J(2,3ex) = 3.8 (H-2); 2.32 dd, 1 H, Jgem = 12.1, J(3en ,2) = 8.7
(H-3en ); 3.99 dd, 1 H, Jgem = 10.7, J(CH2,2) = 8.9 an d 4.02 dd, 1 H, Jgem = 10.8, J(CH2,2) =
6.5 (CH2O); 4.07 m , 1 H (H-5); 4.26–4.30 m , 2 H (H-1 an d H-4); 5.03 d, 1 H, J(OH,5) = 4.1
(OH); 7.53 m , 2 H (H-3´); 7.66 m , 1 H (H-4´); 7.98 m , 2 H (H-2´). 13C NMR: 25.78 (C-3);
38.55 (C-6); 42.28 (C-2); 66.82 (CH2O); 70.15 (C-5); 78.14 (C-4); 78.35 (C-1); 128.98 (C-3´);
129.39 (C-2´); 129.95 (C-1´); 133.54 (C-4´); 165.94 (C=O).
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496
Hřebabecký, Dračínský, De Palma, Neyts, Holý:
(1R*,2S*,4S*,6S*)-6-[(4-Eth oxy-5-m eth ylpyrim idin -2-yl)oxy]-7-oxabicyclo[2.2.1]h eptan e-
2-m eth an ol (12) an d
(1R*,2R*,4R*,5S*)-5-[(4-Eth oxy-5-m eth ylpyrim idin -2-yl)oxy]-7-oxabicyclo[2.2.1]h eptan e-
2-m eth an ol (14)
A solution of diisopropyl azodicarboxylate (1.18 m l, 6 m m ol) in tetrah ydofuran (8 m l) was
added dropwise to a stirred solution of 4-eth oxy-5-m eth ylpyrim idin -2(1H)-on e (924 m g,
6 m m ol), triph en ylph osph in e (2.10 g, 8 m m ol), an d alcoh ol 10 or 11 (1.24 g, 5 m m ol) in
tetrah ydrofuran (20 m l). Th e m ixture was th en h eated to reflux for 4 h an d evaporated. Th e
residue was ch rom atograph ed on a silica gel colum n (250 g) in toluen e–eth yl acetate (18:7)
an d th e fraction s con tain in g pyrim idin e derivative were evaporated. A solution of th e resi-
due in m eth an olic 0.1 M sodium m eth oxide (75 m l) was kept at room tem perature over-
n igh t. Dowex 50 (H+) was th en added un til UV-absorption of th e solution disappeared;
12 or 14 was adsorbed on th e resin . Th e resin was filtered off an d wash ed with m eth an ol–
aqueous 25% am m on ia (8:2; 150 m l). Th e wash in gs were evaporated an d th e residue was
crystallized from water (12) or ch rom atograph ed on silica gel (100 g) in eth yl acetate–
toluen e (4:1) (14).
Compound 12: Yield 1.19 g (85%). M.p. 90–91 °C. For C14H20N2O4 (280.3) calculated:
59.98% C, 7.19% H, 9.99% N; foun d: 59.85% C, 7.18% H, 9.83% N. ESI MS, m/z (%): 304.1
(16) [M + Na + H], 303.1 (100) [M + Na], 281.0 (53) [M + H], 155.1 (6) [base + H]. 1H NMR:
0.99 dm , 1 H, Jgem = 11.8 (H-3ex); 1.30 t, 3 H, J(CH3,CH2) = 7.1 (CH2CH3); 1.51 dd, 1 H,
Jgem = 11.9, J(3en ,2) = 8.5 (H-3en ); 1.62 dm , 1 H, Jgem = 13.1 (H-5ex); 1.89 m , 1 H (H-2);
1.96 d, 3 H, J(CH3,5´) = 0.9 (5´-CH3); 2.07 dd, 1 H, Jgem = 13.1, J(5en ,6) = 7.2 (H-5en );
3.12–3.18 m , 2 H (CH2O); 4.28 q, 2 H, J(CH2,CH3) = 7.1 (OCH2CH3); 4.43 bs, 1 H (H-1);
4.55 bt, 1 H, J(4,3ex) = J(4,5ex) = 5.2 (H-4); 4.74 bt, 1 H, J(OH,CH2) = 5.4 (OH); 5.02 dd,
1 H, J(6,5en ) = 7.1, J(6,5ex) = 2.6 (H-6); 8.08 q, 1 H, J(6´,CH3) = 0.9 (H-6´). 13C NMR: 11.59
(5´-CH3); 14.57 (CH2CH3); 32.44 (C-3); 39.84 (C-5); 40.80 (C-2); 62.70 (OCH2CH3); 63.41
(CH2O); 74.77 (C-4); 78.44 (C-6); 80.81 (C-1); 110.46 (C-5´); 157.99 (C-6´); 163.10 (C-4´);
168.16 (C-2´).
Compound 14: Yield 1.08 g (77%) as a th ick sirup. For C14H20N2O4 (280.3) calculated:
59.98% C, 7.19% H, 9.99% N; foun d: 59.91% C, 7.30% H, 9.75% N. ESI MS, m/z (%): 304.1
(15), 303.1 (100) [M + Na]. 1H NMR: 1.05 ddd, 1 H, Jgem = 12.6, J(3ex,4) = 6.0, J(3ex,2) = 4.0
(H-3ex); 1.30 t, 3 H, J(CH3,CH2) = 7.1 (CH2CH3); 1.57 dd, 1 H, Jgem = 12.6, J(3en ,2) = 8.5
(H-3en ); 1.66 dddd, 1 H, Jgem = 13.1, J(6ex,1) = 5.6, J(6ex,5) = 2.6, Jl.r. = 0.8 (H-6ex); 1.82 m ,
1 H (H-2); 1.96 d, 3 H, J(CH3,6´) = 0.9 (5´-CH3); 2.04 dd, 1 H, Jgem = 13.1, J(6en ,5) = 7.2
(H-6en ); 3.09–3.17 m , 2 H (CH2OH); 4.27 q, 2 H, J(CH2,CH3) = 7.1 (OCH2CH3); 4.44 bd,
1 H, J(1,6ex) = 5.7 (H-1); 4.49 bd, 1 H, J(4,3ex) = 5.9 (H-4); 4.68 bt, 1 H, J(OH,CH2) = 5.3
(OH); 5.00 dd, 1 H, J(5,6en ) = 7.1, J(5,6ex) = 2.6 (H-5); 8.08 q, 1 H, J(6´,CH3) = 0.9 (H-6´).
13C NMR: 11.61 (5´-CH3); 14.54 (CH2CH3); 28.44 (C-3); 39.09 (C-6); 44.42 (C-2); 62.64
(OCH2CH3); 63.69 (CH2OH); 76.09 (C-1); 78.64 (C-5); 79.07 (C-4); 110.59 (C-5´); 157.83
(C-6´); 163.06 (C-4´); 168.26 (C-2´).
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497
1-[(1R*,2S*,4S*,6S*)-6-(Hydroxym eth yl)-7-oxabicyclo[2.2.1]h eptan -2-yl]-5-m eth yl-
pyrim idin e-2,4(1H,3H)-dion e (13) an d
1-[(1R*,2S*,4R*,5R*)-5-(Hydroxym eth yl)-7-oxabicyclo[2.2.1]h eptan -2-yl]-5-m eth yl-
pyrim idin e-2,4(1H,3H)-dion e (15)
A solution of diisopropyl azodicarboxylate (0.59 m l, 3 m m ol) in tetrah ydofuran (4 m l) was
added dropwise to a stirred solution of 3-ben zoyl-5-m eth ylpyrim idin e-2,4(1H,3H)-dion e
(805 m g, 3.5 m m ol), triph en ylph osph in e (1.05 g, 4 m m ol), an d alcoh ol 10 or 11 (620 m g,
2.5 m m ol) in tetrah ydrofuran (10 m l). Th e m ixture was h eated to reflux for 4 h an d th en
evaporated. Th e residue was ch rom atograph ed on a silica gel colum n (120 g) in toluen e–
eth yl acetate (18:7) an d th e fraction s con tain in g th e pyrim idin e derivative were evaporated.
A solution of th e residue in m eth an olic 0.1 M sodium m eth oxide (40 m l) was left at room
tem perature overn igh t. Th e solution was n eutralized with Dowex 50 (H+), filtered, an d evap-
orated. Th e residue was crystallized from dieth yl eth er.
Compound 13: Yield 372 m g (59%). M.p. 179–181 °C. For C12H16N2O4 (252.3) calculated:
57.13% C, 6.39% H, 11.10% N; foun d: 56.96% C, 6.32% H, 10.89% N. ESI MS, m/z (%):
275.0 (100) [M + Na], 253.1 (18) [M + H]. 1H NMR: 1.02 m , 1 H (H-5´ex); 1.57 dd, 1 H, Jgem
=
12.0, J(5´en ,6´) = 8.5 (H-5´en ); 1.65 m , 1 H (H-3´ex); 1.76 d, 3 H, J(CH3,6) = 1.2 (CH3);
1.91 m , 1 H (H-6´); 2.08 dd, 1 H, Jgem = 13.1, J(3´en ,2´) = 8.7 (H-3´en ); 3.10–3.14 m , 2 H
(CH2O); 4.34 s, 1 H (H-1´); 4.64 bt, 1 H, J(4´,3´ex) = J(4´,5´ex) = 5.2 (H-4´); 4.69 dd, 1 H,
J(2´,3´en ) = 8.6, J(2´,3´ex) = 3.9 (H-2´); 4.74 bs, 1 H (OH); 7.48 q, 1 H, J(6,CH3) = 1.2 (H-6);
11.25 bs, 1 H (NH). 13C NMR: 12.60 (CH3); 32.72 (C-5´); 39.32 (C-3´); 43.40 (C-6´); 56.15
(C-2´); 63.40 (CH2O); 75.36 (C-4´); 81.61 (C-1´); 109.51 (C-5); 137.27 (C-6); 151.27 (C-2);
163.97 (C-4).
Compound 15: Yield 380 m g (60%). M.p. 249–251 °C. For C12H16N2O4 (252.3) calculated:
57.13% C, 6.39% H, 11.10% N; foun d: 57.00% C, 6.41% H, 10.91% N. ESI MS, m/z: 275.0
[M + Na]. 1H NMR: 1.05 m , 1 H (H-6´ex); 1.59 dd, 1 H, Jgem = 12.6, J(6´en ,5´) = 8.5 (H-6´en );
1.70 m , 1 H (H-3´ex); 1.76 d, 3 H, J(CH3,6) = 1.2 (CH3); 1.87 m , 1 H (H-5´); 2.06 dd, 1 H,
Jgem = 13.2, J(3´en ,2´) = 8.7 (H-3´en ); 3.08–3.15 m , 2 H (CH2O); 4.48 d, 1 H, J(1´,6´ex) = 5.7
(H-1´); 4.52 d, 1 H, J(4´,3´ex) = 5.6 (H-4´); 4.66 dd, 1 H, J(2´,3´en ) = 8.6, J(2´,3´ex) = 3.8
(H-2´); 4.73 bt, 1 H, J(OH,CH2) = 5.2 (OH); 7.49 q, 1 H, J(6,CH3) = 1.2 (H-6); 11.24 bs (NH).
13C NMR: 12.63 (CH3); 30.96 (C-6´); 38.51 (C-3´); 44.80 (C-5´); 56.57 (C-2´); 63.68 (CH2O);
76.73 (C-4´); 79.97 (C-1´); 109.30 (C-5); 137.38 (C-6); 151.28 (C-2); 163.98 (C-4).
[(1R*,2R*,4S*,6S*)-6-(6-Ch loro-9H-purin -9-yl)bicyclo[2.2.1]h eptan -2-yl]m eth yl
Ben zoate (16) an d
[(1R*,2R*,4R*,5S*)-5-(6-Ch loro-9H-purin -9-yl)-7-oxabicyclo[2.2.1]h eptan -2-yl]m eth yl
Ben zoate (17)
A solution of diisopropyl azodicarboxylate (8.9 m l, 45 m m ol) in tetrah ydrofuran (50 m l) was
slowly added to a solution of alcoh ol 10 or 11 (7.45 g, 30 m m ol), triph en ylph osph in e
(15.74 g, 60 m m ol), an d 6-ch loropurin e (6.96 g, 45 m m ol) in THF (250 m l). Th e reaction
m ixture was th en h eated to reflux for 6 h an d evaporated. Th e residue was ch rom atog-
raph ed on silica gel (1 kg) in eth yl acetate–toluen e (1:1) an d crystallized from butyl acetate.
Compound 16: Yield 6.86 g (59%). M.p. 186.5–188.5 °C. For C19H17ClN4O3 (384.8) calcu-
lated: 59.30% C, 4.45% H, 9.21% Cl, 14.56% N; foun d: 59.21% C, 4.51% H, 9.29% Cl,
14.42% N. ESI MS, m/z (%): 794.5 (15), 793.5 (24), 792.5 (64), 790.5 (100), 789.7 (16),
409.1/407.1 (27/79) [M + Na], 387/385.2 (9/26) [M + H]. 1H NMR: 1.37 dm , 1 H, Jgem = 12.0
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498
Hřebabecký, Dračínský, De Palma, Neyts, Holý:
(H-3ex); 1.84 dd, 1 H, Jgem = 12.1, J(3en ,2) = 8.6 (H-3en ); 2.08 dm , 1 H, Jgem = 13.3 (H-5ex);
2.35 dd, 1 H, Jgem = 13.3, J(5en ,6) = 8.4 (H-5en ); 2.54 m , 1 H (H-2); 4.06 dd, 1 H, Jgem
=
10.9, J(CH2,2) = 9.2 an d 4.14 dd, 1 H, Jgem = 10.9, J(CH2,2) = 6.3 (CH2O); 4.71 bs, 1 H (H-1);
4.86 bt, 1 H, J(4,5ex) = J(4,3ex) = 5.2 (H-4); 5.05 dd, 1 H, J(6,5en ) = 8.4, J(6,5ex) = 3.3 (H-6);
7.50 m , 2 H, 7.64 m , 1 H, an d 7.97 m , 2 H (arom .); 8.66 s, 1 H (H-8´); 8.77 s, 1 H (H-2´).
13C NMR: 33.03 (C-3); 38.82 (C-2); 39.46 (C-5); 56.92 (C-6); 66.09 (CH2O); 75.79 (C-4);
81.81 (C-1); 128.90, 129.44, 129.85, an d 133.54 (C-4´´); 130.96 (C-5´); 145.22 (C-8´); 149.10
(C-6´); 151.54 (C-2´); 151.87 (C-4´); 165.89 (C=O).
Compound 17: Yield 6.50g (56%). M.p. 183–185 °C. For C19H17ClN4O3 (384.8) calculated:
59.30% C, 4.45% H, 9.21% Cl, 14.56% N; foun d: 59.10% C, 4.44% H, 9.42% C, 14.33% N.
ESI MS, m/z (%): 409.1/407.1 (27/78) [M + Na], 391.3 (100), 387.2/385.1 (22/66) [M + H].
1H NMR (DMSO): 1.43 dm , 1 H, Jgem = 12.9 (H-3ex); 1.96 dd, 1 H, Jgem = 12.9, J(3en ,2) = 8.6
(H-3en ); 2.14 dddd, 1 H, Jgem = 13.4, J(6ex,1) = 5.6, J(6ex,5) = 5.6, Jl.r. = 0.9 (H-6ex); 2.38 dd,
1 H, Jgem = 13.4, J(6en ,5) = 8.4 (H-6en ); 2.38 m , 1 H (H-2); 4.06–4.14 m , 2 H (CH2O);
4.73 m , 2 H (H-1 an d H-4); 5.01 dd, 1 H, J(5,6en ) = 8.4, J(5,6ex) = 3.1 (H-5); 7.55 m , 2 H
(H-3´´); 7.68 m , 1 H, 8.01 m , 2 H, an d 8.66 s, 1 H (arom .); 8.79 s, 1 H (H-2´). 13C NMR
(DMSO): 29.87 (C-3); 38.58 (C-6); 41.24 (C-2); 57.21 (C-5); 66.36 (CH2O); 76.96 (C-1); 80.25
(C-4); 128.99, 129.42, 129.89, an d 133.60 (arom .); 130.92 (C-5´); 145.34 (C-8´); 149.12
(C-6´); 151.60 (C-2´); 151.85 (C-4´); 165.92 (C=O).
(1R*,2S*,4S*,6S*)-6-(6-Ch loro-9H-purin -9-yl)-7-oxabicyclo[2.2.1]h eptan e-
2-m eth an ol (18a) an d
(1R*,2R*,4R*,5S*)-5-(6-Ch loro-9H-purin -9-yl)-7-oxabicyclo[2.2.1]h eptan e-
2-m eth an ol (19a)
A 1 M solution of DIBAL-H in dich lorom eth an e (42 m l) was added dropwise to a solution of
com poun d 16 or 17 (5.45 g, 14 m m ol) in dich lorom eth an e (100 m l) at –78 °C un der argon .
Th e reaction m ixture was stirred for 1 h , excess DIBAL-H was decom posed by addition of
m eth an ol an d tem perature was allowed to rise to room tem perature. Th en water (3 m l) an d
m eth an ol (400 m l) were added an d th e m ixture was filtered with a Celite pad. Th e filter was
wash ed with m eth an ol an d th e filtrate was evaporated. Th e residue was crystallized from
m eth an ol.
Compound 18a: Yield 2.8 g (71%). M.p. 191.5–193 °C. For C12H13ClN4O2 (280.7) calcu-
lated: 51.34% C, 4.67% H, 12.63% Cl, 19.96% N; foun d: 51.15% C, 4.74% H, 12.85% Cl,
19.81% N. ESI MS, m/z (%): 305.1/303.1 (10/25) [M + Na], 288.3 (60), 283.1/281.1 (36/100)
[M + H]. HR ESI MS (M + H) calculated 281.0800, foun d 281.0796. 1H NMR (DMSO):
1.11 dtd, 1 H, Jgem = 11.9, J(3ex,4) = J(3ex,2) = 4.9, J(3ex,5ex) = 2.6 (H-3ex); 1.67 dd, 1 H,
Jgem = 11.9, J(3en ,2) = 8.5 (H-3en ); 2.06 dm , 1 H, Jgem = 13.3 (H-5ex); 2.11 m , 1 H (H-2);
2.30 dd, 1 H, Jgem = 13.3, J(5en ,6) = 8.4 (H-5en ); 3.13–3.22 m , 2 H (CH2O); 4.47 s, 1 H (H-1);
4.75 t, 1 H, J(OH,CH2) = 5.4 (OH); 4.77 t, 1 H, J(4,3ex) = J(4,5ex) = 5.2 (H-4); 4.97 dd, 1 H,
J(6,5en ) = 8.4, J(6,5ex) = 3.2 (H-6); 8.63 s, 1 H (H-8´); 8.78 s, 1 H (H-2´). 13C NMR (DMSO):
33.00 (C-3); 39.62 (C-5); 42.34 (C-2); 57.04 (C-6); 63.41 (CH2O); 75.59 (C-4); 82.00 (C-1);
130.89 (C-5´); 145.19 (C-8´); 149.14 (C-6´); 151.60 (C-2´); 151.77 (C-4´).
Compound 19a: Yield 3.47 g (88%). M.p. 182–183.5 °C. For C12H13ClN4O2 (280.7) calculated:
51.34% C, 4.67% H, 12.63% Cl, 19.96% N; foun d: 51.15% C, 4.60% H, 12.59% Cl, 19.80% N.
negESI MS, m/z (%): 281.1/279 (31/88) [M – H], 155/153 (32/100) [6-chloropurine – H]. 1H NMR
(DMSO): 1.15 ddd, 1 H, Jgem = 12.7, J(3ex,4) = 5.8, J(3ex,2) = 3.8 (H-3ex); 1.78 dd, 1 H, Jgem
=
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Novel Carbocyclic Nucleoside Analogues
499
12.7, J(3en ,2) = 8.6 (H-3en ); 1.97 m , 1 H (H-2); 2.10 dddd, 1 H, Jgem = 13.3, J(6ex,1) = 5.7,
J(6ex,5) = 3.2, Jl.r. = 0.8 (H-6ex); 2.27 dd, 1 H, Jgem = 13.3, J(6en ,5) = 8.4 (H-6en ); 3.14 dd,
1 H, Jgem = 10.5, J(CH2,2) = 6.1 an d 3.19 dd, 1 H, Jgem = 10.5, J(CH2,2) = 9.6 (CH2O); 4.60 d,
1 H, J(4,3ex) = 5.8 (H-4); 4.65 d, 1 H, J(1,6ex) = 5.7 (H-1); 4.78 bs, 1 H; 4.94 dd, 1 H, J(5,6en ) =
8.4, J(5,6ex) = 3.2 (H-5); 8.64 s, 1 H (H-8´); 8.76 s, 1 H (H-2´). 13C NMR (DMSO): 29.93
(C-3); 38.82 (C-6); 44.94 (C-2); 57.45 (C-5); 63.61 (CH2O); 76.83 (C-1); 80.23 (C-4); 130.95
(C-5´); 145.29 (C-8´); 149.14 (C-6´); 151.62 (C-2´); 151.87 (C-4´).
(1R*,2S*,4S*,6S*)-6-(6-Am in o-9H-purin -9-yl)-7-oxabicyclo[2.2.1]h eptan e-
2-m eth an ol (18b) an d
(1R*,2R*,4R*,5S*)-5-(6-Am in o-9H-purin -9-yl)-7-oxabicyclo[2.2.1]h eptan e-
2-m eth an ol (19b)
A solution of ch loropurin e derivative 18a or 19a (281 m g, 1 m m ol) in liquid am m on ia
(20 m l) was h eated in an autoclave at 75 °C for 48 h an d th en am m on ia was evaporated.
Th e residue was crystallized from water.
Compound 18b: Yield 188 m g (72%). M.p. 268–269.5 °C. For C12H15N5O2 (261.3) calcu-
lated: 55.16% C, 5.79% H, 26.80% N; foun d: 54.98% C, 5.76% H, 26.62% N. ESI MS, m/z
(%): 284.1 (57) [M + Na], 262.1 (100) [M + H]. 1H NMR: 1.08 m , 1 H (H-3ex); 1.64 dd, 1 H,
Jgem = 11.8, J(3en ,2) = 8.5 (H-3en ); 1.94 dm , 1 H, Jgem = 13.1 (H-5ex); 2.06 m , 1 H (H-2);
2.25 dd, 1 H, Jgem = 13.1, J(5en ,6) = 8.6 (H-5en ); 3.12–3.21 m , 2 H (CH2O); 4.35 s, 1 H (H-1);
4.72–4.77 m , 2 H (H-4 an d OH); 4.80 dd, 1 H, J(6,5en ) = 8.4, J(6,5ex) = 3.2 (H-6); 7.22 bs,
2 H (NH2); 8.08 s, 1 H (H-8´); 8.14 s, 1 H (H-2´). 13C NMR: 32.95 (C-3); 39.97 (C-5); 42.51
(C-2); 55.52 (C-6); 63.47 (CH2O); 75.47 (C-4); 82.35 (C-1); 118.61 (C-5´); 138.39 (C-8´);
149.40 (C-4´); 152.60 (C-2´); 156.19 (C-6´).
Compound 19b: Yield 193 m g (74%). M.p. 225–226.5 °C. For C12H15N5O2 (261.3) calcu-
lated: 55.16% C, 5.79% H, 26.80% N; foun d: 54.97% C, 5.77% H, 26.69% N. ESI MS, m/z
(%): 285.1 (39) [M + Na + H], 284.1 (100) [M + Na], 262.2 (81) [M + H]. 1H NMR: 1.12 ddd,
1 H, Jgem = 12.6, J(3ex,4) = 5.8, J(3ex,2) = 3.8 (H-3ex); 1.73 dd, 1 H, Jgem = 12.6, J(3en ,2) =
8.5 (H-3en ); 1.92–2.02 m , 2 H (H-2 an d H-6ex); 2.23 dd, 1 H, Jgem = 13.1, J(6en ,5) = 8.4
(H-6en ); 3.11–3.20 m , 2 H (CH2O); 4.49 d, 1 H, J(4,3ex) = 5.7 (H-4); 4.62 d, 1 H, J(1,6ex) =
5.6 (H-1); 4.76 bt, 1 H, J(OH,CH2) = 5.3 (OH); 4.78 dd, 1 H, J(5,6en ) = 8.4, J(5,6ex) = 3.3
(H-5); 7.24 bs, 2 H (NH2); 8.10 s, 1 H (H-8´); 8.14 s, 1 H (H-2´). 13C NMR: 30.12 (C-3); 39.12
(C-6); 44.92 (C-2); 56.38 (C-5); 63.66 (CH2O); 76.72 (C-1); 80.55 (C-4); 118.69 (C-5´); 138.46
(C-8´); 149.47 (C-4´); 152.59 (C-2´); 156.20 (C-6´).
(1R*,2S*,4S*,6S*)-6-[6-(Dim eth ylam in o)-9H-purin -9-yl]-7-oxabicyclo[2.2.1]h eptan e-
2-m eth an ol (18c) an d
(1R*,2R*,4R*,5S*)-5-[6-(Dim eth ylam in o)-9H-purin -9-yl]-7-oxabicyclo[2.2.1]h eptan e-
2-m eth an ol (19c)
A solution of ch loropurin e derivative 18a an d 19a (140 m g, 0.5 m m ol) in dim eth yl-
am m on ium dim eth ylcarbam ate (2.5 m l) was left stan din g at room tem perature overn igh t
an d th en evaporated. Th e residue was ch rom atograph ed on a silica gel colum n (20 g) in
eth yl acetate–aceton e–eth an ol–water (95:15:8:7) an d th en crystallized from eth er.
Compound 18c: Yield 114 m g (79%). M.p. 137–139 °C. For C14H19N5O2 (289.3) calculated:
58.12% C, 6.62% H, 24.21% N; foun d: 58.13% C, 6.64% H, 24.10% N. ESI MS, m/z (%):
291.2 (15) [M + 2 H], 290.2 (100) [M + H]. 1H NMR: 1.08 m , 1 H (H-3ex); 1.64 dd, 1 H,
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Hřebabecký, Dračínský, De Palma, Neyts, Holý:
Jgem = 11.9, J(3en ,2) = 8.5 (H-3en ); 1.92 dm , 1 H, Jgem = 13.1 (H-5ex); 2.06 m , 1 H (H-2);
2.25 dd, 1 H, Jgem = 13.1, J(5en ,6) = 8.5 (H-5en ); 3.12–3.20 m , 2 H (CH2O); 3.4 vbs, 6 H
(CH3); 4.34 s, 1 H (H-1); 4.73 t, 1 H, J(4,3ex) = J(4,5ex) = 5.2 (H-4); 4.78 t, 1 H, J(OH,CH2) =
5.4 (OH); 4.83 dd, 1 H, J(6,5en ) = 8.5, J(6,5ex) = 3.4 (H-6); 8.09 s, 1 H (H-8´); 8.21 s, 1 H
(H-2´). 13C NMR: 32.94 (C-3); 40.00 (C-5); 42.57 (C-2); 55.93 (C-6); 63.48 (CH2O); 75.49
(C-4); 82.30 (C-1); 119.16 (C-5´); 137.24 (C-8´); 150.18 (C-4´); 151.94 (C-2´); 154.45 (C-6´).
Compound 19c: Yield 116 m g (80%). M.p. 162–163.5 °C. For C14H19N5O2 (289.3) calcu-
lated: 58.12% C, 6.62% H, 24.21% N; foun d: 57.97% C, 6.64% H, 24.13% N. ESI MS, m/z
(%): 291.2 (16) [M + 2 H], 290.2 (100) [M + H]. 1H NMR: 1.12 ddd, 1 H, Jgem = 12.6,
J(3ex,4) = 5.8, J(3ex,2) = 3.8 (H-3ex); 1.73 dd, 1 H, Jgem = 12.6, J(3en ,2) = 8.6 (H-3en );
1.92–1.99 m , 2 H (H-2 an d H-6ex); 2.23 dd, 1 H, Jgem = 13.2, J(6en ,5) = 8.5 (H-6en );
3.11–3.20 m , 2 H (CH2O); 3.4 vbs, 6 H (CH3); 4.48 d, 1 H, J(4,3ex) = 5.7 (H-4); 4.62 d, 1 H,
J(1,6ex) = 5.7 (H-1); 4.76 t, 1 H, J(OH,CH2) = 5.3 (OH); 4.80 dd, 1 H, J(5,6en ) = 8.4,
J(5,6ex) = 3.3 (H-5); 8.10 s, 1 H (H-8´); 8.20 s, 1 H (H-2´). 13C NMR: 30.15 (C-3); 38.47
(CH3); 39.07 (C-6); 44.91 (C-2); 56.38 (C-5); 63.67 (CH2O); 76.73 (C-1); 80.52 (C-4); 119.23
(C-5´); 137.30 (C-8´); 150.22 (C-4´); 151.90 (C-2´); 154.44 (C-6´).
(1R*,2S*,4S*,6S*)-6-[6-(Cyclopropylam in o)-9H-purin -9-yl]-7-oxabicyclo[2.2.1]h eptan e-
2-m eth an ol (18d ) an d
(1R*,2R*,4R*,5S*)-5-[6-(Cyclopropylam in o)-9H-purin -9-yl]-7-oxabicyclo[2.2.1]h eptan e-
2-m eth an ol (19d )
A solution of ch loropurin e derivative 18a or 19a (140 m g, 0.5 m m ol) in cyclopropylam in e
(2 m l) was left stan din g at room tem perature overn igh t an d th en evaporated. Th e residue
was ch rom atograph ed on a silica gel colum n (20 g) in eth yl acetate–aceton e–eth an ol–water
(90:15:11:9) an d th en crystallized from eth er.
Compound 18d : Yield 125 m g (83%). M.p. 171–173 °C. For C15H19N5O2 (301.4) calculated:
59.79% C, 6.36% H, 23.24% N; foun d: 59.53% C, 6.43% H, 22.99% N. n egESI MS, m/z (%):
623 (28) [2 × (M – H) + Na], 301.1 (17) [M], 300 (100) [M – H], 270 (25), 174.1 (43)
[6-(cyclopropylam in o)purin e – H]. 1H NMR: 0.59 m , 2 H, 0.71 m , 2 H, an d 3.00 bs, 1 H
(cyclopropyl); 1.08 m , 1 H (H-3ex); 1.64 dd, 1 H, Jgem = 11.9, J(3en ,2) = 8.5 (H-3en ); 1.94 m ,
1 H (H-5ex); 2.07 m , 1 H (H-2); 2.25 dd, 1 H, Jgem = 13.1, J(5en ,6) = 8.5 (H-5en ); 3.12–3.20 m ,
2 H (CH2O); 4.35 s, 1 H (H-1); 4.73 t, 1 H, J(4,3ex) = J(4,5ex) = 5.2 (H-4); 4.77 t, 1 H,
J(OH,CH2) = 5.4 (OH); 4.82 dd, 1 H, J(6,5en ) = 8.5, J(6,5ex) = 3.3 (H-6); 7.91 bs, 1 H (NH);
8.09 s, 1 H (H-8´); 8.25 bs, 1 H (H-2´). 13C NMR: 6.63 (cyclopropyl CH2); 32.97 (C-3); 40.02
(C-5); 42.54 (C-2); 55.93 (C-6); 63.50 (CH2O); 75.50 (C-4); 82.38 (C-1); 119.02 (C-5´); 138.26
(C-8´); 149.78 (C-4´); 152.55 (C-2´); 155.76 (C-6´).
Compound 19d : Yield 119 m g (79%). M.p. 199–201 °C. For C15H19N5O2 (301.4) calculated:
59.79% C, 6.36% H, 23.24% N; foun d: 59.55% C, 6.51% H, 22.98% N. ESI MS, m/z (%):
324.1 (23), 302.2 (100) [M + H]. 1H NMR: 0.59 m , 2 H, 0.71 m , 2 H, an d 3.02 bs, 1 H
(cyclopropyl); 1.13 ddd, 1 H, Jgem = 12.6, J(3ex,4) = 5.7, J(3ex,2) = 3.9 (H-3ex); 1.74 dd, 1 H,
Jgem = 12.6, J(3en ,2) = 8.5 (H-3en ); 1.92–2.02 m , 2 H (H-2 an d H-6ex); 2.23 dd, 1 H, Jgem
=
13.1, J(6en ,5) = 8.4 (H-6en ); 3.11–3.22 m , 2 H (CH2O); 4.49 d, 1 H, J(4,3ex) = 5.7 (H-4);
4.62 d, 1 H, J(1,6ex) = 5.3 (H-1); 4.75 t, 1 H, J(OH,CH2) = 5.3 (OH); 4.79 dd, 1 H, J(5,6en ) =
8.4, J(5,6ex) = 3.3 (H-5); 7.87 bs, 1 H (NH); 8.09 s, 1 H (H-8´); 8.23 bs, 1 H (H-2´). 13C NMR:
6.66 (cyclopropyl CH2); 24.30 (cyclopropyl CH); 30.12 (C-3); 39.10 (C-6); 44.91 (C-2); 56.37
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(C-5); 63.66 (CH2O); 76.73 (C-1); 80.55 (C-4); 119.06 (C-5´); 138.29 (C-8´); 148.92 (C-4´);
152.47 (C-2´); 155.74 (C-6´).
6-Ch loro-9-[(1R*,2S*,4S*,6R*)-6-(ch lorom eth yl)-7-oxabicyclo[2.2.1]h eptan -2-yl]-
9H-purin e (20) an d
6-Ch loro-9-[(1R*,2S*,4R*,5S*)-5-(ch lorom eth yl)-7-oxabicyclo[2.2.1]h eptan -2-yl]-
9H-purin e (21)
Th ion yl ch loride (0.13 m l, 1.8 m m ol) was added to a solution of h ydroxym eth yl derivative
18a or 19a (140 m g, 0.5 m m ol) in h exam eth ylph osph oram ide (1.8 m l). Th e solution was
h eated to 80 °C for 2.5 h an d th en poured in to a saturated solution of sodium h ydrogen -
carbon ate (10 m l). Th e resultin g m ixture was extracted with eth yl acetate (10 m l) an d th e
extract was wash ed with water (2 × 5 m l), dried over an h ydrous sodium sulfate, an d evapo-
rated. Th e residue was crystallized from eth yl acetate.
Compound 20: Yield 115 m g (77%). M.p. 193–195 °C. For C12H12Cl2N4O (299.2) calcu-
lated: 48.18% C, 4.04% H, 23.70% Cl, 18.73% N; foun d: 47.91% C, 3.91% H, 23.95% Cl,
18.48% N. ESI MS, m/z (%): 316.4 (56), 303.1/301.1/299.1 (10/40/67) [M + H]. 1H NMR:
1.31 dtd, 1 H, Jgem = 12.2, J(5´ex,4´) = J(5´ex,6´) = 4.9, J(5´ex,3´ex) = 2.6 (H-5´ex); 1.85 dd,
1 H, Jgem = 12.2, J(5´en ,6´) = 8.4 (H-5´en ); 2.07 dm , 1 H, Jgem = 13.3 (H-3´ex); 2.32 dd, 1 H,
Jgem = 13.3, J(3´en ,2´) = 8.5 (H-3´en ); 2.44 m , 1 H (H-6´); 3.44 dd, 1 H, Jgem = 10.7,
J(CH2,6´) = 7.2 an d 3.51 dd, 1 H, Jgem = 10.7, J(CH2,6´) = 8.7 (CH2Cl); 4.52 s, 1 H (H-1´);
4.84 t, 1 H, J(4´,3´ex) = J(4´,5´ex) = 5.1 (H-4´); 5.04 dd, 1 H, J(2´,3´en ) = 8.4, J(2´,3´ex) = 3.3
(H-2´); 8.63 s, 1 H (H-8); 8.78 s, 1 H (H-2). 13C NMR: 35.38 (C-5´); 39.25 (C-3´); 42.61 (C-6´);
47.47 (CH2Cl); 56.74 (C-2´); 76.14 (C-4´); 82.63 (C-1´); 130.92 (C-5); 145.20 (C-8); 149.17
(C-6); 151.64 (C-2); 151.83 (C-4).
Compound 21: Yield 123 m g (82%). M.p. 162–163 °C. For C12H12Cl2N4O (299.2) calcu-
lated: 48.18% C, 4.04% H, 23.70% Cl, 18.73% N; foun d: 47.90% C, 3.99% H, 23.95% Cl,
18.46% N. ESI MS, m/z (%): 303.2/301.1/299.0 (13/68/100) [M + H], 288.3 (50). 1H NMR:
1.36 dm , 1 H, Jgem = 13.1 (H-6´ex); 1.96 dd, 1 H, Jgem = 13.0, J(6´en ,5´) = 8.5 (H-6´en );
2.15 dddd, 1 H, Jgem = 13.5, J(3´ex,4´) = 5.7, J(3´ex,2´) = 3.1, Jl.r. = 0.9 (H-3´ex); 2.26 m , 1 H
(H-5´); 2.34 dd, 1 H, Jgem = 13.5, J(3´en ,2´) = 8.4 (H-3´en ); 3.43 dd, 1 H, Jgem = 10.7,
J(CH2,5´) = 7.0 an d 3.52, dd, 1 H, Jgem = 10.7, J(CH2,5´) = 9.0 (CH2Cl); 4.66 d, 1 H,
J(4´,3´ex) = 5.7 (H-4´); 4.69 d, 1 H, J(1´,6´ex) = 5.8 (H-1´); 4.98 dd, 1 H, J(2´,3´en ) = 8.4,
J(2´,3´ex) = 3.1 (H-2´); 8.64 s, 1 H (H-8); 8.77 s, 1 H (H-2). 13C NMR: 32.04 (C-6´); 38.31
(C-3´); 45.04 (C-5´); 47.64 (CH2Cl); 57.01 (C-2´); 77.56 (C-4´); 80.50 (C-1´); 130.92 (C-5);
145.26 (C-8); 149.13 (C-6); 151.60 (C-2); 151.85 (C-4).
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 study, a part of the research
project Z4 055 0506, was supported by the Ministry of Education, Youth and Sports of the Czech
Republic (Centre for New Antivirals and Antineoplastics No. 1M0508), the Programme of Targeted
Projects of Academy of Sciences of the Czech Republic (1QS400550501), and Gilead Sciences, Inc.
(Foster City, CA, U.S.A.).
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