Cytostatic and antiviral 6-arylpurine ribonucleosides VIII+. Synthesis and evaluation of 6-substituted purine 3′-deoxyribonucleosides

Article abstract of DOI:10.1135/cccc20061484

A series of purine 3′-deoxyribonucleosides bearing diverse C-substituents (alkyl, aryl, hetaryl or hydroxymethyl) in the position 6 was prepared by Pd-catalyzed cross-coupling reactions of 6-iodo-9-[2,5-bis-O-(tert- butyldimethylsilyl)-3-deoxy-β-D-ribofur

Full text of DOI:10.1135/cccc20061484

1484
Hocek, Šilhár, Pohl:
CYTOSTATIC AND ANTIVIRAL 6-ARYLPURINE RIBONUCLEOSIDES
VIII+. SYNTHESIS AND EVALUATION OF 6-SUBSTITUTED PURINE
3′-DEOXYRIBONUCLEOSIDES
1,
Michal HOCEK *, Peter ŠILHÁR and Radek POHL
Gilead Sciences & IOCB Research Center, Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, Flemingovo nám. 2, CZ-16610 Prague 6,
1
Czech Republic; e-mail: hocek@uochb.cas.cz
Received Septem ber 29, 2006
Accepted October 3, 2006
A series of purin e 3′-deoxyribon ucleosides bearin g diverse C-substituen ts (alkyl, aryl, h etaryl
or h ydroxym eth yl) in th e position 6 was prepared by Pd-catalyzed cross-couplin g reaction s
of 6-iodo-9-[2,5-bis-O-(tert-butyldim eth ylsilyl)-3-deoxy-β-D-ribofuran osyl]purin e with th e cor-
respon din g organ om etallics followed by deprotection by (HF)3·Et3N. Non e of th e title
3′-deoxyribon ucleoside sh owed an y cytostatic activity or an ti-HCV effect in replicon assay.
Keyw ord s: Purin es; Nucleosides; Cross-couplin g reaction s; An tivirals; HCV; Cordycepin .
Purin e n ucleosides bearin g C-substituen ts in position 6 are biologically
active compounds (Chart 1). 6-Methyl- and 6-ethylpurine nucleosides are cyto-
toxic1. Ribon ucleosides bearin g h ydroxym eth yl2, fluorom eth yl3, difluoro-
m eth yl4 or trifluorom eth yl5 an d aryl or h etaryl6 groups in position 6 of
purin e are all cytostatic. Moreover, som e 6-h etarylpurin e ribon ucleosides
h ave recen tly been reported to exert7 stron g an ti-HCV activities. However,
th e cytotoxic or cytostatic side-effect preven ts clin ical application s as
an ti-HCV drugs. Th erefore, in order to ach ieve selective in h ibition of HCV
RNA polym erase, som e addition al sugar m odification s m ay be pursued.
From th e previous studies it is kn own th at 2′- an d 5′-deoxyribon ucleosides8,
as well as 2′-m eth ylribon ucleosides9 of th e 6-aryl- or 6-h etarylpurin e series
are all in active, wh ile som e carbocyclic h om on ucleosides still exert10
cytostatic effects. Very recen tly, som e L-ribon ucleosides were foun d11 to
exert weak an ti-HCV effect in replicon assay but th eir triph osh ates did n ot
in h ibit HCV RNA polym erase.
+ Part VII see ref.11
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 10, pp. 1484–1496
© 2006 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20061484

Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
1485
In th is paper we report on th e syn th esis an d evaluation of cytostatic an d
an ti-HCV activity of n ovel 3′-deoxyribon ucleosides derived from diverse
6-substituted purin es. 3′-Deoxyribon ucleosides possess broad spectrum of
biological activities, e.g. an tiviral12, an titum or13, an tiparasitical14, an ti-
fun gal15, etc. In corporation of 3′-deoxyribon ucleotides of n atural n ucleo-
bases by RNA polym erase term in ates16 RNA syn th esis.
R
Cytostatic:
N
N
R = aryl, hetaryl,
methyl, ethyl,
benzyl
N
R
N
N
O
HO
N
N
N
?
Anti-HCV:
R = hetaryl
(5-membered)
this work
OH OH
HO
O
R
R
N
N
N
N
N
OH
N
N
O
N
O
HO
OH
OH OH
inactive
CHART 1
6-Substituted purin e n ucleosides
RESULTS AND DISCUSSION
Chemistry
A suitably protected cordycepin was an obvious startin g com poun d of
ch oice. Th ere are m an y m eth ods17 for th e preparation of 3′-deoxyribo-
n ucleosides but n on e of th em is truly practical for larger scale syn th esis. For
our purpose we h ave ch osen an approach recen tly publish ed by Nair et al.18
con sistin g in silylation of aden osin e, separation of th e two disilylated iso-
m ers, isom erization of th e un wan ted 3′,5′-di-TBDMS-aden osin e to desired
2′,5′-isom er, followed by preparation of ph en yl xan th ate an d radical
deoxygen ation usin g Bu3Sn H an d AIBN (stoich iom etric am oun t of th is
in itiator h as been used in con trast to catalytical am oun t reported18 in th e
origin al paper). By th is kn own sequen ce th e disilylated cordycepin 1 was
prepared in total yield of 30% in a 10-g scale. Th en th e aden in e n ucleoside
1 was con verted to th e correspon din g 6-iodopurin e n ucleoside 2 by iodo-
deam in ation (an alogously to kn own 19 iododeam in ation of acetylated
aden osin e) usin g isoam yl n itrite an d CH2I2 in 41% yield (Sch em e 1).
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 10, pp. 1484–1496

1486
Hocek, Šilhár, Pohl:
NH2
NH2
I
N
N
N
N
N
N
CH2I2, i-AmONO
acetonitrile
N
N
ref.18
30%
N
N
O
N
O
N
HO
TBDMSO
TBDMSO
41%
O
2
1
OH OH
OTBDMS
OTBDMS
cross-coupling
R-M, Pd cat.
see Table I
3,4
R
a
b
c
d
e
f
phenyl
3-thienyl
2-thienyl
2-furyl
R
N
R
N
(HF)3.Et3N
THF, r.t.
N
N
N
N
N
N
methyl
ethyl
HO
TBDMSO
O
O
g
h
i
benzyl
BzOCH2
HOCH2
OH
OTBDMS
4a-4g, 4i
3a-3h
NaOMe
3h
3i
SCHEME 1
TABLE I
Cross-couplin g reaction s of 2 with organ om etallics an d deprotection s
Product Deprotection
En try Reagen t
Catalyst
Additive/Solven t
yield, %
yield, %
1
2
3
4
5
6
7
8
Ph B(OH)2
Pd(OAc)2, Cy2Pbiph en a K3PO4, dioxan e
3a (76)
4a (93)
4b (88)
4c (79)
4d (93)
4e (67)
4f (75)
4g (75)
4i (65)b
3-Th ien ylB(OH)2 Pd(OAc)2, Cy2Pbiph en K3PO4, dioxan e 3b (81)
2-Th ien ylSn Bu3 PdCl2(PPh 3)2
DMF
DMF
THF
THF
THF
THF
3c (91)
3d (75)
3e (96)
3f (41)
3g (43)
3h (92)
2-FurylSn Bu3
Me3Al
PdCl2(PPh 3)2
Pd(PPh 3)4
Pd(PPh 3)4
Pd(PPh 3)4
Pd(PPh 3)4
Et3Al
Bn Zn Cl
BzOCH2Zn I
a
b
Cy2Pbiph en , 2-(dicycloh exylph osph in o)biph en yl. Overall yield of two steps: deben zoylation
an d desilylation .
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 10, pp. 1484–1496

Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
1487
TBDMS-protected iodopurin e n ucleoside 2 served as a versatile in ter-
m ediate for furth er tran sform ation s by m ean s of Pd-catalyzed cross-
couplin g reaction s20. To avoid problem s with partial desilylation durin g th e
Suzuki–Miyaura cross-couplin g reaction s with boron ic acids in presen ce of
stron ger bases, we h ave applied a Laksh m an ’s procedure21 m akin g use of a
m ore reactive catalytical system based on Pd(OAc)2 an d 2-(dicycloh exyl-
ph osph in o)biph en yl in presen ce of K3PO4 in an h ydrous dioxan e. Reaction s
of 2 with ph en yl- an d 3-th ien ylboron ic acids un der such con dition s gave
th e desired 6-arylpurin e n ucleosides 3a an d 3b in good yields (Sch em e 1,
Table I). Th e Stille couplin g reaction s of 2 with 2-th ien yl- an d 2-furyl-
stan n an es un der stan dard con dition s (an alogy to ref.6b) gave th e 6-h etaryl-
purin es 3c an d 3d . Cross-couplin g reaction s of 2 with trim eth yl- an d
trieth ylalum in ium (an alogy to ref.22), as well as with ben zylzin c ch loride
(an alogy to ref.6b) un der stan dard con dition s in THF in presen ce of
Pd(PPh 3)4 also gave th e desired 6-alkylpurin e n ucleosides 3e–3g, th ough in
th e two latter cases in rath er m oderate yields. Cross-couplin g of 2 with
(ben zoyloxym eth yl)zin c iodide in presen ce of Pd(PPh 3)4 in THF at room
tem perature (an alogy to ref.2) gave 6-(ben zoyloxym eth yl)purin e 4h in
excellen t yield.
Th e deprotection of th e silylated n ucleoside in term ediates 3 was per-
form ed usin g (HF)3·Et3N reagen t23 at room tem perature in THF. All th ese re-
action s were quite clean an d th e correspon din g title 6-substituted purin e
3′-deoxyribon ucleosides 4a–4g were obtain ed in good yields. In case of th e
(ben zoyloxym eth yl)purin e 4h , th e acyl protection was cleaved by treat-
m en t with NaOMe prior to desilylation to give th e 6-(h ydroxym eth yl)pu-
rin e n ucleoside 4i in 65%.
Biological Activity Evaluation
All th e title 6-substituted purin e 3′-deoxyribon ucleosides 4a–4i were sub-
jected to biological activity screen in g. Th e cytostatic activity in vitro (in h i-
bition of cell growth ) was studied on th e followin g cell cultures: (i) m ouse
leukem ia L1210 cells (ATCC CCL 219); (ii) h um an prom yelocytic leukem ia
HL60 cells (ATCC CCL 240); (iii) h um an cervix carcin om a HeLaS3 cells
(ATCC CCL 2.2) an d (iv) h um an T lym ph oblastoid CCRF-CEM cell lin e
(ATCC CCL 119). An tiviral activity of n ucleosides 4a–4i was evaluated in a
HCV subgen om ic replicon assay24. Non e of th e com poun ds sh owed an y
con siderable cytostatic or an tiviral activity in th ese assays up to 10 µM con -
cen tration . Apparen tly, rem oval of th e 3′-OH group from th e biologically
active 6-substituted purin e ribon ucleosides causes a com plete loss of activ-
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 10, pp. 1484–1496

1488
Hocek, Šilhár, Pohl:
ity an d, un like biologically active 3′-deoxyribon ucleosides12–16 derived from
can on ical n ucleobases, th ey are n ot prom isin g an titum or or an tiviral agen ts.
EXPERIMENTAL
NMR spectra were recorded on Bruker Avan ce 400 MHz (1H at 400 MHz, 13C at 100.6 MHz)
an d Bruker Avan ce 500 MHz (500 MHz for 1H an d 125.8 MHz for 13C) spectrom eters. Ch em ical
sh ifts (in ppm , δ-scale) were referen ced to TMS as in tern al stan dard. Couplin g con stan ts (J)
are given in Hz. Th e assign m en t of carbon s was based on C,H-HSQC an d C,H-HMBC experi-
m en ts. IR spectra (waven um bers in cm –1) were recorded on a Brucker IFS 88 spectrom eter.
Meltin g poin ts were determ in ed on a Kofler block an d are un corrected. Optical rotation s
were m easured at 25 °C on an Autopol IV (Rudolph Research An alytical) polarim eter, [α]D
values are given in 10–1 deg cm 2 g–1. Mass spectra were m easured on a ZAB-EQ (VG An alyti-
cal) spectrom eter usin g FAB (ion ization by Xe, acceleratin g voltage 8 kV, glycerol m atrix).
THF was dried an d fresh ly distilled from sodium /ben zoph en on e, an h ydrous dioxan e an d DMF
were purch ased from Aldrich an d used with out furth er purification . Trim eth ylalum in ium ,
trieth ylalum in ium an d ben zylzin c ch loride were com m ercial (Aldrich ) solution s in THF.
9-[2,5-Bis-O-(tert-butyldim eth ylsilyl)-3-deoxy-β-D-ribofuran osyl]aden in e (1) was prepared ac-
cordin g to literature procedure18 with th e exception of th e use of stoich iom etric (in stead of
catalytic) am oun t of AIBN in th e last step (total yield over th ree steps 30%). Cytostatic activ-
ity tests were perform ed as described in ref.6a an d th e HCV replicon assay as described in
ref.24
9-[2,5-Bis-O-(tert-butyldim eth ylsilyl)-3-deoxy-β-D-ribofuran osyl]-6-iodopurin e (2)
Isoam yl n itrite (20 m l, 150 m m ol) was added to a solution of 1 (4.4 g, 9.2 m m ol) an d CH2I2
(10 m l, 125 m m ol) in aceton itrile (150 m l). Th e m ixture was irradiated by h alogen lam p
(250 W) for 10 m in an d th en it was stirred at 90 °C for 8 h . After coolin g to am bien t
tem perature, th e solven t was evaporated in vacuo, th e residue was dissolved in ch loroform
(200 m l), and the organ ic ph ase was wash ed with saturated aqueous Na2S2O3 an d water (200 m l
each ), dried over an h ydrous MgSO4 an d evaporated. Th e residue was ch rom atograph ed on a
silica gel colum n (200 g, eth yl acetate/h exan es 1:4 to 1:1) to give th e iodopurin e 1 (2.2 g,
41%). Yellow powder, m .p. 48–52 °C, [α]D –35.6 (c 0.20, CHCl3). FAB MS, m/z (rel.%): 591
(13) [M + H], 533 (8), 345 (5), 213 (28), 73 (100). 1H NMR (500 MHz, CDCl3): 0.090, 0.128,
0.134 an d 0.140 (4 × s, 4 × 3 H, CH3Si); 0.90 an d 0.94 (2 × s, 2 × 9 H, (CH3)3C); 1.88 (ddd,
1 H, Jgem = 13.0, J3′b,4′ = 5.7, J3′b,2′ = 2.3, H-3′b); 2.23 (ddd, 1 H, Jgem = 13.0, J3′a,4′ = 9.7, J3′a,2′
4.8, H-3′a); 3.78 (dd, 1 H, Jgem = 11.6, J5′b,4′ = 2.7, H-5′b); 4.14 (dd, 1 H, Jgem = 11.6, J5′a,4′
=
=
2.5, H-5′a); 4.59 (ddt, 1 H, J4′,3′ = 9.7, 5.7, J4′,5′ = 2.7, 2.5, H-4′); 4.66 (dt, 1 H, J2′,3′ = 4.8, 2.3,
J2′,1′ = 1.5, H-2′); 6.05 (d, 1 H, J1′,2′ = 1.5, H-1′); 8.61 (s, 1 H, H-2); 8.64 (s, 1 H, H-8). 13C NMR
(100.6 MHz, CDCl3): –5.38, –5.28, –5.02 an d –4.75 (CH3Si); 17.91 an d 18.59 (C(CH3)3);
25.63 an d 26.04 ((CH3)3C); 33.52 (CH2-3′); 63.56 (CH2-5′); 77.33 (CH-2′); 81.67 (CH-4′);
92.20 (CH-1′); 121.75 (C-6); 139.25 (C-5); 143.02 (CH-8); 147.15 (C-4); 151.68 (CH-2).
IR: 2956, 29231, 2859, 1578, 1552, 1472, 1331, 1257, 1134. Exact m ass (HR FAB MS) foun d:
591.1699; for C22H40IN4O3Si2 (M + H) calculated: 591.1684. For C22H39IN4O3Si2 (590.6) cal-
culated: 44.74% C, 6.66% H, 9.49% N; foun d: 45.05% C, 6.86% H, 9.37% N.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 10, pp. 1484–1496

Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
1489
Gen eral Procedure for th e Suzuki–Miyaura Cross-Couplin g
Dioxan e (4 m l) was added to an argon -purged flask con tain in g th e protected 6-iodopurin e
n ucleoside 2 (295 m g, 0.5 m m ol), K3PO4 (106 m g, 0.5 m m ol), ph en yl- or 3-th ien ylboron ic
acid (1 m m ol), Pd(OAc)2 (10 m g, 0.05 m m ol) an d (dicycloh exylph osph in o)biph en yl (25 m g,
0.07 m m ol). Th e m ixture was th en stirred at 100 °C for 10 h . After coolin g to am bien t tem -
perature th e m ixture was evaporated in vacuo an d th e residue was ch rom atograph ed on a
silica gel colum n (50 g, eth yl acetate/h exan es 1:2 to 9:1). Evaporation an d dryin g of th e
product con tain in g fraction s afforded 6-arylpurin es 3a or 3b as oils.
9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-β-D-ribofuranosyl]-6-phenylpurine (3a ). Yield
76%. Colorless oil. FAB MS, m/z (rel.%): 541 (25) [M + H], 483 (6), 213 (11), 197 (48), 73 (100).
1H NMR (400 MHz, CDCl3): 0.10, 0.14, 0.15 an d 0.16 (4 × s, 4 × 3 H, CH3Si); 0.91 an d 0.95
(2 × s, 2 × 9 H, (CH3)3C); 1.91 (ddd, 1 H, Jgem = 13.0, J3′b,4′ = 5.7, J3′b,2′ = 2.4, H-3′b); 2.27
(ddd, 1 H, Jgem = 13.0, J3′a,4′ = 9.5, J3′a,2′ = 4.9, H-3′a); 3.80 (dd, 1 H, Jgem = 11.5, J5′b,4′ = 3.0,
H-5′b); 4.13 (dd, 1 H, Jgem = 11.5, J5′a,4′ = 2.8, H-5′a); 4.60 (ddt, 1 H, J4′,3′ = 9.5, 5.7, J4′,5′
=
3.0, 2.8, H-4′); 4.73 (dt, 1 H, J2′,3′ = 4.9, 2.4, J2′,1′ = 1.6, H-2′); 6.13 (d, 1 H, J1′,2′ = 1.6, H-1′);
7.49–7.62 (m , 3 H, H-m,p-Ph ); 8.61 (s, 1 H, H-8); 8.79 (m , 2 H, H-o-Ph ); 8.99 (s, 1 H, H-2).
13C NMR (100.6 MHz, CDCl3): –5.39, –5.27, –5.00 an d –4.70 (CH3Si); 17.95 an d 18.58
(C(CH3)3); 25.61 an d 26.05 ((CH3)3C); 33.88 (CH2-3′); 63.87 (CH2-5′); 77.19 (CH-2′); 81.38
(CH-4′); 91.94 (CH-1′); 128.63 (CH-m-Ph ); 129.78 (CH-o-Ph ); 130.83 (CH-p-Ph ); 131.76 (C-5);
135.81 (C-i-Ph ); 142.78 (CH-8); 151.81 (C-4); 152.15 (CH-2); 154.63 (C-6). Exact m ass (HR
FAB MS) foun d: 541.3020; for C28H45N4O3Si2 (M + H) calculated: 541.3030.
9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-β-D-ribofuranosyl]-6-(3-thienyl)purine (3b). Yield
81%. Colorless oil. FAB MS, m/z (rel.%): 547 (100) [M + H], 489 (25), 213 (6), 203 (11), 73
(60). 1H NMR (400 MHz, CDCl3): 0.10, 0.14, 0.15 an d 0.16 (4 × s, 4 × 3 H, CH3Si); 0.91 an d
0.96 (2 × s, 2 × 9 H, (CH3)3C); 1.90 (ddd, 1 H, Jgem = 13.0, J3′b,4′ = 5.7, J3′b,2′ = 2.3, H-3′b);
2.28 (ddd, 1 H, Jgem = 13.0, J3′a,4′ = 9.6, J3′a,2′ = 4.9, H-3′a); 3.80 (dd, 1 H, Jgem = 11.5, J5′b,4′
=
2.9, H-5′b); 4.14 (dd, 1 H, Jgem = 11.5, J5′a,4′ = 2.6, H-5′a); 4.60 (ddt, 1 H, J4′,3′ = 9.6, 5.7,
J4′,5′ = 2.9, 2.6, H-4′); 4.69 (dt, 1 H, J2′,3′ = 4.9, 2.3, J2′,1′ = 1.6, H-2′); 6.11 (d, 1 H, J1′,2′ = 1.6,
H-1′); 7.45 (dd, 1 H, J5′′,4′′ = 5.1, J5′′,2′′ = 3.0, H-5′′); 8.29 (dd, 1 H, J4′′,5′′ = 5.0, J4′′,2′′ = 1.2,
H-4′′); 8.62 (s, 1 H, H-8); 8.91 (s, 1 H, H-2); 8.93 (dd, 1 H, J2′′,5′′ = 3.0, J2′′,4′′ = 1.2, H-2′′). 13C
NMR (100.6 MHz, CDCl3): –5.42, –5.30, –5.02 an d –4.71 (CH3Si); 17.95 an d 18.57 (C(CH3)3);
25.69 an d 26.05 ((CH3)3C); 33.74 (CH2-3′); 63.77 (CH2-5′); 77.27 (CH-2′); 81.38 (CH-4′);
91.88 (CH-1′); 125.74 (CH-5′′); 127.78 (CH-4′′); 130.61 (CH-2′′); 130.79 (C-5); 138.35 (C-3′′);
142.73 (CH-8); 150.56 (C-6); 151.49 (C-4); 152.29 (CH-2). Exact m ass (HR FAB MS) foun d:
547.2579; for C26H42N4O3SSi2 (M + H) calculated: 547.2594.
Gen eral Procedure for th e Stille Cross-Couplin g
DMF (2.5 m l) was added to an argon -purged flask con tain in g th e 6-iodopurin e 2 (295 m g,
0.5 m m ol), a 2-th ien yl- or 2-furyl(tributyl)tin (1 m m ol) an d PdCl2(PPh 3)2 (20 m g, 0.03 m m ol).
Th e m ixture was stirred at 110 °C for 12 h an d th e solven t was evaporated in vacuo. Th e
residue was ch rom atograph ed on a silica gel colum n (50 g, eth yl acetate/h exan es 1:5 to 9:1)
to give th e 6-h etarylpurin e n ucleosides 3c or 3d as oils.
9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-β-D-ribofuranosyl]-6-(2-thienyl)purine (3c). Yield
91%. Colorless oil. FAB MS, m/z (rel.%): 547 (23) [M + H], 489 (13), 213 (12), 203 (25), 73 (100).
1H NMR (400 MHz, CDCl3): 0.10, 0.14, 0.15 an d 0.16 (4 × s, 4 × 3 H, CH3Si); 0.91 an d 0.96
(2 × s, 2 × 9 H, (CH3)3C); 1.90 (ddd, 1 H, Jgem = 13.0, J3′b,4′ = 6.2, J3′b,2′ = 2.3, H-3′b); 2.27
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Hocek, Šilhár, Pohl:
(ddd, 1 H, Jgem = 13.0, J3′a,4′ = 9.6, J3′a,2′ = 4.9, H-3′a); 3.80 (dd, 1 H, Jgem = 11.5, J5′b,4′ = 3.0,
H-5′b); 4.13 (dd, 1 H, Jgem = 11.5, J5′a,4′ = 2.7, H-5′a); 4.60 (ddt, 1 H, J4′,3′ = 9.6, 6.2, J4′,5′
=
3.0, 2.7, H-4′); 4.69 (dt, 1 H, J2′,3′ = 4.9, 2.3, J2′,1′ = 1.6, H-2′); 6.10 (d, 1 H, J1′,2′ = 1.6, H-1′);
7.26 (dd, 1 H, J4′′,5′′ = 5.0, J4′′,3′′ = 3.7, H-4); 7.60 (dd, 1 H, J5′′,4′′ = 5.0, J5′′,3′′ = 1.2, H-5′′); 8.61
(s, 1 H, H-8); 8.70 (dd, 1 H, J3′′,4′′ = 3.7, J3′′,5′′ = 1.2, H-3′′); 8.85 (s, 1 H, H-2). 13C NMR (100.6 MHz,
CDCl3): –5.41, –5.30, –5.02 an d –4.71 (CH3Si); 17.94 an d 18.56 (C(CH3)3); 25.68 an d 26.04
((CH3)3C); 33.78 (CH2-3′); 63.80 (CH2-5′); 77.24 (CH-2′); 81.40 (CH-4′); 91.92 (CH-1′);
128.81 (CH-4′′); 129.58 (C-5); 130.41 (CH-5′′); 132.80 (CH-3′′); 140.21 (C-2′′); 142.86 (CH-8);
149.87 (C-6); 151.30 (C-4); 152.20 (CH-2). Exact m ass (HR FAB MS) foun d: 547.2588; for
C
26H42N4O3SSi2 (M + H) calculated: 547.2594.
9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-β-D-ribofuranosyl]-6-(2-furyl)purine (3d ). Yield
75%. Colorless oil. FAB MS, m/z (rel.%): 531 (5) [M + H], 473 (2), 213 (8), 187 (10), 73 (100).
1H NMR (400 MHz, CDCl3): 0.10, 0.13, 0.14 an d 0.15 (4 × s, 4 × 3 H, CH3Si); 0.91 an d 0.95
(2 × s, 2 × 9 H, (CH3)3C); 1.90 (ddd, 1 H, Jgem = 13.0, J3′b,4′ = 5.7, J3′b,2′ = 2.4, H-3′b); 2.26
(ddd, 1 H, Jgem = 13.0, J3′a,4′ = 9.6, J3′a,2′ = 5.0, H-3′a); 3.80 (dd, 1 H, Jgem = 11.5, J5′b,4′ = 3.0,
H-5′b); 4.13 (dd, 1 H, Jgem = 11.5, J5′a,4′ = 2.7, H-5′a); 4.60 (ddt, 1 H, J4′,3′ = 9.6, 5.7, J4′,5′
=
3.0, 2.7, H-4′); 4.70 (dt, 1 H, J2′,3′ = 5.0, 2.4, J2′,1′ = 1.6, H-2′); 6.10 (d, 1 H, J1′,2′ = 1.6, H-1′);
6.67 (dd, 1 H, J4′′,3′′ = 3.4, J4′′,5′′ = 1.8, H-4′′); 7.76 (dd, 1 H, J5′′,4′′ = 1.8, J5′′,3′′ = 0.8, H-5′′);
7.89 (dd, 1 H, J3′′,4′′ = 3.4, J3′′,5′′ = 0.8, H-3′′); 8.60 (s, 1 H, H-8); 8.93 (s, 1 H, H-2). 13C NMR
(100.6 MHz, CDCl3): –5.41, –5.30, –5.01 an d –4.72 (CH3Si); 17.93 an d 18.57 (C(CH3)3);
25.67 an d 26.04 ((CH3)3C); 33.79 (CH2-3′); 63.82 (CH2-5′); 77.20 (CH-2′); 81.41 (CH-4′);
91.93 (CH-1′); 112.60 (CH-4′′); 117.49 (CH-3′′); 129.07 (C-5); 143.06 (CH-8); 145.66 (CH-5′′);
145.71 (C-6); 149.65 (C-2′′); 151.29 (C-4); 152.36 (CH-2). Exact m ass (HR FAB MS) foun d:
531.2835; for C26H42N4O4Si2 (M + H) calculated: 531.2823.
Gen eral Procedure for th e Cross-Couplin g Reaction s with Trialkylalum in ium or Ben zylzin c
Ch loride
THF (12 m l) was added to an argon -purged flask con tain in g th e 6-iodopurin e 2 (295 m g,
0.5 m m ol) an d Pd(PPh 3)4 (30 m g, 0.025 m m ol). Th e m ixture was stirred at am bien t tem pera-
ture for 10 m in an d, after dissolution of th e solids, a com m ercial solution of trim eth yl- or
trieth ylalum in ium or ben zylzin c ch loride in THF (2 m m ol) was added dropwise (with in
10 m in ) at am bien t tem perature. Th e stirrin g at am bien t tem perature was con tin ued for 15 m in
followed by stirrin g at 70 °C for 8 h . Th en th e reaction m ixture was allowed to stan d at am -
bien t tem perature overn igh t an d poured in to saturated aqueous NH4Cl (10 m l). To th is m ix-
ture, saturated aqueous Na2EDTA (10 m l) was added an d th e m ixture was stirred for 10 m in .
Th en th e reaction m ixture was extracted with eth yl acetate (3 × 20 m l) an d th e collected or-
gan ic layers were wash ed with saturated aqueous Na2EDTA (20 m l) an d brin e (20 m l), dried
over an h ydrous MgSO4 an d evaporated in vacuo. Colum n ch rom atograph y of th e residue on
silica gel (50 g, eth yl acetate/h exan es 1:2 to 9:1) afforded, after evaporation an d dryin g, th e
6-h etaryl- or 6-ben zylpurin es 3e–3g as oils.
9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-β-D-ribofuranosyl]-6-methylpurine (3e). Yield
96%. Colorless oil. FAB MS, m/z (rel.%): 479 (8) [M + H], 421 (2), 365 (3), 135 (40), 73 (100).
1H NMR (400 MHz, CDCl3): 0.101, 0.145, 0.150 an d 0.166 (4 × s, 4 × 3 H, CH3Si); 0.91 an d
0.96 (2 × s, 2 × 9 H, (CH3)3C); 1.89 (ddd, 1 H, Jgem = 13.1, J3′b,4′ = 5.5, J3′b,2′ = 2.1, H-3′b);
2.27 (ddd, 1 H, Jgem = 13.1, J3′a,4′ = 9.9, J3′a,2′ = 4.7, H-3′a); 3.10 (s, 3 H, CH3); 3.80 (dd, 1 H,
Jgem = 11.8, J5′b,4′ = 2.3, H-5′b); 4.21 (dd, 1 H, Jgem = 11.8, J5′a,4′ = 2.3, H-5′a); 4.69 (dt, 1 H,
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Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
1491
J2′,3′ = 4.7, 2.1, J2′,1′ = 1.3, H-2′); 4.64 (ddt, 1 H, J4′,3′ = 9.9, 5.5, J4′,5′ = 2.3, H-4′); 6.12 (d, 1 H,
J1′,2′ = 1.3, H-1′); 8.92 (s, 1 H, H-8); 8.99 (s, 1 H, H-2). 13C NMR (100.6 MHz, CDCl3): –5.42,
–5.33, –4.99 an d –4.75 (CH3Si); 17.28 (CH3); 17.92 an d 18.58 (C(CH3)3); 25.62 an d 26.02
((CH3)3C); 33.16 (CH2-3′); 63.26 (CH2-5′); 77.63 (CH-2′); 82.03 (CH-4′); 92.36 (CH-1′);
133.30 (C-5); 145.45 (CH-8); 148.24 (CH-2); 150.74 (C-4); 156.23 (C-6). Exact m ass (HR FAB
MS) foun d: 479.2886; for C23H43N4O3Si2 (M + H) calculated: 479.2874.
9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-β-D-ribofuranosyl]-6-ethylpurine (3f). Yield 41%.
Colorless oil. FAB MS, m/z (rel.%): 493 (4) [M + H], 435 (2), 149 (10), 73 (100). 1H NMR (400 MHz,
CDCl3): 0.086, 0.123, 0.132 an d 0.136 (4 × s, 4 × 3 H, CH3Si); 0.90 an d 0.94 (2 × s, 2 × 9 H,
(CH3)3C); 1.44 (t, 3 H, Jvic = 7.6, CH3CH2); 1.89 (ddd, 1 H, Jgem = 13.0, J3′b,4′ = 5.7, J3′b,2′ = 2.4,
H-3′b); 2.26 (ddd, 1 H, Jgem = 13.0, J3′a,4′ = 9.6, J3′a,2′ = 5.0, H-3′a); 3.23 (q, 2 H, Jvic = 7.6,
CH2CH3); 3.78 (dd, 1 H, Jgem = 11.5, J5′b,4′ = 2.9, H-5′b); 4.12 (dd, 1 H, Jgem = 11.5, J5′a,4′
=
2.7, H-5′a); 4.58 (ddt, 1 H, J4′,3′ = 9.6, 5.7, J4′,5′ = 2.9, 2.7, H-4′); 4.69 (dt, 1 H, J2′,3′ = 5.0, 2.4,
J2′,1′ = 1.6, H-2′); 6.07 (d, 1 H, J1′,2′ = 1.6, H-1′); 8.50 (s, 1 H, H-8); 8.85 (s, 1 H, H-2). 13C NMR
(100.6 MHz, CDCl3): –5.41, –5.29, –5.04 an d –4.74 (CH3Si); 12.59 (CH3CH2); 17.93 an d
18.57 (C(CH3)3); 25.67 an d 26.03 ((CH3)3C); 26.41 (CH2CH3); 33.79 (CH2-3′); 63.76 (CH2-5′);
77.20 (CH-2′); 81.33 (CH-4′); 91.85 (CH-1′); 132.90 (C-5); 142.08 (CH-8); 150.01 (C-4);
152.23 (CH-2); 163.61 (C-6). Exact m ass (HR FAB MS) foun d: 493.3035; for C24H45N4O3Si2
(M + H) calculated: 493.3030.
9-[2,5-Bis-O-(tert-butyldimethylsilyl)-3-deoxy-β-D-ribofuranosyl]-6-benzylpurine (3g). Yield 43%.
Colorless oil. FAB MS, m/z (rel.%): 555 (3) [M + H], 211 (10), 73 (100). 1H NMR (400 MHz,
CDCl3): 0.081, 0.120, 0.126 an d 0.138 (4 × s, 4 × 3 H, CH3Si); 0.89 an d 0.94 (2 × s, 2 × 9 H,
(CH3)3C); 1.87 (ddd, 1 H, Jgem = 13.0, J3′b,4′ = 5.7, J3′b,2′ = 2.2, H-3′b); 2.23 (ddd, 1 H, Jgem
=
13.0, J3′a,4′ = 9.7, J3′a,2′ = 4.9, H-3′a); 3.78 (dd, 1 H, Jgem = 11.6, J5′b,4′ = 2.9, H-5′b); 4.11 (dd,
1 H, Jgem = 11.6, J5′a,4′ = 2.7, H-5′a); 4.47 an d 4.57 (2 × d, 2 H, Jgem = 13.6, CH2Ph ); 4.58
(ddt, 1 H, J4′,3′ = 9.7, 5.7, J4′,5′ = 2.9, 2.7, H-4′); 4.68 (dt, 1 H, J2′,3′ = 4.9, 2.2, J2′,1′ = 1.5, H-2′);
6.05 (d, 1 H, J1′,2′ = 1.5, H-1′); 7.19 (m , 1 H, H-p-Ph ); 7.27 (m , 1 H, H-m-Ph ); 7.46 (m , 1 H,
H-o-Ph ); 8.54 (s, 1 H, H-8); 8.84 (s, 1 H, H-2). 13C NMR (100.6 MHz, CDCl3): –5.41, –5.32,
–5.09 an d –4.89 (CH3Si); 17.83 an d 18.49 (C(CH3)3); 25.67 an d 26.03 ((CH3)3C); 33.71
(CH2-3′); 39.40 (CH2Ph ); 63.70 (CH2-5′); 77.15 (CH-2′); 81.46 (CH-4′); 91.97 (CH-1′); 126.52
(CH-p-Ph ); 128.48 (CH-m-Ph ); 129.39 (CH-o-Ph ); 133.09 (C-5); 137.97 (C-i-Ph ); 142.56
(CH-8); 150.36 (C-4); 152.27 (CH-2); 160.40 (C-6). Exact m ass (HR FAB MS) foun d: 555.3199;
for C29H47N4O3Si2 (M + H) calculated: 555.3187.
6-(Ben zoyloxym eth yl)-9-[2,5-bis-O-(tert-butyldim eth ylsilyl)-3-deoxy-β-D-ribofuran osyl]-
purin e (3h )
A solution of 0.9 M (ben zoyloxym eth yl)zin c iodide in THF (1.6 m l, 1.44 m m ol)2 was added
at room tem perature to a solution of 2 (330 m g, 0.56 m m ol), Pd(PPh 3)4 (32 m g, 0.028 m m ol)
in THF (5 m l) un der argon an d stirred at room tem perature for 6 h . Th e reaction was
quen ch ed with 1 M NaH2PO4 (20 m l) an d extracted with CHCl3 (4 × 20 m l). Collected or-
gan ic ph ases were dried over MgSO4, filtered an d th e solven t was evaporated. Colum n ch ro-
m atograph y of th e residue on silica gel (50 g, eth yl acetate/h exan es 1:2 to 9:1) afforded,
after evaporation an d dryin g, th e product 3h (308 m g, 92%) as oil. FAB MS, m/z (rel.%): 599
(6) [M + H], 255 (4), 132 (5), 115 (7), 105 (14), 59 (19). 1H NMR (500 MHz, CDCl3): 0.10,
0.11, 0.12 an d 0.16 (4 × s, 4 × 3 H, CH3Si); 0.91 an d 0.92 (2 × s, 2 × 9 H, (CH3)3C); 1.85
(ddd, 1 H, Jgem = 13.0, J3′b,4′ = 5.5, J3′b,2′ = 1.9, H-3′b); 2.26 (ddd, 1 H, Jgem = 13.0, J3′a,4′
=
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 10, pp. 1484–1496

1492
Hocek, Šilhár, Pohl:
10.0, J3′a,2′ = 4.7, H-3′a); 3.78 (dd, 1 H, Jgem = 11.6, J5′b,4′ = 2.6, H-5′b); 4.15 (dd, 1 H, Jgem
=
11.6, J5′a,4′ = 2.5, H-5′a); 4.60 (ddt, 1 H, J4′,3′ = 10.0, 5.5, J4′,5′ = 2.6, 2.5, H-4′); 4.64 (dt, 1 H,
J2′,3′ = 4.7, 1.9, J2′,1′ = 1.3, H-2′); 5.85 an d 5.89 (2 × d, 2 H, Jgem = 14.3, CH2O); 6.10 (d, 1 H,
J1′,2′ = 1.3, H-1′); 7.45 (m , 2 H, H-m-Ph ); 7.57 (m , 1 H, H-p-Ph ); 8.16 (m , 2 H, H-o-Ph ); 8.66
(s, 1 H, H-8); 8.92 (s, 1 H, H-2). 13C NMR (125.8 MHz, CDCl3): –5.46 an d –5.03 (CH3Si);
17.93 an d 18.53 (C(CH3)3); 25.67 an d 25.99 ((CH3)3C); 33.38 (CH2-3′); 63.25 (CH2O); 63.44
(CH2-5′); 77.44 (CH-2′); 81.62 (CH-4′); 92.00 (CH-1′); 128.32 (CH-m-Ph ); 129.91 (C-i-Ph );
130.03 (CH-o-Ph ); 132.44 (C-5); 133.03 (CH-p-Ph ); 143.40 (CH-8); 150.91 (C-4); 152.07
(CH-2); 154.91 (C-6); 166.42 (CO). IR (CCl4): 3124, 3066, 2899, 1731, 1595, 1492, 1472,
1463, 1331, 1272, 1211, 642. Exact m ass (FAB HR MS) foun d: 599.3077; for C30H47N4O5Si2
calculated: 599.3085.
Gen eral Procedure for Deprotection of Silylated Nucleosides
(HF)3·Et3N (250 µl, 1.9 m m ol) was added to a solution of a TBDMS-protected n ucleoside 3
(0.3–0.5 m m ol) in THF (12 m l) in a PE vial an d th e m ixture was stirred at room tem perature
overn igh t. Th en th e solven t was evaporated an d th e residue was ch rom atograph ed on a
silica gel colum n (50 g, eth yl acetate/MeOH 1:0 to 4:1). Th e crude products 4 were crystal-
lized from MeOH/eth yl acetate/h eptan e.
9-(3-Deoxy-β-D-ribofuranosyl)-6-phenylpurine (4a ). Yield 93%. Colorless crystals, m .p.
181–184 °C, [α]D –57.5 (c 0.24, DMF). FAB MS, m/z (rel.%): 313 (60) [M + H], 197 (100). 1H NMR
(400 MHz, DMSO-d6): 1.95 (ddd, 1 H, Jgem = 13.2, J3′b,4′ = 6.1, J3′b,2′ = 2.5, H-3′b); 2.30 (ddd,
1 H, Jgem = 13.2, J3′a,4′ = 9.4, J3′a,2′ = 5.5, H-3′a); 3.58 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.4,
J5′b,4′ = 3.8, H-5′b); 3.77 (dd, 1 H, Jgem = 12.0, J5′a,OH = 5.4, J5′a,4′ = 3.3, H-5′a); 4.44 (ddt, 1 H,
J4′,3′ = 9.4, 6.1, J4′,5′ = 3.8, 3.3, H-4′); 4.67 (m , 1 H, J2′,3′ = 5.5, 2.5, J2′,OH = 4.0, J2′,1′ = 1.9,
H-2′); 5.11 (t, 1 H, JOH,5′ = 5.4, OH-5′); 5.77 (d, 1 H, JOH,2′ = 4.0, OH-2′); 6.09 (d, 1 H, J1′,2′
=
1.9, H-1′); 7.55–7.64 (m , 3 H, H-m,p-Ph ); 8.83 (m , 2 H, H-o-Ph ); 8.93 (s, 1 H, H-8); 9.01 (s,
1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6): 33.88 (CH2-3′); 62.29 (CH2-5′); 75.10 (CH-2′);
81.48 (CH-4′); 91.12 (CH-1′); 128.86 (CH-m-Ph ); 129.53 (CH-o-Ph ); 130.96 (C-5); 131.28
(CH-p-Ph ); 135.50 (C-i-Ph ); 144.56 (CH-8); 151.97 (C-4); 151.99 (CH-2); 152.92 (C-6). Exact
m ass (HR FAB MS) foun d: 313.1311; for C16H17N4O3 (M + H) calculated: 313.1301. For
C
16H16N4O3 (312.3) calculated: 61.53% C, 5.16% H, 17.94% N; foun d: 61.31% C, 5.21% H,
17.62% N.
9-(3-Deoxy-β-D-ribofuranosyl)-6-(3-thienyl)purine (4b ). Yield 88%. Colorless crystals, m .p.
194–196 °C, [α]D –60.8 (c 0.28, DMF). FAB MS, m/z (rel.%): 319 (60) [M + H], 203 (100). 1H NMR
(400 MHz, DMSO-d6): 1.94 (ddd, 1 H, Jgem = 13.2, J3′b,4′ = 6.1, J3′b,2′ = 2.5, H-3′b); 2.30 (ddd,
1 H, Jgem = 13.2, J3′a,4′ = 9.4, J3′a,2′ = 5.5, H-3′a); 3.57 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.4,
J5′b,4′ = 3.8, H-5′b); 3.76 (dd, 1 H, Jgem = 12.0, J5′a,OH = 5.4, J5′a,4′ = 3.3, H-5′a); 4.43 (ddt, 1 H,
J4′,3′ = 9.4, 6.1, J4′,5′ = 3.8, 3.3, H-4′); 4.66 (m , 1 H, J2′,3′ = 5.5, 2.5, J2′,OH = 3.4, J2′,1′ = 1.9,
H-2′); 5.10 (t, 1 H, JOH,5′ = 5.4, OH-5′); 5.76 (d, 1 H, JOH,2′ = 3.4, OH-2′); 6.07 (d, 1 H, J1′,2′
=
1.9, H-1′); 7.76 (dd, 1 H, J5′′,4′′ = 5.1, J5′′,2′′ = 3.0, H-5′′); 8.24 (dd, 1 H, J4′′,5′′ = 5.1, J4′′,2′′ = 1.2,
H-4′′); 8.90 (s, 1 H, H-8); 8.93 (s, 1 H, H-2); 8.96 (dd, 1 H, J2′′,5′′ = 3.0, J2′′,4′′ = 1.2, H-2′′).
13C NMR (100.6 MHz, DMSO-d6): 33.89 (CH2-3′); 62.31 (CH2-5′); 75.09 (CH-2′); 81.45
(CH-4′); 91.08 (CH-1′); 127.29 (CH-5′′); 127.54 (CH-4′′); 129.89 (C-5); 130.88 (CH-2′′);
138.04 (C-3′′); 144.48 (CH-8); 149.46 (C-6); 151.60 (C-4); 152.17 (CH-2). Exact m ass (HR FAB
MS) foun d: 319.0861; for C14H15N4O3S (M + H) calculated: 319.0865. For C14H14N4O3S
(318.4) calculated: 52.82% C, 4.43% H, 17.60% N; foun d: 52.55% C, 4.50% H, 17.40% N.
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Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
1493
9-(3-Deoxy-β-D-ribofuranosyl)-6-(2-thienyl)purine (4c). Yield 79%. Colorless crystals, m .p.
190–192 °C, [α]D –61.5 (c 0.21, DMF). FAB MS, m/z (rel.%): 319 (60) [M + H], 203 (100). 1H NMR
(400 MHz, DMSO-d6): 1.94 (ddd, 1 H, Jgem = 13.2, J3′b,4′ = 6.1, J3′b,2′ = 2.5, H-3′b); 2.29 (ddd,
1 H, Jgem = 13.2, J3′a,4′ = 9.5, J3′a,2′ = 5.5, H-3′a); 3.57 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.5,
J5′b,4′ = 3.8, H-5′b); 3.76 (dd, 1 H, Jgem = 12.0, J5′a,OH = 5.4, J5′a,4′ = 3.9, H-5′a); 4.43 (ddt, 1 H,
J4′,3′ = 9.5, 6.1, J4′,5′ = 3.9, 3.8, H-4′); 4.65 (m , 1 H, J2′,3′ = 5.5, 2.5, J2′,OH = 4.0, J2′,1′ = 1.9,
H-2′); 5.10 (t, 1 H, JOH,5′ = 5.5, 5.4, OH-5′); 5.76 (d, 1 H, JOH,2′ = 4.0, OH-2′); 6.06 (d, 1 H,
J1′,2′ = 1.9, H-1′); 7.34 (dd, 1 H, J4′′,5′′ = 5.0, J4′′,3′′ = 3.7, H-4′′); 7.92 (dd, 1 H, J5′′,4′′ = 5.0, J5′′,3′′
=
1.2, H-5′′); 8.63 (dd, 1 H, J3′′,4′′ = 3.7, J3′′,5′′ = 1.2, H-3′′); 8.86 (s, 1 H, H-8); 8.90 (s, 1 H, H-2).
13C NMR (100.6 MHz, DMSO-d6): 33.86 (CH2-3′); 62.29 (CH2-5′); 75.12 (CH-2′); 81.51
(CH-4′); 91.13 (CH-1′); 128.69 (C-5); 129.26 (CH-4′′); 131.91 (CH-5′′); 132.57 (CH-3′′);
139.84 (C-2′′); 144.66 (CH-8); 148.72 (C-6); 151.41 (C-4); 152.08 (CH-2). Exact m ass (HR FAB
MS) foun d: 319.0879; for C14H15N4O3S (M + H) calculated: 319.0865. For C14H14N4O3S
(318.4) calculated: 52.82% C, 4.43% H, 17.60% N; foun d: 52.58% C, 4.42% H, 17.29% N.
9-(3-Deoxy-β-D-ribofuranosyl)-6-(2-furyl)purine (4d ). Yield 93%. Colorless crystals, m .p.
103–110 °C, [α]D –54.4 (c 0.24, DMF). FAB MS, m/z (rel.%): 303 (35) [M + H], 187 (100). 1H NMR
(400 MHz, DMSO-d6): 1.93 (ddd, 1 H, Jgem = 13.2, J3′b,4′ = 6.1, J3′b,2′ = 2.5, H-3′b); 2.29 (ddd,
1 H, Jgem = 13.2, J3′a,4′ = 9.4, J3′a,2′ = 5.4, H-3′a); 3.57 (ddd, 1 H, Jgem = 12.1, J5′b,OH = 5.5,
J5′b,4′ = 3.9, H-5′b); 3.75 (dd, 1 H, Jgem = 12.1, J5′a,OH = 5.4, J5′a,4′ = 3.3, H-5′a); 4.42 (ddt, 1 H,
J4′,3′ = 9.4, 6.1, J4′,5′ = 3.9, 3.3, H-4′); 4.64 (m , 1 H, J2′,3′ = 5.4, 2.5, J2′,OH = 4.0, J2′,1′ = 1.9,
H-2′); 5.10 (t, 1 H, JOH,5′ = 5.5, 5.4, OH-5′); 5.76 (d, 1 H, JOH,2′ = 4.0, OH-2′); 6.05 (d, 1 H,
J1′,2′ = 1.9, H-1′); 6.82 (dd, 1 H, J4′′,3′′ = 3.5, J4′′,5′′ = 1.7, H-4′′); 7.89 (dd, 1 H, J3′′,4′′ = 3.5, J3′′,5′′
=
0.9, H-3′′); 8.07 (dd, 1 H, J5′′,4′′ = 1.7, J5′′,3′′ = 0.9, H-5′′); 8.80 (s, 1 H, H-8); 8.90 (s, 1 H, H-2).
13C NMR (100.6 MHz, DMSO-d6): 33.86 (CH2-3′); 62.28 (CH2-5′); 75.09 (CH-2′); 81.48
(CH-4′); 91.08 (CH-1′); 113.07 (CH-4′′); 117.57 (CH-3′′); 128.34 (C-5); 144.59 (CH-8); 144.84
(C-6); 146.67 (CH-5′′); 149.19 (C-2′′); 151.30 (C-4); 152.10 (CH-2). Exact m ass (HR FAB MS)
foun d: 303.1078; for C14H15N4O4 (M + H) calculated: 303.1093. For C14H14N4O4·H2O (320.3)
calculated: 52.50% C, 5.03% H, 17.49% N; foun d: 52.21% C, 5.07% H, 16.98% N.
9-(3-Deoxy-β-D-ribofuranosyl)-6-methylpurine (4e). Yield 67%. Am orph ous solid, [α]D –42.8
(c 0.26, DMF). FAB MS, m/z (rel.%): 251 (10) [M + H], 115 (100). 1H NMR (400 MHz,
DMSO-d6): 1.93 (ddd, 1 H, Jgem = 13.2, J3′b,4′ = 6.1, J3′b,2′ = 2.6, H-3′b); 2.27 (ddd, 1 H, Jgem
13.2, J3′a,4′ = 9.2, J3′a,2′ = 5.5, H-3′a); 2.72 (s, 3 H, CH3); 3.54 (ddd, 1 H, Jgem = 12.0, J5′b,OH
=
=
5.5, J5′b,4′ = 3.9, H-5′b); 3.71 (dd, 1 H, Jgem = 12.0, J5′a,OH = 5.4, J5′a,4′ = 3.4, H-5′a); 4.40 (ddt,
1 H, J4′,3′ = 9.2, 6.1, J4′,5′ = 3.9, 3.4, H-4′); 4.61 (m , 1 H, J2′,3′ = 5.5, 2.6, J2′,OH = 4.1, J2′,1′
=
2.0, H-2′); 5.09 (t, 1 H, JOH,5′ = 5.5, 5.4, OH-5′); 5.76 (d, 1 H, JOH,2′ = 4.1, OH-2′); 6.01 (d,
1 H, J1′,2′ = 2.0, H-1′); 8.76 (s, 1 H, H-8); 8.78 (s, 1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6):
19.25 (CH3); 34.02 (CH2-3′); 62.39 (CH2-5′); 74.98 (CH-2′); 81.32 (CH-4′); 91.02 (CH-1′);
132.94 (C-5); 143.58 (CH-8); 149.82 (C-4); 151.74 (CH-2); 158.26 (C-6). Exact m ass (HR FAB
MS) foun d: 251.1134; for C11H15N4O3 (M + H) calculated: 251.1144. For C11H14N4O3 (250.3)
calculated: 52.79% C, 5.64% H, 22.39% N; foun d: 52.40% C, 5.26% H, 22.02% N.
9-(3-Deoxy-β-D-ribofuranosyl)-6-ethylpurine (4f). Yield 75%. Colorless crystals, m .p. 117–119 °C,
[α]D –34.9 (c 0.18, DMF). FAB MS, m/z (rel.%): 265 (35) [M + H], 149 (100). 1H NMR (400 MHz,
DMSO-d6): 1.34 (t, 3 H, Jvic = 7.6, CH3CH2); 1.92 (ddd, 1 H, Jgem = 13.2, J3′b,4′ = 6.2, J3′b,2′
2.7, H-3′b); 2.27 (ddd, 1 H, Jgem = 13.2, J3′a,4′ = 9.2, J3′a,2′ = 5.7, H-3′a); 3.10 (q, 2 H, Jvic = 7.6,
CH2CH3); 3.54 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.4, J5′b,4′ = 3.9, H-5′b); 3.72 (dd, 1 H, Jgem
=
=
12.0, J5′a,OH = 5.4, J5′a,4′ = 3.5, H-5′a); 4.40 (ddt, 1 H, J4′,3′ = 9.2, 6.2, J4′,5′ = 3.9, 3.5, H-4′);
4.63 (m , 1 H, J2′,3′ = 5.5, 2.7, J2′,OH = 4.2, J2′,1′ = 2.0, H-2′); 5.06 (t, 1 H, JOH,5′ = 5.4, OH-5′);
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Hocek, Šilhár, Pohl:
5.72 (d, 1 H, JOH,2′ = 4.2, OH-2′); 6.01 (d, 1 H, J1′,2′ = 2.0, H-1′); 8.76 (s, 1 H, H-8); 8.83 (s,
1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6): 12.39 (CH3CH2); 25.88 (CH2CH3); 34.02
(CH2-3′); 62.42 (CH2-5′); 74.95 (CH-2′); 81.28 (CH-4′); 91.00 (CH-1′); 132.26 (C-5); 143.58
(CH-8); 150.01 (C-4); 151.92 (CH-2); 162.60 (C-6). Exact m ass (HR FAB MS) foun d: 265.1291;
for C12H17N4O3 (M + H) calculated: 265.1301. For C12H16N4O3·1/2H2O (273.3) calculated:
52.74% C, 6.27% H, 20.50% N; foun d: 52.93% C, 6.08% H, 20.31% N.
9-(3-Deoxy-β-D-ribofuranosyl)-6-benzylpurine (4g). Yield 75%. Colorless crystals, m .p. 167–170 °C,
[α]D –41.7 (c 0.18, DMF). FAB MS, m/z (rel.%): 327 (50) [M + H], 211 (100). 1H NMR (400 MHz,
DMSO-d6): 1.92 (ddd, 1 H, Jgem = 13.1, J3′b,4′ = 6.1, J3′b,2′ = 2.7, H-3′b); 2.27 (ddd, 1 H, Jgem
=
13.1, J3′a,4′ = 9.1, J3′a,2′ = 5.6, H-3′a); 3.54 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.5, J5′b,4′ = 3.9,
H-5′b); 3.72 (dd, 1 H, Jgem = 12.0, J5′a,OH = 5.5, J5′a,4′ = 3.4, H-5′a); 4.39 (ddt, 1 H, J4′,3′ = 9.1,
6.1, J4′,5′ = 3.9, 3.4, H-4′); 4.41 (s, 2 H, CH2Ph ); 4.63 (m , 1 H, J2′,3′ = 5.6, 2.7, J2′,OH = 4.1, J2′,1′
=
2.1, H-2′); 5.06 (t, 1 H, JOH,5′ = 5.5, OH-5′); 5.72 (d, 1 H, JOH,2′ = 4.1, OH-2′); 6.01 (d, 1 H,
J1′,2′ = 2.1, H-1′); 7.18 (m , 1 H, H-p-Ph ); 7.26 (m , 2 H, H-m-Ph ); 7.37 (m , 2 H, H-o-Ph ); 8.81
(s, 1 H, H-8); 8.82 (s, 1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6): 33.99 (CH2-3′); 38.81
(CH2Ph ); 62.38 (CH2-5′); 74.92 (CH-2′); 81.31 (CH-4′); 91.03 (CH-1′); 126.56 (CH-p-Ph );
128.57 (CH-m-Ph ); 129.28 (CH-o-Ph ); 132.46 (C-5); 138.18 (C-i-Ph ); 144.17 (CH-8); 150.47
(C-4); 152.03 (CH-2); 159.75 (C-6). Exact m ass (HR FAB MS) foun d: 327.1449; for
C
17H19N4O3 (M + H) calculated: 327.1457. For C17H18N4O3·H2O (344.4) calculated: 59.29% C,
5.85% H, 16.27% N; foun d: 59.00% C, 5.56% H, 16.88% N.
9-(3-Deoxy-β-D-ribofuran osyl)-6-(h ydroxym eth yl)purin e (4i)
A 1 M m eth an olic MeONa (100 µl, 0.1 m m ol) was added to a solu tion of 3h (295 m g,
0.49 m m ol) in m eth an ol (30 m l) an d th e m ixture was stirred at am bien t tem perature. After
com plete deacylation th e solven t was evaporated an d th e residue was dissolved in eth yl ace-
tate, filtered th rough silica gel an d evaporated. Crude in term ediate 3i was dissolved in THF
an d Et3N·3HF (0.28 m l, 1.7 m m ol) was added. After com plete desilylation , th e solven t was
evaporated an d th e residue was ch rom atograph ed on silica gel (eth yl acetate/m eth an ol).
Product 4i was crystallized from EtOH/h eptan e. Yield 65%. Wh ite h ygroscopic solid, m .p.
20
160–161 °C, [α]D –31.1 (c 0.31, H2O). FAB MS, m/z (%): 267 (19) [M + H], 151 (100), 133
(17). 1H NMR (400 MHz, DMSO-d6): 1.93 (ddd, 1 H, Jgem = 13.2, J3′b,4′ = 6.1, J3′b,2′ = 2.6,
H-3′b); 2.27 (ddd, 1 H, Jgem = 13.2, J3′a,4′ = 9.3, J3′a,2′ = 5.5, H-3′a); 3.54 (ddd, 1 H, Jgem
=
12.1, J5′b,OH = 5.5, J5′b,4′ = 3.9, H-5′b); 3.72 (dd, 1 H, Jgem = 12.1, J5′a,OH = 5.4, J5′a,4′ = 3.3,
H-5′a); 4.40 (ddt, 1 H, J4′,3′ = 9.3, 6.1, J4′,5′ = 3.9, 3.3, H-4′); 4.63 (ddt, 1 H, J2′,3′ = 5.5, 2.6,
J2′,OH = 4.1, J2′,1′ = 1.9, H-2′); 4.89 (d, 2 H, JCH2,OH = 6.2, CH2OH); 5.08 (t, 1 H, JOH,5′ = 5.5,
5.4, OH-5′); 5.44 (t, 1 H, JOH,CH2 = 6.2, HOCH2); 5.75 (d, 1 H, JOH,2′ = 4.1, OH-2′); 6.03 (d,
1 H, J1′,2′ = 1.9, H-1′); 8.81 (s, 1 H, H-8); 8.90 (s, 1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6):
33.96 (CH2-3′); 60.14 (CH2O); 62.37 (CH2-5′); 75.02 (CH-2′); 81.38 (CH-4′); 91.05 (CH-1′);
131.51 (C-5); 144.10 (CH-8); 150.57 (C-4), 151.86 (CH-2); 159.70 (C-6). IR (KBr): 3433, 3251,
3111, 1605, 1581, 1491, 1405, 1335, 1218, 1091, 649. Exact m ass (FAB HR MS) foun d:
267.1105; for C11H15N4O4 (M + H) calculated: 267.1093. For C11H14N4O4·1/2H2O (275.3)
calculated: 48.00% C, 5.49% H, 20.35% N; foun d: 47.87% C, 5.23% H, 19.87% N.
This work is a part of the research project Z4 055 0506. It was supported by the Centre for New
Antivirals and Antineoplastics (1M0508), by the Programme of Targeted Projects of the Academy
of Sciences of the Czech Republic (1QS400550501) and by Gilead Sciences, Inc. (Foster City, CA,
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Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
1495
U.S.A.). Cytostatic activity was studied by Dr I. Votruba (IOCB) and anti-HCV activity by E. Mabery
and Drs I. Shih and R. Mackman (Gilead). The contribution of these scientists is gratefully
acknowledged.
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