Synthesis of 6-amino-, 6-methyl- and 6-aryl-2-(hydroxymethyl)purine bases and nucleosides

Article abstract of DOI:10.1135/cccc20060788

An efficient methodology of the synthesis of 6-substituted 2-(hydroxymethyl)purine derivatives (bases and nucleosides) was developed. Regioselective Pd-catalyzed cross-coupling reactions of 6-chloro-2-iodopurines with [(benzoyloxy)methyl]zinc iodide gave

Full text of DOI:10.1135/cccc20060788

788
Šilhár, Pohl, Votruba, Klepetářová, Hocek:
SYNTHESIS OF 6-AMINO-, 6-METHYL- AND 6-ARYL-
2-(HYDROXYMETHYL)PURINE BASES AND NUCLEOSIDES
Peter ŠILHÁR, Radek POHL, Ivan VOTRUBA, Blanka KLEPETÁŘOVÁ and
1,
Michal HOCEK *
Centre for New Antivirals and Antineoplastics, Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 16610 Prague 6, Czech Republic;
1
e-mail: hocek@uochb.cas.cz
Received April 6, 2006
Accepted May 7, 2006
Dedicated to Professor Antonín Holý on the occasion of his 70th birthday.
An efficien t m eth odology of th e syn th esis of 6-substituted 2-(h ydroxym eth yl)purin e deriva-
tives (bases an d n ucleosides) was developed. Regioselective Pd-catalyzed cross-couplin g reac-
tion s of 6-ch loro-2-iodopurin es with [(ben zoyloxy)m eth yl]zin c iodide gave 2-[(ben zoyloxy)-
m eth yl]-6-ch loropurin es th at were con verted to 2-(h ydroxym eth yl)aden in es by reaction s
with am m on ia an d to 6-m eth yl- or 6-aryl-2-(h ydroxym eth yl)purin es by cross-couplin g reac-
tion s with trim eth ylalum in ium or arylboron ic acids followed by deprotection . Th e title
6-substituted 2-(h ydroxym eth yl)purin e bases an d n ucleosides did n ot exh ibit sign ifican t
cytostatic or an ti-HCV activity.
Keyw ord s: Purin es; Nucleosides; Cross-couplin g reaction s; Hydroxym eth ylation ; Palladium ;
Fun ction alized organ ozin c reagen ts; Cytostatic activity; X-ray diffraction .
Purin e ribon ucleosides bearin g aryl an d h etaryl substituen ts in th e position
6 possess stron g cytostatic1 an d an ti-HCV 2 activity, wh ile som e 6-aryl-
9-substituted purin es were reported to exh ibit an tibacterial an d an tim yco-
bacterial effects3. 6-(Hydroxym eth yl)-4, 6-(fluorom eth yl)-5 an d 6-(difluoro-
m eth yl)purin e6 ribon ucleosides are an oth er class of poten t cytostatic com -
poun ds. 6-Meth ylpurin e an d its ribon ucleoside are h igh ly cytotoxic7 an d its
liberation by purin e n ucleoside ph osph orylases from its n on -toxic deoxy-
ribon ucleoside was proposed as a n ovel prin ciple in th e gen e th erapy of
can cer8.
On ly few exam ples of 2-(h ydroxym eth yl)purin es h ave been prepared in
th e past by h eterocyclization s9,10 or tran sform ation s of 2-vin ylpurin es11.
2-(Hydroxym eth yl)n ebularin e was reported to exh ibit an tiviral activity12
an d 2-(h ydroxym eth yl)in osin e m on oph osph ate to in h ibit IMP deh ydro-
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803
© 2006 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20060788

Modified Purine Bases and Nucleosides
789
gen ase9. Protected 2-(h ydroxym eth yl)in osin e was also used10 in con struc-
tion of in h ibitors of GMP syn th etase. Related 2-(am in om eth yl)purin es
are easily accessible by h eterocyclization s13 an d by reduction of 2-cyan o-
purin es14 an d also possess a wide ran ge of activities (e.g. agon ists of aden o-
sin e receptors15). Here we report on th e syn th esis of 2-(h ydroxym eth yl)-
purin e bases an d n ucleosides bearin g am in o, m eth yl or an aryl group in
position 6 – com poun ds sh arin g th e structural features of th e both above
m en tion ed types of bioactive purin e derivatives.
RESULTS AND DISCUSSION
Cross-couplin g reaction s of dih alopurin es are kn own to proceed regio-
selectively16. Very recen tly we h ave studied17 reaction s of 2,6-dih alopurin es
with [(ben zoyloxy)m eth yl]zin c iodide. 2,6-Dich loropurin es reacted alm ost
exclusively in th e position 6 (even with an excess of th e reagen t) to give
2-ch loro-6-[(ben zoyloxy)m eth yl]purin es, wh ile 6-ch loro-2-iodopurin es 1 re-
acted in position 2 to afford 2-[(ben zoyloxy)m eth yl]-6-ch loropurin es 2 th at
were furth er con verted to 2,6-bis[(ben zoyloxy)m eth yl]purin es 3 by succes-
sive cross-couplin g with an oth er portion of th e reagen t. Here we apply th e
in term ediates 2 for th e syn th esis of 6-substituted 2-(h ydroxym eth yl)purin e
derivatives.
Th e reaction s of tetrah ydropyran -2-yl (THP) protected 6-ch loro-2-iodo-
purin e 1a an d th e correspon din g acyl-protected n ucleosides 1b an d 1c with
1.2 equivalen ts of [(ben zoyloxy)m eth yl]zin c iodide in presen ce of Pd(PPh 3)4
un der argon were perform ed at room tem perature (Sch em e 1). In all cases
th e desired 2-[(ben zoyloxy)m eth yl]-6-ch loropurin es 2a–2c were obtain ed in
very h igh yields (87–90%) besides trace am oun ts of th e disubstituted pur-
in es 3 (1–3%) as reported earlier17
.
Our first efforts focused on in troduction of C-substituen ts in to position 6
by Pd-catalyzed cross-couplin g reaction s18. Th e reaction s of 2-[(ben zoyloxy)-
m eth yl]-6-ch loropurin es 2a–2c with trim eth ylalum in um in THF at 60 °C
gave th e correspon din g 6-m eth ylpurin e derivatives 4a–4c in excellen t
yields of 95–97% (Sch em e 1, Table I). Th e Suzuki–Miyaura reaction s of
2a–2c with ph en ylboron ic acid proceeded sm ooth ly un der stan dard con di-
tion s in toluen e in th e presen ce of K2CO3 un der Pd(PPh 3)4 catalysis to give
th e 6-ph en ylpurin e derivatives 5a–5c in h igh yields of 86–94%. An alogous
reaction s with 2-furylboron ic acid in toluen e were very sluggish an d th ere-
fore DMF was used as solven t un der oth erwise th e sam e con dition s to give
th e 6-(2-furyl)purin es 6a–6c in acceptable yields of 71–76% (but still sign ifi-
can tly lower com pared with th e ph en ylboron ic acid). Con version to aden in e
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

790
Šilhár, Pohl, Votruba, Klepetářová, Hocek:
PhCOO
Cl
Cl
BzOCH2ZnI
(1.2 eq)
N
N
R1
N
N
R1
N
N
R1
N
N
N
+
PhCOO
PhCOO
Pd(PPh3)4 (5 mol%)
THF, r.t., 8 h
I
N
N
N
1a-c
2a-c (87-90 %)
3a-c (1-3 %)
R2M
R1
1-10
a
NH3 / EtOH
60°C, 32 h
Pd(PPh3)4
O
AcO
R2
R2
N
O
b
c
N
N
N
N
R1
MeONa
MeOH
N
N
AcO OAc
O
TolO
PhCOO
HO
N
R1
R2
OTol
H
4-6 a-c
7-10 a, e, f
d
e
4, 8
5, 9
CH3
Dowex 50
(H+ form)
HO
HO
R2
R2
O
HO OH
O
Ph
O
N
EtOH
N
N
N
HO
6, 10
7
N
HO
f
N
N
H
N
THP
7a-10a
7d-10d
NH2
OH
SCHEME 1
TABLE I
Cross-couplin gs of 2-[(ben zoyloxy)m eth yl]-6-ch loropurin es 2
Startin g
com poun d
En try
Reagen ta
Con dition s
Product
Yield, %
1
2
2a
2b
2c
2a
2b
2c
2a
2b
2c
2a
2b
2c
Me3Al
THF, 60 °C
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7e
7f
97
97
95
94
91
86
76
74
71
62
70
68
Me3Al
THF, 60 °C
3
Me3Al
THF, 60 °C
4
Ph B(OH)2
Ph B(OH)2
Ph B(OH)2
FurB(OH)2
FurB(OH)2
FurB(OH)2
NH3
toluen e, 100 °C
toluen e, 100 °C
toluen e, 100 °C
DMF, 100 °C
DMF, 100 °C
DMF, 100 °C
EtOH, 60 °C
EtOH, 60 °C
EtOH, 60 °C
5
6
a
7
8
9
10
11
12
NH3
NH3
a
Fur, 2-furyl.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

Modified Purine Bases and Nucleosides
791
derivatives was ach ieved by sim ple un catalyzed n ucleoph ilic substitution
on h eatin g of 6-ch loropurin es 2a–2c in eth an olic am m on ia at 60 °C for 32 h .
All ester groups at acyl-protected glycon parts an d/or at ben zoyl-protected
2-(h ydroxym eth yl)purin es were cleaved sim ultan eously un der th ese con di-
tion s to directly give 2-(h ydroxym eth yl)-9-(tetrah ydropyran -2-yl)aden in e
(7a) an d th e correspon din g free 2-(h ydroxym eth yl)aden in e n ucleosides 7e
an d 7f in acceptable yields.
The acyl protecting groups in 6-m ethyl- and 6-aryl-2-[(benzoyloxy)m ethyl]-
purin e derivatives 4–6 were cleaved m akin g use of catalytic am oun ts of
NaOMe in m eth an ol to give 9-THP-substituted 2-(h ydroxym eth yl)purin es
8a–10a or free 2-(h ydroxym eth yl)purin e n ucleosides 8e–10e an d 8f–10f
in good yields (Table II). THP-groups in com poun ds 7a–10a were cleaved
by refluxin g of th e com poun ds with TsOH or with acidic Dowex 50 ion
exch an ger in eth an ol to give 9H-purin es 7d –10d .
TABLE II
Cleavage of protectin g groups
Startin g
com poun d
En try
Reagen t
Con dition s
Product
Yield, %
1
2
4a
4b
4c
MeONa
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
MeOH, r.t.
EtOH, reflux
EtOH, reflux
EtOH, reflux
EtOH, reflux
8a
8e
90
87
88
89
74
93
82
80
81
85
71
74
65
MeONa
3
MeONa
8f
4
5a
MeONa
9a
5
5b
5c
MeONa
9e
6
MeONa
9f
7
6a
MeONa
10a
10e
10f
7d
8
6b
6c
MeONa
9
MeONa
10
11
12
13
7a
TsOH (H+)
Dowex (H+)
Dowex (H+)
Dowex (H+)
8a
8d
9a
9d
10a
10d
All com poun ds were fully ch aracterized by spectral an d an alytical
m eth ods. In addition , com poun d 9a gave crystals suitable for X-ray diffrac-
tion an d its crystal structure h as been determ in ed (Fig. 1).
All th e title 2-(h ydroxym eth yl)-6-substituted purin e bases an d n ucleo-
sides 7–10 were subjected to biological activity screen in g. Th e cytostatic
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

792
Šilhár, Pohl, Votruba, Klepetářová, Hocek:
activity in vitro (in h ibition of cell growth ) was studied on th e followin g cell
cultures: (i) m ouse leukem ia L1210 cells (ATCC CCL 219); h um an pro-
m yelocytic leukem ia HL60 cells (ATCC CCL 240); h um an cervix carcin om a
HeLaS3 cells (ATCC CCL 2.2) an d h um an T lym ph oblastoid CCRF-CEM cell
lin e (ATCC CCL 119). Nucleosides 7e–10e an d 7f–10f were also tested on
an ti-HCV activity in replicon system 20. Non e of th e com poun ds sh owed
an y cytostatic or an ti-HCV effect.
In con clusion , 2-[(ben zoyloxy)m eth yl]-6-ch loropurin es are suitable in ter-
m ediates for th e syn th esis of various 6-substituted 2-(h ydroxym eth yl)-
purin e bases an d n ucleosides by cross-couplin g reaction s or by n ucleoph ilic
substitution s. However, in troduction of th e h ydroxym eth yl group to posi-
tion 2 of biologically active 6-m eth yl- an d 6-arylpurin e bases an d n ucleo-
sides causes loss of activity.
FIG. 1
ORTEP 19 drawin g of crystal structure of 9a with th e atom n um berin g sch em e. Th erm al ellip-
soids are drawn at th e 50% probability level
EXPERIMENTAL
Startin g m aterials were prepared as follows: 6-ch loro-2-iodo-9-(tetrah ydropyran -2-yl)purin e
from 6-ch loro-2-(tetrah ydropyran -2-yl)am in o-9-(tetrah ydropyran -2-yl)purin e16h , 9-(2,3,5-tri-
O-acetyl-β-D-ribofuran osyl)-6-ch loro-2-iodopurin e21 an d an alogously 6-ch loro-2-iodo-
9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pen tofuran osyl)purin e17. All preparation s of (ben zoyl-
oxym eth yl)zin c iodide4 an d cross-couplin g reaction s were con ducted un der argon atm o-
sph ere. THF was dried an d distilled from sodium /ben zoph en on e. NMR spectra were recorded
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

Modified Purine Bases and Nucleosides
793
on a Bruker Avan ce 400 MHz spectrom eter (1H at 400 MHz, 13C at 100.6 MHz), an d a Bruker
Avan ce (500 MHz for 1H an d 125.8 MHz for 13C). Ch em ical sh ifts (in ppm , δ scale) were ref-
eren ced to TMS as in tern al stan dard. Th e assign m en t of carbon s was based on C,H-HSQC
an d C,H-HMBC experim 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 a 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 alytical) spectrom eter usin g FAB (ion ization by Xe, acceleratin g voltage 8 kV,
glycerol m atrix). Cytostatic activity tests were perform ed as described in ref.1a an d th e HCV
replicon assay as described in ref.20
Gen eral Procedure for Cross-Couplin gs of (Ben zoyloxym eth yl)zin c Iodide with
6-Ch loro-2-iodopurin es 1
Th e solution of [(ben zoyloxy)m eth yl]zin c iodide (1.35 m l, 1.2 m m ol) in THF was added at
room tem perature to the solution of 2,6-dihalopurine 1 (1 m m ol), Pd(PPh3)4 (57 m g, 0.05 m m ol)
in THF (10 m l) un der Ar an d stirred at room tem perature for 8 h . Th e reaction was
quen ch ed with 1 M NaH2PO4 (40 m l) an d extracted with CHCl3 (4 × 40 m l). Collected
organ ic ph ases were dried over MgSO4, filtered an d th e solven t was evaporated. Crude oily
products were purified by ch rom atograph y on silica gel (h exan es/eth yl acetate) an d th e
correspon din g 2-[(ben zoyloxy)m eth yl]-6-ch loropurin es 2a–2c were isolated in very good
yields (87–90%). Ch aracterization data for com poun ds 2a–2c were publish ed in our previous
paper17
.
Gen eral Procedure for Cross-Couplin gs of 2-[(Ben zoyloxy)m eth yl]-6-ch loropurin es 2 with
Me3Al
A solution of Me3Al (1.0 m l, 2.0 m m ol) in toluen e was added at room tem perature to a solu-
tion of a 2-[(ben zoyloxy)m eth yl]-6-ch loropurin e 2 (1 m m ol), Pd(PPh 3)4 (57 m g, 0.05 m m ol)
in THF (10 m l) un der Ar an d stirred at 60 °C for 6 h . Th e reaction was quen ch ed with ice
cold 1 M NaH2PO4 (40 m l) an d extracted with CHCl3 (4 × 40 m l). Collected organ ic ph ases
were dried over MgSO4, filtered an d th e solven t was evaporated. Crude products 4 were puri-
fied by ch rom atograph y on silica gel (h exan es/eth yl acetate 2:1–1:1).
2-[(Benzoyloxy)methyl]-6-methyl-9-(tetrahydropyran-2-yl)purine (4a ). Yield 97% of wh ite
foam . Exact m ass (FAB HRMS) foun d: 353.1619; calculated for C19H21N4O3: 353.1614. FAB
MS, m/z (%): 353 (MH+, 40); 269 (100); 147 (46); 105 (82); 85 (38). 1H NMR (400 MHz,
CDCl3): 1.56–1.70 an d 1.91–2.10 (m , 6 H, CH2-THP); 2.88 (s, 3 H, CH3); 3.66 (td, 1 H, J =
11.9 an d 2.8, bCH2O-THP); 4.11 (ddt, 1 H, J = 11.9, 3.9 an d 2.1, aCH2O-THP); 5.61 (s, 2 H,
CH2O); 5.66 (m , 1 H, CHO-THP); 7.47 (m , 2 H, H-m-Bz); 7.59 (m , 1 H, H-p-Bz); 8.16 (m , 2 H,
H-o-Bz); 8.21 (s, 1 H, H-8). 13C NMR (100.6 MHz, CDCl3): 19.50 (CH3); 22.59, 24.77 an d
31.49 (CH2-THP); 67.14 (CH2O); 68.62 (CH2O-THP); 82.09 (CHO-THP); 128.30 (CH-m-Bz);
129.87 (CH-o-Bz); 130.29 (C-i-Bz); 132.00 (C-5); 132.96 (CH-p-Bz); 141.80 (CH-8); 150.22
(C-4); 158.50 (C-2); 159.47 (C-6); 166.50 (CO-Bz). IR (CCl4): 2948, 2856, 1729, 1599, 1499,
1452, 1441, 1404, 1323, 1270, 1116, 645.
2-[(Benzoyloxy)methyl]-6-methyl-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (4b). Yield 97%
of wh ite foam . Exact m ass (FAB HRMS) foun d: 527.1759; calculated for C25H27N4O9:
527.1778. FAB MS, m/z (%): 527 (MH+, 20); 269 (35); 259 (10); 105 (100). 1H NMR
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

794
Šilhár, Pohl, Votruba, Klepetářová, Hocek:
(400 MHz, CDCl3): 2.02, 2.06 an d 2.07 (3 × s, 3 × 3 H, CH3-Ac); 2.86 (s, 3 H, CH3-6); 4.27
(dd, 1 H, Jgem = 12.2, J5′b,4′ = 5.3, H-5′b); 4.31 (dd, 1 H, Jgem = 12.2, J5′a,4′ = 3.5, H-5′a); 4.38
(td, 1 H, J4′,3′ = J4′,5′b = 5.3, J4′,5′a = 3.5, H-4′); 5.51 (t, 1 H, J3′,4′ = 5.3, J3′,2′ = 5.2, H-3′); 5.60
an d 5.65 (2 × d, 2 H, Jgem = 14.1, CH2O); 5.92 (t, 1 H, J2′,3′ = 5.2, J2′,1′ = 4.9, H-2′); 6.13 (d,
1 H, J1′,2′ = 4.9, H-1′); 7.47 (m , 2 H, H-m-Bz); 7.59 (m , 1 H, H-p-Bz); 8.14 (s, 1 H, H-8); 8.17
(m , 2 H, H-o-Bz). 13C NMR (100.6 MHz, CDCl3): 19.55 (CH3-6); 20.28, 20.42 an d 20.69
(CH3-Ac); 63.16 (CH2-5′); 66.80 (CH2O); 70.62 (CH-3′); 73.04 (CH-2′); 80.18 (CH-4′); 86.76
(CH-1′); 128.35 (CH-m-Bz); 129.99 (CH-o-Bz); 132.66 (C-i-Bz an d C-5); 133.02 (CH-p-Bz);
142.31 (CH-8); 150.43 (C-4); 159.07 (C-2); 160.14 (C-6); 166.21 (CO-Bz); 169.26, 169.33 an d
170.21 (CO-Ac). IR (CCl4): 1756, 1730, 1598, 1501, 1452, 1430, 1369, 1270, 1222, 1118,
644.
2-[(Benzoyloxy)methyl]-6-methyl-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pentofuranosyl)purine
(4c). Yield 95% of wh ite foam . Exact m ass (FAB HRMS) foun d: 621.2336; calculated for
C
35H33N4O7: 621.2349. FAB MS, m/z (%): 621 (MH+, 18); 269 (53); 163 (6); 149 (12); 119
(100); 105 (48). 1H NMR (400 MHz, CDCl3): 2.40 an d 2.45 (2 × s, 2 × 3 H, CH3-Tol); 2.69
(ddd, 1 H, Jgem = 14.3, J2′b,1′ = 6.0, J2′b,3′ = 2.2, H-2′b); 2.83 (s, 3 H, CH3-6); 3.19 (ddd, 1 H,
Jgem = 14.3, J2′a,1′ = 8.1, J2′a,3′ = 6.3, H-2′a); 4.53–4.59 (m , 2 H, H-5′b an d H-4′); 4.62 (dd, 1 H,
Jgem = 13.0, J5′a,4′ = 6.0, H-5′a); 5.57 (dt, 1 H, J3′,2′ = 6.3, 2.2, J3′,4′ = 2.2, H-3′); 5.60 an d 5.65
(2 × d, 2 H, Jgem = 14.1, CH2O); 6.46 (dd, 1 H, J1′2′ = 8.1, 6.0, H-1′); 7.20 an d 7.27 (2 × m ,
2 × 2 H, H-m-Tol); 7.39 (m , 2 H, H-m-Bz); 7.48 (m , 1 H, H-p-Bz); 7.84 an d 7.91 (2 × m , 2 ×
2 H, H-o-Tol); 8.14 (s, 1 H, H-8); 8.15 (m , 2 H, H-o-Bz). 13C NMR (100.6 MHz, CDCl3): 19.51
(CH3-6); 21.67 an d 21.74 (CH3-Tol); 37.23 (CH2-2′); 64.01 (CH2-5′); 66.85 (CH2O); 75.14
(CH-3′); 83.08 (CH-4′); 85.24 (CH-1′); 126.44 an d 126.63 (C-i-Tol); 128.38 (CH-m-Bz); 129.20
an d 129.25 (CH-m-Tol); 129.60 (CH-o-Tol); 129.78 an d 129.84 (CH-o-Tol an d CH-o-Bz);
130.06 (C-i-Bz); 132.66 (C-5); 133.04 (CH-p-Bz); 142.35 (CH-8); 144.07 an d 144.44 (C-p-Tol);
150.37 (C-4); 158.69 (C-2); 159.84 (C-6); 165.74 an d 166.04 (CO-Tol); 166.38 (CO-Bz). IR
(CCl4): 3064, 1728, 1613, 1598, 1501, 1452, 1409, 1268, 1209, 1178, 1101, 647.
Gen eral Procedure for Suzuki–Miyaura Cross-Couplin gs of
2-[(Ben zoyloxy)m eth yl]-6-ch loropurin es 2
A solution of 2-(ben zoyloxym eth yl)-6-ch loropurin e 2 (1 m m ol), arylboron ic acid (2 m m ol),
Pd(PPh 3)4 (57 m g, 0.05 m m ol) an d K2CO3 (250 m g) eith er in toluen e (20 m l) for
ph en ylboron ic acid or DMF (10 m l) for 2-furylboron ic acid un der Ar was stirred at 100 °C
for 12 h . Th e reaction was quen ch ed with 1 M NaH2PO4 (40 m l) an d extracted with CHCl3
(4 × 40 m l). Collected organ ic ph ases were dried over MgSO4, filtered an d th e solven t was
evaporated. Crude products 5 or 6 were purified by ch rom atograph y on silica gel (h exan es/
eth yl acetate 3:1–2:1).
2-[(Benzoyloxy)methyl]-6-phenyl-9-(tetrahydropyran-2-yl)purine (5a). Yield 94% of wh ite solid,
m .p. 156–157 °C. For C24H22N4O3 (414.5) calculated: 69.55% C, 5.35% H, 13.52% N; foun d:
69.33% C, 5.16% H, 13.47% N. Exact m ass (FAB HRMS) foun d: 415.1779; calculated for
C
24H23N4O3: 415.1770. FAB MS, m/z (%): 415 (MH+, 8); 331 (11); 149 (5); 105 (14); 85 (4).
1H NMR (400 MHz, CDCl3): 1.57–1.76 an d 1.95–2.16 (m , 6 H, CH2-THP); 3.70 (td, 1 H, J =
11.5 an d 2.8, bCH2O-THP); 4.14 (ddt, 1 H, J = 11.5, 4.0 an d 2.2, aCH2O-THP); 5.72 (s, 2 H,
CH2O); 5.74 (dd, 1 H, J = 10.0, 2.9, CHO-THP); 7.46–7.55 (m , 5 H, H-m-Bz an d H-m,p-Ph );
7.61 (m , 1 H, H-p-Bz); 8.21 (m , 2 H, H-o-Bz); 8.30 (s, 1 H, H-8); 8.74 (m , 2 H, H-o-Ph ).
13C NMR (100.6 MHz, CDCl3): 22.65, 24.80 an d 31.61 (CH2-THP); 66.99 (CH2O); 68.70
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

Modified Purine Bases and Nucleosides
795
(CH2O-THP); 82.07 (CHO-THP); 128.34, 128.56, 129.81 an d 129.90 (CH-o,m-Bz an d
CH-o,m-Ph ); 130.06 (C-i-Bz); 130.42 (C-5); 130.94 (CH-p-Ph ); 132.96 (CH-p-Bz); 142.27
(CH-8); 152.25 (C-4); 154.76 (C-6); 158.55 (C-2); 166.61 (CO-Bz). IR (CHCl3): 2951, 2859,
1723, 1582, 1568, 1503, 1452, 1398, 1341, 1274, 1119, 648.
2-[(Benzoyloxy)methyl]-6-phenyl-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (5b). Yield 91%
of wh ite foam . Exact m ass (FAB HRMS) foun d: 589.1937; calculated for C30H29N4O9:
589.1935. FAB MS, m/z (%): 589 (MH+, 19); 331 (44); 259 (13); 225 (9); 105 (100); 77 (21).
1H NMR (400 MHz, CDCl3): 2.04, 2.08 an d 2.09 (3 × s, 3 × 3 H, CH3-Ac); 4.31 (dd, 1 H,
Jgem = 12.2, J5′b,4′ = 5.2, H-5′b); 4.35 (dd, 1 H, Jgem = 12.2, J5′a,4′ = 3.6, H-5′a); 4.42 (td, 1 H,
J4′,5′ = 5.2, 3.6, J4′,3′ = 5.0, H-4′); 5.57 (t, 1 H, J3′,2′ = 5.5, J3′,4′ = 5.0, H-3′); 5.71 an d 5.75 (2 ×
d, 2 H, Jgem = 14.2, CH2O); 5.98 (t, 1 H, J2′,3′ = 5.5, J2′,1′ = 5.1, H-2′); 6.21 (d, 1 H, J1′,2′ = 5.1,
H-1′); 7.45–7.55 (m , 5 H, H-m-Bz an d H-m,p-Ph ); 7.60 (m , 1 H, H-p-Bz); 8.21 (m , 2 H,
H-o-Bz); 8.24 (s, 1 H, H-8); 8.73 (m , 2 H, H-o-Ph ). 13C NMR (100.6 MHz, CDCl3): 20.31,
20.46 an d 20.72 (CH3-Ac); 63.20 (CH2-5′); 66.75 (CH2O); 70.70 (CH-3′); 73.07 (CH-2′); 80.27
(CH-4′); 86.69 (CH-1′); 128.39 an d 128.62 (CH-m-Bz an d CH-m-Ph ); 129.89 an d 130.00
(CH-o-Bz an d CH-o-Ph ); 130.18 (C-i-Bz); 130.67 (C-5); 131.22 (CH-p-Ph ); 133.03 (CH-p-Bz);
135.25 (C-i-Ph ); 142.76 (CH-8); 152.49 (C-4); 155.35 (C-6); 159.12 (C-2); 166.35 (CO-Bz);
169.29, 169.38 an d 170.24 (CO-Ac). IR (CCl4): 3064, 1757, 1731, 1583, 1567, 1503, 1452,
1370, 1345, 1271, 1222, 1117, 645.
2-[(Benzoyloxy)methyl]-6-phenyl-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pentofuranosyl)purine
(5c). Yield 86% of wh ite solid, m .p. 145–146 °C. For C40H34N4O7 (682.7) calculated: 70.37% C,
5.02% H, 8.21% N; foun d: 70.03% C, 4.82% H, 8.02% N. Exact m ass (FAB HRMS) foun d:
683.2531; calculated for C40H35N4O7: 683.2506. FAB MS, m/z (%): 683 (MH+, 19); 331 (29);
226 (5); 119 (36); 105 (25). 1H NMR (500 MHz, CDCl3): 2.34 an d 2.45 (2 × s, 2 × 3 H,
CH3-Tol); 2.76 (ddd, 1 H, Jgem = 14.3, J2′b,1′ = 6.0, J2′b,3′ = 2.2, H-2′b); 3.22 (ddd, 1 H, Jgem
14.3, J2′a,1′ = 8.1, J2′a,3′ = 6.4, H-2′a); 4.57–4.62 (m , 2 H, H-5′b an d H-4′); 4.68 (dd, 1 H, Jgem
=
=
13.5, J5′a,4′ = 6.0, H-5′a); 5.63 (dt, 1 H, J3′,2′ = 6.4, 2.2, J3′,4′ = 2.2, H-3′); 5.71 an d 5.75 (2 × d,
2 H, Jgem = 14.1, CH2O); 6.53 (dd, 1 H, J1′2′ = 8.1, 6.0, H-1′); 7.16 an d 7.28 (2 × m , 2 × 2 H,
H-m-Tol); 7.42 (m , 2 H, H-m-Bz); 7.48–7.55 (m , 4 H, H-m,p-Ph an d H-p-Bz); 7.82 an d 7.93
(2 × m , 2 × 2 H, H-o-Tol); 8.20 (m , 2 H, H-o-Bz); 8.25 (s, 1 H, H-8); 8.71 (m , 2 H, H-o-Ph ).
13C NMR (125.8 MHz, CDCl3): 21.62 an d 21.76 (CH3-Tol); 37.44 (CH2-2′); 64.02 (CH2-5′);
66.78 (CH2O); 75.19 (CH-3′); 83.16 (CH-4′); 85.39 (CH-1′); 126.44 an d 126.56 (C-i-Tol);
128.41 (CH-m-Bz); 128.57 (CH-m-Ph ); 129.20 an d 129.26 (CH-m-Tol); 129.56 (CH-o-Tol);
129.80 an d 129.86 (CH-o-Tol, CH-o-Ph an d CH-o-Bz); 130.19 (C-i-Bz); 130.69 (C-5); 131.08
(CH-p-Ph ); 133.04 (CH-p-Bz); 135.38 (CH-i-Ph ); 142.76 (CH-8); 144.09 an d 144.45 (C-p-Tol);
152.35 (C-4); 155.05 (C-6); 158.70 (C-2); 165.79 an d 166.07 (CO-Tol); 166.49 (CO-Bz).
IR (CCl4): 3064, 1728, 1613, 1582, 1567, 1502, 1452, 1341, 1268, 1178, 1100, 646.
2-[(Benzoyloxy)methyl]-6-(2-furyl)-9-(tetrahydropyran-2-yl)purine (6a). Yield 76% of wh ite
solid, m .p. 165–166 °C. For C22H20N4O4 (404.4) calculated: 65.34% C, 4.98% H, 13.85% N;
foun d: 64.96% C, 4.81% H, 13.61% N. Exact m ass (FAB HRMS) foun d: 405.1554; calculated
for C22H21N4O4: 405.1563. FAB MS, m/z (%): 405 (MH+, 17); 321 (70); 215 (13); 105 (100);
85 (28). 1H NMR (400 MHz, CDCl3): 1.55–1.72 an d 1.91–2.13 (2 × m , 6 H, CH2-THP); 3.66
an d 4.12 (2 × m , 2 H, CH2O-THP); 5.67 (dd, 1 H, J = 9.8, 3.4, CHO-THP); 5.70 (s, 2 H,
CH2O); 6.65 (dd, 1 H, J4,3 = 3.5, J4,5 = 1.8, H-4-furyl); 7.48 (m , 2 H, H-m-Bz); 7.60 (m , 1 H,
H-p-Bz); 7.76 (dd, 1 H, J5,4 = 1.8, J5,3 = 0.9, H-5-furyl); 7.80 (dd, 1 H, J3,4 = 3.5, J3,5 = 0.9,
H-3-furyl); 8.19 (m , 2 H, H-o-Bz); 8.27 (s, 1 H, H-8). 13C NMR (100.6 MHz, CDCl3): 22.58,
24.77 an d 31.54 (CH2-THP); 67.03 (CH2O); 68.64 (CH2O-THP); 82.19 (CHO-THP); 112.54
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

796
Šilhár, Pohl, Votruba, Klepetářová, Hocek:
(CH-4-furyl); 117.45 (CH-3-furyl); 127.43 (C-5); 128.32 (CH-m-Bz); 129.90 (CH-o-Bz); 130.42
(C-i-Bz); 132.94 (CH-p-Bz); 142.59 (CH-8); 145.99 (CH-5-furyl); 146.01 (C-6); 149.85
(C-2-furyl); 151.86 (C-4); 158.89 (C-2); 166.53 (CO-Bz). IR (CCl4): 2948, 2856, 1730, 1591,
1485, 1452, 1441, 1410, 1329, 1268, 1207, 1115, 643.
2-[(Benzoyloxy)methyl]-6-(2-furyl)-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (6b ). Yield
74% of wh ite foam . Exact m ass (FAB HRMS) foun d: 579.1714; calculated for C28H27N4O10
:
579.1727. FAB MS, m/z (%): 579 (MH+, 12); 321 (31); 259 (10); 215 (9); 105 (100). 1H NMR
(500 MHz, CDCl3): 2.01, 2.06 an d 2.07 (3 × s, 3 × 3 H, CH3-Ac); 4.28 (dd, 1 H, Jgem = 12.2,
J5′b,4′ = 5.2, H-5′b); 4.32 (dd, 1 H, Jgem = 12.2, J5′a,4′ = 3.6, H-5′a); 4.39 (td, 1 H, J4′,5′ = 5.2,
3.6, J4′,3′ = 4.8, H-4′); 5.51 (t, 1 H, J3′,2′ = 5.6, J3′,4′ = 4.8, H-3′); 5.68 an d 5.72 (2 × d, 2 H,
Jgem = 14.1, CH2O); 5.93 (t, 1 H, J2′,3′ = 5.6, J2′,1′ = 5.1, H-2′); 6.17 (d, 1 H, J1′,2′ = 5.1, H-1′);
6.66 (dd, 1 H, J4,3 = 3.6, J4,5 = 1.8, H-4-furyl); 7.48 (m , 2 H, H-m-Bz); 7.60 (m , 1 H, H-p-Bz);
7.78 (dd, 1 H, J5,4 = 1.8, J5,3 = 0.9, H-5-furyl); 7.82 (dd, 1 H, J3,4 = 3.6, J3,5 = 0.9, H-3-furyl);
8.19 (m , 2 H, H-o-Bz); 8.20 (s, 1 H, H-8). 13C NMR (125.8 MHz, CDCl3): 20.27, 20.42 an d
20.71 (CH3-Ac); 63.18 (CH2-5′); 66.77 (CH2O); 70.66 (CH-3′); 73.10 (CH-2′); 80.28 (CH-4′);
86.70 (CH-1′); 112.66 (CH-4-furyl); 117.96 (CH-3-furyl); 127.95 (C-5); 128.36 (CH-m-Bz);
130.00 (CH-o-Bz); 130.09 (C-i-Bz); 133.01 (CH-p-Bz); 143.03 (CH-8); 146.28 (CH-5-furyl);
146.44 (C-6); 149.56 (C-2-furyl); 152.04 (C-4); 159.48 (C-2); 166.22 (CO-Bz); 169.25, 169.33
an d 170.21 (CO-Ac). IR (CCl4): 3063, 1756, 1731, 1592, 1570, 1485, 1452, 1372, 1270, 1217,
1117, 639.
2-[(Benzoyloxy)methyl]-6-(2-furyl)-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pentofuranosyl)purine
(6c). Yield 71% of wh ite solid, m .p. 142–143 °C. For C38H32N4O8 (672.7) calculated: 67.85% C,
4.79% H, 8.33% N; foun d: 67.91% C, 4.60% H, 8.11% N. Exact m ass (FAB HRMS) foun d:
673.2318; calculated for C38H33N4O8: 673.2298. FAB MS, m/z (%): 673 (MH+, 12); 353 (4);
321 (31); 215 (14); 119 (100); 105 (61). 1H NMR (500 MHz, CDCl3): 2.36 an d 2.45 (2 × s, 2 ×
3 H, CH3-Tol); 2.71 (ddd, 1 H, Jgem = 14.4, J2′b,1′ = 6.0, J2′b,3′ = 2.2, H-2′b); 3.20 (ddd, 1 H,
Jgem = 14.4, J2′a,1′ = 8.1, J2′a,3′ = 6.4, H-2′a); 4.54–4.60 (m , 2 H, H-5′b an d H-4′); 4.64 (dd, 1 H,
Jgem = 13.8, J5′a,4′ = 6.3, H-5′a); 5.54 (dt, 1 H, J3′,2′ = 6.4, 2.2, J3′,4′ = 2.2, H-3′); 5.68 an d 5.73
(2 × d, 2 H, Jgem = 14.2, CH2O); 6.47 (dd, 1 H, J1′2′ = 8.1, 6.0, H-1′); 6.65 (dd, 1 H, J4,3 = 3.5,
J4,5 = 1.7, H-4-furyl); 7.16 an d 7.27 (2 × m , 2 × 2 H, H-m-Tol); 7.39 (m , 2 H, H-m-Bz); 7.47 (m ,
1 H, H-p-Bz); 7.77 (dd, 1 H, J5,4 = 1.7, J5,3 = 0.8, H-5-furyl); 7.79 (dd, 1 H, J3,4 = 3.5, J3,5
=
0.8, H-3-furyl); 7.81 an d 7.91 (2 × m , 2 × 2 H, H-o-Tol); 8.18 (m , 2 H, H-o-Bz); 8.22 (s, 1 H,
H-8). 13C NMR (125.8 MHz, CDCl3): 21.63 an d 21.75 (CH3-Tol); 37.37 (CH2-2′); 63.98
(CH2-5′); 66.78 (CH2O); 75.16 (CH-3′); 83.21 (CH-4′); 85.43 (CH-1′); 112.60 (CH-4-furyl);
117.75 (CH-3-furyl); 126.43 an d 126.55 (C-i-Tol); 127.97 (C-5); 128.39 (CH-m-Bz); 129.17
an d 129.25 (CH-m-Tol); 129.56 (CH-o-Tol); 129.78 an d 129.84 (CH-o-Tol an d CH-o-Bz);
130.11 (C-i-Bz); 133.04 (CH-p-Bz); 143.07 (CH-8); 144.08 an d 144.44 (C-p-Tol); 146.11
(CH-5-furyl); 146.21 (C-6); 149.67 (C-2-furyl); 151.91 (C-4); 159.03 (C-2); 165.74 an d 166.03
(CO-Tol); 166.39 (CO-Bz). IR (CCl4): 3063, 1728, 1612, 1590, 1485, 1410, 1268, 1206, 1178,
643.
Gen eral Procedure for Nucleoph ilic Am in ation of 2-(Ben zoyloxym eth yl)-6-ch loropurin es 2
2-[(Ben zoyloxy)m eth yl]-6-ch loropurin es 2 (0.5 m m ol) were dissolved in eth an olic am m on ia
(20 m l) an d th e m ixture was stirred at 60 °C for 32 h in a septum sealed flask. After com -
plete substitution an d deprotection th e solven t was evaporated an d th e residue was
ch rom atograph ed (eth yl acetate/m eth an ol 9:1–7:3) an d crystallized from eth an ol/h eptan e.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

Modified Purine Bases and Nucleosides
797
6-Amino-2-(hydroxymethyl)-9-(tetrahydropyran-2-yl)purine (7a). Yield 62% of wh ite solid,
m .p. 210–211 °C. Exact m ass (FAB HRMS) foun d: 250.1299; calculated for C11H16N5O2:
250.1304. FAB MS, m/z (%): 250 (MH+, 23); 166 (15); 149 (3); 85 (5). 1H NMR (500 MHz,
DMSO-d6): 1.53–1.65, 1.68–1.79, 1.89–2.00 an d 2.24 (4 × m , 6 H, CH2-THP); 3.68 an d 4.00
(2 × m , 2 H, CH2O-THP); 4.40 (d, 2 H, J = 5.8, CH2O); 4.80 (t, 1 H, J = 5.8, OH); 5.64 (dd, 1 H,
J = 11.1, 2.3, CHO-THP); 7.24 (bs, 2 H, NH2); 8.29 (s, 1 H, H-8). 13C NMR (125.8 MHz,
DMSO-d6): 22.69, 24.70 an d 30.41 (CH2-THP); 64.77 (CH2O); 67.83 (CH2O-THP); 80.66
(CHO-THP); 117.53 (C-5); 138.81 (CH-8); 149.65 (C-4); 155.91 (C-6); 163.45 (C-2). IR (KBr):
3422, 3323, 3174, 2925, 1658, 1599, 1577, 1506, 1473, 1365, 1341, 1225, 653.
6-Amino-2-(hydroxymethyl)-9-(β-D-ribofuranosyl)purine (7e). Yield 70% of wh ite solid, m .p. >
20
230 °C (decom p.). [α]D –31.7 (c 0.34, MeOH). Exact m ass (FAB HRMS) foun d: 298.1144;
calculated for C11H16N5O5: 298.1151. FAB MS, m/z (%): 298 (MH+, 8); 165 (18); 133 (15).
1H NMR (500 MHz, DMSO-d6): 3.55 (ddd, 1 H, Jgem = 12.1, J5′b,OH = 6.3, J5′b,4′ = 3.4, H-5′b);
3.66 (dt, 1 H, Jgem = 12.1, J5′a,OH = 3.9, J5′a,4′ = 3.9, H-5′a); 3.96 (q, 1 H, J4′,5′ = 3.9, 3.4, J4′,3′
=
2.8, H-4′); 4.15 (dd, 1 H, J3′,OH = 5.0, J3′,4′ = 2.8, H-3′); 4.39 (d, 2 H, JCH2,OH = 5.4, CH2O);
4.59 (t, 1 H, J2′,1′ = 6.4, J2′,OH = 5.0, H-2′); 4.91 (t, 1 H, JOH,CH2 = 5.4, OH); 5.26 (br, 1 H,
OH-3′); 5.35 (br, 1 H, OH-5′); 5.50 (br, 1 H, OH-2′); 5.89 (d, 1 H, J1′,2′ = 6.4, H-1′); 7.31 (bs, 2 H,
NH2); 8.31 (s, 1 H, H-8). 13C NMR (125.8 MHz, DMSO-d6): 61.84 (CH2-5′); 64.70 (CH2O);
70.87 (CH-3′); 73.69 (CH-2′); 86.05 (CH-4′); 87.63 (CH-1′); 118.24 (C-5); 139.85 (CH-8);
149.91 (C-4); 156.06 (C-6); 163.38 (C-2). IR (KBr): 3401, 3214, 1642, 1598, 1410, 650.
6-Amino-2-(hydroxymethyl)-9-(2-deoxy-β-D-erythro-pentofuranosyl)purine (7f). Yield 68% of
20
wh ite solid, m .p. 175–177 °C. [α]D +5.3 (c 0.35, MeOH). Exact m ass (FAB HRMS) foun d:
282.1216; calculated for C11H16N5O4: 282.1202. FAB MS, m/z (%): 282 (MH+, 56); 166 (100);
148 (36); 117 (20). 1H NMR (500 MHz, DMSO-d6): 2.25 (ddd, 1 H, Jgem = 13.1, J2′b,1′ = 6.0,
J2′b,3′ = 2.8, H-2′b); 2.67 (ddd, 1 H, Jgem = 13.1, J2′a,1′ = 8.1, J2′a,3′ = 5.7, H-2′a); 3.52 (ddd, 1 H,
Jgem = 11.8, J5′b,OH = 6.5, J5′b,4′ = 4.2, H-5′b); 3.60 (dt, 1 H, Jgem = 11.8, J5′a,OH = 5.0, J5′a,4′
=
4.2, H-5′a); 3.87 (td, 1 H, J4′,5′ = 4.2, J4′,3′ = 2.5, H-4′); 4.39 (d, 2 H, JCH2,OH = 5.8, CH2O);
4.40 (m , 1 H, J3′,2′ = 5.7, 2.8, J3′,OH = 4.0, J3′,4′ = 2.5, H-3′); 4.92 (t, 1 H, JOH,CH2 = 5.8, OH);
5.21 (dd, 1 H, JOH,5′ = 6.5, 5.0, OH-5′); 5.38 (d, 1 H, JOH,3′ = 4.0, OH-3′); 6.35 (dd, 1 H, J1′,2′
=
8.1, 6.0, H-1′); 7.29 (bs, 2 H, NH2); 8.31 (s, 1 H, H-8). 13C NMR (125.8 MHz, DMSO-d6):
CH2-2′ – overlapped with DMSO sign al; 62.06 (CH2-5′); 64.69 (CH2O); 71.18 (CH-3′); 83.73
(CH-1′); 88.12 (CH-4′); 118.12 (C-5); 139.47 (CH-8); 149.69 (C-4); 156.00 (C-6); 163.35 (C-2).
IR (KBr): 3400, 3210, 1643, 1599, 1404, 650.
Gen eral Procedure for Deacylation Reaction s
A 1 M m eth an olic MeONa (100 µl, 0.1 m m ol) was added to a solution of a protected purin e
or n ucleoside 4–6 (0.5 m m ol) in m eth an ol (25 m l) an d th e m ixture was stirred at am bien t
tem perature. After com plete deprotection th e solven t was evaporated an d th e residue was
ch rom atograph ed (eth yl acetate/m eth an ol 1:0–8:2).
2-(Hydroxymethyl)-6-methyl-9-(tetrahydropyran-2-yl)purine (8a). Yield 90% of wh ite foam .
Exact m ass (FAB HRMS) foun d: 249.1357; calculated for C12H17N4O2: 249.1352. FAB MS, m/z
(%): 249 (MH+, 41); 165 (100); 147 (33); 85 (31). 1H NMR (400 MHz, CDCl3): 1.65–1.88 an d
2.00–2.18 (m , 6 H, CH2-THP); 2.86 (s, 3 H, CH3); 3.79 (td, 1 H, J = 11.6 an d 2.7,
bCH2O-THP); 3.87 (t, 1 H, JOH,CH2 = 4.9, OH); 4.18 (ddt, 1 H, J = 11.6, 4.4 an d 2.0,
aCH2O-THP); 4.88 (d, 2 H, JCH2,OH = 4.9, CH2O); 5.78 (dd, 1 H, J = 10.2, 2.7, CHO-THP);
8.23 (s, 1 H, H-8). 13C NMR (100.6 MHz, CDCl3): 19.42 (CH3); 22.76, 24.83 an d 31.85
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

798
Šilhár, Pohl, Votruba, Klepetářová, Hocek:
(CH2-THP); 64.50 (CH2O); 68.83 (CH2O-THP); 81.77 (CHO-THP); 131.89 (C-5); 141.53
(CH-8); 150.12 (C-4); 159.22 (C-6); 162.05 (C-2). IR (CCl4): 3473, 2949, 2857, 1601, 1501,
1404, 1372, 1347, 1260, 1212, 1087, 645.
2-(Hydroxymethyl)-6-methyl-9-(β-D-ribofuranosyl)purine (8e). Yield 87% of wh ite h ygroscopic
20
solid, m .p. 197–198 °C, wh ich was lyoph ilized from water as a m on oh ydrate. [α]D –36.5
(c 0.48, MeOH). For C12H16N4O5.H2O (314.3) calculated: 45.86% C, 5.77% H, 17.83% N;
foun d: 45.51% C, 5.36% H, 17.49% N. Exact m ass (FAB HRMS) foun d: 297.1205; calculated
for C12H17N4O5: 297.1199. FAB MS, m/z (%): 297 (MH+, 33); 163 (19); 148 (28). 1H NMR
(400 MHz, DMSO-d6): 2.72 (s, 3 H, CH3); 3.57 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 6.2, J5′b,4′
4.0, H-5′b); 3.68 (ddd, 1 H, Jgem = 12.0, J5′a,OH = 5.1, J5′a,4′ = 4.2, H-5′a); 3.97 (q, 1 H, J4′,5′
=
=
4.2, 4.0, J4′,3′ = 3.1, H-4′); 4.18 (td, 1 H, J3′,OH = 4.8, J3′,2′ = 4.8, J3′,4′ = 3.1, H-3′); 4.63 (q, 1 H,
J2′,1′ = 6.1, J2′,OH = 5.7, J2′,3′ = 4.8, H-2′); 4.64 (d, 2 H, JCH2,OH = 6.3, CH2O); 5.11 (t, 1 H,
JOH,5′ = 6.2, 5.1, OH-5′); 5.25 (d, 1 H, JOH,3′ = 4.8, OH-3′); 5.28 (t, 1 H, JOH,CH2 = 6.3, OH);
5.50 (d, 1 H, JOH,2′ = 5.7, OH-2′); 6.02 (d, 1 H, J1′,2′ = 6.1, H-1′); 8.71 (s, 1 H, H-8). 13C NMR
(100.6 MHz, DMSO-d6): 19.29 (CH3); 61.59 (CH2-5′); 65.06 (CH2O); 70.67 (CH-3′); 73.78
(CH-2′); 85.99 (CH-4′); 87.34 (CH-1′); 131.67 (C-5); 143.96 (CH-8); 150.90 (C-4); 158.30
(C-6); 163.14 (C-2). IR (KBr): 3519, 3391, 3271, 1600, 1506, 1488, 1413, 1377, 1345, 1220,
1027, 644.
2-(Hydroxymethyl)-6-methyl-9-(2-deoxy-β-D-erythro-pentofuranosyl)purine (8f). Yield 88% of
wh ite h ygroscopic solid, m .p. 114–115 °C, wh ich was lyoph ilized from water as a h em i-
20
h ydrate. [α]D –6.6 (c 0.43, MeOH). For C12H16N4O4·1/2H2O (289.3) calculated: 49.82% C,
5.92% H, 19.37% N; foun d: 49.94% C, 5.60% H, 19.22% N. Exact m ass (FAB HRMS) foun d:
281.1256; calculated for C12H17N4O4: 281.1250. FAB MS, m/z (%): 281 (MH+, 41); 165 (37);
147 (7). 1H NMR (400 MHz, DMSO-d6): 2.31 (ddd, 1 H, Jgem = 13.3, J2′b,1′ = 6.2, J2′b,3′ = 3.2,
H-2′b); 2.70 (s, 3 H, CH3); 2.75 (ddd, 1 H, Jgem = 13.3, J2′a,1′ = 7.7, J2′a,3′ = 5.7, H-2′a); 3.53
(ddd, 1 H, Jgem = 11.8, J5′b,OH = 5.9, J5′b,4′ = 4.5, H-5′b); 3.62 (dt, 1 H, Jgem = 11.8, J5′a,OH
5.4, J5′a,4′ = 4.7, H-5′a); 3.88 (td, 1 H, J4′,5′ = 4.7, 4.5, J4′,3′ = 2.7, H-4′); 4.43 (m , 1 H, J3′,2′
5.7, 3.2, J3′,OH = 4.1, J3′,4′ = 2.7, H-3′); 4.63 (d, 2 H, JCH2,OH = 6.3, CH2O); 5.00 (t, 1 H, JOH,5′
=
=
=
5.9, 5.4, OH-5′); 5.25 (t, 1 H, JOH,CH2 = 6.3, OH); 5.35 (d, 1 H, JOH,3′ = 4.1, OH-3′); 6.47 (dd,
1 H, J1′,2′ = 7.7, 6.2, H-1′); 8.68 (s, 1 H, H-8). 13C NMR (100.6 MHz, DMSO-d6): 19.26 (CH3);
39.49 (CH2-2′); 61.83 (CH2-5′); 65.08 (CH2O); 70.96 (CH-3′); 83.58 (CH-1′); 88.15 (CH-4′);
131.63 (C-5); 143.75 (CH-8); 150.56 (C-4); 158.17 (C-6); 163.05 (C-2). IR (KBr): 3443, 3360,
3130, 1599, 1507, 1403, 1384, 1223, 1105, 1095, 644.
2-(Hydroxymethyl)-6-phenyl-9-(tetrahydropyran-2-yl)purine (9a). Yield 89% of wh ite solid,
m .p. 103–104 °C. Exact m ass (FAB HRMS) foun d: 311.1502; calculated for C17H19N4O2:
311.1508. FAB MS, m/z (%): 311 (MH+, 22); 227 (100); 209 (25); 85 (34). 1H NMR (400 MHz,
CDCl3): 1.65–1.90 an d 2.02–2.22 (m , 6 H, CH2-THP); 3.82 (td, 1 H, J = 11.7 an d 2.6,
bCH2O-THP); 3.98 (t, 1 H, JOH,CH2 = 4.8, OH); 4.20 (ddt, 1 H, J = 11.7, 4.4 an d 1.8,
aCH2O-THP); 4.96 (d, 2 H, JCH2,OH = 4.8, CH2O); 5.85 (dd, 1 H, J = 10.4, 2.4, CHO-THP);
7.50–7.60 (m , 3 H, H-m,p-Ph ); 8.33 (s, 1 H, H-8); 8.78 (m , 2 H, H-o-Ph ). 13C NMR (100.6 MHz,
CDCl3): 22.80, 24.87 an d 31.92 (CH2-THP); 64.65 (CH2OH); 68.88 (CH2O-THP); 81.80
(CHO-THP); 128.67 (CH-m-Ph ); 129.82 (CH-o-Ph ); 130.06 (C-5); 131.20 (CH-p-Ph ); 135.22
(C-i-Ph ); 142.18 (CH-8); 152.22 (C-4); 154.38 (C-6); 162.04 (C-2). IR (CHCl3): 3469, 2952,
2864, 1583, 1569, 1504, 1454, 1398, 1364, 1355, 1232, 1085, 649.
2-(Hydroxymethyl)-6-phenyl-9-(β-D-ribofuranosyl)purine (9e). Yield 74% of wh ite h ygroscopic
20
solid, m .p. 102–103 °C, wh ich was lyoph ilized from water as a h em ih ydrate. [α]D –26.7
(c 0.15, MeOH). For C17H18N4O5·1/2H2O (367.4) calculated: 55.58% C, 5.21% H, 15.25% N;
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

Modified Purine Bases and Nucleosides
799
foun d: 55.58% C, 5.16% H, 15.07% N. Exact m ass (FAB HRMS) foun d: 359.1353; calculated
for C17H19N4O5: 359.1355. FAB MS, m/z (%): 359 (MH+, 97); 227 (100); 209 (55); 119 (19).
1H NMR (400 MHz, DMSO-d6): 3.60 (ddd, 1 H, Jgem = 11.9, J5′b,OH = 5.9, J5′b,4′ = 3.9, H-5′b);
3.71 (ddd, 1 H, Jgem = 11.9, J5′a,OH = 5.2, J5′a,4′ = 4.5, H-5′a); 4.00 (q, 1 H, J4′,5′ = 4.5, 3.9,
J4′,3′ = 3.0, H-4′); 4.21 (td, 1 H, J3′,2′ = 5.2, J3′,OH = 4.9, J3′,4′ = 3.0, H-3′); 4.67 (q, 1 H, J2′,OH
=
6.0, J2′,1′ = 5.9, J2′,3′ = 5.2, H-2′); 4.76 (d, 2 H, JCH2,OH = 6.2, CH2O); 5.12 (t, 1 H, JOH,5′ = 5.9,
5.2, OH-5′); 5.26 (d, 1 H, JOH,3′ = 4.9, OH-3′); 5.36 (t, 1 H, JOH,CH2 = 6.2, OH); 5.54 (d, 1 H,
JOH,2′ = 6.0, OH-2′); 6.11 (d, 1 H, J1′,2′ = 5.9, H-1′); 7.55–7.64 (m , 3 H, H-m,p-Ph ); 8.86 (m ,
2 H, H-o-Ph ); 8.88 (s, 1 H, H-8). 13C NMR (100.6 MHz, DMSO-d6): 61.52 (CH2-5′); 65.23
(CH2O); 70.61 (CH-3′); 73.84 (CH-2′); 85.99 (CH-4′); 87.35 (CH-1′); 128.81 (CH-m-Ph );
129.66 (CH-o-Ph ); 129.70 (C-5); 131.31 (CH-p-Ph ); 135.48 (C-i-Ph ); 144.91 (CH-8); 152.88
(C-6); 153.11 (C-4); 163.30 (C-2). IR (KBr): 3400, 1583, 1568, 1503, 1452, 1398, 1364, 1310,
1223, 1080, 693.
2-(Hydroxymethyl)-6-phenyl-9-(2-deoxy-β-D-erythro-pentofuranosyl)purine (9f). Yield 93% of
wh ite h ygroscopic solid, m .p. 71–72 °C, wh ich was lyoph ilized from water as a h em ih ydrate.
20
[α]D –6.9 (c 0.26, MeOH). For C17H18N4O4·1/2H2O (351.4) calculated: 58.11% C, 5.45% H,
15.95% N; foun d: 57.99% C, 5.10% H, 15.72% N. Exact m ass (FAB HRMS) foun d: 343.1414;
calculated for C17H19N4O4: 343.1406. FAB MS, m/z (%): 343 (MH+, 86); 227 (100); 209 (20);
149 (6); 117 (8). 1H NMR (400 MHz, DMSO-d6): 2.37 (ddd, 1 H, Jgem = 13.3, J2′b,1′ = 6.2,
J2′b,3′ = 3.4, H-2′b); 2.79 (ddd, 1 H, Jgem = 13.3, J2′a,1′ = 7.5, J2′a,3′ = 5.8, H-2′a); 3.56 (ddd, 1 H,
Jgem = 11.8, J5′b,OH = 5.7, J5′b,4′ = 4.6, H-5′b); 3.65 (dt, 1 H, Jgem = 11.8, J5′a,OH = 5.5, J5′a,4′
=
4.5, H-5′a); 3.91 (td, 1 H, J4′,5′ = 4.6, 4.5, J4′,3′ = 2.8, H-4′); 4.47 (m , 1 H, J3′,2′ = 5.8, 3.4,
J3′,OH = 4.1, J3′,4′ = 2.8, H-3′); 4.76 (d, 2 H, JCH2,OH = 6.2, CH2O); 5.01 (t, 1 H, JOH,5′ = 5.7, 5.5,
OH-5′); 5.35 (t, 1 H, JOH,CH2 = 6.2, OH); 5.38 (d, 1 H, JOH,3′ = 4.1, OH-3′); 6.55 (dd, 1 H,
J1′,2′ = 7.5, 6.2, H-1′); 7.55–7.64 (m , 3 H, H-m,p-Ph ); 8.84 (s, 1 H, H-8); 8.86 (m , 2 H, H-o-Ph ).
13C NMR (100.6 MHz, DMSO-d6): 39.58 (CH2-2′); 61.78 (CH2-5′); 65.25 (CH2O); 70.91
(CH-3′); 83.59 (CH-1′); 88.20 (CH-4′); 128.79 (CH-m-Ph ); 129.63 (CH-o-Ph ); 129.67 (C-5);
131.26 (CH-p-Ph ); 135.52 (C-i-Ph ); 144.75 (CH-8); 152.75 an d 152.77 (C-4 an d C-6); 163.20
(C-2). IR (KBr): 3392, 3067, 1583, 1568, 1504, 1397, 1313, 1228, 1093, 1057, 647.
6-(2-Furyl)-2-(hydroxymethyl)-9-(tetrahydropyran-2-yl)purine (10a). Yield 82% of wh ite solid,
m .p. 142–143 °C. Exact m ass (FAB HRMS) foun d: 301.1296; calculated for C15H17N4O3:
301.1301. FAB MS, m/z (%): 301 (MH+, 88); 217 (100); 199 (14); 85 (19). 1H NMR (400 MHz,
CDCl3): 1.64–1.89 an d 2.01–2.20 (2 × m , 6 H, CH2-THP); 3.77–3.85 (m , 2 H, bCH2O-THP
an d OH); 4.20 (ddt, 1 H, J = 11.7, 4.3, 1.7, aCH2O-THP); 4.95 (d, 2 H, JCH2,OH = 4.4, CH2O);
5.82 (dd, 1 H, J = 10.4, 2.5, CHO-THP); 6.68 (dd, 1 H, J4,3 = 3.5, J4,5 = 1.7, H-4-furyl); 7.79
(dd, 1 H, J5,4 = 1.7, J5,3 = 0.9, H-5-furyl); 7.86 (dd, 1 H, J3,4 = 3.5, J3,5 = 0.9, H-3-furyl); 8.30
(s, 1 H, H-8). 13C NMR (100.6 MHz, CDCl3): 22.78, 24.86 an d 31.94 (CH2-THP); 64.72
(CH2O); 68.88 (CH2O-THP); 81.84 (CHO-THP); 112.64 (CH-4′); 117.71 (CH-3′); 127.40 (C-5);
142.31 (CH-8); 145.73 (C-6); 146.19 (CH-5-furyl); 149.69 (C-2-furyl); 151.66 (C-4); 162.50
(C-2). IR (CHCl3): 3484, 2951, 2864, 1593, 1556, 1501, 1486, 1378, 1354, 1279, 1085, 1045,
644.
6-(2-Furyl)-2-(hydroxymethyl)-9-(β-D-ribofuranosyl)purine (10e). Yield 80% of wh ite h ygro-
20
scopic solid, m .p. 121–122 °C, wh ich was lyoph ilized from water as a h em ih ydrate. [α]D
–43.0 (c 0.21, MeOH). For C15H16N4O6·1/2H2O (357.3) calculated: 50.42% C, 4.80% H,
15.68% N; foun d: 50.78% C, 4.46% H, 15.61% N. Exact m ass (FAB HRMS) foun d: 349.1134;
calculated for C15H17N4O6: 349.1148. FAB MS, m/z (%): 349 (MH+, 15); 215 (8); 148 (3).
1H NMR (500 MHz, DMSO-d6): 3.59 (ddd, 1 H, Jgem = 12.1, J5′b,OH = 6.1, J5′b,4′ = 4.0, H-5′b);
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

800
Šilhár, Pohl, Votruba, Klepetářová, Hocek:
3.70 (ddd, 1 H, Jgem = 12.1, J5′a,OH = 5.2, J5′a,4′ = 4.1, H-5′a); 3.98 (q, 1 H, J4′,5′ = 4.1, 4.0,
J4′,3′ = 3.3, H-4′); 4.20 (q, 1 H, J3′,OH = 4.9, J3′,2′ = 4.9, J3′,4′ = 3.3, H-3′); 4.66 (td, 1 H, J2′,OH
6.0, J2′,1′ = 6.0, J2′,3′ = 4.9, H-2′); 4.20 (d, 2 H, JCH2,OH = 6.3, CH2O); 5.11 (dd, 1 H, JOH,5′
=
=
6.1, 5.2, OH-5′); 5.26 (d, 1 H, JOH,3′ = 4.9, OH-3′); 5.35 (dd, 1 H, JOH,CH2 = 6.3, OH); 5.53 (d,
1 H, JOH,2′ = 6.0, OH-2′); 6.08 (d, 1 H, J1′,2′ = 6.0, H-1′); 6.82 (dd, 1 H, J4,3 = 3.5, J4,5 = 1.8,
H-4-furyl); 7.87 (dd, 1 H, J3,4 = 3.5, J3,5 = 0.9, H-3-furyl); 8.07 (dd, 1 H, J5,4 = 1.8, J5,3 = 0.9,
H-5-furyl); 8.83 (s, 1 H, H-8). 13C NMR (125.8 MHz, DMSO-d6): 61.53 (CH2-5′); 65.17
(CH2O); 70.62 (CH-3′); 73.86 (CH-2′); 86.02 (CH-4′); 87.38 (CH-1′); 113.10 (CH-4-furyl);
117.76 (CH-3-furyl); 127.16 (C-5); 144.85 (C-6); 144.98 (CH-8); 146.64 (CH-5-furyl); 149.16
(C-2-furyl); 152.41 (C-4); 163.60 (C-2). IR (KBr): 3401, 1594, 1558, 1485, 1408, 1377, 1222,
1207, 1059, 1021, 633.
6-(2-Furyl)-2-(hydroxymethyl)-9-(2-deoxy-β-D-erythro-pentofuranosyl)purine (10f). Yield 81% of
wh ite h ygroscopic solid, m .p. 63–64 °C, wh ich was lyoph ilized from water as a h em ih ydrate.
20
[α]D –10.2 (c 0.29, MeOH). For C15H16N4O5·1/2H2O (341.3) calculated: 52.78% C, 5.02% H,
16.41% N; foun d: 53.04% C, 5.02% H, 16.07% N. Exact m ass (FAB HRMS) foun d: 333.1194;
calculated for C15H17N4O5: 333.1199. FAB MS, m/z (%): 333 (MH+, 46); 217 (47); 199 (9);
149 (7). 1H NMR (400 MHz, DMSO-d6): 2.35 (ddd, 1 H, Jgem = 13.3, J2′b,1′ = 6.2, J2′b,3′ = 3.4,
H-2′b); 2.78 (ddd, 1 H, Jgem = 13.3, J2′a,1′ = 7.6, J2′a,3′ = 5.8, H-2′a); 3.55 (ddd, 1 H, Jgem
11.8, J5′b,OH = 5.6, J5′b,4′ = 4.5, H-5′b); 3.64 (dt, 1 H, Jgem = 11.8, J5′a,OH = 5.5, J5′a,4′ = 4.6,
H-5′a); 3.90 (td, 1 H, J4′,5′ = 4.7, 4.5, J4′,3′ = 2.9, H-4′); 4.45 (m , 1 H, J3′,2′ = 5.8, 3.4, J3′,OH
=
=
4.2, J3′,4′ = 2.9, H-3′); 4.69 (d, 2 H, JCH2,OH = 6.2, CH2O); 5.00 (t, 1 H, JOH,5′ = 5.6, 5.5,
OH-5′); 5.33 (t, 1 H, JOH,CH2 = 6.2, OH); 5.36 (d, 1 H, JOH,3′ = 4.2, OH-3′); 6.51 (dd, 1 H,
J1′,2′ = 7.6, 6.2, H-1′); 6.82 (dd, 1 H, J4,3 = 3.4, J4,5 = 1.7, H-4-furyl); 7.85 (dd, 1 H, J3,4 = 3.4,
J3,5 = 0.8, H-3-furyl); 8.06 (dd, 1 H, J5,4 = 1.7, J5,3 = 0.8, H-5-furyl); 8.80 (s, 1 H, H-8).
13C NMR (100.6 MHz, DMSO-d6): 39.59 (CH2-2′); 61.77 (CH2-5′); 65.18 (CH2O); 70.89
(CH-3′); 83.58 (CH-1′); 88.21 (CH-4′); 113.04 (CH-4-furyl); 117.64 (CH-3-furyl); 127.12 (C-5);
144.73 (C-6); 144.78 (CH-8); 146.55 (CH-5-furyl); 149.18 (C-2-furyl); 152.07 (C-4); 163.48
(C-2). IR (KBr): 3409, 1592, 1485, 1406, 1376, 1358, 1318, 1223, 1206, 1094, 1057, 1020,
642.
Gen eral Procedure for Cleavage of THP Protective Group
Eith er p-toluen esulfon ic acid (0.6 m m ol; for 7a) or Dowex 50X8 (H+) (ca. 50 m g; for 8a–10a)
was added to a solution of THP-protected purin es 7a–10a (0.5 m m ol) in eth an ol (25 m l,
96%). Th e reaction m ixture was stirred at 70–75 °C for 3 h , filtered, wash ed resin with
eth an olic am m on ia (3 × 20 m l) an d evaporated to dryn ess. Crude product was ch rom atog-
raph ed (eth yl acetate/m eth an ol 9:1–7:3) to afford wh ite solid th at was crystallized from
eth an ol/h eptan e.
6-Amino-2-(hydroxymethyl)-9H-purine (7d ). Yield 85% of wh ite solid, m .p. 336–338 °C. For
C6H7N5O·1/2H2O (174.2) calculated: 41.38% C, 4.63% H, 40.21% N; foun d: 41.68% C,
4.28% H, 39.89% N. Exact m ass (FAB HRMS) foun d: 166.0721; calculated for C6H8N5O:
166.0729. FAB MS, m/z (%): 166 (MH+, 30); 149 (13). 1H NMR (400 MHz, DMSO-d6): 4.39 (s,
2 H, CH2O); 4.78 (bs, 1 H, OH); 7.11 (bs, 2 H, NH2); 8.06 (s, 1 H, H-8); 12.80 (bs, 1 H, NH).
13C NMR (100.6 MHz, DMSO-d6): 64.75 (CH2O); 116.58 (C-5); 139.34 (CH-8); 151.60 (C-4);
163.04 (C-2); (C-4 n ot observed). IR (KBr): 3391, 3308, 3110, 1645, 1588, 1414, 1359, 1235,
651.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

Modified Purine Bases and Nucleosides
801
2-(Hydroxymethyl)-6-methyl-9H-purine (8d ). Yield 71% of wh ite solid, m .p. 269–270 °C. For
C7H8N4O·H2O (173.2) calculated: 46.15% C, 5.53% H, 30.75% N; foun d: 45.79% C, 5.21% H,
30.28% N. Exact m ass (FAB HRMS) foun d: 165.0783; calculated for C7H9N4O: 165.0776.
FAB MS, m/z (%): 165 (MH+, 17); 147 (4); 131 (20). 1H NMR (400 MHz, DMSO-d6): 2.70 (s,
3 H, CH3); 4.61 (s, 2 H, CH2O); 5.20 (bs, 1 H, OH); 8.46 (s, 1 H, H-8). 13C NMR (100.6 MHz,
DMSO-d6): 19.62 (CH3); 65.14 (CH2O); 128.40 (C-5); 144.69 (CH-8); 154.37 (C-4); 155.54
(C-6); 162.67 (C-2). IR (KBr): 3099, 1594, 1490, 1428, 1377, 1232, 1108, 1080, 643.
2-(Hydroxymethyl)-6-phenyl-9H-purine (9d ). Yield 74% of wh ite solid, m .p. 285–286 °C. For
C
12H10N4O (225.3) calculated: 63.71% C, 4.46% H, 24.76% N; foun d: 63.36% C, 4.15% H,
24.39% N. Exact m ass (FAB HRMS) foun d: 227.0936; calculated for C12H11N4O: 227.0933.
FAB MS, m/z (%): 227 (MH+, 19); 149 (4). 1H NMR (400 MHz, DMSO-d6): 4.74 (s, 2 H,
CH2O); 5.27 (bs, 1 H, OH); 7.53–7.63 (m , 3 H, H-m,p-Ph ); 8.60 (s, 1 H, H-8); 8.85 (m , 2 H,
H-o-Ph ); 13.50 (bs, 1 H, NH). 13C NMR (100.6 MHz, DMSO-d6): 65.31 (CH2O); 128.35 (C-5);
128.71 (CH-m-Ph ); 129.51 (CH-o-Ph ); 130.96 (CH-p-Ph ); 135.87 (C-i-Ph ); 145.10 (CH-8);
151.85 (C-6); 154.76 (C-4); 162.93 (C-2). IR (KBr): 3392, 3293, 3028, 1605, 1586, 1570, 1500,
1485, 1415, 1382, 1357, 1235, 1081, 642.
6-(2-Furyl)-2-(hydroxymethyl)-9H-purine (10d ). Yield 68% of wh ite solid, m .p. 295–296 °C.
For C10H8N4O2 (216.2) calculated: 55.55% C, 3.73% H, 25.91% N; foun d: 55.19% C, 3.70% H,
25.57% N. Exact m ass (FAB HRMS) foun d: 217.0722; calculated for C10H9N4O2: 217.0726.
FAB MS, m/z (%): 217 (MH+, 3); 199 (3); 149 (4). 1H NMR (400 MHz, DMSO-d6): 4.68 (s, 2 H,
CH2O); 5.24 (bs, 1 H, OH); 6.81 (dd, 1 H, J4,3 = 3.5, J4,5 = 1.7, H-4-furyl); 7.78 (bd, 1 H, J3,4
=
3.5, H-3-furyl); 8.05 (dd, 1 H, J5,4 = 1.7, J5,3 = 0.9, H-5-furyl); 8.58 (s, 1 H, H-8); 12.15 (bs,
1 H, NH). 13C NMR (100.6 MHz, DMSO-d6): 65.23 (CH2O); 112.92 (CH-4-furyl); 117.22
(CH-3-furyl); 126.36 (C-5); 144.25 (C-6); 144.80 (CH-8); 146.22 (CH-5-furyl); 149.49
(C-2-furyl); 153.45 (C-4); 163.24 (C-2). IR (KBr): 3413, 1591, 1569, 1481, 1409, 1374, 1236,
1214, 1073, 1011, 652.
Sin gle Crystal X-ray Structure An alysis
X-ray an alysis of a colourless sin gle crystal (n eedle, 0.03 × 0.18 × 0.41 m m ) of 9a was per-
form ed with an Xcalibur X-ray diffractom etr usin g CuKα radiation (λ = 1.54180 Å); dif-
fraction data were collected at 150 K. Th e structure was solved by direct m eth ods with
22
SIR92
an d refin ed by full-m atrix least-squares on F with CRYSTALS 23. All n on -h ydrogen
atom s were refin ed an isotropically. Th e h ydrogen atom s were all located in a differen ce
m ap, but th ose attach ed to carbon atom s were reposition ed geom etrically. All h ydrogen
atom s were in itially refin ed with soft restrain ts on th e bon d len gth s an d an gles to regularize
th eir geom etry after wh ich th e position s were refin ed with ridin g con strain ts. Crystal data:
C
17H18N4O2, orth orh om bic, space group Pna21, a = 8.3389(5) Å, b = 14.7010(8) Å, c =
12.5296(8) Å, V = 1536.01(16) Å3, Z = 4, M = 310.35, 21 464 reflection s m easured, 1672 in -
depen den t reflection s. Fin al R = 0.0333, wR = 0.0358, GOF = 1.0782 for 1456 reflection s
with I > 1.96σ(I) an d 208 param eters.
CCDC 603580 con tain s th e supplem en tary crystallograph ic data for th is paper. Th ese data
can be obtain ed free of ch arge via www.ccdc.cam .ac.uk/con ts/retrievin g.h tm l (or from th e
Cam bridge Crystallograph ic Data Cen tre, 12, Un ion Road, Cam bridge, CB2 1EZ, UK; fax:
+44 1223 336033; or deposit@ccdc.cam .ac.uk).
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

802
Šilhár, Pohl, Votruba, Klepetářová, Hocek:
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, U.S.A.).
The authors thank to Dr. Richard Mackman (Gilead) for anti-HCV activity screening.
REFERENCES
1. a) Hocek M., Holý A., Votruba I., Dvořáková H.: J. Med. Chem. 2000, 43, 1817; b) Hocek M.,
Holý A., Votruba I., Dvořáková H.: Collect. Czech. Chem. Commun. 2001, 66, 483.
2. Hocek M., Nauš P., Pohl R., Votruba I., Furman P. A., Tharnish P. M., Otto M. J.: J. Med.
Chem. 2005, 48, 5869.
3. a) Bakkestuen A. K., Gundersen L.-L., Langli G., Liu F., Nolsoe J. M. J.: Bioorg. Med. Chem.
Lett. 2000, 10, 1207; b) Andresen G., Gundersen L.-L., Nissen-Meyer J., Rise F., Spilsberg B.:
Bioorg. Med. Chem. Lett. 2002, 12, 567; c) Gundersen L.-L., Nissen-Meyer J., Spilsberg D.:
J. Med. Chem. 2002, 45, 1383; d) Bræn dvan g M., Gundersen L.-L.: Bioorg. Med. Chem.
2005, 13, 6360.
4. Šilhár P., Pohl R., Votruba I., Hocek M.: Org. Lett. 2004, 6, 3225.
5. Šilhár P., Pohl R., Votruba I., Hocek M.: Org. Biomol. Chem. 2005, 3, 3001.
6. Šilhár P., Pohl R., Votruba I., Hocek M.: Synthesis 2006, 1848.
7. Montgomery J. A., Hewson K.: J. Med. Chem. 1968, 11, 48.
8. Parker W. B., King S. A., Allan P. W., Bennett L. L., Jr., Secrist III J. A., Montgomery J. A.,
Gilbert K. S., Waud W. R., Wells A. H., Gillespie G. Y., Sorscher E. J.: Hum. Gene Ther.
1997, 8, 1637
9. Zhang H.-Z., Rao K., Carr S. F., Papp E., Straub K., Wu J. C., Fried J.: J. Med. Chem. 1997,
40, 4.
10. Salaski E., Maag H.: Synlett 1999, 897.
11. a) Nair V., Purdy D. F., Sells T. B.: J. Chem. Soc., Chem. Commun. 1989, 878; b) Nair V.,
Lyons A. G.: Tetrahedron 1989, 45, 3653.
12. Nair V., Ussery M. A.: Antiviral Res. 1992, 19, 173.
13. Hocek M., Masojídková M., Holý A.: Synthesis 1994, 1401.
14. Matsuda A., Satoh K., Miyasaka T., Ueda T.: Chem. Pharm. Bull. 1984, 32, 2048.
15. Ohno M., Gao Z.-G., Van Rompaey P., Tchilibon S., Kim S.-K., Harris B. A., Gross A. S.,
Duong H. T., Van Calenbergh S., Jacobson K. A.: Bioorg. Med. Chem. 2004, 12, 2995.
16. a) Havelková M., Dvořák D., Hocek M.: Synthesis 2001, 1704; b) Hocek M., Votruba I.,
Dvořáková H.: Tetrahedron 2003, 59, 607; c) Hocek M., Dvořáková H.: J. Org. Chem.
2003, 68, 5773; d) Hocek M., Holý A., Dvořáková H.: Collect. Czech. Chem. Commun.
2002, 67, 325; e) Hocek M., Hocková D., Štambaský J.: Collect. Czech. Chem. Commun.
2003, 68, 837; f) Hocek M., Pohl R., Císařová I.: Eur. J. Org. Chem. 2005, 3026;
g) Langli G., Gundersen L.-L., Rise F.: Tetrahedron 1996, 52, 5625; h) Nolsoe J. M. J.,
Gundersen L.-L., Rise F.: Acta Chem. Scand. 1999, 53, 366; i) Hocek M., Hocková D.,
Dvořáková D.: Synthesis 2004, 889; j) Hocek M., Pohl R.: Synthesis 2004, 2869.
17. Šilhár P., Pohl R., Votruba I., Hocek M.: Collect. Czech. Chem. Commun. 2005, 70, 1669.
18. For reviews, see: a) Hocek M.: Eur. J. Org. Chem. 2003, 245; b) Agrofoglio L. A., Gillaizeau I.,
Saito Y.: Chem. Rev. 2003, 103, 1875.
19. Farrugia L. J.: J. Appl. Crystallogr. 1997, 30, 565.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803

Modified Purine Bases and Nucleosides
803
20. Stuyver L. J., Whitaker T., McBrayer T. R., Hernandez-Santiago B. I., Lostia S., Tharnish
P. M., Ramesh M., Chu C. K., Jordan R., Shi J. X., Rachakonda S., Watanabe K. A., Otto
M. J., Schinazi R. F.: Antimicrob. Agents Chemother. 2003, 47, 244.
21. Matsuda A., Shinozaki M., Yamaguchi T., Homma H., Nomoto R.: J. Med. Chem. 1992,
35, 241.
22. Altomare A., Cascarano G., Giacovazzo G., Guagliardi A., Burla M. C., Polidori G.,
Camalli M.: J. Appl. Crystallogr. 1994, 27, 435.
23. Betteridge P. W., Carruthers J. R., Cooper R. I., Prout K., Watkin D. J.: J. Appl. Crystallogr.
2003, 36, 1487.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 6, pp. 788–803