Synthesis of 6-(4,5-dihydrofuran-2-yl)- and 6-(tetrahydrofuran-2-yl)purine bases and nucleosides

Article abstract of DOI:10.1002/ejoc.200800174

A novel approach to the synthesis of purine derivatives (bases and nucleosides) bearing 4,5-dihydrofuran-2-yl and tetrahydrofuran-2-yl substituents at the 6-position as partly and fully saturated analogues of biologically active 6-hetarylpurine nucleosides is reported. Palladium-catalyzed cross-coupling reactions of 6-iodopurines with new (4,5-dihydrofuran-2-yl)zinc chloride (1) gave 6-(4,5-dihydrofuran-2-yl)-purines in high yields. Their catalytic hydrogenation gave 6-(tetrahydrofuran-2-yl)purines. These modified purine bases and nucleosides did not exhibit any significant cytostatic or anti-HCV activity. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800174

FULL PAPER
DOI: 10.1002/ejoc.200800174
Synthesis of 6-(4,5-Dihydrofuran-2-yl)- and 6-(Tetrahydrofuran-2-yl)purine
Bases and Nucleosides
[a]
[a]
[a]
ˇ
Vítezslav Bambuch, Radek Pohl, and Michal Hocek*
Keywords: Purines / Nucleosides / Cross-coupling / Zinc / Hydrogenation
A novel approach to the synthesis of purine derivatives
(bases and nucleosides) bearing 4,5-dihydrofuran-2-yl and
tetrahydrofuran-2-yl substituents at the 6-position as partly
and fully saturated analogues of biologically active 6-hetaryl-
purine nucleosides is reported. Palladium-catalyzed cross-
coupling reactions of 6-iodopurines with new (4,5-dihydro-
furan-2-yl)zinc chloride (1) gave 6-(4,5-dihydrofuran-2-yl)-
purines in high yields. Their catalytic hydrogenation gave 6-
(tetrahydrofuran-2-yl)purines. These modified purine bases
and nucleosides did not exhibit any significant cytostatic or
anti-HCV activity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
tially and fully saturated analogues of anti-HCV 6-hetaryl-
purines[2,7,8] and cyclic (conformationally locked) deriva-
tives of the cytostatic 6-(hydroxymethyl)purines.[3] Herein
we report on the development of a synthetic methodology
for the title purines bearing saturated five-membered oxy-
gen heterocycles at the 6-position.
Introduction
Purine nucleosides bearing carbon substituents at the 6-
position possess a broad spectrum of biological activities,
including cytostatic[1] and antimicrobial[2] effects. Recently,
we reported the synthesis and cytostatic activities of 6-(hy-
droxymethyl)-,[3] 6-(fluoromethyl)-,[4] 6-(difluoromethyl)-,[5]
and 6-(trifluoromethyl)purine[6] ribonucleosides. 6-Aryl-, 6-
hetaryl-, and 6-benzylpurine ribonucleosides[7] were also
found to have significant cytostatic effects. Purine ribonu-
cleosides bearing five-membered heterocycles at the 6-posi-
tion exert strong anti-HCV activities.[8]
In some cases, purines bearing functionalized carbon
substituents at the 6-position have been prepared by the
direct cross-coupling[9] of 6-halopurines with functionalized
organometallics. This approach has been successfully used
to synthesize 6-(hydroxymethyl)purines by the coupling of
(acyloxymethyl)zinc iodides,[3] 6-(ethoxycarbonylmethyl)-
purines by coupling with the Reformatsky reagent,[10] and
purin-6-yl amino acids by coupling with protected amino
acid organometallics.[11] Other types of substituents have
been prepared by functional-group transformation[4,5,12] of
6-(hydroxymethyl)purines or by conjugate addition of nu-
cleophiles to 6-ethynyl- and 6-vinylpurines.[13]
In this work we have combined the structural features of
the two above-mentioned types of biologically active com-
pounds, cytostatic 6-(hydroxymethyl)purines and cyto-
static,[7] antiviral[8] and antimicrobial[2] 6-(2-furyl)purines.
We envisaged purines bearing a 4,5-dihydro- and tetra-
hydrofuran-2-yl residue at the 6-position (Figure 1) as par-
Figure 1. Structures of biologically active purine ribonucleosides
and the title compounds.
Results and Discussion
[a] Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic, Gilead & IOCB Research
Center,
The Negishi cross-coupling of halopurines with organo-
zinc reagents is a very versatile method suitable for the in-
troduction of diverse unfunctionalized and functionalized
alkyl, alkenyl, aryl, and hetaryl groups.[14] Several hetaryl-
Flemingovo nám. 2, 16610 Prague 6, Czech Republic
Fax: +420-220183559
E-mail: hocek@uochb.cas.cz
Eur. J. Org. Chem. 2008, 2783–2788
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2783

V. Bambuch, R. Pohl, M. Hocek
FULL PAPER
zinc halides generated by dehydrolithiation of five- or six- Table 1. Cross-coupling of the organozinc compound 1 with iodo-
purine derivatives 2a–d.
membered nitrogen heterocycles have been used in cross-
coupling reactions with 6-iodopurine derivatives to give the
corresponding 6-hetarylpurines in good yields.[15] There-
fore, introduction of the 4,5-dihydrofuran-2-yl residue at the
6-position of the purine scaffold by the Neghishi cross-
coupling reaction could be a method of choice. 2,3-Dihy-
drofuran is lithiated predominantly at the 5-position to give
2-lithio-4,5-dihydrofuran.[16] A few examples of the dehy-
drolithiation of 2,3-dihydrofuran, its further transmet-
alation to the corresponding organostannyl derivatives, and
their use in Stille-type cross-coupling reactions have been
described.[17] However, use of the corresponding organozinc
derivatives for cross-coupling has not been reported.
We have tried to develop a practical new approach to the
synthesis of novel 6-(4,5-dihydrofuran-2-yl)purines based
on the cross-coupling reactions of 6-iodopurines with a new
organozinc compound, (4,5-dihydrofuran-2-yl)zinc chloride
(1). According to the literature,[16a] 2,3-dihydrofuran was
deprotonated with tBuLi in a mixture of pentane and THF
at –78 °C. Subsequent addition of ZnCl2 in THF generated
organozinc compound 1. This organometallic reagent was
used directly in the Pd-catalyzed cross-coupling with 6-
iodopurines 2a–d [9-benzyl-6-iodopurine (2a) was used as
an example of 9-alkylated purines, 9-THP-6-iodopurine 2b
is a 9-protected purine base, and derivatives 2c and 2d are
examples of an acyl-protected ribonucleoside and 2-deoxyr-
ibonucleoside, respectively; Scheme 1]. The reactions were
carried out in THF at ambient temperature with [Pd-
(PPh3)4] as catalyst to give 6-(4,5-dihydrofuran-2-yl)purines
3a–d in good yields (Table 1).
Entry
Iodopurine
Product
Yield [%]
1
2
3
4
2a
2b
2c
2d
3a
3b
3c
3d
78
93
70
70
decomposition to a complex mixture of degradation prod-
ucts. Treatment with trifluoroacetic or acetic acid was more
promising and gave the desired purine in around 50% yield.
The best yield of 54% was obtained when using TsOH in
methanol. Moderate isolated yields were apparently caused
by the limited stability of the 4,5-dihydrofuran-2-yl residue
under acidic conditions. The acetyl-protected nucleosides
3c,d were deprotected by standard treatment with NaOMe
in methanol (Scheme 2) to give free 6-(4,5-dihydrofuran-2-
yl)purine nucleosides 3f and 3g in good yields (Table 2, En-
tries 6 and 7).
Scheme 2.
Table 2. Deprotection of purine base 3b and the nucleosides 3c,d.
Entry
Starting
compound
Conditions
Time Product Yield
[%]
[a]
1
2
3
4
5
6
7
3b
3b
3b
3b
3b
3c
3d
Dowex (H+), EtOH
HCl, EtOH
TFA, CH2Cl2
AcOH, MeOH/H2O
TsOH, MeOH
24 h
3 h
1.5 h
24 h
20 min
6 h
–
–
–
–
[b]
3e
3e
3e
3f
3g
50
49
54
77
99
NaOMe, MeOH
NaOMe, MeOH
6 h
[a] The starting compound/product strongly binds to the resin. [b]
Decomposition occurred.
Scheme 1.
Having an efficient methodology for the synthesis of the
For deprotection of 9-THP-purine 3b to the correspond- 6-(4,5-dihydrofuran-2-yl)purines, we next explored the pos-
ing 9H-purine 3e (Scheme 2), we first tried our standard sibility of reducing the double bond of the 4,5-dihydro-
methodology,[18] treatment with an acidic cation exchange furan-2-yl group to give the tetrahydrofuran-2-yl group.
resin (Dowex, H+ form) in EtOH. However, no product was Catalytic hydrogenation of 9-benzyl-6-(4,5-dihydrofuran-2-
isolated, probably due to strong binding to the resin. There- yl)purine (3a) on Pd/C under atmospheric pressure pro-
fore, we tried some other acids to cleave the THP group ceeded smoothly to give the desired 9-benzyl-6-(tetra-
(see Table 2, Entries 1–5). The use of HCl in EtOH led to hydrofuran-2-yl)purine (4a) in a high yield of 92%
2784
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Eur. J. Org. Chem. 2008, 2783–2788

Dihydro- and Tetrahydrofuranylpurine Bases and Nucleosides
1
1
for H and 100.6 MHz for 13C nuclei, or at 500 MHz for H and
125.7 MHz for 13C in CDCl3 and [D6]DMSO. 1H and 13C NMR
spectra were referenced to the signal of TMS or to the solvent
residual signal. Chemical shifts are given in ppm (δ-scale), coupling
constants (J) in Hz. 1H,13C-HMBC experiments were performed
for complete assignment of all signals. The starting compounds
2a,[20] 2b,[21] 2c,[22] and 2d[23] were prepared according to literature
procedures. Mass spectra were measured using FAB (ionization by
Xe, accelerating voltage 8 kV, glycerol + thioglycerol matrix) or EI
(electron energy 70 eV) techniques with a ZAB-EQ (VG Analytical)
spectrometer.
(Scheme 3, Table 3, Entry 1). The same conditions were
then applied to the reduction of free purine base 3e and
nucleosides 3f,g to give the 6-(tetrahydrofuran-2-yl)purine
base 4e and the nucleosides 4f,g in good yields (Scheme 3,
Table 3, Entries 2–4). A new stereogenic center is generated
by this reaction at the 2-position of the tetrahydrofuran
moiety. In the cases of the nucleosides 4f,g, no diastereo-
selectivity due to the presence of the homochiral sugar unit
was observed, and the compounds were characterized as
epimeric mixtures.
Preparation of Organozinc Reagent 1 from 2,3-Dihydrofuran and Its
Cross-Coupling with 6-Iodopurines 2a–d. General Pocedure. 9-Ben-
zyl-6-(4,5-dihydrofuran-2-yl)purine (3a): THF (75 µL) was added to
an argon-purged dried flask containing 2,3-dihydrofuran (153 µL,
2 mmol), and the mixture was cooled to –78 °C. Then tBuLi
(1.3 mL, 2.2 mmol, 1.7  solution in pentane) was added; after
30 min, a solution of ZnCl2 (315 mg, 2.3 mmol) in THF (3 mL)
was added. The mixture was stirred at –78 °C for 5 min and then
warmed to room temp. during 1.5 h to generate 1. Then, 2a
(504 mg, 1.5 mmol) and [Pd(PPh3)4] (87 mg, 0.075 mmol, 5 mol-%)
in THF (2 mL) were added, and the reaction mixture was stirred
at room temp. overnight. The solvents were removed in vacuo, and
the crude product was diluted with EtOAc, washed with water and
brine, dried with MgSO4, and the solvent evaporated. The product
was purified by chromatography on silica gel with a hexane/EtOAc
gradient (2:1 to 1:2) to give pure 3a (325 mg, 78%) as white crystals,
m.p. 153–155 °C. 1H NMR (500 MHz, CDCl3): δ = 2.99 (td, J4,5
= 9.7, J4,3 = 3.2 Hz, 2 H, 4-H DHF), 4.64 (t, J5,4 = 9.7 Hz, 2 H,
5-H DHF), 5.45 (s, 2 H, CH2-Ph), 6.77 (t, J3,4 = 3.2 Hz, 1 H, 3-H
DHF), 7.26–7.38 (m, 5 H, Ph), 8.07 (s, 1 H, 8-H), 8.98 (s, 1 H, 2-
H) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 31.12 (CH2-4 DHF),
47.08 (CH2-Ph), 69.89 (CH2-5 DHF), 110.79 (CH-3 DHF), 127.61
(CH-o Ph), 128.42 (CH-p Ph), 128.96 (CH-m Ph), 129.69 (C-5),
Scheme 3.
Table 3. Catalytic hydrogenation of purines 6a,e–g.
Entry Starting compound
Solvent
Product Yield [%]
1
2
3
4
3a
3e
3f
MeOH
4a
4e
4f
92
83
72
98
EtOH/H2O
EtOH/H2O
EtOH/H2O
3g
4g
All the substituted purines and nucleosides 3 and 4 were
subjected to biological-activity screening. The in vitro cyto-
static activity (inhibition of cell growth) of the following
cell cultures was studied: (i) Mouse leukemia L1210 cells
(ATCC CCL 219), human promyelocytic leukemia HL60
cells (ATCC CCL 240), human cervix carcinoma HeLaS3 134.91 (C-i Ph), 144.35 (CH-8), 147.00 (C-6), 151.62 (C-4), 152.35
(CH-2), 152.54 (C-2 DHF) ppm. FAB-MS: m/z (%) = 279 (100) [M
cells (ATCC CCL 2.2), and the human T lymphoblastoid
CCRF-CEM cell line (ATCC CCL 119). Antiviral activities
were tested in the HCV genotype 1b replicon.[19] None of
the compounds showed any significant activity in any of
these assays. This shows that the aromatic nature of the
+ H]+, 201 (10), 91 (80). HRMS: calcd. for C16H15N4O [M + H]+
279.1246; found 279.1250. IR (KBr): ν = 3098, 3060, 2927, 1622,
˜
1580, 1501, 1319, 1211, 976 cm–1.
6-(4,5-Dihydrofuran-2-yl)-9-(tetrahydropyran-2-yl)purine (3b): Com-
hetaryl substituent in cytostatic and antiviral 6-hetarylpur- pound 3b was prepared according to the procedure described for
3a starting from 2b (1.65 g, 5 mmol); 3b (1.23 g, 93%) was obtained
as white crystals, m.p. 99–101 °C. H NMR (400 MHz, CDCl3): δ
ine nucleosides is crucial for biological activity.
1
= 1.64–1.87 and 2.02–2.20 (2 m, 2ϫ 3 H, CH2 THP), 3.00 (td, J4,5
= 9.6, J4,3 = 3.2 Hz, 2 H, 4-H DHF), 3.80 (td, J = 11.6, 2.8 Hz, 1
H, CHaHb-O THP), 4.19 (ddt, J = 12.0, 4.0, 2.0 Hz, 1 H, CHaHb-
Conclusion
A new organozinc reagent, (4,5-dihydrofuran-2-yl)zinc O THP), 4.65 (t, J5,4 = 9.6 Hz, 2 H, 5-H DHF), 5.82 (dd, J = 10.4,
2.4 Hz, 1 H, CH-O THP), 6.77 (t, J3,4 = 3.2 Hz, 1 H, 3-H DHF),
8.30 (s, 1 H, 8-H), 8.95 (s, 1 H, 2-H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 22.69, 24.79 (CH2 THP), 31.23 (CH2-4 DHF), 31.79
(CH2 THP), 68.81 (CH2-O THP), 70.01 (CH2-5 DHF), 81.94 (CH-
O THP), 110.94 (CH-3 DHF), 129.99 (C-5), 142.36 (CH-8), 147.15
(C-6), 150.90 (C-4), 152.31 (CH-2), 152.64 (C-2 DHF) ppm. FAB-
MS: m/z (%) = 273 (10) [M + H]+, 189 (100), 85 (38). HRMS:
calcd. for C14H17N4O2 [M + H]+ 273.1352; found 273.1357. IR
chloride (1), has been generated and used in Pd-catalyzed
cross-coupling reactions with 6-iodopurines to afford ef-
ficiently the novel 6-(4,5-dihydrofuran-2-yl)purines. Their
catalytic hydrogenation afforded fully saturated 6-(tetra-
hydrofuran-2-yl)purines. The organozinc reagent 1 can
serve as a good building block for the attachment of di-
and tetrahydrofuran to other types of compounds through
a C–C bond.
(CHCl ): ν = 3125, 3062, 2953, 2858, 1625, 1587, 1493, 1410, 1334,
˜
3
1325, 1146, 913 cm–1.
6-(4,5-Dihydrofuran-2-yl)-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-
Experimental Section
purine (3c): Compound 3c was prepared according to the procedure
described for 3a starting from 2c (7.30 g, 14.48 mmol) to give 3c
(4.52 g, 70%) as a white foam, m.p. 83–85 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.09, 2.13, 2.16 (3 s, 3ϫ 3 H, CH3CO), 3.02 (td, J4,5
General Methods: Melting points were determined with a Kofler
block. Optical rotations were measured at 25 °C; [α]2D0 values are
given in 10–1 degcm2 g–1. NMR spectra were measured at 400 MHz
Eur. J. Org. Chem. 2008, 2783–2788
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2785

V. Bambuch, R. Pohl, M. Hocek
FULL PAPER
= 9.6, J4,3 = 3.2 Hz, 2 H, 4-H DHF), 4.36–4.51 (m, 3 H, 4Ј-H and
4.0 Hz, 1 H, 3Ј-H), 4.49 (t, J5,4 = 9.6 Hz, 2 H, 5-H DHF), 4.62
5Ј-H), 4.67 (t, J5,4 = 9.6 Hz, 2 H, 5-H DHF), 5.68 (t, J3Ј,2Ј = J3Ј,4Ј (ddd, J2Ј,OH = 6.0, J2Ј,1Ј = 5.6, J2Ј,3Ј = 4.4 Hz, 1 H, 2Ј-H), 5.12 (t,
= 5.2 Hz, 1 H, 3Ј-H), 5.96 (t, J2Ј,1Ј = J2Ј,3Ј = 5.2 Hz, 1 H, 2Ј-H), JOH,5Ј = 5.6 Hz, 1 H, 5Ј-OH), 5.24 (d, JOH,3Ј = 4.8 Hz, 1 H, 3Ј-
6.27 (d, J1Ј,2Ј = 5.2 Hz, 1 H, 1Ј-H), 6.80 (t, J3,4 = 3.2 Hz, 1 H, 3-H OH), 5.54 (d, JOH,2Ј = 6.0 Hz, 1 H, 2Ј-OH), 6.05 (d, J1Ј,2Ј = 5.6 Hz,
DHF), 8.29 (s, 1 H, 8-H), 8.98 (s, 1 H, 2-H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 20.30, 20.47, 20.70 (3ϫ CH3CO), 31.24
1 H, 1Ј-H), 6.78 (t, J3,4 = 3.2 Hz, 1 H, 3-H DHF), 8.85, 8.88 (2 s,
2ϫ 1 H, 2-H, 8-H) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
(CH2-4 DHF), 62.93 (CH2-5Ј), 70.10 (CH2-5 DHF), 70.53 (CH- 30.67 (CH2-4 DHF), 61.14 (CH2-5Ј), 69.01 (CH2-5 DHF), 70.18
3Ј), 73.07 (CH-2Ј), 80.38 (CH-4Ј), 86.38 (CH-1Ј), 111.64 (C-3 (CH-3Ј), 73.68 (CH-2Ј), 85.61 (CH-4Ј), 87.57 (CH-1Ј), 111.26 (C-3
DHF), 130.38 (C-5), 142.93 (CH-8), 147.50 (C-6), 151.20 (C-4), DHF), 129.94 (C-5), 144.95 (CH-8), 146.05 (C-6), 151.10 (C-4),
152.32 (C-2 DHF), 152.58 (CH-2), 169.29, 169.52, 170.25 (3ϫ 151.58 (CH-2), 152.09 (C-2 DHF) ppm. FAB-MS: m/z (%) = 321
CH3CO) ppm. FAB-MS: m/z (%) = 447 (20) [M + H]+, 259 (45), (24) [M + H]+, 231 (33), 177 (62), 154 (100), 137 (83), 109 (28).
189 (48), 139 (100), 97 (85). HRMS: calcd. for C20H23N4O8 [M +
HRMS: calcd. for C14H17N4O5 [M + H]+ 321.1198; found
H]+ 447.1516; found 447.1521. IR (CHCl ): ν = 3119, 1751, 1620,
321.1192. IR (CHCl ): ν = 3392, 3280, 3108, 1623, 1591, 1490,
˜
˜
3
3
1587, 1496, 1374, 1049, 937 cm–1.
1410, 1329, 1215, 1061, 977 cm–1.
9-(3,5-Di-O-acetyl-2-deoxy-β-D-erythro-pentofuranosyl)-6-(4,5-dihy-
9-(2-Deoxy-β-D-erythro-pentofuranosyl)-6-(4,5-dihydrofuran-2-yl)pu-
drofuran-2-yl)purine (3d): Compound 3d was prepared according to
the procedure described for 3a. Starting from 2d (1.10 g,
2.46 mmol), 3d (0.67 g, 70%) was obtained as a white solid, m.p.
rine (3g): NaOMe (1  in MeOH, 300 µL, 0.3 mmol) was added
dropwise to a solution of 3d (388 mg, 1.0 mmol) in MeOH (10 mL),
and the mixture was stirred for 6 h. The solvent was evaporated in
vacuo, and the crude product was purified by chromatography on
silica gel with a methanol/chloroform gradient (1:99 to 5:95) to give
3g (302 mg, 99%) as a white solid, m.p. 137–139 °C. [α]2D0 = –14.9
(c = 3.26, DMSO). 1H NMR (400 MHz, [D6]DMSO): δ = 2.31
(ddd, Jgem = 13.6, J2Јb,1Ј = 6.4, J2Јb,3Ј = 3.6 Hz, 1 H, 2Јb-H), 2.73
(ddd, Jgem = 13.6, J2Јa,1Ј = 6.8, J2Јa,3Ј = 6.0 Hz, 1 H, 2Јa-H), 2.87
1
118–120 °C. H NMR (400 MHz, CDCl3): δ = 2.09, 2.15 (2 s, 2ϫ
3 H, CH3CO), 2.68 (ddd, Jgem = 14.0, J2Јb,1Ј = 5.6, J2Јb,3Ј = 2.4 Hz,
1 H, 2Јb-H), 2.98 (ddd, Jgem = 14.0, J2Јa,1Ј = 8.0, J2Јa,3Ј = 6.4 Hz, 1
H, 2Јa-H), 2.99 (td, J4,5 = 9.6, J4,3 = 3.2 Hz, 2 H, 4-H DHF), 4.35–
4.45 (m, 3 H, 4Ј-H, 5Ј-H), 4.65 (t, J5,4 = 9.6 Hz, 2 H, 5-H DHF),
5.46 (ddd, J3Ј,2Ј = 6.4, 2.4, J3Ј,4Ј = 2.0 Hz, 1 H, 3Ј-H), 6.53 (dd,
J1Ј,2Јa = 8.0, J1Ј,2Јb = 5.6 Hz, 1 H, 1Ј-H), 6.78 (t, J3,4 = 3.2 Hz, 1
H, 3-H DHF), 8.27 (s, 1 H, 8-H), 8.95 (s, 1 H, 2-H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 20.71, 20.86 (2ϫ CH3CO), 31.25
(CH2-4 DHF), 37.52 (CH2-2Ј), 63.63 (CH2-5Ј), 70.03 (CH2-5
DHF), 74.39 (CH-3Ј), 82.65 (CH-1Ј), 84.65 (CH-4Ј), 111.29 (C-3
DHF), 130.52 (C-5), 142.59 (CH-8), 147.41 (C-6), 151.07 (C-4),
152.36 (CH-2), 152.51 (C-2 DHF), 170.19, 170.28 (2ϫ CH3CO)
ppm. FAB-MS: m/z (%) = 389 (20) [M + H]+, 279 (15), 189 (100),
81 (70). HRMS: calcd. for C18H21N4O6 [M + H]+ 389.1461; found
(td, J4,5 = 9.6, J4,3 = 2.8 Hz, 2 H, 4-H DHF), 3.49 (ddd, Jgem
11.6, J5Јb,OH = 5.2, J5Јb,4Ј = 4.8 Hz, 1 H, 5Јb-H), 3.58 (ddd, Jgem
11.6, J5Јa,OH = 5.6, J5Јa,4Ј = 4.4 Hz, 1 H, 5Јa-H), 3.85 (ddd, J4Ј,5Ј
=
=
=
4.8, 4.4, J4Ј,3Ј = 2.8 Hz, 1 H, 4Ј-H), 4.07 (dddd, J3Ј,2Ј = 6.0, 3.2,
J3Ј,OH = 4.0, J3Ј,4Ј = 2.8 Hz, 1 H, 3Ј-H), 4.35 (t, J5,4 = 9.6 Hz, 2 H,
5-H DHF), 4.96 (dd, JOH,5Ј = 5.2, 5.6 Hz, 1 H, 5Ј-OH), 5.33 (d,
JOH,3Ј = 4.0 Hz, 1 H, 3Ј-OH), 6.43 (dd, J1Ј,2Ј = 6.8, 6.4 Hz, 1 H,
1Ј-H), 6.71 (t, J3,4 = 2.8 Hz, 1 H, 3-H DHF), 8.75, 8.81 (2 s, 2ϫ 1
H, 2-H, 8-H) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 30.67
(CH2-4 DHF), 39.29 (CH2-2Ј), 61.45 (CH2-5Ј), 68.99 (CH2-5
DHF), 70.52 (CH-3Ј), 83.66 (CH-1Ј), 87.95 (CH-4Ј), 111.14 (C-3
DHF), 129.96 (C-5), 144.86 (CH-8), 145.98 (C-6), 150.82 (C-4),
151.50 (CH-2), 152.14 (C-2 DHF) ppm. FAB-MS: m/z (%) = 305
(10) [M + H]+, 279 (20), 217 (100), 189 (95), 119 (55), 71 (60).
HRMS: calcd. for C14H17N4O4 [M + H]+ 305.1249; found
389.1455. IR (CHCl ): ν = 1745, 1625, 1587, 1493, 1410, 1233 cm–1.
˜
3
6-(4,5-Dihydrofuran-2-yl)-9H-purine (3e): TsOH (380 mg, 2 mmol)
was added to a solution of 3b (136 mg, 0.5 mmol) in MeOH
(5 mL), and the mixture was stirred for 20 min. The solvent was
then evaporated under vacuum, and the crude product was purified
by chromatography on silica gel with a methanol/chloroform gradi-
305.1245. IR (CHCl ): ν = 3339, 3103, 1592, 1577, 1491, 1408,
˜
3
ent (1:99 to 5:95) to give 3e (51 mg, 54%) as a white solid, m.p.
1327, 1216, 1098, 1056 cm–1.
1
206–208 °C. H NMR (400 MHz, [D6]DMSO): δ = 2.87 (td, J4,5
=
9.6, J4,3 = 3.2 Hz, 2 H, 4-H DHF), 4.53 (t, J5,4 = 9.6 Hz, 2 H, 5-
H DHF), 6.47 (br. s, 1 H, 3-H DHF), 8.57 (s, 1 H, 8-H), 8.82 (s, 1
H, 2-H) ppm. 13C NMR (125.7 MHz, [D6]DMSO): δ = 30.53 (CH2-
4 DHF), 70.08 (CH2-5 DHF), 151.85 (C-4), 153.01 (CH-2 and C-
2 DHF) ppm. The signals of C-5,6,8 and C-3 DHF were not de-
tected due to N7,N9 tautomerism. EI-MS: m/z (%) = 188 (22)
[M]+, 159 (19), 149 (32), 119 (20), 69 (52). HRMS: calcd. for
Hydrogenation of Compounds 3a,e–g. General Procedure. 9-Benzyl-
6-(tetrahydrofuran-2-yl)purine (4a): 10% Pd/C (50 mg) was added
to a solution of 3a (188 mg, 0.676 mmol) in MeOH (20 mL) at
room temp. The flask was evacuated, then filled with H2 (100 kPa),
and the mixture was stirred until the reaction was complete (TLC,
ca. 4 h). The catalyst was filtered off, and the solvent was evapo-
rated in vacuo. The crude product was purified by chromatography
on silica gel with a hexane/ethyl acetate/methanol (1:1:0) to hexane/
ethyl acetate/methanol (10:10:1) gradient to give the desired com-
C H N O 188.0698; found 188.0700. IR (CHCl ): ν = 3444, 3118,
˜
9
8
4
3
1646, 1602, 1567, 1458, 1385, 1146, 1009, 940 cm–1.
6-(4,5-Dihydrofuran-2-yl)-9-(β-
D
-ribofuranosyl)purine (3f): NaOMe pound 4a (175 mg, 92%) as a white solid, m.p. 97–98 °C. 1H NMR
(1  in MeOH, 500 µL, 0.5 mmol) was added dropwise to a solu-
tion of 3c (670 mg, 1.5 mmol) in MeOH (15 mL), and the mixture
was stirred for 6 h. The solvent was then evaporated under vacuum,
and the crude product was purified by chromatography on silica
gel with a methanol/chloroform gradient (2:98 to 5:95) to give 3f
(370 mg, 77%) as a white solid, m.p. 188–190 °C. [α]2D0= –45.9 (c =
2.64, DMSO). 1H NMR (400 MHz, [D6]DMSO): δ = 2.93 (td, J4,5
(400 MHz, CDCl3): δ = 2.08, 2.16 (2 m, 2 H, 4-H THF), 2.26, 2.52
(2 m, 2 H, 3-H THF), 4.07 (ddd, Jgem = 8.0, J5b,4 = 7.6, 5.8 Hz, 1
H, 5b-H THF), 4.31 (dt, Jgem = 8.0, J5a,4 = 7.1 Hz, 1 H, 5a-H
THF), 5.45 (s, 2 H, CH2-Ph), 5.58 (t, J2,3 = 7.1 Hz, 1 H, 2-H THF),
7.28–7.39 (m, 5 H, Ph), 8.04 (s, 1 H, 8-H), 8.99 (s, 1 H, 2-H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 26.20 (CH2-4 THF), 32.14
(CH2-3 THF), 47.23 (CH2-Ph), 69.51 (CH2-5 THF), 77.78 (CH-2
= 9.6, J4,3 = 3.2 Hz, 2 H, 4-H DHF), 3.58 (ddd, Jgem = 12.0, J5Јb,OH THF), 127.82 (CH-o Ph), 128.57 (CH-p Ph), 129.10 (CH-m Ph),
= 5.6, J5Јb,4Ј = 4.0 Hz, 1 H, 5Јb-H), 3.70 (ddd, Jgem = 12, J5Јa,OH 131.10 (C-5), 135.05 (C-i Ph), 144.11 (CH-8), 151.57 (C-4), 152.60
5.6, J5Јa,4Ј = 3.2 Hz, 1 H, 5Јa-H), 3.98 (td, J4Ј,3Ј = J4Ј,5Јb = 4.0, J4Ј,5Јa (CH-2), 161.61 (C-6) ppm. FAB-MS: m/z (%) = 281 (100) [M +
= 3.2 Hz, 1 H, 4Ј-H), 4.19 (ddd, J3Ј,OH = 4.8, J3Ј,2Ј = 4.4, J3Ј,4Ј
H]+, 191 (7), 128 (7), 91 (80). HRMS: calcd. for C16H17N4O [M +
=
=
2786
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2783–2788

Dihydro- and Tetrahydrofuranylpurine Bases and Nucleosides
H]+ 281.1402; found 281.1410. IR (CHCl ): ν = 3092, 3069, 3035,
ppm. 13C NMR (125.7 MHz, [D6]DMSO): δ = 26.31 (CH2-4 THF),
31.58, 31.62 (CH2-3 THF), 39.40, 39.45 (CH2-2Ј), 61.74 (CH2-5Ј),
68.95 (CH2-5 THF), 70.82, 70.83 (CH-3Ј), 76.96, 77.00 (CH-2
THF), 83.91, 84.17 (CH-1Ј), 88.18 (CH-4Ј), 131.53, 131.55 (C-5),
144.78 (CH-8), 151.11 (C-4), 151.85 (CH-2), 161.12, 161.15 (C-6)
ppm. FAB-MS: m/z (%) = 307 (22) [M + H]+, 217 (50), 191 (100),
133 (25), 72 (25). HRMS: calcd. for C14H19N4O4 [M + H]+
˜
3
1592, 1500, 1406, 1331, 1073 cm–1.
6-(Tetrahydrofuran-2-yl)-9H-purine (4e): Compound 4e was pre-
pared according to the procedure described for 4a. EtOH/H2O (4:1)
was used as the solvent, and the reaction time was 4 h. Starting
from 3e (50 mg, 0.27 mmol), 4e (42 mg, 83%) was obtained as a
1
white solid, m.p. 177–179 °C. H NMR (500 MHz, [D6]DMSO +
307.1406; found 307.1402. IR (CHCl ): ν = 3318, 2875, 1595, 1498,
˜
3
DCl): δ = 1.8–2.04 (m, 2 H, 4-H THF), 2.12 (ddt, Jgem = 12.4, J3b,2
= 8.1, J3b,4 = 6.4 Hz, 1 H, 3b-H THF), 2.57 (dtd, Jgem = 12.4, J3a,4
1400, 1334, 1229, 1095, 1059 cm–1.
= 8.0, J3a,2 = 6.4 Hz, 1 H, 3a-H THF), 3.93 (dt, Jgem = 8.0, J5b,4
=
6.8 Hz, 1 H, 5b-H THF), 4.20 (ddd, Jgem = 8.0, J5a,4 = 7.0, 6.1 Hz,
1 H, 5a-H THF), 5.56 (dd, J2,3 = 8.1, 6.4 Hz, 1 H, 2-H THF), 9.17
(s, 1 H, 2-H), 9.33 (s, 1 H, 8-H) ppm. 13C NMR (125.7 MHz, [D6]-
DMSO + DCl): δ = 25.84 (CH2-4 THF), 32.88 (CH2-3 THF), 69.84
(CH2-5 THF), 76.14 (CH-2 THF), 124.35 (C-5), 148.63 (CH-2),
149.54 (CH-8), 155.62 (C-4), 156.20 (C-6) ppm. FAB-MS: m/z (%)
= 191 (100) [M + H]+, 147 (5), 93 (8), 57 (6). HRMS: calcd. for
Acknowledgments
This work was supported by the Academy of Sciences of the Czech
Republic (Z4 055 0506), the Ministry of Education (“Centre for
New Antivirals and Antineoplastics”, 1M0508), the Programme for
Targeted Research (1QS400550501) and by Gilead Sciences, Inc.
(Foster City, CA, U.S.A.). The cytostatic activity was studied by
Dr. I. Votruba (IOCB) and the antiviral activity by E. Mabery and
Drs. I. Shih and R. Mackman (Gilead). The contribution of these
scientists is gratefully acknowledged.
C9H11N4O [M + H]+ 191.0933; found 191.0935. IR (CHCl ): ν =
˜
3
3118, 3048, 2981, 2872, 1611, 1563, 1465, 1419, 1374, 1225,
1070 cm–1.
9-(β-D-Ribofuranosyl)-6-[(R,S)-tetrahydrofuran-2-yl]purine (4f):
Compound 4f was prepared according to the procedure described
for 4a. EtOH/H2O (4:1) was used as the solvent, and the reaction
time was 3 h. Starting from 3f (100 mg, 0.31 mmol), 4f (72 mg,
72%) was obtained as a white foam, m.p. 81–82 °C. [α]2D0 = –28.0
(c = 2.01, MeOH). 1H NMR (500 MHz, [D6]DMSO): δ = 1.99,
2.14 (2 m, 2ϫ 2 H, 4-H THF), 2.20, 2.35 (2 m, 2ϫ 2 H, 3-H THF),
3.57, 3.69 (2 dt, Jgem = 12.0, J5Ј,OH = J5Ј,4Ј = 4.4 Hz, 2ϫ 2 H, 5Ј-
H), 3.91 (td, Jgem = 7.6, J5b,4 = 7.6, 5.6 Hz, 2 H, 5b-H THF), 3.98
[1] M. Hocek, A. Holý, I. Votruba, H. Dvoráková, J. Med. Chem.
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(td, J4Ј,5Ј = 4.4, J4Ј,3Ј = 2.9 Hz, 2 H, 4Ј-H), 4.11, 4.12 (2 dt, Jgem
=
7.6, J5a,4 = 6.9 Hz, 2ϫ 1 H, 5a-H THF), 4.19 (ddd, J3Ј,OH = 5.1,
J3Ј,2Ј = 4.6, J3Ј,4Ј = 2.9 Hz, 2 H, 3Ј-H), 4.63 (br. m, 2 H, 2Ј-H), 5.10
(br. t, JOH,5Ј = 4.4 Hz, 2 H, 5Ј-OH), 5.23 (d, JOH,3Ј = 5.1 Hz, 2 H,
3Ј-OH), 5.41, 5.42 (2 dd, J2,3 = 7.8, 6.0 Hz, 2ϫ 1 H, 2-H THF),
5.52 (d, JOH,2Ј = 5.9 Hz, 2 H, 2Ј-OH), 6.04 (d, J1Ј,2Ј = 5.7 Hz, 1 H,
1Ј-H), 8.80 (s, 2 H, 8-H), 8.88 (s, 2 H, 2-H) ppm. 13C NMR
(125.7 MHz, [D6]DMSO): δ = 26.31 (CH2-4 THF), 31.58, 31.65
(CH2-3 THF), 61.45 (CH2-5Ј), 68.97 (CH2-5 THF), 70.51 (CH-3Ј),
73.84, 73.87 (CH-2Ј), 76.96, 77.00 (CH-2 THF), 85.89 (CH-4Ј),
87.80 (CH-1Ј), 131.56 (C-5), 144.87 (CH-8), 151.40 (C-4), 151.94
(CH-2), 161.24, 161.28 (C-6) ppm. FAB-MS: m/z (%) = 323 (8) [M
+ H]+, 191 (100), 147 (18), 134 (14), 71 (16). HRMS: calcd. for
ˇ
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3225–3228.
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[4] P. S ilhár, R. Pohl, I. Votruba, M. Hocek, Org. Biomol. Chem.
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[5] P. S ilhár, R. Pohl, I. Votruba, M. Hocek, Synthesis 2006, 1848–
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dron 1999, 55, 11109–11118.
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Chem. Commun. 2001, 66, 483–499.
C14H19N4O5 [M + H]+ 323.1355; found 323.1345. IR (CHCl ): ν =
˜
3
[8]
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M. Hocek, P. Nausˇ, R. Pohl, I. Votruba, P. A. Furman, P. M.
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3543, 3325, 2990, 2876, 1596, 1498, 1457, 1418, 1333, 1083,
909 cm–1.
9-(2-Deoxy-β-D-erythro-pentofuranosyl)-6-[(R,S)-tetrahydrofuran-2-
yl]purine (4g): Compound 4g was prepared according to the pro-
cedure described for 4a. EtOH/H2O (4:1) was used as the solvent,
and the reaction mixture was stirred overnight. Starting from 3g
(150 mg, 0.5 mmol), 4g (150 mg, 98%) was obtained as a colorless
amorphous solid. [α]2D0 = –10.0 (c = 1.95, DMSO). 1H NMR
(500 MHz, [D6]DMSO): δ = 1.98, 2.14 (2 m, 4 H, 4-H THF), 2.19
(m, 2 H, 3b-H THF), 2.30–2.38 (m, 4 H, 3a-H THF and 2Јb-H),
2.78, 2.79 (2 ddd, Jgem = 13.2, J2Јa,1Ј = 7.2, J2Јa,3Ј = 5.8 Hz, 2ϫ 1
ˇ
[10]
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H, 2Јa-H), 3.52, 3.53 (2ϫ ddd, Jgem = 11.7, J5Јb,OH = 5.6, J5Јb,4Ј
4.7 Hz, 2ϫ 1 H, 5Јb-H), 3.62, 3.63 (2 ddd, Jgem = 11.7, J5Јa,OH
=
=
5.6, J5Јa,4Ј = 5.0 Hz, 2ϫ 1 H, 5Јa-H), 3.87–3.93 (m, 4 H, 4Ј-H and
5b-H THF), 4.10, 4.11 (2 dt, Jgem = 7.6, J5a,4 = 6.9 Hz, 2ϫ 1 H,
5a-H THF), 4.45 (m, 2 H, 3Ј-H), 4.98, 4.99 (2 t, JOH,5Ј = 5.6 Hz,
2ϫ 1 H, 5Ј-OH), 5.36 (d, JOH,3Ј = 4.2 Hz, 2 H, 3Ј-OH), 5.40, 5.41
(2 dd, J2,3 = 7.8, 6.1 Hz, 2ϫ 1 H, 2-H THF), 6.47 (dd, J1Ј,2Јa = 7.2,
J1Ј,2Јb = 6.3 Hz, 1 H, 1Ј-H), 8.76 (s, 2 H, 8-H), 8.87 (s, 2 H, 2-H)
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2787

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Received: February 13, 2008
Published Online: April 15, 2008
2788
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2783–2788