Stereoselective synthesis of novel isonucleoside analogues of purine with a tetrahydropyran ring

Article abstract of DOI:10.1055/s-0029-1217142

New tetrahydropyran isonucleoside derivatives of purine, with cis or trans configuration, were stereoselectively synthesized in moderate yield by a convergent strategy based on Mitsunobu coupling. The key starting material was a bicyclic lactone. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1217142

PAPER
425
Stereoselective Synthesis of Novel Isonucleoside Analogues of Purine with a
Tetrahydropyran Ring
Stereoselective
a
S
ynthesis
o
u
f
Isonucleos
r
ides a Estévez, Pedro Besada, Yagamare Fall, Marta Teijeira, Carmen Terán*
Departamento de Química Orgánica, Facultad de Química, Universidad de Vigo, 36310 Vigo, Spain
Fax +34(986)812262; E-mail: mcteran@uvigo.es
Received 24 July 2009; revised 5 October 2009
To the memory of our colleague and friend Maykel Pérez González
NH2
NH2
N
NH2
Abstract: New tetrahydropyran isonucleoside derivatives of pu-
rine, with cis or trans configuration, were stereoselectively synthe-
sized in moderate yield by a convergent strategy based on
Mitsunobu coupling. The key starting material was a bicyclic lac-
tone.
N
N
N
N
N
N
N
HO
HO
N
HO
N
N
N
O
O
O
Key words: isonucleosides, heterocycles, tetrahydropyran, purine,
Mitsunobu reaction
OH
I
II
III
R
R
N
N
N
N
N
N
Nucleoside analogues play an important role in chemo-
therapy.1 Modifications in the sugar moiety of nucleosides
have led to the development of novel derivatives, includ-
ing acyclic and carbocyclic nucleosides, four- or six-
membered ring analogues, 2¢,3¢-dideoxynucleosides, and
isonucleosides, that have shown interesting antiviral and
anticancer properties.2 These modifications are often
associated with increased stability2 and decreased toxici-
ty,3 together with target specificity.2 In isonucleosides the
heterocyclic base is linked to the non-anomeric carbon
atom of the sugar moiety, in particular at C2¢ or C3¢ of the
furanose ring. The change in the position of the sugar-base
bond keeps the spatial placement between the base and the
5¢-hydroxy group, while the glycosidic bond is more sta-
ble toward enzymatic hydrolysis. Several isonucleosides
show interesting biological activity.4 For example, 2¢-iso-
dideoxynucleoside analogues such as isoddA (I) or the
isonucleoside II (Figure 1) have potent anti-HIV5 and
anti-HCV activity,6 respectively. Nevertheless, the 3¢-iso-
dideoxinucleoside analogue 3¢-isoddA (III) has a low
level of activity.7 Thus, some of the structural factors that
modify the activity of nucleoside analogues are the dis-
tance between the base and the 5¢-hydroxy group, the elec-
tronic effects of the oxygen in the sugar ring, and the lack
of a hydroxy group at 3¢.8 The high stability together with
the significant activity exhibited by some isonucleosides
have led to an increase in the number of analogues report-
ed as promising therapeutic agents.9,10
N
HO
N
O
O
HO
V
IV
Figure 1
in particular against HIV.14 Taking into account the thera-
peutic potential of nucleosides and looking for new active
compounds, our attention has been drawn to the tetrahy-
dropyran isodideoxynucleoside derivatives of structure
IV and V (Figure 1). We are in particular interested in
compounds IV, structural analogues of 3¢-isoddA, where
tetrahydropyran (THP) replaces tetrahydrofuran and a
methylene group enlarges the side chain, transforming it
into a hydroxyethyl group. This keeps the base and the hy-
droxy group separated by four carbon atoms, as in natural
nucleosides.
On the basis of these considerations, in this paper we
describe a convergent and stereoselective synthesis of tar-
get compounds IV as racemic mixtures. This strategy,
also applied to compounds V, is based on Mitsunobu cou-
pling.
In this approach, the key starting material is bicyclic lac-
tone 1 (Scheme 1), which was obtained in good yield in a
four-step sequence from commercially available ethyl 3-
(2-furyl)propionate, by an approach based on the oxida-
tion of the furan ring with singlet oxygen, followed by an
intramolecular Michael addition.15 Treatment of 1 with
lithium aluminum hydride in the presence of boron tri-
fluoride–diethyl ether complex afforded an 85% yield of
a cis–trans mixture of diols 2 and 3 (Scheme 1). Although
the two diols could be separated by column chromatogra-
phy,15 we carried out their stereoselective synthesis here.
Thus, the mixture of compounds 2 and 3 was treated with
tert-butyldiphenylsilyl chloride, imidazole, and 4-(N,N-
In the last few years we have described some modified nu-
cleosides with the hydroxymethyl group and the heterocy-
clic base bound to contiguous positions of a carbocycle.11–14
Several of these carbocyclic analogues have exhibited
significant and selective anticancer11 or antiviral activity,
SYNTHESIS 2010, No. 3, pp 0425–0430
x
x
.
x
x
.2
0
0
9
Advanced online publication: 24.11.2009
DOI: 10.1055/s-0029-1217142; Art ID: T14709SS
© Georg Thieme Verlag Stuttgart · New York

426
L. Estévez et al.
PAPER
OH
H
OH
+
OTBDPS
O
O
O
O
i
ii
O
O
O
85%
95%
OH
OH
OH
OMe
2
3
4
1
OTBDPS
O
iv
OTBDPS
95%
iii
97%
OH
OH
4a
OTBDPS
O
v
O
5
94%
4b
Scheme 1 Reagents and conditions: (i) LAH, BF3·OEt2, Et2O, r.t.; (ii) TBDPSCl, imidazole, DMF, r.t.; (iii) TPAP, NMO, CH2Cl2, MS; (iv)
NaBH4, MeOH–CH2Cl2, –78 °C; (v) L-Selectride, THF, –78 °C to r.t.
dimethylamino)pyridine in N,N-dimethylformamide to methane at –78 °C gave the trans-alcohol 4a in 95% yield.
selectively protect the primary hydroxy group. The result- In addition, ketone 5 on reaction with L-Selectride in tet-
ing secondary alcohol 4 was then oxidized with tetrapro- rahydrofuran at –78 °C gave monoprotected cis-diol 4b in
pylammonium perruthenate (TPAP), affording ketone 5 94% yield. The relative configuration of alcohols 4a and
in excellent yield (97%). Finally, the stereoselective re- 4b was unequivocally established by comparison of the
duction of 5 by use of different reduction agents such as spectroscopic data with those of compounds obtained
sodium borohydride or L-Selectride allowed us to obtain from the selective monoprotection with tert-butyldiphe-
alcohols 4a or 4b selectively (Scheme 1). Thus, treatment nylsilyl chloride of diols 2 and 3, previously separated.15
of 5 with sodium borohydride in methanol–dichloro-
OTBDPS
i
OTBDPS
O
O
N
36%
N
OH
N
4a
6a
Cl
N
OH
O
N
ii
75%
N
iii
80%
N
OH
NH2
IVb
O
O
N
N
N
N
iv
70%
OH
IVa
Cl
N
N
N
N
IVc
OH
N
OTBDPS
i
OTBDPS
OTBDPS
O
OTBDPS
O
O
O
N
+
+
N
OH
N
4b
6b 10%
7 35%
Cl
8 trace
N
ii
77%
OH
OH
O
O
iii
70%
N
N
N
N
N
N
Cl
NH2
Va
Vb
N
N
Scheme 2 Reagents and conditions: (i) 6-chloropurine, Ph3P, DEAD, THF, 0 °C to r.t.; (ii) 1 M TBAF, THF, r.t.; (iii) 25% aq NH3, reflux;
(iv) 0.5 M aq NaOH, reflux.
Synthesis 2010, No. 3, 425–430 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Isonucleosides
427
Mitsunobu coupling of trans-alcohol 4a with 6-chloropu- was observed in any of the cell lines employed in these
rine in the presence of triphenylphosphine and diethyl preliminary assays. Further biological studies are in
azodicarboxylate in tetrahydrofuran gave the cis-6-chlo- progress.
ropurine derivative 6a, in 36% yield (Scheme 2). How-
ever, when the cis-isomer 4b was treated with 6-
Melting points of samples in capillary tubes were determined on a
Gallenkamp apparatus. 1H and 13C NMR spectra were recorded on
a Bruker ARX-400 instrument, using TMS as internal standard.
Mass spectra were recorded on Hewlett-Packard 5988A and Bruker
FTMS APEX XIII spectrometers. Silica gel (Merck 60, 230–400
mesh) was used for flash chromatography. Analytical TLC was car-
ried out on plates precoated with silica gel (Merck 60 F254, 0.25
mm).
chloropurine under identical Mitsunobu conditions, an
important portion of unchanged compound was recov-
ered, affording the desired trans-chloropurine derivative
6b in 10% yield, and giving as major product the dehydra-
tion compound 7 (35%). In addition, a new dehydration
isomer (compound 8) was detected in a trace amount. It
should be mentioned that compound 7 was also obtained
as a secondary product of Mitsunobu reaction of 4a with
6-chloropurine, but in this case it was the only dehydra-
tion product. These results are a consequence of the com-
petition between an SN2 displacement and an E2
elimination, previously described for tetrahydropyran de-
rivatives when Mitsunobu reaction conditions were
used.16
( )-Diols 2 and 3
To a mixture of 1 (598 mg, 3.47 mmol) and BF3·OEt2 (1.07 mL,
10.71 mmol) in anhyd Et2O (75 mL), previously stirred at r.t. for 40
min, and cooled at 0 °C, was added LAH (1.2 g, 34.70 mmol). The
reaction mixture was stirred at r.t. for 1.5 h and carefully quenched
with H2O (2 mL), 1 M aq NaOH (2 mL), and H2O (6 mL). After fil-
tration of the mixture, the residue was purified by flash chroma-
tography (silica gel, CH2Cl2–MeOH, 9:1); this gave a mixture of
trans- and cis-alcohols 2 and 3;15 yield: 430 mg (85%). A 100-mg
portion of this mixture was further rechromatographed (silica gel,
hexane–EtOAc, 1:1); this afforded 2 (46.5 mg), a mixture of 2 and
3 (31.5 mg), and 3 (22 mg).
Deprotection of silyl derivatives 6a and 6b was carried
out by treatment with tetrabutylammonium fluoride in tet-
rahydrofuran, to afford cis- and trans-6-chloropurine de-
rivatives IVa and Va in 75% and 77% yield, respectively
(Scheme 2). The cis and trans configurations were as-
signed by means of NOE correlations.
( )-trans-2-(2-Hydroxyethyl)-2,3,5,6-tetrahydro-4H-pyran-3-ol
(2)
Yellow oil; Rf = 0.21 (EtOAc).
Finally, compounds IVa and Va were transformed into
the adenine derivatives IVb (80% yield) and Vb (82%
yield), respectively, by reflux with 25% aqueous ammo-
nia (Scheme 2). Similarly, reaction of IVa with 0.5 M
aqueous sodium hydroxide afforded the hypoxanthine de-
rivative IVc in 70% yield.
1H NMR (400 MHz, CDCl3): d = 3.90–3.88 (m, 1 H, 1 × H6), 3.84–
3.76 (m, 2 H, H2¢), 3.40–3.30 (m, 2 H, H3 and 1 × H6), 3.21–3.18
(m, 1 H, H2), 2.75 (br s, 1 H, OH), 2.49 (br s, 1 H, OH), 2.12–2.09
(m, 1 H, 1 × H4), 2.05–2.00 (m, 1 H, 1 × H1¢), 1.82–1.77 (m, 1 H,
1 × H1¢), 1.73–1.65 (m, 2 H, H5), 1.43–1.36 (m, 1 H, 1 × H4).
13C NMR (100 MHz, CDCl3): d = 82.9 (C2), 70.2 (C3), 67.7 (C6),
61 (C2¢), 35.3 (C1¢), 32.5 (C4), 25.5 (C5).
In conclusion, new tetrahydropyran isonucleosides, deriv-
atives of purine, with cis (IV) or trans (V) stereochemis-
try, were stereoselectively synthesized in moderate yield,
starting from bicyclic lactone 1 and using a convergent
strategy based on Mitsunobu coupling. Reductive cleav-
age of 1 with lithium aluminum hydride gave a mixture of
trans- and cis-diols (compounds 2 and 3). Protection of
the primary hydroxy group and then oxidation of the sec-
ondary hydroxy group allowed us, in a subsequent reduc-
tion, with sodium borohydride at –78 °C, to obtain
stereoselectively the trans-alcohol 4a, precursor of the
cis-isonucleosides IV. Moreover, the same strategy al-
lowed us, using L-Selectride as reducing agent, to obtain
selectively the cis-alcohol 4b, precursor of trans-iso-
nucleosides V. Both alcohols (4a and 4b) afforded via
Mitsunobu coupling the desired isonucleoside analogues
(IV and V, respectively). However, the trans-alcohol 4a is
a better synthon for the Mitsunobu coupling than the cis-
alcohol 4b.
( )-cis-2-(2-Hydroxyethyl)-2,3,5,6-tetrahydro-4H-pyran-3-ol
(3)
Yellow oil; Rf = 0.10 (EtOAc).
1H NMR (400 MHz, CDCl3): d = 4.03–3.99 (m, 1 H, 1 × H6), 3.86–
3.75 (m, 2 H, H2¢), 3.67–3.40 (m, 3 H, H3, H2, and 1 × H6), 2.32
(br s, 2 H, 2 × OH), 2.02–1.90 (m, 3 H), 1.73–1.62 (m, 2 H), 1.40–
1.30 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 79.6 (C2), 68.6 (C6), 67.1 (C3),
60.6 (C2¢), 34.3 (C1¢), 30.5 (C4), 20.1 (C5).
( )-cis/trans-2-[2-(tert-Butyldiphenylsiloxy)ethyl]-2,3,5,6-tet-
rahydro-4H-pyran-3-ol (4)
Imidazole (213 mg, 3.12 mmol), DMAP (cat.), and TBDPSCl (0.81
mL, 3.12 mmol) were added to a soln of a mixture of alcohols 2 and
3 (416 mg, 2.84 mmol) in DMF (6 mL). The reaction mixture was
stirred at r.t. for 1 h, quenched with H2O (12 mL), and extracted
with t-BuOEt (3 × 30 mL). The combined organic phases were
dried (Na2SO4) and filtered and the solvent was evaporated to dry-
ness. The residue was purified by flash chromatography (hexane–
EtOAc, 9:1 to 8:2); this gave 4.
Compounds IVa–c and Va,b were tested for their in vitro
cytostatic activity in three cell cultures: human cervix car-
cinoma cells (HeLa 229), human breast adenocarcinoma
cells (MCF-7), and human promyelocytic leukemia cells
(HL-60). The five compounds exhibited percent cell
growth inhibition values below 50% at 100 mM. We may
therefore assume that no significant cytostatic activity
Yield: 1.04 g (95%); yellow oil.
( )-2-[2-(tert-Butyldiphenylsiloxy)ethyl]-2,3,5,6-tetrahydro-
4H-pyran-3-one (5)
A suspension of 4 (941 mg, 2.45 mmol) and 4-Å MS (1.48 g) in
CH2Cl2 (45 mL) was stirred at r.t. for 5 min. Then NMO (573 mg,
4.90 mmol) and TPAP (27 mg, 0.12 mmol) were added and the mix-
Synthesis 2010, No. 3, 425–430 © Thieme Stuttgart · New York

428
L. Estévez et al.
PAPER
ture was stirred for 40 min. The solvent was evaporated to dryness
and the residue was purified by flash chromatography (silica gel,
hexane–EtOAc, 9:1); this gave 5.
1H NMR (400 MHz, CDCl3): d = 8.77 (s, 1 H), 8.70 (s, 1 H), 7.61–
7.58 (m, 4 H), 7.42–7.32 (m, 6 H), 4.92–4.90 (m, 1 H), 4.24–4.20
(m, 1 H), 4.12–4.08 (m, 1 H), 3.72–3.68 (m, 1 H), 3.63–3.55 (m, 2
H), 2.17–2.08 (m, 1 H), 2.07–1.90 (m, 1 H), 1.82–1.68 (m, 1 H),
1.61–1.49 (m, 2 H), 1.45–1.38 (m, 1 H), 1.02 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 152.1, 151.7, 151.0, 145.9, 135.4,
133.4, 130.8, 129.7, 127.7, 75.1, 68.6, 59.5, 52.2, 35.1, 29.1, 26.8,
20.6, 19.2.
Yield: 907 mg (97%); colorless oil; Rf = 0.41 (hexane–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): d = 7.67–7.64 (m, 4 H), 7.43–7.35 (m,
6 H), 4.07–3.98 (m, 2 H, H2), 3.84–3.75 (m, 2 H), 3.70–3.64 (m, 1
H), 2.60–2.54 (m, 1 H), 2.47–2.38 (m, 1 H), 2.22–2.10 (m, 2 H),
2.09–2.01 (m, 1 H), 1.82–1.72 (m, 1 H), 1.00 (s, 9 H).
HRMS–FAB: m/z calcd for C28H34ClN4O2Si [M + 1]: 521.2140;
found: 521.2161.
13C NMR (100 MHz, CDCl3): d = 209.0, 135.5, 133.8, 129.5, 127.6,
79.8, 65.6, 59.6, 37.6, 32.5, 26.8, 26.2, 19.2.
HRMS–FAB: m/z calcd for C23H31O3Si [M + 1]: 383.2043; found:
383.2042.
trans-9-{2-[2-(tert-Butyldiphenylsiloxy)ethyl]-2,3,5,6-tetrahy-
dro-4H-pyran-3-yl}-6-chloropurine (6b)
Compound 6b was prepared from 4b (289 mg, 0.75 mmol) in the
same way as 6a from 4a. The residue was purified by flash chroma-
tography (silica gel, hexane–EtOAc, 95:5 to 85:15); this gave com-
pounds 7 (36%) and 6b (10%), both of them as colorless oils.
( )-trans-2-[2-(tert-Butyldiphenylsiloxy)ethyl]-2,3,5,6-tetrahy-
dro-4H-pyran-3-ol (4a)
NaBH4 (62 mg, 1.64 mmol) was added in portions to a soln of 5
(314 mg, 0.82 mmol) in MeOH–CH2Cl2 (1:1; 5.2 mL) at –78 °C.
The mixture was stirred at –78 °C for 40 min, followed by quench-
ing with MeOH (5 mL). The solvent was evaporated to dryness and
the residue was purified by flash chromatography (silica gel,
hexane–EtOAc, 8:2); this gave 4a.
Compound 6b
Yield: 40 mg (10%); colorless oil; Rf = 0.61 (hexane–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): d = 8.68 (s, 1 H), 8.08 (s, 1 H), 7.56–
7.54 (m, 2 H), 7.48–7.45 (m, 2 H), 7.41–7.27 (m, 6 H), 4.33–4.29
(m, 1 H), 4.22–4.09 (m, 1 H), 4.04–3.99 (m, 1 H), 3.80–3.72 (m, 1
H), 3.62–3.51 (m, 2 H), 2.33–2.31 (m, 1 H), 2.20–2.15 (m, 1 H),
1.90–1.82 (m, 2 H), 1.34–1.30 (m, 1 H), 1.28–1.20 (m, 1 H), 0.96
(s, 9 H).
13C NMR (100 MHz, CDCl3): d = 151.8, 151.6, 151.3, 143.9, 135.4,
133.6, 131.8, 129.6, 127.6, 75.3, 67.6, 59.0, 57.1, 34.9, 30.2, 26.8,
25.8, 19.1.
Yield: 297 mg (95%); yellow oil; Rf = 0.69 (hexane–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): d = 7.72–7.65 (m, 4 H), 7.44–7.36 (m,
6 H), 3.90–3.78 (m, 3 H), 3.43–3.37 (m, 1 H), 3.34–3.21 (m, 2 H),
3.19–3.09 (m, 1 H), 2.19–2.07 (m, 1 H), 2.02–1.90 (m, 1 H), 1.80–
1.71 (m, 1 H), 1.69–1.60 (m, 2 H), 1.38–1.30 (m, 1 H), 0.98 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 135.6, 133.1, 129.8, 127.7, 81.0,
70.5, 67.6, 61.1, 36.7, 32.2, 26.8, 25.6, 19.1.
HRMS–FAB: m/z calcd for C28H34ClN4O2Si [M + 1]: 521.2140;
found: 521.2131.
HRMS–FAB: m/z calcd for C23H33O3Si [M + 1]: 385.2199; found:
385.2198.
2-[2-(tert-Butyldiphenylsiloxy)ethyl]-5,6-dihydro-2H-pyran (7)
Yield: 95 mg (36%); colorless oil; Rf = 0.41 (hexane–EtOAc, 95:5).
( )-cis-2-[2-(tert-Butyldiphenylsiloxy)ethyl]-2,3,5,6-tetrahydro-
4H-pyran-3-ol (4b)
1H NMR (400 MHz, CDCl3): d = 7.71–7.68 (m, 4 H), 7.44–7.37 (m,
6 H), 5.84–5.80 (m, 1 H), 5.66 (dd, J = 10.3, 1.8 Hz, 1 H), 4.39–4.29
(m, 1 H), 3.95–3.87 (m, 2 H), 3.77–3.68 (m, 1 H), 3.64–3.57 (m, 1
H), 2.28–2.17 (m, 1 H), 1.95–1.89 (m, 1 H), 1.79 (q, J = 6.4 Hz, 2
H), 1.07 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 135.5, 133.9, 130.6, 129.5, 127.6,
124.5, 70.7, 63.1, 60.4, 38.1, 26.9, 25.3, 19.2.
A 1 M soln of L-Selectride in THF (1.98 mL) was added dropwise
to a soln of 5 (300 mg, 0.79 mmol) in THF (16 mL) at –78 °C. The
reaction mixture was stirred at –78 °C for 1 h, followed by quench-
ing with sat. aq NH4Cl (80 mL). The product was extracted with
EtOAc (3 × 50 mL), the combined organic phases were dried
(Na2SO4), and the solvent was evaporated to dryness. The residue
was purified by flash chromatography (silica gel, hexane–EtOAc,
8:2); this gave 4b.
HRMS–FAB: m/z calcd for C23H31O2Si [M + 1]: 367.2093; found:
367.2102.
Yield: 286 mg (94%); yellow oil; Rf = 0.65 (hexane–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): d = 7.67–7.64 (m, 4 H), 7.44–7.34 (m,
6 H), 4.12–3.92 (m, 1 H), 3.77–3.71 (m, 2 H), 3.64–3.61 (m, 1 H),
3.58–3.51 (m, 1 H), 3.47–3.40 (m, 2 H), 1.99–1.93 (m, 1 H), 1.90–
1.75 (m, 2 H), 1.74–1.60 (m, 2 H), 1.40–1.29 (m, 1 H), 1.04 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 135.6, 133.7, 129.6, 127.6, 76.8,
68.5, 66.8, 60.2, 34.8, 30.6, 26.8, 20.3, 19.2.
cis-6-Chloro-9-[2-(2-hydroxyethyl)-2,3,5,6-tetrahydro-4H-pyr-
an-3-yl]purine (IVa)
A 1 M soln of TBAF in THF (0.36 mL, 0.36 mmol) was added drop-
wise to a soln of 6a (190 mg, 0.364 mmol) in anhyd THF (6 mL).
The reaction mixture was stirred at r.t. for 3 h and then treated with
sat. aq NaHCO3 (7 mL). The product was extracted with t-BuOMe
(3 × 7 mL) and the combined organic layers were dried (Na2SO4),
filtered, and concentrated to dryness. The residue was purified by
flash chromatography (silica gel, CH2Cl2–MeOH, 7:3); this gave
IVa.
HRMS–FAB: m/z calcd for C23H33O3Si [M + 1]: 385.2199; found:
385.2197.
cis-9-{2-[2-(tert-Butyldiphenylsiloxy)ethyl]-2,3,5,6-tetrahydro-
4H-pyran-3-yl}-6-chloropurine (6a)
Yield: 77 mg (75%); white solid; mp 137–139 °C; Rf = 0.5 (MeOH–
CH2Cl2, 1:9).
6-Chloropurine (327 mg, 2.12 mmol) and Ph3P (556 mg, 2.12
mmol) were added to a soln of 4a (408 mg, 1.06 mmol) in THF (30
mL) . The mixture was cooled at 0 °C and treated with a soln of
DEAD (0.33 mL, 2.12 mmol) in THF (3 mL). The reaction mixture
was stirred at 0 °C for 10 min and then for 32 h at r.t. The solvent
was evaporated to dryness and the residue was purified by flash
chromatography (silica gel, hexane–EtOAc, 85:15); this gave 6a.
1H NMR (400 MHz, DMSO-d6): d = 8.91 (s, 1 H), 8.80 (s, 1 H),
4.93–4.91 (m, 1 H), 4.41 (t, J = 4.3 Hz, 1 H), 4.13–4.10 (m, 1 H),
3.99–3.96 (m, 1 H), 3.64–3.58 (m, 1 H), 3.38–3.28 (m, 2 H), 2.20–
2.16 (m, 1 H), 1.94–1.91 (m, 1 H), 1.85–1.81 (m, 1 H), 1.53–1.49
(m, 1 H), 1.33–1.26 (m, 1 H), 1.21–1.15 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 152.2, 151.5, 149.1, 146.6,
129.9, 74.5, 67.5, 56.7, 51.6, 34.7, 27.6, 20.2.
Yield: 198 mg (36%); white solid; mp 123–125 °C; Rf = 0.67 (hex-
ane–EtOAc, 1:1).
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Stereoselective Synthesis of Isonucleosides
429
HRMS (EI): m/z calcd for C12H15N4O2Cl: 282.0884; found:
282.0873.
1H NMR (400 MHz, DMSO-d6): d = 8.25 (s, 1 H), 8.14 (s, 1 H),
7.23 (s, 2 H), 4.30–4.17 (m, 2 H), 3.99–3.87 (m, 2 H), 3.52–3.42 (m,
1 H), 3.34–3.29 (m, 2 H), 2.41–2.32 (m, 1 H), 2.06–1.98 (m, 1 H),
1.82–1.70 (m, 2 H), 1.40–1.34 (m, 1 H), 1.10–0.98 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 155.9, 152.2, 149.3, 139.6,
118.8, 75.9, 66.9, 56.7, 55.1, 35.3, 29.3, 25.7.
cis-9-[2-(2-Hydroxyethyl)-2,3,5,6-tetrahydro-4H-pyran-3-
yl]adenine (IVb)
A mixture of IVa (31 mg, 0.11 mmol) and 25% aq NH3 (3 mL) was
heated under reflux for 8 h. The mixture was concentrated to dry-
ness in vacuo and the residue was purified by flash chromatography
(silica gel, CH2Cl2–MeOH, 92:8); this gave IVb.
ESI-HRMS: m/z calcd for C12H18N5O2: 264.14550; found:
264.14624.
Yield: 29 mg (80%); white solid; mp 204–206 °C; Rf = 0.2 (MeOH–
CH2Cl2, 1:9).
Acknowledgment
1H NMR (400 MHz, DMSO-d6): d = 8.37 (s, 1 H), 8.15 (s, 1 H),
7.24 (s, 2 H), 4.74–4.72 (m, 1 H), 4.35 (br s, 1 H), 4.11–4.09 (m, 1
H), 3.93–3.91 (m, 1 H), 3.61–3.56 (m, 1 H), 3.34–3.31 (m, 2 H),
2.14–2.08 (m, 1 H), 1.85–1.79 (m, 2 H), 1.51–1.48 (m, 1 H), 1.31–
1.28 (m, 1 H), 1.18–1.15 (m, 1 H).
We thank the Universidad de Vigo and the Xunta de Galicia
(PGIDIT07PXIB and INCITE08ENA314019ES) for financial sup-
port. Pedro Besada thanks the Xunta de Galicia for an Isidro Parga
Pondal contract.
13C NMR (100 MHz, DMSO-d6): d = 156.0, 152.4, 149.8, 140.1,
117.7, 74.7, 67.5, 56.7, 50.1, 34.8, 28.0, 20.4.
References
HRMS (EI): m/z calcd for C12H17N5O2: 263.1382; found: 263.1375.
(1) (a) Cheson, D. K.; Keating, M. J.; Plunkett, W. Nucleoside
Analogs in Cancer Therapy; Marcel Dekker: New York,
1997. (b) Chu, C. K. Recent Advances in Nucleosides:
Chemistry and Biological Properties; Gordon and Breach
Science Publishers: Amsterdam, 2001.
(2) Simons, C. Nucleoside Mimetics: Their Chemistry and
Biological Properties; Gordon and Breach Science
Publishers: Amsterdam, 2001.
cis-9-[2-(2-Hydroxyethyl)-2,3,5,6-tetrahydro-4H-pyran-3-
yl]hypoxanthine (IVc)
A mixture of IVa (29 mg, 0.11 mmol) and 0.5 M aq NaOH (3 mL)
was heated under reflux for 6 h. The mixture was concentrated to
dryness in vacuo and the residue was purified by flash chroma-
tography (CH2Cl2–MeOH, 90:10); this gave IVc.
(3) Cookson, R. C.; Dudfield, P. J.; Newton, R. F.; Ravenscroft,
P.; Scopes, D. I. C.; Cameron, J. M. Eur. J. Med. Chem.
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(4) Nair, V. Antiviral Isonucleosides: Discovery, Chemistry and
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Chemistry and Chemotherapy; Chu, C. K., Ed.; Elsevier
Science: Amsterdam, 2002.
(5) Nair, V.; St. Clair, M.; Rearson, J. E.; Krasny, H. C.; Hazen,
R. J.; Paff, M. T.; Boone, L. R.; Tisdale, M.; Nájera, I.;
Dornsife, R. E.; Averett, D. R.; Borroto-Esoda, K.; Yale, J.
L.; Zimmerman, T. P.; Rideout, J. L. Antimicrob. Agents
Chemother. 1995, 39, 1993.
Yield: 19 mg (70%); white solid; mp 219–221 °C; Rf = 0.1 (MeOH–
CH2Cl2, 1:9).
1H NMR (400 MHz, DMSO-d6): d = 8.29 (s, 1 H), 8.04 (s, 1 H),
4.71–4.69 (m, 1 H), 4.40 (br s, 1 H), 4.09–4.07 (m, 1 H), 3.92–3.89
(m, 1 H), 3.60–3.54 (m, 1 H), 3.32–3.30 (m, 2 H), 2.14–2.09 (m, 1
H), 1.85–1.77 (m, 2 H), 1.51–1.47 (m, 1 H), 1.32–1.26 (m, 1 H),
1.19–1.13 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 156.8, 148.6, 145.6, 139.5,
122.9, 74.5, 67.4, 56.7, 50.7, 34.7, 28.0, 20.3.
HRMS (EI): m/z calcd for C12H16N4O3: 264.1222; found: 264.1226.
(6) (a) Nair, V.; Chun, B.-K.; Vadakkan, J. J. Tetrahedron 2004,
60, 10261. (b) Nair, V.; Piotrowska, D. G.; Okello, M.;
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39, 1017.
trans-6-Chloro-9-[2-(2-hydroxyethyl)-2,3,5,6-tetrahydro-4H-
pyran-3-yl]purine (Va)
Compound Va was prepared from 6b (20 mg, 0.038 mmol) in the
same way as IVa from 6a. The residue was purified by flash chro-
matography (hexane–EtOAc, 1:5); this gave compound Va.
Yield: 8.4 mg (77%); Rf = 0.12 (hexane–EtOAc, 1:5).
(8) Mansour, T. K.; Storer, R. Curr. Pharm. Des. 1997, 3, 227.
(9) (a) Chun, B.-K.; Wang, P.; Hassan, A.; Du, J.; Tharnish, P.
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Bhattacharya, R.; Atta, A. K.; Suresh, Ch. G.; Pathak, T.
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K.; Matsui, H.; Tanaka, H.; Takahata, H. Org. Lett. 2006, 8,
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Zhang, L.-H. Tetrahedron: Asymmetry 2007, 18, 2139.
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L.; De Clercq, E. J. Med. Chem. 2000, 43, 1975.
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1H NMR (400 MHz, DMSO-d6): d = 8.86 (s, 1 H), 8.80 (s, 1 H),
4.41–4.37 (m, 1 H), 4.18 (t, J = 5.3 Hz, 1 H), 4.07–3.93 (m, 2 H),
3.52–3.48 (m, 1 H), 3.34–3.30 (m, 2 H), 2.44–2.36 (m, 1 H), 2.12–
2.08 (m, 1 H), 1.81–1.76 (m, 2 H), 1.41–1.36 (m, 1 H), 1.10–1.01
(m, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 152.2, 152.0, 149.7, 146.9,
131.4, 76.0, 67.5, 57.0, 56.7, 35.7, 29.5, 26.1.
ESI-HRMS: m/z calcd for C12H16ClN4O2: 283.09563; found:
283.09556.
trans-9-[2-(2-Hydroxyethyl)-2,3,5,6-tetrahydro-4H-pyran-3-
yl]adenine (Vb)
Compound Vb was prepared from Va (24 mg, 0.085 mmol) in the
same way as IVb from IVa. The residue was purified by flash chro-
matography (silica gel, CH2Cl2–MeOH, 92:8); this gave compound
Vb.
Yield: 18 mg (82%); Rf = 0.28 (MeOH–CH2Cl2, 1:9).
(13) González-Moa, M. J.; Besada, P.; Terán, C. Synthesis 2006,
3973.
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L. Estévez et al.
PAPER
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Tetrahedron 2005, 61, 2021.
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Uriarte, E.; Pannecouque, C.; De Clercq, E. Chem. Pharm.
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Synthesis 2010, No. 3, 425–430 © Thieme Stuttgart · New York