The furan approach to oxacycles: New entry to the synthesis of isodideoxynucleosides

Article abstract of DOI:10.1055/s-0030-1258372

We describe a stereoselective synthesis of isonucleosides of cis and trans configuration using the furan approach, hence enlarging the scope of our methodology. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258372

PAPER
431
The Furan Approach to Oxacycles: New Entry to the Synthesis of
Isodideoxynucleosides
S
ynthesis of Is
i
odideo
l
xynucl
a
eosides
U
si
r
ng the Furan
A
C
pproac
h
anoa, Zoila Gándara, Manuel Pérez, Rafael Gago, Generosa Gómez,* Yagamare Fall*
Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo, Spain
Fax +34(986)812262; E-mail: yagamare@uvigo.es; E-mail: ggomez@uvigo.es
Received 12 August 2010; revised 27 October 2010
adenosine deaminase, which 2¢,3¢-dideoxynucleosides do
not possess. Hence, isonucleosides are being targeted by
many research groups.4 Compounds 4–6 are part of a se-
ries of isodideoxynucleosides recently synthesized by
Papaioannou and co-workers,5 using chiral amino acids.
Abstract: We describe a stereoselective synthesis of isonucleo-
sides of cis and trans configuration using the furan approach, hence
enlarging the scope of our methodology.
Key words: singlet oxygen, stereoselective synthesis, nucleosides,
isonucleosides, Mitsunobu reaction
It was anticipated that we could easily prepare compounds
5 and 6, as well as compound 7, using our furan method-
ology, as depicted in Scheme 1.
We recently described a new methodology for the synthe-
sis of oxacyclic compounds using either methoxyallene1a,b
or furan1c–h as starting material. The scope and limitations
of this very powerful methodology are being determined
and its application to the synthesis of cyclic as well as
polycyclic natural products is currently under way in our
laboratories. We have already shown that we can easily
access the 2-(2-hydroxyethyl)-3-hydroxytetrahydropyra-
nyl ring system.1d This prompted us to seek an application
of our method in the field of biologically relevant com-
pounds, such as nucleosides and analogues,2 some of
which are depicted in Figure 1.
X
X
HO
N
N
N
N
N
HN
N
N
O
10
5 (X = Cl)
6 (X = NH2)
7 (X = OH)
TBDPSO
+
OH
O
H
O
8
OH
Scheme 1 Retrosynthetic analysis for isonucleosides 5–7
O
NH
Y
N
Compounds 6 and 7 can be obtained from 5 by nucleo-
philic substitution of the 6-chloro atom. Reaction of 6-
chloropurine (10, X = Cl) with alcohol 9 under Mitsunobu
conditions would lead to target compound 5. Alcohol 9
would result from the stereoselective reduction of ketone
16, obtained according to Scheme 2.
N
N
HO
N
O
N
O
HO
Z
N3
AZT (1)
O
2 (Y = NH2, Z = H)
3 (Y = OH, Z = NH2)
X
i
ii
HO
HO
TBDPSO
HO
H
N
O
N
O
O
O
O
82%
86%
N
11
8
N
N
O
N
O
O
iv
iii
70%
TBDPSO
O
O
64%
O
4
5 (X = Cl)
6 (X = NH2)
7 (X = OH)
MeO
12
O
MeO
13
O
Figure 1 Nucleosides with therapeutic properties
v
vi
OH
OTBDPS
91%
73%
OH
OH
Nucleoside analogues such as 2¢,3¢-dideoxynucleosides
(ddN), AZT (1) and the isodideoxynucleosides (iso-ddN)
2 and 3 exhibit potent anti-HIV activity;3 however, isonu-
cleosides 2 and 3 possess chemical and metabolic advan-
tages such as glycosyl bond stabilization and resistance to
15
14
O
OTBDPS
16
O
Scheme 2 Reagents and conditions: (i) TBDPSCl, imidazole,
DMAP, DMF, r.t.; (ii) (a) O2, Rose Bengal, MeOH, hn; (b) Ac2O,
DMAP, py; (iii) TBAF, THF, r.t.; (iv) LAH, BF3·OEt2, Et2O, r.t.; (v)
TBDPSCl, imidazole, DMAP, THF, r.t.; (vi) TPAP, NMO, CH2Cl2.
SYNTHESIS 2011, No. 3, pp 0431–0436
Advanced online publication: 05.01.2011
DOI: 10.1055/s-0030-1258372; Art ID: T16110SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1

432
P. Canoa et al.
PAPER
2-(Furan-2-yl)ethanol (8)6 was protected to afford silyl
ether 11.1d Oxidation of 11 with singlet oxygen, followed
by treatment with acetic anhydride in pyridine, afforded
butenolide 12 in 86% yield (2 steps). Treatment of 12 with
tetrabutylammonium fluoride led to bicyclic lactone 13
which was opened with lithium aluminum hydride to give
diol 14 as a diastereomeric mixture. Selective protection
of the primary hydroxy group of 14 afforded alcohol 15
which gave ketone 16 upon oxidation with tetrapropylam-
monium perruthenate (TPAP).
Cl
N
TBDPSO
N
N
OTBDPS
O
N
ii
i
68%
50%
O
OH
9
19a
Cl
HO
N
N
N
N
O
With ketone 16 in hand, the stage was set for the stereo-
selective reduction step. We anticipated that the synthesis
of cis-alcohol 17 followed by a Mitsunobu reaction and
hydrolysis of the benzoyl group in 18 would lead to the
target trans-alcohol 9 (Scheme 3); however, NOE experi-
ments on compound 18 were misleading as we observed
NOE effects for the neighboring protons on C-2 and C-3,
meaning that the stereochemical course of the L-Selec-
tride® reduction of ketone 16 might not be the one we ex-
pected, in sharp contrast with our previous results on
larger ring size cyclic ethers.1b,h,7
5a
Cl
N
TBDPSO
N
N
N
OTBDPS
O
ii
i
71%
O
66%
OH
17
19b
Cl
N
HO
N
N
N
O
OTBDPS
OTBDPS
O
O
5b
i
Scheme 4 Reagents and conditions: (i) 6-chloropurine, Ph3P,
DIAD, THF, 55 °C; (ii) TBAF, THF, r.t.
OH
O
16
86%
17
85% ii
afforded the isonucleosides 5a and 5b in 68% and 71%
yield, respectively (Scheme 4).
OTBDPS
3.3%
OTBDPS
The stereochemistry of the pair of diastereomers, cis- and
trans-19, was unambiguously established by NOE exper-
iments (Figure 2). While cis-19a showed larger NOE ef-
fects, small effects could still be observed in trans-19b.
O
O
H
3.2%
OCOC6H4-p-NO2
H
OCOC6H4-p-NO2
18
NOE correlations for 18
Cl
Cl
96% iii
TBDPSO
H
TBDPSO
H
N
N
N
N
N
N
2.5%
OTBDPS
10.5%
N
N
O
O
O
H
H
19b
19a
OH
9
2.8%
9.9%
Scheme 3 Reagents and conditions: (i) L-Selectride®, THF, –78 °C;
(ii) p-O2NC6H4CO2H, Ph3P, DIAD, THF, r.t.; (iii) K2CO3, MeOH,
–10 °C.
Figure 2 NOE correlations for 19a and 19b
Treatment of isonucleosides 5a and 5b with aqueous am-
monia gave the 6-aminoisonucleosides 6a and 6b, respec-
tively. Similarly, reaction of 5a and 5b with sodium
hydroxide afforded the 6-hydroxyisonucleosides 7a and
7b (Scheme 5).
We have to thank one of the referees of our originally sub-
mitted manuscript for pointing out that there are many re-
ports in the literature with NOE effects of the same order
of magnitude as in 18, for neighboring trans protons in
five-membered rings. We therefore had to carry out the
synthesis of both the cis- and trans-isonucleosides 5–7 for
an unambiguous proof of configuration.
The cis stereochemistry of analogues 6a and 7a was un-
ambiguously established by NOE experiments (Figure 3).
6-Aminoisonucleoside 6a is a known compound and
shows similar spectroscopic data and NOE effects of the
same order of magnitude as in the literature.8
Accordingly, alcohols 9 and 17 were treated with 6-chlo-
ropurine (10, X = Cl) under Mitsunobu conditions giving
a 50% yield of compound 19a and 66% of 19b which,
after deprotection with tetrabutylammonium fluoride,
In conclusion, we have performed a straightforward syn-
thesis of isonucleosides cis-5a–7a and trans-5b–7b using
the furan approach. The biological evaluation of these
Synthesis 2011, No. 3, 431–436 © Thieme Stuttgart · New York

PAPER
Synthesis of Isodideoxynucleosides Using the Furan Approach
433
fording 11 as a yellowish oil; yield: 8.96 g (82%); Rf = 0.69
NH2
(EtOAc–hexane, 1:9).
HO
N
N
N
1H NMR (CDCl3): d = 7.55–7.63 (m, 4 H, CHo-Ph), 7.22–7.39 (m,
6 H, CHm,p-Ph), 7.20 (s, 1 H, CH-5 furan), 6.19 (d, J = 1.2 Hz, 1 H,
CH-4 furan), 5.98 (d, J = 3.2 Hz, 1 H, CH-3 furan), 3.80–3.90 (m, 2
H, CH2-2¢), 2.82–2.85 (m, 2 H, CH2-1¢), 0.98 (s, 9 H, CH3-t-Bu).
N
O
Cl
N
i
HO
6a
N
N
N
13C NMR (CDCl3): d = 153.7 (C-2 furan), 141.4 (CH-5 furan),
136.0 (CHo-Ph), 134.2 (C-Ph), 130.0 (CHp-Ph), 128.1 (CHm-Ph),
110.6 (CH-4 furan), 106.6 (CH-3 furan), 62.8 (CH2-2¢), 32.0 (CH2-
1¢), 27.2 (CH3-t-Bu), 19.6 (C-t-Bu).
97%
OH
N
ii
HO
HO
O
N
N
N
76%
5a
HRMS: m/z calcd for C22H27O2Si: 351.1780; found: 351.1762.
O
O
7a
5-[2-(tert-Butyldiphenylsilyloxy)ethyl]-5-methoxyfuran-2(5H)-
one (12)
NH2
A soln of furan 11 (2.12 g, 6.05 mmol) and Rose Bengal (0.160 g)
in MeOH (90 mL) was cooled to –78 °C, irradiated with a 200-W
UV lamp, and stirred in O2 atmosphere for 4 h. The solvent was re-
moved and the residue was chromatographed on silica gel (EtOAc–
hexane, 6:4), only to remove the Rose Bengal, affording 2.93 g of
the hydroperoxide intermediate as a yellowish oil; Rf = 0.50
(EtOAc–hexane, 1:3).
N
N
N
N
Cl
i
HO
6b
N
N
53%
OH
N
N
N
To a soln of the hydroperoxide and DMAP (catalytic amount) in py-
ridine (11 mL) was added Ac2O (3.6 mL). The mixture turned dark
orange. It was stirred for 15 h at r.t., then MeOH (33 mL) was added
and stirring was continued for 20 min. The solvent was removed by
rotatory evaporation and the residue was taken up in Et2O (66 mL).
The mixture was washed with 10% aq CuSO4 soln (3 × 50 mL) and
the organic phase was dried (Na2SO4). Filtration and evaporation of
the solvent afforded a residue which was chromatographed on silica
gel (EtOAc–hexane, 15:85), giving 12 as a yellowish oil; yield: 2.06
g (86%); Rf = 0.53 (EtOAc–hexane, 1:3).
ii
HO
O
N
N
77%
5b
N
O
7b
Scheme 5 Reagents and conditions: (i) 25% NH4OH, reflux; (ii) 0.5
M NaOH, reflux.
NH2
1H NMR (CDCl3): d = 7.60–7.65 (m, 4 H, CHo-Ph), 7.38–7.42 (m,
6 H, CHm,p-Ph), 7.34 (d, J = 5.7 Hz, 1 H, CH-4 furanone), 6.15 (d,
J = 5.7 Hz, 1 H, CH-3 furanone), 3.85–3.90 (m, 1 H, CH2-2¢), 3.70–
3.76 (m, 1 H, CH2-2¢), 3.20 (s, 3 H, OCH3), 2.23–2.28 (m, 1 H, CH2-
1¢), 2.07–2.13 (m, 1 H, CH2-1¢), 1.03 (s, 9 H, CH3-t-Bu).
OH
HO
H
HO
H
N
N
N
N
N
N
9.3%
7.4%
N
N
O
O
H
H
13C NMR (CDCl3): d = 170.0 (CO), 154.6 (CH-4 furanone), 135.5
(CHo-Ph), 133.1 (C-Ph), 129.8 (CHp-Ph), 127.8 (CHm-Ph), 123.4
(CH-3 furanone), 110.2 (CH-5 furanone), 58.9 (CH2-2¢), 51.1
(OCH3), 40.4 (CH2-1¢), 26.8 (CH3-t-Bu), 19.1 (C-t-Bu).
7a
6a
6.8%
9.6%
Figure 3 NOE correlations for 6a and 7a
HRMS: m/z calcd for C23H29O4Si: 397.1835; found: 397.1825.
new isonucleosides is under way. All the compounds de-
scribed in this paper are racemic and we are now working
on their enantioselective synthesis using our methodolo-
gy.
1-Methoxy-2,6-dioxabicyclo[3.3.0]octan-3-one (13)
1.0 M TBAF in THF (5.77 mL, 5.77 mmol) was added to a soln of
furanone 12 (2.29 g, 5.77 mmol) in anhyd THF (90 mL). The reac-
tion mixture was stirred at r.t. for 1.5 h, then quenched with sat. aq
NaHCO3 soln (100 mL) and extracted with t-BuOMe (3 × 150 mL).
The combined organic phases were washed with brine (2 × 200 mL)
and dried (Na2SO4). The solvent was evaporated and the residue
was chromatographed on silica gel (10–20% EtOAc–hexane), af-
fording 13 as a colorless oil; yield: 641.3 mg (70%); Rf = 0.23
(EtOAc–hexane, 1:3).
1H NMR (CDCl3): d = 4.29 (d, J = 5.9 Hz, 1 H, CH-5), 4.00–4.06
(m, 2 H, CH2-7), 3.47 (s, 3 H, OCH3), 2.86 (dd, J = 18.7, 6.0 Hz, 1
H, CH2-4), 2.62 (d, J = 18.7 Hz, 1 H, CH2-4), 2.39–2.45 (m, 1 H,
CH2-8), 2.25–2.30 (m, 1 H, CH2-8).
Solvents were purified and dried by standard procedures before use.
1
Melting points are uncorrected. H and 13C NMR spectra were re-
corded on a Bruker ARX-400 spectrometer (400 MHz, 1H; 100.61
MHz, 13C) using TMS as internal standard (chemical shifts are in d
values, J in Hz). Mass spectrometry was carried out with a Hewlett
Packard 5988A spectrometer. Flash chromatography was per-
formed on silica gel (Merck 60, 230–400 mesh); analytical TLC
was performed on plates precoated with silica gel (Merck 60 F254,
0.25 mm).
tert-Butyl[2-(furan-2-yl)ethoxy]diphenylsilane (11)
13C NMR (CDCl3): d = 175.7 (CO), 119.3 (C-1), 81.0 (CH-5), 68.7
To a soln of alcohol 8 (3.49 g, 31.16 mmol) in DMF (46 mL) were
added imidazole (2.96 g, 43.48 mmol), DMAP (catalytic amount)
and TBDPSCl (11.95 g, 43.48 mmol). The reaction mixture was
stirred at r.t. for 1.5 h, then quenched with H2O (48 mL) and extract-
ed with t-BuOMe (3 × 48 mL). The combined organic phases were
dried (Na2SO4) and the solvent was evaporated under reduced pres-
sure. The residue was chromatographed on silica gel (hexane), af-
(CH2-7), 54.2 (OCH3), 36.8 (CH2-4), 35.1 (CH2-8).
HRMS: m/z calcd for C7H8O3: 140.0473; found: 140.0473.
cis/trans-2-(2-Hydroxyethyl)tetrahydrofuran-3-ol (14)
To a soln of lactone 13 (891 mg, 5.63 mmol) in anhyd Et2O (60 mL)
at r.t. was added BF3·OEt2 (1.70 mL, 13.53 mmol) and the mixture
Synthesis 2011, No. 3, 431–436 © Thieme Stuttgart · New York

434
P. Canoa et al.
PAPER
was stirred for 1 h. It was then cooled to 0 °C before LAH (882 mg,
23.23 mmol) was added. After the mixture was stirred at r.t. for 2 h,
excess LAH was carefully destroyed by adding a few drops of H2O
at 0 °C. After filtration, the aqueous phase was saturated with NaCl
and extracted with EtOAc (4 × 30 mL). The combined organic
phases were dried (Na2SO4). Filtration and solvent evaporation af-
forded a residue which was chromatographed on silica gel (EtOAc–
hexane, 4:1), giving 14 (as an inseparable mixture of diols) as a col-
orless oil; yield: 480 mg (64%); Rf = 0.14 (EtOAc).
( )-cis-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]tetrahydrofuran-
3-ol (17)
To a soln of ketone 16 (71 mg, 0.19 mmol) in THF (5 mL) at –78 °C
was added 1.0 M L-Selectride® in THF (0.48 mL, 0.48 mmol). After
the mixture was stirred for 1.5 h at –78 °C, sat. aq NH4Cl soln (15
mL) was added. The mixture was stirred at r.t. for 30 min and then
extracted with EtOAc (4 × 15 mL). The extracts were dried
(Na2SO4), the solvent was evaporated and the residue was chro-
matographed on silica gel (EtOAc–hexane, 1:4), affording alcohol
17 as a colorless oil; yield: 61 mg (86%); Rf = 0.16 (EtOAc–hexane,
1:4).
1H NMR (CDCl3): d = 7.65–7.70 (m, 4 H, CHo-Ph), 7.38–7.48 (m,
6 H, CHm,p-Ph), 4.38–4.42 (m, 1 H, CH-3), 4.05 (q, J = 7.8 Hz, 1 H,
0.5 × CH2-5), 3.67–3.85 (m, 4 H, 0.5 × CH2-5, CH2-2¢, CH-2), 3.16
(s, 1 H, OH), 1.90–2.25 (m, 4 H, CH2-4, CH2-1¢), 1.07 (s, 9 H, CH3-
t-Bu).
1H NMR (CDCl3): d = 4.55 (s, 1 H, OH), 4.00–4.20 (m, 4 H, CH-3,
3 × OH), 3.50–3.98 (m, 11 H, CH2-5cis/trans, CH2-2¢cis/trans, CH-
2
cis/trans, CH-3), 2.00–2.15 (m, 2 H, 1 × CH2-4cis/trans), 1.76–1.89 (m,
4 H, 1 × CH2-4cis/trans, CH2-1¢trans), 1.57–1.72 (m, 2 H, CH2-1¢cis).
13C NMR (CDCl3): d = 84.0 (CH-2cis), 81.7 (CH-2trans), 75.6 (CH-
3cis), 72.0 (CH-3trans), 66.2 (CH2-5), 65.7 (CH2-5), 59.6 (CH2-2¢),
59.5 (CH2-2¢), 35.5 (CH2), 34.8 (CH2), 34.0 (CH2), 31.3 (CH2-
1¢trans).
13C NMR (CDCl3): d = 135.5 (CHo-Ph), 135.5 (CHo-Ph), 132.7 (C-
Ph), 132.6 (C-Ph), 129.9 (CHp-Ph), 127.8 (CHm-Ph), 127.8 (CHm-
Ph), 82.3 (CH-2), 72.2 (CH-3), 65.9 (CH2-5), 61.4 (CH2-2¢), 34.9
(CH2-4), 31.5 (CH2-1¢), 26.7 (CH3-t-Bu), 18.9 (C-t-Bu).
cis/trans-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]tetrahydrofu-
ran-3-ol (15)
To a soln of diol 14 (341 mg, 2.57 mmol) in THF (15 mL) were
added imidazole (351 mg, 5.15 mmol), DMAP (catalytic amount)
and TBDPSCl (1.05 mL, 4.06 mmol). The mixture was stirred for
1.5 h. After the solvent was evaporated, the residue was chromato-
graphed on silica gel (EtOAc–hexane, 3:7), to afford 15 (as an in-
separable mixture of alcohols) as a colorless oil; yield: 695 mg
(73%); Rf = 0.16 (EtOAc–hexane, 1:4).
HRMS: m/z calcd for C22H31O3Si: 371.2042; found: 371.2029.
( )-trans-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]tetrahydrofu-
ran-3-yl p-Nitrobenzoate (18)
p-O2NC6H4CO2H (54 mg, 0.32 mmol) was added to a soln of DIAD
(65 mg, 0.32 mmol) in THF (0.4 mL) and the mixture was added to
a soln of alcohol 17 (30 mg, 0.081 mmol) and Ph3P (84 mg, 0.32
mmol) in THF (1 mL). After the mixture was stirred at r.t. over-
night, the solvent was evaporated and the residue was chromato-
graphed on silica gel (EtOAc–hexane, 1:9), giving 18 as a colorless
oil; yield: 36 mg (85%); Rf = 0.57 (EtOAc–hexane, 3:7).
1H NMR (CDCl3): d = 8.21 (d, J = 8.9 Hz, 2 H, CHm-p-
O2NC6H4CO2), 8.03 (d, J = 8.9 Hz, 2 H, CHo-p-O2NC6H4CO2),
7.55–7.70 (m, 4 H, CH-PhSi), 7.35–7.42 (m, 6 H, CH-PhSi), 5.33
(td, J = 2.1, 6.3 Hz, 1 H, CH-3), 4.27 (ddd, J = 2.4, 5.5, 7.5 Hz, 1 H,
CH-2), 4.03 (dt, J = 2.9, 8.4 Hz, 1 H, CH2-5), 3.94 (dt, J = 6.4, 8.7
Hz, 1 H, CH2-5), 3.83 (t, J = 6.2 Hz, 2 H, CH2-2¢), 2.25–2.38 (m, 1
H, CH2-4), 2.05–2.15 (m, 1 H, CH2-4), 1.85 (m, 2 H, CH2-1¢), 1.03
(s, 9 H, CH3-t-Bu).
13C NMR (CDCl3): d = 164.24 (CO), 150.55 (Cp-p-O2NC6H4CO2),
135.51 (CH-Ph), 135.50 (CH-Ph), 135.41 (C-p-O2NC6H4CO2),
133.64 (C-Ph), 133.57 (C-Ph), 130.73 (CHm-p-O2NC6H4CO2),
129.59 (CH-Ph), 127.62 (CH-Ph), 123.54 (CHo-p-O2NC6H4CO2),
80.96 (CH-2), 80.15 (CH-3), 66.52 (CH2-5), 60.43 (CH2-2¢), 36.05
(CH2-1¢), 32.37 (CH2-4), 26.77 (CH3-t-Bu), 19.14 (CH3-t-Bu).
1H NMR (CDCl3): d = 7.65–7.70 (m, 8 H, CHo-Phcis/trans), 7.38–7.45
(m, 12 H, CHm,p-Phcis/trans), 4.38–4.42 (m, 1 H, CH-3cis), 4.05–4.12
(m, 2 H, CH-3trans, 0.5 × CH2-5cis), 3.90–3.94 (m, 2 H, CH2-5trans),
3.67–3.89 (m, 7 H, 0.5 × CH2-5cis, CH2-2¢cis/trans, CH-2cis/trans), 3.22
(s, 1 H, OH), 3.10 (s, 1 H, OH), 1.90–2.25 (m, 6 H, CH2-4cis/trans
,
CH2-1¢cis), 1.77 (m, 2 H, CH2-1¢trans, 1.07 (s, 18 H, CH3-t-Bu).
13C NMR (CDCl3): d = 135.5 (CHo-Ph), 135.5 (CHo-Ph), 133.2
(C-Ph), 133.1 (C-Ph), 132.7 (C-Ph), 132.6 (C-Ph), 129.7 (CHp-Ph),
129.7 (CHp-Ph), 127.8 (CHm-Ph), 127.8 (CHm-Ph), 127.7 (CHm-Ph),
84.0 (CH-2trans), 82.3 (CH-2cis), 76.0 (CH-3trans), 72.1 (CH-3cis),
66.0 (CH2-5trans), 65.9 (CH2-5cis), 61.7 (CH2-2¢trans), 61.4 (CH2-2¢cis),
36.1 (CH2-4trans), 34.9 (CH2-4cis), 34.1 (CH2-1trans), 31.5 (CH2-1¢cis),
26.8 (CH3-t-Bu), 26.7 (CH3-t-Bu), 19.0 (C-t-Bu), 18.9 (C-t-Bu).
HRMS: m/z calcd for C22H31O3Si: 371.2042; found: 371.2037.
2-[2-(tert-Butyldiphenylsilyloxy)ethyl]dihydrofuran-3(2H)-one
(16)
To a soln of alcohol 15 (676 mg, 1.82 mmol) in anhyd CH2Cl2 (20
mL) at r.t. were added powdered molecular sieves (1.11 g), NMO
(427 mg, 3.65 mmol) and TPAP (28 mg, 0.0091 mmol). The mix-
ture was stirred at r.t. for 1 h, the solvent was removed by rotatory
evaporation and the residue was chromatographed on silica gel
(EtOAc–hexane, 15:85), to afford ketone 16 as a colorless oil; yield:
613 mg (91%); Rf = 0.50 (EtOAc–hexane, 1:4).
1H NMR (CDCl3): d = 7.66–7.70 (m, 4 H, CHo-Ph), 7.38–7.42 (m,
6 H, CHm,p-Ph), 4.21 (d, J = 4.6 Hz, 1 H, CH-2), 4.06 (dd, J = 7.5,
1.4 Hz, 1 H, 0.5 × CH2-5), 3.75–3.95 (m, 3 H, 0.5 × CH2-5, CH2-2¢),
2.43–2.59 (m, 2 H, CH2-4), 1.90–2.00 (m, 1 H, 0.5 × CH2-1¢), 1.80–
1.85 (m, 1 H, 0.5 × CH2-1¢), 1.05 (s, 9 H, CH3-t-Bu).
HRMS: m/z calcd for C29H33NO6Si: 519.2132; found: 519.2129.
( )-trans-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]tetrahydrofu-
ran-3-ol (9)
To a soln of benzoate 18 (33 mg, 0.06 mmol) in MeOH (0.3 mL)
was added K2CO3 (4.0 mg, 0.03 mmol) at –10 °C. The mixture was
stirred at –10 °C for 2 h, the solvent was removed and the residue
was extracted with EtOAc (3 × 10 mL). The combined organic
phases were dried (Na2SO4) and the solvent was evaporated under
reduced pressure. The residue was chromatographed on silica gel
(EtOAc–hexane, 1:4), affording 9 as a colorless oil; yield: 22 mg
(96%); Rf = 0.40 (EtOAc–hexane, 3:7).
1H NMR (CDCl3): d = 7.62–7.72 (m, 4 H, CHo-Ph), 7.35–7.45 (m,
6 H, CHm,p-Ph), 4.10 (dd, J = 5.1, 12.1 Hz, 1 H, CH-3), 3.91 (t,
J = 7.1 Hz, 2 H, CH2-5), 3.78–3.85 (m, 2 H, CH2-2¢), 3.72 (td,
J = 5.3, 7.8 Hz, 1 H, CH-2), 2.88 (br s, 1 H, OH), 2.18–2.25 (m, 1
H, CH2-4), 1.85–1.95 (m, 1 H, CH2-4), 1.70–1.82 (m, 2 H, CH2-1¢),
1.07 (s, 9 H, CH3-t-Bu).
13C NMR (CDCl3): d = 216.1 (CO), 135.5 (CHo-Ph), 135.5 (CHo-
Ph), 133.7 (C-Ph), 133.5 (C-Ph), 129.6 (CHp-Ph), 127.6 (CHm-Ph),
76.6 (CH-2), 64.3 (CH2-5), 59.7 (CH2-2¢), 36.8 (CH2-4), 33.4 (CH2-
1¢), 26.8 (CH3-t-Bu), 19.1 (C-t-Bu).
HRMS: m/z calcd for C22H29O3Si: 369.1886; found: 369.1877.
Synthesis 2011, No. 3, 431–436 © Thieme Stuttgart · New York

PAPER
Synthesis of Isodideoxynucleosides Using the Furan Approach
435
13C NMR (CDCl3): d = 135.5 (CHo-Ph), 135.5 (CHo-Ph), 133.35
(C-Ph), 133.1 (C-Ph), 129.8 (CHp-Ph), 127.7 (CHm-Ph), 84.0 (CH-
2), 76.1 (CH-3), 66.0 (CH2-5), 61.7 (CH2-2¢), 36.0 (CH2-4), 34.1
(CH2-1¢), 26.8 (CH3-t-Bu), 19.0 (CH3-t-Bu).
1H NMR (CDCl3): d = 8.71 (s, 1 H, CH-2 purine), 8.14 (s, 1 H, CH-
8 purine), 5.42 (ddd, J = 1.3, 3.7, 8.0 Hz, 1 H, CH-3¢), 4.35 (dt,
J = 5.7, 9.1 Hz, 1 H, CH2-5¢), 4.09 (dt, J = 4.0, 8.3 Hz, 1 H, CH-2¢),
3.99 (dt, J = 6.3, 9.6 Hz, 1 H, CH2-5¢), 3.58–3.70 (m, 2 H, CH2-2¢¢),
2.72–2.82 (m, 1 H, CH2-4¢), 2.20–2.33 (m, 1 H, CH2-4¢), 1.30–1.42
(m, 1 H, CH2-1¢¢), 1.18–1.30 (m, 1 H, CH2-1¢¢).
HRMS: m/z calcd for C22H31O3Si: 371.2042; found: 371.2054.
( )-cis-9-{2-[2-(tert-Butyldiphenylsilyloxy)ethyl]tetrahydrofu-
ran-3-yl}-6-chloro-9H-purine (19a)
13C NMR (CDCl3): d = 151.97 (C-6 purine), 151.83 (CH-2 purine),
151.27 (C-4 purine), 144.09 (CH-8 purine), 130.9 (C-5 purine),
80.51 (CH-2¢), 65.91 (CH2-5¢), 59.95 (CH2-2¢¢), 56.78 (CH-3¢),
33.25 (CH2-1¢¢), 31.46 (CH2-4¢).
A suspension of alcohol 9 (25 mg, 0.06 mmol), 6-chloropurine (31
mg, 0.20 mmol) and Ph3P (52 mg, 0.20 mmol) in anhyd THF (1.2
mL) was treated under ice-cooling with a soln of DIAD (40 mL, 0.20
mmol) in THF (0.3 mL). After the mixture was stirred for 10 min,
the cooling bath was removed and stirring was continued for 24 h at
55 °C. The solvent was removed under reduced pressure and the
residue was purified on silica gel (MeOH–CH2Cl2, 5:95), to afford
19a as a colorless oil; yield: 16 mg (50%); Rf = 0.54 (MeOH–
CH2Cl2, 5:95).
1H NMR (CDCl3): d = 8.71 (s, 1 H, CH-2 purine), 8.18 (s, 1 H, CH-
8 purine), 7.55–7.61 (m, 4 H, CH-Ph), 7.37–7.43 (m, 2 H, CH-Ph),
7.30–7.36 (m, 4 H, CH-Ph), 5.33 (ddd, J = 1.3, 3.7, 7.9 Hz, 1 H,
CH-3¢), 4.30 (dt, J = 5.6, 9.0 Hz, 1 H, CH2-5¢), 4.14 (td, J = 4.1, 8.4
Hz, 1 H, CH-2¢), 3.94 (dt, J = 6.3, 9.6 Hz, 1 H, CH2-5¢), 3.58–3.70
(m, 2 H, CH2-2¢¢), 2.70–2.82 (m, 1 H, CH2-4¢), 2.18–2.25 (m, 1 H,
CH2-4¢), 1.30–1.40 (m, 1 H, CH2-1¢¢), 1.12–1.29 (m, 1 H, CH2-1¢¢),
0.95 (s, 9 H, CH3-t-Bu).
HRMS: m/z calcd for C11H13ClN4O2: 268.0727; found: 268.0723.
( )-trans-6-Chloro-9-[2-(2-hydroxyethyl)tetrahydrofuran-3-
yl]-9H-purine (5b)
A soln of silyl ether 19b (47 mg, 0.093 mmol) in anhyd THF (3 mL)
was treated with 1.0 M TBAF in THF (0.093 mL, 0.093 mmol), and
the mixture was stirred at r.t. for 1.5 h. The solvent was evaporated
and the residue was chromatographed on silica gel (MeOH–CH2Cl2,
2:98), giving 5b as a white solid; yield: 18 mg (71%); mp 108–
110 °C; Rf = 0.26 (MeOH–CH2Cl2, 1:9).
1H NMR (DMSO): d = 8.80 (s, 1 H, CH purine), 8.79 (s, 1 H, CH
purine), 4.97–5.00 (m, 1 H, CH-3¢), 4.35 (t, J = 5 Hz, 1 H, OH),
4.15–4.22 (m, 2 H, CH-2¢, CH2-5¢), 3.98–4.04 (m, 1 H, CH2-5¢),
3.38–3.45 (m, 2 H, CH2-2¢¢), 2.40–2.60 (m, 2 H, CH2-4¢), 1.79–1.84
(m, 2 H, CH2-1¢¢).
13C NMR (CDCl3): d = 151.92 (CH-2 purine), 151.75 (C-4 or C-6
purine), 151.13 (C-4 or C-6 purine), 144.59 (CH-8 purine), 135.43
(CH-Ph), 133.40 (C-Ph), 130.84 (C-5 purine), 129.68 (CH-Ph),
127.62 (CH-Ph), 78.67 (CH-2¢), 65.62 (CH2-5¢), 60.32 (CH2-2¢¢),
56.32 (CH-3¢), 33.79 (CH2-4¢), 31.85 (CH2-1¢¢), 26.79 (CH3-t-Bu),
19.15 (C-t-Bu).
13C NMR (DMSO): d = 151.6 (C-6 purine), 151.3 (CH-2 purine),
149.1 (C-4 purine), 146.1 (CH-8 purine), 131.1 (C-5 purine), 79.6
(CH-2¢), 65.9 (CH2-5¢), 59.2 (CH-3¢), 57.3 (CH2-2¢¢), 35.9 (CH2-
1¢¢), 31.3 (CH2-4¢).
HRMS: m/z calcd for C11H13ClN4O2: 268.0727; found: 268.0731.
HRMS: m/z calcd for C27H32ClN4O2Si: 507.1983; found: 507.2000.
( )-cis-9-[2-(2-Hydroxyethyl)tetrahydrofuran-3-yl]-9H-purin-
6-amine (6a)
( )-trans-9-{2-[2-(tert-Butyldiphenylsilyloxy)ethyl]tetrahydro-
furan-3-yl}-6-chloro-9H-purine (19b)
A soln of chloride 5a (10 mg, 0.04 mmol) in 25% NH4OH (1.4 mL)
was refluxed for 6 h. The solvent was evaporated under reduced
pressure and the residue was chromatographed on silica gel
(MeOH–CH2Cl2, 5:95), to give 6a as a white solid; yield: 9 mg
(97%); mp 169–171 °C (Lit.8 140–142 °C); Rf = 0.25 (MeOH–
CH2Cl2, 1:9).
1H NMR (CD3OD): d = 8.21 (s, 1 H, CH-2 purine), 8.05 (s, 1 H,
CH-8 purine), 5.20–5.29 (m, 1 H, CH-3¢), 4.33 (dt, J = 5.6, 8.9 Hz,
1 H, CH2-5¢), 4.02 (td, J = 4.0, 8.4 Hz, 1 H, CH-2¢), 3.91 (dt, J = 6.4,
9.4 Hz, 1 H, CH2-5¢), 3.45–3.55 (m, 2 H, CH2-2¢¢), 2.70–2.80 (m, 1
H, CH2-4¢), 2.30–2.40 (m, 1 H, CH2-4¢), 1.28–1.35 (m, 1 H, CH2-
1¢¢), 1.05–1.20 (m, 1 H, CH2-1¢¢).
A suspension of alcohol 17 (60 mg, 0.16 mmol), 6-chloropurine (50
mg, 0.324 mmol) and Ph3P (85 mg, 0.324 mmol) in anhyd THF (3
mL) was treated under ice-cooling with a soln of DEAD (56 mg,
0.324 mmol) in THF (1 mL). After the mixture was stirred for 10
min, the cooling bath was removed and stirring was continued for
24 h at r.t. The solvent was removed under reduced pressure and the
residue was purified on silica gel (MeOH–CH2Cl2, 5:95), to afford
19b as a white solid; yield: 53 mg (66%); mp 99–101 °C; Rf = 0.54
(MeOH–CH2Cl2, 5:95).
1H NMR (CDCl3): d = 8.71 (s, 1 H, CH-2 purine), 8.18 (s, 1 H, CH-
8 purine), 7.56–7.60 (m, 2 H, CHo-Ph), 7.50–7.55 (m, 2 H, CHo-Ph),
7.27–7.40 (m, 6 H, CHm,p-Ph), 4.98–5.04 (m, 1 H, CH-3¢), 4.40–
4.45 (m, 1 H, CH-2¢), 4.07–4.42 (m, 2 H, CH2-5¢), 3.75–3.80 (m, 2
H, CH2-2¢¢), 2.58–2.65 (m, 1 H, CH2-4¢), 2.24–2.35 (m, 1 H, CH2-
4¢), 1.78–1.85 (m, 2 H, CH2-1¢¢), 0.95 (s, 9 H, CH3-t-Bu).
13C NMR (CD3OD): d = 157.4 (C-6 purine), 153.8 (CH-2 purine),
151.1 (C-4 purine), 141.4 (CH-8 purine), 119.6 (C-5 purine), 80.4
(CH-2¢), 66.9 (CH2-5¢), 59.9 (CH2-2¢¢), 57.6 (CH-3¢), 33.9 (CH2-4¢),
33.3 (CH2-1¢¢).
13C NMR (CDCl3): d = 151.8 (CH-2 purine), 151.5 (C-4 or C-6 pu-
rine), 151.2 (C-4 or C-6 purine), 143.5 (CH-8 purine), 135.4 (CHo-
Ph), 133.3 (C-Ph), 131.8 (C-5 purine), 129.7 (CHp-Ph), 127.6
(CHm-Ph), 80.1 (CH-2¢), 66.2 (CH2-5¢), 60.2 (CH2-2¢¢), 59.4 (CH-
3¢), 35.8 (CH2-1¢¢), 32.3 (CH2-4¢), 26.7 (CH3-t-Bu), 19.0 (C-t-Bu).
HRMS: m/z calcd for C11H15N5O2: 249.1226; found: 249.1230.
( )-trans-9-[2-(2-Hydroxyethyl)tetrahydrofuran-3-yl]-9H-pu-
rin-6-amine (6b)
A soln of chloride 5b (34 mg, 0.13 mmol) in 25% NH4OH (5 mL)
was refluxed for 6 h. The solvent was evaporated under reduced
pressure and the residue was chromatographed on silica gel
(MeOH–CH2Cl2, 5:95), to give 6b as a white solid; yield: 17 mg
(53%); mp 186–188 °C; Rf = 0.25 (MeOH–CH2Cl2, 1:9).
1H NMR (DMSO): d = 8.25 (s, 1 H, CH-8 purine), 8.15 (s, 1 H, CH-
2 purine), 7.26 (s, 2 H, NH2), 4.75–4.85 (m, 1 H, CH-3¢), 4.39 (s, 1
H, OH), 4.10–4.20 (m, 2 H, CH-2¢, CH2-5¢), 3.99–4.10 (m, 1 H,
CH2-5¢), 3.34–3.47 (m, 2 H, CH2-2¢¢), 2.40–2.60 (m, 2 H, CH2-4¢),
1.60–1.70 (m, 2 H, CH2-1¢¢).
HRMS: m/z calcd for C27H32ClN4O2Si: 507.1983; found: 507.1992.
( )-cis-6-Chloro-9-[2-(2-hydroxyethyl)tetrahydrofuran-3-yl]-
9H-purine (5a)
A soln of silyl ether 19a (70 mg, 0.13 mmol) in anhyd THF (1 mL)
was treated with 1.0 M TBAF in THF (140 mL, 0.137 mmol), and
the mixture was stirred at r.t. for 3 h. The solvent was evaporated
and the residue was chromatographed on silica gel (MeOH–CH2Cl2,
2:98), giving 5a as a white solid; yield: 23 mg (68%); mp 108–
110 °C; Rf = 0.26 (MeOH–CH2Cl2, 1:9).
Synthesis 2011, No. 3, 431–436 © Thieme Stuttgart · New York

436
P. Canoa et al.
PAPER
13C NMR (DMSO): d = 155.8 (C-6 purine), 152.1 (CH-2 purine),
149.2 (C-4 purine), 139.4 (CH-8 purine), 118.9 (C-5 purine), 79.5
(CH-2¢), 65.9 (CH2-5¢), 58.4 (CH-3¢), 57.4 (CH2-2¢¢), 36.1 (CH2-
1¢¢), 31.3 (CH2-4¢).
References
(1) (a) Fall, Y.; Gómez, G.; Fernández, C. Tetrahedron Lett.
1999, 40, 8307. (b) Pérez, M.; Canoa, P.; Gómez, G.;
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44, 4467. (d) Pérez, M.; Canoa, P.; Gómez, G.; Terán, C.;
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(g) García, I.; Gómez, G.; Teijeira, M.; Terán, C.; Fall, Y.
Tetrahedron Lett. 2006, 47, 1333. (h) Canoa, P.; Pérez, M.;
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(2) (a) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17.
(b) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
(c) De Clercq, E. J. Med. Chem. 1995, 38, 2491.
(d) Simons, C. Nucleoside Mimetics; Gordon and Breach
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(b) Sugimoto, I.; Shuto, S.; Mori, S.; Shigeta, S.; Matuda, A.
Bioorg. Med. Chem. Lett. 1999, 9, 385. (c) Ohrui, H.;
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(4) (a) Huryn, D. M.; Sluboscki, B. C.; Tam, S. Y.; Todaro, L.
J.; Weigele, M. Tetrahedron Lett. 1989, 30, 6259.
(b) Nuesca, Z. M.; Nair, V. Tetrahedron Lett. 1994, 35,
2485. (c) Nair, V.; Zintek, L. B.; Jeon, G. S. Nucleosides
Nucleotides 1995, 14, 389. (d) Yoo, S. J.; Kim, H. O.; Lim,
Y.; Kim, J.; Jeong, L. S. Bioorg. Med. Chem. 2002, 10, 215.
(e) Ying, C.; De Clercq, E.; Noyts, J. Curr. Med. Chem.:
Anti-Infective Agents 2003, 2, 227.
HRMS: m/z calcd for C11H15N5O2: 249.1226; found: 249.1219.
( )-cis-9-[2-(2-Hydroxyethyl)tetrahydrofuran-3-yl]-9H-purin-
6-ol (7a)
A soln of chloride 5a (10 mg, 0.03 mmol) in 0.5 M NaOH (1.3 mL)
was refluxed for 4 h. The solvent was evaporated under reduced
pressure and the residue was purified on silica gel (5–10% MeOH–
CH2Cl2), to give 7a as a white solid; yield: 7 mg (76%); mp 163–
165 °C; Rf = 0.10 (MeOH–CH2Cl2, 1:9).
1H NMR (CD3OD): d = 8.03 (s, 1 H, CH-2 purine), 7.92 (s, 1 H,
CH-8 purine), 5.23 (ddd, J = 1.5, 3.8, 8.0 Hz, 1 H, CH-3¢), 4.26 (td,
J = 4.4, 8.9 Hz, 1 H, CH2-5¢), 3.96 (q, J = 4.0 Hz, 1 H, CH-2¢), 3.85
(dt, J = 6.4, 9.4 Hz, 1 H, CH2-5¢), 3.45–3.52 (m, 2 H, CH2-2¢¢),
2.65–2.75 (m, 1 H, CH2-4¢), 2.25–2.32 (m, 1 H, CH2-4¢), 1.20–1.30
(m, 1 H, CH2-1¢¢), 1.05–1.15 (m, 1 H, CH2-1¢¢).
13C NMR (CD3OD): d = 159.6 (C-6 purine), 150.5 (C-4 purine),
147.1 (CH-2 purine), 140.8 (CH-8 purine), 124.6 (C-5 purine), 80.4
(CH-2¢), 66.9 (CH2-5¢), 59.9 (CH2-2¢¢), 58.1 (CH-3¢), 33.9 (CH2-4¢),
33.3 (CH2-1¢¢).
HRMS: m/z calcd for C11H14N4O3: 250.1066; found: 250.1072.
( )-trans-9-[2-(2-Hydroxyethyl)tetrahydrofuran-3-yl]-9H-pu-
rin-6-ol (7b)
A soln of chloride 5b (33 mg, 0.11 mmol) in 0.5 M NaOH (4 mL)
was refluxed for 4 h. The solvent was evaporated under reduced
pressure and the residue was purified on silica gel (5–10% MeOH–
CH2Cl2), to give 7b as a white solid; yield: 22 mg (77%); mp 174–
176 °C; Rf = 0.10 (MeOH–CH2Cl2, 1:9).
1H NMR (CD3OD): d = 8.16 (s, 1 H, CH-8 purine), 8.05 (s, 1 H,
CH-2 purine), 4.90–4.96 (m, 1 H, CH-3¢), 4.07–4.30 (m, 3 H, CH-
2¢, CH2-5¢), 3.55–3.66 (m, 2 H, CH2-2¢¢), 2.55–2.67 (m, 1 H, CH2-
4¢), 2.37–2.49 (m, 1 H, CH2-4¢), 1.80 (q, J = 6.4 Hz, 2 H, CH2-1¢¢).
13C NMR (CD3OD): d = 159.1 (C-6 purine), 150.1 (C-4 purine),
146.6 (CH-2 purine), 140.7 (CH-8 purine), 125.6 (C-5 purine), 81.8
(CH-2¢), 67.6 (CH2-5¢), 61.0 (CH-3¢), 59.6 (CH2-2¢¢), 37.0 (CH2-
1¢¢), 33.0 (CH2-4¢).
(5) Balayiannis, G.; Karigiannis, G.; Gatos, P.; Papaioannou,
D.; De Clercq, E. Tetrahedron Lett. 2000, 41, 6191.
(6) For the preparation of alcohol 8, see: Alcaide, B.; Areces, P.;
Borredon, E.; Biurrun, C.; Castells, J. P.; Plumet, J.
Heterocycles 1990, 31, 1997.
(7) (a) Estévez, L.; Canoa, P.; Gómez, G.; Pérez-González, M.;
Pintos, I.; Teijeira, M.; Terán, C. Abstract of Papers, XIV
Congreso Nacional Sociedad Española de Química
Terapéutica, Bilbao, Sept. 13-16; Sociedad Española de
Química Terapéutica: Madrid, 2005. (b) Estévez, L.;
Besada, P.; Fall, Y.; Teijeira, M.; Terán, C. Synthesis 2010,
425.
HRMS: m/z calcd for C11H14N4O3: 250.1066; found: 250.1060.
Acknowledgment
(8) Zheng, X.; Nair, V. Nucleosides Nucleotides 1999, 18, 1961.
This work was financially supported by the Spanish Ministry of
Education and Science (CTQ2007-61788) and the Xunta de Galicia
(INCITE08PXIB314253PR,
INCITE08ENA314019ES
and
INCITE08PXIB314255PR). The work of the NMR and MS divi-
sions of the research support services of the University of Vigo
(CACTI) is also gratefully acknowledged. M.P. and Z.G. thank the
Xunta de Galicia for an Angeles Alvariño contract.
Synthesis 2011, No. 3, 431–436 © Thieme Stuttgart · New York