An efficient synthesis of phosphonate derivatives of 1,2-disubstituted carbocyclic purine nucleosides with a cyclopentane ring

Article abstract of DOI:10.1055/s-2008-1067166

The synthesis of phosphonate 1,2-disubstituted carbocyclic nucleosides with a cyclopentane ring is described following two different strategies: inclusion of the phosphonomethyl group before or after coupling of the carbocyclic moiety with the heterocyclic base. The diethyl [(trifluoromethanesulfonyl)oxy] methanephosphonate is the key phosphonylating agent for both the strategies. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067166

PAPER
2363
An Efficient Synthesis of Phosphonate Derivatives of 1,2-Disubstituted
Carbocyclic Purine Nucleosides with a Cyclopentane Ring
1
P
, 2-Disubstitu
e
ted Carbocy
d
clic Purine
r
N
ucleosi
od e Phosphonates Besada,* María J. González Moa, Carmen Terán
Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo, Spain
Fax +34(986)812262; E-mail: pbes@uvigo.es
Received 29 January 2008; revised 25 April 2008
Acyclic nucleoside phosphonates such as cidofovir (1),
adefovir (2) and tenofovir (3) are becoming widely useful
for treatment of viral diseases.1 On the other hand, che-
Abstract: The synthesis of phosphonate 1,2-disubstituted carbocy-
clic nucleosides with a cyclopentane ring is described following two
different strategies: inclusion of the phosphonomethyl group before
c,4
or after coupling of the carbocyclic moiety with the heterocyclic motherapeutic properties were found in several phospho-
base. The diethyl [(trifluoromethanesulfonyl)oxy]methanephos- nate derivatives of furanose, for example, in compounds
5
phonate is the key phosphonylating agent for both the strategies.
4
a and 5a; their carbocyclic analogues 4b and 5b were
Key words: nucleosides, phosphonates, carbocycles, Mitsunobu also described (Figure 1).6
reaction
In recent years, we became interested in exploring the
therapeutic potential of 1,2-disubstituted carbonucleo-
sides (OTCs) in which the usual 1,3-substitution pattern
of the carbocycle is replaced by a 1,2-pattern. We have de-
veloped a series of cis and trans purine-based OTCs in
which the pseudosugar is a cyclopentane, a cyclopentene,
Nucleoside analogues are regarded as a very interesting
group of chemotherapeutic agents because their adminis-
tration against a range of cancers and viral infections has
1
been successful. Mostly nucleosides, natural and synthet-
7
or a cyclohexane ring. Some of these compounds, in par-
ic, need to be metabolized by intracellular enzymes to
their respective 5¢-triphosphate derivatives to generate the
active form. The initial formation of the nucleoside mono-
phosphate is normally the limiting step in the enzymatic
ticular with cis-stereochemistry, have shown an interest-
8
ing antitumoral activity and also an antiviral activity
9
against certain viruses such as varicella-zoster virus and
7c
respiratory syncytial virus.
2
phosphorylation sequence. In addition, phosphate deriv-
At this point, and because of the few examples found in
the literature on the synthesis of carbocyclic phosphonate
nucleosides, we considered it very interesting to explore
and establish a synthetic route to prepare phosphonate de-
rivatives of OTCs. Previously we have used two different
methods to synthesize carbonucleosides: construction of
the heterocyclic base on the primary amino group of an
appropriate amino alcohol,7 and a convergent approach
atives of nucleoside analogues cannot be used directly as
therapeutic agents because they rapidly undergo cleavage
2
a
in vivo. For these reasons, there have been numerous at-
tempts to accomplish structural approaches that mimic the
phosphate moiety. In this area, phosphonate analogues,
containing the enzyme stable ether P–C–O moiety, have
been proposed as an interesting alternative and have
a,b
3
emerged as promising candidates.
7
c
based on Mitsunobu coupling. In this study, we were in-
NH2
NH2
NH2
N
N
N
N
N
N
N
O
O
P
N
O
P
N
O
N
HO
P
O
HO
O
HO
O
HO
HO
HO
cidofovir (1)
OH
adefovir (2)
tenofovir (3)
O
P
O
P
HO
O
X
B
HO
O
X
B
HO
HO
4
a, X = O
5a, X = O
5b, X = C
4
b, X = C
B = hypoxantine, adenine, guanine, cytosine, uracil, thymine
Figure 1 Nucleoside phosphonates with therapeutic properties
SYNTHESIS 2008, No. 15, pp 2363–2368
x
x.
x
x
.
2
0
0
8
Advanced online publication: 08.07.2008
DOI: 10.1055/s-2008-1067166; Art ID: T01308SS
Georg Thieme Verlag Stuttgart · New York
©

2
364
P. Besada et al.
PAPER
terested in developing a more possible straightforward compound 10 was recovered, no traces of phosphonate 11
synthetic route, and the convergent strategy seems to be were detected and surprisingly a transesterification prod-
the more adequate.
uct 15a was isolated in a small amount (6% yield)
Figure 2). Similar results were obtained (compound 15b,
% yield) when the tosylphosphonate derivative 14a was
replaced by diethyl [(methanesulfonyl)oxy]methanephos-
phonate (14b) (Figure 2), that to our knowledge has not
been used previously.
(
9
We investigated the synthesis of a representative phos-
phonate derivative of OTCs, a (±)-cis-hypoxanthine ana-
logue 6 with a cyclopentane ring. As the Mitsunobu
reaction normally proceeds with inversion of configura-
tion, the 1,2-trans-diol 7 was required as the starting ma-
7
a
terial (Scheme 1).
O
OEt
O
2
P
OR1
R O
P
O
2
EtO
R O
OEt
O
P
O
OBn
EtO
OR1
iv
4c (Procedure B, C: 13%, 67%)
OEt
14a, R1 = Ts
1
OBn
14b, R = Ms
1
1
15a, R2
4c, R1 = Tf
= Ts
15b, R2 = Ms
1
2
8
9
1
, R = H, R = TBDMS
ii 46%
iii 90%
11
1
2
O
, R = Bn, R = TBDMS
1
2
0, R = Bn, R = H
(EtO) P
O
2
O
v
100%
O
P(OEt)2
i
66%
O
HO
P
O
16
EtO
OEt
Figure 2 Phosphonylating agents 14, transesterification products
5 and dialkylated compound 16
OH
iv
OH vi
43%
1
1
4a (Procedure A: 2%) or
7
14c (Procedure B, C: 30%, 61%)
12
The use of a more reactive sulfonylphosphonate, like the
diethyl [(trifluoromethanesulfonyl)oxy]methanephospho-
nate (14c), was necessary to avoid the formation of
transesterification products. The treatment of the benzyl
ether 10 with the triflate 14c under mild conditions (24
hours at 0 °C) led to the formation of the corresponding
phosphonate derivative 11 in poor yield (13%), a high
proportion of compound 10 was recovered, but no traces
of the transesterification product were detected. This re-
Cl
OH
N
O
O
13
P
O
N
N
P
O
N
N
N
EtO
HO
OEt
OH
2
N
N
vii
3
1
1
00%
4
5
13
6
Scheme 1 Reagents and conditions: (i) TBDMSCl, imidazole,
DMF, r.t.; (ii) NaH, BnBr, Bu NI, THF, r.t.; (iii) TBAF, THF; (iv) sult was highly improved when the reaction was carried
4
Procedure A or B: 14a or 14c, NaH, THF, 0 °C; Procedure C: 14c, n-
out with n-BuLi at –30 °C and 11 was obtained in 67%
yield. Hydrogenolysis of benzyl ether 11 afforded the de-
sired alcohol 12 in quantitative yield.
BuLi, THF, –30 °C; (v) Procedure D: H , 10% Pd/C, MeOH, 2413
2
mbar, r.t.; (vi) 6-chloropurine, DEAD, Ph P, THF, r.t.; (vii) (1) TMS-
3
Br, CH Cl , r.t., (2) H O, acetone, 80 °C.
2
2
2
The effectiveness of the reaction with the triflate 14c en-
couraged us to try the inclusion of the phosphonate moiety
into the diol 7. Direct transformation of 7 into the phos-
phonate derivative 12 was possible using 14c and NaH at
In order to develop a shorter and more versatile method-
ology, we preferred to introduce the phosphonomethyl
moiety into the diol prior to the Mitsunobu coupling. The
0
°C (30% yield). This result was improved when n-BuLi
diethyl
[(p-toluenesulfonyl)oxy]methanephosphonate
at –30 °C was used and 12 was obtained in 60% yield. It
was possible in both cases to control the selectivity of the
phosphonylating reaction through the primary alcohol and
only traces of the dialkylated compound 16 were isolated
(
14a) (Figure 2) is the most common intermediate used in
10–12
the literature to introduce phosphonate groups.
At-
tempts to introduce directly the phosphonomethyl group
into the diol 7 by generation of the alkoxide with NaH,
followed by treatment with the tosylphosphonate 14a in
(
Figure 2).
1
0
anhydrous THF, gave compound 12 in a very poor yield Reaction of 12 with 6-chloropurine (3 equiv) in the pres-
2%). Therefore, the secondary hydroxyl group of the diol ence of diethyl azodicarboxylate (DEAD, 2 equiv) and
was protected as the benzyl ether 10. Compound 10 was Ph P (2 equiv) in THF at room temperature gave the N-9
(
7
3
obtained in three steps: selective protection of primary hy- isomer, cis-6-chloropurine derivative 13, in 43% yield.
droxyl group as tert-butyldimethylsilyl ether, followed by The relative configuration of compound 13 was deter-
1
benzylation of secondary hydroxyl group and selective mined by H NMR spectroscopy, NOE effects are present
deprotection of the previously obtained silyl ether between H-1 and H-2. On the other hand, compound 13
(
1
Scheme 1). However, worse results were obtained when was also prepared from the corresponding (±)-cis-nucleo-
8
0 was treated with the tosylphosphonate derivative under side analogue 17 using the triflate 14c as phosphonylat-
the above-mentioned conditions, since mostly unreacted ing reagent in the presence of sodium hydride at 0 °C
Synthesis 2008, No. 15, 2363–2368 © Thieme Stuttgart · New York

PAPER
1,2-Disubstituted Carbocyclic Purine Nucleoside Phosphonates
2365
Cl
N
Cl
directly for reactions in Procedure A without further purification;
R = 0.41 (CH Cl –MeOH, 95:5).
O
f
2
2
HO
N
N
P
O
N
N
N
i
N
EtO
1
H NMR (CDCl ): d = 4.42 (d, J = 8.9 Hz, 2 H, CH P), 4.22 (m, 4
OEt
3
2
2
8%
H, 2 × CH CH ), 3.13 (s, 3 H, CH ), 1.38 (t, J = 7.1 Hz, 3 H, 2 ×
N
2
3
3
CH CH ).
2
3
1
3
C NMR (CDCl ): d = 63.8 (d, J = 6.4 Hz, CH CH ), 61.5 (d,
3
2
3
17
13
J = 169.7 Hz, CH P), 38.4 (CH ), 16.8 (d, J = 5.7 Hz, CH CH ).
2
3
2
3
Scheme 2 Reagents and conditions: (i) Procedure B: 14c, NaH,
THF, 0 °C
+
+
+
MS (EI): m/z (%) = 247 ([M + 1] , 6), 219 (M – C H , 32), 201 (M
2
3
+
+
–
C H O, 10), 191 (M – C H , 18), 188 (17), 173 (21), 167 (M –
CH SO , 18), 160 (34), 137 (M – C H SO , 63), 109 (M
2 5 4 7
+
+
–
3
2
2
5
3
(
Scheme 2). This last transformation has allowed us to C H SO , 100), 81 (23), 79 (25), 65 (14).
4 9 3
confirm the N-9 substitution and the cis-stereochemistry
of compound 13 obtained previously by Mitsunobu cou-
pling.
(
±)-trans-2-(tert-Butyldimethylsilyloxymethyl)cyclopentanol(8)
7a
To a solution of compound 7 (829 mg, 7.15 mmol) and imidazole
1.17 g, 17.2 mmol) in DMF (8 mL) was added a solution of
(
Finally, the diethyl ester group of the phosphonate 13 was TBDMSCl (1.62 g, 10.7 mmol) in DMF (6.5 mL). The mixture was
hydrolyzed in quantitative yield by treatment with bro- stirred at r.t. for 3 h and diluted with Et O (20 mL). The Et O layer
was washed with H O (3 × 20 mL) and dried (Na SO ). The residue
2
2
motrimethylsilane (TMSBr) followed by heating at 80 °C
2
2
4
1
4
obtained by evaporation of Et O was purified by column chroma-
tography on silica gel (hexane–EtOAc, 95:5) to afford 8 (1.092 g,
6%) as a colorless oil; R = 0.20 (hexane–EtOAc, 9:1).
2
with a mixture of acetone–water (1.5:2). Under these
conditions the chloro atom of C-6 was replaced by an hy-
droxyl group, affording the phosphonate derivative of hy-
poxanthine 6.
6
1
f
H NMR (CDCl ): d = 3.98 (q, J = 7.1 Hz, 1 H, H-1), 3.80 (dd,
J = 9.6, 5.1 Hz, 1 H, HCHO), 3.48 (t, J = 9.6 Hz, 1 H, HCHO), 2.63
3
In conclusion, we have developed two possible strategies (s, 1 H, OH), 1.95 (m, 2 H, H-2, 1H-5), 1.74 (m, 2 H, 1H-3, 1H-4),
to obtain phosphonates of 1,2-disubstituted carbocyclic 1.58 (m, 2 H, 1H-4, 1H-5), 1.16 (m, 1 H, 1H-3), 0.90 [s, 9 H,
(
1
CH ) C], 0.08 and 0.07 [2 s, 6 H, (CH ) Si].
3 3 3 2
purine nucleosides when the carbocycle is a cyclopentane
ring: inclusion of the phosphonomethyl group in an appro-
3
C NMR (CDCl ): d = 78.5 (C-1), 67.0 (CH O), 49.2 (C-2), 33.8
3
2
priate nucleoside precursor prior to the coupling with the (C-5), 25.9 [(CH
)
C], 25.8 (C-3), 21.6 (C-4), 18.2 [(CH ) C], –5.5
3
3
3 3
and –5.6 [(CH ) Si].
heterocyclic base and inclusion of this moiety into the nu-
cleoside analogue in the final step. The first strategy is MS (EI): m/z (%) = 213 (M – OH, 2), 173 (M – C H , 27), 155
3 2
+
+
4
9
+
(
M – C H O, 7), 105 (44), 81 (56), 74 (100).
4 11
more direct and interesting in order to synthesize different
phosphonates of 1,2-disubstituted carbocyclic nucleo- Anal. Calcd for C H O Si: C, 62.55; H, 11.37. Found: C, 62.83;
1
2
26
2
sides from a common synthon. Furthermore, the selectiv- H, 11.12.
ity of the phosphonylating reaction of the diol 7 through
(
±)-trans-1-Benzyloxy-2-(tert-butyldimethylsilyloxymethyl)cy-
the primary alcohol allows us to obtain nucleoside ana-
logue phosphonates in three steps. In both strategies we
have established that the diethyl [(trifluoromethanesulfo-
nyl)oxy]methanephosphonate (14c) is the key phospho-
nylating reagent.
clopentane (9)
A solution of compound 8 (820 mg, 3.57 mmol) in THF (25 mL)
was added dropwise to a suspension of NaH (285 mg, 7.13 mmol,
6
0% dispersion in mineral oil) in THF (13 mL) at 0 °C. After stir-
ring at r.t. for 1 h, BnBr (934 mg, 649 mL, 5.35 mmol) and Bu NI
4
(133 mg, 0.36 mmol) were added. The mixture was stirred at r.t. for
6
8 h, followed by quenching with sat. aq NH Cl (33 mL). The prod-
4
1H and 13C NMR spectra were recorded on a Bruker ARX-400 in-
strument, using TMS as internal standard [chemical shifts (d) in
ppm, J in Hz]. Assignment of the signals was performed by NOE,
DEPT, HMQC, or HMBC experiments. Mass spectra were recorded
using a Hewlett-Packard 5988A spectrometer. Microanalyses were
performed using a PerkinElmer 240B elemental analyzer. Silica gel
uct was extracted with Et O (4 × 30 mL). The combined organic
layers were washed with H O (100 mL), dried (Na SO ), and con-
centrated to dryness. The residue was purified by column chroma-
tography on silica gel (hexane–EtOAc, 99.5:0.5) to afford 9 (527
mg, 46%) as a colorless oil, and to recover compound 8 (358 mg);
Rf = 0.61 (hexane–EtOAc, 9:1).
2
2
2
4
(
(
Merck 60, 230–400 mesh) was used for flash chromatography
FC). Analytical TLC was performed on plates precoated with silica
1
H NMR (CDCl ): d = 7.32 (m, 4 Harom), 7.25 (m, 1 Harom), 4.50 (s,
3
2
H, CH Ph), 3.80 (m, 1 H, H-1), 3.54 (dd, J = 10.0, 5.9 Hz, 1 H,
gel (Merck 60 F254, 0.25 mm).
Phosphonates 14a10–12 and 14c13 were prepared according to the
literature.
2
HCHO), 3.48 (dd, J = 10.0, 5.6 Hz, 1 H, HCHO), 2.16 (m, 1 H, H-
2
1
), 1.84 (m, 1 H, 1H-5), 1.74 (m, 3 H, 1H-3, 1H-4, 1H-5), 1.58 (m,
H, 1H-4), 1.30 (m, 1 H, 1H-3), 0.89 [s, 9 H, (CH ) C], 0.03 [s, 6
3
3
H, (CH ) Si].
3
2
Diethyl Methanesulfonyloxymethanephosphonate (14b)
1
3
1
5
C NMR (CDCl ): d = 139.1, 128.3, 127.6, 127.3, 82.7 (C-1), 70.8,
To a solution of diethyl hydroxymethylphosphonate (100 mg,
.60 mmol) in CH Cl (3 mL) was added dropwise MsCl (74 mg, 50
3
6
1
4.7, 48.1 (C-2), 32.1 (C-5), 27.2 (C-3), 25.9 [(CH ) C], 23.3 (C-4),
8.3 [(CH ) C], –5.4 [(CH ) Si].
0
3 3
2
2
mL, 0.65 mmol) and Et N (0.13 mL) at 0 °C. The mixture was stirred
3 3
3 2
3
+
+
and the temperature was allowed to reach r.t. gradually and then the
MS (EI): m/z (%) = 320 (M , 0.12), 263 (M – C H , 0.96), 171 (7),
4 9
92 (30), 91 (100), 73 (6).
stirring was continued for an additional 4 h. After adding H O (3
2
mL), the product was extracted with CH Cl (2 × 3 mL). The com-
2
2
Anal. Calcd for C H O Si: C, 71.19; H, 10.06. Found: C, 71.25;
H, 10.19.
1
9
32
2
bined organic layers were washed with sat. aq NaHCO (9 mL),
3
brine (9 mL), and dried (Na SO ). The solvent was removed in vac-
2
4
uo to obtain 14b (117 mg, 80%) as a colorless oil, which was used
Synthesis 2008, No. 15, 2363–2368 © Thieme Stuttgart · New York

2
366
P. Besada et al.
PAPER
(
±)-trans-2-Benzyloxycyclopentylmethanol (10)
did not proceed to completion and the purification by column chro-
matography on silica gel (hexane–EtOAc, 1:4) gave 11 and the re-
covered compound 10 (5 mg).
To a solution of compound 9 (527 mg, 1.65 mmol) in THF (25 mL)
was added 1 M solution of TBAF in THF (1.8 mL). The mixture
was stirred at r.t. for 1 h. After removal of the solvent, the residue
was purified by column chromatography on silica gel (CH Cl –
11
2
2
MeOH, 99.5:0.5) to give 10 (306 mg, 90%) as a colorless oil;
Rf = 0.37 (hexane–EtOAc, 1:4).
Rf = 0.55 (hexane–EtOAc, 1:1).
1
H NMR (CDCl ): d = 7.33 (m, 4 Harom), 7.26 (m, 1 Harom), 4.52 (d,
3
1
H NMR (CDCl ): d = 7.33 (m, 4 Harom), 7.28 (m, 1 Harom), 4.57 (d,
J = 11.9 Hz, 1 H, HCHPh), 4.47 (d, J = 11.9 Hz, 1 H, HCHPh),
4.15 (m, 4 H, 2 × CH CH ), 3.78 (d, J = 8.2 Hz, 2 H, CH P), 3.76
(m, 1 H, H-2), 3.49 (m, 2 H, CH O), 2.28 (m, 1 H, H-1), 1.90 (m, 1
3
J = 11.7 Hz, 1 H, HCHPh), 4.47 (d, J = 11.7 Hz, 1 H, HCHPh),
2
3
2
3
.77 (q, J = 5.9 Hz, 1 H, H-2), 3.62 (dd, J = 10.5, 5.9 Hz, 1 H,
2
HCHOH), 3.55 (dd, J = 10.5, 7.8 Hz, 1 H, HCHOH), 2.18 (m, 1 H,
H, 1H-5), 1.75 (m, 3 H, 1H-4, H-3), 1.59 (m, 1 H, 1H-4), 1.32 (t,
H-1), 2.01 (br s, 1 H, OH), 1.87 (m, 2 H, 1H-3, 1H-5), 1.72 (m, 2 H,
J = 7.1 Hz, 6 H, 2 × CH ), 1.31 (m, 1 H, 1H-5).
3
1
H-3, 1H-4), 1.60 (m, 1 H, 1H-4), 1.23 (m, 1 H, 1H-5).
13
C NMR (CDCl ): d = 138.9, 128.3, 127.6, 127.4, 82.9 (C-2), 75.8
3
1
3
C NMR (CDCl ): d = 138.6, 128.4, 127.6, 127.5, 84.1 (C-2), 71.2
(d, J = 11.2 Hz, CH O), 71.0 (CH Ph), 65.2 (d, J = 166.2 Hz,
3
2
2
(
CH Ph), 65.9 (CH O), 47.8 (C-1), 31.4 (C-3), 26.4 (C-5), 22.3 (C-
CH P), 62.4 (d, J = 6.5 Hz, CH CH ), 45.7 (C-1), 31.9 (C-3), 27.6
2
2
2
2
3
4
).
(C-5), 23.1 (C-4), 16.5 (d, J = 5.6 Hz, CH3).
+
+
+
+
+
MS (EI): m/z (%) = 206 (M , 2), 188 (M – H O, 9), 108 (M –
MS (EI): m/z (%) = 357 ([M + 1] , 6), 265 (M – C H , 11), 250
2
7
7
+
+
+
+
C H O, 20), 107 (M – C H O, 28), 92 (24), 91 (M – C H O ,
(M – C H , 72), 169 (M – C H O, 100), 167 (56), 152 (20), 141
6
10
6
11
6
11
2
8 10 13 15
1
00), 82 (24), 79 (8), 67 (12).
(26), 125 (22), 96 (36), 89 (79), 82 (54), 67 (76).
Anal. Calcd for C H O : C, 75.69; H, 8.80. Found: C, 75.43; H,
Anal. Calcd for C H O P: C, 60.66; H, 8.20. Found: C, 60.35; H,
13
18
2
18 29
5
8
.95.
8.31.
Phosphonate Derivatives; General Procedure
(±)-trans-2-(Diethylphosphonomethoxymethyl)cyclopentanol
(12)
Procedure A: A solution of the corresponding alcohol (0.20–0.90
mmol) in THF (0.5 mL) was added dropwise to a suspension of
NaH (1.1 equiv, 60% dispersion in mineral oil) in THF (0.5 mL).
After stirring at r.t. for 1 h, the mixture was cooled to 0 °C and the
phosphonylating agent 14a or 14b (1.1–1.5 equiv) was added. The
mixture was stirred at 0 °C for 3 h and then for 24 h at r.t. After re-
moval of the solvent, the residue was dissolved in EtOAc (8 mL)
Procedure A: Compound 12 (5 mg, 2%) was obtained as a colorless
oil from 7 (100 mg, 0.86 mmol), NaH (38 mg, 0.95 mmol, 60% dis-
persion in mineral oil), and 14a (305 mg, 0.95 mmol). Purification
was done by column chromatography on silica gel (CH Cl –MeOH,
2
2
98:2).
Procedure B: Compound 12 (16 mg, 30%) was obtained as a color-
less oil from 7 (23 mg, 0.20 mmol), NaH (10 mg, 0.25 mmol, 60%
dispersion in mineral oil), and 14c (71 mg, 0.24 mmol). The reac-
tion did not proceed to completion and the purification was done by
column chromatography on silica gel (hexane–EtOAc, 1:2 →
EtOAc) gave 12 and the recovered compound 7 (7 mg).
and washed with H O (2 × 5 mL). The organic layer was dried
2
(
Na SO ), and concentrated to dryness. The residue was purified by
2 4
column chromatography on silica gel to give the corresponding
phosphonate.
Procedure B: A solution of the corresponding alcohol (0.15–0.20
mmol) in THF (0.5 mL) was added dropwise to a suspension of
NaH (1.1 equiv, 60% dispersion in mineral oil) in THF (0.5 mL).
After stirring at r.t. for 1 h, the mixture was cooled to 0 °C and a so-
lution of 14c (1.1–1.5 equiv) in THF (0.4 mL) was added. The mix-
Procedure C: Compound 12 (313 mg, 61%) was obtained as a col-
orless oil from 7 (224 mg, 1.93 mmol), n-BuLi (2.5 M in hexanes,
0
.85 mL, 2.13 mmol) in THF (13 mL), and 14c (1.154 g, 3.85
mmol) in THF (4 mL). The reaction did not proceeded to comple-
tion and the purification was done by column chromatography on
silica gel (EtOAc) to give 12 and the recovered compound 7 (63
mg).
ture was stirred at 0 °C for 24 h, followed by quenching with H O
2
(
5 mL). The product was extracted with Et O (3 × 5 mL). The com-
2
bined organic layers were dried (Na SO ), and concentrated to dry-
2
4
ness. The residue was purified by column chromatography on silica
gel to give the corresponding phosphonate.
Procedure D: A solution of the compound 11 (36 mg, 0.10 mmol)
in MeOH (4.8 mL) was treated with H (2413 mbar) in the presence
2
Procedure C: To a solution of the corresponding alcohol (0.24
mmol) in THF (2 mL), at –30 °C, was added dropwise n-BuLi in
hexanes (1.1 equiv). After stirring for 1 h, a solution of 14c (2.1
equiv) in THF (0.8 mL) was added and stirring was continued at
of 10% Pd/C (14 mg). The mixture was stirred at r.t. for 1 h. After
separation of the catalyst by filtration, the solvent was removed in
vacuo to obtain 12 (27 mg, ~100%) as a colorless oil.
–
30 °C for 24 h. The mixture was quenched with sat. aq NaHCO (2
3
1
2
mL) and the product was extracted with Et O (4 × 3 mL). The com-
bined organic layers were dried (Na SO ), and concentrated to dry-
ness. The residue was purified by column chromatography on silica
gel to give the corresponding phosphonate.
2
Rf = 0.21 (EtOAc).
2
4
1
H NMR (CDCl ): d = 4.18 (m, 4 H, 2 × CH CH ), 4.02 (q, J = 6.6
3
2
3
Hz, 1 H, H-1), 3.80 (d, J = 8.0 Hz, 2 H, CH P), 3.67 (dd, J = 9.1,
2
5
.3 Hz, 1 H, HCHO), 3.49 (t, J = 9.1 Hz, 1 H, HCHO), 2.73 (br s, 1
H, OH), 2.08 (m, 1 H, H-2), 1.93 (m, 1 H, 1H-5), 1.83 (m, 1 H, 1H-
), 1.74 (m, 1 H, 1H-4), 1.60 (m, 2 H, 1H-5, 1H-4), 1.35 (t, J = 7.0
(
±)-trans-1-(Diethylphosphonomethoxymethyl)-2-benzyloxycy-
3
clopentane (11)
Hz, 6 H, 2 × CH ), 1.22 (m, 1 H, 1H-3).
13
Procedure B: Compound 11 (7 mg, 13%) was obtained as a color-
less oil from 10 (30 mg, 0.15 mmol), NaH (7 mg, 0.17 mmol, 60%
dispersion in mineral oil), and 14c (66 mg, 0.22 mmol). The reac-
tion did not proceed to completion and the purification by column
chromatography on silica gel (hexane–EtOAc, 3:1 → 1:1) gave 11
and the recovered compound 10 (20 mg).
3
C NMR (CDCl ): d = 77.4 (C-1), 76.9 (d, J = 11.6 Hz, CH O),
5.0 (d, J = 166.7 Hz, CH P), 62.5 (d, J = 6.5 Hz, CH CH ), 62.4
3
2
6
2
2
3
(
(
d, J = 6.7 Hz, CH CH ), 47.3 (C-2), 34.0 (C-5), 26.4 (C-3), 21.8
C-4), 16.4 (d, J = 5.7 Hz, CH3).
2 3
+
+
MS (EI): m/z (%) = 267 ([M + 1] , 2), 238 (M – C H , 8), 169
2
4
Procedure C: Compound 11 (58 mg, 67%) was obtained as a color-
less oil from 10 (50 mg, 0.24 mmol), n-BuLi (1.48 M in hexanes,
0
+
(
(
M – C H O, 72), 167 (21), 152 (74), 141 (32), 138 (42), 125
M – C H O, 100), 111 (38), 97 (35), 81 (38), 65 (34).
6 9
+
9
17
.18 mL, 0.27 mmol), and 14c (146 mg, 0.49 mmol). The reaction
Synthesis 2008, No. 15, 2363–2368 © Thieme Stuttgart · New York

PAPER
1,2-Disubstituted Carbocyclic Purine Nucleoside Phosphonates
2367
Anal. Calcd for C H O P: C, 49.62; H, 8.71. Found: C, 49.78; H,
(±)-trans-2¢-Benzyloxycyclopentylmethyl Ethyl Methanesulfo-
nyloxymethylphosphonate (15b)
1
1
23
5
8
.56.
Procedure A: Compound 15b (10 mg, 9%) was obtained as a color-
less oil from 10 (59 mg, 0.29 mmol), NaH (14 mg, 0.35 mmol, 60%
dispersion in mineral oil), and 14b (106 mg, 0.43 mmol). The reac-
tion did not proceeded to completion and the purification was done
by column chromatography on silica gel (hexane–EtOAc, 1:1) to
(
±)-cis-6-Chloro-9-[2-(diethylphosphonomethoxymethyl)cyclo-
pentyl]purine (13)
From 12: To a suspension of compound 12 (311 mg, 1.17 mmol),
6
-chloropurine (548 mg, 3.51 mmol), and Ph P (620 mg, 2.34
3
mmol) in THF (15 mL) was added a solution of DEAD (409 mg,
give 15b [R = 0.26 (hexane–EtOAc, 1:1)] and the recovered com-
f
3
70 mL, 2.35 mmol) in THF (3 mL). The mixture was stirred at r.t.
pound 10 (19 mg).
for 22 h. After removal of the solvent, the residue was purified by
column chromatography on silica gel (EtOAc) to give 13 (204 mg,
4
1
H NMR (CDCl ): d = 7.33 (m, 4 Harom), 7.28 (m, 1 Harom), 4.54 (d,
3
J = 11.8 Hz, 1 H, HCHPh), 4.45 (d, J = 11.8 Hz, 1 H, HCHPh),
3%) as a colorless oil.
4
.39 (d, J = 8.9 Hz, 2 H, CH P), 4.19 (m, 2 H, OCH CH ), 4.08 (m,
2
2
3
Procedure B: Compound 13 (18 mg, 28%) was obtained as a color-
less oil from 17 (40 mg, 0.16 mmol), NaH (10 mg, 0.25 mmol, 60%
dispersion in mineral oil) and 14c (57 mg, 0.19 mmol). Reaction
proceeded no completely and the purification by column chroma-
tography on silica gel (CH Cl –MeOH, 95:5) gave 13 and the re-
2 H, OCH ), 3.78 (m, 1 H, H-2¢), 3.08 (s, 3 H, CH ), 2.33 (m, 1 H,
2
3
H-1¢), 1.93 (m, 1 H, 1H-5¢), 1.79 (m, 3 H, H-3¢, 1H-4¢), 1.62 (m, 1
H, 1H-4¢), 1.35 (t, J = 7.1 Hz, 3 H, CH CH ), 1.31 (m, 1 H, 1H-5¢).
2
3
13
C NMR (CDCl ): d = 138.5, 128.4, 127.6, 127.5, 82.0 (C-2¢), 71.1
2 2
3
2
2
(
CH Ph), 68.6 (t, J = 6.2 Hz, OCH ), 63.5 (d, J = 6.2 Hz,
covered compound 17 (9 mg).
OCH CH ), 60.9 (d, J = 169.9 Hz, CH P), 46.3 (C-1¢), 37.9 (CH ),
2
3
2
3
3
1.6 (C-3¢), 26.9 (C-5¢), 22.8 (C-4¢), 16.4 (d, J = 5.6 Hz, CH CH ).
2
3
1
3
f
+
+
MS (EI): m/z (%) = 407 ([M + 1] , 0.03), 219 (M – C H O, 16),
R = 0.32 (CH Cl –MeOH, 95:5).
13 15
2
2
+
1
91 (M – C H O PS, 9), 91 (100), 79 (17).
1
4 8 6
H NMR (CDCl ): d = 8.73 (s, 1 H, H-2), 8.28 (s, 1 H, H-8), 5.15 (q,
3
Anal. Calcd for C H O PS: C, 52.30; H, 6.97. Found: C, 52.42; H,
J = 7.7 Hz, 1 H, H-1¢), 4.11 (m, 4 H, 2 × CH CH ), 3.43 (d, J = 8.6
17 27
6
2
3
6
.75.
Hz, 2 H, CH P), 3.18 (m, 2 H, CH O), 2.67 (m, 1 H, H-2¢), 2.43 (m,
2
2
1
H, 1H-5¢), 2.36 (m, 1 H, 1H-5¢), 2.16 (m, 1 H, 1H-4¢), 2.03 (m, 1
(
±)-cis-9-[2-(Dihydroxyphosphonomethoxymethyl)cyclopen-
H, 1H-3¢), 1.84 (m, 2 H, 1 H-3¢, 1H-4¢), 1.32 (t, J = 7.0 Hz, 6 H,
2
tyl]hypoxanthine (6)
× CH3).
To a solution of compound 13 (41 mg, 0.10 mmol) in CH Cl (2
1
3
2
2
C NMR (CDCl ): d = 152.2, 151.5 (C-2), 150.7, 145.3 (C-8),
3
mL) was added dropwise TMSBr (162 mg, 140 mL, 1.03 mmol).
The mixture was stirred at r.t. for 24 h. After removal of the solvent,
1
31.5 (C-5), 72.8 (d, J = 11.8 Hz, CH O), 64.9 (d, J = 167.2 Hz,
2
CH P), 62.3 (d, J = 6.6 Hz, CH CH ), 62.2 (d, J = 6.5 Hz,
2
2
3
the residue was dissolved in a mixture 1.5:2 of acetone–H O (3.5
2
CH CH ), 58.0 (C-1¢), 42.7 (C-2¢), 30.7 (C-5¢), 27.3 (C-3¢), 22.9 (C-
2
3
mL) and heated overnight at 80 °C. The solvent was removed in
4¢), 16.4 (d, J = 5.4 Hz, CH3).
vacuo to obtain 6 (33 mg, ~100%) as a colorless oil; R = 0.15
f
+
+
MS (EI): m/z (%) = 402 (M , 8), 367 (11), 253 (M – C H PO , 33),
(n-BuOH–H O–AcOH, 10:3:2).
5
+
10
3
2
+
2
3
51 (M – C H PO , 100), 236 (17), 235 (24), 234 (M – C H PO ,
3), 152 (14), 125 (33), 78 (17).
1
5
12
3
5
13
4
H NMR (DMSO-d ): d = 12.90 (br s, 1 H, OH aromatic), 9.05 (s, 1
6
H, H-2), 8.24 (s, 1 H, H-8), 5.07 (q, J = 7.8 Hz, 1 H, H-1¢), 4.81 [br
s, 2 H, P(OH) ], 3.18 (m, 4 H, CH P, CH O), 2.58 (m, 1H, H-2¢),
Anal. Calcd for C H ClN O P: C, 47.71; H, 6.01; N, 13.91.
1
6
24
4
4
2
2
2
Found: C, 47.53; H, 6.21; N, 13.75.
2.26 (m, 2 H, H-5¢), 1.96 (m, 1 H, 1H-4¢), 1.89 (m, 1 H, 1H-3¢), 1.66
(
m, 2 H, 1H-3¢, 1H-4¢).
(
±)-trans-2¢-Benzyloxycyclopentylmethyl Ethyl p-Toluensulfo-
13
C NMR (DMSO-d ): d = 154.4 (C-6), 147.7 (C-2), 139.1 (C-8),
6
nyloxymethylphosphonate (15a)
1
18.3 (C-5), 71.8 (d, J = 11.1 Hz, CH O), 66.3 (d, J = 160.5 Hz,
2
Procedure A: Compound 15a (6 mg, 6%) was obtained as a color-
less oil from 10 (45 mg, 0.22 mmol), NaH (10 mg, 0.25 mmol, 60%
dispersion in mineral oil), and 14a (106 mg, 0.33 mmol). The reac-
tion did not proceeded to completion and the purification by column
chromatography on silica gel (hexane–EtOAc, 1:1) gave 15a
CH P), 58.1 (C-1¢), 41.6 (C-2¢), 30.1 (C-5¢), 27.1 (C-3¢), 22.2 (C-4¢).
2
+
MS (FAB): m/z (%) = 329 ([M + 1] , 100).
Anal. Calcd for C H N O P: C, 43.91; H, 5.22; N, 17.07. Found:
1
2
17
4
5
C, 43.76; H, 5.12; N, 16.87.
[
(
1
Rf = 0.29 (hexane–EtOAc, 1:1)] and the recovered compound 10
26 mg).
Acknowledgment
H NMR (CDCl ): d = 7.78 (d, J = 8.3 Hz, 2 Harom), 7.32 (m, 6
3
Harom), 7.28 (m, 1 Harom), 4.49 (d, J = 11.8 Hz, 1 H, HCHPh), 4.43
We acknowledge the Universidade de Vigo and Xunta de Galicia
(PGIDT04BTF301031PR and PGIDIT07PXIB314220PR) for fi-
nancial support. P.B. thanks the Xunta de Galicia for an Isidro Parga
Pondal contract.
(
(
(
d, J = 11.8 Hz, 1 H, HCHPh), 4.18 (d, J = 9.9 Hz, 2 H, CH P), 4.12
2
m, 2 H, OCH CH ), 4.01 (m, 2 H, OCH ), 3.75 (m, 1 H, H-2¢), 2.44
2
3
2
s, 3 H, CH ), 2.28 (m, 1 H, H-1¢), 1.88 (m, 1 H, 1H-5¢), 1.75 (m, 3
3
H, H-3¢, 1H-4¢), 1.60 (m, 1 H, 1H-4¢), 1.30 (t, J = 7.1 Hz, 3 H,
CH CH ), 1.28 (m, 1 H, 1H-5¢).
2
3
1
3
References
C NMR (CDCl ): d = 145.5, 138.6, 131.6, 130.0, 128.3, 128.2,
3
1
6
27.6, 127.5, 82.0 (C-2¢), 71.1 (CH Ph), 68.5 (t, J = 6.0 Hz, OCH ),
3.5 (d, J = 7.1 Hz, OCH CH ), 61.1 (d, J = 170.0 Hz, CH P), 46.2
2
2
(1) (a) Chu, C. K. Recent Advances in Nucleosides: Chemistry
and Chemotherapy; Elsevier: Amsterdam, 2002.
(b) Simons, C. Nucleoside Mimetics: Their Chemistry and
Biological Properties; Gordon and Breach Science
Publishers: Amsterdam, 2001. (c) De Clercq, E. J. Clin.
Virol. 2004, 30, 115. (d) Johnson, S. A. Expert Opin.
Pharmacother. 2001, 2, 929.
2
3
2
(
C-1¢), 31.7 (C-3¢), 26.8 (C-5¢), 22.8 (C-4¢), 21.7 (CH ), 16.3 (d,
3
J = 5.7 Hz, CH CH ).
2
3
+
+
MS (EI): m/z (%) = 483 ([M + 1] , 0.04), 295 (M – C H O S, 14),
1
8
11
3
55 (14), 91 (100).
Anal. Calcd for C H O PS: C, 59.21; H, 6.70. Found: C, 59.40; H,
23
31
6
6
.53.
Synthesis 2008, No. 15, 2363–2368 © Thieme Stuttgart · New York

2
368
P. Besada et al.
PAPER
(
2) (a) Kukhanova, M.; Krayevsky, A.; Prusoff, W.; Cheng, Y.
C. Curr. Pharm. Des. 2000, 6, 585. (b) El Kouni, M. H.
Curr. Pharm. Des. 2002, 8, 581. (c) Poijärvi-Virta, P.;
Lönnberg, H. Curr. Med. Chem. 2006, 13, 3441.
3) Holý, A. Advances in Antiviral Drug Design; JAI:
Greenwich, 1993.
(8) Estrada, E.; Uriarte, E.; Montero, A.; Teijeira, M.; Santana,
L.; De Clercq, E. J. Med. Chem. 2000, 43, 1975.
(9) Santana, L.; Teijeira, M.; Uriarte, E.; Balzarini, J.; De
Clercq, E. Bioorg. Med. Chem. Lett. 1998, 8, 1349.
(10) Holý, A.; Rosenberg, I. Collect. Czech. Chem. Commun.
1982, 47, 3447.
(
(
(
4) De Clercq, E.; Holý, A. Nat. Rev. Drug Discov. 2005, 4, 928.
5) (a) Kim, C. U.; Luh, B. Y.; Martin, J. C. J. Org. Chem. 1991,
(11) Jeffery, A. L.; Kim, J.-H.; Wiemer, D. F. Tetrahedron 2000,
56, 5077.
5
6, 2642. (b) Kim, C. U.; Luh, B. Y.; Misco, P. F.; Martin, J.
(12) Esteban-Gamboa, A.; Balzarini, J.; Esnouf, R.; De Clercq,
E.; Camarasa, M. J.; Pérez-Pérez, M. J. J. Med. Chem. 2000,
43, 971.
(13) Phillion, D. P.; Andrew, S. S. Tetrahedron Lett. 1986, 27,
1477.
C. Nucleosides Nucleotides 1991, 10, 371.
(
6) Jähne, G.; Müller, A.; Kroha, H.; Rösner, M.; Holzhäuser,
O.; Meichsner, C.; Helsberg, M.; Winkler, I.; Riess, G.
Tetrahedron Lett. 1992, 33, 5335.
(
7) (a) Santana, L.; Teijeira, M.; Terán, M.; Uriarte, E.; Viña, D.
Synthesis 2001, 1532. (b) Besada, P.; González-Moa, M. J.;
Terán, C.; Santana, L.; Uriarte, E. Synthesis 2002, 2445.
(14) McKenna, C. E.; Schmidhauser, J. J. Chem. Soc., Chem.
Commun. 1979, 739.
(15) Kluge, A. F. Org. Synth. 1986, 64, 80.
(
2
c) Viña, D.; Santana, L.; Uriarte, E.; Terán, C. Tetrahedron
005, 61, 473.
Synthesis 2008, No. 15, 2363–2368 © Thieme Stuttgart · New York