Synthesis of new 1′(N)-homocarbanucleosides based on 1-methylcyclopenta[c]pyrazole scaffold

Article abstract of DOI:10.1055/s-2005-918451

A series of 1′-homocarbanucleosides was prepared by coupling a purine or pyrimidine to, or constructing it on, a protected 1-methylcyclopenta[c] pyrazole pseudosugar synthesized from (±)-(exo,exo)-1-methyl-4,5,6,7- tetrahydro-4,7-methanoindazole-5,6-diol

Full text of DOI:10.1055/s-2005-918451

PAPER
73
Synthesis of New 1¢(N)-Homocarbanucleosides Based on 1-Methylcyclopen-
ta[c]pyrazole Scaffold
S
M
ynthesis of
N
ew 1
¢
(
N
a
)-Homocarb
r
a
nucleo
c
side
s
os D. García, Olga Caamaño,* Franco Fernández, Paula Abeijon, José Manuel Blanco
Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela,
Spain
Fax +34(981)594912; E-mail: qoolga@usc.es
Received 20 June 2005
R
Abstract: A series of 1¢-homocarbanucleosides was prepared by
coupling a purine or pyrimidine to, or constructing it on, a protected
N
N
1
-methylcyclopenta[c]pyrazole pseudosugar synthesized from (±)-
B
N
(
exo,exo)-1-methyl-4,5,6,7-tetrahydro-4,7-methanoindazole-5,6-
HO
N
diol by oxidative cleavage of the starting glycol, reduction of the re-
HO
sulting dialdehyde with NaBH , and the protective monosilylation
4
of the bis(hydroxymethyl) reduction product.
1 (B = adenine, guanine
or uracil base)
Key words: methanoindazoles, 1¢(N)-homocarbanucleosides, nu-
cleoside analogues, methylcyclopenta[c]pyrazol, glycol cleavage,
silyl ethers
3
R
HO
B
OH, OMe, OEt
NH2, NHPr, NHPr, NH Pr
i
c
Nucleoside analogues in which the furanose ring has been
replaced by carbocyclic or non-furanose heterocyclic sys-
2
(B = adenine or uracil base)
Ph, p-ClPh, p-MePh, p-MeOPh
tems are of interest because of their biological actions. Figure 1
Carbocyclic nucleoside analogues (carbanucleosides, or
1
CANs) are classified as nucleoside reverse transcriptase
inhibitors, and certain members of this family are clini-
ta[c]pyrazole to be highly active against varicella-zoster
virus and cytomegalovirus at subtoxic concentrations.14
Here we report a more efficient synthesis of purinylmeth-
yl and pyrimidinylmethyl derivatives of an analogous 1-
substituted cyclopenta[c]pyrazole.
2
cally important antiviral agents, particularly for use
against HIV infection. Furthermore, the CAN family ap-
pears to offer sufficient variety to allow solution to current
limitations due to low polymerase selectivity and the sus-
ceptibility of glycoside linkages to enzymatic hydrolysis.
For example, in 1¢(N)-homocarbanucleosides increased
resistance to enzymatic degradation has been sought by
inclusion of a methylene group between the heterocyclic
Key intermediate 5 was prepared from (±)-(exo,exo)-1-
methyl-4,5,6,7-tetrahydro-4,7-methanoindazole-5,6-diol
1
2
(
4) by oxidative cleavage with sodium periodate and sil-
ica gel, followed immediately by reduction of the result-
3
ing crude dialdehyde with NaBH in MeOH (Scheme 1).
base and C1 of the pseudosugar moiety.
4
The desired monoprotected derivatives 6 and 7 were ob-
tained by treating 5 with NaH and TBDPSCl under condi-
tions similar to those described by McDougal for
To explore the dependence of the biological activity of
CANs on their structural characteristics and liposolubility
(
enhancing liposolubility facilitates access to the central
15
monoprotection with TBDMSCl. Clean separation of 6
4
nervous system, an important reservoir of HIV ), our re-
search group has in recent years prepared a number of tri-
methylcyclopentyl 1¢(N)-homocarbanucleosides (1, 2;
Figure 1), and also a series of cyclopentenyl 1¢(N)-ho-
mocarbanucleosides in which the cyclopentene ring is in-
(
58%) and 7 (25%) was achieved via chromatography,
and a small proportion of unreacted 5 was recovered.
Although the popular Mitsunobu condensation reaction16
is often used for direct coupling of heterocyclic bases to
primary alcohols, it requires laborious subsequent work-
5
–7
8
–10
corporated in an indan system (3).
Some of these
17
compounds have shown considerable cytostatic activity.8
up and in our experience has failed to couple certain al-
cohols similar to 6 or 7.14 In order to couple purines to
compound 6, we accordingly opted in the first instance for
an indirect approach via its mesylate 8, which was ob-
tained in almost quantitative yield by treatment of 6 with
With a view to further modify the lipophilicity and polar
interactions while retaining the structural rigidity of the
pseudosugar, we have also prepared analogues of 3 in
which the benzene ring of indan is replaced by a heterocy-
methanesulfonyl chloride, Et N and DMAP (Scheme 1).
1
1–14
3
cle.
Preliminary tests of these compounds have shown
Reaction of crude 8 with adenine in DMF in the presence
certain purinylmethyl derivatives of a 2-benzyl cyclopen-
1
8
of NaH gave the displacement product 9a in 41% yield,
and the desired deprotected product 9b was then obtained
by treating a THF solution of 9a with TBAF (1 M in THF)
for one hour. Similarly, reaction of 8 with 2-amino-6-
SYNTHESIS 2006, No. 1, pp 0073–0080
x
x
.
x
x
.2
0
0
5
Advanced online publication: 27.10.2005
DOI: 10.1055/s-2005-918451; Art ID: P08205SS
Georg Thieme Verlag Stuttgart · New York
©

7
4
M. D. García et al.
PAPER
i) NaIO4 (aq),
Me
HO
OH
SiO2,CH2Cl2
HO
HO
N
ii) MeOH, NaBH4
5
N
N
88%
Me
N
4
60% NaH, THF, TBDPSCl
OTBDPS
TBDPSO
OH
(58%)
HO
7
(25%)
6
+
N
N
Me
Me
N
N
6
-chloropurine, PPh3,
Figure 2 ORTEP projection of the molecular structure of com-
pound 9b, showing atomic numbering sheme.
Et3N, DMAP,
CH2Cl2, MeSO2Cl 97%
DEAD, THF
62%
Cl
N
N
N
N
determined the configurations of purine derivatives 9a
and 10.
TBDPSO
OMs TBDPSO
Compound 11a was also prepared by construction of the
base on protected aminoalcohol 13, which was obtained
21
N
N
11a
8
Me
N
Me
N
from mesylate 8 by treatment with NaN and reduction of
3
2-amino-6-chloropurine,
the resulting azide, 12 (Scheme 2). Condensation of 13
with 5-amino-4,6-dichloropyrimidine afforded diamine
14, and cyclization of the latter with triethyl orthoformate
gave 11a in 34% overall yield from 6. Desilylation of 11a
gave a 66% yield of the unprotected carbanucleoside. By
contrast, desilylation of compound 15a, obtained in 97%
yield by refluxing 11a with cyclopropylamine, afforded a
K2CO3, DMF
6
0% NaH,
41%
31%
adenine, DMF
NH2
N
Cl
N
N
N
N
N
N
N
NH2
RO
RO
9
4% yield of 15b.
N
N
Me
N
Me
N
Finally, uracil was constructed on the protected aminoal-
cohol 13 by condensation with 3-methoxy-2-propenoyl
isocyanate and cyclization of the resulting urea, 16, with
9
a (R = TBDPS)
8% 1 M TBAF in THF
b (R = H)
10a (R = TBDPS)
22
8
99%
1 M TBAF in THF
NH OH. Deprotection of the resulting uracil derivative,
9
10b (R = H)
4
1
7a, afforded the desired carbanucleoside 17b, the struc-
Scheme 1
ture of which was unequivocally determined by single-
crystal X-ray crystallography (Figure 3 shows one of the
enantiomers present in the racemic crystal). This struc-
tural information also determined the configurations of
2
0
chloropurine afforded 10a, from which 10b was obtained
by unproblematic desilylation. However, an attempt to
couple 8 to 6-chloropurine produced a complex mixture in
which the desired displacement product 11a was not ob-
tained. In this case, a standard Mitsunobu reaction19 be-
tween 6-chloropurine and 6 afforded 11a with an
estimated overall yield of 62%; 45% as a pure 11a fraction
obtained by repeated chromatography and the remainder
1
1, 15 and 16.
The above-described syntheses of purine and pyrimidine
1
ta[c]pyrazole scaffold are practical and should be extend-
¢(N)-homocarbanucleosides with 1-methylcyclopen-
1
as an unresolved fraction shown by its H NMR spectrum
to be a 2.5:1 mixture of 11a and triphenylphosphine ox-
ide.
Figure 220 shows an ORTEP representation of the asym-
metric unit of adenine derivative 9b. Note that the position
of the hydroxyl group linked to the C19 has some degree
of indeterminacy, as has that of the molecule of water of
crystallization, the H atoms of which could not be refined.
While the disorder of these atoms prevents complete elu-
cidation of intermolecular interactions, the connectivity
and cis-configuration of adenine 9b is nevertheless un-
Figure 3 ORTEP projection of the molecular structure of com-
equivocally established. This structural information also pound 17b, showing atomic numbering scheme.
Synthesis 2006, No. 1, 73–80 © Thieme Stuttgart · New York

PAPER
Synthesis of New 1¢(N)-Homocarbanucleosides
75
TBDPSO
NaN3, DMF
N3
TBDPSO
NH2
(±)-cis-1-Methylcyclopenta[c]pyrazol-4,6-dimethanol (5)
A 0.65 M aqueous solution of NaIO (1.42 mL, 0.92 mmol) was
Ph3P, THF, H2O
4
8
12
13
added dropwise to a vigorously stirred suspension of chromatogra-
phy grade silica gel (1.42 g) in CH Cl (15 mL). After addition of
72%
N
N
2
2
Me
N
Me
N
compound 4 (0.36 g, 2 mmol) in CH Cl (10 mL) to the resulting
2
2
flaky suspension, stirring was continued for another 5 min and the
solution was then passed through a filter pad onto a small quantity
of Na SO ; the retained silica gel was washed with CH Cl (50 mL)
and the washings were pooled with the filtrate. Removal of the sol-
vent left the dialdehyde as an oily reddish residue, which was dis-
5
-amino-4,6-dichloropyrimidine,
3
-ethoxypropenoyl
Et3N, n-BuOH
57%
isocyanate, C6H6
2
4
2
2
67%
Cl
N
O
H2N
N
HN
solved in MeOH (25 mL). NaBH (0.45 g, 10 mmol) was added in
4
HN
O
a single portion, stirring was continued for 30 min, the reaction was
cooled in an ice bath and water (10 mL) was added. MeOH was re-
moved under reduced pressure, and the residue left was dissolved in
NH OEt
TBDPSO
TBDPSO
16
1
4
NH Cl (25 mL). This solution was extracted with EtOAc (3 × 50
4
N
N
mL), and removal of the solvent from the pooled extracts under re-
duced pressure afforded a white solid (0.9 g) that was further puri-
fied by chromatography on silica gel using CH Cl –MeOH (5:1) as
Me
N
Me
N
2
2
HC(OEt)3, 12 N HCl 74%
N
14 M NH4OH, reflux 99%
eluent.
Cl
N
O
Compound 5
N
Yield: 0.15 g (88%); white solid. An analytical sample was obtained
N
HN
RO
by repeatedly washing a small quantity of 5 with Et O and EtOAc;
mp 111–112 °C.
2
O
N
RO
IR (KBr): 3332, 3149, 2937, 2910, 2863, 1522, 1473, 1438, 1378,
N
–1
1
336, 1313, 1067, 1029, 1002, 793, 750 cm .
Me
N
1
N
H NMR (DMSO-d ): d = 7.03 (s, 1 H, 3-H), 4.93 (t, J = 5.1 Hz, 1
6
1
1a (R = TBDPS)
M TBAF in THF
1b (R = H)
Me
N
H, D O exchange, OH), 4.64 (t, J = 5.1 Hz, 1 H, D O exchange,
2
2
6
6%
1
17a (R = TBDPS)
OH), 3.72 (s, 3 H, NCH ), 3.55–3.50 (m, 1 H, OCHH), 3.49–3.44
3
1
9
9% 1 M TBAF in THF
(m, 1 H, OCHH), 3.41–3.37 (m, 1 H, OCHH), 3.31–3.28 (m, 1 H,
cyclopropylamine, HN
97%
OCHH), 3.14–3.05 (m, 1 H), 2.94–2.85 (m, 1 H), 2.64 (dt, J = 13.5,
8.7 Hz, 1 H, 5-HH), 1.89 (dt, J = 13.5, 4.2 Hz, 1 H, 5-HH).
EtOH
17b (R = H)
N
N
N
13
N
C NMR [DEPT (DMSO-d )]: d = 150.83 (C), 132.45 (CH),
6
RO
15a (R = TBDPS)
128.23 (C), 66.68 (CH ), 64.96 (CH ), 39.68 (CH), 38.87 (CH),
2
2
94% 1 M TBAF in THF
38.00 (CH ), 37.65 (CH ).
2
3
15b (R = H)
EI–MS: m/z (%) = 182 (13) [M], 152 (11), 151 (100), 137 (9), 133
(19), 123 (20), 121 (11), 119 (7), 95 (13), 92 (9), 66 (8), 65 (7), 52
N
Me
N
(
6).
Scheme 2
Anal. Calcd for C H N O (182.22): C, 59.32; H, 7.74; N, 15.37.
9
14
2
2
Found: C, 59.54; H, 7.90; N, 15.24.
able to the preparation of a variety of other nucleoside
analogues. The stereochemistry of the new compounds
and intermediates was confirmed by X-ray crystallo- lyloxymethyl)-1-methylcyclopenta[c]pyrazol-6-methanol (7)
(
±)-cis-6-(tert-Butyldiphenylsilyloxymethyl)-1-methylcyclopen-
ta[c]pyrazol-4-methanol (6) and (±)-cis-4-(tert-Butyldiphenylsi-
graphic determination of the structure of two of the end NaH (60%, 0.40 g, 9.78 mmol) was added in one portion under Ar
to a solution of 5 (1.62 g, 8.89 mmol) in THF (350 mL) at 0 °C. The
resulting suspension was stirred at 0 °C for 10 min, after which a
mixture of TBDPSCl (2.53, 9.78 mmol) and THF (150 mL) was
added dropwise over 1.5 h. After stirring at r.t. for 6 h, this reaction
products.
All chemicals used were of reagent grade and were obtained from
Aldrich Chemical Co and used without further purification. Melting
points were measured with a Reichert Kofler Thermopan and are
uncorrected. IR spectra were recorded on a Perkin-Elmer 1640
FTIR spectrophotometer. H and C NMR spectra were recorded
on a Bruker AMX 300 spectrometer at 300 MHz and 75.47 MHz,
respectively, using TMS as internal standard (chemical shifts in d
values, J in Hz). Mass spectra were recorded on a Kratos MS-59
spectrometer. Microanalyses were performed on a Perkin-Elmer
mixture was partitioned between sat. NaHCO solution (150 mL)
3
and EtOAc (150 mL). The aqueous phase was extracted with EtOAc
(2 × 150 mL), and the organic phases were dried over Na SO . Re-
2
4
1
13
moval of the solvent under reduced pressure left an oily residue
(4.35 g) that was fractionated by column chromatography on silica
gel with hexane–EtOAc (2:1), hexane–EtOAc (1:2) and CH Cl –
2
2
MeOH (5:1) as successive eluents. The monosilylated compounds
6 and 7 were obtained from hexane–EtOAc fractions (2:1 and 1:2),
and unreacted diol 5 (0.17 g, 10%) from CH Cl –MeOH (5:1).
2
40B Elemental Analyser at the University of Santiago Microanal-
2
2
ysis Service; all results shown are within ± 0.4% of the theoretical
values. All air-sensitive reactions were carried out under Ar. Flash
chromatography was performed on silica gel (Merck 60, 230–240
mesh) and analytical TLC on pre-coated silica gel plates (Merck 60
F254, 0.25 mm). X-ray diffraction data were collected on an Enraf-
Nonius CAD4 automatic diffractometer using the program CAD4-
EXPRESS.
Compound 6
Yield: 2.18 g (58%); transparent oil.
IR (film): 3335, 3071, 2931, 2858, 1522, 1472, 1438, 1428, 1388,
–1
1
112, 1073, 999, 823, 741 cm .
1H NMR (CDCl
): d = 7.64–7.61 (m, 4 H), 7.46–7.36 (m, 6 H), 7.19
s, 1 H, 3-H), 3.79 (dd, J = 9.9, 6.8 Hz, 1 H), 3.73–3.69 (m, 1 H),
3
(
Synthesis 2006, No. 1, 73–80 © Thieme Stuttgart · New York

7
6
M. D. García et al.
PAPER
3
1
.71 (s, 3 H, NCH ), 3.59 (dd, J = 10.5, 6.6 Hz, 1 H), 3.53 (dd, J =
0.2, 6.5 Hz, 1 H), 3.28–3.21 (m, 1 H), 3.15–3.09 (m, 1 H), 2.80 (dt,
this mixture was heated at 80 °C for 48 h. The solvent was then re-
moved under reduced pressure and the crude residue was taken up
3
J = 13.9, 8.9 Hz, 1 H, 5-HH), 2.04 (dt, J = 13.9, 4.4 Hz, 1 H, 5-HH),
in NH Cl (50 mL). The resulting solution was extracted with
4
1
.74 (br s, 1 H, D O exchange, OH), 1.06 (s, 9 H, 3 × CH ).
CH Cl (3 × 100 mL), the pooled extract was dried over Na SO ,
2
3
2
2
2
4
1
3
and concentration under reduced pressure then afforded a yellow oil
C NMR [DEPT (CDCl )]: d = 150.55 (C), 135.59 (CH), 135.53
3
(0.30 g) that was chromatographed on a column of silica gel using
(
(
(
(
CH), 133.29 (C), 133.15 (C), 132.80 (CH), 129.86 (CH), 129.83
CH), 127.80 (CH), 127.77 (CH), 127.61 (C), 66.98 (CH ), 66.96
CH ), 39.66 (CH), 38.58 (CH), 37.92 (CH ), 37.57 (CH), 26.91
3 × CH ), 19.20 (C).
CH Cl –MeOH (40:1) as eluent.
2
2
2
2
2
Compound 9a
Yield: 0.14 g (41%); white solid; mp 218–220 °C.
3
FAB–MS: m/z (%) = 421.2 (100) [M + 1].
HRMS: m/z calcd for C H N O Si: 420.2233; found: 420.2251.
IR (KBr): 3251, 3141, 2960, 2934, 2897, 1676, 1604, 1572, 1470,
–1
2
5
32
2
2
1441, 1427, 1412, 1326, 1306, 1240, 1034, 747, 707, 696, 690 cm .
1
H NMR (CDCl ): d = 8.34 (s, 1 H, 2purine-H), 7.60–7.56 (m, 4 H),
3
Compound 7
7
.53 (s, 1 H, 8purine-H), 7.47–7.37 (m, 6 H), 6.79 (s, 1 H, 3-H), 5.69
Yield: 0.93 g (25%); transparent oil.
(
br s, 2 H, D O exchange, NH ), 4.27 (dd, J = 13.5, 6.4 Hz, 1 H,
2
2
IR (film): 3420, 3159, 3069, 2928, 2891, 2855, 1472, 1427, 1378,
NCHH), 4.06 (dd, J = 13.5, 8.5 Hz, 1 H, NCHH), 3.76–3.68 (m, 2
H), 3.67 (s, 3 H, NCH ), 3.61–3.59 (m, 1 H), 3.25–3.22 (m, 1 H),
2.90–2.86 (m, 1 H, 5-HH), 2.08 (dt, J = 13.9, 4.2 Hz, 1 H, 5-HH),
1
–
1
1
089, 1054, 1029, 999, 821, 805, 741 cm .
3
1
H NMR (CDCl ): d = 7.67–7.61 (m, 4 H), 7.42–7.33 (m, 6 H), 7.18
3
(
s, 1 H, 3-H), 3.81 (s, 3 H, NCH ), 3.73–3.66 (m, 2 H), 3.63–3.57
.06 (s, 9 H, 3 × CH3).
3
(
m, 2 H), 3.23–3.17 (m, 2 H), 2.80 (dt, J = 13.8, 8.9 Hz, 1 H, 5-HH),
13
C NMR [DEPT (CDCl )]: d = 155.80 (C), 153.36 (CH), 150.40
3
1
.98 (dt, J = 13.8, 4.3 Hz, 1 H, 5-HH), 1.79 (br s, 1 H, D O ex-
2
(C), 141.22 (CH), 135.96 (CH), 135.92 (CH), 130.41 (CH), 130.36
(C), 128.31 (CH), 127.75 (C), 120.08 (C), 66.82 (CH ), 50.07
(CH ), 39.88 (CH), 39.31 (CH ), 37.87 (CH), 36.55 (CH), 27.36
(
change, OH), 1.07 (s, 9 H, 3 × CH ).
3
2
1
3
C NMR [DEPT (CDCl )]: d = 149.94 (C), 135.58 (CH), 135.52
2
2
3
3 × CH ), 19.66 (C).
(
(
(
(
CH), 133.65 (C), 133.09 (C), 133.20 (CH), 129.56 (CH), 129.52
CH), 127.57 (C), 127.55 (CH), 68.42 (CH ), 65.79 (CH ), 39.59
CH), 38.62 (CH), 37.67 (CH ), 37.65 (CH), 26.99 (3 × CH ), 19.38
C).
3
2
2
EM–BAR: m/z (%) = 538.15 (58) [M].
2
3
Anal. Calcd for C H N OSi (537.73): C, 67.01; H, 6.56; N, 18.23.
Found: C, 67.32; H, 6.76; N, 18.52.
3
0
35
7
HRMS: m/z calcd for C H N O Si: 420.2233; found: 420.2256.
2
5
32
2
2
(
±)-cis-4-[(2-Amino-6-chloro-9H-purin-9-yl)methyl]-6-(tert-
butyldiphenylsilyloxymethyl)-1-methylcyclopenta[c]pyrazole
10a)
A mixture of crude 8 (0.4 g, 0.8 mmol), K CO (0.16 g, 1.2 mmol)
(
±)-cis-{6-(tert-Butyldiphenylsilyloxymethyl)-1-methylcyclo-
penta[c]pyrazol-4-yl}methyl Methanesulfonate (8)
Mesyl chloride (182 mL, 2.38 mmol) was added under Ar, with stir-
ring, to a solution of 6 (0.66 g, 1.57 mmol), Et N (0.33 mL) and a
(
2
3
3
and 2-amino-6-chloropurine (0.2 g, 1.2 mmol) in anhyd DMF (25
mL) was heated for 24 h at 80 °C, after which the solvent was re-
moved under reduced pressure and the resulting residue was dis-
solved in CH Cl (100 mL). This solution was washed with water
catalytic amount of DMAP in anhyd CH Cl (10 mL) at 0 °C. This
2
2
solution was stirred at r.t. for 1 h and washed successively with sat.
NaHCO solution (2 × 30 mL), H O (2 × 30 mL) and brine (30 mL).
The organic phase was dried over Na SO , and concentration under
3
2
2
2
2
4
(50 mL), dried over Na SO and concentrated to dryness. When the
2 4
reduced pressure then afforded 8.
resulting solid residue (0.65 g) was chromatographed on silica gel
with hexane–EtOAc (1:2) and hexane–EtOAc (1:3) as successive
eluents, the initial fractions afforded unreacted 8 (0.22 g, 55%) and
the product-bearing fractions 10a.
Compound 8
Yield: 0.76 g (97%); transparent viscous oil.
IR (film): 3071, 2933, 2858, 1472, 1438, 1428, 1356, 1175, 1113,
–
1
Compound 10a
Yield: 0.14 g (31%); white solid; mp 79–81 °C.
9
52, 824, 743, 704 cm .
1
H NMR (CDCl ): d = 7.60–7.57 (m, 4 H), 7.46–7.35 (m, 6 H), 7.20
3
IR (KBr): 3324, 3197, 2930, 2857, 1616, 1560, 1541, 1521, 1508,
(
s, 1 H, 3-H), 4.14–4.12 (m, 2 H), 3.79 (dd, J = 10.3, 6.6 Hz, 1 H),
–
1
1
458, 1406, 1112, 703 cm .
3
.73 (dd, J = 10.3, 5.1 Hz, 1 H), 3.68 (s, 3 H, NCH ), 3.35 (ddd,
3
J = 11.5, 7.2, 4.3 Hz, 1 H), 3.29–3.23 (m, 1 H), 2.97–2.83 (m, 1 H,
1
H NMR (CDCl ): d = 7.61–7.56 (m, 4 H), 7.53 (s, 1 H, 8purine-H),
3
5
1
-HH), 2.90 (s, 3 H, OCH ), 2.08 (dt, J = 13.9, 4.5 Hz, 1 H 5-HH),
.06 (s, 9 H, 3 × CH3).
3
7.45–7.36 (m, 6 H), 6.87 (s, 1 H, 3-H), 4.97 (br s, 2 H, D O ex-
2
change, NH ), 4.13–4.10 (m, 1 H, NCHH), 4.02 (dd, J = 21.6, 13.7
2
1
3
Hz, 1 H, NCHH), 3.83 (dd, J = 10.3, 6.1 Hz, 1 H, OCHH), 3.69 (dd,
J = 10.3, 5.6 Hz, 1 H, OCHH), 3.68 (s, 3 H, NCH ), 3.67–3.49 (m,
C NMR [DEPT (CDCl )]: d = 149.97 (C), 135.43 (CH), 135.39
3
(
(
(
(
CH), 132.99 (C), 132.83 (CH), 129.86 (CH), 129.82 (CH), 127.79
CH), 127.76 (CH), 126.16 (C), 73.32 (CH ), 66.39 (CH ), 39.52
CH), 37.98 (CH ), 37.58 (CH), 37.36 (CH), 35.56 (CH), 26.99
3 × CH ), 19.31 (C).
3
1
2
H), 3.25–3.19 (m, 1 H), 2.84 (dt, J = 13.9, 8.9 Hz, 1 H, 5-HH),
.08–2.02 (m, 1 H, 5-HH), 1.04 (s, 9 H, 3 × CH3).
2
2
2
13
3
C NMR [DEPT (CDCl )]: d = 158.94 (C), 153.82 (C), 151.34 (C),
3
1
1
1
3
1
49.95 (C), 142.49 (CH), 135.52 (CH), 135.48 (CH), 133.06 (C),
32.99 (C), 132.66 (CH), 130.03 (CH), 129.99 (CH), 127.92 (CH),
27.89 (CH), 127.09 (C), 125.28 (C), 66.36 (CH ), 49.47 (CH ),
FAB–MS: m/z (%) = 499.2 (100) [M + 1].
HRMS: m/z calcd for C H N O SSi: 498.2009; found: 498.2034.
2
6
34
2
4
2
2
9.43 (CH), 38.89 (CH ), 37.45 (CH), 35.99 (CH), 26.94 (3 × CH ),
2
3
(
±)-cis-4-[(6-Amino-9H-purin-9-yl)methyl]-6-(tert-butyldiphe-
9.25 (C).
nylsilyloxymethyl)-1-methylcyclopenta[c]pyrazole (9a)
FAB–MS: m/z (%) = 572.2 (100) [M + 1].
A suspension of adenine (0.11 g, 0.82 mmol) and 60% NaH (26 mg,
0
.82 mmol) in anhyd DMF (15 mL) was heated at 80 °C under Ar,
with stirring for 45 min. After cooling to r.t., a solution of 8 (0.32 g,
.64 mmol) in anhyd DMF (10 mL) was added via a cannula and
Anal. Calcd for C H ClN OSi (572.17): C, 67.97; H, 5.99; N,
3
0
34
7
1
7.14. Found: C, 68.22; H, 6.07; N, 17.31.
0
Synthesis 2006, No. 1, 73–80 © Thieme Stuttgart · New York

PAPER
Synthesis of New 1¢(N)-Homocarbanucleosides
77
(
±)-cis-{6-(tert-Butyldiphenylsilyloxymethyl)-1-methylcyclo-
umn chromatography on silica gel with hexane–EtOAc (1:1) as
eluent.
penta[c]pyrazol-4-yl}methyl Azide (12)
NaN (0.5 g, 7.85 mmol) was added in one portion to a solution of
3
8
(0.78 g, 1.56 mmol) in anhyd DMF (50 mL) stirred under Ar at r.t.
Compound 14
This mixture was heated for 20 h at 90 °C, the DMF was removed
under reduced pressure, and the residue was partitioned between
Yield: 0.4 g (67%); white solid that was recrystallized twice from
hexane–EtOAc (4:1); mp 120–122 °C.
water (150 mL) and Et O (100 mL). The aqueous phase was extract-
2
IR (KBr): 3343, 3242, 3070, 3048, 2930, 2857, 1581, 1470, 1427,
ed with Et O (2 × 100 mL), and the pooled organic phases were
–1
2
1
361, 1336, 1112, 823, 741, 703 cm .
washed with sat. NaCl solution (50 mL). Removal of the solvent af-
1
H NMR (CDCl ): d = 8.02 (s, 1 H, 2pyrimidine-H), 7.61–7.58 (m, 4 H),
forded azide 12.
3
7
.43–7.34 (m, 6 H), 7.17 (s, 1 H, 3-H), 5.07 (t, J = 5.4 Hz, D O ex-
2
change, 1 H, NH), 3.79 (dd, J = 10.1, 6.8 Hz, 1 H, NHCHH), 3.73–
Compound 12
Yield: 0.68 g (98%); faintly yellowish oil.
3
.61 (m, 1 H), 3.72 (s, 3 H, NCH ), 3.40–3.24 (m, 4 H, 2 × D O ex-
3
2
change, NH ), 2.85 (dt, J = 13.9, 8.6 Hz, 1 H, 5-HH), 1.99 (dt, J =
2
IR (film): 3071, 2932, 2858, 2097, 1472, 1438, 1428, 1264, 1113,
1
3.9, 4.7 Hz, 1 H, 5-HH), 1.05 (s, 9 H, 3 × CH3).
–
1
9
98, 823, 702, 689 cm .
1
3
C NMR [DEPT (CDCl )]: d = 155.73 (C), 150.87 (C), 150.18
1
3
H NMR (CDCl ): d = 7.65–7.58 (m, 4 H), 7.47–7.36 (m, 6 H), 7.22
s, 1 H, 3-H), 3.90–3.84 (m, 1 H), 3.80 (dd, J = 10.2, 6.2 Hz, 1 H,
3
(
(
(
(
CH), 143.84 (C), 135.94 (CH), 135.91 (CH), 133.61 (C), 133.06
C), 130.33 (CH), 130.30 (CH), 128.58 (C), 128.25 (CH), 128.23
CH), 121.97 (C), 67.31 (CH ), 47.0 (CH ), 40.11 (CH), 39.32
(
N CHH), 3.72 (dd, J = 10.2, 5.9 Hz, 1 H, N CHH), 3.69 (s, 3 H,
3
3
2
2
NCH ), 3.32–3.23 (m, 2 H), 3.21–3.11 (m, 1 H), 2.91–2.84 (m, 1 H,
3
CH ), 38.04 (CH), 35.96 (CH), 27.32 (3 × CH ), 19.63 (C).
2
3
5
-HH), 2.02 (t, J = 4.6 Hz, 1 H, 5-HH), 1.06 (s, 9 H, 3 × CH3).
FAB–MS: m/z (%) = 547.2 [M] (100).
Anal. Calcd for C H ClN OSi (547.17): C, 63.66; H, 6.45; N,
1
3
C NMR [DEPT (CDCl )]: d = 150.22 (C), 135.99 (CH), 135.93
3
(
(
(
CH), 133.44 (C), 133.30 (C), 130.33 (CH), 130.29 (CH), 128.26
CH), 128.23 (CH), 66.91 (CH ), 57.33 (CH ), 40.03 (CH), 39.50
CH ), 37.91 (CH), 36.34 (CH), 27.23 (3 × CH ), 19.62 (C).
29 35
6
1
5.36. Found: C, 63.89; H, 6.66; N, 15.56.
2
2
2
3
(
±)-cis-6-(tert-Butyldiphenylsilyloxymethyl)-4-[(6-chloro-9H-
FAB–MS: m/z (%) = 446.2 (100) [M + 1].
HRMS: m/z calcd for C H N OSi: 445.2298; found: 445.2309.
purin-9-yl)methyl]-1-methylcyclopenta[c]pyrazole (11a)
Method A: DEAD (0.87 mL, 1.9 mmol) was added dropwise under
Ar to a solution of 6 (0.44 g, 0.95 mmol), triphenylphosphine (0.50
g, 1.91 mmol) and 6-chloropurine (0.29 g, 1.91 mmol) in anhyd
THF (30 mL), and the mixture was stirred for 24 h at r.t. Removal
of the solvents under reduced pressure left a yellow oil (1.72 g) that
when chromatographed on silica gel with mixtures of hexane and
EtOAc (1:2, 1:3 and 1:4) as successive eluents afforded a mixture
of 11a and triphenylphosphine oxide. Chromatography of this mix-
ture was performed on silica gel with mixtures of CH Cl and
2
5
31
5
(
±)-cis-6-(tert-Butyldiphenylsilyloxymethyl)-1-methylcyclopen-
ta[c]pyrazol-4-methanamine (13)
Triphenylphosphine (0.84 g, 3.2 mmol) was added to a solution of
1
2 (0.68 g, 1.53 mmol) in THF–H O (25:1, 24 mL), and the mixture
2
was refluxed for 6 h. The THF was removed under reduced pres-
sure, and the oily residue was dissolved in CH Cl (25 mL). This so-
lution was dried over Na SO and condensed to dryness, leaving a
2
2
2
4
2
2
yellowish oil (1.56 g) that was chromatographed on silica gel using
mixtures of CH Cl and MeOH (20:1 and 1:1) as successive eluents.
MeOH (150:1 and 40:1) as successive eluents.
2
2
Removal of solvent from the first CH Cl –MeOH (1:1) fractions
Compound 11a
2
2
yielded amine 13.
Yield: 0.26 g (45%); white solid; mp 104–106 °C after washing
with pentane.
Compound 13
Yield: 0.46 g (72%); thick whitish oil.
IR (KBr): 3070, 2930, 2856, 1590, 1559, 1427, 1401, 1332, 1112,
–1
9
38, 703 cm .
IR (film): 3278, 3128, 3070, 2930, 2879, 2858, 1654, 1608, 1559,
1
H NMR (CDCl ): d = 8.71 (s, 1 H, 2purine-H), 7.83 (s, 1 H, 8purine-H),
–
1
3
1
428, 1112, 703, 675 cm .
7
.59–7.55 (m, 4 H), 7.46–7.36 (m, 6 H), 6.78 (s, 1 H, 3-H), 4.35 (dd,
J = 13.6, 6.7 Hz, 1 H, NCHH), 4.18 (dd, J = 13.6, 8.3 Hz, 1 H,
NCHH), 3.80 (dd, J = 10.3, 5.8 Hz, 1 H, OCHH), 3.71 (dd, J = 10.3,
1
H NMR (CDCl ): d = 7.63–7.60 (m, 4 H), 7.44–7.35 (m, 6 H), 7.21
3
(
s, 1 H, 3-H), 3.78 (dd, J = 10.1, 6.7 Hz, 1 H, H NCHH), 3.71 (s, 3
2
H, NCH ), 3.69 (dd, J = 10.1, 5.9 Hz, 1 H, H NCHH), 3.25–3.16 (m,
5.5 Hz, 1 H, OCHH), 3.65 (s, 3 H, NCH ), 3.61–3.58 (m, 1 H), 3.27–
3
2
3
3
H, 2 × D O exchange, NH ), 3.05–2.96 (m, 1 H), 2.87–2.65 (m, 3
3.23 (m, 1 H), 2.90 (dt, J = 13.9, 8.7 Hz, 1 H, 5-HH), 2.12 (dt, J =
2
2
H), 1.97–1.89 (m, 1 H, 5-HH), 1.05 (s, 9 H, 3 × CH3).
13.9, 4.3 Hz, 1 H, 5-HH), 1.07 (s, 9 H, 3 × CH ).
3
1
3
13
C NMR [DEPT (CDCl )]: d = 150.52 (C), 135.98 (CH), 135.93
C NMR [DEPT (CDCl )]: d = 152.33 (CH), 151.54 (C), 150.31
3
3
(
(
(
(
CH), 133.65 (C), 133.52 (C), 133.05 (C), 130.28 (CH), 130.24
(C), 145.73 (CH), 135.93 (CH), 135.90 (CH), 133.4 (C), 132.93 (C),
132.0 (C), 130.47 (CH), 130.44 CH), 128.32 (CH), 127.29 (C),
66.62 (CH ), 50.48 (CH ), 39.81 (CH), 39.37 (CH ), 37.83 (CH),
CH), 129.06 (C), 128.22 (CH), 128.19 (CH), 67.37 (CH ), 48.08
2
CH ), 40.14 (CH ), 39.51 (CH), 39.18 (CH), 37.99 (CH), 27.31
2
2
2
2
2
3 × CH ), 19.60 (C).
36.53 (CH), 27.37 (3 × CH ), 19.70 (C).
3
3
FAB–MS: m/z (%) = 420.2 (100) [M + 1].
FAB–MS: m/z (%) = 557.3 (82) [M + 1].
HRMS: m/z calcd for C H N OSi: 419.2393; found: 419.2419.
Anal. Calcd for C H ClN OSi (557.16): C, 64.67; H, 5.97; N,
30 33 6
2
5
33
3
1
5.08. Found: C, 64.92; H, 6.12; N, 15.34.
Method B: A mixture of 14 (0.4 g, 0.73 mmol), triethyl orthoformate
4.1 mL, 39.20 mmol) and 12 N HCl (0.25 mL) was stirred at r.t. for
4 h and then concentrated under vacuum to obtain a residue that
(
±)-cis-N-[(5-Amino-6-chloropyrimidin-4-yl)-6-(tert-butyl-
diphenylsilyloxymethyl)]-1-methylcyclopenta[c]pyrazol-4-
(
2
methanamine (14)
A solution of 13 (0.46 g, 1.1 mmol) and 5-amino-4,6-dichloropyri-
midine (0.27 g, 1.95 mmol) in anhyd n-BuOH (20 mL) and anhyd
was treated with 0.5 N HCl (15 mL) and THF (5 mL) for 2 h at r.t.
The resulting solution was brought to pH 7 with 1 N NaOH, and
evaporation of the solvents under reduced pressure left a solid resi-
due (1.28 g) that upon purification by column chromatography on
Et N (1 mL) was refluxed under Ar for 24 h. Evaporation of the sol-
3
vents under vacuum left a residue (1.0 g) that was purified by col-
Synthesis 2006, No. 1, 73–80 © Thieme Stuttgart · New York

7
8
M. D. García et al.
PAPER
silica gel using hexane–EtOAc (1:3) as eluent afforded 11a as a
white solid (0.30 g, 74%).
H), 3.42–3.32 (m, 1 H), 3.28–3.16 (m, 3 H), 2.83 (dt, J = 13.7, 8.4
Hz, 1 H, 5-HH), 1.92 (dt, J = 13.7, 4.6 Hz, 1 H, 5-HH), 1.34 (t, J =
7
13
.1 Hz, 3 H, CH CH ), 1.05 (s, 9 H, 3 × CH ).
2
3
3
(
±)-cis-9-{[6-(tert-Butyldiphenylsilyloxymethyl)-1-methylcyclo-
C NMR [DEPT (CDCl )]: d = 167.96 (C), 163.47 (CH), 154.85
3
penta[c]pyrazol-4-yl]methyl}-6N-cyclopropyl-9H-purin-6-
amine (15a)
(C), 150.43 (C), 135.97 (CH), 135.92 (CH), 133.65 (C), 133.50 (C),
1
9
3
1
33.20 (CH), 130.27 (CH), 128.83 (C), 128.23 (CH), 128.20 (CH),
8.19 (CH), 68.13 (CH ), 67.33 (CH ), 46.04 (CH ), 40.19 (CH),
Cyclopropylamine (0.12 g, 0.2 mL, 2.88 mmol) was added to a
stirred solution of chloropurine 11a (0.12 g, 0.22 mmol) in EtOH (3
mL). The mixture was refluxed for 6 h, and after cooling to r.t., the
solvent was evaporated under reduced pressure. Chromatography of
the solid residue (0.14 g) was performed on silica gel using hexane–
2
2
2
9.59 (CH ), 38.01 (CH), 36.33 (CH), 27.31 (3 × CH ), 19.61 (C),
2
3
4.93 (CH).
FAB–MS: m/z (%) = 561.4 (100) [M + 1].
HRMS: m/z calcd for C H N O Si: 560.2819; found: 560.2832.
EtOAc (1:5) and CH Cl –MeOH (10:1) as successive eluents.
2
2
3
1
40
4
4
Compound 15a
Yield: 0.12 g (97%); a white, waxy solid.
(
±)-cis-1-{[6-(tert-Butyldiphenylsilyloxymethyl)-1-methylcyclo-
penta[c]pyrazol-4-yl]methyl}-1,2,3,4-tetrahydropyrimidine-
,4-dione (17a)
A solution of 16 (0.20 g, 0.36 mmol) in a mixture of 14 M NH OH
2
IR (KBr): 3261, 2930, 2856, 1617, 1475, 1427, 1354, 1297, 1112,
–
1
7
03 cm .
4
(20 mL) and dioxane (5 mL) was refluxed for 48 h, after which re-
1
H NMR (CDCl ): d = 8.47 (s, 1 H, 2purine-H), 7.59–7.57 (m, 4 H),
3
moval of the solvents left a brown solid (0.20 g) that was partitioned
between NH Cl (50 mL) and CH Cl (100 mL). The aqueous phase
was extracted with CH Cl (2 × 100 mL), and the organic phases
were dried over Na SO . Removal of the solvent left a residue that
when chromatographed on silica gel with hexane–EtOAc (1:4) as
eluent yielded the pure product.
7
.48 (s, 1 H, 8purine-H), 7.45–7.36 (m, 6 H), 6.77 (s, 1 H, 3-H), 5.93
4
2
2
(
br, 1 H, D O exchange, NH), 4.26 (dd, J = 13.5, 6.3 Hz, 1 H,
2
2
2
NCHH), 4.04 (dd, J = 13.5, 8.5 Hz, 1 H, NCHH), 3.74–3.70 (m, 2
H), 3.65 (s, 3 H, NCH ), 3.61–3.53 (m, 1 H), 3.28–3.17 (m, 1 H),
2
4
3
3
.06–3.03 (m, 1 H), 2.88 (dt, J = 13.9, 8.7 Hz, 1 H, 5-HH), 2.07 (dt,
J = 13.9, 4.2 Hz, 1 H, 5-HH), 1.06 (s, 9 H, 3 × CH ), 0.99–0.88 (m,
3
2
H, cyclopropyl), 0.69–0.64 (m, 2 H, cyclopropyl).
Compound 17a
1
3
C NMR [DEPT (CDCl )]: d = 156.18 (C), 153.59 (CH), 150.41
Yield: 0.18 g (99%); white solid. An analytical sample was obtained
by washing a small quantity of this solid with pentane; mp 78–80
°C.
3
(
(
(
(
(
C), 140.58 (CH), 135.96 (CH), 135.91 (CH), 133.52 (C), 133.42
C), 133.17 (CH), 130.40 (CH), 130.34 (CH), 128.30 (CH), 128.28
CH), 127.81 (C), 120.33 (C), 66.85 (CH ), 50.03 (CH ), 39.89
CH), 39.30 (CH ), 37.88 (CH), 36.57 (CH), 27.36 (3 × CH ), 24.10
CH), 19.66 (C), 7.79 (CH ), 7.76 (CH ).
2
2
IR (KBr): 3447, 3049, 2930, 2856, 1684, 1458, 1427, 1388, 1112,
7
2
3
–1
04 cm .
2
2
1
H NMR [DEPT (CDCl )]: d = 9.14 (s, 1 H, D O exchange,
3
2
EM: m/z (%) = 578 (3), 577 (6) [M], 520 (5), 519 (12), 404 (7), 403
20), 347 (9), 346 (32), 345 (100), 199 (8), 197 (4), 183 (6).
2pyrimidine-H), 7.59–7.54 (m, 4 H), 7.47–7.35 (m, 6 H), 7.0 (s, 1 H, 3-
H), 6.79 (d, J = 7.9 Hz, 1 H, 6pyrimidine-H), 5.56 (dd, J = 7.9, 2.04 Hz,
1 H, 5pyrimidine-H), 3.99 (dd, J = 12.9, 5.5 Hz, 1 H, NCHH), 3.85–3.75
(
HRMS: m/z calcd for C H N OSi: 577.2985; found: 577.3006.
3
3
39
7
(m, 1 H), 3.80 (dd, J = 5.8, 3.5 Hz, 1 H, OCHH), 3.69 (s, 3 H, CH3),
(
±)-cis-1-{[6-(tert-Butyldiphenylsilyloxymethyl)-1-methylcyclo-
3.45–3.37 (m, 1 H, OCHH), 3.30–3.21 (m, 2 H), 2.90 (dt, J = 13.9,
8.7 Hz, 1 H, 5-HH), 1.99 (dt, J = 13.9, 4.2 Hz, 1 H, 5-HH), 1.07 (s,
penta[c]pyrazol-4-yl]methyl}-3-(3-ethoxypropenoyl)urea (16)
Silver cyanate (12.0 g, 80 mmol), previously dried at 100 °C under
vacuum over P O , was added to anhyd benzene (80 mL) in the dark
9 H, 3 × CH ).
3
2
5
13
C NMR [DEPT (CDCl )]: d = 163.96 (C) 151.18 (C), 150.38 (C),
3
under Ar, and the suspension was refluxed with vigorous stirring for
.5 h. A solution of 3-ethoxypropenoyl chloride (4.82 g, 40 mmol)
1
45.78 (CH), 135.93 (CH), 135.89 (CH), 133.43 (CH), 130.44
0
(
(
(
CH), 130.39 (CH), 128.32 (CH), 128.30 (CH), 127.94 (C), 101,67
in anhyd benzene (15 mL) was then added dropwise, and the result-
ing suspension was refluxed for a further 0.5 h with vigorous stir-
ring and then allowed to settle at r.t. for 3 h. A sample of the
supernatant (8.53 mL, theoretically containing 5.97 mmol of 3-
ethoxypropenoyl isocyanate) was transferred to a dry dropping fun-
nel and added dropwise to a solution of 13 (0.50 g, 1.19 mmol) in
anhyd DMF (10 mL) at –25 °C. The mixture was allowed to warm
to r.t. over 1 h, stirred overnight at r.t., and concentrated under re-
duced pressure (oil pump) at a temperature below 40 °C by driving
off the solvent by repeated co-evaporation with toluene (3 × 10 mL)
and EtOH (3 × 10 mL). The residue (1.3 g) was chromatographed
on silica gel with hexane–EtOAc (1:1 and 1:2) as successive elu-
ents, and the product-bearing fractions were pooled to obtain 16.
CH), 66.75 (CH ), 55.38 (CH ), 39.77 (CH), 39.10 (CH ), 37.84
2
2
2
CH), 35.25 (CH), 27.37 (3 × CH ), 19.91 (C).
3
FAB–MS: m/z (%) = 515.27 (16) [M + 1].
Anal. Calcd for C H N O Si (514.69): C, 67.67; H, 6.66; N, 10.89.
2
9
34
4
3
Found: C, 67.89; H, 6.78; N, 11.09.
Cleavage of the tert-Butyldiphenylsilyl Group from Compounds
9
a–11a, 15a, and 17a; General Procedure
A 1 M solution of TBAF in THF (1.1 mmol) was added under Ar to
a stirred solution of the compound to be deprotected (1 mmol) in an-
hyd THF (10 mL) in an ice bath. This mixture was allowed to reach
r.t., and stirring was continued for 1 h, after which the solvent was
removed under reduced pressure and the residue so obtained was
chromatographed on silica gel with an appropriate eluent. Finally,
product-bearing fractions were concentrated to dryness.
Compound 16
Yield: 0.38 g (57%); greenish solid, a sample of which was washed
with pentane resulting in a white solid of low mp.
(
±)-cis-4-[(6-Amino-9H-purin-9-yl)methyl]-1-methylcyclopen-
ta[c]pyrazol-6-methanol (9b)
Eluent: CH Cl –MeOH (20:1). Yield: 86%; white solid; mp 262.5–
IR (KBr): 2931, 1705, 1677, 1616, 1551, 1243, 1167, 1112, 703
cm .
–
1
1
2
2
H NMR (CDCl ): d = 8.76 (br s, 1 H, D O exchange, CONHCO),
3
2
2
64 °C.
8
7
7
3
.23 (br s, 1 H, D O exchange, CONHCH ), 7.65–60 (m, 5 H),
2
2
IR (KBr): 3143, 1670, 1643, 1603, 1573, 1474, 1448, 1416, 1304,
1
.46–7.35 (m, 6 H), 5.22 (d, J = 12.2 Hz, 1 H, COCH), 3.95 (q, J =
.1 Hz, 2 H, CH CH ), 3.78 (dd, J = 10.1, 6.9 Hz, 1 H, OCHH),
–
1
247, 1068, 1009, 721 cm .
3
2
.72–3.67 (m, 1 H, OCHH), 3.71 (s, 3 H, NCH ), 3.69–3.67 (m, 1
3
Synthesis 2006, No. 1, 73–80 © Thieme Stuttgart · New York

PAPER
Synthesis of New 1¢(N)-Homocarbanucleosides
79
1
H NMR (DMSO-d ): d = 8.12 (s, 1 H, 2purine-H), 8.05 (s, 1 H, 8purine
-
IR (KBr): 3383, 2985, 2930, 1621, 1506, 1480, 1381, 1354, 1234,
1120, 1047, 922 cm .
6
–
1
H), 7.19 (br s, 2 H, D O exchange, NH ), 6.60 (s, 1 H, 3-H), 5.0 (t,
2
2
J = 5.03 Hz, 1 H, D O exchange, OH), 4.18 (d, J = 7.4 Hz, 2 H,
1
2
H NMR (CDCl ): d = 8.44 (s, 1 H, 2purine-H), 7.63 (s, 1 H, 8purine-H),
3
NCH ), 3.73 (s, 3 H, NCH ), 3.59–3.35 (m, 3 H), 3.15–3.11 (m, 1
2
3
6
=
.96 (s, 1 H, 3-H), 6.20 (br s, 1 H, D O exchange, NH), 4.43 (dd, J
2
H), 2.69 (dt, J = 13.7, 8.7 Hz, 1 H, 5-HH), 1.95 (dt, J = 13.7, 4.3 Hz,
13.9, 9.2 Hz, 1 H, NCHH), 4.22 (dd, J = 13.9, 6.6 Hz, 1 H,
1
H, 5-HH).
NCHH), 3.86 (dd, J = 11.5, 4.2 Hz, 1 H, OCHH), 3.79 (s, 3 H,
NCH ), 3.75 (dd, J = 11.5, 4.6 Hz, 1 H, OCHH), 3.51–3.48 (m, 1 H),
3.24–3.20 (m, 1 H), 3.05 (br s, 1 H, D O exchange, OH), 2.82 (dt,
J = 14.1, 9.0 Hz, 1 H, 5-HH), 2.12 (dt, J = 14.1, 2.7 Hz, 1 H, 5-HH),
1
3
C NMR [DEPT (DMSO-d )]: d = 156.33 (C), 152.75 (CH),
6
3
1
1
3
50.98 (C), 149.98 (C), 141.28 (CH), 131.97 (CH), 127.09 (C),
19.05 (C), 64.35 (CH ), 48.88 (CH ), 39.65 (CH), 38.5 (CH ),
7.67 (CH), 36.1 (CH).
2
2
2
2
1.0–0.92 (m, 2 H), 0.91–0.87 (m, 1 H), 0.69–0.63 (m, 2 H).
1
3
FAB–MS: m/z (%) = 300.2 [M + 1] (40).
Anal. Calcd for C H N O (299.33): C, 56.18; H, 5.72; N, 32.76.
Found: C, 56.42; H, 5.97; N, 33.03.
C NMR [DEPT (CDCl )]: d = 156.61 (CH), 153.56 (C), 150.41
3
(
6
3
C), 149.95 (C), 140.50 (CH), 132.96 (CH), 127.88 (C), 120.23 (C),
4.11 (CH ), 49.25 (CH ), 40.03 (CH), 38.68 (CH ), 37.75 (CH),
7.68 (CH), 24.84 (CH), 7.79 (2 × CH2).
14
17
7
2
2
2
(
±)-cis-4-[(2-Amino-6-chloro-9H-purin-9-yl)methyl]-1-methyl-
FAB–MS: m/z (%) = 340.14 (100) [M + 1].
cyclopenta[c]pyrazol-6-methanol (10b)
Eluents: CH Cl –MeOH (60:1, 40:1, 20:1). Yield: 99%; white solid
washed with Et O–pentane; mp 185–187 °C.
Anal. Calcd for C H N O (339.39): C, 60.16; H, 6.24; N, 28.89.
1
7
21
7
2
2
Found: C, 60.41; H, 6.50; N, 29.04.
2
IR (KBr): 3364, 2993, 2934, 1617, 1585, 1562, 1537, 1520, 1496,
(±)-cis-1-{[6-(Hydroxymethyl)-1-methylcyclopenta[c]pyrazol-
4-yl]methyl}-1,2,3,4-tetrahydropyrimidine-2,4-dione (17b)
–
1
1
467, 1428, 1407, 1162, 1002, 914 cm .
1
Eluent: CH Cl –MeOH (15:1). Yield: 99%; white solid (recrystal-
lized from EtOAc–EtOH); mp 196–197 °C.
2 2
H NMR (DMSO-d ): d = 8.23 (s, 1 H, 8purine-H), 6.91 (br s, 2 H,
6
D O exchange, NH ), 6.63 (s, 1 H, 3-H), 5.0 (t, J = 5.0 Hz, 1 H, D O
2
2
2
exchange, OH), 4.10 (dd, J = 7.2 Hz, 2 H, NCH ), 3.72 (s, 3 H,
IR (KBr): 3434, 2956, 2765, 1703, 1690, 1670, 1439, 1389, 1354,
1292, 1242, 1012, 806, 767 cm .
2
–
1
NCH ), 3.60–3.52 (m, 1 H, OCHH), 3.52–3.42 (m, 2 H), 3.19–3.12
3
(
4
m, 1 H), 2.70 (dt, J = 13.7, 8.7 Hz, 1 H, 5-HH), 1.94 (dt, J = 13.7,
.5 Hz, 1 H, 5-HH).
1
H NMR (DMSO-d ): d = 11.22 (br s, 1 H, D O exchange, 2pyrimidine-
6
2
H), 7.53 (d, J = 7.8 Hz, 1 H, 6pyrimidine-H), 6.88 (s, 1 H, 3-H), 5.52 (d,
J = 7.8 Hz, 1 H, 5pyrimidine-H), 4.97 (t, J = 5.0 Hz, 1 H, D O exchange,
OH), 3.80–3.76 (m, 1 H, NCHH), 3.73 (s, 3 H, NCH ), 3.72–3.47
1
3
C NMR [DEPT (DMSO-d )]: d = 160.13 (C), 154.53 (C), 150.95
6
2
(C), 149.72 (C), 143.74 (CH), 131.98 (CH), 126.92 (C), 123.63 (C),
3
6
3
4.18 (CH ), 48.97 (CH ), 39.62 (CH), 38.50 (CH ), 37.67 (CH),
5.58 (CH).
(m, 3 H), 3.29–3.24 (m, 1 H), 3.18–3.11 (m, 1 H), 2.70 (dt, J = 13.6,
8.7 Hz, 1 H, 5-HH), 1.88 (dt, J = 13.6, 4.2 Hz, 1 H, 5-HH).
2
2
2
1
3
FAB–MS: m/z (%) = 334.1 (50) [M + 1].
Anal. Calcd for C H ClN O (333.77): C, 50.38; H, 4.83; N, 29.38.
Found: C, 50.67; H, 4.99; N, 29.56.
C NMR [DEPT (DMSO-d )]: d = 164.02 (C), 151.43 (C), 150.96
6
(
(
(
C), 146.47 (CH), 132.30 (CH), 126.90 (C), 100.75 (CH), 64.31
CH ), 53.29 (CH ), 39.61 (CH ), 38.25 (CH ), 37.67 (CH), 34.99
CH).
14
16
7
2
2
3
2
(
±)-cis-4-[(6-Chloro-9H-purin-9-yl)methyl]-1-methylcyclopen-
FAB–MS: m/z (%) = 300.09 (100) [(M + 1) + Na].
ta[c]pyrazol-6-methanol (11b)
Purification required serial chromatography on three columns with
the following eluents: first column, CH Cl –MeOH (30:1); second
Anal. Calcd for C H N O (276.29): C, 56.51; H, 5.84; N, 20.28.
1
3
16
4
3
Found: C, 56.79; H, 6.03; N, 20.45.
2
2
column, CH Cl –MeOH (15:1, 10:1 and 5:1); third column,
EtOAc–MeOH (15:1). Yield: 66%; white solid recrystallized from
acetone–hexane; mp 133–134 °C.
2
2
Crystal Structure Determination of 9b (see Figure 2)
Crystal Data: C H N O , M = 315.35, Monoclinic, P 21/c, a =
1
5
18
2
2
r
1
4.456(5) Å, b = 8.260(5) Å, c = 12.908(5) Å, a = 90.000(5)°, b =
3
IR (KBr): 3261, 2932, 1592, 1577, 1562, 1443, 1403, 1337, 1217,
93.825(5)°, g = 90.000(5)°, T = 293(2) K, V = 1537.9(12) Å , Z =
–
1
3 –1
1
178, 1018, 940 cm .
4, Dx (calculated) = 1.362 Mg/m , m = 0.097 mm , F(000) = 664.
Date Collection and Reduction: Crystal size: 0.31 × 0.27 × 0.05
1
H NMR (CDCl ): d = 8.74 (s, 1 H, 2purine-H), 8.05 (s, 1 H, 8purine-H),
3
3
6
.87 (s, 1 H, 3-H), 4.5 (dd, J = 13.8, 7.7 Hz, 1 H, NCHH), 4.38 (dd,
mm , q-range 2.82–26.02°, index ranges: –17 £ h £ 17, 0 £ k £ 10,
J = 13.8, 7.2 Hz, 1 H, NCHH), 3.88–3.84 (m, 1 H), 3.81 (s, 3 H,
0 £ l £ 15, reflections collected: 15648, independent reflections:
NCH ), 3.72–3.67 (m, 1 H), 3.64–3.56 (m, 1 H), 3.30–3.25 (m, 1 H),
3012 [R(int) = 0.0462], absorption correction: semi-empirical from
3
2
3
.05 (br s, 1 H, D O exchange), 2.92 (dt, J = 14.0, 9.0 Hz, 1 H, 5-
equivalents, refinement method: full-matrix least-squares on F ,
data/restraints/parameters: 3012/0/228, goodness-of-fit on F :
2
2
HH), 2.08 (dt, J = 14.0, 3.2 Hz, 1 H, 5-HH).
1
3
1.047, final R indices [I > 2s (I)]: R1 = 0.0580, wR2 = 0.1570, R in-
C NMR [DEPT (CDCl )]: d = 152.33 (CH), 151.74 (C), 150.44
3
dices (all data): R1 = 0.0974, wR2 = 0.1740, largest diff. peak and
(
C), 145.92 (CH), 132.9 (CH), 131.97 (CH), 130.07 (C), 127.45 (C),
–
3
hole: 0.470 and –0.363 e·Å . Enraf Nonius FR590, computing data
collection: CAD4 Express (Enraf Nonius, 1994), computing cell re-
finement: CAD4 Express (Enraf Nonius, 1994), computing data re-
duction: XCAD4 (Harms & Wocadlo, 1995), computing structure
solution: SIR-97 (Altomare et al., 1999), computing structure re-
finement: SHELXL-97 (Sheldrick, 1997), computing molecular
graphics: Ortep-3 for Windows (Farrugia, 1997), computing publi-
cation material: WinGX publication routines (Farrugia, 1999).
6
3
4.59 (CH ), 49.94 (CH ), 39.69 (CH ), 38.96 (CH ), 37.84 (CH),
6.97 (CH).
2
2
3
2
FAB–MS: m/z (%) = 319.1 (43) [M + 1].
Anal. Calcd for C H ClN O (318.76): C, 52.75; H, 4.74; N, 26.36.
Found: C, 52.48; H, 4.91; N, 26.52.
14
15
6
(
±)-cis-4-[(6-Cyclopropylamino-9H-purin-9-yl)methyl]-1-meth-
ylcyclopenta[c]pyrazol-6-methanol (15b)
Crystal Structure Determination of 17b (see Figure 3)
Eluent: CH Cl –MeOH (30:1 and 15:1). Yield: 95%; white solid re-
crystallized from acetone–hexane; mp 195–196 °C.
2
2
Crystal Data: C H N O , M = 276.30, monoclinic, P 21/c, a =
13 16
4
3
r
5
.107(5) Å, b = 11.483(5) Å, c = 22.499(5) Å, a = 90.000(5)°, b =
Synthesis 2006, No. 1, 73–80 © Thieme Stuttgart · New York

8
0
M. D. García et al.
PAPER
(5) Blanco, J. M.; Caamaño, O.; Fernández, F.; Gómez, G.;
3
9
4
0.361(5)°, g = 90.000(5)°, T = 293(2) K, V = 1319.4(14) Å , Z =
, Dx (calculated) = 1.391 Mg/m , m = 0.102 mm , F(000) = 584.
3
–1
Nieto, M. I.; Balzarini, J.; Padalko, E.; De Clercq, E.
Nucleosides Nucleotides 1997, 16, 159.
Date Colletion and Reduction: Crystal size: 0.54 × 0.51 × 0.03
3
(6) Nieto, M. I.; Blanco, J. M.; Caamaño, O.; Fernández, F.;
García-Mera, X.; Balzarini, J.; Padalko, E.; Neyts, J.; De
Clercq, E. Nucleosides Nucleotides 1998, 17, 1255.
(7) Nieto, M. I.; Blanco, J. M.; Caamaño, O.; Fernández, F.;
Gómez, M.; Balzarini, J.; De Clercq, E. Nucleosides,
Nucleotides Nucleic Acids 2002, 21, 243.
mm , q-range 1.81–28.28°, index ranges: –6 £ h £ 6, 0 £ k £ 15, 0 £
l £ 29, reflections collected: 3174, independent reflections: 3174
[
R(int) = 0.0000], absorption correction: semi-empirical from
2
equivalents, refinement method: full-matrix least-squares on F ,
data/restraints/parameters: 3174/0/198, goodness-of-fit on F :
2
1
.027, final R indices [I > 2s (I)]: R1 = 0.0511, wR2 = 0.1200, R in-
(
8) Fernández, F.; García-Mera, X.; Morales, M.; Rodríguez-
Borges, J. E.; De Clercq, E. Synthesis 2002, 1084.
9) Yao, S.-W.; López, V. H. C.; Fernández, F.; García-Mera,
X.; Morales, M.; Rodríguez-Borges, J. E.; Cordeiro, M. N.
D. S. Bioorg. Med. Chem. 2003, 11, 4999.
dices (all data): R1 = 0.0988, wR2 = 0.1423, largest diff. peak and
–
3
hole: 0.196 and –0.203 e·Å . Enraf Nonius FR590, computing data
collection: CAD4 Express (Enraf Nonius, 1994), computing cell re-
finement: CAD4 Express (Enraf Nonius, 1994), computing data re-
duction: XCAD4 (Harms & Wocadlo, 1995), computing structure
solution: SIR-97 (Altomare et al., 1999), computing structure re-
finement: SHELXL-97 (Sheldrick, 1997), computing molecular
graphics: Ortep-3 for Windows (Farrugia, 1997), computing publi-
cation material: WinGX publication routines (Farrugia, 1999).
(
(
(
(
(
(
(
10) Fernández, F.; García-Mera, X.; Morales, M.; Vilariño, L.;
Caamaño, O.; De Clercq, E. Tetrahedron 2004, 60, 9245.
11) López, C.; Caamaño, O.; Hergueta, A. R.; Fernández, F.;
García, M. D. Tetrahedron Lett. 2002, 43, 5311.
12) García, M. D.; Caamaño, O.; Fernández, F.; Figueira, M. J.;
Gómez, G. Synthesis 2003, 2138.
13) Hergueta, A. R.; López, C.; García-Mera, X.; Fernández, F.
Acknowledgment
Tetrahedron 2004, 60, 10343.
14) García, M. D.; Caamaño, O.; Fernández, F.; López, M. C.;
De Clercq, E. Synthesis 2005, 925.
The authors thank the Xunta de Galicia for financial support of this
work under project PGIDT02BTF20305PR.
15) McDougal, P. G.; Rico, J. G.; Oh, Y.-L.; Condon, B. D. J.
Org. Chem. 1986, 51, 3388.
16) Mitsunobu, O. Synthesis 1981, 1.
17) Dembinski, R. Eur. J. Org. Chem. 2004, 2763.
18) Hossain, N.; Blaton, N.; Peeters, O.; Rozenski, J.;
Herdewijn, P. A. Tetrahedron 1996, 52, 5563.
References
(
(
(
(
1) Reviews of the literature on CANs include: (a) Crimmins,
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Challand, S. R. Acyclic, Carbocyclic and l-Nucleosides;
Kluwer Academic: Dordrecht, The Netherlands, 1998, 1–
(
19) (a) Gunaga, P.; Baba, M.; Jeong, L. S. J. Org. Chem. 2004,
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9, 3208. (b) Russ, P.; Schelling, P.; Scapozza, L.; Folkers,
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000, 19, 651.
5
(
(
2) (a) Madhavan, G. V. B.; Martin, J. C. J. Org. Chem. 1986,
(
20) The crystallographic data of 9b and 17b have been deposited
at the Cambridge Crystallographic Data Centre as
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65, 1865.
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(
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Synthesis 2006, No. 1, 73–80 © Thieme Stuttgart · New York