A convenient synthesis of new purinyl-homo-carbonucleosides on a cyclopentane ring fused with pyridazine

Article abstract of DOI:10.1055/s-2004-834870

The new purinyl homo-carbonucleosides 10 and 17a were prepared from 1,4-diphenyl-5,8-dihydro-5,8-methanophthalazine by one-pot ozonolysis and reductive cleavage, followed by monoprotection with an Ac or TBDMS group, mesylation of the resulting diol and replacement of the mesyl group with 6-chloropurine in the presence of NaH and 18-crown-6 ether. Homo- carbonucleosides 12 and 13 were then obtained from 10 by substitution of the chlorine in purine position 6. Compounds 17b and 19 were obtained from 17a in the same way.

Full text of DOI:10.1055/s-2004-834870

PAPER
2855
A Convenient Synthesis of New Purinyl-homo-carbonucleosides on a Cyclo-
pentane Ring Fused with Pyridazine
C
onvenientSynthe
l
sisof
N
g
ewPurinyl-
a
homo-carbonucle
C
osides aamaño,*a Generosa Gómez,*b Franco Fernández,a Marcos Daniel García,a Xerardo García-Mera,a
Eric De Clercqc
a
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
Departamento de Química Orgánica, Facultade de Química, Lagoas-Marcosende, Universidade de Vigo, 36200 Vigo, Spain
b
Fax +34(986)813663; E-mail: ggomez@uvigo.es.
Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
c
Received 30 July 2004; revised 6 August 2004
order to modify the lipophilicity and polar interactions of
Abstract: The new purinyl homo-carbonucleosides 10 and 17a
the pseudosugar moiety while retaining its rigidity, we
have also begun to explore a class of analogues in which
were prepared from 1,4-diphenyl-5,8-dihydro-5,8-methanophthala-
zine by one-pot ozonolysis and reductive cleavage, followed by
monoprotection with an Ac or TBDMS group, mesylation of the re-
the benzene ring of 3 is replaced by an aromatic heterocy-
sulting diol and replacement of the mesyl group with 6-chloropurine cle.8 Here we describe the synthesis of a number of com-
in the presence of NaH and 18-crown-6 ether. Homo-carbonucleo-
sides 12 and 13 were then obtained from 10 by substitution of the
pounds of this kind in which the heterocycle is pyridazine.
The key intermediate 6 was prepared from 1,4-diphenyl-
chlorine in purine position 6. Compounds 17b and 19 were obtained
5,8-dihydro-5,8-methanophthalazine (4, obtained9 from
from 17a in the same way.
2,3-dibenzoylbicyclo[2.2.1]hepta-2,5-diene). Initially,
Key words: ozonolysis, acylation, diols, carbocyclic nucleosides,
this was achieved by a method which parallels that previ-
ously employed8b to prepare 1- and 2-alkyl derivatives of
exo,exo-5,6-dihydroxy-4,5,6,7-tetrahydro-4,7-methano-
indazoles. In this method (Method A), hydroxylation of
the ‘exposed’ double bond of 4 was followed by oxidative
cleavage of the resulting diol 5 (with sodium periodate
and silica gel)8,10 and reduction of the dialdehyde product
by NaBH4 in MeOH (Scheme 1). Subsequently, we dis-
covered that 4 can be transformed cleanly into 6 in high
yield (93%) in a one-pot process consisting of ozonolysis
followed by reductive cleavage of the resulting ozonide
(Method B).
heterocycles, pyridazine
In keeping with the general antineoplastic and antileuke-
mic properties of purine bases and their nucleosides,1 nat-
ural and synthetic carbocyclic nucleosides can have
significant antitumour and/or antiviral activity.2 In partic-
ular, carbovir3 (1) and abacavir4 (2) have potent anti-HIV
activity. In previous work, our research group synthesized
several abacavir analogues with structures of type 3
(Figure 1),5 some of which have shown marked cytostatic
activity against human T lymphocytes (Molt4/C8 and
CEM/0 cells).6
To monoprotect compound 6 in readiness for its coupling
with the nucleobase, and in the light of previous experi-
ence,5 we first attempted to acetylate it by enzymatic
transesterification from vinyl acetate in dimethylform-
amide with Novozym® 435 as catalyst. However, several
attempts under various reaction conditions (temperatures
of 20–50 °C and reaction times of 1–18 h) failed to pro-
vide acetylated products, so chemical acetylation was re-
sorted to. Refluxing a 1:1.06:2.3 mixture of compound 6,
acetic anhydride and pyridine in anhydrous THF for 8
hours afforded a 58% yield of 7 accompanied by a 32%
yield of the diacetylate 8.
X
X
N
N
N
N
N
N
HO
N
N
NH2
( )n
HO
1: X = OH
2: X = NH-cPr
3: X = Cl, OR, NHR', Ph(R'')
n = 0,1
Although Mitsunobu coupling11 of purines to indans anal-
ogous to 7 only provides yields of around 40%,5 and the
present substrate was expected to be even less reactive, we
nevertheless attempted to couple 7 with 6-chloropurine in
THF containing triphenylphosphine and diethyl azodicar-
boxylate. Not unexpectedly, these attempts failed and the
desired compound 10 was not detected despite careful
separation of the products of reaction. We therefore tried
an indirect route via mesylate 9, which was obtained from
7 by treatment with methanesulphonyl chloride, Et3N and
DMAP at 0 °C. Heating crude 9 for 24 hours at 55 °C with
Figure 1
Most of these analogues have had an oxo or amino group
at purine position 6 so as to maintain the ability of the nat-
ural nucleobase to form hydrogen bonds with polymeras-
es and other key enzymes of nucleic acid metabolism.7 In
SYNTHESIS 2004, No. 17, pp 2855–2862
Advanced online publication: 15.10.2004
DOI: 10.1055/s-2004-834870; Art ID: P08204SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
4

2856
O. Caamaño et al.
PAPER
HO
Ph
N
Ph
N
OsO4, NMO,
H2O, acetone HO
91%
N
N
Ph
Ph
5
4
28%
i) O3, MeOH, HCCl3
ii) NaBH4
i) SiO2, NaIO4, H2O, CH2Cl2
ii) NaBH4, MeOH
93%
HO
OH
Ac2O,
AcO
OAc
AcO
OH
THF, pyridine
+
Ph
Ph
Ph
Ph
7 (58%)
Ph
Ph
8 (32%)
N
N
N
N
6
N N
Et3N, DMAP,
CH2Cl2, MeSO2Cl
87%
OSO2Me
AcO
Ph
Ph
N
N
9
60% NaH,
18-crown-6,
6-chloropurine,
DMF
HN
OR
Cl
N
N
N
N
N
N
N
N
N
N
N
N
R'O
Ph
HO
AcO
cyclopropylamine, EtOH
91%
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
N
10 (28%)
13a (R' = Ac)
NaOH, EtOH
K2CO3, MeOH
65%
12a (R = H)
12b (R = CH3)
+
77%
13b (R' = H)
K2CO3, MeOH
AcO
89%
Ph
Ph
11 (32%)
N
N
Scheme 1
6-chloropurine, NaH and 18-crown-6 ether in DMF af- all the ester hydrolysis conditions that were tried, the chlo-
forded a 28% yield of 10 (lower temperatures and shorter ropurinyl carbonucleoside 17b (Scheme 2) was obtained
reaction times gave lower yields) together with a 32% from the TBDMS-protected analogue 17a by treatment
yield of 11. The latter compound is the product of a com- with a 1 M solution of TBAF in THF. Compound 17a was
peting elimination reaction shown by TLC monitoring prepared by TBDMS-protection of diol 6, mesylation of
(with 1:1 hexane–EtOAc as eluent) which produced de- the resulting compound 14, and replacement of the mesyl
tectable amounts of 11 within just a few minutes of the group of 15 with chloropurinyl in analogy to the prepara-
start of the reaction.
tion of 10 from 9. In view of the reported preparation of
methylene-linked nucleoside analogues by reaction be-
tween the tetrabutylammonium salt of 6-chloropurine and
a primary triflate,12 we also tried to obtain 17a by gener-
ating the triflate of pseudosugar 14 (compound 18) and
treating it with the Bu4N+ salt in question, but the yield of
17a obtained by this method never exceeded 8%.
Purinyl carbonucleosides in which purine position 6 bears
a OH (12a), OMe (12b) or cyclopropylamino group (13a)
were obtained directly from 9 by treatment with the corre-
sponding nucleophiles, with simultaneous deprotection in
the cases of 12a and 12b. Thus reaction of 10 with NaOH
and EtOH for 48 hours at room temperature afforded 12a
directly, while stirring 10 with Na2CO3 in MeOH for 40 Finally, reaction of 17a with cyclopentylamine and subse-
hours gave the methyl ether 12b. Refluxing 10 with cyclo- quent deprotection of the resulting compound 19a with a
propylamine in EtOH gave 13a, basic hydrolysis of which 1 M solution of TBAF in THF afforded the new purinyl
then afforded the deprotected product 13b.
carbonucleoside 19b.
Since direct deprotection of 10 resulted in simultaneous Compounds 12a, 12b, 13b, 17a, 17b and 19b were evalu-
replacement of the chlorine by an hydroxyl group under ated for antiviral activity13 against a wide variety of virus-
Synthesis 2004, No. 17, 2855–2862 © Thieme Stuttgart · New York

PAPER
Convenient Synthesis of New Purinyl-homo-carbonucleosides
2857
TBDMSO
60%, NaH, THF, TBDMSCl
OH
TBDMSO
OSO2Me
Et3N, DMAP,
CH2Cl2, MeSO2Cl
6
Ph
Ph
14
65%
Ph
Ph
15
91%
N
N
N
N
pyridine, H2Cl2, (CF3SO2)2O
60% NaH, 18-crown-6,
6-chloropurine, DMF
TBDMSO
OSO2CF3
TBDMSO
Cl
Ph
Ph
N
N
Ph
Ph
N
CH2Cl2
,
N
N
N N
16 (17%)
N
18
Bu4N
Cl
Cl
+
8%
N
N
N
N
N
N
N
N
TBDMSO
HO
1 M TBAF in THF
62%
Ph
Ph
Ph
Ph
N
N
N
N
17a (20%)
17b
76%
cyclopentylamine
EtOH
HN
N
N
N
N
RO
Ph
Ph
N
N
19a (R = TBDMS)
1 M TBAF in THF
88%
19b (R = H)
Scheme 2
endo,endo-1,4-Diphenyl-5,6,7,8-tetrahydro-5,8-methano-
phthalazine-6,7-diol (5)
es, including herpes simplex virus type 1 (strain KOS),
herpes simplex virus type 2 (strain G), vaccinia virus, a
thymidine kinase-deficient HSV-1 strain (KOS, ACVR)
and vesicular stomatitis virus (VSV) in HEL cell cultures;
respiratory syncytial virus, Coxsackie virus B4 and vesic-
ular stomatitis virus in HeLa cell cultures; and type 3
parainfluenza virus, type 1 reovirus, Sindbis virus, Cox-
sackie virus B4 and Punta Toro virus in Vero cell cultures.
None of the compounds showed inhibitory activity
against any of the virus strains at 400 mg/mL.
A solution of phthalazine 4 (2.65 g, 8.78 mmol) in acetone–water
mixture (4:1, 60 mL) at 40 °C was treated with N-methylmorpholine
N-oxide (1.13 g, 9.65 mmol) followed by a 4% solution of osmium
tetraoxide (0.25 mL) in water. After 5 h at this temperature the mix-
ture was allowed to cool to r.t., and 5 was filtered out as a white sol-
id (2.48 g). The filtrate was concentrated to dryness, the resulting
residue was taken up in sat. NH4Cl solution (130 mL), and this so-
lution was extracted with EtOAc (3 × 100 mL). The pooled organic
phases were dried over Na2SO4, and evaporation of the solvent left
another small amount of 5 (0.22 g,) as a white solid; yield: 91%. An
analytical sample was obtained by recrystallization from EtOH; mp
210–211 ºC.
All chemicals used were of reagent grade and were obtained from
Aldrich Chemical Co and used without further purification. Melting
points were measured in a Gallenkamp apparatus and are uncorrect-
ed. IR spectra were recorded on a MIDAC Prospect spectrophoto-
meter. 1H and 13C NMR spectra were recorded on a Bruker AMX
300 spectrometer at 300 MHz and 75.47 MHz, respectively, using
tetramethylsilane as internal standard (chemical shifts, d , in ppm; J
in Hz). Mass spectra were recorded on a Fisons VG Autoespec M
spectrometer. Ozonolysis was performed with Erwin Sander ozone
generator. All air-sensitive reactions were carried out under Ar.
Flash chromatography was performed on silica gel (Merck 60, 230–
240 mesh) and analytical TCL on pre-coated silica gel plates
(Merck 60 F254, 0.25 mm).
IR (KBr): 3420, 3063, 3008, 2918, 1646, 1576, 1558, 1417, 1382,
1071, 972, 774, 683, 658 cm–1.
1H NMR (DMSO-d6): d = 1.60, and 1.69 (AB system, J = 16.8, 10.3
Hz, 2 H, 9-HH), 3.65 (virtual s, 2 H, 5-H, 8-H), 4.54 (virtual s, 2 H,
6-H, 7-H), 4.88 (d, D2O exchange, J = 5.2 Hz, 2 H, 2 × OH), 7.44–
7.57 (m, 6 H), 8.09–8.11 (m, 4 H).
13C NMR (DMSO-d6): d = 154.8 (C), 143.9 (C), 136.5 (C), 128.9
(CH), 128.7 (CH), 128.3 (CH), 68.7 (CH), 47.9 (CH), 42.83 (CH2).
Synthesis 2004, No. 17, 2855–2862 © Thieme Stuttgart · New York

2858
O. Caamaño et al.
PAPER
EIMS: m/z (%) = 331 (24) [M + 1], 330 (M, 100), 299 (16), 283
(12), 272 (23), 271 (85), 270 (55), 242 (29), 241 (55), 239 (31), 215
(16), 165 (33), 128 (16), 115 (33), 77 (17).
49:1) eluent. From the early fractions, diacetate 8 (0.8 g, 32%) was
isolated as a brown solid whereas the middle fractions yielded com-
pound 7 (1.3 g, 58%), likewise as a brown solid. From the fractions
eluted with MeOH, unreacted compound 6 (0.2 g) was obtained.
HRMS: m/z calcd for C21H18N2O2: 330.1368; found: 330.1347.
Compound 8
Mp 73–74 ºC.
cis-1,4-Diphenyl-6,7-dihydro-5H-cyclopenta[d]pyridazine-5,7-
dimethanol (6)
Method A: A 0.65 M aq solution of NaIO4 (4.28 mL, 2.77 mmol)
was added dropwise to a vigorously stirred suspension of chroma-
tography grade silica gel (4.28 g) in CH2Cl2 (175 mL). After addi-
tion of compound 5 (0.50 g, 1.5 mmol) in CH2Cl2 (10 mL) to the
resulting flaky solution stirring was continued for another 5 min and
the mixture was then passed through a filter pad onto a small quan-
tity of Na2SO4. The retained silica gel was washed with CH2Cl2 (50
mL) and the washings were pooled with the filtrate. Removal of the
solvent left the dialdehyde as an oily reddish residue, which was dis-
solved in MeOH (25 mL). NaBH4 (0.23 g, 2.34 mmol) was added in
a single portion and stirring was continued for 30 min. After cooling
with an ice bath, water (5 mL) was added. MeOH was removed un-
der reduced pressure and the resulting residue was dissolved in
NH4Cl (25 mL). This solution was extracted with EtOAc (3 × 100
mL), and removal of the solvent from the pooled extracts under re-
duced pressure afforded a greenish solid (0.17 g). Upon purification
by chromatography on silica gel using CH2Cl2–MeOH (40:1) as
eluent 6 (0.14 g, 28%) was obtained as a white solid; mp 217–218
ºC (dec).
IR (KBr): 3055, 2993, 1738, 1553, 1444, 1383, 1252, 1024, 906,
763, 699 cm–1.
1H NMR (CDCl3): d = 1.84 (s, 6 H, 2 × OCOCH3), 1.91 (dt, J = 14.3,
5.6 Hz, 1 H, 6-HH), 2.66 (dt, J = 14.3, 5.6 Hz, 1 H, 6-HH), 3.78 (dd,
J = 11.1, 7.4 Hz, 2 H, 5-H, 7-H), 3.90 (dd, J = 11.1, 4.4 Hz, 2 H,
OCH2), 4.10–4.17 (m, 2 H, OCH2), 7.47–7.55 (m, 6 H), 7.78–7.80
(m, 4 H).
13C NMR (CDCl3): d = 170.6 (C), 157.9 (C), 141.9 (C), 136.6 (C),
128.5 (CH), 128.9 (CH), 128.3 (CH), (CH), 64.9 (CH2), 42.6 (CH),
30.2 (CH2), 20.6 (3 CH3).
EIMS: m/z (%) = 416 (100) [M], 373 (19), 356 (18), 355 (17), 314
(11), 313 (45), 298 (11), 297 (49), 296 (28), 295 (72), 285 (20), 284
(10), 283 (42), 271 (20), 268 (28), 267 (20), 253 (13), 252 (18), 241
(10), 239 (17), 215 (10), 202 (11), 180 (12), 165 (10), 128 (21), 127
(13), 91 (12), 77 (28), 71 (13), 69 (11).
HRMS: m/z calcd for C25H24N2O4: 416.1736; found: 416.1946.
Compound 7
Mp 165 ºC.
IR (KBr): 3296, 2938, 2877, 1739, 1569, 1447, 1395, 1092, 1046,
1021, 763, 701, 672 cm–1.
1H NMR (DMSO-d6): d = 2.14–2.18 (m, 1 H, 6-HH), 2.44–2.49 (m,
1 H, 6-HH), 3.03–3.10 (m, 2 H, CH2OH), 3.18–3.22 (m, 2 H,
CH2OH), 3.96–3.91 (m, 2 H, 5-H, 7-H), 4.57 (t, D2O exchange, J =
5.0 Hz, 2 H, 2 OH), 7.51–7.59 (m, 6 H), 7.79–7.81 (m, 4 H).
13C NMR (DMSO-d6): d = 157.4 (C), 143.4 (C), 137.2 (C), 128.9
(CH), 128.5 (CH), 128.2 (C), 128.1 (CH), 61.9 (CH2), 45.7 (CH),
29.2 (CH2).
IR (KBr): 3378, 2945, 1738, 1538, 1447, 1383, 1234, 1030, 770,
700 cm–1.
1H NMR (CDCl3): d = 1.87 (s, 3H, OCOCH3), 2.05 (dt, J = 14.2, 7.8
Hz, 1 H, 6-HH), 2.62 (dt, J = 14.2, 5.5 Hz, 1 H, 6-HH), 3.30 (dd,
J = 9.5, 5.8 Hz, 1 H, 5-H), 3.50 (dd, J = 9.4, 5.1 Hz, 1 H, 7-H), 3.81
(dd, J = 11.0, 4.7 Hz, 1 H, HOCHH), 3.99 (dd, J = 7.5, 4.3 Hz, 1 H,
HOCHH), 4.00–3.98 (m, 1 H, AcOCHH), 4.11–4.17 (m, 1 H, AcO-
CHH), 7.47–7.55 (m, 6 H), 7.77–7.80 (m, 4 H).
13C NMR (CDCl3): d = 171.0 (C), 158.0 (C), 157.9 (C), 142.7 (C),
142.1 (C), 136.9 (C), 136.8 (C), 129.4 (CH), 129.3 (CH), 128.9
(CH), 128.8 (CH), 128.4 (CH), 128.3 (CH), 65.1 (CH2), 63.2 (CH2),
46.0 (CH), 42.9 (CH), 29.8 (CH2), 20.7 (3 × CH3).
EIMS: m/z (%) = 333 (24) [M + 1], 332 (100) [M], 331 (16), 315
(39), 302 (24), 301 (10), 289 (16), 283 (23), 274 (16), 272 (14), 271
(57), 241 (11), 239 (14), 165 (14), 128 (12), 115 (17), 91 (10), 77
(10).
HRMS: m/z calcd for C21H20N2O2: 332.1525; found: 332.1517.
EIMS: m/z (%) = 375 (28) [M + 1], 374 (100) [M], 331 (35), 315
(36), 314 (20), 297 (13), 285 (29), 284 (16), 283 (58), 271 (33), 255
(31), 128 (13), 115 (12), 73 (12).
Method B: Ozone was bubbled for 15 min through a vigorously
stirred solution of phthalazine 4 (4.32 g, 14.4 mmol) in MeOH–
CHCl3 (1:1, 200 mL) at –78 °C. NaBH4 (2.43 g, 64.2 mmol) was
added in small portions over 1 h at the same temperature, and after
further 15 min at –78 °C the mixture was allowed to reach r.t. Re-
moval of the solvents under reduced pressure left an oily yellow res-
idue from which compound 6 precipitated as a white solid (4.47 g,
93%) upon addition of water (600 mL). The spectroscopic data of
this product were identical to those of the compound obtained by
Method A.
HRMS: m/z calcd for C23H22N2O3: 374.1630; found: 374.1629.
( )-cis-[7-(Mesyloxymethyl)-1,4-diphenyl-6,7-dihydro-5H-cy-
clopenta[d]pyridazin-5-yl]methyl Acetate (9)
Mesyl chloride (0.24 mL, 2.09 mmol) was added dropwise to a so-
lution of 7 (0.23 g, 0.61 mmol), Et3N (0.28 mL) and a cat. amount
of DMAP in anhyd CHCl3 (3 mL) stirred under Ar at 0 °C. After
stirring for 5 h at r.t., the mixture was diluted with CHCl3 (15 mL)
and washed successively with water (15 mL), 1 M NaOH (15 mL)
and brine (15 mL). The organic phase was then dried over Na2SO4
and concentrated under reduced pressure, leaving a brown residue
(0.31 g) that following chromatography on a silica gel column with
CH2Cl2–MeOH (99:1) as eluent afforded 9 (0.24 g, 87%) as a light
brown solid; mp 63–65 ºC.
( )-cis-[7-(Hydroxymethyl)-1,4-diphenyl-6,7-dihydro-5H-cy-
clopenta[d]pyridazin-5-yl]methyl Acetate (7) and cis-(1,4-
Diphenyl-6,7-dihydro-5H-cyclopenta[d]pyridazine-5,7-
diyl)bis(methylene) Diacetate (8)
A stirred suspension of diol 6 (2.0 g, 6.02 mmol) in THF (50 mL)
was refluxed for 1 h under Ar. Anhydrous pyridine (1.1 g, 13.7
mmol) and acetic anhydride (0.65 g, 6.37 mmol) were added, and
refluxing was continued for further 8 h. The solvent was removed
under reduced pressure and the residue was taken into sat. NaHCO3
solution (100 mL). This solution was extracted with EtOAc (3 × 150
mL), and the pooled organic phases were dried over Na2SO4 and
concentrated to dryness, leaving an oily residue (3 g) that was frac-
tionated on a silica gel column using CH2Cl2–MeOH (99:1 and then
IR (KBr): 3446, 2956, 1739, 1448, 1384, 1358, 1237, 1175, 1035,
955, 921, 830, 771, 701 cm–1.
1H NMR (CDCl3): d = 1.85 (s, 3 H, OCOCH3), 2.06 (dt, J = 14.3,
7.1 Hz, 1 H, 6-HH), 2.63–2.73 (m, 1 H, 6-HH), 2.71 (s, 3 H,
SO2CH3), 3.74 (dd, J = 11.02, 7.0 Hz, 1 H, 7-H), 3.86–3.92 (m, 2 H,
AcOCHH, 5-H), 3.99 (dd, J = 9.8, 3.4 Hz, 1 H, AcOCHH), 4.09–
4.23 (m, 2 H, SO2OCH2), 7.49–7.59 (m, 6 H), 7.76–7.81 (m, 4 H).
Synthesis 2004, No. 17, 2855–2862 © Thieme Stuttgart · New York

PAPER
Convenient Synthesis of New Purinyl-homo-carbonucleosides
2859
13C NMR (CDCl3): d = 181.1 (C), 170.6 (C), 157.9 (C), 157.6 (C),
142.3 (C), 140.5 (C), 136.3 (C), 129.8 (CH), 129.7 (CH), 129.0
(CH), 128.9 (CH), 128.3 (CH), 69.1 (CH2), 64.5 (CH2), 43.2 (CH),
42.7 (CH), 36.9 (CH3), 29.9 (CH2), 20.6 (CH3).
( )-cis-9-{[7-(Hydroxymethyl)-1,4-diphenyl-6,7-dihydro-5H-
cyclopenta[d]pyridazin-5-yl]methyl}-1,9-dihydropurin-6-one
(12a)
A solution of 10 (0.10 g, 0.20 mmol) and NaOH (7.8 mg, 0.20
mmol) in EtOH (6 mL) was stirred at r.t. for 48 h, and after removal
of the solvent the resulting residue was dissolved in EtOAc (10
mL). This solution was washed with brine (2 × 10 mL) and the sol-
vent was removed under reduced pressure, leaving a solid (96 mg)
that upon recrystallization from MeOH afforded 12a (60 mg, 77%)
as a white solid; mp 236–238 ºC.
EIMS: m/z (%) = 452 (2) [M], 357 (8), 356 (20), 355 (6), 298 (7),
297 (29), 296 (49), 295 (100), 283 (14), 281 (8), 267 (8), 266 (7),
253 (12), 252 (23), 239 (7), 165 (6), 127 (11), 126 (71), 115 (6), 78
(6), 77 (10).
HRMS: m/z calcd for C24H24N2O5S: 452.1405; found: 452.1419.
IR (KBr): 3183, 2929, 2869, 1595, 1496, 1444, 1046, 1380, 1332,
1286, 1256, 1117, 1022, 942, 767, 697, 678, 640 cm–1.
( )-cis-{7-[(6-Chloro-9H-purin-9-yl)methyl]-1,4-diphenyl-6,7-
dihydro-5H-cyclopenta[d]pyridazin-5-yl}methyl Acetate (10)
and ( )-(7-Methylidene-1,4-diphenyl-6,7-dihydro-5H-cyclopen-
ta[d]pyridazin-5-yl)methyl Acetate (11)
1H NMR (DMSOd6): d = 1.93–1.96 (m, 1 H, 6-HH), 2.53 (dt, J =
13.7, 9.8 Hz, 1 H, 6-HH), 3.18 (dd, J = 10.7, 6.4 Hz, 1 H, 7-H), 3.29
(dd, J = 10.7, 3.1 Hz, 1 H, HOCHH), 4.29–4.21 (m, 1 H, HOCHH),
4.25–4.27 (m, 1 H, 5-H), 4.56–4.58 (m, 1 H, NCHH), 4.66–4.68 (m,
1 H, NCHH), 4.80 (br s, 1 H D2O exchange, OH), 7.21–7.35 (m, 3
H), 7.45–7.56 (m, 5 H), 7.77–7.82 (m, 2 H), 8.25, 8.60 (2 × s, 2 H,
2purine-H, 8purine-H), 11.15 (br s, 1 H, D2O exchange, 1purine-H).
13C NMR (CDCl3): d = 157.3 (C), 156.8 (C), 151.5 (C), 151.0 (CH),
148.7 (C), 146.7 (CH), 143.5 (C), 142.8 (C), 136.8 (C), 136.0 (C),
130.6 (C), 129.0 (CH), 128.5 (CH), 128.4 (CH), 128.1 (CH), 128.0
(CH), 127.8 (CH), 127.7 (CH), 61.12 (CH2), 47.6 (CH2), 45.4 (CH),
42.0 (CH), 30.0 (CH2).
A solution of 6-chloropurine (0.16 g, 1.03 mmol), 60% NaH (40
mg, 1.6 mmol) and 18-crown-6 ether (0.16 g, 0.59 mmol) in anhyd
DMF (10 mL) was stirred at 55 °C for 1.5 h. A solution of 9 (0.27
g, 0.59 mmol) in DMF (6 mL) was added, and stirring at 55 °C was
continued for further 24 h, after which the reaction mixture was di-
luted with CH2Cl2 (35 mL) and washed with H2O (4 × 25 mL). The
organic phase was dried over Na2SO4, and removal of the solvent
left a solid residue (0.31 g) that was fractionated on a silica gel col-
umn using hexane–EtOAc (1:1) as eluent. The early fractions af-
forded 11 (0.11 g, 32%) as an oil that slowly crystallized. The
middle fractions gave unreacted 9 (42 mg) and the late fractions
provided 10 (84 mg, 28%) as a pale yellow solid.
EIMS: m/z (%) = 450 (4) [M], 449 (17), 441 (17), 440 (22), 439
(46), 438 (29), 315 (20), 314 (41), 313 (55), 297 (22), 296 (14), 295
(18), 285 (25), 284 (69), 283 (100), 272 (13), 271 (57), 255 (16),
253 (12), 252 (12), 239 (15), 153 (11), 142 (14), 128 (25), 127 (13),
115 (23), 89 (11), 74 (11), 73 (19).
Compound 11
Mp 113–115 ºC (after washing with hexane).
IR (KBr): 3056, 2939, 1732, 1685, 1534, 1491, 1445, 1424, 1375,
1364, 1266, 1244, 1219, 1037, 914, 903, 769, 705 cm–1.
HRMS: m/z calcd for C26H22N6O2: 450.1804; found: 450.1802.
1H NMR (CDCl3): d = 1.80 (s, 3 H, OCOCH3), 2.69 (dd, J = 16.2,
1.7 Hz, 1 H, 6-HH), 3.09 (ddt, J = 13.7, 8.5, 2.6 Hz, 1 H, 6-HH),
3.72–3.78 (m, 1 H, OCOCHH), 3.85–3.91 (m, 1 H, OCOCHH),
4.01–4.09 (m, 1 H, 5-H), 5.20 (s, 1 H, =CHH), 5.26 (s, 1 H, =CHH),
7.49–7.56 (m, 6 H), 7.69–7.71 (m, 2 H), 7.79–7.82 (m, 2 H).
13C NMR (CDCl3): d = 170.5 (C), 158.6 (C), 144.3 (C), 142.5 (C),
137.5 (C), 136.7 (C), 136.5 (C), 129.3 (CH), 129.2 (CH), 128.9
(CH), 128.7 (CH), 128.5 (CH), 128.4 (CH), 114.5 (CH2), 64.8
(CH2), 40.5 (CH), 36.0 (CH2), 20.6 (CH3).
( )-cis-{7-[(6-Methoxy-9H-purin-9-yl)methyl]-1,4-diphenyl-
6,7-dihydro-5H-cyclopenta[d]-pyridazin-5-yl}methanol (12b)
A solution of chloropurine 10 (100 mg, 0.20 mmol) and K2CO3
(40.6 mg, 0.7 mmol) in MeOH (7 mL) was stirred at r.t. for 40 h.
The solvent was evaporated under reduced pressure, leaving a solid
residue (175 mg) that after chromatography on silica gel with
CH2Cl2–MeOH (97:3) as eluent afforded 12b as a white solid (80
mg, 89%); mp 156–157 ºC.
IR (KBr): 3308, 2941, 2869, 1602, 1484, 1447, 1414, 1379, 1342,
1227, 1060, 1011, 767, 700, 644 cm–1.
EIMS: m/z (%) = 357 (9) [M + 1], 356 (38) [M], 357 (21), 313 (16),
295 (100), 284 (6), 283 (23), 281 (14), 267 (12), 253 (13), 252 (24),
239 (6), 207 (6).
1H NMR (CDCl3): d = 1.81–1.89 (m, 1 H, 6-HH), 2.38–2.46 (m, 1
H, 6-HH), 3.37–3.41 (m, 1 H, 5-H), 3.59 (dd, J = 11.8, 2.7 Hz, 1 H),
3.82–3.84 (d, J = 8.7 Hz, 1 H, NCHH), 3.92–3.94 (m, 1 H, NCHH),
4.15 (s, 3 H, OCH3), 4.3–4.36 (m, 2 H, OCH2), 4.78 (br s, 1 H, D2O
exchange, OH), 7.46–7.57 (m, 7 H), 7.74–7.77 (m, 2 H), 7.85–7.87
(m, 2 H), 8.44 (s, 1 H, 2purine-H).
HRMS: m/z calcd for C23H20N2O2: 356.1525; found: 356.1742.
Compound 10
Mp 195–196 ºC.
IR (KBr): 3450, 2893, 2360, 1736, 1594, 1558, 1384, 1349, 1243,
1107, 966, 938, 769, 696 cm–1.
1H NMR (CDCl3): d = 1.91 (s, 3 H, OCOCH3), 1.92–1.96 (m, 1 H,
6-HH), 2.57 (dt, J = 14.3, 5.2 Hz, 1 H, 6-HH), 3.83–3.91 (m, 2 H),
4.08–4.21 (m, 3 H), 4.54–4.60 (m, 1 H), 7.44–7.58 (m, 6 H), 7.68
(s, 1 H, 8purine-H), 7.78–7.85 (m, 4 H), 8.67 (s, 1 H, 2purine-H).
13C NMR (CDCl3): d = 170.5 (C), 158.2 (C), 157.6 (CH), 151.9
(CH), 151.8 (C), 151.2 (C), 144.7 (CH), 141.6 (C), 136.3 (C), 136.0
(C), 131.4 (C), 129.8 (CH), 129.1 (CH), 129.0 (CH), 128.4 (CH),
128.3 (CH), 64.5 (CH2), 47.4 (CH2), 43.9 (CH), 42.9 (CH), 30.4
(CH2), 20.8 (CH3).
13C NMR (CDCl3): d = 161.3 (C), 158.4 (C), 157.3 (C), 152.1 (C),
152.0 (CH), 143.4 (C), 142.1 (C), 142.0 (CH), 136.7 (C), 136.6 (C),
129.7 (CH), 129.5 (C), 129.3 (CH), 129.0 (CH), 128.8 (CH), 128.4
(CH), 128.3 (CH), 121.4 (C), 62.2 (CH2), 54.4 (CH), 46.4 (CH),
45.3 (CH2), 45.2 (CH), 29.3 (CH2).
EIMS: m/z (%) = 466 (34) [M + 2], 465 (100) [M + 1], 464 (4) [M],
435 (10), 316 (9), 315 (33), 313 (6), 307 (9), 285 (11), 284 (7), 283
(17), 271 (9), 155 (10), 154 (36).
HRMS: m/z calcd for C27H25N6O2: 465.2039; found: 465.2046.
( )-cis-{7-[(6-Cyclopropylamine-9H-purin-9-yl)methyl]-1,4-
diphenyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-yl}methyl
Acetate (13a)
HRMS: m/z calcd for C28H23ClN6O2; 510.1571; found: 510.1552.
A solution of 10 (114 mg, 0.22 mmol) and cyclopropylamine (127
mg, 2.22 mmol) in EtOH (10 mL) was refluxed for 22 h. Removal
of the solvent under reduced pressure left a solid from which, fol-
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O. Caamaño et al.
PAPER
lowing chromatography on silica gel with CH2Cl2–MeOH (95:5) as
eluent, 13a (108 mg, 91%) was isolated as a white solid; mp 137–
138 ºC.
washed successively with 10% K2CO3 solution (2 × 50 mL) and wa-
ter (50 mL). After removal of the solvent under reduced pressure the
resulting residue was fractionated on a silica gel column with hex-
ane–EtOAc (1:1) and EtOAc–MeOH (95:5) as successive eluents.
Compound 14 (0.52 g, 65%) was isolated as a white solid from the
fractions eluted with hexane–EtOAc, and unreacted 6 (115 mg) was
recovered from those eluted with EtOAc–MeOH.
IR (KBr): 3413, 2362, 1738, 1616, 1476, 1382, 1296, 1235, 1039,
767, 699, 646 cm–1.
1H NMR (CDCl3): d = 0.59–0.63 (m, 2 H, cyclopropyl), 0.86–0.91
(m, 2 H, cyclopropyl), 1.84 (s, 3 H, OCOCH3), 2.04 (dt, J = 14.3,
3.1 Hz, 1 H, 6-HH), 2.51 (dt, J = 14.3, 9.8 Hz, 1 H, 6-HH), 2.96–
2.99 (m, 1 H, 1cyclopropyl-H), 3.57 (dd, J = 11.2, 7.2 Hz, 1 H, 5-H),
3.81 (dd, J = 11.2, 4.3 Hz, 1 H, 7-H), 4.00–4.06 (m, 2 H), 4.10–4.12
(m, 1 H), 4.47–4.53 (m, 1 H, CHHO), 5.92 (br s, 1 H, D2O ex-
change, NH), 7.22 (s, 1 H, 8purine-H), 7.43–7.53 (m, 6 H), 7.74–7.76
(m, 2 H), 7.86–7.88 (m, 2 H), 8.35 (s, 1 H, 2purine-H).
13C NMR (CDCl3): d = 170.4 (C), 158.0 (C), 157.6 (C), 155.7 (C),
153.1 (CH), 141.9 (C), 141.8 (C), 139.3 (CH), 136.4 (C), 136.2 (C),
129.6 (CH), 129.5 (CH), 128.9 (CH), 128.4 (CH), 128.2 (CH),
119.6 (C), 64.6 (CH2), 46.1 (CH2), 44.2 (CH), 42.7 (CH), 30.0
(CH2), 20.6 (CH3), 7.8 (2 × CH2).
Compound 14
Mp 168–169 ºC.
IR (KBr): 3433, 2927, 2855, 1555, 1446, 1386, 1252, 1121, 1030,
1002, 834, 769, 700 cm–1.
1H NMR (CDCl3): d = –0.26 [s, 3 H, Si(CH3)2], –0.22 [s, 3 H,
Si(CH3)2], 0.68 [s, 9 H, C(CH3)3], 1.90 (br s, 1 H, D2O exchange,
OH), 2.14 (dt, J = 14.2, 3.6 Hz, 1 H, 6-HH), 2.64 (dt, J = 14.2, 10.3
Hz, 1 H, 6-HH), 3.34–38. (m, 2 H, 5-H, 7-H), 3.46–3.49 (m, 2 H),
3.90–3.97 (m, 2 H), 7.43–7.55 (m, 6 H), 7.75–7.79 (m, 4 H).
13C NMR (CDCl3): d = 158.0 (C), 157.8 (C), 143.1 (C), 143.0 (C),
137.2 (C), 137.1 (C), 129.2 (CH), 128.8 (CH), 128.7 (CH), 128.4
(CH), 128.3 (CH), 64.1 (CH2), 63.9 (CH2), 46.1 (CH), 46.0 (CH),
29.9 (CH2), 25.8 [C(CH3)3], 18.23 (C), -5.7 (CH3), –5.8 (CH3).
EIMS: m/z (%) = 532 (21) [M + 1], 531 (56) [M], 516 (14), 505 (10),
504 (30), 502 (21), 471 (14), 444 (23), 358 (16), 357 (59), 298 (22),
297 (100), 296 (36), 295 (58), 284 (14), 283 (53), 281 (13), 253
(11), 252 (18), 236 (11), 188 (11), 187 (12), 175 (22), 174 (44), 160
(27), 77 (10).
EIMS: m/z (%) = 446 (10) [M], 432 (14), 431 (40), 415 (31), 390
(28), 389 (100), 388 (11), 387 (33), 298 (10), 297 (44), 285 (11),
283 (23), 282 (12), 281 (19), 253 (10), 252 (12), 194 (53), 75 (14).
HRMS: m/z calcd for C31H29N7O2: 531.2382; found: 531.2401.
HRMS: m/z calcd for C27H34N2O2Si: 446.2390; found: 446.2383.
( )-cis-{7-[(6-Cyclopropylamino-9H-purin-9-yl)methyl]-1,4-
diphenyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-yl}metha-
nol (13b)
A solution of 13a (0.1 g, 0.19 mmol) and K2CO3 (39 mg, 0.28
mmol) in anhyd MeOH (5 mL) was refluxed under Ar for 24 h. Re-
moval of the solvent under reduced pressure left a residue from
which, following chromatography on silica gel with CH2Cl2–
MeOH (97:3) as eluent, 13b (60 mg, 65%) was isolated as a white
solid; mp 191–192 ºC.
( )-cis-{7-[(tert-Butyldimethylsilyloxy)methyl]-1,4-diphenyl-
6,7-dihydro-5H-cyclopenta[d]pyridazin-5-yl]methyl Mesylate
(15)
Mesyl chloride (0.77 g, 6.72 mmol) was added to a solution of 14
(1.0 g, 2.24 mmol), Et3N (0.94 mL) and a catalytic amount of
DMAP in anhyd CH2Cl2 (15 mL) stirred under Ar at –10 °C. After
stirring for 1 h at r.t., the mixture was diluted with CH2Cl2 (60 mL)
and washed successively with water (2 × 80 mL), 1 M NaOH (2 ×
40 mL) and brine (80 mL). The organic phase was then dried over
Na2SO4 and concentrated under reduced pressure, leaving a residue
that following chromatography on a silica gel column with CH2Cl2–
MeOH (99:1) as eluent afforded 15 (1.07 g, 91%) as a white solid;
mp 56–57 ºC.
IR (KBr): 3354, 2362, 1628, 1540, 1483, 1446, 1354, 1303, 1235,
1071, 761, 701, 646 cm–1.
1H NMR (CDCl3): d = 0.54–0.58 (m, 2 H, cyclopropyl), 0.80–0.93
(m, 2 H, cyclopropyl), 2.13–2.20 (m, 1 H, 6-HH), 2.26–2.33 (m, 1
H, 6-HH), 2.93–2.98 (m, 1 H, 1cyclopropy-H), 3.36 (dd, J = 11.1, 5.1
Hz, 1 H, 5-H), 3.48 (dd, J = 11.1, 3.3 Hz, 1 H, 7-H), 3.72 (dd, J =
8.1, 3.6 Hz, 1 H, NCHH), 3.93, 4.02 (ABM system, J = 13.9, 8.7,
5.2 Hz, 2 H, HOCH2), 4.43–4.50 (m, 1 H, CHHN), 6.24 (br s, 1 H,
D2O exchange, NH), 7.06 (s, 1 H, 8purine-H), 7.41–7.43 (m, 6 H),
7.54–7.56 (m, 2 H), 7.68–7.70 (m, 2 H), 8.34 (s, 1 H, 2purine-H).
13C NMR (CDCl3): d = 158.1 (C), 157.6 (C), 155.5 (C), 153.2 (CH),
143.2 (C), 142.6 (C), 138.9 (CH), 136.6 (C), 136.3 (C), 129.5 (CH),
129.4 (CH), 128.8 (CH), 128.7 (CH), 128.4 (CH), 128.4 (CH),
119.1 (C), 62.8 (CH2), 46.3 (CH2), 45.3 (CH), 44.2 (CH), 32.0
(CH2), 29.6 (CH), 7.2 (2 × CH2).
IR (KBr): 2928, 2856, 2360, 2341, 1540, 1494, 1471, 1449, 1360,
1256, 1176, 1095, 956, 834, 770, 699, 669 cm–1.
1H NMR (CDCl3): d = –0.27 [s, 3 H, Si(CH3)2], –0.21 [s, 3 H,
Si(CH3)2], 0.65 [s, 9 H, C(CH3)3], 2.11 (dt, J = 14.2, 3.2 Hz, 1 H, 6-
HH), 2.65–2.73 (m, 1 H, 6-HH), 2.68 (s, 3 H, SO2CH3), 3.31 (dd,
J = 10.0, 5.5 Hz, 1 H, 5-H), 3.47 (dd, J = 10.0, 2.8 Hz, 1 H, 7-H),
3.91–4.00 (m, 3 H, CH3SO2CHH + TBDMSiOCH2), 4.15–4.20 (m,
1 H, CH3SO2CHH), 7.49–7.57 (m, 6 H), 7.80–7.82 (m, 4 H).
13C NMR (CDCl3): d = 158.0 (C), 157.4 (C), 143.3 (C), 140.8 (C),
136.7 (C), 129.6 (CH), 129.4 (CH), 129.1 (CH), 128.8 (CH), 128.5
(CH), 128.3 (CH), 70.4 (CH2), 63.5 (CH2), 46.3 (CH), 43.5 (CH),
36.7 (CH), 30.4 (CH2), 25.8 [C(CH3)3], 18.1 (C), –5.7 (CH3), –5.8
(CH3).
EIMS: m/z (%) = 490 (11) [M + 1], 316 (27), 315 (100), 313 (18),
299 (10), 298 (15), 297 (45), 295 (11), 285 (17), 284 (15), 283 (46),
281 (10), 272 (11), 271 (26), 189 (15), 188 (14), 176 (36), 174 (13),
165 (11), 160 (10).
EIMS: m/z (%) = 526 (38) [M + 1], 525 (100) [M], 468 (8), 467 (24),
429 (7), 297 (10), 285 (5), 283 (10), 271 (5).
HRMS: m/z calcd for C29H28N7O: 490.2355; found: 490.2337.
HRMS calcd. for C28H37N2O4SSi, 525.2243; found, 525.2240.
( )-cis-{7-[(tert-Butyldimethylsilyloxy)methyl]-1,4-diphenyl-
6,7-dihydro-5H-cyclopenta[d]pyridazin-5-yl}methanol (14)
A suspension of diol 6 (0.60 g, 1.81 mmol) and 60% NaH (72.32
mg, 1.81 mmol) in anhyd THF (40 mL) was stirred under Ar at r.t.
for 50 min, after which a solution of tert-butyldimethylsilyl chloride
(0.27g, 1.81 mmol) in 5 mL of the same solvent was added dropwise
and stirring was continued for further 16 h. THF was removed under
reduced pressure, the crude was dissolved in EtOAc (50 mL) and
( )-cis-5-[(tert-Butyldimethylsilyloxy)methyl]-7-methylidene-
1,4-diphenyl-6,7-dihydro-5H-cyclopenta[d]pyridazine (16) and
( )-cis-5-[(tert-Butyldimethylsilyloxy)methyl]-7-[(6-chloro-9H-
purin-9-yl)methyl]-1,4-diphenyl-6,7-dihydro-5H-cyclopen-
ta[d]pyridazine (17a)
Method A: A solution of 6-chloropurine (0.16 g, 0.98 mmol), 60%
NaH (39.14 mg, 0.98 mmol) and 18-crown-6 ether (93.54 mg, 0.35
mmol) in anhyd DMF (12 mL) was stirred at 55 °C for 1.5 h and
Synthesis 2004, No. 17, 2855–2862 © Thieme Stuttgart · New York

PAPER
Convenient Synthesis of New Purinyl-homo-carbonucleosides
2861
then allowed to cool to r.t. A solution of 15 (0.30 g, 0.57 mmol) in
anhyd DMF (8 mL) was added via a cannula, and stirring was con-
tinued for further 24 h at 55 °C, after which the reaction mixture was
allowed to cool, diluted with CH2Cl2 (50 mL) and washed with H2O
(4 × 50 mL). The organic phase was concentrated to dryness, leav-
ing a solid residue (0.35 g) that was fractionated on a silica gel col-
umn using hexane–EtOAc (1:1) as eluent. The early fractions
afforded 16 (43 mg, 17%) as a white solid. The middle fractions
gave unreacted 15 (120 mg) whereas and the late fractions yielded
17a (65 mg, 20%) as a pale yellow solid.
20 mL in vacuo. This concentrate was stirred with 4 Å molecular
sieves (ca. 2.5 g) for 1 h at 0 ºC, and then treated with the tetrabutyl-
ammonium salt of 6-chloropurine (0.27 mg, 0.68 mmol), previously
prepared from 6-chloropurine as described Franzyk et al.12 Stirring
was continued for 64 h at –10 ºC, after which the mixture was fil-
tered and the filtrate was concentrated to dryness, leaving a residue
(0.57 g) that was fractionated on a silica gel column using hexane–
EtOAc (1:1), hexane–EtOAc (1:3) and 2% MeOH–EtOAc as suc-
cessive eluents. The middle fractions afforded 17a (27 mg, 8%) as
a white solid with spectroscopic data identical to those of the com-
pound obtained by Method A.
Compound 16
Mp 116–118 ºC.
( )-cis-{7-[(6-Chloro-9H-purin-9-yl)methyl]-1,4-diphenyl-6,7-
dihydro-5H-cyclopenta[d]pyridazin-5-yl}methanol (17b)
A 1 M solution of TBAF in THF (0.4 mL, 0.40 mmol) was added
dropwise to a solution of 17a (0.11 g, 0.20 mmol) in the same sol-
vent (4 mL) stirred under Ar in an ice bath. The solution was al-
lowed to reach r.t., and stirring was continued for a further 30 min.
The solvent was removed under reduced pressure and the residue
was chromatographed on a silica gel column using EtOAc–hexane
(9:1) as eluent. Concentration to dryness of the non-void fractions
afforded 17b (55 mg, 62%) as a white solid; mp 217–219 ºC.
IR (KBr): 3080, 2926, 2854, 1542, 1492, 1465, 1382, 1253, 1109,
1003, 923, 835, 768, 697 cm–1.
1H NMR (CDCl3): d = –0.27 [s, 3 H, Si(CH3)2], –0.20 [s, 3 H,
Si(CH3)2], 0.68 [s, 9 H, C(CH3)3], 2.81–2.86 (m, 1 H, 6-HH), 3.02
(ddd, J = 16.4, 8.5, 2.7 Hz, 1 H, 6-HH), 3.17 (dd, J = 9.9, 6.7 Hz, 1
H, TBSOCHH), 3.41 (dd, J = 9.9, 3.4 Hz, 1 H, TBDMSiOCHH),
3.77–3.82 (m, 1 H, 5-H), 5.12–5.14 (m, 1 H, =CHH), 5.20–5.21 (m,
1 H, =CHH), 7.45–7.53 (m, 6 H), 7.66–7.69 (m, 2 H), 7.77–7.80 (m,
2 H).
13C NMR (CDCl3): d = 158.8 (C), 156.3 (C), 145.7 (C), 143.9 (C),
138.3 (C), 137.1 (C), 137.0 (C), 129.2 (CH), 129.1 (CH), 129.0
(CH), 128.7 (CH), 128.5 (CH), 128.4 (CH), 113.7 (CH2), 63.4
(CH2), 43.8 (CH), 35.6 (CH2), 25.6 [C(CH3)3], 18.0 (C), -5.7 (CH3),
–5.8(CH3).
IR (KBr): 3178, 2924, 2867, 1595, 1567, 1497, 1443, 1379, 1332,
1292, 1254, 1215, 1175, 1074, 1021, 941, 911, 766, 696, 638 cm–1.
1H NMR (DMSO-d6): d = 1.91–1.98 (m, 1 H, 6-HH), 2.54–2.64 (m,
1 H, 6-HH), 3.14–3.19 (m, 1 H, 5-H), 3.28–3.36 (m, 1 H, 7-H),
3.98–4.04 (m, 1 H, OCHH), 4.18 (dd, J = 13.8, 7.9 Hz, 1 H, OCHH),
4.28 (dd, J = 13.8, 7.5 Hz, 1 H, NCHH), 4.65–4.70 (m, 1 H, NCHH),
4.81 (t, D2O exchange, J = 4.9 Hz, 1 H, OH), 7.23–7.33 (m, 4 H),
7.52–7.67 (m, 4 H), 7.84–7.86 (m, 2 H), 8.25 (s, 1 H, 8purine-H), 8.69
(s, 1 H, 2purine-H).
EIMS: m/z (%) = 430 (38) [M + 2], 429 (100) [M + 1], 428 (5) [M],
427 (6), 372 (6), 371 (15), 297 (13), 295 (7), 285 (7), 284 (7), 283
(26).
13C NMR (DMSO-d6): d = 157.4 (C), 156.9 (C), 151.5 (C), 151.0
(CH), 148.7 (C), 146.7 (CH), 143.6 (C), 142.8 (C), 136.8 (C), 136.0
(C), 130.6 (C), 129.0 (CH), 128.6 (CH), 128.4 (CH), 128.2 (CH),
128.0 (CH), 127.9 (CH), 127.8 (CH), 61.1 (CH2), 47.6 (CH2), 42.0
(CH), 30.6 (C), 30.1 (CH2).
HRMS: m/z calcd for C27H33N2Osi: 429.2373; found: 429.2362.
Compound 17a
Mp 87–89 ºC.
IR (KBr): 3059, 2951, 2929, 2856, 1592, 1559, 1496, 1443, 1381,
1334, 1254, 1214, 1178, 1142, 1102, 937, 835, 771, 699, 637 cm–1.
EIMS: m/z (%) = 471 (22) [M + 2], 470 (18), 469 (59) [M], 453 (20),
439 (17), 316 (19), 315 (75), 297 (7), 286 (20), 285 (100), 284 (26),
283 (89), 271 (26).
1H NMR (CDCl3): d = –0.28 [s, 3 H, Si(CH3)2], –0.22 [s, 3 H,
Si(CH3)2], 0.63 [s, 9 H, C(CH3)3], 1.99–2.03 (m, 1 H, 6-HH), 2.58
(ddd, J = 14.1, 10.0, 4.1 Hz, 1 H, 6-HH), 3.35 (dd, J = 10.2, 4.5 Hz,
1 H, OCHH), 3.52 (dt, J = 10.2, 2.8 Hz, 1 H, OCHH), 3.96–3.99 (m,
1 H, 5-H), 4.12 (dd, J = 13.8, 5.8 Hz, 1 H, NCHH), 4.25 (dd, J =
13.8, 8.6 Hz, 1 H, NCHH), 4.49–4.54 (m, 1 H, 7-H), 7.34–7.43 (m,
3 H), 7.47–7.52 (m, 3 H), 7.56 (s, 1 H, 8purine-H), 7.75–7.80 (m, 4
H), 8.64 (s, 1 H, 2purine-H).
13C NMR (CDCl3): d = 157.9 (C), 157.3 (C), 151.8 (C), 151.7 (CH),
151.0 (C), 144.7 (CH), 142.8 (C), 142.2 (C), 136.6 (C), 136.2 (C),
131.4 (C), 129.5 (CH), 129.4 (CH), 128.8 (CH), 128.7 (CH), 128.5
(CH), 128.3 (CH), 63.5 (CH2), 47.7 (CH2), 46.2 (CH), 43.5 (CH),
31.1 (CH2), 25.8 [(CH3)3], 18.2 [C(CH3)3], –5.6 [(CH3)2].
HRMS: m/z calcd for C26H22ClSiN6O: 471.1530; found: 471.1508.
( )-cis-9-({7-[(tert-Butyldimethylsilyloxy)methyl]-1,4-diphenyl-
6,7-dihydro-5H-cyclopenta[d]pyridazin-5-yl}methyl)-N-cyclo-
pentyl-9H-purin-6-amine (19a)
A solution of 17a (133 mg, 0.24 mmol) and cyclopentylamine (0.13
mL, 0.12 mg, 1.37 mmol) in anhyd EtOH (10 mL) was refluxed un-
der Ar for 8 h. Removal of the solvent under reduced pressure left a
solid residue that after chromatography on a silica gel column with
hexane–EtOAc (1:2) as eluent afforded 19a (109 mg, 76%) as a
white solid; mp 110–112 ºC.
IR (KBr): 3338, 2952, 2858, 2362, 1616, 1475, 1382, 1296, 1252,
1103, 925, 836, 771, 698 cm–1.
EIMS: m/z (%) = 585 (45) [M + 2], 584 (44) [M + 1], 583 (100) [M],
528 (5), 527 (14), 526 (30), 430 (9), 429 (24), 297 (7), 285 (5), 284
(4), 283 (15), 271 (5).
1H NMR (CDCl3): d = –0.27 [s, 3 H, Si(CH3)2], –0.22 [s, 3 H,
Si(CH3)2], 0.67 [s, 9 H, C(CH3)3], 1.52–1.55 (m, 2 H), 1.65–1.76
(m, 5 H), 2.03–2.14 (m, 3 H, 6-HH + CHHcyclopentyl), 2.55 (dd, J =
14.1, 10.0 Hz, 1 H, 6-HH), 3.24 (dd, J = 10.1, 5.2 Hz, 1 H, 7-H),
3.48 (dd, J = 10.1, 2.9 Hz, 1 H, 5-H), 3.94 (dd, J = 7.4, 2.5 Hz, 1 H,
OCHH), 4.06–4.08 (m, 2 H, OCHH + NCHH), 4.55–4.59 (m, 2 H,
NCHH), 5.57 (d, D2O exchange, J = 6.78 Hz, 1 H, NH), 7.16 (s, 1
H, 8purine-H), 7.36–7.53 (m, 6 H), 7.79–7.85 (m, 4 H), 8.30 (s, 1 H,
HRMS: m/z calcd for C32H36ClSiN6O: 583.2408; found: 583.2114.
Method B: To a solution of anhyd pyridine (0.13 mL, 1.66 mmol)
in anhyd CH2Cl2 (5 mL) at –40 ºC was slowly added a solution of
(CF3SO2)2O (0.16 mL, 0.96 mmol) in anhyd CH2Cl2 (5 mL). After
the mixture had been stirred for 50 min, 14 (0.27 g, 0.61 mmol) in
CH2Cl2 (5 mL) was added dropwise, the temperature was allowed
to rise to –20 ºC over 2 h, and stirring was continued at this temper-
ature for another 19 h. The resulting solution was diluted with an-
hyd CH2Cl2 (35 mL), ice (5 g) was added, and the organic phase was
washed successively with 3% aq HCl (10 mL), sat. aq NaHCO3 (30
mL) and brine (20 mL), dried over Na2SO4, and concentrated to ca.
2
purine-H).
13C NMR (DMSO-d6): d = 157.8 (C), 157.5 (C), 154.3 (C), 153.0
(CH), 142.9 (C), 142.6 (C), 139.1 (CH), 136.8 (C), 136.3 (C), 129.3
(CH), 129.2 (CH), 128.7 (CH), 128.6 (CH), 128.5 (CH), 128.4
Synthesis 2004, No. 17, 2855–2862 © Thieme Stuttgart · New York

2862
O. Caamaño et al.
PAPER
(CH), 119.5 (C), 63.5 (CH2), 47.0 (CH2), 46.2 (CH), 43.6 (CH),
33.5 (CH2), 30.8 (CH2), 25.8 [(CH3)3], 23.6 (CH2), 18.20 [C(CH3)3],
–5.7 [(CH3)2], –5.9 [(CH3)2].
References
(1) (a) Cheson, B. D. Hematol. Cell. Ther. (Suppl. 2) 1996, 38,
109. (b) Bergmann, L. Leukemia: (Suppl. 2) 1997, 11, 29.
(2) (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48,
571. (b) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.;
Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50,
10611. (c) Huryn, D.; Okabe, M. Chem. Rev. 1992, 92,
1745. (d) Mansour, T. S.; Storer, R. Curr. Pharm. Des. 1997,
3, 227. (e) Ichikewa, E.; Kato, K. Curr. Med. Chem. 2001, 8,
385.
(3) Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192.
(4) (a) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.;
Wayne, H.; St. Clair, M. H.; Boone, L. R.; Tisdale, M.;
Parry, N. R.; Reardon, J. E.; Dornsife, R. E.; Averett, D. R.;
Krenitsky, T. A. Antimicrob. Agents Chemother. 1997, 41,
1082. (b) Faletto, M. B.; Miller, W. H.; St. Clair, E. P.;
Garvey, M. H.; Daluge, S. M.; Good, S. S. Antimicrob.
Agents Chemother. 1997, 41, 1099. (c) Foster, R. H.;
Faulds, D. Drugs 1998, 729.
EIMS: m/z (%) = 633 (30) [M + 1], 632 (88) [M], 631 (10), 602 (11),
583 (11), 575 (10), 574 (22), 451 (11), 431 (11), 430 (36), 429
(100), 297 (14), 283 (28), 202 (10), 154 (12).
HRMS: m/z calcd for C37H46SiN7O: 632.3507; found: 632.3482.
( )-cis-{7-[(6-Cyclopentylamino-9H-purin-9-yl)methyl]-1,4-
diphenyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-yl}metha-
nol (19b)
A 1 M solution of TBAF in THF (0.51 mL, 0.51 mmol) was added
dropwise to a solution of 19a (0.16 g, 0.25 mmol) in the same sol-
vent (6 mL) stirred under Ar in an ice bath. The solution was al-
lowed to reach r.t., and stirring was continued for a further 4.5 h.
The solvent was removed under reduced pressure and the residue
was chromatographed on a silica gel column using CH2Cl2–MeOH
(95:5) as eluent. Concentration to dryness of the non-void fractions
afforded 19b (114 mg, 88%) as a white solid; mp 158–160 ºC.
(5) (a) Fernández, F.; García-Mera, X.; Morales, M.;
Rodríguez-Borges, J. E.; De Clercq, E. Synthesis 2002,
1084. (b) Fernández, F.; García-Mera, X.; Morales, M.;
Vilariño, L.; Caamaño, O. Tetrahedron 2004, 60, 9245.
(6) Yao, S.-W.; Lopes, 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.
(7) Hocek, M.; Hol, A.; Votruba, I.; Dvoráková, H. J. Med.
Chem. 2000, 43, 1817.
(8) (a) López, C.; Caamaño, O.; Hergueta, A. R.; Fernández, F.;
García, M. D. Tetrahedron Lett. 2002, 43, 5311. (b)García,
M. D.; Caamaño, O.; Fernández, F.; Figueira, M. J.; Gómez,
G. Synthesis 2003, 2138.
IR (KBr): 3187, 2941, 2865, 1626, 1483, 1448, 1381, 1319, 1231,
770, 698, 643 cm–1.
1H NMR (CDCl3): d = 1.25–1.32 (m, 1 H), 1.48–1.59 (m, 2 H),
1.61–1.64 (m, 3 H, one exchanging with D2O, OH + CHHcyclopentyl),
1.67–1.72 (m, 2 H), 1.90 (d, J = 14.4 Hz, 1 H), 2.03–2.10 (m, 2 H,
6-HH + 1Hcyclopentyl), 2.34–2.43 (m, 1 H, 6-HH), 3.37 (dd, J = 12.0,
3.6 Hz, 1 H, 5-H), 3.56 (dd, J = 12.0, 7.1 Hz, 1 H, 7-H), 3.71–3.74
(m, 1 H, HOCHH), 3.87–3.90 (m, 1 H, HOCHH), 4.19–4.28 (m, 1
H, NCHH), 4.46–4.60 (m, 1 H, NCHH), 6.16 (d, D2O exchange,
J = 7.1 Hz, 1 H, NH), 7.32 (s, 1 H, 8purine-H), 7.42–7.55 (m, 6 H),
7.72–7.75 (m, 2 H), 7.83–7.85 (m, 2 H), 8.21 (s, 1 H, 2purine-H).
13C NMR (CDCl3): d = 158.4 (C), 157.3 (C), 154.5 (C), 152.9 (CH),
143.6 (C), 142.3 (C), 139.1 (CH), 136.7 (C), 136.6 (C), 129.5 (CH),
129.2 (CH), 128.9 (CH), 128.7 (CH), 128.3 (CH), 128.2 (CH),
119.1 (C), 62.0 (CH2), 52.4 (CH2), 46.6 (CH), 45.4 (CH), 44.9
(CH2), 29.2 (CH2), 23.7 (CH2).
(9) Kobayashi, T.; Sugawara, H.; Nikaeen, B. Bull. Chem. Soc.
Jpn. 1998, 71, 497.
(10) Dumas, M.; Vo-Quang, Y.; Vo-Quang, L.; Le Goffic, F.
Synthesis 1989, 64.
(11) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967,
40, 2380. (b) Mitsunobu, O. Synthesis 1981, 1.
(c) Mitsunobu, O.; Wata, M.; Sano, T. J. Am. Chem. Soc.
1972, 94, 679. (d) Hughes, D. L. In Organic Reactions, Vol.
42; Paquette, L. A., Ed.; John Wiley and Sons: New York,
1992, 344.
EIMS: m/z (%) = 518 (100) [M + 1], 517 (10) [M], 516 (8), 488 (18),
316 (15), 315 (62), 313 (8), 307 (8), 285 (17), 284 (8), 283 (20), 271
(9), 243 (9), 242 (47), 204 (13), 186 (57), 155 (18), 154 (52).
HRMS: m/z calcd for C31H32N7O: 518.2667; found: 518.2624.
(12) Franzyk, H.; Rasmussen, J. H.; Mazzei, R. A.; Jensen, S. R.
Acknowledgment
Eur. J. Org. Chem. 1998, 2931.
(13) De Clercq, E. In Vivo and Ex Vivo Text Systems to
Rationalize Drug Design and Delivery; Cromelin, D.;
Couvreur, P.; Duchene, D., Eds.; Editions de Santé: Paris,
1994.
The authors thank the Xunta de Galicia for financial support under
projects PGIDT01PXI20302PR and PGIDT02BTF20305PR.
Synthesis 2004, No. 17, 2855–2862 © Thieme Stuttgart · New York