Synthesis of cyclopenta[d]pyridazinediol precursors of carbanucleosides

Article abstract of DOI:10.1055/s-2007-983827

The hemiprotected diols 7 and 8, which are prospective precursors of carbanucleosides of this family, were prepared from the mesylates of the corresponding higher homologues by elimination of the mesyloxy group using l,8-diazabicyclo[5.4.0]undec-7-ene fol

Full text of DOI:10.1055/s-2007-983827

PAPER
2621
Synthesis of Cyclopenta[d]pyridazinediol Precursors of Carbanucleosides
S
ynthesi
s
s
of Cyclo
a
penta[
d
]py
b
ridazinediol
Precursors
of
CarbanucleP
osides érez-Castro,a Olga Caamaño,*a Marcos D. García,a Generosa Gómez,*b Franco Fernández,a Joana Ferreira,a
Carmen Lópeza
a
Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela,
Spain
Fax +34(981)584912; E-mail: qoolga@usc.es
Departamento de Química Orgánica, Facultade de Química, Lagoas-Marcosende, Universidade de Vigo, 36200 Vigo, Spain
Fax +34(986)813663; E-mail: ggomez@uvigo.es
b
Received 20 March 2007; revised 30 April 2007
X
N
Abstract: The hemiprotected diols 7 and 8, which are prospective
precursors of carbanucleosides of this family, were prepared from
the mesylates of the corresponding higher homologues by elimina-
tion of the mesyloxy group using 1,8-diazabicyclo[5.4.0]undec-7-
ene followed by ozonolysis and reduction of the ozonide with sodi-
um borohydride.
N
N
X
N
N
N
N
N
( )n
HO
NH2
HO
1: X = OH
2: X = NHc-Pr
3
Key words: cyclopenta[d]pyridazines, silyl ethers, diols, ozonoly-
sis, Mitsunobu reaction
X
X = Cl, OMe, OEt, NH2, NHPr,
NHi-Pr, NHc-Pr, Ph, p-MePh,
p-MePh, p-MeOPh
N
N
N
Owing to their biological and chemotherapeutic proper-
ties,1 nucleoside mimetics constitute an important target
of chemical synthesis.2 Natural and synthetic carbocyclic
nucleosides can possess significant antitumour and/or an-
tiviral activity; in particular, carbovir (1)3 and abacavir
(2)4 have potent anti-HIV activity (Figure 1). On the basis
of these interesting biological results, a significant amount
of synthetic effort has been directed toward finding more
selective analogues. As part of these efforts in previous
work, our research group synthesised several 1¢(N)-ho-
mocarbanucleosides in which the double bond of the cy-
clopentene ring of carbovir and abacavir analogues was
replaced with a fused benzene,5 pyrazole,6 or pyridazine7
ring (e.g., 3–6, Figure 1). The fact that a number of these
1¢(N)-homocarbanucleosides exhibited interesting cyto-
static activity against human T lymphocytes,5a,6c and mu-
rine leukaemia cells, as well as antiviral activity against
the varicella zoster virus and cytomegalovirus,6a encour-
aged us to synthesise the lower homologues of com-
pounds 3–6 in which the purine or pyrimidine rings are
directly linked to the cyclopentene-like moiety, with a
view to correlating activity and structure.
Y
N
n = 0,1
X
HO
N
N
4
N
N
N
N
Y
X = Cl, I,OH, Ph, p-MePh,
HO
NH2, NHc-Pr
Y = H, NH2
X
5
N
N
N
N
Ph
N
N
X = Cl, OH, NH2, NHc-Pr
Y = H, NH2
HO
X = Cl, OH, OMe, NH2,
NHc-Pr, NHc-Pe
Ph
Ph
N
N
6
Figure 1
unsaturated alcohol together with the corresponding com-
pound of substitution.7 Preparation of methylidene deriv-
ative 10 was achieved in high yield from mesylate 9 by
treatment
with
1,8-diazabicyclo[5.4.0]undec-7-ene
Here we describe the synthesis of diols 7 and 8 (Figure 2),
which can be used to prepare the lower homologues of 67
and their nonphenylated counterparts, respectively. It was
envisaged that these diols could be converted into car-
bocyclic nucleosides by Mitsunobu reactions with the ap-
propriate purine or pyrimidine derivatives.5a,8
OH
OH
TBDMSO
Ph
TBDMSO
trans-7
cis-7
Ph
Ph
Ph
N
N
N
N
Heating mesylate 9 for 24 hours at 55 °C with 6-chloropu-
rine, sodium hydride, and 18-crown-6 in N,N-dimethyl-
formamide afforded a significant proportion of the
OH
TBDPSO
8
SYNTHESIS 2007, No. 17, pp 2621–2626
Advanced online publication: 30.07.2007
x
x.
x
x
.
2
0
0
7
N
N
DOI: 10.1055/s-2007-983827; Art ID: P03307SS
© Georg Thieme Verlag Stuttgart · New York
Figure 2

2622
I. Pérez-Castro et al.
PAPER
(DBU) in dry benzene9 (Scheme 1). The exocyclic double
bond of 10 then underwent ozonolysis, and the resulting
ozonide was treated either with dimethyl sulfide to afford
ketone 11, or with sodium borohydride (NaBH4) to direct-
ly afford a mixture of the desired alcohols cis- and trans-
7 in 97% yield from 10.
TBDMSO
O
Ph
Ph
i) O3, MeOH,CH2Cl2
ii) Me2S
91%
N
N
11
TBDMSO
OMs
TBDMSO
DBU, benzene
91%
Ph
Ph
Ph
Figure 3 ORTEP projection of the molecular structure of com-
pound cis-7, showing the atomic numbering scheme
Ph
N
N
N
N
9
10
i) O3, MeOH,CH2Cl2
ii) NaBH4
bearing the hydroxy group is inverted. Because the sub-
stituents on the cyclopentene rings of the biologically ac-
tive carbanucleosides carbovir (1) and abacavir (2) are cis
to each other, trans-7 is of greater interest than cis-7. To
increase the overall yield of the former, cis-7 was first
transformed into the trans-benzoate 12 in 12% yield by
reaction with benzoic acid for 15 hours under Mitsunobu
conditions.11 Longer reaction times resulted in the loss of
cis-7 without increasing the yield of 12; with a 15-hour re-
action, most untransformed cis-7 was recovered. Ben-
zoate 12 was then saponified with 1 M sodium hydroxide
in methanol–tetrahydrofuran, affording trans-7 in 77%
yield.
97%
OH
OH
TBDMSO
TBDMSO
+
Ph
Ph
Ph
Ph
N
N
N
N
trans-7
cis-7
BzOH, DEAD,
Ph3P, THF
77%
12%
1 M NaOH, THF,
MeOH
OBz
Ph
TBDMSO
Alcohol cis-8, the nonphenylated analogue of cis-7, was
obtained in a similar manner from 17. Methylidene-sub-
stituted compound 17 was prepared via mesylate 16 from
Ph
N
N
12
5,8-dihydro-5,8-methanophthalazine
(13)
(itself
obtained12
from bicyclo[2.2.1]hepta-2,5-diene-2,3-
dicarbaldehyde13). Compound 13 was cleanly trans-
formed into diol 14 in one pot and in 81% yield by ozo-
nolysis followed by reductive cleavage of the resulting
ozonide with NaBH4 (Scheme 2).7 Because protection
with a tert-butyldimethylsilyl group was less efficient for
14 than it was for the diol precursor of 9,7 diol 14 was re-
acted with tert-butyldiphenylsilyl chloride, giving silyl-
protected 15 in 32% yield and with 50–60% recovery of
substrate 14. Mesylation, too, was less efficient for 15
than it was for the corresponding precursor of 9.7 Howev-
er, reaction of mesylate 16 with DBU afforded an 89%
yield of alkene 17, which upon ozonolysis and subsequent
reduction of the ozonide with NaBH4 gave a 62% yield of
cis- and trans-8 in a 15:1 ratio. The major product was
Scheme 1
1
The H NMR spectroscopic analysis of this mixture
showed the cis/trans ratio to be approximately 21:1. The
two isomers were efficiently separated by chromatogra-
phy on silica gel with 7:1 and 3:1 mixtures of hexane–eth-
yl acetate as successive eluents. The product cis-7 (84%
from 10) eluted in the early fractions of the 7:1 mixture, a
mixture of cis- and trans-7 (9%) was obtained in the later
fractions, and trans-7 (4%) was eluted using the 3:1 sol-
vent mixture.
The cis configuration of the major alcohol was unequivo-
cally determined by single-crystal X-ray crystallography;
Figure 3 shows one of the enantiomers present in the race-
mic crystal.10 This structural information was also used to
determine the trans configuration of the other isomer.
1
identified as cis from the H NMR spectrum of the mix-
ture, in which the CH2 at C-6 signals (1.95 and 2.62 ppm)
lay upfield and downfield, respectively, of those of the
minor product (2.15 and 2.35 ppm). All these chemical
shifts were very similar to those of the corresponding pro-
tons of cis- and trans-7.
The synthesis of carbanucleosides from alcohols such as
7 is conveniently performed by means of a Mitsunobu
coupling11 or by nucleophilic substitution of a suitable de-
rivative. In both cases, the stereochemistry of the carbon
Synthesis 2007, No. 17, 2621–2626 © Thieme Stuttgart · New York

PAPER
Synthesis of Cyclopenta[d]pyridazinediol Precursors of Carbanucleosides
2623
O3 was bubbled through the mixture until, after 25 min, blue color-
ation showed the presence of excess O3, which was removed by
bubbling N2 through. The mixture was then treated with Me2S (1
mL, 13.6 mmol) under an inert atmosphere and was left stirring un-
til it reached r.t. The solvents were removed under reduced pressure,
and the resulting green paste (1 g) was purified by chromatography
(silica gel, hexane–EtOAc, 5:1 and then 3:1 mixtures as successive
eluents). Concentration of the nonvoid fractions to dryness afforded
11 as a greenish oil that slowly solidified.
OH
HO
i) O3, MeOH, CHCl3
ii) NaBH4
N
81%
N
N
N
14
13
NaH, DMF, TBDPSCl
TBDPSO
32%
OH
Yield: 0.79 g (91%).
Mp 91–93 °C.
N
N
15
IR (KBr): 2928, 2875, 2855, 2341, 1736, 1595, 1506, 1450, 1385,
1106, 836 cm–1.
Et3N, DMAP,
CH2Cl2, MsCl
58%
1H NMR (300 MHz, CDCl3): d = 7.92–7.89 (m, 2 H), 7.86–7.82 (m,
2 H), 7.58–7.52 (m, 6 H), 4.05–4.03 (m, 1 H, 7-H), 3.62 (dd, J = 9.7,
2.8 Hz, 1 H, OCHH), 3.36 (dd, J = 9.7, 3.8 Hz, 1 H, OCHH), 2.89
(dd, J = 18.7, 7.6 Hz, 1 H, 6-HH), 2.73 (dd, J = 18.7, 2.0 Hz, 1H, 6-
HH), 0.60 [s, 9 H, C(CH3)3], –0.22 [s, 3 H, Si(CH3)2], –0.35 [s, 3 H,
Si(CH3)2].
13C NMR (75 MHz, CDCl3): d = 203.8 (C), 160.2 (C), 155.5 (C),
152.0 (C), 135.9 (C), 134.0 (C), 132.1 (C), 130.2 (CH), 129.9 (CH),
129.0 (CH), 128.5 (CH), 128.0 (CH), 62.3 (CH2), 40.5 (CH2), 39.2
(CH), 25.4 [C(CH3)3], 17.8 (C), –5.8 (CH3), –6.0 (CH3).
TBDPSO
TBDPSO
OMs
DBU, benzene
89%
N
N
N
N
17
16
i) O3, MeOH,CH2Cl2
ii) Me2S
62%
TBDPSO
OH
MS (FAB): m/z (%) = 431.3 (100) [M + 1].
TBDPSO
OH
Anal. Calcd for C26H30N2O2Si: C, 72.52; H, 7.02; N, 6.51. Found:
C, 72.65; H, 7.10; N, 6.59.
+
cis-8
N
N
trans-8
( )-cis-7-[(tert-Butyldimethylsiloxy)methyl]-1,4-diphenyl-6,7-
dihydro-5H-cyclopenta[d]pyridazin-5-ol (cis-7) and ( )-trans-7-
[(tert-Butyldimethylsiloxy)methyl]-1,4-diphenyl-6,7-dihydro-
5H-cyclopenta[d]pyridazin-5-ol (trans-7)
N
N
Scheme 2
Method A: A solution of 10 (0.3 g, 0.70 mmol) in CH2Cl2–MeOH
(1:1, 50 mL) was cooled to –78 °C in a bath of acetone and liquid
N2. Then, O3 was bubbled through the mixture until, after 35 min,
blue coloration showed the presence of excess O3, which was re-
moved by bubbling N2 through. The mixture was then treated with
NaBH4 (0.11 g, 2.8 mmol) under an inert atmosphere and was left
stirring until it reached r.t. The solvents were removed under re-
duced pressure, and the resulting residue (0.8 g) was purified by
chromatography (silica gel, hexane–EtOAc, 7:1 and 3:1 mixtures as
successive eluents). Upon concentration to dryness, the combined
early nonvoid fractions eluted with the first solvent mixture afford-
ed cis-7 as a white solid, the later fractions gave a mixture of cis-
and trans-7 (0.026 g, 9%), and the fractions eluted with the second
eluent produced trans-7 as a white solid.
All chemicals used were of reagent grade and were obtained from
Aldrich Chemical Co. and used without further purification. Melt-
ing points were measured in a Reichert Kofler Thermopan and are
uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1640
1
FTIR spectrophotometer. H and 13C NMR spectra were recorded
on a Bruker AMX 300 spectrometer at 300 and 75 MHz, respective-
ly, using TMS as an internal standard. Mass spectra were recorded
on Hewlett-Packard HP5988A or Micromass Autospec spectrome-
ters. Microanalyses were performed in a FISONS EA 1108 Elemen-
tal Analyser at the University of Santiago Microanalysis Service; all
results shown are within 0.4% of the theoretical values. X-ray dif-
fraction data were collected on an Enraf-Nonius CAD4 automatic
diffractometer using the program CAD4-EXPRESS. All air-sensi-
tive reactions were carried out under argon. Flash chromatography
was performed on silica gel (Merck 60, 230–240 mesh) and analyt-
ical TLC on precoated silica gel plates (Merck 60 F254, 0.25 mm).
cis-7
Yield: 0.25 g (84%).
Mp 178–179 °C.
( )-5-[(tert-Butyldimethylsiloxy)methyl]-7-methylidene-1,4-
diphenyl-6,7-dihydro-5H-cyclopenta[d]pyridazine (10)
To a solution of compound 9 (1.3 g, 2.47 mmol) in dry benzene (25
mL) was added DBU (325 mL, 2.48 mmol) dropwise, and this mix-
ture was stirred at r.t. for 16 h. The mixture was then heated at 50
°C for a further 2 h and concentrated to dryness under reduced pres-
sure. The resulting residue (1.6 g) was chromatographed (silica gel,
hexane–EtOAc, 5:1), and concentration of the nonvoid fractions to
dryness afforded 10 as a yellowish white solid with physical and
spectroscopic characteristics identical to those reported previously.7
Yield: 0.86 g (91%).
IR (KBr): 3159, 2990, 2929, 1441, 1382, 1252, 1081, 843, 770, 692
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.31–8.28 (m, 2 H), 7.80–7.77 (m,
2 H), 7.58–7.47 (m, 6 H), 5.18 (dd, J = 11.6, 6.6 Hz, 1 H, 5-H), 4.52
(d, J = 11.6 Hz, 1 H, D2O exchange, OH), 3.95 (d, J = 8.9 Hz, 1 H,
7-H), 3.68 (dd, J = 10.0, 2.3 Hz, 1 H, OCHH), 3.54 (dd, J = 10.0,
2.3 Hz, 1 H, OCHH), 2.66 (ddd, J = 14.3, 9.0, 6.8 Hz, 1 H, 6-HH),
2.08 (d, J = 14.3 Hz, 1 H, 6-HH), 0.67 [s, 9 H, C(CH3)3], –0.15 [s,
3 H, Si(CH3)2], –0.26 [s, 3 H, Si(CH3)2].
13C NMR (75 MHz, CDCl3): d = 157.6 (C), 157.1 (C), 143.6 (C),
141.4 (C), 136.9 (C), 136.7 (C), 129.6 (CH), 129.4 (CH), 129.3
(CH), 128.8 (CH), 128.6 (CH), 72.8 (CH), 63.01 (CH2), 44.8 (CH),
38.7 (CH2), 25.6 [C(CH3)3], 18.2 (C), –5.8 (CH3), –5.9 (CH3).
( )-7-[(tert-Butyldimethylsiloxy)methyl]-1,4-diphenyl-6,7-dihy-
dro-5H-cyclopenta[d]pyridazin-5-one (11)
A solution of 10 (0.86 g, 2.0 mmol) in CH2Cl2–MeOH (1:1, 142
MS (FAB): m/z (%) = 433.26 (100) [M + 1].
mL) was cooled to –78 °C in a bath of acetone and liquid N2. Then,
Synthesis 2007, No. 17, 2621–2626 © Thieme Stuttgart · New York

2624
I. Pérez-Castro et al.
PAPER
Anal. Calcd for C26H32N2O2Si: C, 72.18; H, 7.46; N, 6.48. Found:
C, 72.55; H, 7.60; N, 6.69.
1H NMR (300 MHz, CDCl3): d = 7.83–7.70 (m, 5 H), 7.56–7.41 (m,
6 H), 7.35–7.21 (m, 4 H), 6.88 (dd, J = 7.0, 6.4 Hz, 1 H, 5-H), 4.03–
4.00 (m, 1 H, 7-H), 3.65 and 3.41 (part AB of ABX system, J = 13.0,
10.0, 9.7 Hz, 2 H, OCH2), 2.86 (ddd, J = 13.8, 10, 7.6 Hz, 1 H, 6-
HH), 2.35–2.25 (m, 1 H, 6-HH), 0.73 [s, 9 H, C(CH3)3], –0.12 [s, 3
H, Si(CH3)2], –0.25 [s, 3 H, Si(CH3)2].
13C NMR (75 MHz, CDCl3): d = 166.0 (C), 157.9 (C), 157.1 (C),
142.9 (C), 140.4 (C), 136.8 (C), 136.2 (C), 133.0 (CH), 129.4 (CH),
129.1 (CH), 128.7 (CH), 128.6 (CH), 128.5 (CH), 128.4 (CH),
128.1 (CH), 77.1 (CH), 63.6 (CH2), 45.2 (CH), 37.2 (CH2), 25.7
[C(CH3)3], 18.0 (C), –5.7 (CH3), –5.8 (CH3).
A single crystal of cis-7 that was suitable for X-ray diffractometry
was obtained by dissolving the chromatographically purified prod-
uct in the smallest possible quantity of cold EtOAc in a vial. The
vial was then surrounded by hexane in a container with a perforated
lid and left in a cool, dark, vibration-free place for 15 d.
trans-7
Yield: 0.013 g (4%).
Mp 157–160 °C.
MS (FAB): m/z (%) = 537.27 (100) [M + 1].
IR (KBr): 3263, 3091, 3011, 2926, 2874, 2854, 1452, 1388, 1257,
1114, 1044, 992, 834, 774 cm–1.
Anal. Calcd for C33H36N2O3Si: C, 73.85; H, 6.76; N, 5.22. Found:
C, 74.07; H, 6.97; N, 5.49.
1H NMR (300 MHz, CDCl3): d = 7.96–7.93 (m, 2 H), 7.76–7.72 (m,
2 H), 7.56–7.48 (m, 6 H), 5.78–5.73 (m, 1 H, 5-H), 4.01–3.95 (m, 1
H, 7-H), 3.57 (dd, J = 9.9, 2.9 Hz, 1 H, OCHH), 3.31 (dd, J = 9.9,
4.4 Hz, 1 H, OCHH), 2.53 (ddd, J = 13.6, 7.3, 3.3 Hz, 1 H, 6-HH),
2.37 (d, J = 4.8 Hz, 1 H, D2O exchange, OH), 2.25 (ddd, J = 13.6,
8.5, 5.1 Hz, 1 H, 6-HH), 0.68 [s, 9 H, C(CH3)3], –0.19 [s, 3 H,
Si(CH3)2], –0.3 [s, 3 H, Si(CH3)2].
13C NMR (75 MHz, CDCl3): d = 158.5 (C), 157.2 (C), 144.0 (C),
142.8 (C), 137.3 (C), 136.9 (C), 129.9 (CH), 129.6 (CH), 129.4
(CH), 129.1 (CH), 129.0 (CH), 74.8 (CH), 63.9 (CH2), 45.1 (CH),
39.0 (CH2), 26.1 [C(CH3)3], 18.4 (C), –5.3 (CH3), –5.4 (CH3).
cis-6,7-Dihydro-5H-cyclopenta[d]pyridazine-5,7-dimethanol
(14)
Ozone was bubbled for 10 min through a vigorously stirred solution
of phthalazine 1311 (1.29 g, 8.99 mmol) in MeOH–CHCl3 (1:1, 150
mL) at –78 °C. Then, NaBH4 (1.47 g, 38.8 mmol) was added in
small portions over 1 h at the same temperature and, after a further
15 min at –78 °C, the mixture was allowed to reach r.t. The solvents
were removed under reduced pressure and the resulting residue was
extracted with hot EtOAc (4 × 50 mL). Concentration of the com-
bined organic phase to dryness gave 14 as a white solid.
MS (EI, 70 eV): m/z (%) = 377 (8), 376 (28), 375 (100) [M – t-Bu],
300 (16), 299 (54), 271 (17), 241 (10), 239 (12), 228 (10), 202 (16),
180 (15), 128 (17), 127 (18), 77 (39), 75 (90), 73 (68), 59 (27), 58
(22), 57 (70), 56 (19).
Yield: 1.32 g (81%).
Mp 137–139 °C.
IR (KBr): 3405, 3199, 2965, 2922, 2846, 2229, 1663, 1574, 1340,
1277, 1043, 786, 682, 592 cm–1.
Anal. Calcd for C26H32N2O2Si: C, 72.18; H, 7.46; N, 6.48. Found:
C, 72.43; H, 7.64; N, 6.72.
1H NMR (300 MHz, DMSO-d6): d = 9.19 (s, 1 H, Hpyridazine), 9.17 (s,
1 H, Hpyridazine), 4.92–4.95 (m, 2 H, D2O exchange, 2 OH), 3.66 (dd,
J = 10.4, 4.8 Hz, 2 H, CHHOH), 3.56 (dd, J = 10.4, 4.8 Hz, 2 H,
CHHOH), 3.40–3.29 (m, 2 H, 5-H, 7-H), 2.28 (dt, J = 13.2, 8.8 Hz,
1 H, 6-HH), 1.54 (dt, J = 13.2, 7.5 Hz, 1 H, 6-HH).
13C NMR (75 MHz, DMSO-d6): d = 149.12 (CH), 149.00 (CH),
145.58 (C), 145.56 (C), 63.42 (CH2), 63.34 (CH2), 45.06 (CH),
44.88 (CH), 30.06 (CH2).
Method B: 1 M NaOH (0.6 mL) was added to a solution of 12 (0.032
g, 0.06 mmol) in MeOH (0.6 mL) and THF (0.6 mL) at 0 °C, and
the mixture was stirred for 4.5 h at r.t. Then, 1 M NaHSO4 (1.5 mL)
was added, and the mixture was diluted with H2O (5 mL) and ex-
tracted with EtOAc (3 × 10 mL). The organic layers were dried
(Na2SO4) and concentrated under reduced pressure to give trans-7
as a white solid. Yield: 0.02 g (77%).
MS (EI, 70 eV): m/z (%) = 181 (8), 180 (70) [M], 150 (79), 149 (9),
133 (25), 132 (40), 131 (17), 120 (14), 119 (100), 118 (10), 104
(15), 103 (23), 92 (11), 91 (10), 89 (11), 78 (10), 77 (15).
( )-trans-7-[(tert-Butyldimethylsiloxy)methyl]-1,4-diphenyl-
6,7-dihydro-5H-cyclopenta[d]pyridazin-5-yl Benzoate (12)
Under an inert atmosphere, a solution of DEAD (0.17 g, 0.96 mmol)
in dry THF (4 mL) was added dropwise over 20 min to a solution of
cis-7 (0.21 g, 0.48 mmol), Ph3P (0.25 g, 0.96 mmol), and BzOH
(0.12 g, 0.96 mmol) in THF (11 mL). This mixture was stirred for
15 h with TLC monitoring (CH2Cl2–MeOH, 20:1) of the reaction.
The solvent was then removed under reduced pressure, and the re-
sulting residue was dissolved in sat. NaHCO3 soln (40 mL) and ex-
tracted with CH2Cl2 (3 × 40 mL) and EtOAc (40 mL). The
combined organic phase was dried (Na2SO4), and removal of the
solvents under reduced pressure afforded a yellow oil (0.77 g) that
was chromatographed (silica gel, hexane–EtOAc, 10:1, 8:1, 5:1,
4:1, and 3:1 mixtures as successive eluents). The fractions eluted
with the 5:1 solvent mixture contained compound 12 together with
other products; the following fractions contained unreacted cis-7
(0.18 g). The fractions containing 12 were rerun twice using hex-
ane–EtOAc (15:1) in the first run and hexane–EtOAc (10:1) in the
second. The resulting fractions, upon removal of the solvent, gave
12 as a yellowish solid.
Anal. Calcd for C9H12N2O2: C, 59.99; H, 6.71; N, 15.55. Found: C,
60.33; H, 6.97; N, 15.67.
( )-cis-{7-[(tert-Butyldiphenylsiloxy)methyl]-6,7-dihydro-5H-
cyclopenta[d]pyridazin-5-yl}methanol (15)
A suspension of diol 14 (0.20 g, 1.11 mmol) and 60% NaH (0.032
g, 1.33 mmol) in dry DMF (4 mL) was stirred under Ar at r.t. for 45
min, after which a solution of TBDPSCl (0.37 g, 1.33 mmol) was
added. Stirring was continued for a further 4.5 h and the DMF was
removed under reduced pressure. The resulting residue was frac-
tionated on a silica gel column (hexane–acetone, 2:1 and CH2Cl2–
MeOH, 20:1 and 10:1 mixtures as successive eluents). Compound
15 was isolated as a yellow oil from the fractions eluted with hex-
ane–acetone, and unreacted 14 (0.11 g) was recovered from those
eluted with CH2Cl2–MeOH.
Yield: 0.15 g, (32%).
IR (film): 3414, 2932, 1636, 1428, 1109, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.23 (s, 1 H, 1-H), 9.20 (s, 1 H, 4-
H), 7.63–7.58 (m, 4 H), 7.57–7.35 (m, 6 H), 3.86 (dd, J = 10.3, 5.7
Hz, 2 H, CH2), 3.80–3.69 (m, 2 H, CH2), 3.48–3.42 (m, 2 H, 5-H, 7-
H), 2.37 (dt, J = 13.3, 8.8 Hz, 1 H, 6-HH), 1.95–2.03 (m, 1 H, D2O
Yield: 0.032 g (12%).
Mp 120–122 °C.
IR (KBr): 2931, 2885, 2858, 1717, 1449, 1384, 1270, 1007, 841,
703 cm–1.
Synthesis 2007, No. 17, 2621–2626 © Thieme Stuttgart · New York

PAPER
Synthesis of Cyclopenta[d]pyridazinediol Precursors of Carbanucleosides
2625
exchange, OH), 1.59 (dt, J = 13.4, 7.4 Hz, 1 H, 6-HH), 1.02 [s, 9 H,
C(CH3)3].
13C NMR (75 MHz, CDCl3): d = 150.55 (CH), 145.81 (C), 145.25
(C), 144.80 (CH), 139.99 (C), 135.54 (CH), 135.50 (C), 132.96 (C),
129.92 (CH), 129.86 (C), 127.84 (CH), 110.33 (CH2), 65.99 (CH2),
43.99 (CH), 33.58 (CH2), 26.75 [C(CH3)3], 19.17 (C).
13C NMR (75 MHz, CDCl3): d = 149.40 (CH), 149.07 (CH), 145.46
(C), 145.05 (C), 135.58 (CH), 135.50 (CH), 132.99 (C), 132.93 (C),
129.90 (CH), 129.82 (CH), 127.81 (CH), 127.77 (CH), 65.91(CH2),
64.97 (CH2), 45.45 (CH), 45.23 (CH), 29.78 (CH2), 26.81
[C(CH3)3], 19.16 (C).
MS (FAB): m/z (%) = 401.22 (100) [M + 1].
Anal. Calcd for C25H28N2OSi: C, 74.96; H, 7.05; N, 6.99. Found: C,
75.24; H, 6.97; N, 7.15.
MS (ESI-TOF): m/z (%) = 419.21 (100) [M + 1].
( )-cis-7-[(tert-Butyldimethylsiloxy)methyl]-6,7-dihydro-5H-
cyclopenta[d]pyridazin-5-ol (cis-8)
Compound cis-8 was obtained from 17 (0.17 g, 0.43 mmol) as a
white solid in the same way as cis-7 and trans-7 were obtained from
10. Workup afforded a small quantity of pure cis-8 and a larger
quantity of cis-8 containing a small portion of what may be the iso-
mer trans-8; yield: 0.18 g (62%).
Anal. Calcd for C25H30N2O2Si: C, 71.73; H, 7.22; N, 6.69. Found:
C, 71.98; H, 7.38; N, 6.91.
( )-cis-{7-[(tert-Butyldiphenylsiloxy)methyl]-6,7-dihydro-5H-
cyclopenta[d]pyridazin-5-yl}methyl Mesylate (16)
Mesyl chloride (0.29 g, 2.49 mmol) was added to a solution of 15
(0.35 g, 0.83 mmol), Et3N (0.35 mL), and a catalytic amount of
DMAP in dry CH2Cl2 (60 mL) stirred under Ar at –10 °C. After stir-
ring for 1 h at r.t., the mixture was diluted with CH2Cl2 (60 mL) and
washed successively with H2O (2 × 40 mL), 2 M NaOH (2 × 60
mL), and brine (60 mL). The organic phase was then dried (Na2SO4)
and concentrated under reduced pressure, leaving a residue that was
column chromatographed (silica gel, hexane–EtOAc, 1:1.5). The
resulting fractions gave, upon removal of the solvent, 16 as thick
oil.
cis-8
Mp 166–168 °C.
IR (KBr): 3187, 2929, 2881, 2857, 1583, 1466, 1387, 1331, 1110,
1092, 1072, 801, 706, 505 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.31 (s, 1 H, 1-H), 9.15 (s, 1 H, 4-
H), 7.54 (t, J = 1.4 Hz, 2 H), 7.43–7.32 (m, 8 H), 5.23 (ddd, J = 10.1,
7.3, 3.0 Hz, 1 H, 5-H), 3.86–3.84 (m, 2 H, OCH2), 3.37 (dd, J = 8.5,
4.0 Hz, 1 H, 7-H), 3.22 (d, J = 10.0 Hz, 1 H, OH), 2.62 (ddd, J =
14.3, 8.8, 7.3 Hz, 1 H, 6-HH), 1.95 (dt, J = 14.3, 3.5 Hz, 1 H, 6-HH),
0.92 [s, 9 H, C(CH3)3].
13C NMR (75 MHz, CDCl3): d = 149.5 (CH), 148.7 (CH), 145.5 (C),
143.9 (C),135.5 (CH), 135.4 (CH), 132.4 (C), 132.2 (C), 130.1
(CH), 129.9 (CH), 127.8 (CH), 73.5 (CH), 73.0 (CH), 65.8 (CH2),
44.0 (CH), 38.0 (CH2), 26.7 [C(CH3)3], 19.0 (C).
Yield: 0.24 g (58%).
IR (film): 2933, 1467, 1358, 1175, 1110, 956, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.27 (s, 1 H, Hpyrazine), 9.24 (s, 1
H, Hpyrazine), 7.61–7.59 (m, 4 H), 7.57–7.26 (m, 6 H), 4.44 (dd, J =
10.0, 6.0 Hz, 1 H, O2SOCHH), 4.28 (dd, J = 10.0, 7.3 Hz, 1 H,
O2SOCHH), 3.91 (dd, J = 10.2, 5.3 Hz, 1 H, SiOCHH), 3.81 (dd,
J = 10.2, 6.7 Hz, 1 H, SiOCHH), 3.72–3.68 (m, 1 H, 5-H), 3.54–
3.49 (m,1 H, 7-H), 2.96 (s, 3 H, CH3), 2.49 (dt, J = 13.5, 8.8 Hz, 1
H, 6-HH), 1.69 (dt, J = 13.7, 7.6 Hz, 1 H, 6-HH), 1.03 [s, 9 H,
C(CH3)3].
13C NMR (75 MHz, CDCl3): d = 149.36 (CH), 148.19 (CH), 146.19
(CH), 146.86 (C), 144.10 (C), 135.53 (CH), 132.61 (C), 130.08
(CH), 130.00 (CH), 127.94 (CH), 127.89 (CH), 69.56 (CH2), 65.29
(CH2), 45.51 (CH), 42.59 (CH), 37.58 (CH3), 29.86 (CH2), 26.75
[C(CH3)3], 19.18 (C).
MS (FAB): m/z (%) = 405.18 (100) [M + 1].
Anal. Calcd for C24H28N2O2Si: C, 71.25; H, 6.98; N, 6.92. Found:
C, 71.56; H, 7.09; N, 7.08.
Acknowledgment
The authors thank the Xunta de Galicia for financial support of this
work under project PGIDT02BTF20305PR.
MS (FAB): m/z (%) = 497.23 (100) [M + 1].
Anal. Calcd for C26H32N2O4SSi: C, 62.87; H, 6.49; N, 5.64. Found:
C, 63.14; H, 6.61; N, 5.93.
References
(1) (a) Simons, C. Nucleoside Mimetics Their Chemistry and
Biological Properties; Gordon and Breach Science
Publishers: Amsterdam, 2001. (b) Rodriguez, J. B.; Comin,
M. J. Mini-Rev. Med. Chem. 2003, 3, 95. (c) Pan, S.;
Amankulor, N. M.; Zhao, K. Tetrahedron 1998, 54, 6587.
(2) (a) Amblard, F.; Nolan, S. P.; Agrofoglio, L. A. Tetrahedron
2005, 61, 7067. (b) 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.;
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.; Garvey, E. P.; St. Clair, M.
H.; Daluge, S. M.; Good, S. S. Antimicrob. Agents
Chemother. 1997, 41, 1099. (c) Foster, R. H.; Faulds, D.
Drugs 1998, 55, 729.
( )-5-[(tert-Butyldiphenylsiloxy)methyl]-7-methylidene-6,7-di-
hydro-5H-cyclopenta[d]pyridazine (17)
Over 10 min, DBU (81 mL, 0.53 mmol) was added dropwise to a so-
lution of compound 16 (0.24 g, 0.48 mmol) in dry benzene (10 mL),
and this mixture was stirred at r.t. for 8 h. The solvent was removed
under reduced pressure, and the resulting residue (0.32 g) was chro-
matographed (silica gel, pure CH2Cl2 and CH2Cl2–MeOH, 30:1, as
successive eluents). Concentration of the nonvoid fractions to dry-
ness afforded 17 as a white solid.
Yield: 0.17g (89%).
Mp 95–98 °C.
IR (KBr): 3067, 2930, 2856, 2099, 1581, 1466, 1427, 1383, 1260,
1108, 872, 819, 741, 701 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.28 (s, 2 H, 1-H, 4-H), 7.59–7.56
(m, 4 H), 7.47–7.33 (m, 6 H), 5.80–5.78 (m, 1 H, =CHH), 5.38–5.37
(m, 1 H, =CHH), 3.81 (dd, J = 9.9, 5.5 Hz, 1 H, OCHH), 3.70 (dd,
J = 9.9, 7.0 Hz, 1 H, OCHH), 3.55–3.47 (m, 1 H, 5-H), 2.92 (ddt,
J = 17.2, 8.8, 2.6 Hz, 1 H, 6-HH), 2.62–2.55 (m, 1 H, 6-HH) 1.00
[s, 9 H, C(CH3)3].
(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.
Synthesis 2007, No. 17, 2621–2626 © Thieme Stuttgart · New York

2626
I. Pérez-Castro et al.
PAPER
weight: 432.63; crystal size: 0.51 × 0.33 × 0.06; crystal
colour, habit: colourless, prismatic; crystal system:
monoclinic; lattice type: plate; lattice parameters: a = 6.309
(5) Å, b = 12.889 (5) Å, c = 15.172 (5) Å, a = 90 (5)°, b =
96.818 (5)°, g = 90 (5)°, V = 1225 0(12) Å3; space group:
P21; Z = 2; Dcalcd = 1.173 Mg/m3; F(000) = 464; R1 = 0.0702,
wR2 = 0.1624. Diffractometer: Smart-1000 BRUKER.
These data can be obtained free of charge from the CCDC
via www.ccdc.ac.uk/data_request/cif.
(6) (a) García, M. D.; Caamaño, O.; Fernández, F.; López, C.;
De Clercq, E. Synthesis 2005, 925. (b) García, M. D.;
Caamaño, O.; Fernández, F.; García-Mera, X.; Pérez Castro,
I. Synthesis 2006, 73. (c) García, M. D.; Caamaño, O.;
Fernández, F.; López, C.; De Clercq, E. Synthesis 2006,
3967.
(7) Caamaño, O.; Gómez, G.; Fernández, F.; García, M. D.;
García-Mera, X. Synthesis 2004, 2855.
(8) Fernández, F.; García-Mera, X.; López, C.; Morales, M.;
Rodríguez-Borges, J. E. Synthesis 2005, 3549.
(9) Alcaide, B.; Almendros, P.; Salgado, N. J. Org. Chem. 2000,
65, 3310.
(11) Mitsunobu, O. Synthesis 1981, 1.
(12) Kobayashi, T.; Sugawara, H.; Nikaeen, B. Bull. Chem. Soc.
Jpn. 1998, 71, 497.
(10) The crystallographic data of cis-7 have been deposited with
the Cambridge Crystallographic Data Centre (CCDC) with
number 630734. Empirical formula: C26H32N2O2Si; formula
(13) Gorgues, A.; Simon, A.; Coq, A. L.; Hercouet, A.; Corre, F.
Tetrahedron 1986, 42, 351.
Synthesis 2007, No. 17, 2621–2626 © Thieme Stuttgart · New York