Divergent synthesis and biological evaluation of carbocyclic α-, iso- and 3′-epi-nucleosides and their lipophilic nucleotide prodrugs

Article abstract of DOI:10.1055/s-2006-926411

A new divergent approach towards carbocyclic α-, iso- and 3′-epi-nucleosides starting from enantiomerically pure (1S,2R)-2-benzyloxymethylcyclopent-3-enol (5) is described. In the key step, isomeric cyclopentanols were condensed with a N3-protected pyrimi

Full text of DOI:10.1055/s-2006-926411

PAPER
1313
Divergent Synthesis and Biological Evaluation of Carbocyclic a-, iso- and
3¢-epi-Nucleosides and their Lipophilic Nucleotide Prodrugs
S
ynthesis of Carbo
l
cyclic
a
N
ucleoside
f
s
R. Ludek,a Tobias Krämer,a Jan Balzarini,b Chris Meier*a
a
Institut für Organische Chemie, Universität Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax +49(40)428382495; E-mail: chris.meier@chemie.uni-hamburg.de
b
Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
Received 26 September 2005; revised 21 November 2005
Abstract: A new divergent approach towards carbocyclic a-, iso-
and 3¢-epi-nucleosides starting from enantiomerically pure (1S,2R)-
2-benzyloxymethylcyclopent-3-enol (5) is described. In the key
step, isomeric cyclopentanols were condensed with a N3-protected
pyrimidine nucleobase using a modified Mitsunobu protocol. More-
over, the conversion into the cycloSal-pronucleotides and the effect
of the orientation of the nucleobase on anti-HIV activity are report-
ed.
O
N
NH
N
N
N
N
N
NH
NH2
HO
HO
N
NH2
Carbovir 1
Abacavir 2
O
Key words: stereoselective synthesis, hydroborations, carbocycles,
nucleosides, Mitsunobu reaction
O
N
Br
N
N
HN
NH
NH2
HO
HO
O
N
Nucleoside analogues have attracted considerable interest
due to their wide range of biological activity.1 Several
structural modifications were applied to both the hetero-
cyclic base and the sugar moiety.2 Carbocyclic nucleo-
sides in which the furanose oxygen is replaced by a
methylene unit are stable towards hydrolysis by phospho-
rylases. This enzyme cleaves the glycosidic bond in con-
ventional nucleosides. Consequently carbocyclic
nucleosides display an enhanced biostability.3 However,
the removal of the aminal oxygen abolishes the anomeric
and gauche effects, responsible for forcing the furan sys-
tem into two distinct conformations.4 Since the conforma-
tion of the five-membered ring is believed to play a
critical role in modulating biological activity, the behav-
iour of nucleosides with a cyclopentane moiety some-
times differs significantly from that of their natural
counterparts.5
OH
OH
carba-BVdU 4
Entecavir 3
Figure 1 Carbocyclic nucleoside analogues 1–4
volves an initial synthesis of
a
functionalised
cyclopentylamine. Then the heterocyclic base is built in a
step-wise manner. The second strategy is the convergent
approach. Here, the appropriate heterocycle is coupled di-
rectly to a functionalised carbocyclic moiety, leading to a
variety of carbocyclic nucleosides starting from one com-
mon cyclopentane precursor.
Recently, we published a new convergent route to car-
bocyclic nucleoside analogues,9 starting from enantio-
merically pure (1S,2R)-2-benzyloxymethylcyclopent-3-
enol (5).10 In the key step cyclopentanol 6a is condensed
with a N3-protected pyrimidine nucleobase using a modi-
fied Mitsunobu-protocol (Scheme 1).11 Here we report
that this strategy can also be used for the synthesis of car-
bocyclic a-, iso- and 3¢-epi-nucleosides. The latter can be
considered as precursors for nucleophilic substitutions at
the 3¢-position.12
While hydroboration13 of cyclopentene 5a with 9-BBN or
dicyclohexylborane almost exclusively led to the forma-
tion of cyclopentanol 6b (the side product in this reaction
is cyclopentanol 8a and not 6a as reported before9), the
corresponding reaction with BH3·THF is far more unse-
lective. After oxidative work-up, three isomers 6b, 8a and
8b were obtained in 83% yield in a 4:3:3 ratio, respective-
ly. These isomers could easily be separated by column
chromatography. Interestingly as observed before9 even
with this method cyclopentanol 6a was not formed. How-
ever, cyclopentanol 6a can be prepared easily from cyclo-
pentanol 6b by a Mitsunobu inversion. Compound 6a was
Recently, carbocyclic nucleoside analogues like carbovir
(1)6 and the structurally related abacavir (2)2g (ZiagenTM
)
were found to be potent inhibitors of HIV reverse tran-
scriptase. Moreover, the guanine derivative entecavir (3)7
(BaracludeTM) was approved by FDA in early 2005 for the
treatment of chronic HBV infections, a common co-infec-
tion in people with HIV. Beside carbocyclic purine ana-
logues, an example of a bioactive pyrimidine analogue is
carba-BVdU (4) that showed significant anti-HSV-1 ac-
tivity (Figure 1).8
A great number of strategies, which can be subdivided
into two categories, have been designed for the prepara-
tion of carbocyclic nucleosides. The linear approach in-
SYNTHESIS 2006, No. 8, pp 1313–1324
x
x
.
x
x
.2
0
0
6
Advanced online publication: 27.03.2006
DOI: 10.1055/s-2006-926411; Art ID: T13605SS
© Georg Thieme Verlag Stuttgart · New York

1314
O. R. Ludek et al.
PAPER
O
N
NH
BnO
BnO
HO
O
selective
Mitsunobu
reaction
OH
hydroboration
OH
OBn
6α
OH
7
5
Scheme 1 Synthetic approach towards carbocyclic nucleoside analogues.
then used as starting material for the synthesis of carbocy- ing to mixtures of isomers. In the case of the pyrimidines
clic nucleoside analogues of the natural nucleosides bases N1- and O2-isomers are sometimes found, while
(Scheme 2).9
N7- and N9-isomers were found in the purine series. The
product ratio seems to be dependent upon the reaction
temperature,14b the solvent,14g the protected nucleobase,14f
the alcohol14c and the order in which the components are
added to the reaction mixture.14e For the synthesis of car-
bocyclic pyrimidine nucleosides with the natural configu-
ration we developed a Mitsunobu protocol, leading
predominantly to the N1-alkylated regioisomers, e.g.
uracil couplings led to a 9:1 ratio in favour of the N1-iso-
mers.9
To confirm the structure of cyclopentanol 8a the optically
inactive meso-compound 9 was prepared. Thus, the hy-
droxy group was protected with a benzyl group using so-
dium hydride, benzyl bromide and tetrabutylammonium
iodide (TBAI) in 85% yield. This material 9 in which the
two OBn residues are trans-orientated to the exocyclic
benzyloxymethyl group showed the expected reduced set
of signals in the 1H NMR spectra (Figure 2).
In the past few years, the Mitsunobu reaction has become
an important tool for the direct coupling of alcohols with
heterocyclic bases under mild conditions.14 Unfortunate-
ly, the nucleobases react as ambident nucleophiles, lead-
Using the same experimental protocol, the separated cy-
clopentanols 6b, 8a and 8b as well as cyclopentanol 6a
were reacted with N3-benzoylthymine15 (Scheme 2). In
R3
BnO
BnO
R1
BnO
b
R4
+
R2
83%
OR
OBn
OBn
R1 = H, R2 = OH: 6α
R
R
3 = H, R4 = OH: 8α (22%)
3 = OH, R4 = H: 8β (24%)
a
R = H: 5
R = Bn: 5a
R1 = OH, R2 = H: 6β (37%)
(90%)
c (85%)
R3 = H, R4 = OBn: 9
R3
R4
R3
BnO
R1
HO
R1
R2
f
d,e
40–70%
R4
82–84%
R2
OBn
OH
from 6α: R2 = H; R1 = thymine 10
from 6β: R1 = H; R2 = thymine 11
from 8α: R4 = H; R3 = thymine 12
from 8β: R3 = H; R4 = thymine 13
R2 = H; R1 = thymine 7a
R
R
R
1 = H; R2 = thymine 15
4 = H; R3 = thymine 16
3 = H; R4 = thymine 17
g
60–65%
side product of the Mitsunobu
reaction of 8β:
O
O
P
BnO
O
ONucl
OBn
14
29: Nucl = 5´-carba-dT
30: Nucl = 5´-carba-α-dT
31: Nucl = 5´-carba-iso-dT
32: Nucl = 5´-carba-iso-α-dT
Scheme 2 Reagents and conditions: (a) NaH, BnBr, TBAI, r.t. 12 h; (b) BH3·THF, 0 °C, 12 h, 3 N NaOH, 30% H2O2, r.t., 12 h; (c) NaH,
BnBr, TBAI, r.t., 12 h; (d) Ph3P, DIAD, N3-Bz-thymine, MeCN, –40 °C to r.t., 16 h; (e) 1% NaOH in MeOH, 12 h, r.t.; (f) Pd/C, H2, EtOH,
12 h, r.t.; (g) 3-methyl-cyclosaligenylphosphorchloridate, pyridine, –40 °C, 2 h.
Synthesis 2006, No. 8, 1313–1324 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbocyclic Nucleosides
1315
good chemical yields the reaction led to the N1-isomer as
the major product. However, the chemical yields of the
coupling reaction were significantly lower in the case of
the iso-nucleosides 12 (48%) and 13 (40%) without
changing the N1/O2-ratio. This may be explained by steric
hindrance of the cyclopentane ring and the incoming nu-
cleophile or the bulky leaving group with the benzyl-
oxymethyl substituent in the neighbouring position.
Table 1 Reaction of Cyclopentene 18a with Different Hydrobora-
tion Agents
Method Hydroboration
reagent
Productsa
Yield (%)b
c
9-BBN
19a (48%) + 20a (52%)
92
87
d
BH3·THF
19a (45%) + 19b (5%) +
20a (45%) + 20b (5%)
In the case of cyclopentanol 8b elimination to cyclopen-
tene 14 (Scheme 2) occurred as major side reaction in ad-
dition to the nucleophilic substitution. Here, the H2-
proton and the leaving group are in perfect antiperiplanar
orientation for b-elimination. The benzylated carbocyclic
nucleosides 10–13 were subsequently deprotected by hy-
drogenolysis on Pd/C in ethanol. The yields of the deben-
zylation are summarised in Scheme 2.
e
f
(–)-(ipc)2BH
(+)-(ipc)2BH
19a (65%) + 20a (35%)
19a + 20a + 20bc
90
53
a Determined after chromatography.
b Total yields of both products.
c Ratio was not determined.
For the synthesis of the carbocyclic 3¢-epi-nucleoside se-
ries the hydroxy group in the chiral cyclopentenol 5 was
inverted using a classical Mitsunobu reaction with benzo-
ic acid. After deprotection with 1% NaOH in methanol cy-
clopentenol 18 was obtained in 80% yield (Scheme 3).
was observed. Even with the small BH3·THF complex
only a minor amount of the two b-configured products
was formed. Using the chiral (–)-diisopinocampheylbo-
rane, cyclopentanol 19a was formed preferentially com-
pared to cyclopentanol 20a (65:35 ratio). Interestingly,
the enantiomer of this chiral borane was far less regiose-
lective and the products were only obtained in poor chem-
ical yields (53%). To prove the assigned structure of
cyclopentanol 20a, the configuration at C1 was inverted
using again the Mitsunobu reaction conditions11 to yield
cyclopentanol 20b in 72% (Scheme 3).
Benzylation of the hydroxy group in compound 18 led to
cyclopentene 18a in 71% which was subsequently reacted
with a variety of hydroboration agents.13 Due to the steric
demand of the two substituents on the b-face, the pre-
ferred approach of the hydroboration reagent was as-
sumed to proceed from the a-face (Table 1).
As before, benzylation of the hydroxy group in 20b (78%
yield) led to the optically inactive meso-compound 21 in
which the two OBn groups are cis-orientated to the exocy-
As expected, the reaction using 9-BBN led to the forma-
tion of only two of the four possible products, 19a and
20a. However, no preference for one of the two isomers
Figure 2 1H NMR experiment to prove the structure of cyclopentanol 8a.
Synthesis 2006, No. 8, 1313–1324 © Thieme Stuttgart · New York

1316
O. R. Ludek et al.
PAPER
R1
R2
R1
R2
BnO
BnO
Bn
R1
R2
BnO
Bn
O
O
methods c–f
see Table 2
+
R1 = H, R2 = OH: 5
1 = OH, R2 = H: 18
R1 = OBn, R2 = H: 18a
R1 = H, R2 = OH: 19α
R1 = OH, R2 = H: 19β
R1 = H, R2 = OH: 20α
R1 = OH, R2 = H: 20β
a
(80%)
b
(71%)
R
i,j 74%
g
72%
O
NH
OH
BnO
Bn
O
BnO
Bn
N
O
O
k
20β
24
88%
h
78%
Bn
O
HO
BnO
Bn
T
O
OH
25
21
Scheme 3 Reagents and conditions: (a) PPh3, DIAD, PhCO2H, Et2O, 0 °C to r.t., 12 h; (b) NaH, BnBr, TBAI, THF, r.t., 12 h; (c)–(f) different
hydroboration reagents (see Table 1); (g) Ph3P, DIAD, PhCO2H, Et2O, 0 °C to r.t., 12 h; (h) NaH, BnBr, TBAI, THF, r.t., 12 h; (i) Ph3P, DIAD,
N3-benzoylthymine, MeCN, –40 °C to r.t., 16 h; (j) 1% NaOH, MeOH, r.t., 12 h; (k) Pd/C, H2, EtOH, r.t., 12 h.
1
clic benzyloxymethyl group. As expected, the H NMR cleoside 24 and 26 were obtained in 74% and 62% yields.
spectra showed the reduced set of signals. Alternatively, The N1/O2-selectivities were comparable to the erythro-
chiral cyclopentenol 18 was reacted with tert-butyldi- nucleoside series. Hydrogenolysis of the benzyl groups in
methylsilyl chloride, leading to the protected cyclopen- 24 led to the target compound 3¢-epi-carba-dT (25)16 in
tene 18b in 90% yield. Hydroboration of 18b with 9-BBN 88% yield (Scheme 3). 3¢-epi-iso-carba-dT (28) was ob-
led in contrast to the dibenzylated derivative 18a to a 6:4 tained after cleavage of the silyl ether by 1M TBAF in
ratio of cyclopentanols 23a and 22a. Apparently, the in- THF at room temperature (72% yield) and hydrogenolysis
teractions of the protecting groups result in different ring of the benzyl ether in 98% yield (Scheme 4).
conformations leading finally to differences in the hy-
droboration pattern (Scheme 4).
The described synthetic approaches towards carbocyclic
analogues of thymidine open the possibility to study the
As before, cyclopentanols 19a and 23a were coupled to bioactivity of these compounds as well as the correspond-
N3-benzoylthymine using our Mitsunobu-protocol. After ing nucleotides after conversion into their membrane-per-
methanolysis of the benzoyl group, carbocyclic 3¢-epi-nu- meable cycloSal-phosphate triesters.17 It has been shown
BnO
BnO
BnO
b
OR
O
O
+
TBDMS
OH
TBDMS
OH
22α (28%)
R = H: 18
a
23α (50%)
(90%)
R = TBDMS: 18b
c,d 62%
O
N
O
NH
NH
f
O
N
O
HO
OH
BnO
O
98%
R
28
R = TBDMS: 26
R = H: 27
e
(72%)
Scheme 4 Reagents and conditions: (a) TBDMS-Cl, imidazole, DMF, r.t., 12 h; (b) 9-BBN, THF, r.t, 12 h, 3 N NaOH, 30% H2O2, 0 °C, 12 h;
(c) PPh3, DIAD, N3-benzoylthymine, MeCN, –40 °C to r.t., 16 h; (d) 1% NaOH, MeOH, r.t., 12 h; (e) TBAF, THF, r.t., 5 h; (f) Pd/C, H2, EtOH,
r.t., 10 h.
Synthesis 2006, No. 8, 1313–1324 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbocyclic Nucleosides
1317
before, that cycloSal-phosphate triesters release the nucle- Table 2 Antiviral Evaluation of the Inhibitory Effect on HIV-1 and
HIV-2-Replication of Carbocyclic Nucleosides 7, 15–17, 25, 28 and
cycloSal-Compounds 29–32 in CEM/0 Cells and in Thymidine Ki-
nase-Deficient CEM/TK Cells
otides and the masking group selectively by a controlled,
chemically induced tandem reaction.18,19 Often an im-
provement in the biological activity has been observed.20
Com-
pound
EC50 [mM]a
CC50 [mM]b
The phosphate triesters were easily obtained by reaction
of 3-methyl-cyclosaligenylphosphorchloridate with the
appropriate carbocyclic nucleoside analogue 7, 15–17 in
60–65% yield in anhydrous pyridine (Scheme 2).21 How-
ever, the method failed for the synthesis of cycloSal phos-
phate triesters of 3¢-epi-nucleosides 25 and 28 most
probably due to steric reasons or intramolecular cyclisa-
tion.
CEM/0
CEM/TK–
HIV-2
HIV-1
HIV-2
7
15
16
17
0.5 0.14
3.83 2.02
10 0.0
0.4 0.0
2.67 0.58
26.0 15.6
103 45
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
8.0 3.5
63.3 5.5
250
>250
Compounds 7, 15–17, 25 and 28 were evaluated for their
antiviral potential against HIV replication in CEM/0 cells
190 104
>250
>250
and in mutant CEM-thymidine-kinase (TK) deficient cells 25
>250
(Table 2). These two cell lines were used to study the de-
pendence of the nucleoside analogues to the presence of
28
>250
>250
>250
thymidine kinase as first activating kinase. Most thymine
nucleoside analogues are activated by the cellular salvage
pathway enzyme TK. This dependence can be studied
with the use of the cycloSal-phosphate triesters because
they act as TK-bypass agents. In contrast to earlier reports
by Béres et al.,5 carba-dT (7) showed comparable anti-
HIV activity as the reference compound 2¢,3¢-dideoxy-
2¢,3¢-didehydrothymidine (d4T) in the CEM/0 cell system
with only moderate cytotoxicity. The change from the nat-
ural b-configuration to the a-nucleoside 15 and iso-nucle-
oside 16 results in an eight- and 20-fold decrease in
antiviral activity. Carba-iso-a-derivative 17, as well as
carba-3¢-epi-nucleosides 25 and 28 did not show any pro-
tection against HIV-1 and HIV-2 (Table 2). Interestingly,
in all cases the cycloSal-modification 29–32 did not lead
to an improvement in antiviral protection. This proves that
the inactivity of the nucleosides prepared here can not be
attributed to a non-phosphorylation by TK. Probably the
triphosphates are not substrate analogues for the poly-
merase reverse transcriptase. However, this has to be
proven.
29
0.65 0.07
25.0 0.0
27.5 3.5
80.0 28.3
0.37 0.24
0.7 0.14
23.3 7.6
37.5 17.7
125 35.4
0.35 0.09
77 22
167 3.5
250
30
31
32
250
d4T
250
a 50% effective concentration.
b 50% cytotoxic concentration.
spectra were recorded at r.t., and all 13C and 31P NMR spectra were
recorded in proton-decoupled mode. Mass spectra were obtained
with a VG Analytical VG/70-250 F spectrometer (FAB, matrix was
m-nitrobenzyl alcohol). Analytical HPLC was performed on a
Merck-Hitachi-System with LiChroCART 250-3 containing Li-
Chrospher 100-3 RP-18 (5mm). Standard gradient: 5–100% MeCN
in H2O in 20 min, then 10 min 5% MeCN in H2O, flow: 0.5 mL/min.
Optical rotations were measured on a Perkin-Elmer Polarimeter 241
and a Jasco DIP-370 digital polarimeter at 589 nm. IR spectra were
recorded using a ThermoNicolet Avatar 370 FT-IR spectrometer.
(1S,2R)-1-Benzyloxy-2-benzyloxymethylcyclopent-3-ene (5a)
Alcohol 5 (6.00 g, 29.4 mmol) was added dropwise to a stirred sus-
pension of NaH (1.45 g, 36.3 mmol, 60% in oil) in THF (100 mL)
at 0 °C under N2. After 1 h at r.t., benzyl bromide (4.50 mL, 40.0
mmol) and tetrabutylammonium iodide (TBAI, 220 mg) were add-
ed. The mixture was kept overnight at r.t. Crushed ice was added
and the mixture was stirred for 0.5 h, then poured into EtOAc (200
mL), washed with H2O and brine, dried (Na2SO4) and concentrated.
The residue was purified on silica gel (hexanes–EtOAc, 10:1) to
yield 5a (7.96 g, 90%) as a light-yellow oil; [a]D20 +83.6 (c 1.23,
CHCl3).
All experiments involving water-sensitive compounds were con-
ducted under scrupulously dry conditions (N2 atmosphere) using
standard syringe, cannula and septa apparatus. Solvents: Benzene,
Et2O and THF were distilled from sodium or potassium benzophe-
none and stored over molecular sieves. CH2Cl2, pyridine and MeCN
were distilled from CaH2 and stored over molecular sieves. EtOAc,
CH2Cl2, and MeOH employed in chromatography were distilled be-
fore use. Chromatography: Chromatotron (Harrison Research
7924), silica gel 60Pf (Merck, ‘gipshaltig’); UV detection at 254 nm.
TLC: analytical TLC was performed on Merck precoated aluminum
plates 60 F254 with a 0.2 mm layer of silica gel containing a fluores-
cence indicator; sugar-containing compounds were visualised with
the sugar spray reagent (0.5 mL of 4-methoxybenzaldehyde, 9 mL
of EtOH, 0.5 mL of conc. H2SO4, and 0.1 mL of glacial AcOH) by
heating with a drying fan. NMR spectra were recorded using Bruker
WM 400 at 400 MHz (1H NMR); Bruker WM 400 at 101 MHz (13C
NMR) (calibration was done in both cases with the solvent); and
Bruker AMX 400 at 162 MHz (31P NMR, H3PO4 as external stan-
dard). All 1H and 13C NMR chemical shifts (d) are quoted in parts
per million (ppm) downfield from tetramethylsilane,
(CD3)(CD2H)SO being set at dH 2.49 as a reference. 31P NMR chem-
ical shifts are quoted in ppm using H3PO4 as external reference. The
IR (neat): 3061, 3030, 2856, 1495, 1453, 1359, 1308, 1272, 1204,
1174, 1096, 1072, 734, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37–7.22 (m, 10 Harom), 5.75
(ddd, J = 6.5, 4.3, 2.0 Hz, 1 H, H-3), 5.65 (ddd, J = 6.1, 4.2, 2.1 Hz,
1 H, H-4), 4.56–4.51 (m, 4 H, CH2Ph), 4.08 (ddd, J = 6.9, 3.4, 3.3
Hz, 1 H, H-1), 3.45 (dd, J = 9.3, 5.7 Hz, 1 H, OCHH), 3.33 (dd,
J = 9.3, 5.3 Hz, 1 H, OCHH), 3.10–3.03 (m, 1 H, H-2), 2.68 (dddd,
J = 17.2, 6.5, 4.5, 2.0 Hz, 1 H, H-5a), 2.46–2.37 (m, 1 H, H-5b).
13C NMR (101 MHz, CDCl3): d = 139.2, 138.9 (Carom), 130.5 (C-3),
130.3 (C-4), 128.8, 128.8, 128.7, 128.2, 128.1, 128.0, 127.9
Synthesis 2006, No. 8, 1313–1324 © Thieme Stuttgart · New York

1318
O. R. Ludek et al.
PAPER
(CHarom), 81.8 (C-1), 73.5, 72.1 (CH2Ph), 71.2 (OCH2), 53.4 (C-2),
HRMS-FAB: m/z calcd for C20H24O3 (M + H): 313.1804; found:
39.5 (C-5).
313.1796.
HRMS-FAB: m/z calcd for C20H22O2 (M + H): 295.1698; found:
295.1682.
meso-(1R,2S,3S)-1,3-Benzyloxy-2-benzyloxymethyl-
cyclopentane (9)
The reaction has been carried out as described for cyclopentenol 5
with NaH (20.0 mg, 0.42 mmol, 50% in oil) in THF (1.5 mL), cy-
clopentanol 8a (100 mg, 0.32 mmol), benzyl bromide (83.0 mg,
0.485 mmol) und TBAI (4.00 mg). The residue was purified by
chromatography on a chromatotron (CH2Cl2–MeOH, gradient 0–
5%) to yield 9 (109 mg, 85%) as a colourless oil; [a]D20 0 (c 0.75,
CHCl3).
Hydroboration of (1S,2R)-1-Benzyloxy-2-benzyloxymethyl-
cyclopent-3-ene (5a) with BH3
A 1.0 M solution of BH3 in THF (4.5 mL, 4.5 mmol) was added
dropwise to cyclopentene 5a (2.00 g, 6.79 mmol) at 0 °C under N2
and stirred at that temperature overnight. The reaction mixture was
treated sequentially with 3 N NaOH solution (1.7 mL) and 33%
H2O2 (1.7 mL). The resulting mixture was stirred overnight at r.t.
The precipitate was filtered and washed with EtOAc (50 mL). To
this suspension, H2O was added (50 mL) and after separation of the
phases, the aqueous layer was extracted with EtOAc (3 × 20 mL).
The combined organic layers were dried (Na2SO4) and concentrated
to dryness. The crude product was purified on silica gel (hexane–
EtOAc, 1:1) to yield 6b, 8a and 8b as colourless oils.
IR (neat): 3062, 3029, 2932, 2859, 1495, 1453, 1357, 1204, 1093,
1027, 753, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.26 (m, 15 Harom), 4.54 (d,
J = 12.0 Hz, 2 H, 2 × CHHPh-A), 4.48 (d, J = 12.0 Hz, 2 H,
2 × CHHPh-A), 4.47 (s, 2 H, CH2Ph-B), 3.82–3.72 (m, 2 H, H-1, H-
3), 3.51 (d, J = 5.3 Hz, 2 H, OCH2), 2.33–2.24 (m, 1 H, H-2), 1.88–
1.78 (m, 4 H, 4-CH2, 5-CH2).
13C NMR (101 MHz, CDCl3): d = 139.3, 139.0, 128.7, 128.1, 128.0,
127.9, 127.8 (C and CH, Ar), 81.1 (C-1, C-3), 73.5 (OCH2), 71.4,
70.3 (CH2Ph), 52.8 (C-2), 30.0 (C-4, C-5).
(1R,3S,4R)-3-Benzyloxy-4-benzyloxymethylcyclopentanol (6b)
Yield: 786 mg (37%); [a]D20 +35.48 (c 0.73, CHCl3).
IR (neat): 3395, 3087, 3062, 3029, 2929, 2859, 1496, 1453, 1360,
1308, 1246, 1205, 1166, 1096, 1028, 736 cm–1.
HRMS-FAB: m/z calcd for C27H30O3 (M + H): 403.2273; found:
403.2275.
1H NMR (400 MHz, CDCl3): d = 7.35–7.25 (m, 10 Harom), 4.52 (s,
2 H, CH2Ph), 4.49 (d, J = 11.8 Hz, 1 H, CHHPh), 4.44 (d, J = 11.8
Hz, 1 H, CHHPh), 4.33–4.28 (m, 1 H, H-1), 4.07 (ddd, J = 6.6, 6.6,
4.1 Hz, 1 H, H-3), 3.53 (dd, J = 9.0, 4.2 Hz, 1 H, OCHH), 3.49 (d,
J = 9.0, 4.3 Hz, 1 H, OCHH), 2.35–2.25 (m, 2 H, H-4, H-5a), 2.05
(dddd, J = 13.5, 6.7, 3.5, 1.7 Hz, 1 H, H-2a), 1.89–1.82 (m, 1 H, H-
2b), 1.52–1.46 (m, 1 H, H-5b).
13C NMR (101 MHz, CDCl3): d = 139.1, 138.2 (Carom), 128.9,
128.8, 128.2, 128.1 (CHarom), 82.4 (C-1), 74.1, 73.7 (2 × CH2Ph),
72.8 (C-3), 71.5 (OCH2), 44.9 (C-4), 40.8 (C-2), 37.8 (C-5).
Coupling of Pyrimidines to Cyclopentanols 6b, 8a, 8b; General
Procedure
To a suspension of Ph3P (787 mg, 3.00 mmol) in anhyd MeCN (11
mL), was added slowly diisopropylazodicarboxylate (DIAD, 545
mL, 2.80 mmol) and the solution was stirred for 0.5 h at 0 °C. This
preformed complex was slowly added to a suspension of the pro-
tected thymine (506 mg, 2.2 mmol) and the appropriate cyclopen-
tanol 6b, 8a, or 8b (312 mg, 1.00 mmol) in anhyd MeCN (6.0 mL)
at –40 °C under N2. The reaction was slowly warmed to r.t. and
stirred overnight. The solvent was removed from the reaction mix-
ture and a 1% NaOH solution in MeOH (15 mL) was added and the
mixture stirred overnight at r.t. The solution was neutralised by ad-
dition of 1 M HCl and then concentrated. The crude was purified on
silica gel (hexanes–EtOAc, 1:2) to yield the protected carbocyclic
nucleosides as colourless syrups.
HRMS-FAB: m/z calcd for C20H24O3 (M + H): 313.1804; found:
313.1808.
(1R,2S,3S)-3-Benzyloxy-2-benzyloxymethylcyclopentanol (8a)
Yield: 470 mg (22%); [a]D20 +43.24 (c 1.04, CHCl3).
IR (neat): 3415, 3029, 2923, 2860, 1496, 1453, 1359, 1206, 1095,
1028, 1000, 735 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.20 (m, 10 Harom), 4.55–
4.40 (m, 4 H, 2 × CH2Ph), 4.02–3.96 (m, 1 H, H-1), 3.74–3.69 (m,
1 H, H-3), 3.59 (dd, J = 9.1, 5.6 Hz, 1 H, OCHH), 3.44 (dd, J = 9.1,
7.9 Hz, 1 H, OCHH), 2.29–2.22 (m, 1 H, H-2), 1.95–1.75 (m, 4 H,
4-CH2, 5-CH2).
13C NMR (101 MHz, CDCl3): d = 138.9, 138.6, 128.9, 128.8, 128.1,
128.0 (C and CH, Ar), 81.2 (C-3), 76.2 (C-1), 73.7, 71.6
(2 × CH2Ph), 71.2 (OCH2), 54.5 (C-2), 32.4 (C-4), 29.4 (C-5).
1-(3¢,5¢-Di-O-benzyl-6¢-carba-2¢-desoxy-a-D-erythro-pento-
furanosyl)thymine (11)
The reaction was carried out with cyclopentanol 6b according to the
general coupling procedure. The O2-alkylated isomer could not be
separated completely on this stage.
Yield: 360 mg (86%, 3:1 N1-/O2-isomeric mixture).
1H NMR (400 MHz, DMSO-d6): d = 11.22 (br s, 1 H, NH), 7.67 (q,
J = 1.2 Hz, 1 H, H-6), 7.42–7.30 (m, 10 Harom), 4.94 (quin, J = 8.1
Hz, 1 H, H-1¢), 4.55–4.48 (m, 4 H, 2 × CH2Ph), 3.94–3.89 (m, 1 H,
H-3¢), 3.47–3.41 (m, 2 H, 2 × H-5¢), 2.51–2.47 (m, 1 H, H-4¢), 2.38–
2.32 (m, 1 H, H-2¢a), 1.98–1.82 (m, 3 H, H-6¢a, H-6¢b, H2¢b), 1.74
(d, J = 1.2 Hz, 3 H, H-7).
13C NMR (101 MHz, DMSO-d6): d = 164.1 (C-4), 150.2 (C-2),
138.9, 138.7 (Carom), 138.3 (C-6), 128.9, 128.6, 127.9, 127.8
(CHarom), 109.6 (C-5), 80.8 (C-3¢), 72.5, 71.4 (CH2-Ph), 70.6 (C-5¢),
52.9 (C-1¢), 44.2 (C-4¢), 37.2 (C-2¢), 32.8 (C-6¢), 12.5 (C-7).
HRMS-FAB: m/z calcd for C20H24O3 (M + H): 313.1804; found:
313.1794.
(1S,2S,3S)-3-Benzyloxy-2-benzyloxymethylcyclopentanol (8b)
Yield: 504 mg (24%); [a]D20 +80.32 (c 0.63, CHCl3).
IR (neat): 3445, 3062, 3029, 2934, 2863, 1496, 1453, 1362, 1309,
1256, 1205, 1173, 1069, 1027, 958, 736 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.27 (m, 10 Harom), 4.56–
4.38 (m, 5 H, 2 × CH2Ph, H-1), 4.02–3.96 (m, 1 H, H-3), 3.79 (dd,
J = 9.4, 4.3 Hz, 1 H, OCHH), 3.73 (dd, J = 9.4, 6.9 Hz, 1 H,
OCHH), 2.20–2.10 (m, 2 H, H-2, H-4a), 2.05–1.95 (m, 1 H, H-5a),
1.70–1.60 (m, 2 H, H-4b, H-5b).
13C NMR (101 MHz, CDCl3): d = 139.1, 138.2, 129.0, 128.8, 128.3,
128.1 (C and CH, Ar), 81.2 (C-3), 74.2 (C-1), 73.9, 71.5
(2 × CH2Ph), 69.1 (OCH2), 51.2 (C-2), 33.0 (C-5), 29.5 (C-4).
MS (ESI–): m/z calcd for C25H27N2O4 (M – H): 419.2; found: 419.
(1¢S,2¢R,3¢S)-1-(3¢-Benzyloxy-2¢-benzyloxymethylcyclo-
pentyl)thymine (12)
The reaction was carried out with cyclopentanol 8a according to the
general coupling procedure; yield: 180 mg (43%).
Synthesis 2006, No. 8, 1313–1324 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbocyclic Nucleosides
1319
1H NMR (400 MHz, CDCl3): d = 8.38 (br s, 1 H, NH), 7.35–7.25
(m, 10 Harom), 7.01 (q, J = 1.0 Hz, 1 H, H-6), 4.48–4.80 (m, 1 H, H-
1¢), 4.48 (d, J = 12.0 Hz, 1 H, CHHPh-A), 4.43 (d, J = 12.0 Hz, 1 H,
CHHPh-A), 4.22 (d, J = 11.7 Hz, 1 H, CHHPh-B), 4.19 (d, J = 11.7
Hz, 1 H, CHHPh-B), 4.15–4.09 (m, 1 H, H-3¢), 3.40 (dd, J = 9.9, 4.8
Hz, 1 H, H-6¢a), 3.27 (dd, J = 9.9, 3.0 Hz, 1 H, H-6¢b), 2.57–2.50
(m, 1 H, H-2¢), 2.30–2.23 (m, 1 H, H-4¢a), 2.02–1.90 (m, 2 H, H-5¢a,
H-5¢b), 1.68 (d, J = 1.0 Hz, 3 H, H-7), 1.65–1.58 (m, 1 H, H-4¢b).
13C NMR (101 MHz, CDCl3): d = 164.2 (C-4), 151.7 (C-2), 139.7
(C-6), 138.8, 138.7, 128.8, 128.7, 128.2, 128.1, 127.9 (C and CH,
Ar), 109.2 (C-5), 81.2 (C-3¢), 73.8, 71.9 (2 × CH2Ph), 69.1 (C-5¢),
58.3 (C-6¢), 46.9 (C-4¢), 30.6 (C-2¢), 28.1 (C-1¢), 12.8 (C-7).
HRMS-FAB: m/z calcd for C11H16N2O4 (M + H): 241.1188; found:
241.1185.
(1¢S,2¢R,3¢S)-1-(3¢-Hydroxy-2¢-hydroxymethylcyclo-
pentyl)thymine (carba-iso-dT, 16)
The reaction was carried out according to the general debenzylation
procedure with compound 12 (200 mg, 0.48 mmol) in EtOH
(7.0 mL) und 10% Pd/C (50 mg) as catalyst; yield: 97.1 mg (83%);
[a]D20 –128.0 (c 0.25, H2O).
IR (KBr): 3414, 3036, 2953, 1685, 1475, 1401, 1369, 1273, 1047,
765, 590, 486 cm–1.
1H NMR (400 MHz, D2O): d = 7.74 (q, J = 1.0 Hz, 1 H, H-6), 4.98
(dd, J = 17.4, 8.7 Hz, 1 H, H-6¢), 4.17 (dd, J = 14.6, 6.7 Hz, 1 H, H-
3¢), 3.56 (dd, J = 11.6, 5.3 Hz, 1 H, H-5¢a), 3.45 (dd, J = 11.6, 7.8
Hz, 1 H, H-5¢b), 2.36–2.25 (m, 2 H, H-4¢, H-2¢a), 2.24–2.18 (m, 1
H, H-1¢a), 2.04–1.97 (m, 1 H, H-1¢b), 1.87 (d, J = 1.0 Hz, 3 H, H-
7), 1.65–1.57 (m, 1 H, H-2¢b).
13C NMR (101 MHz, D2O): d = 167.0 (C-4), 153.1 (C-2), 141.3 (C-
6), 110.4 (C-5), 73.9 (C-3¢), 59.7 (C-5¢), 57.6 (C-6¢), 50.4 (C-4¢),
31.9 (C-2¢), 26.8 (C-1¢), 11.8 (C-7).
MS (ESI–): m/z calcd for C25H27N2O4 (M – H): 419.2; found: 419.
(1¢R,2¢R,3¢S)-1-(3¢-Benzyloxy-2¢-benzyloxymethylcyclo-
pentyl)thymine (13)
The reaction was carried out with cyclopentanol 8b according to the
general coupling procedure. The O2-alkylated isomer could not be
separated completely on this stage;
yield: 230 mg (55%, 3:1 N1-/O2-isomeric mixture).
1H NMR (400 MHz, CDCl3): d = 8.30 (br s, 1 H, NH), 7.35–7.27
(m, 11 Harom, H-6), 4.89 (m, 1 H, H-6¢), 4.56 (d, J = 11.8 Hz, 1 H,
CHHPh-A), 4.50 (d, J = 11.9 Hz, 1 H, CHHPh-B), 4.48 (d, J = 11.8
Hz, 1 H, CHHPh-A), 4.46 (d, J = 11.9 Hz, 1 H, CHHPh-B), 3.95–
3.90 (m, 1 H, H-3¢), 3.52 (dd, J = 9.4, 5.6 Hz, 1 H, H-5¢a), 3.40 (dd,
J = 9.4, 7.1 Hz, 1 H, H-5¢b), 2.33–2.26 (m, 1 H, H-4¢), 2.15–2.10
(m, 1 H, H-1¢a), 2.06–2.01 (m, 1 H, H-2¢a), 1.87–1.82 (m, 1 H, H-
1¢b), 1.80 (d, J = 1.2 Hz, 3 H, H-7), 1.77–1.72 (m, 1 H, H-2¢b).
13C NMR (101 MHz, CDCl3): d = 163.9 (C-4), 151.5 (C-2), 138.6,
138.4 (Carom), 138.1 (C-6), 128.9 128.8, 128.2, 128.1, 128.0
(CHarom), 111.8 (C-5), 81.6 (C-3¢), 73.8, 71.7 (2 × CH2Ph), 70.7 (C-
5¢), 57.2 (C-6¢), 52.5 (C-4¢), 30.4 (C-2¢), 30.4 (C-1¢), 12.9 (C-7).
HRMS-FAB: m/z calcd for C11H16N2O4 (M + H): 241.1188; found:
241.1181.
(1¢R,2¢R,3¢S)-1-(3¢-Hydroxy-2¢-hydroxymethylcyclo-
pentyl)thymine (carba-iso-a-dT, 17)
The reaction was carried out according to the general debenzylation
procedure with compound 13 (230 mg, 0.547 mmol) in EtOH
(10 mL) and 10% Pd/C (60 mg) as catalyst; yield: 110 mg (84%);
[a]D20 +6.7 (c 0.88, H2O).
IR (KBr): 3422, 3052, 2951, 1685, 1578, 1474, 1396, 1307, 1271,
1072, 1046, 764, 590, 489, 420 cm–1.
1H NMR (400 MHz, D2O): d = 7.61 (s, 1 H, H-6), 4.68 (dd,
J = 17.2, 8.5 Hz, 1 H, H-6¢), 4.10 (dd, J = 10.8, 5.4 Hz, 1 H, H-3¢),
3.64 (d, J = 5.6 Hz, 2 H, 5¢-CH2), 2.18–2.05 (m, 2 H, H-4¢, 1¢a),
2.04–1.94 (m, 2 H, H-2¢a, H-1¢b), 1.90 (s, 3 H, H-7), 1.88–1.80 (m,
1 H, H-2¢b).
13C NMR (101 MHz, D2O): d = 166.8 (C-4), 152.8 (C-2), 140.3 (C-
6), 111.9 (C-5), 72.9 (C-3¢), 60.9 (C-5¢), 57.5 (C-6¢), 54.1 (C-4¢),
32.0 (C-2¢), 28.0 (C-1¢), 11.8 (C-7).
MS (ESI–): m/z calcd for C25H27N2O4 (M – H): 419.2; found: 419.
Debenzylation of 11–13; General Procedure
A mixture of the appropriate benzyl ether 11–13 and Pd/C in EtOH
was stirred under an atmosphere of H2 at r.t. until complete conver-
sion was observed by TLC. The mixture was filtered through Celite
and washed with MeOH. The filtrate was concentrated and the res-
idue purified by chromatography on a chromatotron (CH2Cl2–
MeOH gradient 0–20%) to yield the carbocyclic nucleosides as co-
lourless foams. After lyophilisation (MeCN–H2O, 1:1), the target
compounds were obtained as colourless cottons.
HRMS-FAB: m/z calcd for C11H16N2O4 (M + H): 241.1188; found:
241.1189.
(1R,2R)-2-Benzyloxymethylcyclopent-3-enol (18)
To a suspension of Ph3P (1.93 g, 7.36 mmol), benzoic acid (890 mg,
7.29 mmol) and the alcohol 5 (1.00 g, 4.90 mmol) in anhyd Et2O
(60 mL) at 0 °C under N2 was slowly added DIAD (1.4 mL,
7.30 mmol). The reaction was slowly warmed to r.t., and stirred
overnight. The solid was removed by filtration and washed with
Et2O. The solvent was removed and a 1% NaOH solution in MeOH
(40 mL) was added. Stirring was continued overnight at r.t. The so-
lution was neutralised by addition of 1 M HCl and then concentrat-
ed. The crude material was purified on silica gel (hexanes–EtOAc,
1-(6¢-Carba-2¢-desoxy-a-D-erythro-pentofuranosyl)thymine
(carba-a-dT, 15)
The reaction was carried out according to the general debenzylation
procedure with 3¢,5¢-di-O-benzyl-carba-a-dT (11; 300 mg,
0.71 mmol) in EtOH (10.0 mL) and 10% Pd/C (50 mg) as catalyst;
yield: 140 mg (82%); [a]D20 +8.18 (c 0.44, H2O).
IR (KBr): 3407, 3048, 2934, 1682, 1475, 1396, 1274, 1076, 1040,
764, 581 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.20 (br s, 1 H, NH), 7.73 (q,
J = 1.0 Hz, 1 H, H-6), 4.99 (d, J = 4.1 Hz, 1 H, 3¢-OH), 4.87 (quin,
J = 8.3 Hz, 1 H, H-1¢), 4.59 (dd, J = 5.1, 5.1 Hz, 1 H, 5¢-OH), 3.95–
3.90 (m, 1 H, H-3¢), 3.45–3.36 (m, 2 H, 2 × H-5¢), 2.24 (ddd,
J = 13.3, 8.3, 5.9 Hz, 1 H, H-2¢a), 2.15–2.07 (m, 1 H, H-4¢), 1.90–
1.83 (m, 2 H, 2 × H-6¢), 1.81 (d, J = 1.0 Hz, 3 H, H-7), 1.68 (ddd,
J = 13.3, 7.9, 5.6 Hz, 1 H, H-2¢b).
13C NMR (101 MHz, DMSO-d6): d = 164.1 (C-4), 151.3 (C-2),
138.5 (C-6), 109.6 (C-5), 72.2 (C-3¢), 62.3 (C-5¢), 52.7 (C-1¢), 49.4
(C-4¢), 39.3 (C-2¢), 32.6 (C-6¢), 12.6 (C-7).
1:2) to yield alcohol 18 (800 mg, 80%) as a colourless oil; [a]D
20
+44.6 (c 0.68, CHCl3) {Lit.22 [a]D20 +49 (c 0.02, CHCl3)}.
IR (neat): 3431, 3060, 2915, 2859, 1453, 1362, 1206, 1175, 1088,
736, 697, 606 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.40–7.33 (m, 5 Harom), 5.71 (ddd,
J = 6.0, 4.7, 2.4 Hz, 1 H, H-3), 5.56 (ddd, J = 6.0, 4.2, 1.9 Hz, 1 H,
H-4), 4.54–4.49 (m, 1 H, H-1), 4.46 (s, 2 H, CH2Ph), 3.64–3.59 (m,
2 H, OCH2), 2.94–2.86 (m, 1 H, H-2), 2.62–2.55 (m, 1 H, H-5a),
2.32–2.25 (m, 1 H, H-5b), 2.11 (br s, 1 H, OH).
Synthesis 2006, No. 8, 1313–1324 © Thieme Stuttgart · New York

1320
O. R. Ludek et al.
PAPER
13C NMR (101 MHz, CDCl3): d = 138.7 (Carom), 130.7 (C-3), 129.7
(C-4), 128.9, 128.2, 127.5 (CHarom), 73.3 (C-1), 69.6 (CH2Ph), 65.8
(OCH2), 50.1 (C-2), 42.5 (C-5).
OCHH), 3.67 (dd, J = 9.0, 9.0 Hz, 1 H, OCHH), 2.16–2.07 (m, 1 H,
H-2), 2.05–2.00 (m, 1 H, H-5a), 1.95–1.85 (m, 1 H, H-5b), 1.73
(dddd, J = 13.9, 10.6, 5.4, 5.4 Hz, 1 H, H-4a), 1.52–1.42 (m, 1 H, H-
4b).
13C NMR (101 MHz, CDCl3): d = 139.2, 138.7, 128.9, 128.7, 128.1,
127.8, 127.7, 127.6 (C and CH, Ar), 80.3 (C-1), 77.0 (C-3), 74.0,
71.2 (CH2Ph), 70.5 (OCH2), 53.0 (C-2), 32.0 (C-5), 29.4 (C-4).
HRMS-FAB: m/z calcd for C13H16O2 (M + H): 205.1229; found:
205.1224.
(1R,2R)-1-Benzyloxy-2-benzyloxymethylcyclopent-3-ene (18a)
The reaction was carried out as described for cyclopentene 5a with
NaH (350 mg, 7.29 mmol, 50% in oil) in anhyd THF (25 mL), cy-
clopentenol 18 (1.25 g, 6.12 mmol), benzyl bromide (1.36 g,
7.95 mmol) and TBAI (40.0 mg). The residue was purified on silica
gel (hexanes–EtOAc, 10:1) to yield 18a (1.28 g, 71%) as a light-yel-
low oil.
1H NMR (400 MHz, CDCl3): d = 7.35–7.28 (m, 10 Harom), 5.79–
5.75 (m, 2 H, H-3, H-4), 4.57–4.50 (m, 4 H, 2 × CH2Ph), 4.27 (ddd,
J = 6.5, 6.5, 4.6 Hz, 1 H, H-1), 3.81 (dd, J = 9.2, 6.8 Hz, 1 H,
OCHH), 3.57 (dd, J = 9.2, 7.4 Hz, 1 H, OCHH), 3.07–3.02 (m, 1 H,
H-2), 2.52–2.47 (m, 1 H, H-5a, H-5b).
HRMS-FAB: m/z calcd for C20H24O3 (M + H): 313.1804; found:
313.1815.
(1S,2S,3R)-3-Benzyloxy-2-benzyloxymethylcyclopentanol (20b)
The reaction was carried out as described for alcohol 18 with Ph3P
(262 mg, 1.00 mmol), benzoic acid (122 mg, 1.00 mmol), cyclo-
pentanol 20a (160 mg, 0.51 mmol) in anhyd THF (8.0 mL), DIAD
(208 mL, 1.00 mmol), and 1% NaOH solution in MeOH (8.0 mL).
The residue was purified on silica gel (hexanes–EtOAc, 1:1) to
yield the title compound 20b (115 mg, 72%) as a colourless oil;
[a]D20 –44.0 (c 0.61, CHCl3).
13C NMR (101 MHz, CDCl3): d = 139.2, 139.1 (Carom), 132.0 (C-3),
129.5 (C-4), 128.7, 128.1, 127.9, 127.8 (CHarom), 79.9 (C-1), 73.8,
72.1 (CH2Ph), 70.0 (OCH2), 49.2 (C-2), 38.8 (C-5).
1H NMR (400 MHz, CDCl3): d = 7.35–7.25 (m, 10 Harom), 4.61 (d,
J = 12.0 Hz, 1 H, CHHPh-A), 4.58 (d, J = 11.8 Hz, 1 H, CHHPh-B),
4.53 (d, J = 11.8 Hz, 1 H, CHHPh-B), 4.37 (d, J = 12.0 Hz, 1 H,
CHHPh-A), 4.25–4.20 (m, 1 H, H-1), 4.15–4.11 (m, 1 H, H-3), 3.87
(d, J = 7.0 Hz, 2 H, OCH2), 2.75 (d, J = 10.8 Hz, 1 H, OH), 2.11
(dddd, J = 14.0, 9.1, 4.9, 1.3 Hz, 1 H, H-4a), 2.06–1.99 (m, 2 H, H-
2, H-5a), 1.88 (dddd, J = 14.0, 9.1, 6.1, 1.5 Hz, 1 H, H-5b), 1.69
(dddd, J = 14.0, 11.0, 6.2, 4.9 Hz, 1 H, H-4b).
13C NMR (101 MHz, CDCl3): d = 139.0, 138.7, 128.8, 128.2, 128.0,
127.9, 127.8 (C and CH, Ar), 81.6 (C-1), 74.6 (C-3), 73.9, 71.6
(2 × CH2Ph), 66.8 (OCH2), 50.8 (C-2), 34.0 (C-5), 29.3 (C-4).
HRMS-FAB: m/z calcd for C20H22O2 (M + H): 295.1698; found:
295.1697.
Hydroboration of (1R,2R)-1-Benzyloxy-2-benzyloxymethyl-
cyclopent-3-ene (18a) with (–)-Diisopinocampheylborane
A 1.0 M suspension of (–)-diisopinocampheylborane in THF [5.0
mL, 5.0 mmol, prepared from (+)-a-pinene (1.50 g, 11.0 mmol) and
BH3·THF complex (1.0 M, 5.0 mL, 5.0 mmol)] was added dropwise
to cyclopentene 18a (740 mg, 2.51 mmol) at 0 °C under N2 and
stirred at that temperature overnight. The reaction was treated se-
quentially with 3 N NaOH solution (3.0 mL) and 33% H2O2 solution
(3.0 mL). The resulting mixture was stirred overnight at r.t. The pre-
cipitate was filtered and washed with EtOAc (50 mL). To this sus-
pension, H2O was added (50 mL) and after separation of the phases,
the aqueous layer was extracted with EtOAc (3 × 20 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated to dry-
ness. The crude product was purified on silica gel (hexanes–EtOAc,
1:1) to yield 19a and 20a as colourless oils.
HRMS-FAB: m/z calcd for C20H24O3 (M + H): 313.1804; found:
313.1796.
meso-(1S,2S,3R)-1,3-Dibenzyloxy-2-benzyloxymethylcyclo-
pentane (21)
The reaction was carried out as described for cyclopentenol 5a with
NaH (0.900 mg, 18.8 mmol, 50% in oil) in DMF (0.5 mL), cyclo-
pentanol 20b (5.00 mg, 16.0 mmol), benzyl bromide (3.6 mg,
20 mmol) und TBAI (0.5 mg). The residue was purified by chroma-
tography on silica gel (CH2Cl2 as eluent) to yield 21 (5.00 mg, 78%)
as a colourless oil; [a]D20 0 (c 0.25, CHCl3).
(1R,3R,4R)-3-Benzyloxy-4-benzyloxymethylcyclopentanol
(19a)
Yield: 450 mg (58%).
IR (neat): 3062, 3029, 2961, 2925, 2857, 1496, 1453, 1361, 1261,
1172, 1093, 1027, 734, 696 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.26 (m, 15 Harom), 4.62 (d,
J = 12.5 Hz, 2 H, 2 × CHHPh-A), 4.53 (s, 2 H, CH2Ph-B), 4.48 (d,
J = 12.5 Hz, 2 H, CHHPh-A), 4.05–4.00 (m, 2 H, H-1, H-3), 3.82
(d, J = 6.6 Hz, 2 H, OCH2), 2.22 (tt, J = 6.6, 6.6 Hz, 1 H, H-2), 1.99–
1.90 (m, 2 H, H-4a, H-5a), 1.78–1.69 (m, 2 H, H-4b, H-5b).
13C NMR (101 MHz, CDCl3): d = 139.7, 138.8, 128.2, 128.1, 127.8,
127.6 (C and CH, Ar), 79.6 (C-1, C-3), 73.8, 71.4 (CH2Ph), 66.9
(OCH2), 49.2 (C-2), 30.2 (C-4, C-5).
1H NMR (400 MHz, CDCl3): d = 7.37–7.27 (m, 10 Harom), 4.53 (AB
System, J = 12.0 Hz, 2 H, CH2Ph-A), 4.52 (d, J = 12.2 Hz, 1 H,
CHHPh-B), 4.51–4.46 (m, 1 H, H-1), 4.42 (d, J = 12.2 Hz, 1 H,
CHHPh-B), 4.15 (ddd, J = 5.3, 5.3, 2.7 Hz, 1 H, H-3), 3.74 (dd,
J = 9.2, 7.9 Hz, 1 H, OCHH), 3.51 (dd, J = 9.2, 6.1 Hz, 1 H,
OCHH), 2.65–2.55 (m, 1 H, H-4), 2.25 (ddd, J = 14.4, 6.7, 2.8 Hz,
1 H, H-2a), 1.89 (ddd, J = 13.6, 10.8, 6.7 Hz, 1 H, H-5a), 1.81–1.70
(m, 2 H, H-2b, H-5b).
13C NMR (101 MHz, CDCl3): d = 139.4, 139.1 (Carom), 128.9,
128.8, 128.1, 127.9, 127.8 (CHarom), 80.3 (C-1), 73.6 (CH2Ph-A),
71.9 (C-3), 71.5 (CH2Ph-B), 70.2 (OCH2), 43.0 (C-4), 42.4 (C-2),
38.0 (C-5).
HRMS-FAB: m/z calcd for C27H30O3 (M + H): 403.2273; found:
403.2271.
(1R,2R)-2-Benzyloxymethyl-1-tert-butyldimethylsilyloxycyclo-
pent-3-enol (18b)
HRMS-FAB: m/z calcd for C20H24O3 (M + H): 313.1804; found:
To a solution of cyclopentenol 18 (800 mg, 3.92 mmol) in anhyd
DMF (3.0 mL) at r.t., were added imidazole (765 mg, 11.2 mmol)
and TBDMS-Cl (1.01 g, 6.70 mmol) in portions. The reaction was
stirred overnight at r.t., and quenched with ice. The resulting mix-
ture was evaporated to remove DMF, and the residue was parti-
tioned between EtOAc (50 mL) and H2O (50 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc (2 × 20
mL). The combined organic fractions were dried (Na2SO4) and con-
centrated. The residue was purified by chromatography on silica gel
313.1802.
(1R,2S,3R)-3-Benzyloxy-2-benzyloxymethylcyclopentanol (20a)
Yield: 200 mg (26%); [a]D20 –42.9 (c 1.04, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.30–7.15 (m, 10 Harom), 4.47 (s,
2 H, CH2Ph-A), 4.43 (d, J = 12.2 Hz, 1 H, CHHPh-B), 4.24 (d,
J = 12.2 Hz, 1 H, CHHPh-B), 4.23–4.20 (m, 1 H, H-1), 3.95 (ddd,
J = 5.5, 5.5, 2.6 Hz, 1 H, H-3), 3.76 (dd, J = 9.0, 6.0 Hz, 1 H,
Synthesis 2006, No. 8, 1313–1324 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbocyclic Nucleosides
1321
(hexanes–EtOAc, 2:1) to yield the title compound 18b (1.12 g,
90%) as a light-yellow oil.
(C-5), 44.9 (C-2), 37.5 (C-4), 26.4 [SiC(CH3)3], 19.0 [SiC(CH3)3],
–4.0 (SiCH3), –4.5 (SiCH3).
1H NMR (400 MHz, CDCl3): d = 7.35–7.30 (m, 5 Harom), 5.79–5.71
(m, 2 H, H-3, H-4), 4.56–4.51 (m, 1 H, H-1), 4.55 (d, J = 11.9 Hz,
1 H, CHHPh), 4.49 (d, J = 11.9 Hz, 1 H, CHHPh), 3.73 (dd, J = 9.0,
6.0 Hz, 1 H, OCHH), 3.48 (dd, J = 9.0, 8.3 Hz, 1 H, OCHH), 2.91–
2.84 (m, 1 H, H-2), 2.49 (dddd, J = 16.4, 6.4, 2.9, 1.6 Hz, 1 H, H-
5a), 2.32–2.25 (m, 1 H, H-5b), 0.87 [s, 9 H, SiC(CH3)3], 0.10 (s, 3
H, SiCH3), 0.04 (s, 3 H, SiCH3).
HRMS-FAB: m/z calcd for C19H32O3Si (M + H): 337.2199; found:
337.2193.
1-(3¢,5¢-Di-O-benzyl-6¢-carba-2¢-desoxy-b-D-threo-pento-
furanosyl)thymine (24)
The reaction was carried out according to the general coupling pro-
cedure with Ph3P (880 mg, 3.36 mmol) in anhyd MeCN (12 mL),
DIAD
(610 mL,
3.13 mmol),
and
3-N-benzoylthymine
13C NMR (101 MHz, CDCl3): d = 138.2 (Carom), 132.0 (C-3), 129.3
(C-4), 128.7, 128.6, 128.1 (CHarom), 73.7 (C-1), 73.4 (CH2Ph), 70.4
(OCH2), 50.4 (C-2), 42.5 (C-5), 26.4 [SiC(CH3)3], 18.4
[SiC(CH3)3], –4.0 (SiCH3), –4.5 (SiCH3).
(560 mg, 2.43 mmol), cyclopentanol 19a (350 mg, 1.12 mmol) in
anhyd MeCN (6.0 mL) and 1% NaOH in MeOH (15 mL). The
crude product was purified by chromatography on silica gel (hex-
anes–EtOAc, 1:2) to yield 24 (350 mg, 74%) as a colourless syrup.
1H NMR (400 MHz, CDCl3): d = 8.44–8.40 (br s, 1 H, NH), 7.46 (q,
J = 1.2 Hz, 1 H, H-6), 7.35–7.27 (m, 10 Harom), 5.36–5.30 (m, 1 H,
H-1¢), 4.57–4.49 (m, 4 H, 2 × CH2Ph), 4.08 (dd, J = 3.8, 3.8 Hz, 1
H, H-3¢), 3.77 (dd, J = 9.0, 8.8 Hz, 1 H, H-5¢a), 3.57 (dd, J = 9.0, 5.2
Hz, 1 H, H-5¢b), 2.35–2.21 (m, 3 H, H-4¢, H-2¢a, H-6¢a), 1.82 (dd,
J = 15.5, 3.6 Hz, 1 H, H-2¢b), 1.62 (d, J = 1.2 Hz, 3 H, H-7), 1.56–
1.51 (m, 1 H, H-6¢b).
HRMS-FAB: m/z calcd for C19H30O2Si (M + H): 319.2093; found:
319.2104.
Hydroboration of (1R,2R)-2-Benzyloxymethyl-1-tert-butyl-
dimethylsilyloxycyclopent-3-enol (18b) with 9-BBN
A 0.5 M solution of 9-BBN in THF (12 mL, 6.0 mmol) was added
dropwise to 18b (900 mg, 2.83 mmol) at 0 °C under N2. The reac-
tion was slowly warmed to r.t. overnight. The reaction was cooled
to 0 °C and treated sequentially with 3 N NaOH solution (3.0 mL)
and 33% H2O2 (3.0 mL). The resulting mixture was stirred over-
night at r.t. The precipitate was filtered and washed with EtOAc (50
mL). To this suspension, H2O was added (50 mL) and after separa-
tion of the phases, the aqueous layer was extracted with EtOAc
(3 × 20 mL). The combined organic layers were dried (Na2SO4) and
the solvent was evaporated to dryness. The crude product was puri-
fied on silica gel (hexanes–EtOAc, 1:1) to yield 22a and the isomer
23a as light-yellow oils.
13C NMR (101 MHz, CDCl3): d = 164.0 (C-4), 151.5 (C-2), 138.7
(C-6), 138.4, 129.6, 129.0, 128.9, 128.3, 128.2, 128.0 (C and CH,
Ar), 112.0 (C-5), 79.5 (C-3¢), 73.8 (C-5¢), 71.8, 69.1 (2 × CH2Ph),
53.0 (C-1¢), 45.7 (C-4¢), 38.3 (C-2¢), 31.4 (C-6¢), 12.8 (C-7).
(1¢S,2¢R,3¢R)-1-(2¢-Benzyloxymethyl-3¢-tert-butyldimethylsilyl-
oxycyclopentyl)thymine (26)
The reaction was carried out according to the general coupling pro-
cedure with Ph3P (787 mg, 3.00 mmol) in anhyd MeCN (11 mL),
DIAD
(545 mL, 2.80 mmol),
and
3-N-benzoylthymine
(1R,2S,3R)-2-Benzyloxymethyl-3-tert-butyldimethylsilyloxy-
cyclopentanol (23a)
(505 mg, 2.20 mmol), cyclopentanol 23a (340 mg, 1.00 mmol) in
anhyd MeCN (6.0 mL) and 1% NaOH in MeOH (15 mL). The
crude product was purified by chromatography on silica gel (hex-
anes–EtOAc, 1:2) to yield 26 (275 mg, 62%) as a colourless syrup;
[a]D20 –16.4 (c 0.34, MeCN).
1H NMR (400 MHz, CDCl3): d = 8.25 (br s, 1 H, NH), 7.62 (q,
J = 1.2 Hz, 1 H, H-6), 7.34–7.20 (m, 5 Harom), 5.42 (ddd, J = 10.6,
9.5, 7.2 Hz, 1 H, H-1¢), 4.46 (d, J = 11.6 Hz, 1 H, CHHPh), 4.36–
4.32 (m, 1 H, H-3¢), 4.28 (d, J = 11.6 Hz, 1 H, CHHPh), 3.39 (dd,
J = 9.2, 7.6 Hz, 1 H, OCHH), 3.25 (dd, J = 9.2, 7.0 Hz, 1 H,
OCHH), 2.50–2.42 (m, 1 H, H-2¢), 2.33–2.23 (m, 1 H, H-5¢a), 1.90–
1.86 (m, 2 H, H-5¢b, H-4¢a), 1.86 (d, J = 1.2 Hz, 3 H, H-7), 1.57–
1.52 (m, 1 H, H-4¢b), 0.93 [s, 9 H, SiC(CH3)3], 0.13 (s, 3 H, SiCH3),
0.09 (s, 3 H, SiCH3).
Yield: 466 mg (50%).
1H NMR (400 MHz, CDCl3): d = 7.35–7.30 (m, 5 Harom), 4.55 (d,
J = 11.8 Hz, 1 H, CHHPh), 4.50 (d, J = 11.8 Hz, 1 H, CHHPh),
4.29–4.22 (m, 2 H, H-1, H-3), 3.72 (dd, J = 9.0, 6.0 Hz, 1 H,
OCHH), 3.62 (dd, J = 9.0, 7.8 Hz, 1 H, OCHH), 2.25–2.17 (m, 1 H,
H-4), 2.05–1.95 (m, 2 H, H-2a, H-2b), 1.60–1.51 (m, 2 H, H-5a, H-
5b), 0.84 [s, 9 H, SiC(CH3)3], 0.04 (s, 3 H, SiCH3), 0.01 (s, 3 H,
SiCH3).
13C NMR: (101 MHz, CDCl3): d = 138.3 (Carom), 128.6, 128.3,
128.0 (CHarom), 74.7 (C-3), 73.8 (CH2Ph), 72.5 (C-1), 70.4 (OCH2),
53.4 (C-4), 34.2 (C-5), 32.7 (C-2), 26.5 [SiC(CH3)3], 18.4
[SiC(CH3)3], –4.0 (SiCH3), –4.5 (SiCH3).
13C NMR (101 MHz, CDCl3): d = 164.0 (C-4), 151.0 (C-2), 139.6
(C-6), 138.0, 128.8, 128.4, 128.2 (C and CH, Ar), 110.1 (C-5), 74.2
(C-3¢), 74.0 (CH2Ph), 66.6 (OCH2), 54.2 (C-1¢), 48.4 (C-2¢), 34.6
(C-4¢), 30.5 (C-5¢), 26.3 [SiC(CH3)3], 18.8 [SiC(CH3)3], 12.7 (C-7),
–4.3 (SiCH3), –4.7 (SiCH3).
HRMS-FAB: m/z calcd for C19H32O3Si (M + H): 337.2199; found:
337.2193.
(1S,3R,4R)-4-Benzyloxymethyl-3-tert-butyldimethylsilyloxy-
cyclopentanol (22a)
Yield: 260 mg (28%); [a]D20 –0.9 (c 1.1, CHCl3).
HRMS-FAB: m/z calcd for C14H36N2O4Si (M + H): 445.2523;
found: 445.2563.
IR (neat): 3373, 3064, 3030, 2928, 1496, 1471, 1408, 1363, 1250,
1206, 1171, 1042, 911, 836, 807, 775, 734, 697 cm–1.
(1¢S,2¢R,3¢R)-1-(2¢-Benzyloxymethyl-3¢-hydroxycyclo-
pentyl)thymine (27)
1H NMR (400 MHz, CDCl3): d = 7.35–7.27 (m, 5 Harom), 4.54 (d,
J = 11.9 Hz, 1 H, CHHPh), 4.50 (ddd, J = 9.2, 4.5, 2.3 Hz, 1 H, H-
1), 4.43 (d, J = 11.9 Hz, 1 H, CHHPh), 4.37 (m, 1 H, H-3), 3.53 (dd,
J = 8.9, 7.6 Hz, 1 H, OCHH), 3.39 (dd, J = 8.9, 6.6 Hz, 1 H,
OCHH), 2.50–2.40 (m, 1 H, H-2), 2.05 (ddd, J = 13.9, 6.7, 2.3 Hz,
1 H, H-4a), 1.85 (ddd, J = 13.5, 10.7, 7.0 Hz, 1 H, H-5a), 1.74 (ddd,
J = 13.9, 4.8, 4.8 Hz, 1 H, H-4b), 1.66 (ddd, J = 13.5, 7.9, 2.3 Hz, 1
H, H-5b), 0.85 [s, 9 H, SiC(CH3)3], 0.05 (s, 3 H, SiCH3), 0.02 (s, 3
H, SiCH3).
A solution of TBAF in THF (1.0 M, 840 mL, 0.840 mmol) was add-
ed dropwise to a solution of nucleoside 26 (260 mg, 0.585 mmol) in
THF (8.0 mL) and the reaction was stirred at r.t. for 5 h. TLC
showed the completion of the reaction. Ice was added and the mix-
ture was poured into EtOAc (50 mL), washed with H2O, dried
(Na2SO4) and concentrated. The residue was purified by chroma-
tography on a chromatotron (CH2Cl2–MeOH gradient 0–10%) to
20
yield compound 27 (140 mg, 72%) as a colourless syrup; [a]D
+13.2 (c 0.26, MeCN).
13C NMR (101 MHz, CDCl3): d = 138.3 (Carom), 128.5, 128.3, 128.1
(CHarom), 74.8 (CH2Ph), 74.6 (C-3), 72.6 (C-1), 71.0 (OCH2), 46.1
Synthesis 2006, No. 8, 1313–1324 © Thieme Stuttgart · New York

1322
O. R. Ludek et al.
PAPER
IR (KBr): 3439, 3058, 2926, 1683, 1474, 1400, 1384, 1271, 1103,
748, 699 cm–1.
under N2 and the 3-methyl-cycloSal-phosphorchloridate (1.23 M in
toluene, 280 mL) was added dropwise over a period of 2 h. Stirring
was continued for an additional 0.5 h at –40 °C. The reaction was
warmed to r.t. and the pyridine was evaporated off. The crude was
purified by chromatography on a chromatotron (CH2Cl2–MeOH
gradient 0–10%) to yield the cycloSal-phosphate triesters as colour-
less foams. After lyophilisation (MeCN–H2O, 1:1), the products
were obtained as colourless cottons.
1H NMR (400 MHz, DMSO-d6): d = 11.20 (br s, 1 H, NH), 7.87 (q,
J = 1.2 Hz, 1 H, H-6), 7.35–7.25 (m, 5 Harom), 5.26 (ddd, J = 10.0,
9.6, 7.0 Hz, 1 H, H-1¢), 5.16 (d, J = 3.0 Hz, 1 H, 3¢-OH), 4.43 (d,
J = 12.0 Hz, 1 H, CHHPh), 4.28 (d, J = 12.0 Hz, 1 H, CHHPh),
4.20–4.17 (m, 1 H, H-3¢), 3.48 (dd, J = 9.8, 6.4 Hz, 1 H, OCHH),
3.23 (dd, J = 9.8, 8.3 Hz, 1 H, OCHH), 2.45–2.36 (m, 1 H, H-2¢),
2.22–2.15 (m, 1 H, H-5¢a), 1.86–1.75 (m, 2 H, H-4¢a, H-4¢b), 1.74
(d, J = 1.2 Hz, 3 H, H-7), 1.69–1.61 (m, 1 H, H-5¢b).
13C NMR (101 MHz, DMSO-d6): d = 164.0 (C-4), 151.8 (C-2),
140.0 (C-6), 138.7, 128.5, 127.8, 127.6 (C and CH, Ar), 108.2 (C-
5), 72.7 (CH2Ph), 71.5 (C-3¢), 66.5 (OCH2), 53.8 (C-1¢), 47.3 (C-2¢),
33.8 (C-4¢), 30.1 (C-5¢), 12.8 (C-7).
3-Methyl-cyclosaligenyl[1-(6¢-carba-2¢-desoxy-a-D-erythro-
pentofuranosyl)thyminyl]monophosphate (3-Me-cycloSal-
carba-a-dTMP, 30)
The reaction was carried out according to the described general pro-
cedure with nucleoside 15.
Yield: 58.1 mg (65%); HPLC: tR 10.61, 10.79 min.
HRMS-FAB: m/z calcd for C18H22N2O4 (M + H): 331.1658; found:
331.1663.
IR (KBr): 3431, 3054, 2954, 1685, 1472, 1369, 1280, 1191, 1019,
939, 866, 819, 775, 651, 487, 421 cm–1.
1-(6¢-Carba-2¢-desoxy-b-D-threo-pentofuranosyl)thymine
(carba-3¢-epi-dT, 25)
The reaction was carried out according to the general debenzylation
procedure with 3¢,5¢-di-O-benzyl-carba-3¢-epi-dT (24; 330 mg,
0.781 mmol) in EtOH (10 mL) and 10% Pd/C (60.0 mg) as catalyst;
yield: 165 mg (88%); [a]D20 –57.5 (c 0.6, H2O).
1H NMR (400 MHz, CDCl3): d = 8.76 (br s, 2 H, 2 × NH), 7.29 (q,
J = 1.2 Hz, 1 H, H-6), 7.28 (q, J = 1.2 Hz, 1 H, H-6), 7.20–7.15 (m,
2 H, 2 × H-6arom), 7.04 (d, J = 7.6 Hz, 1 H, H-4arom), 7.02 (d, J = 7.6
Hz, 1 H, H-4arom), 6.94–6.90 (m, 2 H, 2 × H-5arom), 5.38–5.30 (m, 4
H, 2 × CH2Ph), 4.90–4.80 (m, 2 H, 2 × H-1¢), 4.22 (ddd, J = 10.6,
7.9, 5.5 Hz, 1 H, H-5¢a), 4.20–4.10 (m, 4 H, 2 × H-3¢, 5¢-CH2), 4.07
(ddd, J = 10.6, 8.8, 6.4 Hz, 1 H, H-5¢b), 3.44 (br d, J = 4.7 Hz, 1 H,
3¢-OH), 3.35 (br d, J = 4.7 Hz, 1 H, 3¢-OH), 2.52–2.40 (m, 4 H,
2 × H-4¢, 2 × H-2¢a), 2.29 (s, 3 H, 3-CH3), 2.28 (s, 3 H, 3-CH3),
2.10–2.20 (m, 2 H, 2 × H-6¢a), 2.01–1.92 (m, 2 H, 2 × H-6¢b), 1.91
(d, J = 1.2 Hz, 6 H, 2 × H-7), 1.90–1.82 (m, 2 H, 2 × H-2¢b).
13C NMR (101 MHz, CDCl3): d = 164.0 (C-4), 151.3 (C-2), 148.9
(C-2arom), 138.7 (C-6), 138.6 (C-6), 131.6 (C-6arom), 128.4 (C-1arom),
128.3 (C-1arom), 124.5 (C-4arom), 123.3 (C-5arom), 120.9 (d, J = 2.0
Hz, C-3arom), 120.8 (d, J = 2.4 Hz, C-3arom), 111.8 (C-5), 73.8 (C-3¢),
73.6 (C-3¢), 69.4 (d, J = 6.0 Hz, CH2Ph), 69.3 (C-5¢), 69.2 (d,
J = 6.3 Hz, C-5¢), 55.1 (C-1¢, C-5¢), 48.3 (d, J = 5.5 Hz, C-4¢), 48.2
(d, J = 5.6 Hz, C-4¢), 39.6 (C-2¢) 39.6 (C-2¢), 32.3 (C-6¢), 32.2 (C-
6¢), 15.8 (3-CH3), 13.0 (C-7).
IR (KBr): 3415, 3050, 2933, 1685, 1474, 1394, 1276, 1214, 1127,
1060, 1060, 1018, 991, 935, 869, 762, 596, 558, 479, 420 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.25 (br s, 1 H, NH), 7.76 (q,
J = 1.2 Hz, 1 H, H-6), 5.08 5.00 (m, 1 H, H-1¢), 4.90 (d, J = 3.6 Hz,
1 H, 3¢-OH), 4.40 (t, J = 5.2 Hz, 1 H, 5¢-OH), 4.17–4.12 (m, 1 H, H-
3¢), 3.64 (dd, J = 10.6, 7.4 Hz, 1 H, H-5¢a), 3.46 (dd, J = 10.6, 5.9
Hz, 1 H, H-5¢b), 2.35–2.27 (m, 1 H, H-2¢a), 2.06–2.00 (m, 1 H, H-
6¢a), 1.96–1.87 (m, 1 H, H-4¢), 1.81 (d, J = 1.2 Hz, 3 H, H-7), 1.56
(ddd, J = 14.8, 4.5, 1.2 Hz, 1 H, H-2¢b), 1.50–1.40 (m, 1 H, H-6¢b).
13C NMR (101 MHz, DMSO-d6): d = 164.1 (C-4), 151.4 (C-2),
138.6 (C-6), 109.7 (C-5), 70.4 (C-3¢), 60.5 (C-5¢), 52.9 (C-1¢), 47.5
(C-4¢), 39.3 (C-2¢), 33.4 (C-6¢), 12.8 (C-7).
31P NMR (162 MHz, CDCl3): d = –8.15, –8.22.
HRMS-FAB: m/z calcd for C11H26N2O4 (M + H): 241.1188; found:
241.1179.
HRMS-FAB: m/z calcd for C19H24N2O7P (M + H): 423.1321;
found: 423.1331.
(1¢S,2¢R,3¢R)-1-(3¢-Hydroxy-2¢-hydroxymethylcyclo-
pentyl)thymine (28)
UV (MeCN): lmax = 262.2 nm.
The reaction was carried out according to the general debenzylation
procedure with compound 27 (120 mg, 0.360 mmol) in EtOH
(3.0 mL) in the presence of 10% Pd/C (25 mg) as catalyst; yield:
85.2 mg (98%); [a]D20 –83.7 (c 0.68, H2O).
(1¢S,2¢R,3¢S)-3-Methyl-cyclosaligenyl-(3¢-hydroxy-1¢-thyminyl-
cyclopent-2¢-ylmethyl)monophosphate (3-Me-cycloSal-carba-
iso-dTMP, 31)
The reaction was carried out according to the described general pro-
cedure with nucleoside 16.
IR (KBr): 3423, 3055, 2953, 1682, 1475, 1401, 1270, 1218, 1102,
1042, 937, 766, 559, 485, 420 cm–1.
Yield: 53.9 mg (61%); HPLC: tR 9.80, 9.96 min.
1H NMR (400 MHz, DMSO-d6): d = 11.14 (br s, 1 H, NH), 7.91 (q,
J = 1.0 Hz, 1 H, H-6), 5.21 (ddd, J = 10.2, 9.5, 6.7 Hz, 1 H, H-1¢),
5.05 (d, J = 2.7 Hz, 1 H, 3¢-OH), 4.31 (dd, J = 5.0, 5.0 Hz, 1 H, 6¢-
OH), 4.20–4.16 (m, 1 H, H-3¢), 3.47–3.43 (m, 1 H, H-6¢a), 3.20
(ddd, J = 10.7, 7.1, 5.0 Hz, 1 H, H-6¢b), 2.23–2.15 (m, 2 H, H-2¢, H-
5¢a), 1.84–1.80 (m, 1 H, H-5¢b), 1.78 (d, J = 1.0 Hz, 3 H, H-7), 1.78–
1.74 (m, 1 H, H-4¢a), 1.65–1.57 (m, 1 H, H-4¢b).
13C NMR (101 MHz, DMSO-d6): d = 164.1 (C-4), 152.1 (C-2),
140.3 (C-6), 108.0 (C-5), 71.0 (C-3¢), 57.3 (C-6¢), 53.9 (C-1¢), 49.9
(C-2¢), 33.8 (C-4¢), 30.1 (C-5¢), 12.8 (C-7).
IR (KBr): 3433, 3049, 2957, 1686, 1472, 1275, 1191, 1087, 1020,
942, 772, 480 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.30 (br s, 1 H, NH), 8.20 (br s, 1
H, NH), 7.20–7.15 (m, 2 H, 2 × H-6arom), 7.04 (d, J = 7.4 Hz, 1 H,
H-4arom), 7.02 (d, J = 7.4 Hz, 1 H, H-4arom), 6.95–6.87 (m, 4 H,
2 × H-6, 2 × H-5arom), 5.35–5.20 (m, 4 H, 2 × CH2Ph), 5.03–4.90
(m, 2 H, 2 × H-1¢), 4.40–4.31 (m, 2 H, 2 × H-6¢a), 4.30–4.20 (m, 2
H, 2 × H-6¢b), 2.48–2.40 (m, 2 H, 2 × H-2¢), 2.38–2.28 (m, 4 H,
2 × H-4¢a, 2 × H-5¢a), 2.25 (s, 3 H, 3-CH3), 2.23 (s, 3 H, 3-CH3),
1.92–1.88 (m, 2 H, 2 × H-4¢b), 1.85 (d, J = 1.2 Hz, 3 H, H-7), 1.78
(d, J = 1.2 Hz, 1 H, H-7), 1.74–1.65 (m, 2 H, 2 × H-5¢b).
HRMS-FAB: m/z calcd for C11H26N2O4 (M + H): 241.1188; found:
241.1184.
13C NMR (101 MHz, CDCl3): d = 164.5 (C-4), 151.7 (C-2), 148.7
(C-2arom), 138.7 (C-6), 131.9 (C-6arom), 128.3 (C-1arom), 124.6 (C-
cycloSal-Phosphate Triesters 30–32; General Procedure
The appropriate nucleoside 15–17 (50.0 mg, 0.21 mmol) was dis-
solved in anhyd pyridine (0.5 mL) and 5 pieces of activated molec-
ular sieves (3 Å) were added. The mixture was cooled to –40 °C
4
arom), 123.3 (C-5arom), 122.5 (C-3arom), 110.8 (C-5), 73.3 (C-3¢),
69.3 (d, J = 6.5 Hz, CH2Ph), 69.2 (d, J = 7.0 Hz, CH2Ph), 66.5 (d,
J = 6.0 Hz, H-6¢), 57.6 (C-1¢), 57.4 (C-1¢), 50.6 (C-2¢), 32.5 (C-4¢),
Synthesis 2006, No. 8, 1313–1324 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbocyclic Nucleosides
1323
31.9 (C-4¢), 27.4 (C-5¢), 27.0 (C-5¢), 15.7 (3-CH3), 13.0 (C-7), 12.9
(3) For reviews, see (a) Borthwick, A. D.; Biggadike, K.
(C-7).
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) Marquez, V. E. In
Advances in Antiviral Drug Design, Vol. 2; De Clercq, E.,
Ed.; JAI Press: Greenwich, 1996, 89. (d) Crimmins, M. T.
Tetrahedron 1998, 54, 9229.
31P NMR (162 MHz, CDCl3): d = –7.63, –8.14.
HRMS-FAB: m/z calcd for C19H24N2O7P (M + H): 423.1321;
found: 423.1334.
UV (MeCN): lmax = 264.5 nm.
(4) Marquez, V. E.; Ezzitouni, A.; Russ, P.; Siddiqui, M. A.;
Ford, H.; Feldman, R. J.; Mitsuja, H.; George, C.; Barchi, J.
J. J. Am. Chem. Soc. 1998, 120, 2780.
(1¢R,2¢R,3¢S)-3-Methyl-cyclosaligenyl-(3¢-hydroxy-1¢-thyminyl-
cyclopent-2¢-ylmethyl)monophosphate (3-Me-cycloSal-carba-
iso-a-dTMP, 32)
The reaction was carried out according to the described general pro-
cedure with carba-iso-a-dT (17; 60.0 mg, 0.25 mmol) in pyridine
(600 mL) and 3-methyl-cyclosaligenylchlorophosphate (1.23 M in
toluene, 340 mL).
(5) Béres, J.; Sági, G.; Tömösközi, I.; Gruber, L.; Baitz-Gács,
E.; Ötvos, L.; De Clercq, E. J. Med. Chem. 1990, 33, 1353.
(6) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17.
(7) Bisacchi G. S., Chao S. T., Bachard C., Daris J. P., Innaimo
S., Jacobs G. A., Kocy O., Lapointe P., Martel A., Merchant
Z., Slusarchyk W. A., Sundeen J. E., Young M. G., Colonno
R., Zahler R.; Bioorg. Med. Chem. Lett.; 1997, 7: 127.
(8) (a) Balzarini, J.; Baumgartner, H.; Bodenteich, M.; De
Clercq, E.; Griengl, H. Nucleosides Nucleotides 1989, 8,
855. (b) Wyatt, P. G.; Anslow, A. S.; Coomber, B. A.;
Cousins, R. P. C.; Evans, D. N.; Gilbert, V. S.; Humber, D.
C.; Paternoster, I. L.; Sollis, S. L.; Tapolczay, D. J.;
Weingarten, G. G. Nucleosides Nucleotides 1995, 14, 2039.
(9) Ludek, O. R.; Meier, C. Synthesis 2003, 2101.
(10) Biggadike, K.; Borthwick, A. D.; Evans, D.; Exall, A. M.;
Kirk, B. E.; Roberts, S. M.; Stephenson, L.; Youds, P. J.
Chem. Soc., Perkin Trans.1 1988, 549.
Yield: 66.0 mg (63%); HPLC: tR 9.93 min.
IR (KBr): 3431, 3056, 2957, 1685, 1472, 1370, 1272, 1191, 1020,
941, 867, 773 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.64 (br s, 1 H, NH), 8.47 (br s, 1
H, NH), 7.20 (q, J = 1.0 Hz, 1 H, H-6), 7.19 (q, J = 1.0 Hz, 1 H, H-
6), 7.17–7.12 (m, 2 H, 2 × H-6arom), 7.05–7.00 (m, 2 H, 2 × H-4arom),
6.94–6.88 (m, 2 H, 2 × H-5arom), 5.37–5.28 (m, 4 H, 2 × CH2Ph),
4.65–4.55 (m, 2 H, 2 × H-1¢), 4.28–4.18 (m, 4 H, 2 × 6¢-CH2), 4.17–
4.10 (m, 2 H, 2 × H-3¢), 3.36 (br s, 2 H, 2 × 3¢-OH), 2.42–2.36 (m,
2 H, 2 × H-2¢), 2.27 (s, 3 H, 3-CH3), 2.22 (s, 3 H, 3-CH3), 2.12–2.02
(m, 4 H, 2 × H-4¢a, 2 × H-5¢a), 1.92–1.84 (m, 4 H, 2 × H-2¢b, 2 × H-
5¢b), 1.90 (d, J = 1.0 Hz, 3 H, H-7), 1.88 (d, J = 1.0 Hz, 3 H, H-7).
13C NMR (101 MHz, CDCl3): d = 163.7 (C-4), 151.2 (C-2), 148.8
(C-2arom), 138.7 (C-6), 131.7 (C-6arom), 128.3 (C-1arom), 124.5 (C-
4arom), 123.3 (C-5arom), 122.8 (d, J = 2.5 Hz, H-3arom), 122.7 (d,
J = 2.1 Hz, H-3arom), 73.6 (C-3¢), 73.3 (C-3¢), 69.4 (d, J = 6.6 Hz,
CH2Ph), 69.3 (d, J = 6.6 Hz, CH2Ph), 68.1 (d, J = 5.6 Hz, C-6¢),
68.0 (d, J = 5.6 Hz, C-6¢), 58.7 (C-1¢), 53.6 (C-2¢), 33.2 (C-4¢), 28.5
(C-5¢), 15.8 (3-CH3), 12.9 (C-7).
(11) Mitsunobu, O. Synthesis 1981, 1.
(12) Herdewijn, P.; Balzarini, J.; De Clercq, E.; Pauwels, R.;
Baba, M.; Broder, S.; Vanderhaeghe, H. J. Med. Chem.
1987, 30, 1270.
(13) (a) Brown, H. C. Organic Syntheses via Boranes; Wiley:
New York, 1975. (b) Brown, H. C.; Jadhav, P. K.; Mandal,
A. K. Tetrahedron 1981, 37, 3547. (c) Brown, H. C.;
Ayyangar, N. R.; Zweifel, G. J. Org. Chem. 1964, 86, 397.
(d) Brown, H. C.; Knights, E. F.; Scouten, C. G. J. Am.
Chem. Soc. 1974, 96, 7765.
31P NMR (162 MHz, CDCl3): d = –10.63, –10.82.
(14) (a) Jenny, T. F.; Previsani, N.; Benner, S. A. Tetrahedron
Lett. 1991, 32, 7029. (b) Jenny, T. F.; Horlacher, J.;
Previsani, N.; Benner, S. A. Helv. Chim. Acta 1992, 75,
1944. (c) Bonnal, C.; Chavis, C.; Lucas, M. J. Chem. Soc.,
Perkin Trans. 1994, 1, 1401. (d) Pérez-Pérez, M. -J.;
Rozenski, J.; Busson, R.; Herdewijn, P. J. Org. Chem. 1995,
60, 1531. (e) Borthwick, A. D.; Crame, A. J.; Exall, A. M.;
Weingarten, G. G.; Mahmoudian, M. Tetrahedron Lett.
1995, 36, 6929. (f) Schmitt, L.; Caperelli, C. A. Nucleosides
Nucleotides 1997, 16, 2165. (g) Choo, H.; Chong, Y.; Chu,
C. K. Org. Lett. 2001, 3, 1471. (h) Comins, D. L.; Jianhua,
G. Tetrahedron Lett. 1994, 35, 2819.
(15) Cruickshank, K. A.; Jiricny, J.; Reese, C. B. Tetrahedron
Lett. 1984, 25, 681.
(16) Tomoskozi, I.; Gruber, L.; Baitz Gacs, E.; Otvos, L.; De
Clercq, E. J. Med. Chem. 1990, 33, 1353.
(17) (a) Meier, C. Mini-Rev. Med. Chem. 2002, 2, 219.
(b) Meier, C. Advances in Antiviral Drug Design, Vol. 4;
Elsevier: Amsterdam, 2004, 147.
(18) Meier, C.; Lorey, M.; De Clercq, E.; Balzarini, J. J. Med.
Chem. 1998, 41, 1417.
HRMS-FAB: m/z calcd for C19H24N2O7P (M + H): 423.1321;
found: 423.1321.
UV (MeCN): lmax = 264.1 nm.
References
(1) For selected reviews, see (a) De Clercq, E. Ann. New York
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(2) (a) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.;
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Synthesis 2006, No. 8, 1313–1324 © Thieme Stuttgart · New York

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O. R. Ludek et al.
PAPER
(20) (a) Meier, C.; Knispel, T.; Marquez, V. E.; Siddiqui, M. A.;
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Synthesis 2006, No. 8, 1313–1324 © Thieme Stuttgart · New York