New convergent synthesis of carbocyclic nucleoside analogues

Article abstract of DOI:10.1055/s-2003-41455

Two convergent approaches towards the synthesis of carbocyclic nucleoside analogs will be described. Both approaches start from the stereochemically pure cyclopentenol 8 that has been prepared enantioselectively from an alkylated cyclopentadiene. Using these approaches, carbocyclic analogues of dT, FdU and BVdU have been prepared. Moreover, the conversion into the cycloSalpronucleotide and the corresponding nucleotide will be presented for one example.

Full text of DOI:10.1055/s-2003-41455

FEATURE ARTICLE
2101
New Convergent Synthesis of Carbocyclic Nucleoside Analogues
New
Convergent
S
l
ynthes
a
is of Carbo
f
cyclic
N
ucleos
R
ide
A
nalogue
s
. Ludek, Chris Meier*
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
Received 8 July 2003
Abstract: Two convergent approaches towards the synthesis of
carbocyclic nucleoside analogs will be described. Both approaches
start from the stereochemically pure cyclopentenol 8 that has been
prepared enantioselectively from an alkylated cyclopentadiene. Us-
ing these approaches, carbocyclic analogues of dT, FdU and BVdU
have been prepared. Moreover, the conversion into the cycloSal-
pronucleotide and the corresponding nucleotide will be presented
for one example.
Keywords: carbocyclic nucleosides, stereoselective synthesis,
Mitsunobu reaction, cycloSal-pronucleotides, nucleotides
Recently carbocyclic nucleosides have been the focus of
much attention in the development of new antitumor and
antiviral therapeutic agents.1 The bioactivity of the natu-
rally occurring carbocyclic nucleosides (–)-aristeromycin
(1)2 and (–)-neplanocin A (2),3 led to an interest in this
class of compounds, resulting in the generation of a di-
verse range of antiviral carbocyclic nucleosides4 such as
Carbovir (3),5 Abacavir (ZiagenTM, 4),6 Lobucavir (5),7
and more recently BMS-200475 (6).8 Beside carbocyclic
purine analogs, an example of a bioactive pyrimidine an-
alog is carba-BVdU (7) that showed anti-HSV-1 activity
(Figure 1).9,10
Carbocyclic nucleosides, in which the D-ribose moiety of
the nucleoside is replaced by a cyclopentane system, are
stable towards hydrolysis by phosphorylases and conse-
quently display enhanced biostability.11 In addition, the
replacement of the oxygen of furanose by a methylene
group results also in reduced toxicity of the carbocyclic
nucleosides.12
Figure 1
Carbocyclic nucleosides are synthetically the most chal-
lenging class of nucleosides, requiring multi-step and of-
Detailed experiments showed that intermediate 10
isomerizes to yield two thermodynamically more stable
cyclopentadiene derivatives 11 and 12 at temperatures
above 0 °C. Moreover, higher temperatures and concen-
trated solutions favor the formation of Diels–Alder prod-
ucts. Therefore, diluted solutions and temperatures
between –60 °C and 0 °C were used in the alkylation re-
action. Consequently, the following stereoselective hy-
droboration has also to be carried out at temperatures
below 0 °C and intermediate 10 was immediately convert-
ed into the chiral, non-racemic cyclopentenol 8 using (–)-
diisopinocampheylborane. The chemical yield was 36%
(four steps), the relative configuration was proven by
NOE-spectroscopy and the optical purity of the cyclopen-
tenol 8 was > 96%ee (chiral GC on a modified cyclodex-
trine column or 31P NMR after transformation into
diastereomers using the Anderson–Shapiro reagent).14
ten elaborate syntheses to introduce the necessary
stereochemistry. Different synthetic approaches have
been reviewed.1a
In our search for a convenient convergent synthesis to-
wards carbocyclic 2¢-deoxynucleoside analogues, we de-
cided to start with (1S,2R)-2-benzyloxymethylcyclopent-
3-enol (8) which has been described by Biggadike et al.13
The preparation of the enol 8 starts from cyclopentadiene
(9) that was first deprotonated (NaH) and alkylated using
benzylchloromethylether to give cyclopentadiene 10
(Scheme 1).
SYNTHESIS 2003, No. 13, pp 2101–2109
1
8.
0
9
.
2
0
0
3
Advanced online publication: 10.09.2003
DOI: 10.1055/s-2003-41455; Art ID: E09503ss.pdf
© Georg Thieme Verlag Stuttgart · New York

2102
O. R. Ludek, C. Meier
FEATURE ARTICLE
explanation of this unexpected result may be a complex-
ation of the borane to the oxygen atom of the benzyloxy
side chain of 10 and thus the borane can only add to the
double bond from that side without stereospecificity (sub-
strate directed reaction). However, compound 13 offers
new perspectives as a starting material in the synthesis of
carbocyclic nucleoside analogs after separation into its
enantiomers, e.g. for the synthesis of carba-nucleosides
with deoxy-xylo-configuration (results not shown).
Then, cyclopentenol 8 was converted into epoxide 14 by
t-butylhydroperoxide in the presence of Mo(CO)6 which
led to a stereoselective introduction of the epoxide from
the si,re-face.15 After benzylation (NaH, benzylbromide
and tetrabutylammonium iodide), epoxide 15 was regi-
oselectively opened with the sodium or lithium salt of
thymine with introduction of the heterocycle at the C1¢-
position leading to the carbocyclic thymidine derivative
16 (Scheme 2).16
Scheme 1 Reagents and Conditions: (a) NaH, THF, 0 °C, 0.5 h
(b) Benzylchloromethylether, THF, –60 °C, 2 h (c) (ipc)2BH, THF,
–60 °C, 1 h, then 0 °C, 16 h, 3 N NaOH, 30% H2O2, 0 °C, 12 h
(d) BH3, THF, –60 °C, 1 h, then 0 °C, 16 h, 3 N NaOH, 30% H2O2,
0 °C, 12 h.
No difference in the chemical yield (40% and 42%, re-
spectively) was found for the two salts, which have been
formed from thymine in the presence of sodium or lithium
hydride. Alternatively, the epoxide activation was carried
out by the addition of triethylaluminium in THF and ultra-
sonification at room temperature.17 After two days, 46%
of the target thymidine analog 16 had formed. The correct
stereochemistry at C1¢ was proven by NOE-spectroscopy.
It was unequivocally shown that only the desired N1-
product and no N3-coupling product formed (HMBC-
NMR). Subsequently, a Barton–McCombie deoxygen-
From model reactions with cyclopentadiene it became ap-
parent that the hydroboration has to be performed in a
very concentrated solution in order to increase the chemi-
cal yields. Therefore, the solvent THF was nearly com-
pletely evaporated in high vacuum at –10 °C after
alkylation. Interestingly, attempts to prepare the racemic
mixture of 10 using the borane·THF adduct were unsuc-
cessful. However, the racemic mixture of the correspond-
ing stereoisomer 13 with cis-configuration of the two
substituents was formed instead (Scheme 1). A possible
Biographical Sketches
Olaf R. Ludek was born in University of Hamburg under the guidance of Prof.
1973 in Hamburg, Germa- (2001) and is currently Dr. Chris Meier.
ny. He received his diploma working on his PhD thesis at
degree in chemistry at the the University of Hamburg
Chris Meier was born in nucleosides,
oligonucle- Professor of Organic Chem-
1962 in Berlin, Germany. otides, and prodrugs. In istry. His research interests
He studied Chemistry at the 1991 he returned to the Uni- are pronucleotide design for
University of Marburg- versity of Frankfurt-Main antiviral nucleoside ana-
Lahn, where he received his and finished his habilitation logues, stereoselective syn-
diploma degree in 1987 and in 1996. In 1994 he received thesis
his PhD degree in 1989 with the Adolf-Messer-Award nucleoside analogues, anti-
Prof. G. Boche. During that for interdisciplinary re- sense oligonucleotides,
of
carbocyclic
time he became interested in search. In 1997 he became DNA-damage induced by
bioorganic chemistry. Dur- Associate Professor of Or- arylamine carcinogens, and
ing his postdoctoral studies ganic Chemistry at the Uni- new syntheses of activated
at the Pasteur-Institute in versity of Würzburg and sugar-nucleotides.
Paris, France he got in- 1999 he moved to the Uni-
volved in the chemistry of versity of Hamburg as a Full
Synthesis 2003, No. 13, 2101–2109 © Thieme Stuttgart · New York

FEATURE ARTICLE
New Convergent Synthesis of Carbocyclic Nucleoside Analogues
2103
85:15 in favor of the R-configured 20b at C1¢ after oxida-
tive work-up. Although the yield was slightly lower
(90%), the use of dicyclohexylborane gave also predomi-
nately product 20b (75:25 ratio). Interestingly, the chiral
(–)-diisopinocampheylborane gave no reaction at all,
while the (+)-enantiomer led for the first time to the for-
mation of the trans,trans-regioisomer 21a in 42% yield.
Moreover, a diastereomeric mixture of the C1¢-alcohol
20a/b was isolated after oxymercuration21 with
Hg[OC(O)CF3]2 in 74% yield (Table 1). Interestingly,
none of the reagents led to the formation of the cis,trans-
isomer 21b.
Besides the oxidative cleavage of the trialkylborane inter-
mediate, an amino group was selectively introduced.
Therefore, the trialkylborane resulted from the 9-BBN re-
action with 19 was treated with hydroxylaminesulfonate22
and the C1¢ amino derivative 22 was isolated in a b:a-ratio
of 87:13. This intermediate allows the linear synthesis of
the heterocyclic ring according to literature procedures
(Scheme 3).
Scheme 2 Reagents and Conditions: (a) Mo(CO)6, t-BuOOH, ben-
zene, 80 °C, 3 h (b) NaH, BnBr, TBAI, THF, r.t. 12 h (c) Thymine,
LiH, DMF, 140 °C, 3 d or NaH, DMF, 140 °C, 3 d or Et3Al, THF, r.t.,
ultrasound, 12 h (d) PTC-Cl, pyridine, DMAP, r.t, 16 h (e) AIBN,
Bu3SnH, toluene, 3.5 h (f) FeCl3, CH2Cl2, 0 °C, 2 h
However, direct substitution of the hydroxyl group in 20b
would lead to a-configured nucleoside analogs. Thus,
Mitsunobu-inversion using triphenylphosphine, DIAD,
and benzoic acid23 followed by deprotection with NaOH
in methanol led to diastereomer 20a in 77% yield. A sub-
sequent Mitsunobu-reaction with PPh3, DIAD and N3-
benzoylthymine24,25 in THF at –78 °C to room tempera-
ture led to the known formation of two regioisomers. Al-
though both products showed complete inversion of
configuration at the C1¢-atom, the bond is formed via the
N1-atom in 23 or via the O2-atom of thymine in 24 in 87%
yield. The product ratio was 27:73 (23:24), respectively.
A second attempt using Vilsmeyer’s reagent [DMF/
(COCl)2] in THF for activating the hydroxyl group and
subsequent substitution by deprotonated N3-benzoylth-
ymine.26followed by deprotection with NaOH/MeOH led
again to the same mixture of regioisomers. However, the
ratio was 68:32 (23:24). The best N1/O2 ratio was
achieved by using the Mitsunobu protocol and MeCN as
solvent. Here, the ratio was found to be 75:25 (23:24).
Separation of both products was easily achieved by chro-
matography on silica gel. Finally, the regioisomer 23 was
debenzylated by BCl3 treatment in CH2Cl2 to give 18 in
90% yield (Scheme 3).
ation using phenoxythiocarbonyl chloride18 and tri-n-bu-
tylstannane gave protected carba-dT 17 in 72% yield.
Finally, both benzyl protecting groups were cleaved by
15,19
treatment of 17 with FeCl3
in CH2Cl2 at 0 °C to give
carba-dT 18 in 92% yield (Scheme 2). Starting from car-
ba-dT 18, further modifications in the cyclopentane ring
are possible, e.g. elimination to carba-d4T, deoxygen-
ation to carba-ddT and substitution of the 3¢-hydroxyl
group.
Alternatively, key intermediate 8 was fully protected by
benzylation to yield cyclopentene 19 with trans-configu-
ration of the two substituents in 92% yield. Then, com-
pound 19 was reacted with a variety of hydroboration
agents20 (Table 1).
The reaction using 9-BBN led to the formation of only
two of the four possible products. Only cyclopentenols 20
were obtained in 91% yield. The ratio of 20b:20a was
Table 1 Reaction of Cyclopentene 19 with Different Hydroxylation
Agents
Meth- Hydroxylation Agent
od
Products
Yielda Product
Distributionb
According to the last procedure, further carba-nucleoside
analogues have been prepared. Introduction of the ben-
zoylated 5-fluorouracil or 5-[(E)-bromovinyl]uracil led to
the formation of the carbocyclic analogs of the antitumor
active nucleoside analog 5-fluorouridine (5-FdU) and of
the anti-Herpes active nucleoside 5-[(E)-bromovinyl]uri-
dine (BVdU), carba-FdU 26 and carba-BVdU 7, respec-
tively. The N1/O2-ratios were 50:50 in the case of carba-
FdU 26 and 80:20 for carba-BVdU 7 and the yields were
found to be 42% and 53% (Scheme 3). The N1/O2-ratio
was determined from the 1H NMR spectra from the unpu-
rified reaction mixtures. Only the N1-product was isolated
and used for further reactions.
a
9-BBN, H2O2–NaOH
20a + 20b 91% 20b: 85%;
20a: 15%
b
c
d
(–)-(ipc)2BH, H2O2–NaOH
—
—
—
(+)-(ipc)2BH, H2O2–NaOH 21a
42% 21a: 100%
(C6H11)2BH, H2O2–NaOH
20a + 20b 90% 20b: 75%;
20a: 25%
e
Hg(F3CC(O)O)2, H2O
20a + 20b 74% 20b: 50%;
20a: 50%
a Yield of all isolated products.
b Determined after chromatography.
Synthesis 2003, No. 13, 2101–2109 © Thieme Stuttgart · New York

2104
O. R. Ludek, C. Meier
FEATURE ARTICLE
Scheme 4 Reagents and Conditions: (a) 3-methyl-cyclosaligenyl-
chlorophosphane, i-Pr2EtN, MeCN–DMF, 2:1, –40 °C to 0 °C, 2 h, t-
BuOOH, –40 °C to r.t. 2 h (b) Et3N, H2O, MeCN, r.t. 18 h
improvement in the biological activity has been ob-
served.30–32Moreover, the cycloSal-triesters of the
carbocyclic nucleoside analogues can be used for the
chemical synthesis of nucleotides (Scheme 4).33 As an ex-
ample, carba-dTMP was prepared from the correspond-
ing cycloSal-triester in 76% yield by chemical hydrolysis
(Scheme 4). The nucleotides will be used for studies
concerning their substrate properties on thymidylate ki-
nase (TMP-K),33,34an essential enzyme in the activation of
nucleotides into the ultimate bioactive triphosphates.35
Work on this is currently in progress in our laboratories.
All experiments involving water-sensitive compounds were con-
ducted under scrupulously dry conditions (nitrogen atmosphere) us-
ing standard syringe, cannula, and septa apparatus. Solvents:
benzene, Et2O, and THF were distilled from sodium or potassium
benzophenone and stored over molecular sieves. CH2Cl2 and MeCN
were distilled from CaH2 and stored over molecular sieves. EtOAc,
CH2Cl2, hexane, and MeOH employed in chromatography were dis-
tilled before used. i-Pr2EtN was distilled from sodium prior to use.
Chromatography: Chromatotron (Harrison Research 7924), silica
gel 60Pf (Merck, ‘gipshaltig’), UV detection at 254 nm. TLC: ana-
lytical thin layer chromatography was performed on Merck precoat-
ed aluminium plates 60 F254 with a 0.2 mm layer of silica gel
containing a fluorescence indicator; sugar-containing compounds
Scheme 3 Reagents and Conditions: (a) NaH, BnBr, TBAI, THF,
r.t. 12 h (b) 9-BBN, THF, r.t, 12 h, 3N NaOH, 30% H2O2, 0 °C, 12 h
(d) 9-BBN, THF, r.t, 12 h, hydroxylamine-O-sulfonic acid, THF,
70 °C, 3 h (e) PPh3, DIAD, N3-benzoylpyrimidine, MeCN, –40 °C to
r.t, 16 h (f) BCl3, CH2Cl2, 5 h, –78 °C, MeOH, –25 °C to r.t., 12 h
The described synthetic approaches towards carbocyclic
nucleoside analogs opens the possibility to study the bio- were visualized with the sugar spray reagent [4-methoxybenzalde-
hyde (0.5 mL), EtOH (9 mL), concd H2SO4 (0.5 mL), and HOAc
activity of these nucleoside analogous as well as the cor-
(0.1 mL)] by heating with a fan or a hot plate. NMR spectra were
responding nucleotides after conversion into their
recorded using (1H NMR) Bruker AC 250 at 250 MHz, Bruker WM
membrane-permeable cycloSal-phosphate triesters.27The
400 at 400 MHz, Bruker AMX 400 at 400 MHz or Bruker DMX
synthetic access for the conversions of carba-dT 18 and
carba-BVdU 7 into the cycloSal-triesters 27 and 28, re-
spectively, are summarized in Scheme 4. CycloSal-tri-
esters were obtained in 60% and 15% yield.
500 at 500 MHz; (13C NMR) Bruker WM 400 at 101 MHz, Bruker
AMX 400 at 101 MHz or Bruker DMX 500 at 123 MHz (Calibra-
tion was done in both cases with the solvent), (31P NMR) Bruker
AMX 400 at 162 MHz or Bruker DMX 500 at 202 MHz (H3PO4 as
1
external standard). All H and 13C NMR chemical shifts (d) are
It has been shown that cycloSal-triesters of active antiviral
nucleoside analogs are cleaved intracellularly to deliver
the corresponding nucleotides efficiently.28,29 Often an
quoted in ppm downfield from TMS, (CD3)(CD2H)SO was refer-
enced to dH 2.49 as a. 31P NMR chemical shifts are quoted in ppm
using H3PO4 as external reference. The spectra were recorded at r.t.,
Synthesis 2003, No. 13, 2101–2109 © Thieme Stuttgart · New York

FEATURE ARTICLE
New Convergent Synthesis of Carbocyclic Nucleoside Analogues
2105
and all 13C and 31P NMR were recorded in proton-decoupled mode.
Mass spectra were obtained with a VG Analytical VG/70-250 F
spectrometer (FAB, matrix was m-nitrobenzylalcohol).
1H NMR (400 MHz, CDCl3): d = 7.36–7.26 (m, 10 H, CH-arom.),
4.48–4.45 (m, 4 H, 2 × CH2-benzyl), 3.91–3.87 (m, 1 H, H-3), 3.55–
3.53 (m, 1 H, H-5), 3.46 (d, 1 H, J = 2.8 Hz, H-1), 3.42 (dd, 1 H,
J = 9.4 Hz, 5.8 Hz, OCHH), 3.39 (dd, 1 H, J = 9.4 Hz, 5.8 Hz,
OCHH), 2.61 (dd, 1 H, J = 5.8 Hz, 5.8 Hz, H-2), 2.18–2.13 (m, 1 H,
H-4a), 2.04 (ddd, 1 H, J = 15.3 Hz, 2.6 Hz, 1.6 Hz, H-4b).
(1S,2R)-2-Benzyloxymethylcyclopent-3-enol (8)
To a suspension of NaH (2.40 g, 0.10 mol) in anhyd THF (50 mL)
at 0 °C, was added freshly distilled cyclopentadiene (9) (10 mL,
0.11 mol) under nitrogen. The slightly pink solution was stirred for
1 h at 0 °C and then added dropwise to a solution of benzylchlorom-
ethylether (14 mL, 0.10 mol) in anhyd THF (50 mL) at –60 °C. The
reaction mixture was stirred for 2 h at –40 °C and the solvent was
evaporated under reduced pressure. The residue, 10 was cooled to
–60 °C and a suspension of (–)-diisopinocampheylborane [28.7 g,
0.10 mol, prepared from (+)-a-pinene] in THF (100 mL) was added
dropwise. The solution was stirred for 1 h at–60 °C, slowly warmed
to 0 °C and stirred at this temperature for a further 16 h. Half of the
THF was evaporated, the temperature was kept below 5 °C, and
Et2O (50 mL) and 3 M aq NaOH (35 mL) solution was added. The
temperature was kept below 10 °C and an aq H2O2 solution (30%,
35 mL) was added. The mixture was stirred overnight at 0 °C. The
formed solid was removed by filtration and washed with Et2O. After
phase separation the aq layer was washed with Et2O (3 × 50 mL),
the combined organic fractions were dried (Na2SO4), and the sol-
vent was removed under reduced pressure. The residue was purified
by silica gel chromatography (hexane–EtOAc, 2:1) yielding 8 (8.20
g, 40%) as a slightly yellow oil.
13C NMR (101 MHz, CDCl3): d = 138.63, 138.44 (Cq-arom.),
128.82, 128.73, 128.22, 128.16, 127.93, 127.86 (C-arom.), 81.54
(C-3), 73.67, 71.33 (2 × CH2-benzyl), 69.72 (OCH2), 60.14 (C-1),
58.45 (C-5), 47.92 (C-2), 35.25 (C-4).
HRMS-FAB: m/z calcd for C20H22O3 (M + H): 311.1647; found:
311.1664.
1-(3¢,5¢-Di-O-benzyl-2¢-deoxy-6¢-hydroxy-6¢-carba-b-D-ribo-
furanosyl)thymine (16)
A 1 M solution of triethylaluminum in hexane (12.8 mL, 12.8
mmol) was slowly added to a suspension of thymidine (1.61 g, 12.8
mmol) in THF (60 mL) at r.t. After 1 h at r.t., the epoxide 15 (2.00
g, 6.40 mmol) was added and the mixture was placed in an ultra-
sound bath for 48 h at r.t. After quenching with glacial HOAc (2
mL) and dilution with water (200 mL), the mixture was extracted
with EtOAc (3 × 75 mL). The combined organic extracts were
washed with a sat. aq NaHCO3 solution (100 mL) and concentrated
under reduced pressure. Purification of the residue was accom-
plished by chromatography on silica gel (CH2Cl2–MeOH, 20:1) to
yield 16 (1.28 g, 46%) as a light yellow oil.
1H NMR (400 MHz, DMSO-d6): d = 11.22 (br s, 1 H, NH), 7.60 (q,
1 H, J = 1.0 Hz, H-6), 7.36–7.26 (m, 10 H, CH-arom.), 5.28 (d, 1 H,
J = 4.5 Hz, 6¢-OH), 4.86–4.79 (m, 1 H, H-1¢), 4.58–4.48 (m, 4 H,
2 × CH2-benzyl), 3.95–3.90 (m, 2 H, H-3¢, H-6¢), 3.53 (dd, 1 H,
J = 9.4 Hz, 6.9 Hz, H-5¢a), 3.46 (dd, 1 H, J = 9.4 Hz, 6.1 Hz, H-5¢b),
2.11–2.01 (m, 3 H, H-4¢, H-2¢a, H-2¢b), 1.80 (d, 3 H, J = 1.0 Hz, H-
7).
The spectroscopic data were identical with those reported.13
(1S,2R,3S,5R)-2-benzyloxymethyl-6-oxabicyclo[3.1.0]hexan-3-
ol (14)
Mo(CO)6 (434 mg, 1.60 mmol) was added to alcohol 8 (2.80 g, 13.7
mmol) in anhyd benzene (100 mL) and the mixture was heated to
reflux under nitrogen. Then, t-butylhydroperoxide (5.60 mL, 28.0
mmol, 5 M in decane) was added dropwise and the reaction mixture
was stirred for a further 3 h under reflux. An ice-cold 20% aq solu-
tion of sodium sulfite (50 mL) was added at r.t. After 1 h the layers
were separated, the aq phase was extracted with EtOAc (3 × 20
mL), the combined organic phases were dried (Na2SO4), and the
solvent was removed under reduced pressure. The crude material
was purified on silica gel (hexane–EtOAc, 1:1) yielding 14 (2.50 g,
82%) as a slightly yellow oil.
1H NMR (400 MHz, CDCl3): d = 7.38–7.28 (m, 5 H, CH-arom.),
4.49 (s, 2 H, CH2-benzyl), 3.93–3.87 (m, 1 H, H-3), 3.66–3.64 (m,
1 H, H-5), 3.63–3.61 (m, 1 H, H-1), 3.45 (dd, 1 H, J = 9.5, 5.5 Hz,
OCHH), 3.39 (dd, 1 H, J = 9.5 Hz, 6.5 Hz, OCHH), 2.52 (dd, 1 H,
J = 6.5, 5.5 Hz, H-2), 2.25 (d, 1 H, J = 12.0 Hz, OH), 2.09–2.05 (m,
2 H, H-5).
13C NMR (101 MHz, DMSO-d6): d = 164.13 (C-4), 150.52 (C-2),
138.82, 138.58 (Cq-arom.), 138.01 (C-6), 128.74, 128.62, 128.55,
128.35, 128.02, 127.84 (C-arom.), 109.63 (C-5), 77.30 (C-1¢),
73.35, 72.45 (C-benzyl), 70.24 (C-5¢), 53.89 (C-3¢), 44.33 (C-4¢),
35.93 (C-2¢), 32.46 (C-6¢), 12.37 (C-7).
HRMS-FAB: m/z calcd for C25H28N2O5 (M + H): 437.2076; found:
437.2094.
1-(3¢,5¢-Di-O-benzyl-2¢-deoxy-6¢-carba-b-D-ribofuranosyl)thy-
mine (17)
Alcohol 16 (0.75 g, 1.72 mmol) was dissolved in anhyd MeCN (23
mL) and portions of DMAP (420 mg, 3.44 mmol) and phenoxythio-
carbonylchloride (PTC–Cl) (384 mg, 2.23 mmol) were added under
nitrogen at r.t. After stirring for 16 h at r.t., the solvent was evapo-
rated under reduced pressure and the residue was partitioned be-
tween water (50 mL) and EtOAc (100 mL). The organic phase was
washed with a 1 M aq HCl solution, water, sat. NaHCO3 solution
and brine, dried (Na2SO4), and concentrated. The crude material of
the thiocarbonate was sufficiently pure to be used directly in the fol-
lowing reduction.
1H NMR (400 MHz, CDCl3): d = 7.96 (br s, 1 H, NH), 7.40–7.27
(m, 10 H, CH-arom.), 7.16–7.11 (m, 2 H, CH-arom.), 7.09 (q, 1 H,
J = 1.2 Hz, H-6), 6.83–6.75 (m, 3 H, CH-arom.), 5.15–5.08 (m, 1 H,
H-1¢), 4.53 [d, 1 H, J = 12.0 Hz, CHH-benzyl (5¢)], 4.52 (d, 1 H,
J = 10.4 Hz, H-5¢a), 4.49 [d, 1 H, J = 10.4 Hz, CHH-benzyl (3¢)],
4.49 [d, 1 H, J = 10.4 Hz, CHH-benzyl (3¢)], 4.45 [d, 1 H, J = 12.0
Hz, CHH-benzyl (5¢)], 4.08–3.97 (m, 2 H, H-3¢, H-6¢), 3.59 (dd, 1
H, J = 9.2 Hz, 4.3 Hz, H-5¢a), 3.53 (dd, 1 H, J = 9.2 Hz, 4.6 Hz, H-
5¢b), 2.40–2.30 (m, 2 H, H-4¢, H-2¢a), 1.95 (ddd, 1 H, J = 13.2 Hz,
10.2 Hz, 6.4 Hz, H-2¢b), 1.78 (d, 3 H, J = 1.2 Hz, H-7).
13C NMR (101 MHz, CDCl3): d = 138.42, 128.89, 128.24, 127.93
(C-arom.), 73.75 (CH2-benzyl), 73.43 (C-3), 68.98 (OCH2), 60.12
(C-5), 58.35 (C-1), 50.36 (C-2), 37.64 (C-4).
HRMS-FAB: m/z calcd for C13H16O3 (M + H): 221.1178; found:
221.1201.
(1S,2R,3S,5R)-3-Benzyloxy-2-benzyloxymethyl-6-oxabicyclo
[3.1.0]hexane (15)
Alcohol 14 (2.40 g, 11.0 mmol) was added dropwise to a stirred sus-
pension of NaH (520 mg, 13.0 mmol) in THF (40 mL) at 0 °C under
nitrogen. After 1 h at r.t., benzyl bromide (1.65 mL, 14.0 mmol) and
tetrabutylammonium iodide (TBAI, 50 mg) were added. The reac-
tion mixture was kept overnight at r.t. Crushed ice was added, the
mixture was stirred for 0.5 h, poured into EtOAc (100 mL), washed
with water and brine, dried (Na2SO4), and concentrated. The residue
was purified on silica gel (hexane–EtOAc, 1:1) to yield 15 (3.07 g,
86%) as a light-yellow oil.
13C NMR (101 MHz, CDCl3): d = 192.32 (C=S), 164.64 (C-4),
156.91 (Cq-arom.), 151.34 (C-2), 138.24, 138.13 (Cq-arom.),
Synthesis 2003, No. 13, 2101–2109 © Thieme Stuttgart · New York

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O. R. Ludek, C. Meier
FEATURE ARTICLE
135.56 (C-6), 130.12, 129.98, 128.73, 128.65, 128.34, 127.97,
127.75, 127.68, 127.34, 127.10, 121.21, 115.34 (C-arom.), 110.23
(C-5), 77.67 (C-1¢), 74.02, 73.87 (C-benzyl), 68.34 (C-5¢), 58.31
(C-6¢), 55.65 (C-3¢), 44.23 (C-4¢), 28.54 (C-2¢), 15.88 (C-7).
HRMS-FAB: m/z calcd for C20H22O2 (M + H): 295.1698; found:
295.1711.
(1R,3S,4R)-3-Benzyloxy-4-benzyloxymethylcylopentan-1-ol
(20)
The thiocarbonate was dissolved in anhyd toluene (35 mL), AIBN
(55.0 mg, 0.33 mmol) and n-Bu3SnH (750 mg, 2.60 mmol) were
added. The solution was degassed with oxygen-free N2 for 15 min
and then heated to 75 °C for 3.5 h. The solvent was evaporated un-
der reduced pressure and the residue was purified on silica gel (hex-
ane–EtOAc, 1:2) yielding 17 (398 mg, 55% over both steps) as a
colorless syrup.
1H NMR (400 MHz, DMSO-d6): d = 11.20 (br s, 1 H, NH), 7.54 (q,
1 H, J = 1.2 Hz, H-6), 7.36–7.26 (m, 10 H, CH-arom.), 4.97–4.88
(m, 1 H, H-1¢), 4.53–4.43 (m, 4 H, 2 × CH2-benzyl), 3.90–3.85 (m,
1 H, H-3¢), 3.50 (dd, 1 H, J = 9.4 Hz, 6.9 Hz, H-5¢a), 3.45 (dd, 1 H,
J = 9.4 Hz, 6.1 Hz, H-5¢b), 2.38–2.30 (m, 1 H, H-4¢), 2.22–2.12 (m,
1 H, H-6¢a), 2.06–2.00 (m, 2 H, H2¢a, H2¢b), 1.79 (d, 3 H, J = 1.2
Hz, H-7), 1.50–1.42 (m, 1 H, H-6¢b).
A 0.5 M solution of 9-BBN in THF (88 mL, 44 mmol) was added
dropwise to a solution of 19 (6.50 g, 22.0 mmol) in anhyd THF (10
mL) at 0 °C under nitrogen. The reaction was slowly warmed to r.t.
overnight. The reaction was cooled to 0 °C and treated sequentially
with EtOH (7 mL), 3 N NaOH solution (20 mL), and H2O2 (33%, 20
mL). The resulting mixture was stirred at r.t. overnight. The result-
ing residue was filtered and washed with EtOAc (200 mL). To this
suspension, water was added (150 mL) and after separation of the
phases, the aq layer was extracted with EtOAc (3 × 50 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 20b and the epimer 20a as light yellow oils.
Cyclopentanol 20b
Yield: 5.42 g (79%).
13C NMR (101 MHz, DMSO-d6): d = 164.24 (C-4), 150.62 (C-2),
138.86, 138.57 (Cq-arom.), 137.97 (C-6), 128.63, 128.55, 128.48,
128.25, 127.95, 127.76 (C-arom.), 109.47 (C-5), 80.07 (C-1¢),
72.44, 71.94 (C-benzyl), 70.16 (C-5¢), 53.89 (C-3¢), 44.33 (C-4¢),
35.93 (C-2¢), 32.46 (C-6¢), 12.37 (C-7).
1H NMR (400 MHz, CDCl3): d = 7.35–7.25 (m, 10 H, CH-arom.),
4.52 (s, 2 H, CH2-benzyl), 4.49 (d, 1 H, J = 11.8 Hz, CHH-benzyl),
4.44 (d, 1 H, J = 11.8 Hz, CHH-benzyl), 4.33–4.28 (m, 1 H, H-1),
4.07 (ddd, 1 H, J = 6.6 Hz, 6.6 Hz, 4.1 Hz, H-3), 3.53 (dd, 1 H,
J = 9.0 Hz, 4.2 Hz, OCHH), 3.49 (d, 1 H, J = 9.0 Hz, 4.3 Hz,
OCHH), 2.35–2.25 (m, 2 H, H-4, H-5a), 2.05 (dddd, 1 H, J = 13.5
Hz, 6.7 Hz, 3.5 Hz, 1.7 Hz, H-2a), 1.89–1.82 (m, 1 H, H-2b), 1.52–
1.46 (m, 1 H, H-5b).
HRMS-FAB: m/z calcd for C25H28N2O4 (M + H): 421.2127; found:
421.2146.
rac-2-Benzyloxymethylcyclopent-3-enol (13)
13C NMR (101 MHz, CDCl3): d = 139.07, 138.23 (Cq-arom.),
128.90, 128.86, 128.78, 128.21, 128.19, 128.10 (CH-arom.), 82.36
(C-1), 74.08, 73.70 (2 × CH2-benzyl), 72.80 (C-3), 71.51 (OCH2),
44.94 (C-4), 40.82 (C-2), 37.76 (C-5).
The reaction was carried out as described for cyclopentene 8 with
NaH (240 mg, 10 mmol) in THF (10 mL), cyclopentadiene (1.00
mL, 12.0 mmol), benzylchloromethylether (1.40 mL, 10.0 mmol) in
THF (5 mL), 1 M borane·THF complex (3.0 mL, 3.00 mmol), aq
3 M NaOH (3.5 mL), H2O2 (30%; 3.5 mL). The residue was purified
on silica gel (hexane–EtOAc 2:1) to yield 13 (633 mg, 31%) as a
light-yellow oil.
HRMS-FAB: m/z calcd for C20H24O3 (M + H): 313.1804; found:
313.1808.
1H NMR (400 MHz, CDCl3) d = 7.40–7.33 (m, 5 H, CH-arom.),
5.71 (ddd, 1 H, J = 6.0 Hz, 4.7 Hz, 2.4 Hz, H-3), 5.56 (ddd, 1 H,
J = 6.0 Hz, 4.2 Hz, 1.9 Hz, H-4), 4.54–4.49 (m, 1 H, H-1), 4.46 (s,
2 H, CH2-benzyl), 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, 1-OH).
13C NMR (101 MHz, CDCl3) d = 138.72 (Cq-arom.), 130.71 (C-3),
129.72 (C-4), 128.94, 128.23, 127.49 (C-arom.), 73.34 (C-1), 69.63
(C-benzyl), 65.75 (OCH2), 50.12 (C-2), 42.45 (C-5).
Cyclopentanol 20a
Yield: 0.82 g (12%).
1H NMR (400 MHz, CDCl3): d = 7.38–7.28 (m, 10 H, CH-arom.),
4.56–4.48 (m, 4 H, 2 × CH2-benzyl), 4.31–4.26 (m, 1 H, H-1), 4.01–
3.97 (m, 1 H, H-3), 3.43 (dd, 1 H, J = 9.4 Hz, 5.6 Hz, OCHH), 3.28
(dd, 1 H, J = 9.4 Hz, 7.5 Hz, OCHH), 2.72–2.68 (m, 1 H, H-4),
2.11–2.00 (m, 2 H, H-2a, H-5a), 1.86 (ddd, 1 H, J = 14.2 Hz, 5.2 Hz,
5.2 Hz, H-2b), 1.57 (ddd, 1 H, J = 13.9 Hz, 7.6 Hz, 5.2 Hz, H-5b).
13C NMR (101 MHz, CDCl3): d = 138.67, 138.46 (Cq-arom.),
128.83, 128.76, 128.70, 128.56, 128.34, 127.89 (CH-arom.), 78.34
(C-1), 73.67, 73.23 (2 × CH2-benzyl), 72.34 (C-3), 71.41 (OCH2),
45.67 (C-4), 41.32 (C-2), 36.34 (C-5).
HRMS-FAB: m/z calcd for C13H16O2 (M + H): 205.1229; found:
205.1224.
(1S,2R)-1-Benzyloxy-2-benzyloxymethylcyclopent-3-ene (19)
The reaction has been carried out as described for hexane 15 with
NaH (1.60 g, 0.04 mol) in THF (100 mL), alcohol 8 (6.00 g, 30
mmol), benzyl bromide (4.5 mL, 40 mmol) and TBAI (120 mg).
The residue was purified on silica gel (hexane–EtOAc, 10:1) to
yield 19 (7.00 g, 92%) as a light-yellow oil.
1H NMR (400 MHz, CDCl3): d = 7.37–7.22 (m, 10 H, CH-arom.),
5.75 (ddd, 1 H, J = 6.5 Hz, 4.3 Hz, 2.0 Hz, H-3), 5.65 (ddd, 1 H,
J = 6.1 Hz, 4.2 Hz, 2.1 Hz, H-4), 4.56–4.51 (m, 4 H, CH2-benzyl),
4.08 (ddd, 1 H, J = 6.9 Hz, 3.4 Hz, 3.3 Hz, H-1), 3.45 (dd, 1 H,
J = 9,3 Hz, 5.7 Hz, OCHH), 3.33 (dd, 1 H, J = 9.3 Hz, 5.3 Hz,
OCHH), 3.10–3.03 (m, 1 H, H-2), 2.68 (dddd, 1 H, J = 17.2 Hz, 6.5
Hz, 4.5 Hz, 2.0 Hz, H-5a), 2.46–2.37 (m, 1 H, H-5b).
HRMS-FAB: m/z calcd for C20H24O3 (M + H), 313.1804; found:
313.1824.
(1R,3S,4R)-3-Benzyloxy-4-benzyloxymethylcylopentanamine
(22)
A 0.5 M solution of 9-BBN in THF (4 mL, 2.00 mmol) was slowly
added to cyclopentene 19 (294 mg, 1.00 mmol) at 0 °C under nitro-
gen. The mixture was stirred overnight at r.t. To this mixture hy-
droxylamine-O-sulfonic acid (680 mg, 6.00 mmol) in THF (2 mL)
was added dropwise. The mixture was heated to reflux for 3 h,
cooled to r.t., and the medium was acidified by addition of hydro-
chloric acid (2 M, 10 mL). After extraction with Et2O (3 × 10 mL),
the pH value of the aq layer was changed to pH 11 by addition of a
3 M solution of NaOH and extracted again with Et2O (3 × 10 mL).
The combined organic extracts were dried and concentrated under
reduced pressure. The crude material was purified on a chroma-
totron (CH2Cl2–MeOH, gradient 0→20%) to yield 22 (149 mg,
52%) as a 87:13 mixture of 22b:22a as a light yellow oil.
13C NMR (101 MHz, CDCl3): d = 139.18, 138.93 (Cq-arom.),
130.45 (C-3), 130.29 (C-4), 128.83, 128.76, 128.72, 128.21,
128.14, 128.05, 127.98, 127.93 (CH-arom.), 81.83 (C-1), 73.48,
72.06 (C-benzyl), 71,18 (O-CH2), 53.37 (C-2), 39.50 (C-5).
Synthesis 2003, No. 13, 2101–2109 © Thieme Stuttgart · New York

FEATURE ARTICLE
New Convergent Synthesis of Carbocyclic Nucleoside Analogues
2107
1H NMR (400 MHz, DMSO-d6): d = 7.38–7.26 (m, 10 H, CH-
arom.), 4.55 (s, 2 H, CH2-benzyl), 4.50 (d, 1 H, J = 12.0 Hz, CHH-
benzyl), 4.46 (d, 1 H, J = 12.0 Hz, CHH-benzyl), 3.87–3.80 (m, 1
H, H-3), 3.47 (dd, 1 H, J = 9.6 Hz, 5.7 Hz, OCHH), 3.40–3.33 (m,
3 H, OCHH, H-1), 2.28–2.21 (m, 1 H, H-4), 2.11–2.03 (m, 1 H, H-
5a), 1.95 (ddd, 1 H, J = 13.9 Hz, 6.0 Hz, 5.2 Hz, H-2a), 1.54 (ddd,
1 H, J = 13.9 Hz, 7.2 Hz, 5.2 Hz, H-2b), 1.09–1.00 (m, 1 H, H-5b).
night at r.t. The solution was neutralized by addition of 1M HCl and
then concentrated. The crude was chromatographed on silica gel
(hexane–EtOAc, 1:2) to yield the N-1 alkylated compounds 23, 25a,
and 25b as colorless syrups.
1-(3¢,5¢-Di-O-benzyl-2¢-deoxy-6¢-carba-b-D-ribofuranosyl)thy-
mine (23)
Yield: 260 mg (62%).
13C NMR (101 MHz, DMSO-d6): d = 138.88, 138.15 (Cq-arom.),
128.92, 128.79, 128.72, 128.41, 128.33, 127.95 (CH-arom.), 74.22,
73.86 (2 × CH2-benzyl), 71.65 (C-3), 70.40 (OCH2), 53.36 (C-1),
47.56 (C-4), 41.43 (C-2), 35.23 (C-5).
The spectroscopic data were identical to those described above.
1-(3¢,5¢-Di-O-benzyl-2¢-deoxy-6¢-carba-b-D-ribofuranosyl)-5-
[(E)-bromovinyl]uracil (25b)
Yield: 98 mg (53%).
HRMS-FAB: m/z calcd for C20H25NO2 (M + H): 312.1964; found:
312.1975.
1H NMR (400 MHz, DMSO-d6): d = 11.60 (s, 1 H, NH), 8.03 (s, 1
H, H-6), 7.45–7.38 (m, 10 H, CH-arom.), 7.35 (d, 1 H, J = 13.5 Hz,
H-8), 6.93 (d, 1 H, J = 13.5 Hz, H-7), 5.05–4.97 (m, 1 H, H-1¢),
4.63–4.54 (m, 4 H, 2 × CH2-benzyl), 3.59 (dd, 1 H, J = 9.4 Hz, 7.0
Hz, H-5¢a), 3.54 (dd, 1 H, J = 9.4 Hz, 6.1 Hz, H-5¢b), 2.54–2.38 (m,
1 H, H-4¢), 2.30–2.23 (m, 1 H, H-6¢a), 2.15–2.05 (m, 2 H, H-2¢a, H-
2¢b), 1.62–1.53 (m, 1 H, H-6¢b).
13C NMR (101 MHz, DMSO-d6): d = 161.96 (C-4), 150.23 (C-2),
141.57 (C-6), 138.85, 138.32 (Cq-arom.), 130.27 (C-7), 128.63,
128.56, 128.21, 127.87, 127.77, 127.69 (CH-arom.), 109.98 (C-5),
106.59 (C-8), 79.87 (C-1¢), 72.43, 71.86 (C-benzyl), 70.20 (C-5¢),
54.64 (C-3¢), 44.34 (C-4¢), 36.01 (C-2¢), 32.70 (C-6¢).
(1R,2S,3S)-2-Benzyloxymethyl-3-benzyloxycyclopentan-1-ol
(21a)
To cyclopentene 19 (100 mg, 0.34 mmol) at 0 °C under nitrogen, a
suspension of (+)-di-isopinocampheylborane (115 mg, 0.40 mmol)
in THF (400 mL) was added dropwise. The reaction was stirred for
16 h at 4 °C. The reaction was cooled to 0 °C and treated sequential-
ly with 3 N NaOH solution (150 mL) and H2O2 (33%; 150 mL) while
stirring. The mixture was stirred for 12 h at r.t. The residue was fil-
tered of and washed with EtOAc (2 mL). The mixture was evapo-
rated to dryness and the crude product was purified on silica gel
(hexane–EtOAc 1:1) to yield 21a (44.6 mg, 42%) as a light yellow
oil.
1H NMR (400 MHz, CDCl3): d = 7.35–7.20 (m, 10 H, CH-arom.),
4.55–4.40 (m, 4 H, 2 × CH2-benzyl), 4.02–3.96 (m, 1 H, H-1), 3.74–
3.69 (m, 1 H, H-3), 3.59 (dd, 1 H, J = 9.1 Hz, 5.6 Hz, OCHH), 3.44
(dd, 1 H, J = 9.1 Hz, 7.9 Hz, OCHH), 2.29–2.22 (m, 1 H, H-2),
1.95–1.75 (m, 4 H, 4-CH2, 5-CH2).
HRMS-FAB: m/z calcd for C26H27BrN2O4 (M + H): 511.1232 and
513.1212; found: 511.1249 and 513.1237.
1-(3¢,5¢-Di-O-benzyl-2¢-deoxy-6¢-carba-b-D-ribofuranosyl)-5-
fluorouracil (25a)
Yield: 182 mg (42%)
13C NMR (101 MHz, CDCl3): d = 138.91, 138.61, 128.85, 128.79,
128.10, 128.05, 128.00, 127.97 (C-arom.), 81.20 (C-3), 76.16 (C-1),
73.71, 71.55 (2 × CH2-benzyl), 71.18 (O-CH2), 54.48 (C-2), 32.39
(C-4), 29.41 (C-5).
1H NMR (400 MHz, DMSO-d6): d = 11.80–11.70 (br s, 1 H, NH),
7.87 (d, 1 H, J = 3.6 Hz, H-6), 7.41–7.30 (m, 10 H, CH-arom.),
5.00–4.90 (m, 1 H, H-1¢), 4.56–4.46 (m, 4 H, 2 × CH2-benzyl),
3.97–3.85 (m, 1 H, H-3¢), 3.52 (dd, 1 H, J = 9.6 Hz, 6.9 Hz, H-5¢a),
3.44 (dd, 1 H, J = 9.6 Hz, 6.1 Hz, H-5¢b), 2.40–2.30 (m, 1 H, H-4¢),
2.22–2.13 (m, 1 H, H-6¢a), 2.06–1.95 (m, 2 H, H-2¢a, H-2¢b), 1.52–
1.44 (m, 1 H, H-6¢b).
13C NMR (101 MHz, DMSO-d6): d = 156.52 (d, J = 27 Hz, C-4),
148.64 (C-2), 140.05 (d, J = 230 Hz, C-5), 138.95, 138.06 (Cq-
arom.), 128.79, 128.66, 128.34, 127.64, 127.24, 127.11 (CH-
arom.), 125.25 (d, J = 32 Hz, C-6), 79.89 (C-1¢), 72.88, 72,42 (C-
benzyl), 70.53 (C-5¢), 54.66 (C-3¢), 43.97 (C-4¢), 37.32 (C-2¢), 32.38
(C-6¢).
HRMS-FAB: m/z calcd for C20H24O3 (M + H): 313.1804; found:
313.1826.
(1S,3S,4R)-3-Benzyloxy-4-benzyloxymethylcylopentan-1-ol
(20a)
To a suspension of PPh3 (6.82 g, 26.0 mmol) in anhyd Et2O (100
mL) at 0 °C under nitrogen was slowly added DIAD (5.05 mL, 26.0
mmol) and the suspension was stirred for 0.5 h. This preformed
complex was slowly added to a suspension of benzoic acid (3.18 g,
26 mmol) and alcohol 20b (4.10 g, 13 mmol) in anhyd Et2O (60 mL)
at 0 °C under nitrogen. 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 NaOH solution in MeOH
(1%, 100 mL) was added. Stirring was continued overnight at r.t.
The solution was neutralized by addition of 1M HCl and then con-
centrated. The crude material was purified on silica gel (hexane–
EtOAc, 1:2) to yield the title alcohol 20a (3.70 g, 91%) as a color-
less oil.
HRMS-FAB: m/z calcd for C24H25FN2O4 (M + H): 425.1877;
found: 425.1898.
Debenzylation; General Procedure
BCl3 (7.2 mL, 1 M in CH2Cl2) was added slowly to a stirred solution
of the benzylated carba-nucleosides (250 mg) in anhyd CH2Cl2 (28
mL) at –78 °C. The reaction mixture was stirred for 5 h at –78 °C.
The reaction mixture was warmed to –25 °C and MeOH (14 mL)
was added dropwise. The mixture was allowed to warm to r.t. and
stirred overnight. The solvent was removed and the residue was
concentrated three times with MeOH (10 mL). The crude product
was purified by chromatography on a Chromatotron (CH2Cl2–
MeOH gradient 5∆ 20%) to yield the carba-nucleosides (140 mg,
95%) as white solids. After lyophilization (CH3CN–water), the de-
benzylated nucleoside analogs were obtained as colorless solids.
The spectroscopic data were identical to those described above.
Coupling of the Pyrimidines to the Cyclopentanol 20a; General
Procedure
To a suspension of PPh3 (787 mg, 3 mmol) in anhyd MeCN (11
mL), DIAD (585 L, 2.8 mmol) was added slowly and the solution
was stirred for 0.5 h at 0 °C. This preformed complex was slowly
added to a suspension of the protected nucleobases (2 mmol) and
the alcohol 20a (312 mg, 1 mmol) in anhyd MeCN (6 mL) at –40 °C
under nitrogen. The reaction was slowly warmed to r.t. and stirred
overnight. The solvent was removed from the reaction mixture and
a NaOH solution in MeOH (1%, 15 mL) was added and stirred over-
1-(2¢-Deoxy-6¢-carba-b-D-ribofuranosyl)thymine (carba-dT) 18
Yield: 130 mg (90%).
1H NMR (400 MHz, DMSO-d6): d = 11.20 (s, 1 H, NH), 7.57 (q, 1
H, J = 1.0 Hz, H-6), 5.02–4.96 (m, 1 H, H-1¢), 4.73 (d, 1 H, J = 4.5
Synthesis 2003, No. 13, 2101–2109 © Thieme Stuttgart · New York

2108
O. R. Ludek, C. Meier
FEATURE ARTICLE
Hz, 3¢-OH), 4.61 (t, 1 H, J = 5.2 Hz, 5¢-OH), 4.03–3.98 (m, 1 H, H-
3¢), 3.53 (ddd, 1 H, J = 10.6 Hz, 5.5 Hz, 5.2 Hz, H-5¢a), 3.43 (ddd,
1 H, J = 10.6 Hz, 5.7 Hz, 5.2 Hz, H-5¢b), 2.11–2.04 (m, 1 H, H-6¢a),
1.99–1.89 (m, 2 H, H-4¢, H-2¢a), 1.82 (d, 3 H, J = 1.0 Hz, H-7),
1.82–1.74 (m, 1 H, H-2¢b), 1.45–1.37 (m, 1 H, H-6¢b).
13C NMR (101 MHz, DMSO-d6): d = 164.08 (C-4), 151.35 (C-2),
138.06 (C-6), 109.44 (C-5), 71.72 (C-1¢), 63.01 (C-5¢), 53.58 (C-3¢),
49.33 (C-4¢), 36.35 (C-2¢), 32.70 (C-6¢), 12.43 (C-7).
2 H, 2 × H-3¢), 2.24 (s, 6 H, 2 × CH3-arom.), 2.13–1.93 (m, 6 H,
2 × H-2¢a, 2 × H-4¢, 2 × H-6¢a), 1.82–1.74 (m, 8 H, 2 × H-2¢b,
2 × H-7), 1.42–1.30 (m, 2 H, 2 × H-6¢b).
13C NMR (101 MHz, DMSO-d6): d = 164.06 (C-4), 151.49 (C-2),
148.11 (C-2arom.), 138.21 (C-6), 131.18 (C-4arom.), 127.54 (C-
3arom.), 124.22 (C-5arom.), 123.93 (C-6arom.), 121.46 (d, J = 3.5
Hz, C-1arom.), 109.50 (C-5), 71.09 (C-1¢), 69.46 (d, J = 7.0 Hz,
CH2-benzyl), 68.74 (d, J = 3.8 Hz, C-5¢), 53.35 (C-3¢), 47.28 (C-4¢),
38.62 (C-2¢), 32.41 (C-6¢), 15.30 (CH3-arom.), 12.41 (C-7).
HRMS-FAB: m/z calcd for C11H16N2O4 (M + H): 241.1188; found:
241.1195
31P NMR (202 MHz, DMSO-d6): d = –6.52, –6.64
HRMS-FAB: m/z calcd for C19H23N2O7P (M + H): 423.1321;
found: 423.1331.
1-(2¢-Deoxy-6¢-carba-b-D-ribofuranosyl)-5-[(E)-bromovinyl]
uracil (carba-BVdU) (7)
Yield: 42 mg (88%).
3-Methyl-cyclosaligenyl-5¢-O-[1-(2¢-deoxy-6¢-carba-b-D-ribo-
furanosyl)-5-(E)-bromovinyl]uracilyl)-phosphate (3-Me-cy-
cloSal-carba-BVdU) (28)
1H NMR (400 MHz, DMSO-d6): d = 11.50 (br s, 1 H, NH), 7.92 (s,
1 H, H-6), 7.26 (d, 1 H, J = 13.5 Hz, H-8), 6.90 (d, 1 H, J = 13.5 Hz,
H-7), 5.00–4.90 (m, 1 H, H-1¢), 4.72 (d, 1 H, J = 4.6 Hz, 3¢-OH),
4.60 (t, 1 H, J = 5.2 Hz, 5¢-OH), 4.01–3.95 (m, 1 H, H-5¢a), 3.43–
3.38 (m, 1 H, H-5¢b), 2.13–2.06 (m, 1 H, H-6¢a), 1.97–1.87 (m, 2 H,
H-4¢, H-2¢a), 1.83–1.76 (m, 1 H, H-2¢b), 1.42–1.35 (m, 1 H, H-6¢b).
13C NMR (101 MHz, DMSO-d6): d = 164.68 (C-4), 151.02 (C-2),
141.70 (C-7), 130.36 (C-8), 109.23 (C-5), 106.48 (C-6), 71.56 (C-
1¢), 63.11 (C-5¢), 54.35 (C-3¢), 49.34 (C-4¢), 38.35 (C-2¢), 33.00 (C-
6¢).
Yield: 12 mg (15%).
1H NMR (500 MHz, DMSO-d6): d = 11.48 (br s, 2 H, 2 × NH), 7.96
(s, 1 H, H-6), 7.83 (s, 1 H, H-6), 7.28 (d, 1 H, J = 13.5 Hz, H-8), 7.26
(d, 1 H, J = 13.5 Hz, H-8), 7.24–7.20 (m, 2 H, CH-arom.), 7.10–
7.04 (m, 4 H, CH-arom.), 6.85 (d, 1 H, J = 13.5 Hz, H-7), 6.81 (d, 1
H, J = 13.5 Hz, H-7), 5.49–5.38 (m, 4 H, 2 × CH2-benzyl), 5.02–
4.90 (m, 4 H, 2 × H-1¢, 2 × 3¢-OH), 4.29 (ddd, 2 H, J = 9.8, 6.2, 6.2
Hz, H-5¢a), 4.24 (ddd, 2 H, J = 9.8, 6.6, 6,6 Hz, H-5¢b), 4.11 (ddd, 2
H, J = 10.1, 7.2, 7.2, H-5¢a), 4.04 (ddd, 2 H, J = 10.1, 7.2, 7.2 Hz,
H-5¢b), 4.02–4.96 (m, 2 H, 2 × H-3¢), 2.25 (s, 6 H, 2 × CH3-arom.),
2.15–1.91 (m, 6 H, 2 × H-2¢a, 2 × H-4¢, 2 × H-6¢a), 1.82–1.77 (m, 2
H, 2 × H-2¢b), 1.45–1.35 (m, 2 H, 2 × H-6¢b).
13C NMR (101 MHz, DMSO-d6): d = 164.20 (C-4), 151.34 (C-2),
149.24 (C-2arom.), 142.55 (C-7), 132.63 (C-4arom.), 130.36 (C-8),
127.22 (C-3arom.), 123.97 (C-5arom.), 123.12 (C-6arom.), 121.22
(d, J = 3.5 Hz, C-1arom.), 109.44 (C-5), 106.35 (C-6), 72.35 (C-1¢),
70.62 (d, J = 7.0 Hz, CH2-benzyl), 67.47 (d, J = 3.8 Hz, C-5¢), 54.25
(C-3¢), 49.35 (C-4¢), 38.33 (C-2¢), 32.25 (C-6¢), 15.36 (CH3-arom.).
HRMS-FAB: m/z calcd for C12H15BrN2O4 (M + H): 331.0293 and
333.0273; found: 331.0314 and 333.0310.
1-(2¢-Deoxy-6¢-carba-b-D-ribofuranosyl)-5-fluorouracil (carba-
FdU) (26)
Yield: 86 mg (82%).
1H NMR (400 MHz, DMSO-d6): d = 11.82–11.75 (br s, 1 H, NH),
7.90 (d, 1 H, J = 4.0 Hz, H-6), 5.01–4.94 (m, 1 H, H-1¢), 3.95–3.86
(m, 1 H, H-3¢), 3.60 (dd, 1 H, J = 9.8 Hz, 7.0 Hz, H-5¢a), 3.48 (dd,
1 H, J = 9.8 Hz, 6.0 Hz, H-5¢b), 2.43–2.35 (m, 1 H, H-4¢), 2.28–
2.20 (m, 1 H, H-6¢a), 2.02–1.91 (m, 2 H, H-2¢a, H-2¢b), 1.54–1.48
(m, 1 H, H-6¢b).
13C NMR (101 MHz, DMSO-d6): d = 156.88 (d, J = 28 Hz, C-4),
148.54 (C-2), 140.12 (d, J = 230 Hz, C-5),), 126.02 (d, J = 32 Hz,
C-6), 79.72 (C-1¢), 71.11 (C-5¢), 54.43 (C-3¢), 44.03 (C-4¢), 36.87
(C-2¢), 33.21 (C-6¢).
31P NMR (202 MHz, DMSO-d6): d = –6.79, –6.92.
HRMS-FAB: m/z calcd for C20H22BrN2O7P (M + H): 513.0426;
found: 513.0441.
5¢-O-[1-(2¢-Deoxy-6¢-carba-b-D-ribofuranosyl)thymidinyl]
monophosphate (carba-dTMP) (29)
Triester 28 (25.0 mg, 0.06 mmol) was dissolved in MeCN (3 mL)
and water (500 mL). To this solution Et3N (10 drops) was slowly
added and the mixture was stirred at r.t. until complete hydrolysis
of the triester was observed by TLC. The reaction mixture was di-
luted with water (5 mL) and MeCN (5 mL) and the solution was lyo-
philized. The crude product was purified by chromatography on
RP-C18-silica gel (Merck). The obtained triethylammonium salt
was transferred into the sodium salt by ion-exchange (Dowex 50X8,
sodium form). After lyophilization the product 29 (16.6 mg, 76%)
was obtained as a colorless solid.
1H NMR (400 MHz, D2O): d = 7.46 (q, 1 H, J = 1.2 Hz, H-6), 5.05–
4.99 (m, 1 H, H-1¢), 4.67–4.60 (m, 1 H, H-3¢), 4.31 (ddd, 1 H,
J = 21.2 Hz, 10.6 Hz, 4.3 Hz, H-5¢a), 4.15 (ddd, 1 H, J = 11.0 Hz,
10.6 Hz, 1.8 Hz, H-5¢b), 2.27–2.17 (m, 4 H, H-4¢, 2 × H-2¢; H-6¢a),
1.88 (d, 3 H, J = 1.2 Hz, H-7), 1.58–1.50 (m, 1 H, H-6¢b).
HRMS-FAB: m/z calcd for C10H13FN2O4 (M + H): 245.0938;
found: 245.0954.
Preparation of the cycloSal-phosphate Triesters of the carba-
Nucleosides
The reaction has been performed as previously described by our
laboratories.27,28 However, instead of CH3CN, a mixture of CH3CN
and DMF (2:1) was used. The reactions have been carried out at
–40 °C. CycloSal-triesters 27 and 28 were obtained as colorless
foams.
3-Methyl-cyclosaligenyl-5¢-O-[1-(2¢-deoxy-6¢-carba-b-D-ribo-
furanosyl)thymidinyl]-phosphate (3-Me-cycloSal-carba-dT)
(27)
Yield: 107 mg (60%).
1H NMR (500 MHz, DMSO-d6): d = 11.20 (br s, 2 H, 2 × NH), 7.51
(q, 1 H, J = 1.2 Hz, H-6), 7.49 (q, 1 H, J = 1.2 Hz, H-6), 7.28–7.23
(m, 2 H, CH-arom.), 7.11–7.06 (m, 4 H, CH-arom.), 5.52–5.40 (m,
4 H, 2 × CH2-benzyl), 5.00–4.85 (m, 4 H, 2 × H-1¢, 2 × 3¢-OH),
4.27 (ddd, 2 H, J = 10.1, 6.4, 6.4 Hz, H-5¢a), 4.22 (ddd, 2 H,
J = 10.1, 6.6, 6,6 Hz, H-5¢b), 4.12 (ddd, 2 H, J = 10.2, 7.4, 7.4 Hz,
H-5¢a), 4.06 (ddd, 2 H, J = 10.2, 7.2, 7.2 Hz, H-5¢b), 4.00–4.95 (m,
13C NMR (101 MHz, D2O): d = 164.12 (C-4), 151.37 (C-2), 141.26
(C-6), 109.88 (C-5), 80.89 (C-1¢), 70.35 (d, J = 6.2 Hz, C-5¢), 54.91
(C-3¢), 42.23 (d, J = 4.5 Hz, C-4¢), 34.86 (C-2¢), 29.23 (C-6¢), 11.74
(C-7).
31P NMR (202 MHz, D2O): d = 2.21.
MS (ESI+): m/z calcd for C11H15N2O7PNa2: 364.04; found 365.21.
Synthesis 2003, No. 13, 2101–2109 © Thieme Stuttgart · New York

FEATURE ARTICLE
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New Convergent Synthesis of Carbocyclic Nucleoside Analogues
2109
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Synthesis 2003, No. 13, 2101–2109 © Thieme Stuttgart · New York