Preparation of C-5-substituted 6,5′-O-anhydrouridine by Sn-Pd transmetallation-coupling process and their use

Article abstract of DOI:10.1016/j.tet.2009.09.075

The palladium-catalyzed reaction of 5-tributylstannyluridine derivative (9) with a variety of aryl, vinyl halides provides an efficient method for the synthesis of the corresponding 5-substituted 6,5′-O-anhydrouridines. Additionally the 5-fluoro 6,5′-O-an

Full text of DOI:10.1016/j.tet.2009.09.075

Tetrahedron 65 (2009) 9791–9796
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of C-5-substituted 6,50-O-anhydrouridine by Sn–Pd
transmetallation-coupling process and their use
y
*
Adam Mieczkowski , Jerome Blu, Vincent Roy, Luigi A. Agrofoglio
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universite´ d’Orle´ans, BP 6759, 45067 Orle´ans Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2009
Received in revised form
17 September 2009
Accepted 18 September 2009
Available online 22 September 2009
The palladium-catalyzed reaction of 5-tributylstannyluridine derivative (9) with a variety of aryl, vinyl
halides provides an efficient method for the synthesis of the corresponding 5-substituted 6,50-O-anhy-
drouridines. Additionally the 5-fluoro 6,50-O-anhydrouridine (16) via fluoro-destannylation with Se-
lectfluor is described. A dialkylphosphonate moiety was then introduced at C5 from the allyl derivative
10a under cross-metathesis conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
O
N
O
N
O
N
Br
N
O
N
O
N
O
Modified pyrimidine and purine nucleoside derivatives play
a prominent role as bioactive compounds.1 Recently, some cyclo-
nucleosides,2 bearing additional linkage between the heterocyclic
ring and the sugar moiety, have been shown to possess a wide
range of antiviral3 or antitumor4 activities. Among them, the 2,50-O-
anhydrouridine (1) analog of BVDU exhibited an anti-HSV-1 ac-
tivity5 while 2,50-O-bridged analogs of AZT (2) and AZU (3) were
tested against HIV and R-MuLV.6 The anhydroadenosine (4)
inhibited uridine phosphorylase,8 while the 2,50-O-anhydrouridine
(5) inhibited uridine phosphorylase,7 (Fig. 1).
To achieve heterocycle modifications, the Pd(0) cross-coupling
reactions and especially under Stille conditions, allowed us and
others to synthesize broad range of modified nucleosides.9 The
classic method for the synthesis of C5-substituted pyrimidines by
the Stille protocol involves the Pd-mediated cross-coupling of
a haloaromatic or aryltriflate with an organostannane.
O
O
O
N3
N3
OH
cyclo-AZT (2)
cyclo-AZU (3)
cyclo-BVDU (1)
NH2
O
R
O
N
N
N
NH
N
O
O
N
O
O
N
O
N
O
O
HO OH
cyclo-Adenosine (4)
HO OH
targeted compounds
HO OH
cyclo-Uridine (5)
Figure 1. Some bioactive anhydrornucleosides.
Thus, following our research on the synthesis and modification
of 6,50-O-anhydrouridines,10 we decided to report herein the syn-
thesis of hitherto unknown C5-substituted-6,50-O-anhydronucleo-
side derivatives through the Stille palladium-catalyzed reaction
starting from 5-iodo-6,50-O-anhydrouridine. Although the palla-
dium-mediated reactions are very useful tool for the synthesis of
modified nucleosides, the Pd(0) cross-coupling for anhy-
dronucleoside modification has not been explored to date. As a re-
sult of our interest in studying Pd-mediated C–C bond formation
and cyclonucleosides, we became involved in addressing this
problem.
2. Results and discussion
In first attempt, we tried to react the 5-iodo-20,30-iso-
propylidene-6,50-O-anhydrouridine (7)10,11 with related reagents
including organostannane (Stille), organoboron reagents (Suzuki)
or alkene (Heck), under various Pd catalytic systems (such as
Pd2dba3, Pd(PPh)3, Pd(PPh3)Cl2/As3P, (2-furyl)3P, PPh3/CuI), (IPr)P-
d(Allyl)Cl (Scheme 1), with or without the addition of an inorganic
salt as co-catalyst. Unfortunately in all cases, no reaction occurred
and after work-up, the iodo derivative 7 was fully recovered
(Scheme 1).
* Corresponding author. Tel.: þ33 2 3849 4582; fax: þ33 2 3841 72 81.
E-mail address: luigi.agrofoglio@univ-orleans.fr (L.A. Agrofoglio).
y
Present address: Department of Chemistry, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.075

9792
A. Mieczkowski et al. / Tetrahedron 65 (2009) 9791–9796
O
N
O
N
O
N
O
O
N
R
I
R
X
NH
NH
NH
NH
NH
O
O
O
HO
O
O
a
O
O
N
O
O
O
O
O
O
O
a or b or c
ref. 10
O O
O O
O O
O O
not obtained
O O
6
7
9 R = Bu3Sn (50%)
7 X = I
8 X = Br
Scheme 1. Reagents and conditions: (a) Bu3SnAll, Pd(0), dioxane or DMF, heating; (b)
PhB(OH)2, Pd(0), AsPh3, dioxane, 70 ꢁC, overnight; (c) acrylonitrile or vinyl-
methylketone, NBu3, Pd(0), AsPh3, DMF, 70 ꢁC, 2 days.
Scheme 3. Reagents and conditions: (a) i. 1 equiv NaH, 10 min., rt, THF then 2 equiv
BuLi, ꢀ78 ꢁC; ii. Bu3SnCl.
Based on the well admitted mechanism for Pd(0) cross-coupling
(Scheme 2) and to explain the lack of reactivity of cyclonucleoside 7
for Pd(0) chemistry, we hypothesized that the Ar-X (7) oxidative
addition to the active Pd(0)L2 species does not proceed. In fact, in
the catalytic cycle of a series of important palladium-catalyzed
reactions (Heck, Suzuki, Stille, Negishi), an electrophilic aryl halide
is oxidatively added to a nucleophilic palladium(0) d10 complex
before being transferred onto the other coupling partner. The 6,50-
O-linkage leading to the 6-alkoxy-5-iodo-pyrimidine moiety in-
creases the nucleophilic character at C5, the vinyl ether group
having a strong electron-donating character.
O
N
O
N
O
N
Bu3Sn
O
NH
NH
NH
+
O
O
a
O
O
O
O
O
O
see Table
O O
O O
O O
9
10a
10b
Scheme 4. Reagents and conditions: (a) AllBr, Pd(0) catalytic system (see Table 1),
dioxane or DMF, heating.
O
O
R
O
I
NH
NH
N
O
N
Table 1
O
O
(7)
Entry Catalyst
(0.1 equiv)
Pd2dba3
Ligand
As3P
(2-furyl)3P CuI
As3P
d
Co-catalyst Solvent Temp. Yield of Yield of
R' R"
Pd(0)L2
(ꢁC)
10a [%] 10b [%]
R''-X
(0.2 equiv)
1
2
3
4
5
d
dioxane 70
No reaction
reductive
elimination
oxidative addition
R''-Pd(II)-X
Pd2dba3
Pd2dba3
Pd(PPh3)4
Pd(PPh3)2Cl2
dioxane 70
dioxane 70
45
46
52
62
37
37
28
22
CuI
CuI
CuI
R"-Pd(II)-R'
DMF
60
d
DMF
60
transmetallation
Under those Pd(0) optimized conditions, the 5-tri-(n-butyls-
tannyl)-20,30-isopropylidene-6,50-O-anhydrouridine (9) was reacted
with several aryl or vinyl iodide, which led to various C5-
substituted cyclouridine 11a–d with yields ranging from 37 to 60%,
Scheme 5. As expected, best yields were obtained with aryl iodide
bearing an EWG favoring the oxidative insertion with Pd(0). The
vinyl analog 12a was isolated with 30% yield while the styryl de-
rivative (12b) was isolated as the only E isomer (J¼16.5 Hz) with
20% yield.
X-SnR3
R'-SnR3
Scheme 2.
Thus, to circumvent this problem, we decided to introduce
a tributylstannyl substituent at C5 position and to use the obtained
5-trialkylstannyl nucleoside for the transmetallation step. Similar
approaches have been used for the synthesis of C5 labeling12 and
C4-substituted nucleosides.13 The C5-trialkylstannyl nucleosides
were obtained from the 5-halo nucleoside parent and hexa-n-
14
R
O
butyldistannane in the presence of Pd2(PPh3)2Cl2 or by a direct
O
N
O
N
lithiation method.15 Thus, either the 5-iodo- (7) or the 5-bromo-
20,30-isopropylidene-6,50-O-anhydrouridine (8),10 obtained by bro-
midation of 6 with an excess of N-bromosuccinimide,11a were
lithiated at ꢀ78 ꢁC with n-butyllithium and treated with a large
excess of tributyltin chloride (Scheme 3). After reaction, 5-(tri-n-
butylstannyl)-20,30-isopropylidene-6,50-O-anhydrouridine (9) was
isolated with 50%.
Bu3Sn
R
NH
NH
NH
a
O
O
O
N
O
O
O
O
O
O
O O
O O
O O
Having the 5-(tri-n-butylstannyl)-20,30-isopropylidene-6,50-O-
anhydrouridine (9) in hand, we decided to optimize the Stille re-
action with allyl bromide in a presence of various catalytic systems
(Scheme 4). Obtained results are presented in Table 1. The addition
of CuI as co-catalyst was necessary to form the desired product 10a
(entries 2–5). In all cases, the byproduct of destannylation 10b was
isolated. Optimized conditions were obtained with the
Pd(PPh3)Cl2/CuI catalytic system (entry 5), leading the desired
product 10a in 62% with 22% of 10b.
9
11a R = H
(52%)
R = OMe (37%)
R = F (57%)
R = CF3 (60%)
12a R = H (30%)
b R = Ph (20%)
b
c
d
Scheme 5. Reagents and conditions: (a) Aryl or vinyl iodide, Pd(PPh3)Cl2/CuI, DMF,
70 ꢁC.
We then turned our attention to the introduction at C5 of a fluo-
rine. The access to C5-florinated nucleosides is rather limited to few

A. Mieczkowski et al. / Tetrahedron 65 (2009) 9791–9796
9793
methods including enzymatic synthesis using phosphorylases,16
O
N
O
O
O
P
O
P
direct fluorination using F2 in AcOH17 or cesium fluoroxy phospha-
tedCsSO4F.18 Following a recent procedure from Yu et al.19 tri-
(n-butylstannyl)-20,30-isopropylidene-6,50-O-anhydrouridine (9) was
treated with Selectfluor in THF to give the 5-fluoro-20,30-iso-
propylidene-6,50-O-anhydrouridine (13) with 51% together with 49%
of destanyllated product 5 (Scheme 6).
EtO
EtO
EtO
EtO
NH
NH
O
O
O
O
N
O
b
O
O
NH
69%
a
O
O
HO
OH
N
O
O
O
60%
18
20
a
O
O
P
O
P
O
N
O
O
N
O
MeO
O
N
MeO
O
N
90%
F
NH
NH
MeO
MeO
Bu3Sn
10a
NH
NH
NH
O
O
O
O
O
O
O
O
b
O
N
O
O
O
N
N
O
O
Mes
O
Mes
a
+
89%
Cl
Ru
O
HO
OH
Cl
Ph
O O
PCy3
O O
O O
19
21
[Ru]= catalyst 17
Scheme 8. Reagents and conditions (a) [Ru] catalyst 17 (6 mol %), dry CH2Cl2, rfx, 7 h,
diethyl vinylphosphonate (for 18) or dimethylallyl phosphonate (for 19); b) 10% TFA in
H2O, 70 ꢁC, 1 h.
5
9
13
Scheme 6. Reagents and conditions: (a) Selectfluor, MeCN, 4 h, rt, 51%.
Finally, all obtained allyl, aryl or vinyl derivatives 11a–d, 13 were
successfully deprotected with 10% TFA solution to final products
14a–d, 16, respectively, with moderate to good yields (Scheme 7).
Compound 12b was deprotected with scandium triflate to 15,
however all efforts leading to deprotection of vinyl derivative 12a
resulted in the decomposition of the substrate.
Finally, it is known that organophosphorus compounds are re-
markable for their diverse and potent biological activities,20 often
enhanced by their association with various heterocycles and es-
pecially azaheterocycle.21 For instance, Qu et al.22 synthesized
novel C6-phosphonated purine nucleosides by SNAr-Arbuzov re-
action of trialkyl phosphite with 6-chloropurine nucleosides. Pre-
viously, Honjo et al. have described the sysnthesis and biological
properties of several di-Et and mono-Et esters of phosphonopyr-
imidine and purine ribonucleosides and shown that the di-Et-6-
After treatment of 18 and 19 with 10% TFA solution, the depro-
tected products 20 and 21 were isolated with 69% and 89%,
respectively.
The C5-diphenylphosphonate 24 was directly obtained from 5-
bromo-6,50-O-anhydrouridine 22,10 by a lithiation/alkylation step,
(Scheme 9). Thus, the 50-bromoderivative 22 was treated with
1 equiv NaH and 2 equiv of BuLi followed by the addition of 5 equiv
of diphenyl chlorophosphate to afford 23 with moderate yield.
Deprotection of 23 with 10% TFA solution led the desired product 24
in a low yield.
O
N
O
O
P
O
N
O
O
P
O
N
PhO
PhO
PhO
PhO
Br
O
NH
NH
NH
O
O
chloro-9-(
b-
D-ribofuranosyl)purine-8-phosphonates
exhibited
O
O
O
O
O
O
b
a
some antiviral and cytostotic activities, which were comparable to
those of the unphosphornylated compounds.
O
O
HO
OH
Thus, we turn our attention to the introduction on a dia-
lkylphosphonate moiety at C5 from the allyl derivative 10a under
cross-metathesis conditions.23 Compound 10a was reacted with
the commercially available vinyl phosphonic acid diethyl ester
with catalyst 17,24 to afford the desired heterodimer 18 as the E-
isomer. Under the same conditions, reaction between allyl de-
rivative 10a and dimethylallyl phosphonate afforded 19 in 90%
yield as the major and thermodynamically stable E-isomer,
(Scheme 8).
22
23
24
Scheme 9. Reagents and conditions: (a) 1 equiv NaH, 10 min., rt, THF then 2 equiv
BuLi, ꢀ78 ꢁC then (PhO)2POCl; b) 10% TFA:H2O 1:2, rt, 3 days.
For all 6,50-O-anhydronucleosides, characteristic AB systems
were observed by 1H NMR data. For protected compounds, two AB
systems appeared, e.g., for C50 protons and for C20/C30 protons. For
deprotected compounds, only AB system for C50 protons still exis-
ted, while C20/C30 protons usually had identical shifts giving one
multiplet.
O
O
R
R
O
NH
NH
a
O
3. Conclusion and perspectives
N
O
O
N
O
O
6,50-O-Anhydrouridine derivatives bearing aryl or vinyl sub-
stituents at C5 position were synthesized by Sn–Pd trans-
metallation cross-coupling protocol starting from the easily
available 5-tri-(n-butylstannyl)-20,30-isopropylidene-6,50-O-anhy-
drouridine (9). The 5-fluoro derivative was also obtained from
tributystannyl intermediate. This procedure allows the synthesis
of broad range of C5-substituted 6,50-O-anhydronucleosides not
accessible by other methods (e.g.. lithiation at C5 position). A
dialkylphosphonate moiety was then introduced at C5 position
using cross-metathesis or lithiation. No significant activity against
HCV was found.
HO OH
O O
11a R = Ph
14a R = Ph (57%)
b R = 4-MeO-Ph (67%)
c R = 4-F-Ph (79%)
d R = 4-CF3-Ph (66%)
b R = 4-MeO-Ph
c R = 4-F-Ph
d R = 4-CF3-Ph
12b R = Ph-CH=CH
13 R = F
15 R = Ph-CH=CH (52%)
16 R = F (59%)
Scheme 7. Reagents and conditions: (a) 10% TFA in H2O, 70 ꢁC, 1 h or 10 mol % of
Sc(OTf)3, 1% AcCN in water, 1 h, 120 ꢁC, microwaves.

9794
A. Mieczkowski et al. / Tetrahedron 65 (2009) 9791–9796
4. Experimental
J¼5.6 Hz), 4.96–5.11 (2H, m), 5.72–9.94 (1H, m), 6.60 (1H, s), 9.44 (s,
1H); 13C NMR (62 MHz, CDCl3)
24.6, 26.2, 28.6, 77.1, 82.4, 84.0,
d
4.1. General
85.5, 89.9, 101.3, 113.0, 115.3, 135.3, 149.0, 157.8, 163.4, HRMS (ESI):
m/z calcd for C15H18N2O6 (MþNa)þ: 345.3067, found: 345.3065.
Commercially available chemicals were used as-received. Mi-
crowave reactions were carried out in a Biotage Initiator with
a maximum power of 300 W and temperatures were measured by
IR-sensor. Reactions were monitored by thin-layer chromatography
(TLC) analysis using silica gel plates (Kieselgel 60 F254). Compounds
were visualized by UV irradiation and/or spraying with ethanol
solution 2.5% in phosphomolybdic acid, followed by charring at
150 ꢁC. Column chromatography was performed on Silica Gel 60 M
(0.040–0.063 mm).
4.3.2. 5-Phenyl-20,30-isopropylidene-6,50-O-anhydrouridine (11a). [
a]
D
þ49 (c 1.0, MeOH). 1H NMR (250 MHz, CDCl3)
d 1.34 (3H, s), 1.54 (3H,
s), 3.93 (1H, dd, J¼0.6, 12.4 Hz), 4.27 (1H, dd, J¼1.0, 12.4 Hz), 4.58 (1H,
s), 4.88 (2H, s), 6.66 (1H, s), 7.32 (5H, m), 9.06 (1H, s); 13C NMR
(62 MHz, CDCl3)
d 24.6, 26.2, 77.6, 82.3, 84.0, 85.5, 90.9, 104.8, 113.1,
127.9, 128.1, 129.2, 130.3, 148.7, 157.5, 162.5; HRMS (ESI): m/z calcd for
C18H18N2O6 (MþNa)þ: 381.3397, found: 381.3395.
The 1H and 13C NMR spectra were recorded on a Bruker AVANCE
DPX 250 (1H 249.88 MHz, 13C: 62.84 MHz) and Varian InovaUnity
400 spectrometer (1H 399.91 MHz, 13C: 100.54 MHz) in DMSO-d6 or
mixture of CDCl3/DMSO-d6. The NMR spectra were recorded at
room temperature. The chemical shifts are given in ppm relative to
the residual signal of the solvent, TMS being used as calibration
standard with different deuteriated solvents. Signals are reported
as s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q
(quartet), qi (quintuplet) and m (multiplet) with the relevant cou-
pling constants J in Hertz. For protected compounds to differentiate
signals from aliphatic chain and isopropylidene group: idsignals
derived from isopropylidene group, cdsignals from aliphatic chain
in C5 position. Polarity index was measured on: Perkin Elmer
Model 341 Polarimeter. Evidence of purity has been done from
a proton-decoupled 13C NMR spectrum with a signal-to-noise ratio
sufficient to permit seeing peak with 5% of the intensity of the
strongest peak.
4.3.3. 5-(4-Methoxyphenyl)-20,30-isopropylidene6,50-O-anhydrour-
idine (11b). [
a
]
þ37 (c 0.6, MeOH). 1H NMR (250 MHz, CDCl3)
D
d
1.34 (3H, s), 1.54 (3H, s), 3.82 (3H, s), 3.96 (1H, dd, J¼0.5, 12.4 Hz),
4.36 (1H, dd, J¼1.0, 12.4 Hz), 4.58 (1H, s), 4.89 (2H, s), 6.66 (1H, s),
6.92 (2H, d, J¼8.8 Hz), 7.21 (2H, d, J¼8.8 Hz), 8.78 (1H, s); 13C NMR
(62 MHz, CDCl3) d 24.6, 26.2, 55.3, 77.6, 82.3, 84.0, 85.6, 90.2, 104.5,
113.1, 113.7, 31.4, 121.3, 148.6, 157.2, 159.2, 162.6; HRMS (ESI): m/z
calcd for C19H20N2O7 (MþNa)þ: 411.3659, found: 411.3658.
4.3.4. 5-(4-Fluorophenyl)-20,30-isopropylidene-6,50-O-anhydrouridine
(11c). [
a
]
D þ52 (c 1.0, MeOH). 1H NMR (250 MHz, CDCl3)
d 1.35 (3H,
s), 1.54 (3H, s), 3.95 (1H, dd, J¼0.6, 12.4 Hz), 4.35 (1H, dd, J¼1.0,
12.4 Hz), 4.58 (1H, s), 4.89 (2H, s), 6.66 (1H, s), 7.06 (2H, t, J¼8.6 Hz),
7.26 (2H, t, J¼8.6 Hz), 9.07 (1H, s); 13C NMR (62 MHz, CDCl3)
d 24.6,
26.2, 77.6, 82.3, 83.9, 85.5, 90.2, 103.8, 113.1, 115.2, 125.3, 132.1, 148.6,
157.6, 162.2, 162.5; HRMS (ESI): m/z calcd for C18H17FN2O6 (MþNa)þ:
399.3302, found: 399.3298.
4.2. 5-(Tri-n-butylstannyl)-20,30-isopropylidene-6,50-O-
anhydrouridine (9)
4.3.5. 5-[4-(Trifluoromethyl)phenyl]-20,30-isopropylidene-6,50-O-an-
hydrouridine (11d). [
a
]
þ49 (c 1.0, MeOH). 1H NMR (400 MHz,
D
CDCl3)
d
1.35 (3H, s), 1.54 (3H, s), 3.98 (1H, dd, J¼0.8, 12.4 Hz), 4.37
1 equiv of 5-halo-20,30-isopropylidene-6,50-O-anhydrouridine (7
for X¼I or 8 for X¼Br)10 was dissolved in dry THF (20 mL) and
1 equiv of sodium hydride was added. The reaction mixture was
cooled at ꢀ78 then 2 equiv of n-Buli was added. After stirring
30 min, 5 equiv tributyltin chloride were added. The reaction
mixture was stirred at ꢀ78 ꢁC overnight, then warm up to room
temperature. NH4Cl satd was added, organic phase was separated
and aqueous phase was extracted three times with CH2Cl2. Organic
phases were evaporated and the residue was purified by liquid
chromatography on silica gel using petroleum ether/EtOAc, 7:3. Re-
(1H, dd, J¼1.2, 12.4 Hz), 4.60 (1H, d), 4.90 (2H, m), 6.67 (1H, s), 7.43
(2H, d, J¼8.1 Hz), 7.63 (2H, d, J¼8.1 Hz), 9.05 (1H, s); 13C NMR
(100 MHz, CDCl3)
d 24.6, 26.2, 77.8, 82.3, 83.9, 85.5, 90.3, 103.5,
113.3, 124.0, 125.0, 129.9, 130.8, 133.1, 148.5, 158.0, 162.1; HRMS
(ESI): m/z calcd for C19H17F3N2O6 (MþNa)þ: 449.3380, found:
449.3379.
4.3.6. 5-Vinyl-20,30-isopropylidene-6,50-O-anhydrouridine (12a). [
a]
D
þ93 (c 1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3)
d 1.36 (3H, s),1.54 (3H,
s), 4.00 (1H, dd, J¼0.7,12.4 Hz), 4.56 (1H, dd, J¼1.1,12.4 Hz), 4.62 (1H,
s), 4.86 (1H, d, J¼5.6 Hz), 4.96 (1H, d, J¼5.6 Hz), 5.33 (1H, dd, J¼2.1,
11.9 Hz), 6.20 (1H, dd, J¼2.1, 17.8 Hz, CH2¼), 6.45 (1H, dd, J¼11.9,
17.8 Hz), 6.62 (1H, s, H10), 8.92 (1H, s); 13C NMR (100 MHz, CDCl3)
crystallization of 9 from hexane gave white crystals. [
a
]
D þ50 (c 1.0,
MeOH). 1H NMR (250 MHz, CDCl3)
d
0.89 (9H, t, J¼7.3 Hz), 1.00–1.11
(6H, m), 1.23–1.41 (9H, m), 1.42–1.57 (19H, m), 4.12 (1H, dd, J¼0.7,
12.3 Hz), 4.33 (1H, dd, J¼1.3, 12.3 Hz), 4.56 (1H, s), 4.80 (1H, d,
J¼5.6 Hz), 4.89 (1H, d, J¼5.6 Hz), 6.60 (1H, s), 8.28 (1H, s); 13C NMR
d
24.6, 26.2, 77.1, 82.4, 84.0, 85.6, 90.2, 101.1, 113.2, 118.4, 123.5, 148.2,
157.4, 162.0; HRMS (ESI): m/z calcd for C14H16N2O6 (MþNa)þ:
(62 MHz, CDCl3)
d
11.3, 14.1, 24.7, 26.2, 27.7, 29.4, 76.8, 82.4, 83.7,
331.2799, found: 331.2796.
85.6, 89.6, 98.6, 113.1, 140.4, 163.0, 166.3; HRMS (ESI): m/z calcd for
C24H40N2O6Sn (MþNa)þ: 594.2902, found: 594.2897.
4.3.7. 5-(E)-Styryl-20,30-isopropylidene-6,50-O-anhydrouridine
(12b). [
a
]
D þ76 (c 1.0, CH2Cl2). 1H NMR (250 MHz, CDCl3)
d 1.37 (3H,
4.3. Procedure for Stille reaction
s), 1.55 (3H, s), 4.04 (1H, dd, J¼0.7, 12.4 Hz), 4.59–4.66 (2H, m), 4.89
(1H, d, J¼5.6 Hz), 4.99 (1H, d, J¼5.6 Hz), 6.65 (1H, s), 6.85 (1H, d,
J¼16.5 Hz), 7.18–7.56 (5H, m), 7.72 (1H, d, J¼16.5 Hz), 8.89 (1H, s);
1 equiv of tri-n-butylstannyl derivative 9 was dissolved in dry
DMF (20 mL), 0.1 equiv of Pd(PPh3)Cl2, 0.2 equiv of CuI and 3 equiv
of RX were added under argon. Reaction mixture was heated on
oil bath in 70 ꢁC for an 8 h, then solvent was evaporated, and
residue was chromatographed using petroleum ether/EtOAc, 7:3
then 6:4.
13C NMR (62 MHz, CDCl3)
d 24.7, 26.2, 77.3, 82.4, 84.0, 85.6, 90.3,
101.3, 113.2, 115.7, 126.4, 127.6, 128.6, 132.1, 137.9, 148.0, 157.1, 161.9;
HRMS (ESI): m/z calcd for C20H20N2O6 (MþNa)þ: 407.3775, found:
407.3772.
4.4. General deprotection with TFA solution
4.3.1. 5-Allyl-20,30-isopropylidene-6,50-O-anhydrouridine (10a). [
a]
D
þ96 (c 1.0, CH2Cl2). 1H NMR (250 MHz, CDCl3)
d
1.36 (3H, s), 1.54
The isopropylidene derivatives were treated with 10% TFA in
H2O for 1 h in 70 ꢁC, respectively. Solvent was evaporated and co-
evaporated with toluene. The residue was dissolved and purified by
(3H, s), 2.97–3.21 (2H, m), 3.93 (1H, dd, J¼0.7,12.4 Hz), 4.47 (1H, dd,
J¼1.2, 12.5 Hz), 4.59 (1H, s), 4.84 (1H, d, J¼5.6 Hz), 4.94 (1H, d,

A. Mieczkowski et al. / Tetrahedron 65 (2009) 9791–9796
9795
liquid chromatography on silica gel (petroleum ether/EtOAc, from
5/5 to 7/3).
4.7. 5-[(E)-3-Diethoxyphosphinyl-2-propenyl]-20,30-
isopropylidene-6,50-O-anhydrouridine (18)
4.4.1. 5-Phenyl-6,50-O-anhydrouridine (14a).
a
]
D
þ47 (c 1.0, DMF).
To a dry CH2Cl2 (10 mL) solution of N1-allyl-5-substituted
anhydrouridine 10 (100 mg, 0.0.31 mmol) and diethyl vinyl-
phosphonate (254 mg, 0.26 mL, 1.55 mmol), catalyst 17 (15 mg,
0.02 mmol) was added. This solution was refluxed for 7 h under
positive pressure of dry Ar. After evaporation of all volatiles, the
residue was purified by chromatography on silica gel (EtOAc/
MeOH¼15:1) to afford 18 (66 mg, 60%). 1H NMR (250 MHz, CDCl3)
1H NMR (400 MHz, DMSO-d6)
d
4.08 (1H, d, J¼12.3 Hz), 4.19–4.26
(1H, m), 4.30–4.45 (3H, m), 5.19 (1H, d, J¼4.6 Hz), 5.47 (1H, d,
J¼7.2 Hz), 6.27 (1H, s), 7.20–7.40 (5H, m), 11.55 (1H, s); 13C NMR
(100 MHz, DMSO-d6) d 72.0, 76.5, 77.5, 86.3, 91.6, 103.3, 126.9, 127.5
130.5, 130.7, 149.2, 157.5, 162.7; HRMS (ESI): m/z calcd for
C15H14N2O6 (MþNa)þ: 341.2751, found: 341.2748.
d
1.31 (6H, t, J¼7.3 Hz), 1.36 (3H, s), 1.54 (3H, s), 3.12 (2H, m), 3.93
4.4.2. 5-(4-Methoxyphenyl)-6,50-O-anhydrouridine (14b). [
(c 0.6, DMF). 1H NMR (400 MHz, DMSO-d6)
3.74 (1H, s), 4.02 (1H,
a
]
þ36
(1H, d, J¼0.7, 12.4 Hz), 4.07 (2H, q, J¼7.3 Hz), 4.12 (2H, q, J¼7.3 Hz),
4.47 (1H, dd, J¼1.2, 12.5 Hz), 4.59 (1H, s), 4.84 (1H, d, J¼5.6 Hz),
4.94 (1H, d, J¼5.6 Hz), 5.85 (1H, t, J¼16.9 Hz), 6.78 (1H, ddt, J¼5.0,
16.9, 21.9 Hz), 6.59 (1H, s), 9.82 (1H, s); 13C NMR (62 MHz, CDCl3)
D
d
d, J¼11.8 Hz), 4.18–4.27 (1H, m), 4.30–4.43 (3H, m), 5.20 (1H, d,
J¼3.3 Hz), 5.50 (1H, d, J¼6.6 Hz), 6.25 (1H, s), 6.85–9.94 (2H, m),
7.12–7.21 (2H, m), 11.50 (1H, s); 13C NMR (100 MHz, DMSO-d6)
d
16.2, 16.3, 24.6, 26.2, 28.6, 61.2, 61.4, 77.1, 82.4, 84.0, 85.5, 89.9,
d
55.2, 72.3, 76.7, 77.7, 86.6, 91.8, 103.3, 113.3, 122.8, 131.8, 158.5,
101.3, 113.0, 117.4 (JCP), 149.0, 149.2 (JCP), 149.0, 157.8, 163.4; HRMS
(ESI): m/z calcd for C19H27N2O9P (MþNa)þ: 481.3937, found:
481.3935.
149.4, 157.6, 163.2; HRMS (ESI): m/z calcd for C16H16N2O7 (MþNa)þ:
371.3013, found: 371.3011.
4.4.3. 5-(4-Fluorophenyl)-6,50-O-anhydrouridine (14c). [
1.0, DMF). 1H NMR (400 MHz, DMSO-d6)
4.20–4.27 (1H, m), 4.32–4.45 (3H, m), 5.18 (1H, br s), 5.45 (1H, d,
a
]
þ58 (c
D
4.8. 5-[(E)-4-Dimethoxyphosphinyl-2-butenyl]-20,30-
isopropylidene-6,50-O-anhydrouridine (19)
d
4.10 (1H, d, J¼12.3 Hz),
J¼6.9 Hz), 6.27 (1H, s), 7.13–7.21 (2H, m), 7.25–7.35 (2H, m), 11.57
A mixture of protected N1-allyl-5-substituted anhydrouridine
10 (100 mg, 0.0.31 mmol), dimethylallyl phosphonate (223 mg,
0.2 mL, 1.5 mmol), and catalyst 17 (15 mg, 0.02 mmol) in CH2Cl2
(10 mL) was refluxed for 4 h under positive pressure of dry Ar.
After evaporation of all volatiles, the residue was purified by
chromatography on silica gel (EtOAc/MeOH¼20:1) to yield the
desired compound 19 (112 mg, 90%). 1H NMR (250 MHz, CDCl3)
(1H, s); 13C NMR (100 MHz, DMSO-d6)
d 72.0, 76.4, 77.5, 86.3, 91.6,
102.3, 114.5, 126.9, 132.5, 149.1, 157.6, 161.1, 162.7; HRMS (ESI): m/z
calcd for C15H13FN2O6 (MþNa)þ: 359.2656, found: 359.2654.
4.4.4. 5-[4-(Trifluoromethyl)phenyl]-6,50-O-anhydrouridine
(14d). [
a
]
þ61 (c 1.0, DMF). 1H NMR (400 MHz, DMSO-d6)
d 4.15
D
(1H, d, J¼12.1 Hz), 4.20–4.27 (1H, m), 4.33–4.41 (2H, m), 4.45 (1H, d,
J¼12.1 Hz), 5.20 (1H, br s), 5.44 (1H, d), 6.28 (1H, s), 7.52 (2H, d,
J¼8.3 Hz), 7.70 (2H, d, J¼8.3 Hz), 11.66 (1H, s); 13C NMR (100 MHz,
d
1.36 (3H, s), 1.54 (3H, s), 2.51 (1H, d, J¼7.5 Hz), 2.60 (1H, d,
J¼7.5 Hz), 3.09 (2H, m), 3.7 (6H, m), 3.92 (1H, d, J¼12.5 Hz), 4.53
(1H, d, J¼12.5 Hz), 4.59 (1H, s), 4.82 (1H, d, J¼5.6 Hz), 4.93 (1H, d,
J¼5.6 Hz), 5.44 (1H, m), 5.62 (1H, m) 6.57 (1H, s), 9.33 (1H, s); 13C
DMSO-d6)
d 71.9, 76.6, 77.7, 86.3, 91.7, 101.9, 124.2, 124.3, 127.4,
131.3, 135.3, 149.2, 158.1, 162.4; HRMS (ESI): m/z calcd for
C16H13F3N2O6 (MþNa)þ: 409.2734, found: 409.2731.
NMR (62 MHz, CDCl3)
d 24.6, 25.5, 26.2, 28.6 (JCP), 56.2, 77.0, 82.3,
84.1, 85.5, 89.9, 101.3, 113.0, 119.4 (JCP), 132.5 (JCP), 149.0, 157.8,
163.4; HRMS (ESI): m/z calcd for C18H25N2O9P (MþNa)þ: 467.3669,
found: 467.3666.
4.5. 5-(E)-Styryl-6,50-O-anhydrouridine (15)
54 mg of styrene derivative 12b were dissolved in 3 mL of 1%
AcCN in H2O, then 7 mg (0.1 equiv) of scandium triflate were added.
The reaction mixture was heated in 120 ꢁC for a 1 h under the mi-
crowaves conditions in a sealed tube. Then solvent was evaporated
and residue was purified by liquid chromatography on silica gel
column using petroleum ether/EtOAc 3:7. 25 mg (52%) of product
4.9. 5-[(E)-3-Diethoxyphosphinyl-2-propenyl]-6,50-O-
anhydrouridine (20)
Compound 20 was deprotected with 10% TFA following the
general procedure reported above. 1H NMR (250 MHz, MeOH-d4)
d
1.31 (6H, t, J¼7.3 Hz), 3.3 (2H, m), 4.04 (5H, m), 4.45 (3H, m), 4.57
were obtained. [
d6)
a
]
D þ108 (c 1.0, DMSO). 1H NMR (400 MHz, DMSO-
(1H, d, J¼12.6 Hz), 5.76 (1H, m), 6.4 (1H), 6.74 (1H, m), 5.44 (1H, d,
J¼6.4 Hz), 5.66–5.87 (1H, m), 6.19 (1H, s); 13C NMR (67 MHz,
d
4.05 (1H, d, J¼12.5 Hz), 4.34–4.44 (2H, m), 4.46 (1H, s), 4.80
(1H, d, J¼12.5 Hz), 5.28 (1H, br s), 5.50 (1H, d, J¼6.3 Hz), 6.27 (1H, s),
6.91 (1H, d, J¼16.5 Hz), 7.27 (1H, d, J¼7.3 Hz), 7.35 (2H, t, J¼7.5 Hz),
7.46 (2H, d, J¼7.5 Hz), 7.60 (1H, d, J¼16.5 Hz), 11.66 (1H, s); 13C NMR
MeOH-d4)
d
16.2, 16.3, 26.2, 61.2, 72.1 (C30), 76.6 (C20), 77.0 (C50),
86.3 (C40), 91.4 (C10), 100.9 (C5), 117.4 (JCP), 149.2 (JCP), 149.2 (C2),
157.9 (C6), 163.5 (C4); HRMS (ESI): m/z calcd for C16H23N2O9P
(MþH)þ:418.3394, found: 418.3391.
(100 MHz, DMSO-d6) d 72.2, 76.6, 77.6, 86.5, 91.9, 117.7, 125.9, 127.2,
128.7, 129.0, 138.9, 148.6, 158.2, 162.5; HRMS (ESI): m/z calcd for
C17H16N2O6 (MþNa)þ: 367.3129, found: 367.3125.
4.10. 5-[(E)-4-Dimethoxyphosphinyl-2-butenyl]-6,50-O-
anhydrouridine (21)
4.6. 5-Fluoro-6,50-O-anhydrouridine (16)
Compound 21 was deprotected with 10% TFA following the
general procedure reported above. 1H NMR (250 MHz, MeOH-d4)
The fluorinated compound 13 was deprotected with 10% TFA
following the general procedure reported above. [
a
]
þ84 (c 1.0,
d
2.60 (1H, d, J¼7.5 Hz), 2.68 (1H, d, J¼7.5 Hz), 3.09 (2H, m), 3.73
D
DMSO). 1H NMR (400 MHz, DMSO-d6)
d
4.11 (1H, dd, J¼0.7,12.4 Hz),
(6H, m), 3.95 (1H, d, J¼12.5 Hz), 4.47 (3H, m), 4.53 (1H, d,
4.27–4.33 (1H, m), 4.33–4.39 (1H, m), 4.41 (1H, m), 4.69 (1H, dd,
J¼12.5 Hz), 5.44 (1H, m), 5.62 (1H, m) 6.38 (1H, s); 13C NMR
J¼1.2, 12.4 Hz), 5.25 (1H, s), 5.45 (1H, s), 6.15 (1H, s), 11.89 (1H, s);
(62 MHz, MeOH-d4) d 25.5, 28.6 (JCP), 56.2, 77.0, 82.3, 84.1, 85.5,
13C NMR (100 MHz, DMSO-d6)
d
71.9, 76.4, 78.4, 86.6, 92.2, 129.9,
89.9, 101.3, 113.0, 119.4 (JCP), 132.5 (JCP), 149.0, 157.8, 163.4; HRMS
(ESI): m/z calcd for C15H21N2O9P (MþH)þ: 405.3205, found:
405.3204.
147.6, 149.0, 157.2; HRMS (ESI): m/z calcd for C9H9FN2O6 (MþNa)þ:
283.1680, found: 283.1677.

9796
A. Mieczkowski et al. / Tetrahedron 65 (2009) 9791–9796
4.11. 5-[Diphenylphosphinyl]-20,30-isopropylidene-6,50-O-
anhydrouridine (23)
3. (a) Hamamura, E. K.; Prystasz, M.; Verheyden, J. P. H.; Moffat, J. G.; Yamaguchi,
K.; Uchida, N.; Sato, K.; Nomura, A.; Shiratori, O.; Takase, S.; Katagiri, K. J. Med.
Chem. 1976, 19, 654–662; (b) Sato, K.; Nomura, A.; Moffat, J. G. Antimicrob.
Agents Chemother. 1977, 11, 191–197; (c) Nishiyama, S.; Nomura, A,; Yamanaka,
T.; Moffat, J. G. Antimicrob. Agents Chemother. 1977, 11, 198–201; (d) Hsu, L.-Y.;
Chang, Y.-M.; Lin, C.-H.; Drach, J. C. Nucleosides Nucleotides 1996, 15, 1835–1847.
4. (a) Hirayama, H.; Sugihara, K.; Wakigawa, K.; Iwamura, M.; Hikita, J.; Ohkuma,
H. Pharmacometrics 1972, 6, 1255–1258; (b) Hirayama, H.; Sugihara, K.; Waki-
gawa, K.; Hikita, J.; Sugihara, T.; Kubota, T.; Ohkuma, H.; Oguro, K. Pharmaco-
metrics 1972, 6, 1259–1266; (c) Hirayama, H.; Sugihara, K.; Sugihara, T.;
Wakigawa, K.; Iwamura, M.; Ohkuma, H.; Hikita, J. Pharmacometrics 1974, 8,
353–384; (d) Hoshi, A.; Kanzawa, F.; Kuretani, K.; Saneyoshi, M.; Arai, Y. Gann
Monogr. Cancer. Res. 1971, 62, 145–146.
1 equiv of 5-bromo-20,30-isopropylidene-6,50-O-anhydrouridine
2210 (1.5 g, 4.15 mmol) was dissolved in dry THF (50 mL) and
1 equiv of sodium hydride (0.17 g) was added followed by 3 equiv of
HMPA (2.16 mL, 12.45 mmol). The reaction mixture was cooled
down under nitrogen to ꢀ78 ꢁC, then 2 equiv of 2.5 M n-BuLi
(3.34 mL, 8.30 mmol) was added. After stirring for a 30 min, 5 equiv
of diphenyl chlorophosphate (4.29 mL, 20.75 mmol) was added.
The reaction mixture was stirred at ꢀ78 ꢁC overnight, then warmed
up to rt. Satd NH4Cl was added, organic phase was separated, and
aqueous phase was extracted three times with CH2Cl2. Organic
phases were evaporated and the residue was purified by liquid
chromatography on silica gel (petroleum ether/EtOAc, 7:3 then 6:4)
to led the desired product 23 (400 mg, 20%). 1H NMR (250 MHz,
5. Harnden, M.R. Eur. Pat. Appl. EP 0060099, 1982.
6. Lin, T.-S.; Shen, Z.-Y.; August, E. M.; Brankovan, V.; Yang, H.; Ghazzouli, I.;
Prusoff, W. H. J. Med. Chem. 1989, 32, 1891–1895.
7. (a) Niedzwicki, J. G.; El Kouni, M. H.; Chu, S. H.; Cha, S. Biochem. Pharmacol. 1983,
ˇ
´
´
32, 339–415; (b) Dvorakova, H.; Holy, A. Chem. Listy 1991, 85, 171–195; (c) El
Kouni, M. H.; Naguib, F. N. M.; Panzica, R. P.; Otter, B. A.; Chu, S.-H.; Gosselin, G.;
Chu, C. K.; Schinazi, R. F.; Shealy, Y. F.; Goudgaon, N.; Ozerou, A. A.; Ueda, T.;
Iltzsch, M. H. Biochem. Pharmacol. 1996, 51, 1687–1700.
8. Palczewski, K.; Kahn, N.; Hargrave, P. A. Biochemistry 1990, 29, 6276–6282.
9. For a report on Pd(0)-mediated synthesis of nucleosides, see: Agrofoglio, L. A.;
Gillaizeau, I.; Saito, Y. Chem. Rev. 2003, 103, 1875–1916.
10. Mieczkowski, A.; Peltier, P.; Agrofoglio, L. A. Tetrahedron 2009, 65, 4053–4059.
11. (a) Sako, M.; Saito, T.; Kemeyama, K.; Hirota, K.; Maki, Y. Synthesis 1987, 829–
831; (b) Qu, G.-R.; Ren, B.; Niu, H.-Y.; Mao, Z.-J.; Guo, H.-M. J. Org. Chem. 2008,
73, 2450–2453.
12. (a) Wust, F. R.; Kniess, T. J. Labelled Compd. Radiopharm. 2004, 47, 457–468; (b)
Samuelsson, L.; Langstrom, B. J. Labelled Compd. Radiopharm. 2003, 46, 263–272.
13. Hennecke, U.; Kuch, D.; Carell, T. Synthesis 2007, 929–935.
14. (a) Gutierrez, A. J.; Terhost, T. J.; Matteucci, M. D.; Froehler, B. C. J. Am. Chem. Soc.
1994, 116, 5540–5544; (b) Peters, D.; Ho¨rnfeldt, A.-B.; Gronowitz, S. J. Hetero-
cycl. Chem. 1991, 28, 529–531.
CDCl3)
d
1.32 (3H, s), 1.52 (3H, s), 3.89 (1H, dd, J1¼0.9, 12.4 Hz), 4.58
(1H, s), 4.60 (1H, dd, J1¼1.3, 12.4 Hz), 4.76 (1H, d, J¼5.6 Hz), 4.89
(1H, d, J¼5.6 Hz), 6.55 (1H, s), 6.55–7.38 (m, 10H), 9.36 (1H, br s);
13C NMR (62 MHz, CDCl3)
d 24.6, 26.2, 76.7, 82.2, 84.2, 85.4, 90.4,
91.2 (JCP), 113.2, 120.7, 125.3, 129.6, 148.1, 150.1 160.2, 167.2; HRMS
(ESI): m/z calcd for C24H23N2O9P (MþþNa): 537.4171, found:
537.4169.
4.12. 5-[Diphenylphosphinyl]-6,50-O-anhydrouridine (24)
15. Palmisano, G.; Santagostino, M. Tetrahedron 1993, 49, 2533–2542.
16. Chae, W.-G.; Cauchon, N. S.; Kozlowski, J. F.; Chang, C.-J. J. Org. Chem. 1992, 57,
1002–1005.
17. (a) Mercer, J. R.; Knaus, E. E.; Wiebe, L. I. J. Med. Chem. 1987, 30, 670–675; (b)
Visser, G. W. M.; Herder, R. A.; Noordhuis, P.; Zwaagstra, O.; Herscheid, J. D. M.;
de Kanter, F. J. J. J. Chem. Soc., Perkin Trans. 1 1988, 2547–2554; (c) Holy´, A.;
Koenig, J.; Vesely, J.; Cech, D.; Votruba, I.; De Clercq, E. Collect. Czech. Chem.
Commun. 1987, 52, 1589–1608; (d) Misra, H. K.; Wiebe, L. I.; Knaus, E. E. J. La-
belled Compd. Radiopharm. 1987, 24, 1107–1116.
Compound 24 was deprotected with 10% TFA following the
general procedure reported except the reaction occurred at rt. 1H
NMR (250 MHz, MeOH-d4)
m), 4.51 (1H, dd, J1¼1.3, 12.4 Hz), 6.27 (1H, s), 6.55–7.38 (m, 10H);
13C NMR (62 MHz, MeOH-d4)
73.8, 78.3, 80.01, 88.3, 94.3, 121.6,
d
3.83 (1H, dd, J1¼0.9, 12.4 Hz), 4.2 (3H,
d
126.6, 130.9, 150.3, 151.6, 162.9, 169.9; HRMS (ESI): m/z calcd for
C9H11N2O9P (MþþNa): 345.1573, found: 345.1571.
18. Stavber, S.; Zupan, M. Tetrahedron 1990, 46, 3093–3100.
19. Yu, C.-S.; Chiang, L.-W.; Wu, C.-H.; Hsu, Z.-K.; Lee, M.-H.; Pan, S.-D.; Pei, K.
Synthesis 2006, 3835–3840.
Acknowledgements
20. (a) Engel, R. Handbook of Organophosphorus Chemistry; Marcel Dekker: New
York, NY, 1992; (b) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem.
1991, 63, 193–215.
21. Moonem, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004, 104, 6177–6215.
22. Qu, G.-R.; Xia, R.; Yang, X.-N.; Li, J.-G.; Wang, D.-C.; Guo, H.-M. J. Org. Chem.
2008, 73, 2416–2419.
This work was supported in part by Idenix Pharmaceuticals.
References and notes
23. (a) Amblard, F.; Nolan, S. P.; Agrofoglio, L. A. Tetrahedron 2005, 61, 7067–7080
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1558; (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043; (d) Grubbs, R.
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S. R. Acyclic, Carbocyclic and L-Nucleosides; Kluwer Academic: Dordrecht, 1998;
(b) Ichikawa, E.; Kato, K. Curr. Med. Chem. 2001, 8, 385–423; (c) Merino, P. Curr.
Med. Chem. 2002, 1, 389–411; (d) Agrofoglio, L. A. Curr. Org. Chem. 2006, 10,
333–362.
24. Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem. Soc. 1999, 121,
2674–2678.
2. For a report on the synthesis of cyclonucleosides having a C–C bridge, see: Len,
C.; Mondon, M.; Lebreton, J. Tetrahedron 2008, 64, 7453–7475.