Expeditious convergent procedure for the preparation of bis(POC) prodrugs of new (E)-4-phosphono-but-2-en-1-yl nucleosides

Article abstract of DOI:10.1016/j.tet.2011.05.017

A series of unsaturated acyclonucleoside bis(POC) prodrugs of E configuration were synthesized through an expeditious, highly efficient and stereoselective one-step procedure from corresponding bis(POC)allylphosphonate through Ru catalyzed cross-coupling metathesis reaction. The [RuCl ₂(PCy₃)(SIPr)(Indenylidene)] and [RuCl ₂(PCy₃)(IMes)(benzylidene)] catalysts were employed; the unsaturated ANP were used bore C5-halovinyl uracil, C5-dihalovinyluracil or furanopyrimidine motifs. The chemical cleavage of biolabile (POC) group is a useful pathway to acid phosphonate derivatives.

Full text of DOI:10.1016/j.tet.2011.05.017

Tetrahedron 67 (2011) 5319e5328
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Expeditious convergent procedure for the preparation of bis(POC) prodrugs of
new (E)-4-phosphono-but-2-en-1-yl nucleosides
a
a
a
b
a,
*
ꢀ
ꢀ
Aurelien Montagu , Ugo Pradere , Vincent Roy , Steven P. Nolan , Luigi A. Agrofoglio
a
ꢀ
ꢀ
ꢀ
Institut de Chimie Organique et Analytique (ICOA), UMR 6005, Universite d’Orleans, 45067 Orleans, France
b EaStCHEM, University of St Andrews, St Andrews, KY16 9ST, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of unsaturated acyclonucleoside bis(POC) prodrugs of E configuration were synthesized through
an expeditious, highly efficient and stereoselective one-step procedure from corresponding bis(POC)al-
lylphosphonate through Ru catalyzed cross-coupling metathesis reaction. The [RuCl2(PCy3)(SIPr)(Inde-
nylidene)] and [RuCl2(PCy3)(IMes)(benzylidene)] catalysts were employed; the unsaturated ANP were
used bore C5-halovinyl uracil, C5-dihalovinyluracil or furanopyrimidine motifs. The chemical cleavage of
biolabile (POC) group is a useful pathway to acid phosphonate derivatives.
Received 28 February 2011
Received in revised form 3 May 2011
Accepted 5 May 2011
Available online 12 May 2011
Keywords:
Acyclonucleoside phosphonates
Prodrug
Ó 2011 Elsevier Ltd. All rights reserved.
Olefin cross metathesis
O
N
NH2
N
NH2
N
1. Introduction
Me
N
N
N
N
NH
Acyclonucleoside phosphonates (ANPs)1 represent a unique and
prominent class of antiviral drugs, which has attracted considerable
attention. Among ANPs, 9-[2-(phosphonomethoxy)ethyladenine
(PMEA, 1a) and its prodrug bis(POM)PMEA (1b),2 or (R)-[2-(phos-
phonomethoxy)-propyl]adenine (PMPA, 2a) and its prodrug bis(POC)
PMPA (2b)3 are approved for the treatment of severe viral infections
(Fig. 1). Their efficiency as drugs depends on several factors, such as
their cell penetration and the ability of human/viral kinases to pro-
vide their triphosphate active forms at a high concentration at the
right location. ANPs possess a phosphonomethyl ether moiety and
bypass the limiting first phosphorylation step.
O
P
O
P
O
O
N
N
RO
RO
RO
RO
O
O
RO
P
OR
Me
2a R = H, PMPA
b R = POC, tenofovir
3 R = H
4 R = POM
1a R = H, PMEA
b R = POM, adefovir
POM = CH2OCOtBu; POC = CH2OCO2iPr
O
N
O
N
Me
Me
NH
NH
O
O
HO
P
HO
P
O
O
O
O
OH
OH
Our laboratory recently reported a new type of antiviral acy-
clic nucleoside phosphonates with the (E)-4-phosphono-but-20-
en-10-yl moiety.4,5 By X-ray studies of thymidylate kinase in
complex with our thymine ANP analogue 3 (TbutP) and with the
natural substrate dTMP (thymidine 50-monophosphate), we have
demonstrated that only this (E)-but-2-enyl side-chain moiety can
mimic the conformation of the C1eO4eC4eC5 atoms from the 2-
deoxyribose in TMP. However, contrary to PMEA and PMPA,
which exhibit in vitro cellular antiviral activities, all free phos-
phonate analogues were not active and required their conversion
to a phosphonodiester form of reduced polarity, to exhibit
OH
[E]-TbutP
dTMP
Fig. 1. Some ANPs and but-20-enyl ANPs.
pronounced in vitro antiviral activity [e.g., for (4): EC50 3.1
mM
(HSV-1), 6.1
mM (HSV-2), 0.41 m mM (VZV
M (VZV TKþ) and 0.19
TKꢀ)].
In this paper, we describe efficient convergent synthesis of ef-
fective bis(POC) prodrugs of new (E)-4-phosphono-but-2-en-1-yl
nucleosides (21aef and 23aef), (Fig. 2). However, due to low sta-
bility and easy hydrolysis of the disoproxil side-chain of POC moi-
ety6,7 compared to POM, we cannot follow the exact synthetic
scheme and must design a new assembly.
* Corresponding author. E-mail address: luigi.agrofoglio@univ-orleans.fr (L.A.
Agrofoglio).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.017

5320
A. Montagu et al. / Tetrahedron 67 (2011) 5319e5328
subsequently crotylated at N1-position to 6. A debenzoylation of 6
R
O
N
O
N
Y
X
O
by treatment of ammonia in methanol solution afforded 7 in 60%
overall yield (on three steps), (Scheme 3). C5-Acrylated uracil 8 was
synthesized under conventional Pd-mediated Heck conditions in
92% yield. A saponification of 8 by NaOH (1 M) solution and sub-
sequent acidification by HCl (6 N) afforded the pure carboxylic acid
9. N1-Crotyl-C5-iodovinyl-uracil 10a and N1-crotyl-C5-bromovinyl-
uracil 10b were prepared in moderate yield (54% and 60% yield,
NH
NH
N
X
O
P
O
O
O
O
P
N
O
POCO
POCO
POCO
POCO
P
POCO
POCO
21c-f
23a-f
21a,b
Fig. 2. Targeted new unsaturated ANP.
respectively),
under
HunsdieckereBorodin
decarboxy-
lationehalogenation reaction, by treatment with NIS or NBS, re-
spectively, in the presence of KHCO3 in DMF, insuring the vinyl
functionality retention.9 No side halogenation reaction of the crotyl
double bond was observed as confirmed by 1H and 13C NMR.
2. Results and discussion
Typically, the bis(POM)-ButP analogues of 4 were obtained in
three steps5 (Scheme 1): (step one), cross metathesis (ACM) with
allylphosphonate; (step two), the hydrolysis of phosphonate diester
via a Lewis acid-promoted nucleophilic dealkylation (typically,
6 equiv of TMSBr are needed). TMSBr is a strong Lewis acid which
requires careful handling and anhydrous conditions. The obtained
phosphonic acids are only soluble in DMF or DMSO; (step three),
a base-promoted alkylation with excess of POMCl. This linear
approach cannot be use for the synthesis of bis(POC) analogues.
2.2. Preparation of N1-crotyl-C5-dihalovinyluracil moiety
C5-Dihalovinyl base analogues were readily prepared following
the procedure previously introduced by our team (Scheme 4). This
synthesis proceeded on a Pd-catalysed coupling reaction under
Sonogashira conditions.10 Treatment of 6 with trimethylsilylacety-
O
O
O
O
R'
R'
R'
R O
P
1
NH
NH
NH
R O
1
TMSBr
[Ru]=
N
O
O
P
N
O
O
P
N
O
R1O
R1O
HO
HO
step 2
step 1
R1 = Me, Et
O
R'
NH
POMCl
O
N
O
step 3
POMO
POMO
P
Scheme 1. General approach to bis(POM) ANPs.
O
N
O
N
Our one-step synthetic strategy to hitherto unknown bis(POC)-
C5-substituted-(E)-4-phosphono-but-2-en-1-yl acyclic nucleosides,
shown in Scheme 2, directly introduces the bis(POC) phosphonate
moiety through cross-coupling metathesis of the bulky bis(POC)
allylphosphonate 19 with various C5-substituted crotylated uracils
(10a,b, 14aed and 17aef). This step is the most critical point of
this contribution as, based on Grubbs work,8 generally diethyl- (or
dimethyl) allylphosphonates are preferred partners for ACM.
O
O
I
I
NBz
O
NH
I
I
NH
NBz
O
c
a
b
O
N
H
O
N
H
94%
90%
71%
5
6
7
d
92%
O
O
N
O
N
X
HO2C
MeO2C
O
NH
NH
NH
R
f
e
N
O
O
NH
O
O
91%
N
O
R
NH
O
O
8
10a : X = I (54%)
10b : X = Br (60%)
[Ru]=
9
N
O
O
P
10, 14, 17
O
O
O
O
O
O
step 1
+
O
O
Scheme 3. Reagent and conditions: (a) BzCl, MeCN/pyridine, rt, 15 h; (b) crotyl bro-
mide, K2CO3, DMF, rt, 5 h; (c) NH3/MeOH (7 N), 4 ꢁC, 16 h; (d) PPh3, Pd(OAc)2, methyl
acrylate, Et3N, dioxane, 80 ꢁC, 12 h; (e) NaOH 1 M, rt, 1 h, then HCl 6 N; (f) KHCO3, NIS
or NBS, DMF, rt, 2 h.
O
O
O
O
O
O
O
21, 23
P
19
lene, PdCl2(PPh3)2, Copper iodine, triethylamine in dime-
thylformamide afford 11 in good yield. Protected N3-benzoyl-N1-
crotyl-C5-iodouracil was chosen as starting materiel because of
unsuccess Sonogashira reaction11 with N3-H free uracil 7. Depro-
tected compound 13 was obtained through successive N3-deben-
zoylation followed by treatment with n-Bu4NF in high efficiency.
Dihalogenation of ethynyl group was performed in MeCN at 0 ꢁC
with corresponding dihalogen I2, IBr, ICl and Br2 to give, respectively,
Scheme 2. General convergent approach to bis(POC) ANPs.
2.1. Preparation of N1-crotyl-C5-halovinyluracil moiety
Compounds 10a,b were obtained through the key intermediate
N1-crotyl-5-iodo-uracil (7). Thus, a regioselective N3-benzoylation
of the commercially available 5-iodo uracil afforded 5, which was

A. Montagu et al. / Tetrahedron 67 (2011) 5319e5328
5321
O
N
TMS
O
N
TMS
O
N
I
NBz
O
NBz
O
NH
b
a
O
84%
94%
6
11
12
O
O
Y
NH
NH
X
c
d
N
O
N
O
88%
14a: X= I and Y = I (87%)
14b: X= I and Y = Br (78%)
14c: X= I and Y = Cl (82%)
14d: X= Br and Y = Br (74%)
13
Scheme 4. Reagent and conditions: (a) PdCl2(PPh3)2, trimethylsilyl acetylene, CuI, Et3N, DMF, rt, 16 h; (b) NH3/MeOH (7 N), 4 ꢁC, 16 h; (c) n-Bu4NF, rt, 2 h; (d) halogen (XeY), MeCN,
ꢁC, 3 h.
0
14aed average 74% yield. In this case, the low temperature (0 ꢁC) is
critical to avoid halogenation of the crotyl group. For 14aec, the
formation of vicinal halo-iodoalkenes occurred with exclusive anti-
stereospecificity, through an iodonium intermediate. The regiose-
lectivity of this dihalogenation is based on 13C NMR and is in
agreement with our previous publications12 and the literature.13
(Scheme 6). Bis(POC)-allylphosphonate synthon was obtained in
85% yield without any purification but need to be stored over 3 A
molecular sieves.
ꢁ
O
O
a
Cl
O
Cl
Cl
O
O
>98%
18
O
2.3. Preparation of N3-crotyl-6-substituted-furano-[2,3-d]-
pyrimidin-2-one moiety
O
O
O
O
P
b
P
OMe
O
OMe
85%
The
N3-crotyl-6-substituted-furano-[2,3-d]-pyrimidin-2-one
O
O
O
O
was obtained from 7 through a first Sonogashira reaction yielding
C5-substituted bases 15aef in 74e86%. After debenzoylation, the
C5-alkynyl bases 16aef were employed in the synthesis of fused
bicyclic pyrimidinone through copper-catalyzed 5-endo-dig cycli-
sation (Scheme 5). Compounds 16aef were then treated with CuI
and Et3N in MeOH at reflux,14 to give the desired bicyclic derivatives
17aef, respectively, in 70% yield.
19
Scheme 6. Reagent and conditions: (a) i-PrOH, NEt3, 0 ꢁC; (b) NaI, 18, MeOH, 70 ꢁC,
72 h.
2.5. Olefin cross metathesis reaction
Since their discovery, second-generation Grubbs systems have
evolved into a large family of catalysts.15 Due to the potential in-
stability of the C5-halovinyl-(10a,b) and C5-dihalovinyl (14aed)
moieties at solvent reflux, we have performed the olefin cross
metathesis reaction at milder conditions using [RuCl2(PCy3)(SI-
Pr)(indenylidene)] catalyst 20,16 which has been reported to be one
of the most efficient catalyst working at room temperature. Thus,
the C5-substituted N1-crotylated uracil analogues 10a,b and 14cef,
unprotected at N3 position, were then treated in anhydrous CH2Cl2
with a bis(POC) allylphosphonate 19 (1.3 equiv) and the [Ru]¼cat-
alyst 20 (5 mol%). The cross-metathesis products of major E- and
minor Z-isomers (Scheme 7) were separated by column chroma-
tography and pure 21aef (E-isomers) were obtained in moderate
yields (40e53%). Due to the 1H NMR signals superposition of ole-
finic protons, the E/Z stereochemistry at the double bond was
assigned from the 13C NMR by observing the signals of the allylic
O
R
O
N
R
O
N
I
NBz
NBz
NH
a
b
N
O
O
O
(74-86%)
91-96%
15a-f
16a-f
6
R
O
,
C3H7
R
=
d
a
N
c
,
C5H11
70-78%
N
O
e
b
C8H17
,
17a-f
c
f
carbons NCH2 at
with Goux et al.17 and our previous work4 (which reported a NCH2
at w48 ppm and 44 ppm for the E and Z isomers of similar system,
d 49.4 ppm for the E isomer. This is in agreement
Scheme 5. Reagent and conditions: (a) PdCl2(PPh3)2, ethynyl derivatives, CuI, NEt3,
DMF, rt, 16 h; (b) NH3/MeOH (7 N), 4 ꢁC, 16 h (c) CuI, Et3N, MeOH, 70 ꢁC, 5 h.
d
2.4. Preparation of bis(POC)-allylphosphonate synthon
respectively).
For the cross metathesis of the thermally more stable N1-cro-
tylated analogues 17aef with bis(POC)allyl phosphonate 19 at
reflux CH2Cl2, the thermally robust [RuCl2(PCy3)(IMes)(benzyli-
dene)] catalyst 2218 was chosen (Scheme 8). The reactions gave,
after purification, the E-isomers 23aef from 54 to 64% yields.
Bis(POC)-allylphosphonate (19), the key compound for olefin
cross metathesis with various alkenes, was obtained by reacting
dimethyl allylphosphonate with freshly prepared chloromethyl
isopropylcarbonate 18 in the presence of sodium iodine during 72 h

5322
A. Montagu et al. / Tetrahedron 67 (2011) 5319e5328
basic conditions, in ultrapure water (Scheme 9). Among various
N
N
tested basic conditions (sodium and potassium hydroxide, car-
bonates and hydrogenocarbonate), at different concentrations (1 M,
0.1 M, 0.05 M and 0.01 M), only hydrogenocarbonates failed to
remove the POC moiety. pH measurement showed that the POC
deprotection was initiated for pH ranging from 10.5 to 11.0. A 0.1 M
Elga water solution of sodium hydroxide was finally chosen to
achieve POC saponification at room temperature with the reaction
monitored by TLC.
Ph
Cl
Cl
Ru
PCy3
20
X
O
N
X
O
NH
NH
a
O
O
N
O
POCO
P
OPOC
10a,b
21a,b
Z-isomers
not isolated
O
Y
O
Y
O
Y
O
Y
NH
NH
X
X
NH
NH
a
X
X
O
N
O
O
N
O
a
O
N
O
N
O
HO
P
P
POCO
POCO
P
OH
OPOC
OPOC
14a-d
21a-f
24a-f
21c-f
Scheme 9. Reagent and conditions: (a) NaOH (0.1 M Elga water), rt, 5 h then Dowex
Scheme 7. Synthesis of C5-halovinyl- and C5-dihalovinyl-ANP derivatives. Reagent
and conditions: (a) bis(POC) allylphosphonate (1.3 equiv), [Ru]¼catalyst (5 mol%),
CH2Cl2, rt.
50W8 resin (Hþ ion exchange).
The solution containing ANP salt and an excess of base was then
neutralized through a Dowex 50W8 acidic ion exchange resin car-
tridge to give after dichloromethane extraction and evaporation of
all volatiles the pure desired acid ANPs 24aef in excellent yield
(quantitative). No further purification is required.
This chemical deprotection mimics the intracellular enzymatic
degradation of the POC moiety by an esterase as it leads to the
desired phosphonate salt and isopropanol, CO2 and formaldehyde
as degradation products (Scheme 10).
N
N
R
R
O
O
Cl
Cl
Ru
PCy3
Ph
N
N
22
Z-isomers
not isolated
O
P
N
N
O
O
+
a
POCO
OPOC
This approach shortens the usual pathway to acid phosphonate,
which is based on the harsh deprotection of a dialkylated allyl-
phosphonate with trimethylsilylbromide (TMSBr). In our case, no
by-product formation or partial deprotection was observed.
17a-f
23a-f
Scheme 8. Synthesis of furanopyrimidine ANP derivatives. Reagent and conditions: (a)
bis(POC) allylphosphonate (1.3 equiv), [Ru]¼ catalyst (5 mol%), CH2Cl2, reflux.
For all those reactions, we did not observe any olefin isomerised
by-product, which could hamper the metathesis efficiency as
reported in the literature.19
2.7. Biological activity screening
The title bis(POC) (E)-4-phosphono-but-2-en-1-yl acyclic nucle-
osides 21 and 23aef were subjected to a standard in vitro antiviral
screeningusingawidespectrumofviruses, inHELandHeLacelllines,
for Vaccinia (VV), Herpes Simplex Virus-1(KOS) (HSV-1), Herpes
Simplex virus-2(G) (HSV-2), Vesicular Stomatitis Virus (VSV),
Varicella-Zoster Virus (VZV TKþ and TKꢀ), Human Cytomegalovirus
and (AD-169 strain and Davis strain) in HEL cells and Coxsackie B4,
Respiratory syncytial in HeLa cells. None of the compounds exhibited
2.6. Chemical cleavage of POC group
To study the enzymatic phosphorylation mechanism of un-
saturated acyclonucleoside phosphonates by various human and
viral kinases, it is necessary to have in hand those compounds
under their acid form (and not the prodrug form). We thus run the
cleavage of the POC moiety by carbonate saponification under soft
O
O
O
1. base (2 equiv)
R
P
OH
R
P
O
O
O
+
-
2. resin H
OH
OH
+
OPOC
resin H
O
iPrOH
O
+
O
P
R
P
O
Na
+
Na
+
O
R
O
O
Na
O
OPOC
Decarboxylation
-
O
O
P
OH
+
Na
+
Na
R
P
O
O
R
O
OPOC
OPOC
CO
2
HCOH
Scheme 10. Mechanism of chemical cleavage of POC group.

A. Montagu et al. / Tetrahedron 67 (2011) 5319e5328
5323
any significant antiviral activity or cytotoxicity in HEL and Vero cells.
In order to estimate the influence of the prodrug moiety on those
results, the biological activity and toxicity of acid phosphonates
24aef were also investigated but these compounds were devoid of
antiviral activity. The nucleotide binding study of 24aef to (human)
UMP-CMPkinase, TMPkinaseandvacciniavirusTMPkinasewasthus
performed and no significant activities were observed.
and then washed with an aqueous saturated NH4Cl solution. The
aqueous phase was extracted with EtOAc and the combined organic
layers were dried over MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexanes, 3/7) to give compound 6 as col-
ourless oil (95%) as mixture of E/Z isomers (8/2). 1H NMR (400 MHz,
CDCl3)
d
7.90 (d, J¼7.8 Hz, 2H), 7.71 (s, 1H), 7.70 (s, 1H), 7.64 (t, J¼7.5,
Thus, the lack of activity of those compounds can likely be
explained by the lack of an efficient phosphorylation.
1H), 7.48 (t, J¼7.8 Hz, 2H), 5.94e5.77 (m, 1H), 5.56e5.41 (m, 1H),
4.41 (d, J¼7.2 Hz, 2H), 4.29 (d, J¼6.7 Hz, 2H), 1.74 (t, J¼9.5 Hz, 3H).
13C NMR (100 MHz, CDCl3)
d 167.8, 159.1, 149.3, 147.9, 147.8, 135.1,
3. Conclusion
133.4, 131.9, 130.9, 130.4, 129.1, 123.5, 122.3, 67.2, 50.1, 44.7, 17.7,
13.0. HRMS (MþH): found 397.0062 calculated for C15H14N2O3I
397.0049.
In summary, an expeditious and convergent route to various
bis(POC) (E)-4-phosphono-but-20-en-10-yl acyclic nucleosides
based on an olefin cross metathesis has been achieved. A chemical
cleavage of biolabile (POC) group was also successfully applied for
the development of new ANPs. This method offers two pathways to
biological interesting compounds: (1) an easy access to the bis(-
POC) prodrugs for biological evaluation in which the polar char-
acter at physiological pH is masked; (2) an easy access to the free
acid phosphonates for metabolic and pharmacokinetic evaluations,
by a soft chemical decomposition of the bis(POC) moiety.
4.4. N1-Crotyl-5-iodo-uracil (7)
The debenzoylation of 6 (100 mg) was carried out at 0 ꢁC
overnight in a methanol solution 7 N of ammonia (5 mL). After
evaporation of all the volatiles, the residue was purified by silica gel
column chromatography (EtOAc/hexanes, 1/1) to yield the desired
compound in 95% yield (E/Z, 8/2) as a white solid. Mp: 165 ꢁC
(CHCl3). 1H NMR (250 MHz, CDCl3)
d 9.23 (s, 1H), 7.60 (s, 1H),
5.88e5.74 (m, 2H), 5.56e5.44 (m, 2H), 4.42 (d, J¼7.5 Hz, 2H), 4.30
4. Experimental section
4.1. General
(d, J¼6.6 Hz, 2H), 1.80e1.75 (m, 3H). 13C NMR (63 MHz, CDCl3)
d
159.9, 150.1, 147.6, 132.4, 131.2, 123.3, 122.2, 67.3, 49.4, 43.9, 17.3,
12.6.
Commerciallyavailable chemicals were of reagent grade and used
as received. Acetonitrile was distilled from CaH2. The reactions were
monitored by thin layer chromatography (TLC) analysis using silica
gel plates (Kieselgel 60F254, E. Merck). Column chromatography was
performed on Silica Gel 60 M (40e63 mm, E. Merck). Melting points
are uncorrected and were measured on a Kofler apparatus. NMR
spectra were recorded on a Varian InovaUnity 400 NMR spectrom-
4.5. N1-Crotyl-5-acrylicmethylester-uracil (8)
To a DMF solution (60 mL) of N1-crotyl-5-iodo uracil 7 (850 mg,
2.91 mmol) were added triphenylphosphine (191 mg, 0.73 mmol),
Pd(OAc)2 (0.2 equiv) and triethylamine (1.18 g, 11.6 mmol). After
15 min stirring at 85 ꢁC, methyl acrylate was added and the solution
warmed at 85 ꢁC for 12 h. The mixture was filtrated on Celite and
the filtrate evaporated to dryness. Purification of residue by silica
gel column chromatography (EtOAc/hexanes, 1/1) gave compound
8 (675 mg, 2.72 mmol, 92%) as white crystals. 1H NMR (400 MHz,
eter. Chemical shifts (
solvent: references for CDCl3 were 7.26 ppm (1H NMR) and 77.16 ppm
13C NMR), for DMSO-d6 2.50 ppm (1H NMR) and 39.51 ppm (13
d) are given in parts per million relative to
(
C
NMR), for MeOD-d4 3.31 ppm (1H NMR) and 49.00 ppm (13C NMR).
For the 1H and 13C NMR spectra, TMS was used as the internal ref-
erence, whilefor the31P NMR spectra, H3PO4 wasused asthe external
reference (inner-capillary method). The resonance assignments are
based on peak integration, peak multiplicity and 2D correlation
experiments. Multiplets were assigned as s (singlet), d (doublet), t
(triplet), dd (doublet of doublet), m (multiplet), mc (centred multi-
plet) and br s (broad singlet). High Resolution Mass spectra were
performed by the Mass Spectrometry Center of Blaise Pascal Uni-
CDCl3)
d
8.72 (s, 1H), 7.41 (s, 1H), 7.40 (s, 1H), 7.28 (d, J¼15.8 Hz, 1H),
7.00 (d, J¼15.8 Hz, 1H), 5.98e5.78 (m, 1H), 5.57e5.44 (m, 1H), 4.46
(d, J¼7.5 Hz, 2H), 4.34 (d, J¼6.6 Hz, 2H), 3.77 (s, 3H), 1.78 (dd, J¼6.5,
1.4 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d 167.9, 161.1, 149.4, 145.5,
135.9, 133.2, 123.7, 122.5, 119.3, 109.9, 51.7, 50.0, 44.4, 17.8, 13.2.
HRMS (ESI): m/z [MþNa]þ calcd for C12H14N2NaO4: 273.0851,
found: 273.0852.
4.6. N1-Crotyl-5-acrylicacid-uracil (9)
ꢂ
versity (Program Masslynx 4.0) (Aubiere, France).
To a 1 M aqueous solution of sodium hydroxide (2 mL) was
added ester 8 (100 mg, 0.4 mmol). After 1 h stirring at room tem-
perature, a 6 N aqueous solution of hydrochloric acid was added
dropwise to precipitation. The mixture was filtrated and the solid
washed with water to pH 7 giving pure compound 9 (86 mg,
0.36 mmol, 91%) as a white powder. 1H NMR (400 MHz, CD3OD)
4.2. N3-Benzoyl-5-iodouracil (5)
To a solution of 5-iodouracil (1 g) in a 2/5 mixture of pyridine
and acetonitrile (21 mL) was added benzoyl chloride (3 equiv). The
reaction mixture was for stirred 24 h at room temperature. After
evaporation of all the volatiles, the residue was purified by silica gel
column chromatography (hexanes/EtOAc, 5/5 to 0/1) to give com-
d
7.95 (s, 1Hminor), 7.94 (s, 1Hmajor), 7.35 (d, J¼15.8 Hz, 1H), 6.88 (d,
J¼15.8 Hz, 1H), 5.87e5.78 (m, 1H), 5.63e5.50 (m, 1H), 4.47 (d,
J¼6.9 Hz, 2H), 4.34 (d, J¼6.3 Hz, 2H), 1.78 (d, J¼6.9 Hz, 2H), 1.73 (dd,
pound 5 (92%). 1H NMR (250 MHz, acetone-d6)
d 8.02 (m, 2H), 8.01
(s, 1H), 7.72 (t, J¼7.5 Hz, 1H), 7.56 (t, J¼7.5 Hz, 2H). 13C NMR
J¼6.4, 1.0 Hz, 2H). 13C NMR (100 MHz, CD3OD)
d 171.0, 164.0, 151.6,
(100 MHz, acetone-d6)
d
167.8, 159.1, 149.3, 147.9, 147.8, 135.1, 130.9,
149.0,138.7,132.7,125.7,119.3,110.4, 51.1, 49.7, 46.1,17.9,13.2. HRMS
(ESI): m/z [MþNa]þ calcd for C11H12N2NaO4: 259.0695, found:
259.0699.
130.4, 129.1, 67.2.
4.3. N3-Benzoyl-N1-crotyl-5-iodo-uracil (6)
4.7. N1-Crotyl-5-bromovinyl-uracil (10a)
To a DMF (12 mL) solution of N3-benzoyl-5-iodouracil (1 g) were
added K2CO3 (1.05 equiv) and crotyl bromide (1.05 equiv) under
argon atmosphere. After 3 h stirring at room temperature, the re-
action mixture was evaporated. The residue was diluted with EtOAc
A DMF solution (10 mL) of carboxylic acid 9 (120 mg, 0.51 mmol)
and potassium hydrogenocarbonate (178 mg, 1.78 mmol) was
stirred for 20 min at room temperature. To this mixture was added

5324
A. Montagu et al. / Tetrahedron 67 (2011) 5319e5328
N-bromosuccinimide (109 mg, 0.61 mmol). After 2 h stirring at
room temperature, volatiles were removed under reduced pressure
and residue diluted into water (10 mL). The solution was extracted
three times by CH2Cl2 (10 mL), and the combined organic layers
dried over MgSO4, filtrated and evaporated to dryness. Purification
of residue by silica gel column chromatography (EtOAc/hexanes, 1/
3) gave compound 10a (83 mg, 0.31 mmol, 60%) as a colourless oil.
4.11. N1-Crotyl-5-(ethynyl)uracil (13)
To a solution of 12 (2 mmol) in dry acetonitrile (24 mL) was
added tetrabutylammonium fluoride (1 equiv). The mixture was
stirred for 2 h at room temperature. Then acetonitrile is evaporated
under reduced pressure and the obtained crude is purified on
chromatography by using column silica packed in hexanes with
hexanes/ethyl acetate (8:2) as the eluant to yield product 13 as
1H NMR (400 MHz, CDCl3)
d
9.80 (s, 1H), 7.42 (d, J¼13.6 Hz, 1H), 7.14
(s, 1Hmajor), 7.13 (s, 1Hminor), 6.65 (d, J¼13.6 Hz, 1H), 5.87e5.75 (m,
1H), 5.56e5.46 (m,1H), 4.43 (d, J¼7.2 Hz, 2H), 4.31 (d, J¼6.5 Hz, 2H),
white solid (74%). 1H NMR (250 MHz, CDCl3)
d
8.50 (s, 1H, HNH), 7.49
0
0
(s, 1H, H6), 6.00e5.71 (m, 1H, H3 ), 5.60e5.38 (m, 1H, H2 ), 4.43
1.76 (d, J¼6.5 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
161.9, 149.8,
( d, J¼7.2 Hz, 2H, H1 minor), 4.40 (d, J¼7.0 Hz, 2H, H1 major), 3.20 (s,
0
0
1H, Halcyne), 1.77 (dd, J¼6.5, 1.6 Hz, 3H, H4 ). 13C NMR (100 MHz,
0
141.3, 132.5, 131.4, 128.0, 123.9, 122.8, 111.3, 109.9, 49.7, 44.3, 17.7,
13.1. HRMS (ESI): m/z [MþNa]þ calcd for C10H11N2NaO2Br:
271.0082, found: 271.0084.
CDCl3)
d 167.8, 159.1, 149.3, 147.9, 147.8, 133.4, 131.9, 123.5, 122.3,
105.7, 94.8, 59.7, 50.1, 44.7, 17.7, 13.0. HRMS (MþNa): found
213.0634 calculated for C10H10N2O2Na 213.0640.
4.8. N1-Crotyl-5-iodovinyl-uracil (10b)
A DMF solution (3 mL) of carboxylic acid 9 (100 mg, 0.42 mmol)
and potassium hydrogenocarbonate (148 mg, 1.48 mmol) was
stirred for 20 min at room temperature. To this mixture was added
N-iodosuccinimide (191 mg, 0.85 mmol). After 24 h stirring at room
temperature, volatiles were removed under reduced pressure and
residue diluted into water (10 mL). The solution was extracted three
times by CH2Cl2 (10 mL) and the combined organic layers dried
over MgSO4, filtrated and evaporated to dryness. Purification of
residue by silica gel column chromatography (EtOAc/hexanes,1/3)
gave compound 10b (72 mg, 0.23 mmol, 54%) as a colourless oil. 1H
4.12. General procedure 1 for dihalogenation of compound 13
5-Ethynyl-uracil derivatives 13 (0.5 mmol) was dissolved in
5 mL dry CH3CN and the mixture was cooled in an ice bath.
0.6 mmol (1.2 equiv) of a solution of the halogenating reagent (i.e.,
I2, IBr, ICl or Br2) in 1 mL dry CH3CN was added dropwise and the
mixture was stirred at 0 ꢁC until completion (typically 3 h, checked
by TLC). The reaction mixture was quenched at 0 ꢁC by a saturated
Na2S2O3 solution (2 mL) then extracted with AcOEt (3ꢂ10 mL). The
organic layer was washed with water (2ꢂ5 mL) and brine (10 mL)
then dried over MgSO4 and concentrated in vacuo to give the de-
sired di-halogenated compound. Pure analytical samples were
obtained using flash chromatography (hexanes/AcOEt, 1/1).
NMR (400 MHz, CDCl3)
d
9.90 (s, 1H), 7.37 (d, J¼14.5 Hz, 1H), 7.14 (s,
1Hmajor), 7.12 (s, 1Hminor), 6.96 (d, J¼14.6 Hz, 1H), 5.84e5.73 (m, 1H),
5.54e5.43 (m, 1H), 4.41 (d, J¼7.1 Hz, 2Hminor), 4.30 (t, J¼6.5 Hz,
2Hmajor), 1.74 (dd, J¼6.52, 0.9 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
162.0, 149.8,141.4,135.4,132.5, 131.4,123.9,122.8,112.8, 80.5, 49.7,
4.12.1. N1-Crotyl-5-(1,2-diiodovinyl)uracil (14a). Yellow crystals
44.3, 17.7, 13.1. HRMS (ESI): m/z [MþNa]þ calcd for C10H12N2NaO2I:
(87%). 1H NMR (250 MHz, CDCl3)
d 9.17 (s, 1H), 7.35 (s, 1H), 7.30 (s,
318.9944, found: 318.9945.
1H), 5.83 (dq, J¼12.9, 6.4 Hz, 1H), 5.62e5.42 (m, 1H), 4.45 (d,
J¼6.9 Hz, 2Hminor), 4.43(d, J¼6.4 Hz, 2Hmajor), 1.76 (dd, J¼6.5, 1.2 Hz,
4.9. N3-Benzoyl-N1-crotyl-5-[2-(trimethylsilyl)ethynyl]uracil
(11)
3H). 13C NMR (100 MHz, CDCl3)
d 168.0, 159.3, 149.5, 148.0, 147.9,
133.4, 132.0, 123.4, 122.2, 105.7, 94.8, 59.7, 50.1, 44.7, 18.1, 12.8.
HRMS (MþNa): found 467.0129 calculated for C10H10N2O2NaI
467.0122.
A deoxygenated DMF solution (30 mL) of derivative 6 (1 equiv),
Et3N (3 mL), (trimethylsilyl)acetylene (1.2 equiv), (PPh3)2PdCl2
(0.2 equiv) and CuI (0.2 equiv) was stirred at room temperature for
16 h under argon, then thoroughly evaporated until brown solid
foam. The crude was purified by silica gel column chromatography
with hexanes/ethyl acetate (8/2) to give 11 as a yellow solid (84%) as
4.12.2. N1-Crotyl-5-(1-bromo-2-iodovinyl)uracil (14b). Yellow crys-
tals (81%). 1H NMR (250 MHz, CDCl3)
d 8.33 (s, 1H), 7.35 (s, 1H), 7.11
(s, 1H), 5.86 (ddt, J¼14.1, 12.9, 3.8 Hz,1H), 5.64e5.41 (m, 1H), 4.42 (d,
J¼6.8 Hz, 2Hminor), 4.36 (d, J¼6.0 Hz, 2Hmajor), 1.77 (dd, J¼6.4, 1.4 Hz,
mixture of E/Z isomers. 1H NMR (250 MHz, CDCl3)
d 7.92 (s,1H), 7.89
3H). 13C NMR (100 MHz, CDCl3)
d 167.8, 159.1, 149.3, 147.9, 147.8,
(d, J¼1.4 Hz, 1H), 7.69e7.60 (m, 1H), 7.56 (s, 1H), 7.55e7.44 (m, 2H),
5.86 (dq, J¼13.0, 6.5 Hz, 1H), 5.53 (dtd, J¼15.1, 6.6, 1.6 Hz, 1H), 4.32
(d, J¼7.0 Hz, 2Hminor), 4.27 (d, J¼6.5Hz, 2Hmajor), 1.79 (dd, J¼6.5,
133.4, 131.9, 123.5, 122.3, 105.7, 94.8, 59.7, 50.1, 44.7, 17.7, 13.0. HRMS
(MþNa): found 420.0018 calculated for C10H10N2O2NaIBr 420.0022.
1.2 Hz, 3H), 0.22 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 167.8, 159.1,
4.12.3. N1-Crotyl-5-(1-chloro-2-iodovinyl)uracil (14c). Yellow crys-
tals (80%). 1H NMR (250 MHz, CDCl3)
d 8.98 (s, 1H), 7.41 (s, 1H), 6.90
149.3,147.9, 147.8, 135.1, 133.4, 131.9, 130.9, 130.4, 129.1, 123.5, 122.3,
105.7, 59.7, 50.1, 44.7, 17.7, 13.0, 0.15, 0.14.
(s, 1H), 5.87 (dq, J¼12.9, 6.5 Hz, 1H), 5.57 (dtd, J¼7.9, 6.4, 1.6 Hz, 1H),
4.43 (d, J¼6.9 Hz, 2Hminor), 4.39 (d, J¼6.5 Hz, 2Hmajor), 1.80 (dd,
4.10. N1-Crotyl-5-[2-(trimethylsilyl)ethynyl]uracil (12)
J¼9.2, 3.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 167.8, 159.1, 149.3,
147.9, 147.8, 133.4, 131.9, 123.5, 122.3, 105.7, 94.8, 59.7, 50.1, 44.7,
17.7, 13.0. HRMS (MþH): found 352.9540 calculated for
C10H11N2O2ClI 352.9554.
5-Substituted uracil analogue (100 mg) (11) was dissolved in
methanol solution 7 N of ammonia (5 mL). The mixture is cooled at
4
ꢁC for 16 h. After evaporation of solvents, the crude product was
purified by silica gel column with CH2Cl2/MeOH; 98/2, to give pure
4.12.4. N1-Crotyl-5-(1,2-dibromovinyl)uracil (14d). Yellow crystals
debenzoylated product 12. White solid (94%). 1H NMR (250 MHz,
(74%). 1H NMR (250 MHz, CDCl3)
d 8.37 (s, 1H), 7.37 (s, 1H), 6.86
CDCl3)
d
8.27 (s, 1H), 7.46 (s, 1H), 5.81 (dq, J¼12.9, 6.4 Hz, 1H),
(s, 1H), 5.84 (dd, J¼15.2, 6.5 Hz, 1H), 5.63e5.42 (m, 1H), 4.33
5.58e5.38 (m, 1H), 4.41 (d, J¼7.1 Hz, 2Hminor), 4.34 (d, J¼6.9 Hz,
(d, J¼6.4 Hz, 2Hminor), 4.29 (d, J¼6.0 Hz, 2Hmajor), 1.76 (dd, J¼9.2,
2Hmajor),1.76 (dd, J¼6.4,1.2 Hz, 3H), 0.23 (s, 9H). 13C NMR (100 MHz,
3.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 167.9, 159.0, 149.3, 147.9,
CDCl3)
d
167.8, 159.1, 149.3, 147.9, 147.8, 133.4, 131.9, 123.5, 122.3,
148.0, 133.4, 132.0, 123.4, 122.3, 105.6, 94.8, 59.9, 50.1, 44.7, 17.9,
12.8. HRMS (MþH): found 348.9195 calculated for C10H11N2O2Br2
253.0589.
105.7, 59.7, 50.1, 44.7, 17.7, 13.0, 0.15, 0.14. HRMS (MþH): found
263.3942 calculated for C13H18N2O2Si 263.3948.

A. Montagu et al. / Tetrahedron 67 (2011) 5319e5328
5325
4.13. General procedure 2 for Sonogashira reaction at C5
position of 6
J¼6.9 Hz, 2Hminor), 4.47 (d, J¼6.5 Hz, 2Hmajor), 2.34 (t, J¼6.4 Hz, 2H),
1.65 (d, J¼6.7 Hz, 3H), 1.39e1.35 (m, 4H), 1.35e1.17 (m, 8H), 0.99
(t, J¼12.1 Hz, 3H). 13C NMR (63 MHz, CDCl3)
d 164.52,163.88,152.93,
To 300 mL of deoxygenated Et3N was added 6 (1 equiv) followed
by alkyne (1.2 equiv), (PPh3)2PdCl2 (0.2 equiv) and CuI (0.2 equiv).
The suspension was stirred at room temperature for 16 h under
argon, evaporated thoroughly to brown foam. Chromatography was
performed by using column silica gel packed in hexanes with
hexanes/ethyl acetate (8:2) as eluant to give desired product.
151.02, 134.99, 131.38, 128.82, 128.59, 127.00, 104.91, 86.23, 81.48,
50.33, 31.65, 29.06, 28.87, 28.50, 22.94, 18.79, 17.03, 14.02. HRMS
(MþH): found 407.2330 calculated for C25H31N2O3 407.2335.
4.14. General procedure 3 for deprotection of benzoyl groups
The necessary amount of 5-substituted uracil derivatives is
dissolved in a solution of ammonia in methanol. The mixture is
cooled at 4 ꢁC for 16 h. After evaporation of solvents, the crude
product was purified by silica gel column with CH2Cl2/MeOH; 98/2
as eluant, to give pure debenzoyled product.
4.13.1. N3-Benzoyl-N1-crotyl-5-((4-propylphenyl)1-ethynyl)-uracil
(15a). White solid (78%). 1H NMR (250 MHz, CDCl3)
d 8.02e7.92 (m,
2H), 7.72e7.58 (m, 2H), 7.56e7.39 (m, 4H), 7.15 (d, J¼8.2 Hz, 2H),
5.85 (dq, J¼12.9, 6.5 Hz, 1H), 5.62e5.45 (m, 1H), 4.38 (d, J¼6.9 Hz,
0
2 minor), 4.32 (d, J¼6.4 Hz, 2Hminor), 2.59 (t, J¼7.3 Hz, 2H), 1.77 (d,
J¼6.5 Hz, 3H), 1.64 (m, J¼7.5 Hz, 2H), 0.94 (t, J¼7.3 Hz, 3H). 13C NMR
4.14.1. N1-Crotyl-5-(2(4-propylphenyl)-1-ethynyl)-uracil
(63 MHz, CDCl3)
d
164.52, 163.88, 152.93, 148.95, 148.26, 134.99,
(16a). White solid (95%). 1H NMR (250 MHz, CDCl3)
d 9.93 (s, 1H),
133.83, 133.43, 131.38, 128.82, 128.59, 127.31, 127.10, 127.00, 117.56,
97.62, 86.68, 71.97, 50.33, 38.12, 24.48, 17.03, 12.98. HRMS (MþH):
found 413.1848 calculated for C26H25N2O3 413.1865.
8.02e7.92 (m, 2H), 7.62 (s, 1H), 7.15 (d, J¼8.2 Hz, 2H), 5.85 (dq,
J¼12.9, 6.5 Hz, 1H), 5.62e5.45 (m, 1H), 4.38 (d, J¼6.9 Hz, 2Hminor),
4.34 (d, J¼6.4 Hz, 2Hmajor), 2.59 (t, J¼7.3 Hz, 2H), 1.77 (d, J¼6.5 Hz,
3H), 1.64 (m, J¼7.5 Hz, 2H), 0.94 (t, J¼7.3 Hz, 3H). 13C NMR (63 MHz,
4.13.2. N3-Benzoyl-N1-crotyl-5-((4-pentylphenyl)1-ethynyl)-uracil
CDCl3) d 165.18, 152.41, 149.51, 148.95, 133.83, 133.43, 127.31, 127.10,
(15b). White solid (86%). 1H NMR (250 MHz, CDCl3)
d
8.04e7.90 (m,
127.00, 117.56, 103.59, 92.47, 72.97, 49.88, 38.12, 24.48, 17.03, 12.98.
2H), 7.73e7.59 (m, 2H), 7.56e7.39 (m, 4H), 7.14 (d, J¼8.1 Hz, 2H),
HRMS (MþH): found 309.1585 calculated for C19H21N2O2 309.1603.
0
5.87 (dq, J¼12.9, 6.4 Hz, 1H), 5.63e5.47 (m, 1H, H2 ), 4.38
(d, J¼6.9 Hz, 2Hminor), 4.32 (d, J¼6.6 Hz, 2Hmajor), 2.60 (t, J¼7.4 Hz,
2H), 1.79 (d, J¼6.5 Hz, 3H), 1.37 (m, 4H), 1.20 (m, J¼7.5 Hz, 2H), 0.94
4.14.2. N1-Crotyl-5e((4-pentylphenyl)ethynyl)-uracil (16b). White
solid (97%). 1H NMR (250 MHz, CDCl3)
d 9.93 (s,1H), 7.51 (s,1H), 7.43
(t, J¼7.3 Hz, 3H). 13C NMR (63 MHz, CDCl3)
d
164.52, 163.88, 152.93,
(d, J¼8.2 Hz, 2H), 7.14 (d, J¼8.3 Hz, 2H), 5.81 (dq, J¼12.9, 6.4 Hz, 1H),
5.59e5.41 (m, 1H), 4.34 (d, J¼7.0 Hz, 2Hminor), 4.31 (d, J¼6.5 Hz,
2HmaJor), 2.67e2.52 (m, 2H), 1.75 (dd, J¼6.5, 1.4 Hz, 3H), 1.69e1.52
(m, 2H), 1.43e1.21 (m, 4H), 0.90 (t, J¼6.8 Hz, 3H). 13C NMR (63 MHz,
148.22, 134.99, 133.75, 133.54, 131.38, 128.82, 128.59, 128.10, 127.70,
127.00, 118.09, 97.62, 86.68, 71.97, 50.33, 36.41, 30.64, 30.02, 22.07,
17.03, 14.02. HRMS (MþH): found 441.5556 calculated for
C28H29N2O3 441.5559.
CDCl3) d 165.18, 152.41, 149.51, 148.19, 133.75, 133.54, 128.10, 127.70,
127.00, 118.09, 103.59, 92.47, 72.97, 49.88, 36.41, 30.64, 30.02, 22.94,
17.03, 14.02. HRMS (MþNa): found 359.1742 calculated for
C21H24N2O2Na 359.1735.
4.13.3. N3-Benzoyl-N1-crotyl-5-(4-phenyl-1-butynyl)uracil
(15c). White solid (80%). 1H NMR (250 MHz, CDCl3)
d 8.01e7.89 (m,
2H), 7.67 (dd, J¼10.5, 4.3 Hz, 1H), 7.52 (t, J¼7.6 Hz, 2H), 7.44 (s, 1H),
7.36e7.15 (m, 5H), 6.03e5.77 (m, 1H), 5.63e5.42 (m, 1H), 4.38
(d, J¼7.0 Hz, 2Hminor), 4.34 (d, J¼6.5 Hz, 2Hmajor), 2.93 (t, J¼8.1 Hz,
2H), 2.70 (t, J¼7.4 Hz, 2H), 1.81 (d, J¼6.7 Hz, 3H). 13C NMR (63 MHz,
4.14.3. N1-Crotyl-5-((4-phenyl)butynyl)-uracil (16c). White solid
(91%). 1H NMR (250 MHz, CDCl3)
d 9.93 (s, 1H), 8.01e7.89 (m, 2H),
7.67 (dd, J¼10.5, 4.3 Hz, 1H), 7.52 (t, J¼7.6 Hz, 2H), 7.44 (s, 1H),
6.03e5.77 (m, 1H), 5.64e5.42 (m, 1H), 4.37 (d, J¼7.0 Hz, 2Hminor),
4.32 (d, J¼6.5 Hz, 2Hmajor), 2.93 (t, J¼8.1 Hz, 2H), 2.70 (t, J¼7.4 Hz,
CDCl3) d 168.15, 161.12, 148.86, 145.02, 140.40, 135.05, 133.77, 133.36,
132.04, 131.31, 130.70, 130.59, 129.13, 126.42, 123.61, 122.45, 100.55,
95.00, 71.38, 60.89, 50.21, 46.81, 34.81, 21.82, 21.22, 17.85. HRMS
(MþNa): found 421.1519 calculated for C25H22N2O3Na 421.1528.
2H), 1.80 (d, J¼6.5 Hz, 3H). 13C NMR (250 MHz, CDCl3)
d 165.18,
153.51, 152.41, 141.00, 129.05, 128.65, 127.00, 126.53, 109.65, 96.48,
81.44, 49.88, 34.86, 19.95, 17.03. HRMS (MþNa): found 317.1277
calculated for C18H18N2O2Na 317.1266.
4.13.4. N3-Benzoyl-N1-crotyl-5-(1-pentynyl)uracil
solid (81%). 1H NMR (250 MHz, CDCl3)
8.08e7.95 (m, 2H), 7.63 (s,
(15d). White
d
1H), 7.42(t, J¼8.7 Hz, 3H), 5.75 (m, 1H), 5.58 (m, 1H), 4.80 (d,
J¼7.1 Hz, 1Hminor), 4.74 (d, J¼6.5 Hz, 2Hmajor), 2.37 (t, J¼6.4 Hz, 2H),
1.64 (m, 2H), 1.07 (t, J¼11.9 Hz, 3H). 13C NMR (250 MHz, CDCl3)
4.14.4. N1-Crotyl-5-pentynyl-uracil (16d). White solid (94%). 1H
NMR (250 MHz, CDCl3) d 9.84 (s, 1H), 7.63 (s, 1H), 5.70 (m, 1H), 5.55
(m, 1H), 4.81 (d, J¼7.1 Hz, 2Hminor), 4.74 (d, 2H, J¼6.4 Hz, 2Hmajor),
d
164.52, 163.88, 152.93, 151.02, 134.99, 131.38, 128.82, 128.59,
2.38 (t, J¼6.7 Hz, 2H), 1.64 (m, 2H), 0.95 (t, J¼12.0 Hz, 3H). 13C NMR
127.00, 104.91, 86.03, 83.83, 50.33, 22.71, 21.14, 17.03, 12.98. HRMS
(100 MHz, CDCl3) d 165.18, 153.51, 152.41, 127.00, 109.65, 92.49,
(MþNa): found 336.0901 calculated for C20H20N2O3Na 336.0906.
82.28, 49.88, 22.71, 21.14, 17.03, 12.98. HRMS (MþH): found
232.2789 calculated for C13H17N2O2 232.2790.
4.13.5. N3-Benzoyl-N1-crotyl-5-(1-heptynyl)uracil
solid (81%). 1H NMR (250 MHz, CDCl3)
8.05e7.95 (m, 2H), 7.65
(15e). White
d
4.14.5. N1-Crotyl-5-heptynyl-uracil (16e). White solid (93%). 1H
(s, 1H), 7.46 (t, J¼8.9 Hz, 3H), 5.76 (m, 1H), 5.58 (m, 1H), 4.82
(d, J¼7.0 Hz, 1Hminor), 4.75 (d, J¼6.6 Hz, 2Hmajor), 2.34 (t, J¼6.5 Hz,
2H), 1.65 (m, 2H), 1.58e1.41 (m, 4H), 1.00 (t, J¼12.1 Hz, 3H). 13C NMR
NMR (250 MHz, CDCl3) d 9.78 (s, 1H), 7.65 (s, 1H), 5.73 (m, 1H), 5.58
(m, 1H), 4.80 (d, J¼7.0 Hz, 2Hminor), 4.74 (d, 2H, J¼6.5 Hz, 2Hmajor),
2.34 (t, J¼6.4 Hz, 2H), 1.65 (m, 2H), 1.60e1.40 (m, 4H), 0.97
(63 MHz, CDCl3)
d
164.52, 163.88, 152.93, 151.02, 134.99, 131.38,
(t, J¼12.1 Hz, 3H). 13C NMR (63 MHz, CDCl3)
d 165.18, 153.51, 152.41,
128.82, 128.59, 127.00, 104.91, 86.23, 81.48, 50.33, 30.64, 28.21,
22.94, 18.79, 17.03, 14.02. HRMS (MþNa): found 364.4579 calcu-
lated for C22H24N2O3Na 364.4582.
127.00, 109.65, 93.12, 79.54, 49.88, 30.64, 28.21, 22.94, 18.79, 17.03,
14.02. HRMS (MþH): found 261.1585 calculated for C15H21N2O2
261.1603.
4.13.6. N3-Benzoyl-N1-crotyl-5-(1-decynyl)-uracil (15f). White solid
4.14.6. N1-Crotyl-5-decynyl-uracil (16f). White solid (94%). 1H NMR
(84%). 1H NMR (250 MHz, CDCl3)
d
7.99 (s, 1H), 7.68e7.56 (m, 2H),
(250 MHz, CDCl3)
d 9.85 (s, 1H), 7.44 (s, 1H), 5.76 (m, 1H), 5.59
7.44 (s, 1H), 7.39e7.33 (m, 2H), 5.76 (m, 1H), 5.59 (s, 1H), 4.51 (d,
(s, 1H), 4.51 (d, J¼6.9 Hz, 2Hminor), 4.47 (d, J¼6.5 Hz, 2Hmajor), 2.32

5326
A. Montagu et al. / Tetrahedron 67 (2011) 5319e5328
(t, J¼6.4 Hz, 2H), 1.65 (d, J¼6.7 Hz, 3H), 1.39e1.35 (m, 4H), 1.35e1.17
6.07 (s, 1H), 5.77 (dq, J¼21.5, 6.3 Hz, 1H), 5.66e5.45 (m, 1H), 4.57
(d, J¼6.8 Hz, 2Hminor), 4.51 (d, J¼6.3 Hz, 2Hmajor), 2.58 (t, J¼7.3 Hz,
2H), 1.82e1.52 (m, 5H), 1.24 (d, J¼12.3 Hz, 10H), 0.82 (t, J¼6.6 Hz,
(m, 8H), 0.97 (t, J¼12.1 Hz, 3H). 13C NMR (63 MHz, CDCl3)
d 165.18,
153.51, 152.41, 127.00, 109.65, 93.12, 79.54, 49.88, 31.65, 29.06,
28.87, 28.50, 22.94,18.79,17.03,14.0. HRMS (MþH): found 303.2061
calculated for C18H27N2O2 303.2073.
3H). 13C NMR (63 MHz, CDCl3)
d 163.72, 162.33, 152.74, 138.22,
127.00, 111.39, 103.63, 50.95, 31.88, 31.65, 29.26, 28.82, 26.11, 22.94,
17.03, 14.02. HRMS (MþH): found 303.2063 calculated for
C18H27N2O2 303.2073.
4.15. General procedure 4: bicyclic base synthesis
Linear compound 16 was solubilized in methanol and triethyl-
amine mixture (7/3) with CuI (0.2 equiv). The solution was heated
at 70 ꢁC for 5 h. After completion of the reaction (monitored by
TLC), solvents were removed under reduced pressure and the
obtained crude product was purified on silica gel (hexanes/ethyl
acetate, 4/6), to obtain a mixture of E (major) and Z (minor) isomers.
4.16. Bis(POC)allylphosphonate (19)
To an acetonitrile (23 mL) solution of dimethyl allylphosph-
onate (3.4 g, 22.6 mmo1), anhydrous sodium iodide (6.8 g,
45.2 mmol), chloromethyl isopropylcarbonate (18) (8.50 g,
56.7 mmol) was added. This solution was stirred at reflux for 72 h
under positive pressure of dry Ar. After cooling, this solution was
added to 220 mL of diethyl ether and washed by 45 mL of water.
The organic layer was dried over magnesium sulfate, evaporated
and purified by silica gel column chromatography (EtOAc/hex-
anes, 1/4) to give 5.75 g (16.9 mmol, 75%) of pure bis(POC)
allylphosphonate as a slightly yellow oil. 1H NMR (400 MHz,
4.15.1. N1-Crotyl-6-(4-n-propylphenyl)-2,3-dihydrofuro[2,3-d]pyr-
imidin-2-one (17a). White solid (77%). 1H NMR (250 MHz, CDCl3)
d
7.87 (s, 1H), 7.67 (d, J¼8.3 Hz, 2H), 7.25 (d, J¼7.9 Hz, 2H), 6.63 (s,
1H), 5.84 (dq, J¼12.9, 6.5 Hz, 1H), 5.71e5.55 (m, 1H), 4.64 (d,
J¼7.1 Hz, 2Hminor), 4.59 (d, J¼6.5 Hz, 2Hmajor), 2.69e2.56 (m, 2H),
1.84e1.73 (m, 3H),1.73e1.56 (m, 2H), 0.95 (t, J¼7.3 Hz, 3H). 13C NMR
CDCl3)
d
5.82e5.71 (m, 1H), 5.68 (dd, J¼11.6, 5.4 Hz, 2H), 5.65 (dd,
(63 MHz, CDCl3)
d
144.85, 138.47, 132.52, 129.07, 125.87, 124.95,
J¼11.6, 5.4 Hz, 2H), 5.30e5.22 (m, 2H), 4.94 (m, J¼6.2 Hz, 2H),
124.63, 108.43, 96.30, 52.79, 37.90, 24.33, 17.84, 13.75. HRMS
(MþH): found 309.1605 calculated for C19H21N2O2 309.1603.
2.74 (tdd, J¼22.8, 7.4, 1.1 Hz, 2H), 1.33 (d, J¼6.28 Hz, 12H). 13C
NMR (100 MHz, CDCl3) d 153.2, 125.7, 125.6, 121.3, 121.2, 84.1,
84.0, 73.2, 32.9, 31.5, 21.6. 31P NMR (162 MHz, CDCl3)
d
¼27.99.
4.15.2. N1-Crotyl-6-(4-n-pentylphenyl)-2,3-dihydrofuro[2,3-d]pyr-
HRMS (ESI): m/z [MþNa]þ calcd for C13H23NaO9Pr: 377.0977,
imidin-2-one (17b). White solid (72%). 1H NMR (250 MHz, CDCl3)
found: 377.0990.
d
7.87 (s, 1H), 7.67 (d, J¼8.3 Hz, 2H), 7.25 (d, J¼7.9 Hz, 2H), 6.63 (s,
1H), 5.84 (dq, J¼12.9, 6.5 Hz, 1H), 5.71e5.55 (m, 1H), 4.65 (d,
J¼6.9 Hz, 2H),4.59 (d, J¼6.5 Hz, 2H), 2.67e2.52 (m, 2H), 1.75 (dd,
J¼6.5, 1.4 Hz, 3H), 1.69e1.52 (m, 2H), 1.43e1.21 (m, 4H), 0.90 (t,
4.17. General procedure 5: cross metathesis between N3-
crotyl-C5-halo- and dihalovinyl-uracils and bis(POC)-
allylphosphonate
J¼6.8 Hz, 3H). 13C NMR (63 MHz, CDCl3)
d 171.44, 162.33, 151.54,
143.94, 143.62, 131.04, 128.08, 127.87, 127.00, 124.31, 124.10, 102.19,
50.95, 36.41, 30.64, 30.02, 22.94, 17.03, 14.02. HRMS (MþH): found
337.1928 calculated for C21H25N2O2 337.1916.
To a CH2Cl2 (25 mL/mmol) solution of N1-crotyl-C5-substituted
uracil 16 (1 equiv), bis(POC) allylphosphonate 19 (1.3 equiv) under
dry argon was added [RuCl2(PCy3)(SIPr)(indenylidene)] catalyst 20
(0.05 equiv). After 3 h or 3.5 h stirring at room temperature, the
solution was directly deposed on silica gel and purified (pure
CH2Cl2 then MeOH/CH2Cl2 1:200) to afford pure E compounds
(21aef).
4.15.3. N1-Crotyl-6-(2-phenyl-1-ethyl)-2,3-dihydrofuro[2,3-d]pyr-
imidin-2-one (17c). White solid (70%). 1H NMR (250 MHz, CDCl3)
d
8.01e7.89 (m, 2H), 7.67 (dd, J¼10.5, 4.3 Hz, 1H), 7.52 (t, J¼7.6 Hz,
2H), 7.44 (s, 1H), 6.60 (s, 1H), 6.03e5.77 (m, 1H), 5.64e5.42 (m, 1H),
4.37 (d, J¼7.0 Hz, 2Hminor) 4.32 (d, J¼6.4 Hz, 2Hmajor), 2.93 (t,
J¼8.1 Hz, 2H), 2.70 (t, J¼7.4 Hz, 2H), 1.80 (d, J¼6.5 Hz, 3H). 13C NMR
4.17.1. (E)-N1-(40-Bis(POC)-phosphinyl-but-20-enyl)-5-iodovinyl-ura-
cil (21a). Light yellow oil in 47% yield. 1H NMR (400 MHz, CDCl3)
(63 MHz, CDCl3)
d
163.72, 162.33, 148.01, 141.00, 138.22, 129.05,
d
8.78 (s, 1H), 7.42 (d, J¼14.6 Hz, 1H), 7.21 (s, 1H), 7.02 (d, J¼14.6 Hz,
128.65, 127.00, 126.53, 108.20, 103.63, 50.95, 32.83, 31.96, 17.03.
HRMS (MþH): found 295.1436 calculated for C18H19N2O2 295.1447.
1H), 5.82e5.60 (m, 6H), 4.94 (m, J¼6.3 Hz, 2H), 4.36 (t, J¼4.5 Hz,
2H), 2.77 (dd, J¼23.0, 5.6 Hz, 2H), 1.33 (d, J¼6.3 Hz, 12H). 13C NMR
(100 MHz, CDCl3)
d 161.4, 153.1, 149.4, 141.1, 135.2, 129.5, 129.4,
4.15.4. N1-Crotyl-6-propyl-2,3-dihydrofuro[2,3-d]pyrimidin-2-one
124.3, 124.2, 113.2, 84.2, 84.1, 80.8, 73.5, 49.3, 31.3, 29.9, 21.6. 31P
(17d). White solid (71%). 1H NMR (250 MHz, CDCl3)
d
7.80 (s, 1H),
NMR (162 MHz, CDCl3)
C20H28N2NaO11IP: 653.0373, found: 653.0355.
d
26.7. HRMS (ESI): m/z [MþNa]þ calcd for
6.05 (s, 1H), 5.74 (dq, J¼21.9, 6.1 Hz, 1H), 5.69e5.46 (m, 1H), 4.57 (d,
J¼6.7 Hz, 2Hminor), 4.50 (d, J¼6.3 Hz, 2Hminor), 2.32 (t, J¼6.6 Hz, 2H),
1.64 (m, 2H), 1.04 (t, J¼12.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
4.17.2. (E)-N1-(40-Bis(POC)-phosphinylbut-20-enyl)-5-bromovinyl-
d
163.72, 162.33, 151.55, 138.22, 127.00, 109.96, 103.63, 50.95, 33.19,
uracil (21b). Light yellow oil in 51% yield. 1H NMR (400 MHz, CDCl3)
20.39, 17.03, 13.57. HRMS (MþH): found 233.2809 calculated for
d
8.98 (s, 1H), 7.41 (d, J¼13.6 Hz, 1H), 7.20 (s, 1H), 6.67 (d, J¼13.6 Hz,
C13H17N2O2 233.2817.
1H), 5.69 (m, 6H), 4.93 (m, J¼6.2 Hz, 2H), 4.36 (t, J¼4.5 Hz, 2H), 2.76
(dd, J¼23.1, 5.5 Hz, 2H), 1.32 (d, J¼6.3 Hz, 12H). 13C NMR (100 MHz,
4.15.5. N1-Crotyl-6-pentyl-2,3-dihydrofuro[2,3-d]pyrimidin-2-one
CDCl3) d 161.4,153.1,149.5,141.1,129.6,129.4,127,124.3,124.2,111.6,
(17e). White solid (78%). 1H NMR (250 MHz, CDCl3)
d
7.82 (s, 1H),
110.1, 84.2, 84.1, 73.5, 49.2, 31.3, 29.9, 21.6. 31P NMR (162 MHz,
6.02 (s, 1H), 5.77 (dq, J¼21.5, 6.3 Hz, 1H), 5.66e5.45 (m, 1H), 4.56 (d,
J¼6.9 Hz, 2Hminor), 4.51 (d, J¼6.3 Hz, 2Hmajor), 2.34 (t, J¼6.4 Hz, 2H),
1.65 (m, 2H), 1.60e1.40 (m, 4H), 0.99 (t, J¼12.1 Hz, 3H). 13C NMR
CDCl3)
d
26.8. HRMS (ESI): m/z [MþNa]þ calcd for
C20H28N2NaO11BrP: 605.0512, found: 605.0495.
(63 MHz, CDCl3)
d
163.72, 162.33, 152.74, 138.22, 127.00, 111.39,
4.17.3. (E)-N1-(40-Bis(POC)phosphinylbut-20-enyl)-5-(1,2-diiodo-
103.63, 50.95, 31.88, 30.83, 25.86, 22.94, 17.03, 14.02. HRMS (MþH):
vinyl)uracil (21c). Yellow oil (51%). 1H NMR (400 MHz, CDCl3)
d 8.35
found 261.1601 calculated for C15H21N2O2 261.1603.
(s, 1H), 7.38 (s, 1H), 7.33 (s, 1H), 5.79e5.61 (m, 6H), 4.95 (m,
J¼6.3 Hz, 2H), 4.38 (t, J¼4.6 Hz, 2H), 2.78 (dd, J¼23.1, 5.5 Hz, 2H),
4.15.6. N1-Crotyl-6-octyl-2,3-dihydrofuro[2,3-d]pyrimidin-2-one
1.33 (d, J¼6.3 Hz, 12H). 13C NMR (100 MHz, CDCl3)
d 159.1, 153.0,
(17f). White solid (75%). 1H NMR (250 MHz, CDCl3)
d
7.84 (s, 1H),
149.7, 148.7, 140.4, 129.3, 129.2, 124.5, 124.4, 109.0, 116.58, 85.4,

A. Montagu et al. / Tetrahedron 67 (2011) 5319e5328
5327
84.2, 84.1, 73.4, 49.4, 31.3, 29.9, 21.6, 21.5. 31P NMR (162 MHz, CDCl3)
124.31, 124.10, 122.27, 102.19, 85.18, 84.27, 72.53, 72.22, 51.10, 36.41,
32.31, 30.64, 30.02, 22.94, 22.65, 22.44, 14.02. 31P NMR (163 MHz,
d
26.70. HRMS (MþNa): found 778.9355 calculated for
C20H27N2O11PNa 778.9340.
CDCl3)
d
27.04. HRMS (MþNa): found 671.6524 calculated for
C31H41N2O11NaP 671.6533.
4.17.4. (E)-N1-(40-Bis(POC)-phosphinylbut-20-enyl)-5-(1-iodo-2-bro-
movinyl)uracil (21d). Light yellow oil (40%). 1H NMR (400 MHz,
4.18.3. N1-(40-Bis(POC)-phosphinylbut-20-enyl)-6-(2-phenyl-1-
CDCl3)
d 8.26 (s, 1H), 7.42 (s, 1H), 7.15 (s, 1H), 5.85e5.61 (m, 6H),
ethyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one
(23c). Yellow oil
(58%). 1H NMR (400 MHz, CDCl3)
d
7.81 (s, 1H), 7.37e7.15 (m, 5H),
4.95 (m, J¼6.3 Hz, 2H), 4.42 (t, J¼4.6 Hz, 2H), 2.76 (dd, J¼23.1,
5.5 Hz, 2H), 1.36 (d, J¼6.3 Hz, 12H). 13C NMR (100 MHz, CDCl3)
6.09 (s, 1H), 5.95e5.58 (m, 6H), 4.90 (hept, J¼6.2 Hz, 2H), 4.67
(t, J¼4.7 Hz, 2H), 3.10e2.93 (m, 4H), 2.80 (dd, J¼22.7, 6.7 Hz, 2H),1.34
d
159.2, 153.2, 149.7, 148.7, 140.4, 129.3, 129.2, 124.5, 124.4, 109.0,
116.58, 85.4, 84.2, 84.1, 73.4, 49.4, 31.3, 29.9, 21.6, 21.5. 31P NMR
(400 MHz, CDCl3)
(d, J¼6.3 Hz, 12H). 13C NMR (100 MHz, CDCl3)
d 163.72, 162.33,
d
26.80. HRMS (MþNa): found 732.2228 calcu-
155.38, 154.95, 148.01, 141.00, 138.22, 131.59, 129.05, 128.65, 126.53,
122.27, 108.20, 103.63, 85.18, 84.27, 72.53, 72.22, 51.10, 33.25, 28.37,
lated for C20H27N2O11PNaIBr 732.2230.
22.65, 22.44. 31P NMR (163 MHz, CDCl3)
d
27.10. HRMS (MþNa):
4.17.5. (E)-N1-(40-Bis(POC)-phosphinylbut-20-enyl)-5-(1-iodo-2-
found 643.2049 calculated for C29H37N2O11NaP 643.2033.
chlorovinyl)uracil (21e). Light yellow oil (45%). 1H NMR (400 MHz,
4.18.4. N1-(40-Bis(POC)-phosphinylbut-20-enyl)-6-propyl-2,3-dihy-
CDCl3)
d 8.63 (s, 1H), 7.45 (s, 1H), 6.91 (s, 1H), 5.83e5.59 (m, 6H),
drofuro[2,3-d]pyrimidin-2-one (23d). Yellow oil (51%). 1H NMR
4.96 (m, J¼6.3 Hz, 2H), 4.41 (t, J¼4.6 Hz, 2H), 2.80 (dd, J¼23.2,
5.5 Hz, 2H), 1.35 (d, J¼6.3 Hz, 12H). 13C NMR (100 MHz, CDCl3)
(400 MHz, CDCl3)
d 7.84 (s, 1H), 6.07 (s, 1H), 5.88e5.59(m, 6H),
d
159.3, 152.9, 149.7, 148.9, 140.4, 129.3, 129.0, 124.5, 124.3, 109.0,
4.92 (m, J¼6.2 Hz, 2H), 4.65e4.55 (m, 2H), 2.71 (dd, J¼22.5,
7.3 Hz, 2H), 2.60 (t, J¼7.3 Hz, 2H), 1.62e1.54 (m, 2H), 1.40 (d,
J¼5.7 Hz, 12H), 1.05 (t, J¼6.6 Hz, 3H), 0.87 (dd, J¼8.5, 5.6 Hz, 3H).
116.58, 85.5, 84.7, 84.1, 73.6, 49.4, 31.3, 29.9, 21.4, 21.3. 31P NMR
(163 MHz, CDCl3)
d
26.70. HRMS (MþH): found 665.0179 calculated
13C NMR (100 MHz, CDCl3)
d 163.72, 162.33, 155.38, 154.95,
for C20H28N2O11PClI 665.0164.
151.55, 138.22, 131.59, 122.27, 109.96, 103.63, 85.18, 84.27, 72.53,
4.17.6. (E)-N1-(40-Bis(POC)-phosphinylbuten-20-yl)-5-(1,2-di-
72.22, 51.10, 32.75, 22.65, 22.44, 20.39, 13.57. 31P NMR (162 MHz,
bromovinyl)uracil (21f). Light yellow oil (48%). 1H NMR (400 MHz,
CDCl3)
C23H34N2O11P 540.4997.
d
27.09. HRMS (MþH): found 540.5002 calculated for
CDCl3)
d 8.54 (s, 1H), 7.40 (s, 1H), 6.86 (s, 1H), 5.79e5.61 (m, 6H),
4.93 (m, J¼6.3 Hz, 2H), 4.39 (t, J¼4.6 Hz, 2H), 2.77 (dd, J¼23.0,
5.6 Hz, 2H), 1.32 (d, J¼6.3 Hz, 12H). 13C NMR (100 MHz, CDCl3)
4.18.5. N1-(40-Bis(POC)-phosphinylbut-20-enyl)-6-pentyl-2,3-dihy-
drofuro[2,3-d]pyrimidin-2-one (23e). Yellow oil (49%). 1H NMR
d
159.1, 153.0, 149.7, 148.7, 140.4, 129.3, 129.2, 124.5, 124.4, 109.0,
116.58, 85.4, 84.2, 84.1, 73.4, 49.4, 31.3, 29.9, 21.6, 21.5. 31P NMR
(163 MHz, CDCl3)
(400 MHz, CDCl3) d 7.79 (s, 1H), 6.09 (s, 1H), 5.88e5.56 (m, 6H), 4.89
d
26.80. HRMS (MþNa): found 685.7984 calcu-
(sept, J¼6.3 Hz, 2H), 4.63e4.55 (m, 2H), 2.74 (dd, J¼22.7, 7.1 Hz, 2H),
lated for C20H27N2O11PNaBr2 685.7988.
2.61 (t, J¼7.4 Hz, 2H), 1.71e1.60 (m, 2H), 1.37e1.24 (m, 16H), 0.87
(dd, J¼8.5, 5.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 171.94, 160.04,
4.18. General procedure 6: cross metathesis between N3-
crotyl-bicyclic bases and bis(POC)-allylphosphonate
155.36, 153.09, 137.97, 130.27, 123.87, 108.21, 98.57, 84.11, 73.42,
52.00, 31.44, 31.13, 30.05, 28.21, 26.40, 22.26, 21.59, 13.88. 31P NMR
(163 MHz, CDCl3)
for C25H38N2O11P 573.2213.
d
27.06. HRMS (MþH): found 573.2208 calculated
To a CH2Cl2 (25 mL/mmol) solution of N1-crotyl-C5-substituted
uracil 17 (1 equiv) and bis(POC) allylphosphonate (1.3 equiv) 19
under dry argon was added [RuCl2(PCy3)(IMes)(benzylidene)] cat-
alyst 22 (0.05 equiv). After 16 h stirring at reflux, the solution was
cooled and then directly deposed on silica gel chromatography and
purified (pure CH2Cl2 then MeOH/CH2Cl2 1:200) to afford pure E
compounds (23aef).
4.18.6. N1-(40-Bis(POC)-phosphinylbuten-20-yl)-6-octyl-2,3-dihy-
drofuro[2,3-d]pyrimidin-2-one (23f). Yellow oil (51%). 1H NMR
(400 MHz, CDCl3) d 7.79 (s, 1H), 6.09 (s, 1H), 5.88e5.57 (m, 6H), 4.89
(m, J¼6.3 Hz, 2H), 4.74 (t, J¼4.5 Hz, 2H), 2.75 (dd, J¼22.7, 7.2 Hz, 2H),
2.61 (t, J¼7.4 Hz, 2H), 1.70e1.59 (m, 2H), 1.27 (m, 22H), 0.85
(t, J¼6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 171.95,160.08, 155.36,
4.18.1. N1-(40-Bis(POC)-phosphinylbut-20-enyl)-6-(4-n-propyl-
phenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one (23a). Yellow oil
153.09, 137.92, 130.28, 123.88, 108.21, 98.54, 84.11, 73.43, 52.01,
31.77, 31.44, 30.05, 29.28, 28.82, 28.26, 26.73, 22.59, 21.60,14.05. 31P
(52%). 1H NMR (400 MHz, CDCl3)
d
7.97 (s, 1H), 7.69 (d, J¼8.2 Hz,
NMR (163 MHz, CDCl3)
calculated for C28H44N2O11P 615.2683.
d
27.07. HRMS (MþH): found 615.2682
2H), 7.35e7.18 (m, 2H), 6.71 (s, 1H), 5.98e5.58 (m, 6H), 4.95 (m,
J¼6.3 Hz, 2H), 4.38 (t, J¼4.6 Hz, 2H), 2.81 (dd, J¼22.7, 6.6 Hz, 2H),
2.64 (t, J¼7.6 Hz, 2H), 1.68 (dq, J¼14.6, 7.3 Hz, 2H), 1.32 (d, J¼6.3 Hz,
12H), 0.97 (t, J¼7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 171.44,
4.19. General procedure 7: deprotection of POC biolabile
group via chemical cleavage
162.33, 155.38, 154.95, 151.54, 144.56, 143.62, 131.59, 130.92, 127.57,
127.18, 124.39, 124.18, 122.27, 102.19, 85.18, 84.27, 72.53, 72.22,
51.10, 38.12, 32.31, 24.48, 22.65, 22.44, 12.98. 31P NMR (400 MHz,
To compounds 21aef (20 mg) was added a 0.1 M Elga water
solution of sodium hydroxide (4 mL, 0.4 mmol). After 5 h stirring
at room temperature, the solution was passed through a cartridge
of acidic ion exchange DOWEX 50W8 resin. The neutral solution
was washed two times with CH2Cl2 (2 mL) and evaporated to
dryness to give pure compound 24aef (generally quantitative
reaction).
CDCl3)
d
27.00. HRMS (MþNa): found 643.2049 calculated for
C29H37N2O11NaP 643.2033.
4.18.2. N1-(40-Bis(POC)-phosphinylbut-20-enyl)-6-(4-n-pentyl-
phenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one (23b). Yellow oil
(55%). 1H NMR (400 MHz, CDCl3)
d
7.96 (s, 1H), 7.69 (d, J¼8.2 Hz,
2H), 7.27 (d, J¼8.1 Hz, 2H), 6.70 (s, 1H), 5.97e5.61 (m, 6H), 4.93 (m,
J¼6.3 Hz, 2H), 4.72e4.62 (t, J¼4.6 Hz), 2.81 (dd, J¼22.7, 6.6 Hz, 2H),
2.71e2.59 (m, 2H), 1.65 (dt, J¼15.1, 7.5 Hz, 2H), 1.41e1.24 (m, 16H),
4.19.1. (E)-N1-(40-Dihydroxyphosphinylbut-20-enyl)-5-iodovinyl-ura-
cil (24a). Amorphous solid (97%). 1H NMR (400 MHz, CD3OD)
d 7.56
0.92 (t, J¼6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
171.44, 162.33,
(s,1H), 7.23 (d, J¼14.6 Hz,1H), 7.02 (d, J¼14.6 Hz,1H), 5.72e5.60 (m,
155.38, 154.95, 151.54, 143.94, 143.62, 131.59, 131.04, 128.08, 127.87,
2H), 4.27 (t, J¼4.6 Hz, 2H), 2.49 (dd, J¼21.7, 6.9 Hz, 2H). 13C NMR

5328
A. Montagu et al. / Tetrahedron 67 (2011) 5319e5328
(100 MHz, CD3OD)
d
164.2, 151.8, 144.6, 137.6, 129.2, 129.1, 127.8,
Acknowledgements
0
127.7, 113.7, 78.6, 50.5 (2C, C1 ), 33.4, 32.0. 31P NMR (163 MHz,
CD3OD)
398.9607, found: 398.9620.
d
23.8. HRMS (ESI): m/z [MþH]þ calcd for C10H13N2O5IP:
For the portion of the work performed at the University of St
Andrew, funding for this project was provided by the EC through
the seventh framework program (grant CP-FP 211468-2 EUMET).
We thank Umicore AG for generous gift of materials. We thank also
Pr. Balzarini, Pr. Snoeck and Pr. Andreï (Rega Institute, Leuven) for
the biological evaluation of these compounds. We thank Dr. C. El
Amri (Institut Monod, UPMC) for the nucleotide binding study to
various human and viral nucleos(t)ide kinases. SPN is a Royal
Society-Wolfson Research Merit Award holder.
4.19.2. (E)-N1-(40-Dihydroxyphosphinylbut-20-enyl)-5-bromovinyl-
uracil (24b). Amorphous solid (quantitative). 1H NMR (400 MHz,
CD3OD)
5.84e5.66 (m, 2H), 4.35 (t, J¼4.5 Hz, 2H), 2.57 (dd, J¼21.9, 6.6 Hz,
2H). 13C NMR (100 MHz, CD3OD)
164.1, 151.8, 144.5, 130.2, 129.3,
d
7.63 (s, 1H), 7.31 (d, J¼13.6 Hz, 1H), 6.77 (d, J¼13.6 Hz, 1H),
d
129.2, 127.6, 127.5, 112.1, 108.8, 50.5, 33.3, 31.9. 31P NMR (163 MHz,
CD3OD)
350.9745, found: 350.9760.
d
24.1. HRMS (ESI): m/z [MþH]þ calcd for C10H13N2O5BrP:
References and notes
4.19.3. (E)-N1-(40-Dihydroxyphosphinylbut-20-enyl)-5-(1,2-diiodo-
1. De Clercq, E.; Holy, A. Nature 2005, 4, 928e940.
2. De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini, J.; Maudgal, P. C.
Nature 1986, 323, 464e467.
vinyl)uracil (24c). Amorphous yellow solid (91%). 1H NMR
ꢀ
(400 MHz, CD3OD)
4.30 (m, 2H), 2.49 (m, 2H), 1.77 (s, 3H). 13C NMR (100 MHz, CDCl3)
166.8, 152.9, 142.5, 129.7, 126.6, 111.4, 69.7, 50.1, 25.3, 12.2. 31P
NMR (163 MHz, CDCl3)
d 7.28 (s, 1H), 7.23 (s, 1H), 5.70e5.57 (m, 2H),
3. Balzarini, J.; Holy, A.; Jindrich, J.; Naesens, L.; Snoeck, R.; Schols, D.; De Clercq, E.
Antimicrob. Agents Chemother. 1993, 37, 332e338.
ꢂ
4. (a) Kumamoto, H.; Topalis, D.; Broggi, J.; Pradere, U.; Roy, V.; Berteina-Raboin,
d
S.; Nolan, S. P.; Deville-Bonne, D.; Andrei, G.; Snoeck, R.; Garin, D.; Crance, J. M.;
Agrofoglio, L. A. Tetrahedron 2008, 64, 3517e3526; (b) Roy, V.; Mieczkowski, A.;
Topalis, D.; Berteina-Raboin, S.; Deville-Bonne, D.; Nolan, S. P.; Agrofoglio, L. A.
Synthesis 2008, 2127e2133.
d
23.58. HRMS (MþNa): found 546.9895
calculated for C10H11N2O5PNaI2 546.9897.
5. Topalis, D.; Pradere, U.; Roy, V.; Caillat, C.; Azzouzi, A.; Broggi, J.; Snoeck, R.;
Andrei, G.; Lin, J.; Eriksson, S.; Alexandre, J. A. C.; El-Amri, C.; Deville-Bonne, D.;
Meyer, P.; Balzarini, J.; Agrofoglio, L. A. J. Med. Chem. 2011, 54, 222e232.
6. Oliyai, R.; Yuan, L.-C.; Dahl, T. Nucleosides, Nucleotides Nucleic Acids 2001, 20,
1295e1298.
4.19.4. (E)-N1-(40-Dihydroxyphosphinylbuten-20-yl)-5-(1-bromo-2-
iodo vinyl)uracil (24d). Light yellow solid (97%). 1H NMR
(400 MHz, CD3OD)
d
7.77 (d, J¼6.3 Hz, 1H), 7.15 (s, 1H), 5.86e5.67
(m, 2H), 4.34e4.30 (m, 2H), 2.63 (dd, J¼21.5, 6.0 Hz, 2H). 13C NMR
7. Ripin, D. H. B.; Teager, D.; Fortunak, J.; Basha, K.; Bivins, N.; Boddy, C. N.; Byrn, S.;
Catlin, K.; Houghton, S. R.; Jagadeesh, S. T.; Kumar, K. A.; Melton, J.; Muneer, K.; Rao,
L. N.; Rao, R. V.; Reddy, N. G.; Reddy, R. M.; Shekar, K. C.; Silverton, T.; Smith, D. T.;
Stringham, R.; Talley, F.; Williams, A. Org. Process Res. Dev. 2010, 14, 1194e1201.
8. Scholl, M.; Sanders, D. P.; Toste, F. D.; Trnka, T. M.; Love, J. A.; Goldberg, S. D.;
Chatterjee, A. K.; Grubbs, R. H.; Morgan J. P. Patent PCT/US02/10196; WO02/079126.
9. Jones, A. S.; VerhelstG; Walker, R. T. Tetrahedron Lett. 1979, 45, 4415e4418.
10. For reviews on Pd(0) cross-coupling reactions, see: (a) Sonogashira, K.; Tohda,
Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467e4770; (b) Sonogashira, K.
Comprehensive Organic Synthesis; Pergamon: New York, NY, 1991; p 521; (c)
Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980,
627e630; (d) Agrofoglio, L. A. Curr. Org. Chem. 2006, 10, 333e362.
11. Petriccini, E.; Radi, M.; Corelli, F.; Botta, M. Tetrahedron Lett. 2003, 44, 9181e9184.
12. (a) Escuret, V.; Aucagne, V.; Joubert, N.;Durantel, D.;Rapp, K. L.; Schinazi, R. F.; Zoulim,
F.; Agrofoglio, L. A. Bioorg. Med. Chem. 2005,13, 6015e6024; (b) Joubert, N.; Amblard,
F.; Rapp, K. L.; Schinazi, R. F.; Agrofoglio, L. A. Tetrahedron 2008, 64, 4444e4452.
13. (a) Bellina, F.; Colzi, F.; Mannima, L.; Rossi, R.; Viel, S. J. Org. Chem. 2003, 68,
10175e10177; (b) Heasly, V. L.; Buczala, D. M.; Chappell, A. E.; Hill, D. J.; Whi-
senand, J. M.; Shellhamer, D. F. J. Org. Chem. 2002, 67, 2183e2187.
(100 MHz, CDCl3)
d 160.0, 151.3, 141.2, 130.5, 129.5, 127.1, 103.8,
69.7 50.4, 26.3. 31P NMR (163 MHz, CDCl3)
d 24.15. HRMS
(MþNa): found 499.9999 calculated for C10H11N2O5PNaIBr
499.9992.
4.19.5. (E)-N1-(40-Dihydroxyphosphinylbut-20-enyl)-5-(1-chloro-2-
iodovinyl)uracil (24e). Amorphous yellow solid (94%). 1H NMR
(400 MHz, CD3OD)
d 7.87 (s, 1H), 6.91 (s, 1H), 5.84e5.68 (m, 2H),
4.44e4.35 (m, 2H), 2.70 (dd, J¼22.6, 6.3 Hz, 2H). 13C NMR (100 MHz,
CDCl3) d 162.7, 152.5, 144.5, 130.0, 128.1, 109.7, 103.8, 69.7, 52.1, 33.3.
31P NMR (163 MHz, CDCl3)
d
23.93. HRMS (MþNa): found 455.5412
calculated for C10H11N2O5PNaICl 455.5415.
4.19.6. (E)-N1-(40-Dihydroxyphosphinylbut-20-enyl)-5-(1,2-di-
bromovinyl)uracil (24f). Amorphous light yellow solid (99%). 1H
14. (a) Robins, M. J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854; (b) Robins, M. J.; Barr, P. J.
Tetrahedron Lett. 1981, 22, 421e424.
15. Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40, 45e52.
NMR (400 MHz, DMSO)
d 11.65 (s, 1H), 7.98 (s, 1H), 6.86 (s, 1H),
5.83e5.69 (m, 2H), 4.37 (m, 2H), 2.63 (dd, J¼21.0, 6.3 Hz, 2H). 13C
16. Boeda, F.; Clavier, H.; Nolan, S. P. Chem. Commun. 2008, 2726e2740.
ꢀ
17. Goux, C.; Sigismondi, S.; Sinou, D.; Perez, M.; Moreno-Manas, M.; Pleixats, R.;
NMR (100 MHz, DMSO)
d 162.0, 152.1, 146.1, 129.4, 127.1, 103.8,
69.7, 96.6, 50.6, 33.0. 31P NMR (163 MHz, CDCl3)
d 24.31. HRMS
Villarroya, M. Tetrahedron 1996, 52, 9521e9534.
18. Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem. Soc. 1999, 121,
2674e2678.
(MþNa): found 452.9987 calculated for C10H11N2O5PNaBr2
452.9981.
19. Cadot, C.; Dalko, P. I.; Cossy, J. Tetrahedron Lett. 2002, 43, 1839e1841.