A new route to acyclic nucleosides via palladium-mediated allylic alkylation and cross-metathesis

Article abstract of DOI:10.1016/j.tetlet.2003.10.029

A method for the syntheses of E-unsaturated acyclic nucleosides via a combination of palladium-catalyzed allylic alkylation and ruthenium-based cross metathesis is described. This approach provides a concise, efficient and reliable route to new nucleoside

Full text of DOI:10.1016/j.tetlet.2003.10.029

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9177–9180
A new route to acyclic nucleosides via palladium-mediated allylic
alkylation and cross-metathesis
Franck Amblard,a Steven P. Nolan,b Isabelle Gillaizeaua and Luigi A. Agrofoglioa,*
aInstitut de Chimie Organique et Analytique, UMR CNRS 6005, Universite´ d’Orle´ans, 45067 Orle´ans, France
bDepartment of Chemistry, University of New Orleans, New Orleans, LA 70148 USA
Received 19 August 2003; revised 2 October 2003; accepted 6 October 2003
Abstract—A method for the syntheses of E-unsaturated acyclic nucleosides via a combination of palladium-catalyzed allylic
alkylation and ruthenium-based cross metathesis is described. This approach provides a concise, efficient and reliable route to new
nucleoside analogues.
© 2003 Elsevier Ltd. All rights reserved.
Interest in acyclic nucleosides began in the mid-1970s
when Acyclovir (ACV) was first reported as a potent
anti-herpes drug.1 The unprecedented selectivity of
ACV as an anti-viral drug and the subsequent clarifica-
tion of its mode of action towards virally coded
enzymes provided massive impetus for further synthesis
of related compounds and investigation of their bio-
chemical fate.2 The use of palladium-catalyzed allylic
alkylation3 (Tsuji–Trost reaction) and olefin cross-
metathesis4 have proven to be powerful and versatile
procedures which have gained recognition due to their
broad scope. To the best of our knowledge, a combina-
tion of these two important reaction types has not yet
been employed in the synthesis of unsaturated acyclic
nucleosides. To date, only one application by Freer et
al.5 has reported the chemical synthesis of acyclic
nucleosides by utilizing a palladium-catalyzed allyla-
tion. In general such unsaturated acyclic nucleosides
can be synthesized from a protected glyceraldehyde
using a Wittig–Horner–Emmons reaction; nevertheless,
the Z-a,b-unsaturated ester was obtained exclusively,
without any trace of E-isomer.6 Thus, as part of our
drug discovery program, this contribution reports a
straightforward synthesis of hitherto unknown unsatu-
rated acyclic nucleosides by a tandem catalytic process
involving a ruthenium-based metathesis as well as a
palladium-catalyzed allylic alkylation.
bases, which could be obtained from alkylation of the
heterocyclic ring with 1,2-dibromoproane followed by
dehydrobromination.7 Nevertheless, the reported poor
yields prompted us to examine the Pd(0)-catalyzed reac-
tion of allylic acetate with various pyrimidines (Table
1).
According to the literature,8 reaction of uracil 2a with
allyl acetate 1 in the presence of freshly prepared
Pd(PPh3)4 and dppf [(1,1%-bis(diphenylphosphinofero-
cene)], led to a 4/1 mixture of N-1 monoallylated 3a
and the N-1,N-3-diallylated analogue in a yield of 45%
(entry 1). When using 6-methyluracil 2b, only the N-1
allylation to 3b was observed in a 55% yield (entry 2).
Table 1. Palladium-catalyzed allylation of pyrimidines
Entry
Nucleobase
X
Y
Product
Yield (%)
1
2
3
4
2a
2b
2c
2d
OH
OH
OH
NHBz
H
CH3
I
3a
3b
3c
3d
45a
55
35
45
The first step of this chemical pathway consists in the
regioselective synthesis of N-allyl derivatives of nucleo-
H
Keywords: palladium-mediated allylic alkylation; cross-metathesis;
acyclonucleosides.
a Total yield: formation of a 4/1 mixture of monoallylated and
* Corresponding author. E-mail: luigi.agrofoglio@univ-orleans.fr
diallylated compounds separable by chromatography.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.029

9178
F. Amblard et al. / Tetrahedron Letters 44 (2003) 9177–9180
Table 3. Synthesis of acyclic nucleosides via cross-
metathesis reaction between protected diol 9 and allylic
base 3
Application of the same procedure with iodouracil 2c
and N-4-benzoylated cytosine 2d afforded selectively
the monoallylated products 3c9 and 3d in 35 and 45%
yields, respectively (entries 3 and 4).
The Pd-catalyzed coupling of an allylic acetate with a
purine base can, in principle, lead to a mixture of N-7
and N-9 regioisomers. This problem, which is classic in
Vorbru¨ggen coupling of purines with sugars,10 has been
recognized only recently in Pd(0)-catalyzed couplings.
Gundersen et al.11 reported that the coupling of purines
with allylic esters led to a mixture of regioisomers, the
ratio of which could be modified by incorporation of
larger groups at the 6-position of the purine. The best
compromise, in agreement with Crimmins’ work,12 was
obtained with a 6-chloropurine analogue 4 or a 6-
aminocyclopropylpurine derivative 5 leading, in our
hands, to a mixture of N-9 isomer 6 and N-7 isomer 6%
1
(determined by H NMR) in a 3/2 ratio and 7 as the
only N-9 derivative, respectively (Table 2).
Entry
Compound
X
Y
H
Product
Yield (%)
With these allylic heterocycles in hand and with the aim
of synthesizing acyclic nucleosides using an efficient
procedure, we turned our attention to establishing the
best conditions for a cross-metathesis reaction. In this
area, we13 and others14 have mainly used a ruthenium-
mediated metathesis for the synthesis of carba- or
labelled nucleosides. Based on our previous results illus-
trating the user-friendly character of ruthenium-carbene
species bearing one imidazol-2-ylidene ligand 815 and its
proven tolerance towards an array of polar groups
(particularly the amide group), we were prompted to
probe the performance of 8 in this specific application.
1
2
3
4
3a
3b
3c
3d
OH
OH
OH
NHBz
10a
78
50
56
57
CH3 10b
I
H
10c
10d
the target acyclic nucleosides 10a–d,17 respectively, in
good to moderate yields (Table 3). No self-metathesis
products were observed. The cross-metathesis product
stereochemistry was confirmed by H NMR. Only the
E-stereoisomer was obtained.
1
Thus, reacting the protected allylic diol16 9 with allylic
pyrimidine derivatives 3a–d in the presence of catalytic
amounts of 8 in refluxing dichloromethane delivered
Even more challenging was the cross-metathesis of pro-
tected allylic diol 9 with allylic purine 6, due to the
presence of several tertiary basic nitrogens. The toler-
ance of the ruthenium metathesis catalyst towards basic
tertiary amines is less understood as most examples
reported in the literature use a deactivated nitrogen
(amide, carbamate, sulfonamide).4 Tertiary basic nitro-
gen probably interferes with the catalytic cycle by coor-
dination to the ruthenium. To circumvent this problem,
the deactivation of the basic nitrogen of purine is
imperative before the final metathesis step. However,
only a few literature reports describe and/or propose a
solution to this problem. It is noteworthy to mention
that no previous report has appeared tackling this issue
with the purine system. To address this issue, we either
used PTSA18 (p-toluenesulfonic acid) to form a tosylate
salt or protonated the basic nitrogens with HCl.19 How-
ever, after optimization, the addition of HCl to 6 gave
the best results, leading to the purine acyclonucleoside
1120 (14%) in the presence of starting material (Scheme
1).
Table 2. Palladium-catalyzed allylation of purines
Entry
Nucleobase
X
Ratio N-9/N-7a Yield (%)b
1
2
4
5
Cl
6:6% 3/2
7:7% 1/0
80
60
These results led us to investigate an alternative syn-
thetic route, utilizing first the cross-metathesis step
leading to an allylic acetate which then could be used in
a Regioisomers separable by chromatography.
b Total yield for the two regioisomers.

F. Amblard et al. / Tetrahedron Letters 44 (2003) 9177–9180
9179
Scheme 3. Deprotection step.
Scheme 1. Synthesis of acyclic nucleosides via cross-metathe-
sis reaction in the purine series.
developed based on two metal-mediated transforma-
tions: a palladium(0) catalyzed coupling of a nucleo-
base and an allylic acetate side chain and a ruthenium-
based cross-metathesis. Extension of this strategy to the
preparation of other systems, which may represent a
new class of drugs and/or tools for chemical biology, is
currently in progress in our laboratories.
the palladium-mediated allylic allylation of a nucleo-
base (Scheme 2).
Thus the straightforward cross-metathesis of 9 with
allyl acetate 1 in the presence of catalyst 8 afforded the
expected acetate 1221 in 65% yield; it is important to
mention here that some homodimeric compounds
obtained from the self-metathesis of 9 and of 1, respec-
tively, were isolated. Subsequent treatment of 12 with
6-chloropurine 4 under Tsuji–Trost Pd(0) allylation
conditions afforded a 1:1 mixture of N-9/N-7 isomers
11 and 11% (easily separated by column chromatography
on silica gel) in an overall yield of 37%. Meanwhile, by
applying the Pd(0) allylation conditions to the 6-
aminocyclopropyl purine 5, the N-9 regioisomer 13 was
the only product isolated in moderate yield (30%).
Finally, to complete the synthesis of unsaturated acyclic
nucleosides, the acetonide protecting groups of 10a–d,
11 and 13 were removed by treatment with a mixture of
TFA/H2O (1:2, v/v) affording the acyclic nucleosides
14a–d, 15 and 16, respectively, in quantitative yields
(Scheme 3).
Acknowledgements
We thank the CNRS and MENRT for financial sup-
port. F. Amblard thanks the MENRT for a Ph.D.
fellowship. Work performed at the University of New
Orleans was supported by the National Science
Foundation.
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Scheme 2. Alternative synthesis of unsaturated purine acy-
clonucleosides 11, 11% and 13.

9180
F. Amblard et al. / Tetrahedron Letters 44 (2003) 9177–9180
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1
35%). H NMR (250 MHz, CDCl3) l 4.36 (d, 2H, J=5.9
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8.49 (bs, NH); 13C NMR (250 MHz, CDCl3) l 50.5, 68.1,
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1
mg, 14%). H NMR (250 MHz, CDCl3) l 1.36 (s, 3H),
1.40 (s, 3H), 3.57 (dd, 1H, J=7.3, 8.1 Hz), 4.10 (dd; 1H,
J=6.3, 8.1 Hz), 4.49–4.57 (m, 1H), 4.91 (d, 2H, J=6.1
Hz), 5.74 (ddt; 1H, J=1.2, 6.8, 15.5 Hz), 6.02 (ddt, 1H,
J=0.8, 6.1, 15.5 Hz), 8.12 (s, 1H), 8.74 (s, 1H); 13C NMR
(250 MHz, CDCl3) l 25.8, 26.7, 45.3, 69.3, 75.7, 110.0,
126.1, 131.7, 133.7, 144.9, 151.3, 151.8, 152.2; MS: m/z
295 [M+H]+, 297 [(M+2)+H]+; UV (MeOH) umax 265 nm.
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