Cross-metathesis mediated synthesis of new acyclic nucleoside phosphonates

Article abstract of DOI:10.1080/15257770701534196

With the commercial availability of well-defined ruthenium metathesis catalysts which combine high stability and broad functional group compatibility, olefin metathesis is now routinely integrated in various syntheses. We will report here the overwhelming power and scope of cross-metathesis in the area of new acyclic nucleoside phosphonates. Scope and limitations of this approach, and especially the E/Z stereocontrol, are discussed on selected examples from our drug discovery group. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701534196

Nucleosides, Nucleotides, and Nucleic Acids, 26:1399–1402, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701534196
CROSS-METATHESIS MEDIATED SYNTHESIS OF NEW ACYCLIC
NUCLEOSIDE PHOSPHONATES
Vincent Roy, Hiroki Kumamoto, and Sabine Berteina-Raboin
Institut de
2
Chimie Organique et Analytique, UMR 6005, Universite´ d’Orle´ans, Orle´ans, France
Steven P. Nolan Institute of Chemical Research of Catalonia, Tarragona, Spain
Dimitri Topalis and Dominique Deville-Bonne
2
Laboratory Enzymology and
2
Molecular Function, FRE CNRS 2852, University of Pierre & Marie Curie,
Pairs, France
Jan Balzarini, Johan Neyts, Gracelia Andrei, and Robert Snoeck
2
Department Microbiology & Immunology, Rega Institute for Medicinal Research,
Leuven, Belgium
Luigi A. Agrofoglio
Institut de Chimie Organique et Analytique, UMR 6005,
2
Universite´ d’Orle´ans, Orle´ans, France
With the commercial availability of well-defined ruthenium metathesis catalysts which combine
2
high stability and broad functional group compatibility, olefin metathesis is now routinely integrated
in various syntheses. We will report here the overwhelming power and scope of cross-metathesis in the
area of new acyclic nucleoside phosphonates. Scope and limitations of this approach, and especially
the E/Z stereocontrol, are discussed on selected examples from our drug discovery group.
Keywords Acyclic nucleoside phosphonate; cidofovir; cross-metathesis
INTRODUCTION
The emergence of life threatened viral diseases has driven chemistry
for the development of nucleosides. Acyclic nucleoside phosphonates—
possessing the biologically stable carbon-phosphorus bond—are analogs of
acyclic nucleotide monophosphates and do not require initial phosphory-
lation by kinase. Several acyclic nucleoside phosphonates show excellent
therapeutic potential, such as PMEA, PMPA for the therapy of HSV, VZV,
These studies were supported in part by a grant from Sanofi-Aventis France and Bayer Pharma as
part of a multi-organism call for proposals, and in part by an “ANR-05-BLAN-0368-03.”
Address correspondence to Luigi A. Agrofoglio, Institut de Chimie Organique et Analytique, UMR
6005, Universite´ d’Orle´ans, Orle´ans, France. E-mail: luigi.agrofoglio@univ-orleans.fr
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V. Roy et al.
CMV, and AIDS, including thymidine-kinase deficient strains. The cidofovir
recently was reported to be a potent antiviral agent with activity against sev-
eral DNA viruses that cause coetaneous disease, including poxviruses. Nev-
ertheless, cidofovir suffers from severe side effects and poor bioavailability.
Thus, as part of an on-going program on smallpox, we will detail the synthe-
sis and the biological data of several hitherto unknown acyclic nucleoside
phosphonates related to cidofovir and analogs. Many variations, both on the
heterocycle have been done through Pd(0) chemistry. The introduction of
vinyl or allyl phosphonate moiety has been realized through an olefin cross-
metathesis reaction.
RESULTS AND DISCUSSION
Over the past decade, olefin metathesis has become a powerful tool
for advanced organic synthesis.[1] This mainly is due to the introduc-
tion of either the alkoxy imido molybdenum catalyst, [Mo], developed by
Schrock[2] and various ruthenium carbene catalysts such as those developed
by Grubbs,[3] [Ru]-I, [Ru]-II, the Hoveyda, [Ru]-III, the Hoveyda-ligand
modified Grubbs catalyst, [Ru]-IV,[4] the ruthenium catalyst bearing an im-
idazolydidene developed by Nolan,[5] [Ru]-V (Figure 1).
Phosphorus containing compounds have gained considerable attention
due to the diverse biological profile, such as the antiviral acyclic nucleoside
phosphonates. The Michaelis-Arbuzov reaction between organic halides and
trialkyl phosphates is used primarily for the synthesis of allylphosphonates.
In this article, we propose to study a new way to synthesize quickly acy-
clophosphonate nucleosides using cross-coupling metathesis (CM). For this
purpose, Nolan’s catalyst [Ru]-V has been employed due to its excellent
functional group tolerance and ease of use, between uracil analogues and
vinylic or allylic phosphonates. During our first investigations, we observed
the exclusive formation of homodimers issuing from the self-metathesis of
N1-allylthymine and allylphosphonic acid dimethyl ester,[6] respectively. We
hypothesized that the N1-crotyl phosphonate may be more reactive than the
N1-allyl thymine in the CM reaction. Another hypothesis is based on the
FIGURE 1 Main catalysts used in metathesis reactions.

New Acyclic Nucleoside Phosphonates
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TABLE 1 Synthesis of vinylphosphonate nucleosides through CM
Entry
Vinyl phosphonate (eq.) Time (h)
yield (%)
1
2
3
4
2
4
4
6
15
15
64
15
56 + homodimer (20%)
67 + homodimer (traces)
54
67
reversible nature of CM reaction which ensures the preferential formation
of the most thermodynamically stable product. When reacting the more re-
active N1-crotyl thymine (2.5 eq.) with the diethylvinyl phosphonate (6 eq.)
in the presence of Nolan’s catalyst [Ru]-V (5 mol%) in reflux CH2Cl2, the
desired cross-coupling product was isolated as the only E isomer. An opti-
mization of the reaction was necessary and best results were obtained using
4 or 6 equiv. of vinylic phosphonate (entries 3 and 4, respectively), Table 1.
This methodology was also successfully applied to the CM of various
C5-substituted N1-crotyluracil. It is important to quote that the reaction pro-
ceeded without the protection at the N3 position of the heterocycle. The C5-
substituent has a direct incidence on the yield of the reaction; for instance,
when substituted at the C5 by an alkyne, under those conditions, no reaction
occurred. We next examined the cross-metathesis of various C5-substituted
N1-crotyl uracil with dimethyl allyl phosphonate. Our preliminary results
indicated that the expected cross-coupling products were isolated in only
low yields (20–30%). We hypothesized that the active N3-proton of the
SCHEME 1 Synthesis of allylphosphonate nucleosides through CM.

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V. Roy et al.
pyrimidine would avoid for the proceedings of this metathesis reaction.
Thus, after an N3-benzoylation, the CM reaction between pyrimidine deriva-
tives and allylphosphoante gave the desired products, respectively, in >85%,
as a mixture of E (major) and Z (minor) isomers, (Scheme 2). These results
indicated that the allyl phosphonate would be more active metathesis part-
ner than the vinyl analogue.
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