Synthesis of carbocyclic phosphononucleosides

Article abstract of DOI:10.1081/NCN-100002345

Syntheses of carbocyclic analogs of phosphononucleosides are described by two different methods (introduction of the heterocycle under Mitsunobu conditions or build-up of the base around a cyclopentylamine moiety).

Full text of DOI:10.1081/NCN-100002345

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SYNTHESIS OF CARBOCYCLIC
PHOSPHONONUCLEOSIDES
B. Legeret a , Z. Sarakauskaite a , F. Pradaux a , Y. Saito a , S. Tumkevicius b & L. A.
Agrofoglio c
a I.C.O.A. associé CNRS , Faculté des Sciences, Orléans, 45100, France
b Dept of Organic Chemistry, Faculty of Chemistry , University of Vilnius , Lithuania
c I.C.O.A. associé CNRS , Faculté des Sciences, Orléans, 45100, France
Published online: 07 Feb 2007.
To cite this article: B. Legeret , Z. Sarakauskaite , F. Pradaux , Y. Saito , S. Tumkevicius & L. A. Agrofoglio (2001)
SYNTHESIS OF CARBOCYCLIC PHOSPHONONUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 661-664, DOI:
10.1081/NCN-100002345
To link to this article: http://dx.doi.org/10.1081/NCN-100002345
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 661–664 (2001)
SYNTHESIS OF CARBOCYCLIC
PHOSPHONONUCLEOSIDES
B. Legeret,1 Z. Sarakauskaite,1,2 F. Pradaux,1 Y. Saito,1
S. Tumkevicius,2 and L. A. Agrofoglio1,∗
1I.C.O.A. associe´ CNRS, Faculte´ des Sciences, 45100 Orle´ans, France
2Dept of Organic Chemistry, Faculty of Chemistry,
University of Vilnius, Lithuania
ABSTRACT
Synthesesofcarbocyclicanalogsofphosphononucleosidesaredescribedbytwo
different methods (introduction of the heterocycle under Mitsunobu conditions
or build-up of the base around a cyclopentylamine moiety).
In case of several viruses, to be active, the nucleosides must be mono-, di- and
triphosphorylated by nucleotidases or kinases enzymes. The first phosphorylation
is known to be selective and limiting. To circumvent this step, pronucleotide (1,2)
or nucleotide analogs, i.e. compounds in which a phosphonate group is mimicking
the phosphate monoester, have been designed (3). Phosphonate analogs have also
the advantage over monophosphates in that P-C bonds are not cleaved by the phos-
phatases which dephosphorylate monophosphates. Thus, in part of our drug dis-
covery group, we have been investigating the syntheses of carbocyclic nucleosides
(4–6), and we will report herein some carbocyclic analogues of phosphononucle-
osides (Fig. 1).
Considering different synthetic approaches towards the targeted compounds,
we developed both convergent methods allowing the connection of the intact het-
erocycle moiety under Mitsunobu conditions (7), and linear methods in which
the heterocycle moiety is built up around a functionalized cyclopentylamine. The
∗Corresponding author.
661
ꢀ
C
Copyright 2001 by Marcel Dekker, Inc.
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ORDER
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662
LEGERET ET AL.
O
O
B
RO P
B
RO P
OR
OR
OH
NH2
N
O
NH2
N
Cl
N
H2N
HN
O2N
HN
O2N
HN
NH
N
Base =
N
N
O
N
R = H, ester group
Figure 1.
requested cyclopentenyl phosphonates have been obtained from cyclopent-3-enoic
acid according to Scheme 1.
The stereochemical control of the process requires that the oxirane interme-
diate 3 be preferentially formed on the less hindered face of the cyclopentylamine
ring to direct the nucleophilic attack of the heterocycle or its precursors. Thus the
epoxidation of ester 2 by MCPBA afforded a 70/30 mixture of stereoisomeric epox-
ides easily separated by chromatography. The only trans-epoxide 3 was used for
the rest of the synthesis. The key synthon 5 (8) was then converted (Scheme 2)
into the allylic alcohol ( )-7 by the “selenylation-oxidation” method. Thymine
Scheme 1.

ORDER
REPRINTS
CARBOCYCLIC PHOSPHONONUCLEOSIDES
663
O
N
O
P
O
P
NH
O
1. PBu3, TBZ, DEAD, THF
2. MeOH/NH3
1. Se2PH2, NaBH4, MeOH
2. H2O2, THF, pyridine
O
P
iPrO
iPrO
OiPr
OiPr
iPrO
58%
39%
OiPr
OH
O
5
-7
(–)
-9
(–)
Scheme 2.
Scheme 3.
analogue ( )-9 was successfully obtained by Mitsunobu reaction of ( )-7 with
N3-benzoylthymine as described into Scheme 2. Compound ( )-7 could be also
obtained by deacylation of ( )-6.
The linear approach as depicted in Scheme 3 was used to reach other carbo-
cyclic phosphononucleosides with an exocyclic aminopyrimidine moiety.
Thus, the meso-epoxide 5 after treatment with NaN3 was converted into
( )-10, which was reduced by hydrogenation to provide the cyclopentylamine
( )-11. The amine ( )-11 was coupled with 4,6-dichloro-5-nitropyrimidine to
afford after deprotection the phosphononucleoside ( )-12 (10). Reaction of the
aromatic chlorine with methanolic ammonia gave ( )-13a, while hydrogenation
of ( )-13a afforded ( )-13b as a new exocyclic amino carbocyclic analogue of a
phosphononucleoside.
In summary, several syntheses of these hitherto unknown carbocyclic phos-
phononucleosides have been accomplished (11). Biological evaluations of those
compounds for antiviral activity are in progress.

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LEGERET ET AL.
ACKNOWLEDGMENT
This work was supported by a research grant from the Foundation pour la
Recherche Me´dicale (SIDACTION).
REFERENCES
1. Meier, C. Synlett 1998, 233–242 (review).
2. Naesens, L.; Snoeck, R.; Andrei, G.; Balzarini, J.; Neyts, J.; De Clercq, E. Antiviral
Chem. Chemother. 1997, 8, 1–23 (review).
3. Pe´rigaud, C.;Girardet, J.-L.;Gosselin, G.;Imbach, J.-L. inꢁAntiviralDrugDesignꢂ;
De Clercq, E., Ed.; JAI Press: London, 1996; Vol. 2, pp 147–172.
4. Agrofoglio, L. A.; Challand, S. R. in ꢁAcyclic, Carbocyclic and L-Nucleosidesꢂ;
Kluwer Academic Publishers: Dordrecht, Boston, London, 1998, 385 pp.
5. Agrofoglio, L. A.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl, R. A.;
Guedj, R. Tetrahedron 1994, 50(36), 10611–10670 (review).
6. Agrofoglio, L. A.; Condom, R.; Guedj, R.; Challand, S. R.; Selway, J. Tetrahedron
Lett. 1993, 34(39), 6271–6272.
7. Mitsunobu, O. Synthesis 1981, 1–28.
8. Physico-chemical data for 2-(6-Oxabicyclo[3.1.0]hex-3-yl)ethyl phosphonic acid di-
1
isopropyl ester, 5: H-NMR (CDCl3) δ4.71–4.63 (m, 2H, CH(CH3)2), 3.45 (s, 2H,
H1, H5), 2.17 (dd, 2H, J = 6.9 Hz , J = 13.5 Hz H4a, H2a), 1.73–1.41 (m, 5H, PCH2,
PCH2CH2, H3), 1.30 (d, 12H, J = 6.2 Hz, 2 × (CH3)2CH), 1.28–1.24 (m, 2H, H4b,
H2b); NMR-31P (CDCl3) δ 51.7 (s, 1P).
9. Physico-chemical data for ( )-2ꢃꢃ-[1ꢃ-(1-thyminyl)cyclopent-2ꢃ-enyl]ethyl phospho-
nic acid diisopropyl ester, ( )-9: 1H-NMR (CDCl3) δ 8.49 (s, 1H, NH), 7.05 (s, 1H,
ꢃ
ꢃ
ꢃ
H6), 6.17(m, 1H, H2 ), 5.76–5.71(m, 2H, H3 , H1 ), 4.80–4.70(m, 2H, 2×CH(CH3)2),
ꢃ
ꢃ
2.87–2.80 (m, 1H, H4 ), 1.98 (s, 3H, CH3), 1.84–1.75 (m, 5H, PCH2, PCH2CH2, H5 a),
ꢃ
1.38 (d, 12H, J = 6.2 Hz, 2 × (CH3)2CH), 1.38–1.35 (m, 1H, H5 b); MS m/z = 385.50
(M + 1).
10. Physico-chemical data for ( )-2ꢃꢃ-(2ꢃ-hydroxy-1ꢃ-N-(4-chloro-5-nitro-6-aminopyr-
imidine)-cyclopentyl)ethylphosphonic acid, ( )-12: 1H-NMR (CDCl3) δ 8.1 (s, 1H,
ꢃ
ꢃ
ꢃ
H2), 7.9 (s, 1H, NH), 4.4 (m, 1H, H1 ), 4.2 (m, 1H, H2 ), 2.4 (m, 1H, H5 b), 2.3 (m, 1H,
ꢃ
ꢃ
ꢃ
ꢃꢃ
ꢃꢃ
ꢃ
H4 ), 1.9 (m, 1H, H3 b), 1.7 (m, 3H, H3 a, H1 , H2 ), 1.3 (m, 1H, H5a ); MS (ion spray)
m/z 366 (M+), 368 (M + 2).
11. All synthesized products have been fully characterized by 1H, 13C NMR and MS.

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