Ribo-, Xylo-, and Arabino-configured adenine-based nucleoside phosphonates: Synthesis of monomers for solid-phase oligonucleotide assembly

Article abstract of DOI:10.1081/NCN-120022734

Adenine-based, regioisomeric nucleoside phosphonates with ribo, xylo and arabino configuration were synthesized in the protected form suitable for the phosphotriester-like, solid-phase synthesis of oligonucleotides. Phosphonate moiety was protected by 4-m

Full text of DOI:10.1081/NCN-120022734

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Ribo-, Xylo-, and Arabino-Configured Adenine-Based
Nucleoside Phosphonates: Synthesis of Monomers for
Solid-Phase Oligonucleotide Assembly
Ondřej Páv a , Miloš Buděšínský a & Ivan Rosenberg a b
a Institute of Organic Chemistry and Biochemistry , Academy of Sciences , Prague, Czech
Republic
b Institute of Organic Chemistry and Biochemistry , Academy of Sciences , Flemingovo nám.
2, 166 10, Prague 6, Czech Republic
Published online: 31 Aug 2006.
To cite this article: Ondřej Páv , Miloš Buděšínský & Ivan Rosenberg (2003) Ribo-, Xylo-, and Arabino-Configured Adenine-
Based Nucleoside Phosphonates: Synthesis of Monomers for Solid-Phase Oligonucleotide Assembly, Nucleosides, Nucleotides
and Nucleic Acids, 22:5-8, 1053-1056, DOI: 10.1081/NCN-120022734
To link to this article: http://dx.doi.org/10.1081/NCN-120022734
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1053–1056, 2003
Ribo-, Xylo-, and Arabino-Configured Adenine-Based
Nucleoside Phosphonates: Synthesis of Monomers for
Solid-Phase Oligonucleotide Assembly
*
ˇ
Ondrej Pav, Milos Budesınsky, and Ivan Rosenberg
´
ˇ
ˇˇ
´
´
Institute of Organic Chemistry and Biochemistry, Academy of Sciences,
Prague, Czech Republic
ABSTRACT
Adenine-based, regioisomeric nucleoside phosphonates with ribo, xylo and
arabino configuration were synthesized in the protected form suitable for the
phosphotriester-like, solid-phase synthesis of oligonucleotides. Phosphonate
moiety was protected by 4-methoxy-1-oxido-2-picolyl group and the furanose
hydroxyl by the dimethoxytrityl group.
Key Words: Nucleoside phosphonic acids; Adenosine; 9-(Arabinofuranosyl)-
adenine; 9-(Xylofuranosyl)adenine; Protection; Phosphonylation; Nonisosteric
phosphoester-like moiety.
RESULTS AND DISCUSSION
Nucleoside phosphonic acids have been systematically studied in our laboratory
for a long time.[1–4] These compounds with absolute stability against phosphomo-
noesterases and nucleotidases represent a pool of compounds for the construction
*Correspondence: Ivan Rosenberg, Institute of Organic Chemistry and Biochemistry,
´
Academy of Sciences, Flemingovo nam. 2, 166 10 Prague 6, Czech Republic; Fax:
þ420 2 3333 5268; E-mail: ivan@uochb.cas.cz.
1053
DOI: 10.1081/NCN-120022734
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

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Pav, Budesınsky, and Rosenberg
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1054
of internucleotide linkage-modified short oligonucleotides.[5–7] In the frame of our
investigation of phosphonate-based nucleotide and oligonucleotide analogues we
report here a novel class of monomers in the ß-D-series derived from appropriate
riboA, xyloA and araA phosphonic acids.
Starting from adenine b-D-nucleosides with ribo, xylo and arabino configura-
tion, we have elaborated the synthesis of two series of protected nucleoside deri-
vatives with free 20 and 50 hydroxy group, resp. (Sch. 1–6). These compounds were
phosphonomethylated with diisopropyl tosyloxymethylphosphonate to afford fully
protected nucleoside phosphonates in both 20 and 50 series. Further transformation
of these compounds gives the monomeric building blocks in the 50 (1, 3, 5) and 20 (2,
4, 6) series. Phosphonylation reaction in the step (iv) g) in Sch. 3 has led, surprisingly,
to the 30-O-methylphosphonate 3 instead of the expected 50-derivative. In the pre-
sence of NaH, the 30-O-benzoyl group migrates completely to the 50-hydroxyl so that
phosphonylation takes place at the 30-hydroxy function.
Scheme 1.
Scheme 2.
Scheme 3.

Adenine-Based Nucleoside Phosphonates
1055
Scheme 4.
Scheme 5.
Scheme 6.
A key importance for the synthesis of the oligonucleotides has the protection of
the 30-hydroxyl of monomers 1 and 5. In case of trans configuration of the free 30-
hydroxyl and the DMTr group-protected hydroxyl (2–5) we can use benzoyl protect-
ing group, although, for cis configured compounds (1, 6) the use of benzoyl or silyl
protecting groups is excluded because of their hydroxyl-to-hydroxyl migration under
conditions of phosphotriester condensation method. We have checked, therefore,
the use of several types protecting groups to find among them the group stable both
under detritylation conditions and towards migration. This study is underway.
Figure 1.

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Pav, Budesınsky, and Rosenberg
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1056
For the solid-phase synthesis of oligomers were also prepared ‘‘first letters’’
(Fig. 1), which were anchored to LCAA-CPG via hemisuccinate, resulting in starting
units for the synthesis of modified 20-50 linked oligoadenylates with the regioisomeric
20-O-CH2-P-O-500 and 20-O-P-CH2-O-500 linkage, resp.
ABBREVIATIONS
Bz
Benzoyl
Dibutylaminomethylen
Dimethoxytrityl
4-Methoxy-1-oxido-2-picolyl
Triisopropylsilyloxymethyl
DBAM
DMTr
MOP
TOM
ACKNOWLEDGMENTS
Support by grants # A4055101 (Acad. Sci., Czech Republic) and #203=01=1166
(GA, Czech Republic) under research project Z4055905 is gratefully acknowledged.
REFERENCES
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1. Endova, M.; Masojıdkova, M.; Budesınsky, M.; Rosenberg, I. 2 ,3 -O-Phos-
phonoalkylidene derivatives of ribonucleosides: synthesis and reactivity. Tetra-
hedron 1998, 54, 11,151–11,186.
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0
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ˇˇ´
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2. Endova, M.; Masojıdkova, M.; Budesınsky, M.; Rosenberg, I. 3 ,5 -O-phos-
phonoalkylidene derivatives of 1-(2-deoxy-b-D-threo-pentofuranosyl)thymine:
synthesis and reactivity. Tetrahedron 1998, 54, 11,187–11,208.
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´ ´
´
ˇˇ´
´
´
´
3. Kralıkova, S.; Budesınsky, M.; Masojıdkova, M.; Rosenberg, I. Efficient synth-
esis of nucleoside 30-C-phosphonates: reactivity of geminal hydroxyphosphonate
moiety. Nucleosides, Nucleotides & Nucleic Acids 2000, 19 (7), 1159–1183.
ˇ
´ ´
´
ˇˇ´
´
´
´
4. Kralıkova, S.; Budesınsky, M.; Masojıdkova, M.; Rosenberg, I. Geminal
hydroxy phosphonate derivatives of nucleosides: a novel class of nucleoside 50-
monophosphate analogs. Tetrahedron Lett. 2000, 41, 955–958.
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ˇ´
5. Pressova, M.; Endova, M.; Tocık, Z.; Liboska, R.; Rosenberg, I. UV spectro-
scopy of complexes of poly(U) with ApA analogs: prediction of oligonucleotide
properties? Bioorg. Med. Chem. Lett. 1998, 8, 1225–1230.
ˇ
´ˇ
ˇ´
ˇ
´ ´
´
6. Rejman, D.; Snasel, J.; Liboska, R.; Tocık, Z.; Paces, O.; Kralıkova, S.;
´
ˇ
Rinnova, M.; Kois, P.; Rosenberg, I. Oligonucleotides with isopolar phospho-
nate internucleotide linkage: a new perspective for antisense compounds?
Nucleosides, Nucleotides & Nucleic Acids 2001, 20, 819–823.
ˇ
ˇ
´
´
´
ˇ ´
7. Hanus, J.; Barvık, I.; Ruszova-Chmelova, K.; Stepanek, J.; Turpin, P.-Y.;
´
´
Bok, J.; Rosenberg, I.; Petrova-Endova, M. -CH2-lengthening of the internucleo-
tide linkage in the ApA dimer can improve its conformational compatibility with
its natural polynucleotide counterpart. Nucl. Acids Res. 2001, 29, 5182–5194.
8. Pitsch, S.; Weiss, P.A.; Jenny, L.; Stutz, A.; Wu, X. Helv. Chim. Acta 2001, 84,
3773–3795.