Synthesis of fluorinated indoles as RNA analogues

Article abstract of DOI:10.1080/15257770701505220

Nucleoside analogues are chemical means to investigate hydrogen bonds, base stacking, and solvation as the three predominant forces that are responsible for the stability of secondary structure of nucleic acids. To obtain deeper insight into the contributions of these interactions to RNA stability apart from the ones exerted by the predominant nucleosides we decided to synthesize some novel nucleic acid analogues where the nucleobases are replaced by fluoroindoles. Fluorinated indoles can be compared to fluorinated benzimidazoles to determine the role of nitrogen in five membered ring system. The synthesis of fluoroindole ribonucleosides is described here. Copyright Taylor & Francis Group, LLC.

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Synthesis of Fluorinated Indoles as RNA
Analogues
a
Jelena Božilović & Joachim W. Engels a
a Institute for Organic Chemistry and Chemical Biology , Johann
Wolfgang Goethe University , Frankfurt am Main, Germany
Published online: 10 Dec 2007.
To cite this article: Jelena Božilović & Joachim W. Engels (2007) Synthesis of Fluorinated
Indoles as RNA Analogues, Nucleosides, Nucleotides and Nucleic Acids, 26:8-9, 869-871, DOI:
10.1080/15257770701505220
To link to this article: http://dx.doi.org/10.1080/15257770701505220
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Nucleosides, Nucleotides, and Nucleic Acids, 26:869–871, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701505220
SYNTHESIS OF FLUORINATED INDOLES AS RNA ANALOGUES
Jelena Bozˇilovic´ and Joachim W. Engels
Institute for Organic Chemistry and
2
Chemical Biology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
Nucleoside analogues are chemical means to investigate hydrogen bonds, base stacking, and
2
solvation as the three predominant forces that are responsible for the stability of secondary structure
of nucleic acids. To obtain deeper insight into the contributions of these interactions to RNA stability
apart from the ones exerted by the predominant nucleosides we decided to synthesize some novel
nucleic acid analogues where the nucleobases are replaced by fluoroindoles. Fluorinated indoles can
be compared to fluorinated benzimidazoles to determine the role of nitrogen in five membered ring
system. The synthesis of fluoroindole ribonucleosides is described here.
Keywords Fluorinated inoles; RNA; fluorinated benzimidazoles
INTRODUCTION
A series of fluorobenzimidazole nucleosides has been already synthe-
sized in our group.[1,2] The fluorobenzimidazole analogues investigated
so far all show very similar properties. Thus, we decided to synthesize
and evaluate the similar pattern of substitution on fluoroindoles. As the
charge distribution and dipole moment between those two classes of
compounds differ significantly, we expected also to observe differences in
RNA oligonucleotide stability containing those building blocks. Here, we
report strategies for the synthesis of fluoroindole building blocks.
SYNTHESIS
The synthesis of fluoroindoles (which are not commercial available) was
achieved very efficiently in a four step procedure as shown in Figure 1.[3,4]
Methyl azidoacetate, an intermediate in indole synthesis was synthesized by
literature procedure.[5]
The authors thank SFB 579 for financial support.
Address correspodence to Joachim W. Engels, Institute for Organic Chemistry and Chemical Bi-
ology, Johann Wolfgang Goethe University, Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany.
E-mail: Joachim.engels@chemie.uni-frankfurt.de
869

870
J. Boˇzilovic´ and J. W. Engels
FIGURE 1 Synthesis of fluoroindoles.
FIGURE 2 The direct glycosylation of fluoroindoles with halogenated ribose derivative.
FIGURE 3 Efficient synthesis of fluoroindolenucleosides.
The direct synthesis of ribonucleosides (using halogenated ribose
derivative) gave very poor yields below 5% and separation of the obtained
products was very complicated[5] (Figure 2).
As none of the tried direct glycosylations was successful, we decided to
synthesize first deoxy derivative and than the ribo derivative of the corre-
sponding nucleosides as shown in Figure 3. For glycosylation, chlorodeoxyri-
bose derivative was used.[6] The key point is that glycosylation reaction is
very fast and, therefore, only ß isomer is obtained (isomerisation of the sugar

Fluorinated Indoles as RNA Analogues
871
5 does not take place due to the fast reaction time). This reaction furnished
the deoxynucleosides 1, 4FI-7FI, in very high yields (92–98%). The succes-
sive deprotection led to the corresponding unprotected ribose derivatives
in almost quantitative yields. The synthesis of the ribo derivatives were then
accomplished converting the deoxynucleosides into the corresponding ri-
boderivatives. The synthesis of the ribo derivative was done in three steps
with an overall yield of 57%. Despite the formal, “long way” of synthesis all
procedures are worked out as routine and overall yields are very good[7]
(Figure 3.).
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