Different strategies for the synthesis of 2′-O-aminoethyl adenosine building blocks

Article abstract of DOI:10.1080/15257770701505295

The chemical modification of the 2′-O-position of nucleosides proved to be of great importance for the RNA stability. Greater stability of RNA duplexes allows a longer half life in the cell and, therefore, a better effect of RNA Interference. Here we inve

Full text of DOI:10.1080/15257770701505295

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Different Strategies for the Synthesis of
2′- O -Aminoethyl Adenosine Building
Blocks
Dalibor Odadzic a & 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: Dalibor Odadzic & Joachim W. Engels (2007) Different Strategies for the Synthesis
of 2′- O -Aminoethyl Adenosine Building Blocks, Nucleosides, Nucleotides and Nucleic Acids, 26:8-9,
873-877, DOI: 10.1080/15257770701505295
To link to this article: http://dx.doi.org/10.1080/15257770701505295
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Nucleosides, Nucleotides, and Nucleic Acids, 26:873–877, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701505295
DIFFERENT STRATEGIES FOR THE SYNTHESIS OF
2ꢀ-O-AMINOETHYL ADENOSINE BUILDING BLOCKS
Dalibor Odadzic and Joachim W. Engels
Institute for Organic Chemistry and
2
Chemical Biology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
The chemical modification of the 2ꢁ-O-position of nucleosides proved to be of great importance
2
for the RNA stability. Greater stability of RNA duplexes allows a longer half life in the cell and,
therefore, a better effect of RNA Interference. Here we investigated the synthesis of 2ꢁ-O-aminoethyl
adenosine as a cationic modified building block.
Keywords 2ꢁ-O- position; RNA stability; building blocks
INTRODUCTION
The availability of chemically modified nucleosides has shown to be of
great importance for antisense and RNA Interference mediated gene silenc-
ing applications.[1] A large number of oligonucleotides derivates that have a
2ꢁ-O-tethered modification have been reported.[2] As the result of the high
nuclease resistance and affinity for complementary oligonucleotides of 2ꢁ-
O-aminopropyl[3] and 2ꢁ-O-guanidinoethyl,[4] we decided to synthesize 2ꢁ-O-
aminoethyl modified adenosine with cationic modification and to analyze
their stabilizing effect in the duplex. The rationale for the synthesis of 2ꢁ-O-
cationic modified nucleosides is, on one hand, a higher nuclease resistance
and, on the other hand, a potentially better cellular uptake.
Here, we report different strategies for the synthesis of the 2ꢁ-O-
aminoethyl adenosine. The main problem regarding adenosine is the N6
exocylic amino group, so we chose different protecting group strategies to
get the desired product in good yield and in few steps. Scheme 1 shows the
2ꢁ-O-aminoethyl adenosine building block A1.
We would like to thank the “Sonderforschungsbereich 579” and the RIGHT EU-Project NoLSHB-
CT-2004-005276 for financial support.
Address correspondence 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
873

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D. Odadzic and J. W. Engels
SCHEME 1 2ꢁ-O-aminoethyl adenosine building block.
SCHEME 2 Advantage of dibenzoyl-strategy.

Synthesis of 2ꢁ-O-Aminoethyl Adenosine
RESULTS AND DISCUSSION
875
For the synthesis of A1 we tried different strategies. Scheme 2 (see be-
low) highlights the advantage of the dibenzoyl-strategy over the monoben-
zoyl strategy.[5]
Without two benzoyl groups at N6, we always got two products during the
allylation with a high amount of 2ꢁ-O-N6-di-allyl-adenosine (20) as side prod-
uct. The alkylation with bromo-acetate was unsuccessful with the monoben-
zoylated compound. Here we got the 2ꢁ-O-N6-di-methoxycarbonyl- adeno-
sine (21) as main product. The synthesis of A1 with the dibenzoylstrategy[6]
is shown in Scheme 3.
The problem of using the dibenzoylstrategy was the deprotection of only
one benzoyl group on N6. During the reaction we could indentify on TLC
the deprotection of both benzoyl groups. We could not synthesize the com-
pound 12 by using the dibenzoylstrategy. Nevertheless, we point out here
some steps in this strategy. The first step is a transient protection method[7]
with good yield of 80%. The next steps are the Pd catalysed allylation[8] with
a yield of 96% and the introduction of the phthalimide group via Mitsunobu
conditions[9] in 85%.
SCHEME 3 Dibenzoyl-strategy. TMS-Cl; pyridine; RT; 3 hours; Bz-Cl; RT; 8 hours b TIPDS-Cl; pyridine;
RT; 24 hours c Allyl-Ethyl-Carbonate; Pd2(dpa)2; dppb; 70◦C; 1 hour d OsO4; NMO; dioxane; RT; 15
hours e NaIO4; CH2Cl2; RT; 4 hours f NaCNBH3; PPTS; RT; 4.5 hours g Phthalimide; PPh3; DEAD;
THF; RT; 2 hours h TBAF/THF; THF; RT; 1 hour i DMTr-Cl; NEt3; pyridine; RT; 24 hours j 30% NH4OH;
pyridine; RT 0.5 hour k 1-Methylimidazole; sym. Collidine; CEP-Cl; acetonitrile; 0◦C.

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D. Odadzic and J. W. Engels
SCHEME 4 Methoxycarbonyl-strategy. a BrCH2COOMe; NaH; RT; 8 hours b TBDMS-Cl; Imidazole;
pyridine; RT; 24 hours c LiAlH4; ether; 0◦C; 0.5 hours d Phthalimide; PPh3; DEAD; THF; RT; 1 hour e
TBAF/THF; THF; RT; 16 hours f DMTr-Cl; NEt3; pyridine; RT; 24 hours g DMF-dimethyl acetal; DMF;
60◦C; 1 hour h 1-Methylimidazole; sym. Collidine; CEP-Cl; acetonitrile; 0◦C.
Finally, we tried the synthesis of A1 without protection of the N6 amino
group. The synthesis of the building block A1 with the methoxycarbonyl
strategy is shown in Scheme 4.
With this strategy we could synthesize the 2ꢁ-O-aminoethyl adenosine
building block in good yield. The first step of this strategy is the direct
alkylation of unprotected adenosine with NaH and bromo acetate with a
yield of 47%.[10] Thus, we found an efficient method for the synthesis of 2ꢁ-
O-aminoethyl modified adenosine building block in 8 steps and an overall
yield of 12%.
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Synthesis of 2ꢁ-O-Aminoethyl Adenosine
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