Microwave-assisted ribosylation of modified heterocyclic bases by Vorbrueggen method

Article abstract of DOI:10.1080/15257770701505485

During the last decades the nucleoside synthesis has proven to be important. The modified silyl-Hilbert-Johnson nucleoside synthesis modified by Vorbrueggen is one of the most often used methods. We have studied N-glycosilation of modifieded heterocyclic bases by Vorbrueggen method with microwave irradiation and we were able to shorten the reaction time and obtain higher yields. The method was demonstrated by fluoroquinolone and purine. Copyright Taylor & Francis Group, LLC.

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Microwave-assisted Ribosylation
of modified heterocyclic bases by
Vorbrüggen method
a
Nadja V. Nikolaus 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: Nadja V. Nikolaus , Jelena Božilović & Joachim W. Engels (2007) Microwave-
assisted Ribosylation of modified heterocyclic bases by Vorbrüggen method, Nucleosides, Nucleotides
and Nucleic Acids, 26:8-9, 889-892, DOI: 10.1080/15257770701505485
To link to this article: http://dx.doi.org/10.1080/15257770701505485
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Nucleosides, Nucleotides, and Nucleic Acids, 26:889–892, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701505485
MICROWAVE-ASSISTED RIBOSYLATION OF MODIFIED
¨
HETEROCYCLIC BASES BY VORBRUGGEN METHOD
Nadja V. Nikolaus, Jelena Bozˇilovic´, and Joachim W. Engels
Institute for
2
Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe University, Frankfurt
am Main, Germany
During the last decades the nucleoside synthesis has proven to be important. The modified silyl-
2
Hilbert-Johnson nucleoside synthesis modified by Vorbru¨ggen is one of the most often used methods.
We have studied N-glycosilation of modifieded heterocyclic bases by Vorbru¨ggen method with mi-
crowave irradiation and we were able to shorten the reaction time and obtain higher yields. The
method was demonstrated by fluoroquinolone and purine.
Keywords Ribosylation; modified heterocyclic bases
INTRODUCTION
Nucleosides and nucleotides have provided a productive area of chemi-
cal and biological research. The monomeric units of DNA and RNA are in-
volved in the regulation of a myriad of cellular metabolic pathways and have
been the subject of intense areas of research seeking to identify therapeu-
tic agents for a varaiety of diseases including viral infection, cancer, cardio-
vascular diseases, central nervous system diseases, etc. Among the various
synthetic methods the reaction of silylated heterocyclic bases with peracy-
lated sugars in the presence of Lewis acid catalysts has become the standard
procedure which affords nucleosides routinely in high yields.[1] In short,
nucleoside synthesis includes the silylation of a heterocyclic base, the gener-
ative sugar cation from peracylated ribose and the nucleophilic attack of a
heterocyclic base on C1.[2]
Here we present some examples of ribosylation of modified heterocyclic
bases (1–4) by the conventional Vorbru¨ggen method and with the use of
We would like to thank the EU project (EU Leuren LSHB-CT-2003-503480/TrioH) 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
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N. V. Nikolaus et al.
SCHEME
1 Reagents and conditions: a) 1,2,3,5-O-tetraacetyl-D-ribofuranose, MeCN,
bis(trimethylsilyl)acetamide, trimethylsilyl triflate, ꢀ, 3 hours, 82–92% or 1,2,3,5-O-tetraacetyl-D-
ribofuranose, MeCN, bis(trimethylsilyl)acetamide, trimethylsilyl triflate, MW, 50 minutes, 80–96%.
microwave irridiation (MWI). The last approach permits us to get higher
yields of target nucleosides in a shorter time compared to the standard
method (Scheme 1 and Table 1).
RESULTS AND DISCUSSION
In the synthesis of the heterocycles high temperatures are needed, and
we decided to use microwave applicator. Therefore, we modified the pro-
cedure of Kidwai et al.[3] on the first step. 2-, 3-, and 4-Fluoroanilines
were N -substituted with diethyl (ethoxymethylidene)malonate to give di-
ethyl[(fluoroanilino)methylidene]malonates. The electrophilic ring clo-
sure was performed in diphenyl ether according to Koga’s procedure.[4]
The synthesis of fluoroquinolones was reduced from a two-step synthesis by
hydrolysis and decarboxylation to a single-step, one-pot reaction.[5] Using
this method we were able to shorten the synthesis by one step and to obtain
very good yields (87–96%).
Several attempts to synthesize the nucleosides failed due to the lack of
solubility of the fluoroquinolones during Vorbru¨ggen reaction. A slightly
modified Vorbru¨ggen method of Moore et al.[6] gave better results then
general procedure, but we improved efficiency of the method by using mi-
crowave irradiation on steps of the silylation of heterocyclic bases and ribo-
sylation of them. We do explain these results by a combination of optimal
solubility and heat distribution due to the microwave irradiation.
The microwave-assisted glycosylation is the best method for the prepa-
ration of fluoroquinolone nucleosides 7 and 8 because the yields are
higher and the reaction time is much shorter compared to the conven-
tional method. But in the case of ethyl-6- fluoro-4-oxo-1,4-dihydroquinoline-
3-carboxylate, the yield of nucleoside 6 microwave irradiated synthesis is

891

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N. V. Nikolaus et al.
lower than the one of the conventional method. It is still a good method
to prepare a nucleoside due to the shorter reaction time and so we can
save time in the synthesis. The synthesis of compound 10 with making use
of MWI also is preferential, because it seems to favor a kinetic controlled
reaction and the ratio of desired nucleoside 10 in the total yield of isomeric
N-7 and N-9 nucleosides is changed from 1:5.7 to 1:3.7 (compound 10 to
compound 9).
REFERENCES
1. Vorbru¨ggen, H.; Ho¨fle, G. On the mechanism of nucleoside synthesis. Chem. Ber. 1981, 114, 1256–
1268.
2. Zivkovic, A. RNA recognition by fluoro aromatic substituted nucleic acid analogues. Dissertation 2005,
49–50.
3. Kidwai, M.; Misra, P.; Kumar, R.; Safena, R. K.; Gupta, R.; Bradoo, S. Microwave assisted synthesis and
antibacterial activity of new quinolone derivatives. Monatsh. Chem. 1998, 129, 961–965.
4. Koga H.; Itoh, A.; Murayama, S.; Suzue, S; Irikura, T. Structure-activity relationships of antibacterial
6,7- and 7,8-disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids. J. Med. Chem. 1980,
23, 1358–1363.
5. Adams, M.M.; Bats, J.W.; Nikolaus, N.V.; Witvrouw, M.; Debeyser, Z.; Engels, J. W. Microwave-assisted
synthesis of fluoroquinolone nucleosides as inhibitors of HIV integrase. Collection of Czechoslovak
Chemical Communications 2006, 71(7), 978–990.
6. Moore, C.L.; Zivkovic, A.; Engels, J.W.; Kuchta, R.D.; Human DNA primase uses Watson-Crick hydro-
gen bonds to distinguish between correct and incorrect nucleoside triphosphates. Biochemistry 2004,
43, 12367–12374.