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Synthesis 2002(6): 0789-0796
DOI: 10.1055/s-2002-25755
SPECIALTOPIC
© Georg Thieme Verlag Stuttgart · New York

Synthesis and Incorporation into α-DNA of a Novel Conformationally Constrained α-Nucleoside Analogue

Bernhard M. Keller, Christian J. Leumann*
Department of Chemistry & Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
Fax: +41(31)6313422; e-Mail: leumann@ioc.unibe.ch;
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Publication History

Received 9 February 2002
Publication Date:
26 April 2002 (online)

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Abstract

The synthesis and incorporation into α-DNA of a novel conformationally constrained α-nucleoside analogue is described. The carbohydrate part of this analogue was prepared in 4 steps from the known bicyclic precursor 1 via a stereospecific, intramolecular, Et3B-mediated radical addition to a keto function as the key step. The thus obtained intermediate 4 was transformed stereoselectively into the corresponding α-nucleoside analogues 7 and 8 containing the bases adenine and thymine, and were further elaborated into the phosphoramidite building blocks 11 and 12. Both building blocks were incorporated into α-oligodeoxynucleotides and their pairing behavior to parallel complementary DNA was studied by UV-melting experiments. Single substitutions of α-deoxyribnucleoside units by the new analogues in the center of duplexes were found to be thermally destabilizing by only -0.8 to -3.1 °C.

Key words

radical reactions - DNA - nucleosides - antisense agents - bioorganic chemistry

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