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Tricyclanos: conformationally constrained nucleoside analogues with a new heterotricycle obtained from a D-ribofuranose unit

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Abstract

A novel type of nucleoside analogue in which the sugar part is replaced by a new tricycle, 3,7,10-trioxa-11-azatricyclo[5.3.1.05,11]undecane has been prepared by substrate-controlled asymmetric synthesis. 1,5-Dialdehydes obtained from properly protected or unprotected uridine, ribothymidine, cytidine, inosine, adenosine and guanosine by metaperiodate oxidation reacted readily with tris(hydroxymethyl)aminomethane to provide the corresponding tricyclic derivatives with three new stereogenic centers. Through a double cyclisation cascade process the tricyclic compounds were obtained in good to high yields, with very high diastereoselectivity. Formation of one stereoisomer, out of the eight possible, was observed in all cases. The absolute configuration of the new stereotriad-containing tricyclic systems was aided by conventional NMR experiments followed by chemical shift calculations using an X-ray crystal structure as reference that was in good agreement with H–H distances obtained from a new ROESY NMR method. The synthesis was compatible with silyl, trityl and dimethoxytrityl protecting groups. A new reagent mixture containing ZnCl2, Et3SiH and hexafluoroisopropanol was developed for detritylation of the acid-sensitive tricyclano nucleosides.

Graphical abstract: Tricyclanos: conformationally constrained nucleoside analogues with a new heterotricycle obtained from a d-ribofuranose unit

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Publication details

The article was received on 13 Sep 2017, accepted on 17 Oct 2017 and first published on 17 Oct 2017


Article type: Paper
DOI: 10.1039/C7OB02296D
Citation: Org. Biomol. Chem., 2017, Advance Article
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    Tricyclanos: conformationally constrained nucleoside analogues with a new heterotricycle obtained from a D-ribofuranose unit

    M. Kicsák, A. Mándi, S. Varga, M. Herczeg, G. Batta, A. Bényei, A. Borbás and P. Herczegh, Org. Biomol. Chem., 2017, Advance Article , DOI: 10.1039/C7OB02296D

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