Issue 10, 2023

Triaza-tricyclanos – synthesis of a new class of tricyclic nucleoside analogues by stereoselective cascade cyclocondensation

Abstract

Herein, we report a stereoselective synthesis of a novel type of conformationally constrained nucleoside analogue in which the sugar part is replaced by a new symmetrical tricycle consisting of a morpholine ring condensed with two imidazolidines. 1,5-Dialdehydes obtained from trityl- and dimethoxytrityl-protected uridine, ribothymidine, inosine, cytidine, adenosine and guanosine by metaperiodate oxidation were reacted with N1,N3-dibenzyl-1,2,3-triaminopropane; the latter reactant was produced using a new method that avoids explosive intermediates. Reactions of dialdehydes with propane-triamine via cascade tricyclization resulted in the corresponding triaza-tricyclic derivatives bearing three new stereogenic centers in high yields. Out of the eight possible diastereoisomers, one stereoisomer was formed in each case due to the chiral control of the starting nucleoside-dialdehydes and the steric constraint of the condensed ring system. The absolute configuration of the new stereotriad was determined by X-ray diffraction and NMR experiments. A mechanistic study performed under reductive conditions to trap the presumed bicyclic intermediate showed that the triamine reactant first attacks the 2′-aldehyde group, followed by a rapid bicyclization to form the imidazolidino-morpholine unit.

Graphical abstract: Triaza-tricyclanos – synthesis of a new class of tricyclic nucleoside analogues by stereoselective cascade cyclocondensation

Supplementary files

Article information

Article type
Paper
Submitted
31 Jan 2023
Accepted
15 Feb 2023
First published
16 Feb 2023

Org. Biomol. Chem., 2023,21, 2213-2219

Triaza-tricyclanos – synthesis of a new class of tricyclic nucleoside analogues by stereoselective cascade cyclocondensation

M. Bege, M. Herczeg, I. Bereczki, N. Debreczeni, A. Bényei, P. Herczegh and A. Borbás, Org. Biomol. Chem., 2023, 21, 2213 DOI: 10.1039/D3OB00154G

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