Cyclization reactions of 1-[3′-hydroxy-2′-(hydroxymethyl)prop-1′-enyl]pyrimidine nucleobases: intramolecular Michael additions to the C(5)C(6) bonds and intramolecular dehydrations

Abstract

The tendency of a series of acyclic nucleoside analogues 1a-f to undergo intramolecular cyclization reactions was investigated. All compounds, when treated with NaOD, were in equilibrium with the bicyclic compounds 2a-f, arising from Michael addition of a hydroxy group to the C(5)=C(6) bonds. Derivatives of 2,4-pyrimidinediones (1a,b) had the highest tendency to undergo intramolecular Michael addition when treated with triethylamine, whereas the cyclization of 4-amino-2-pyridones (1c-f) proceeded best with acid. The exocyclic double bond of was essential for the cyclization to occur. Commonly used N-protecting groups as the benzoyl- and the dibutylaminomethylene group enhanced cyclization. Under acidic anhydrous conditions 1b and 1e cyclized to the 2,4'-anhydro compounds 1b and 1e.

Synthesis and Hybridization Studies of 2‘-Amino-α-L-LNA and Tetracyclic “Locked LNA”

“…Validation of the proposed structures of 22 and 23 , which have a conformationally locked furanose ring, a conformationally restricted glycosidic torsion angle, and a nonaromatic nucleobase moiety, is presented in a subsequent section. Intramolecular Michael additions of oxygen or nitrogen nucleophiles on the C6-position of pyrimidines have been previously reported. In comparison to the extensive work on nucleosides with conformationally restricted furanose rings, remarkably few nucleosides with conformationally restricted glycosidic torsion angles have been incorporated into oligonucleotides, even though such modifications could provide insight on the influence of the glycosidic torsion angle on nucleic acid duplex stability.…”

Preparation of Cyclonucleosides

“…Recently, a similar intermolecular Michael addition was also observed for the oxygen nucleophiles during synthesis on novel acyclic analogues of pyrimidine nucleosides. 197,198…”

Improved synthesis of oligonucleotides with an allylic backbone. Oligonucleotides containing acyclic, achiral nucleoside analogues: N-1 or N-9-[3-hydroxy-2-(hydroxymethyl)prop-1-enyl]nucleobases

“…This is in accord with the high tendency of the cytosine compounds 1c, 1d, and their N-protected derivatives to cyclise. 7 The A* phosphoramidite 3b and the G* phosphoramidite 3e were prepared in the same way as the T* phosphoramidite 3a, and used together with the Beaucage T phosphoramidite 6a and the A analogue 6b 10 which are necessary as the 10th base in the 14-mers. The remaining T and A phosphoramidites were commercial cyanoethyl phosphoramidites…”

“…1). [3][4][5][6][7] Fig. 1 The central C=C bond restricts the molecules conformationally, and molecular modelling and geometry calculations indicate that Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100, Copenhagen, Denmark.…”