Synthesis and Structural Characterization of Pyrimidine Bi- and Tricyclic Nucleosides with Sugar Puckers Conformationally Locked into the Eastern Region of the Pseudorotational Cycle

Abstract

Reaction of 5'-O-tosyl TSAO-m(3)T (1) with amines has led to the synthesis of new classes of bi- and tricyclic nucleosides. Full details about the synthesis of these compounds and a plausible mechanism to explain their obtention are reported. In addition, we describe the development of a second, more efficient, and higher yielding synthetic route as a general approach for the synthesis of some of these bicyclic nucleosides. To study the conformational behavior of the bi- and tricyclic nucleosides described in this paper, intensive NMR investigations and molecular modeling studies were performed. Conformational analysis indicates that the furanose ring of the compounds described here prefers the eastern side of the pseudorotation cycle with the base substituents preferentially in the anti range. The torsion angle gamma describing the C-4'[bond]C-5' is found to prefer the +sc range. These compounds represent a novel class of E-type conformationally restricted bicyclic ribo-nucleosides containing a [3.3.0]-fused carbohydrate moiety. The bicyclic nucleosides described herein present an interesting potential for diverse and selective chemical treatments on the 2'-hydroxyl and/or the functionalities incorporated at the bridge between C-3' and C-5'.

Synthesis of Novel Bi-, Tri-, and Tetracyclic Nucleosides by Reaction of a Common Cyclic Enamine Derived from TSAO-T with Nucleophiles

“…This reaction did not lead to the expected 5′-alkylamino derivative 2. Instead, new classes of highly functionalized bicyclic nucleosides 3 and 4, 21 together with the 4′,5′-didehydro nucleoside 5, were obtained. 21,22 Formation of the bicyclic nucleosides was explained by the attack of the alkylamine at the C-4′′ carbon atom of the 3-N-methyl thymine cyclic enamine 6 ( Figure 2).…”

“…Instead, new classes of highly functionalized bicyclic nucleosides 3 and 4, 21 together with the 4′,5′-didehydro nucleoside 5, were obtained. 21,22 Formation of the bicyclic nucleosides was explained by the attack of the alkylamine at the C-4′′ carbon atom of the 3-N-methyl thymine cyclic enamine 6 ( Figure 2). 21 This was demonstrated by the isolation and subsequent treatment of 6 with different alkylamines to afford, in high yields, the new bicyclic nucleosides.…”

“…21,22 Formation of the bicyclic nucleosides was explained by the attack of the alkylamine at the C-4′′ carbon atom of the 3-N-methyl thymine cyclic enamine 6 ( Figure 2). 21 This was demonstrated by the isolation and subsequent treatment of 6 with different alkylamines to afford, in high yields, the new bicyclic nucleosides. 21 Therefore, the cyclic enamine 6 could be considered as a versatile intermediate useful for obtaining bicyclic nucleosides in high yield.…”

“…21 This was demonstrated by the isolation and subsequent treatment of 6 with different alkylamines to afford, in high yields, the new bicyclic nucleosides. 21 Therefore, the cyclic enamine 6 could be considered as a versatile intermediate useful for obtaining bicyclic nucleosides in high yield.…”

One-Pot Synthesis of Polycyclic Nucleosides with Unusual Molecular Skeletons

“…A subsequent opening of the spiroaminooxathioledioxide ring, due to the basic conditions used, was proposed to give 4 (Scheme 2). 80 ºC (pH = 5-6) H 2 O/ CH 3 Although this mechanism satisfactorily explained the formation of 4, no direct experimental verification for the existence of the postulated hydroxy tricyclic intermediates 2 and/or 3 was presented. The initial aim of this paper was to unequivocally intercept and characterize intermediates 2 and/or 3 to provide evidence for their participation in the formation of 4.…”