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

Abstract

We report here the efficient regio- and stereoselective synthesis of new polycyclic nucleosides using a common cyclic enamine (7) as the starting material. In fact, the reaction of 7, easily prepared by reaction of 5'-O-Tosyl TSAO-T under basic nonnucleophilic conditions (potassium carbonate), with different classes of nucleophiles, for example, nitrogen-, oxygen-, sulfur-, and carbon-based nucleophiles, or with amino acids afforded, with total regio- and stereoselectivity, new bi-, tri-, and tetracyclic nucleosides. This straighforward route represents an original and unambiguously regio- and stereoselective pathway to these compounds. Some of these polycyclic nucleosides may be useful intermediates for a second series of reactions that may lead to the generation of structurally new nucleosides.

A Cyclic Enamine Derived from 1,2-O-Isopropylidene-α-d-xylofuranose As a Novel Carbohydrate Intermediate To Achieve Skeletal Diversity

“…One explanation for the formation of this compound is that the amino group attacks the C-4‘ position of the sugar to give the intermediate I , and then the NH of the pyrroline ring spontaneously displaces the ester group of the amino acid to form a new fused five-membered ring (Scheme ). This extremely facile intramolecular attack is consistent with the previously observed high reactivity of the NH of the pyrroline ring toward reagents that contain carbonyl groups reported by our group 5 gHMBC NMR correlations, indicated by arrows. …”

“…Encouraged by this preliminary result, we investigated whether this reaction could be used as the basis for the synthesis of different classes of bi-, tri-, and tetracyclic nucleosides. In a subsequent study of the reactivity of the non-methylated thymine cyclic enamine 6 against different nucleophiles (Figure ), we found that this enamine is in fact a very useful and versatile intermediate that can be used to prepare novel types of polycyclic nucleosides in high yields in a regio- and stereoselective manner 1 Structures of compounds 6 , 7 , and 8 . …”

Unprecedented Lability of the 5‘-O-tert-Butyldimethylsilyl Group from 3‘-Spiro-5‘ ‘-(4‘ ‘-acylamino-1‘ ‘,2‘ ‘-oxathiole-2‘ ‘,2‘ ‘-dioxide) Nucleoside Derivatives via Neighboring Group Participation of the 4‘ ‘-Acylamino Residue

“…The structure of this tricyclic nucleoside 19 was unequivocally assigned from mono- and bidimensional 1 H and 13 C NMR (1D and 2D) techniques. Similar tricyclic structures have been recently described by our group. , …”

“…Similar tricyclic structures have been recently described by our group. 13,14 Next, modifications were performed at the 5′-position by replacing the 5′-TBDMS group of compounds 3 with other 5′- Comparative chemical stability studies of the 5′-TBDMS group on the 4′′-N-acyl or 4′′-N-alkyl TSAO derivatives 5-15 (Figure 3) 8 and compounds 17 and 25-28 were carried out in DMSO, and their conversion into the corresponding 5′-O-deprotected derivatives was followed by HPLC. In all the experiments, the 4′′-N-methoxalyl TSAO derivative 3 was included as a reference compound.…”

TSAO Derivatives, Inhibitors of HIV-1 Reverse Transcriptase Dimerization: Recent Progress

“…(11)) [84]. The novelty of these structures prompted us to carry out extensive studies aimed at determining the mechanism of formation of these of highly functionalized nucleosides and subsequent studies of chemical reactivity [85]. These studies led to the identification of entirely new families of nucleosides that specifically inhibited HIV-1 replication [86].…”