Synthesis of Pyrimidine 2‘-Deoxy Ribonucleosides Branched at the 2‘-Position via Radical Atom-Transfer Cyclization Reaction with a Vinylsilyl Group as a Radical-Acceptor Tether¹

Abstract

Recently, we developed a regio- and stereoselective method for introducing a vinyl group at the position beta to a hydroxyl group in halohydrins or alpha-phenylselenoalkanols via a radical atom-transfer cyclization reaction with a vinylsilyl group as a temporary connecting radical-acceptor tether. The synthesis of 2'-deoxy-2'-C-vinyl- and 2'-deoxy-2'-C-hydroxymethyluridines (7 and 8, respectively) and the corresponding 2'-deoxycytidine congeners (10 and 11, respectively), which were designed as potential antitumor and/or antiviral agents, was achieved using this radical atom-transfer cyclization as the key step. When the 2'-deoxy-2'-iodo-5'-O-monomethoxytrityl (MMTr) uridine derivative 19a, bearing a vinylsilyl group at the 3'-hydroxyl group, was heated with (Me(3)Sn)(2) and AIBN in benzene, the corresponding radical atom-transfer product was generated, which in turn was successively treated with tetrabutylammonium fluoride and TBSCl/imidazole to give the desired 2'-deoxy-5'-O-MMTr-3'-O-TBS-2'-C-vinyluridine (25). Compound 25 was successfully converted into the target 2'-deoxy-2'-branched pyrimidine ribonucleosides 7, 8, 10, and 11.

Truncated phosphonated C-1′-branched N,O-nucleosides: A new class of antiviral agents

“…Besides their potential biological activity as antiviral agents, the C1 0 -branched nucleosides show further great interest, linked to the availability of model nucleosides which may allow the study of the formation and evolution of radical species generated during DNA/RNA damage. 4 N,O-psiconucleosides 4 constitute a particular class of modified psiconucleosides where an isoxazolidine system mimics the ribose ring of natural nucleosides and a hydroxymethyl group is linked at the anomeric carbon atom. 5 These derivatives show synthetic interest for their potential antiviral or anticancer activity which have been also discovered in other N,O-nucleosides.…”

2′‐Deoxy‐2′‐α‐C‐(hydroxymethyl)adenosine as Potential anti‐HCV Agent

“…A variety of procedures for preparing synthetic branched-chain sugar nucleosides have been described. However, the number of 2Ј-deoxy-2Ј-α-C-branched ribonucleosides reported are limited, [10][11][12][13][14][15] and their biological activities have not yet been investigated in a systematic manner, perhaps because of a lack of the availability of efficient synthetic methods leading to 2Ј-deoxy-2Ј-α-C-branched ribonucleosides.…”

“…Only few publications report the synthesis of 2Ј-deoxy-2Ј-α-C-hydroxymethylpyrimidine nucleosides. [10][11][12][13][14][15] As far as we know, the synthesis of 2Ј-deoxy-2Ј-α-C-(hydroxymethyl)purine nucleosides has not been reported yet. Two schemes are used to synthesize such pyrimidine nucleosides.…”

“…The first one consists of a direct introduction of the vinyl or styryl group at the 2Ј position. [14] The second one involves a double bond migration on the readily available allyl nucleoside through an ene reaction. [15] Another possibility, using an intramolecular radical C-C bond formation reaction, as described for the synthesis of branched aldopentopyranosyl nucleosides, [16] has not been considered yet.…”

Fine Synthetic Nucleoside Chemistry Based on Nucleoside Natural Products Synthesis

“…8,9) Considerable attention has been focused on branched chain sugar nucleosides because of their biological importance. During the course of synthetic studies aiming to develop antitumor agents, our group has found that branched-chain sugar nucleosides [10][11][12][13][14][15][16] are promising antitumor drug candidates 17) such as 1-(2-deoxy-2-methylene-b-Derythro-pentofuranosyl)cytosine [18][19][20][21] (DMDC, Fig. 1, 1) and 1-(2-C-cyano-2-deoxy-b -D-arabino-pentofuranosyl)cytosine [22][23][24][25][26][27] (CNDAC, 2).…”