Synthesis of Phosphonate Isosteres of 2‘-Deoxy-1‘,2‘-seco-nucleotides

Abstract

Practical and convergent syntheses of 2‘-deoxy-1‘,2‘-seco-nucleophosphonates and 1‘,2‘-seco-nucleophosphonates are described. Phosphonate chirons derived from d-isoascorbic acid were used in alkylation of functionalized nucleobases to provide the title phosphonate isosteres in good yields. Subsequent deprotection and deesterification led to the 5‘-C-methylenephosphonic acids which were conveniently purified using gravity flow C18 reverse phase column chromatography.

Synthesis and Antiviral Evaluation of Novel Cyclopropyl Nucleosides, Phosphonate Nucleosides and Phosphonic Acid Nucleosides

“…Desilylation and sequential mesylation of the corresponding hydroxyl group of 20 gave key intermediate 21, which was also coupled with nucleosidic bases (uracil, thymine, cytosine, adenine) under similar S N 2 substitution conditions to give the cyclopropyl phosphonate nucleoside derivatives 22 -25, respectively. Isopropyl groups of phosphonates were readily removed using trimethylsilylbromide [12] leading to the target nucleoside phosphonic acids 26 -29.…”

Synthesis and Antiviral Evaluation of Novel Exomethylene Acyclic Nucleosides and Phosphonic Acid Nucleosides

“…Isopropyl groups of phosphonates 18Ϫ21 were readily hydrolyzed using trimethylsilylbromide (CH 3 SiBr) [15] to give the target nucleoside phosphonic acids 22Ϫ25.…”

Antiviral Activity Enhancement through the SATE Prodrug of a 2'-Modified 5'-Norcarbocyclic Adenine Analogue

“…For the synthesis of phosphonate nucleoside, the hydroxyl group of 14 was phosphonated by treating them with diisopropyl bromomethylphosphonate 14 in anhydrous DMF to give the phosphonate nucleoside intermediate 15 (Scheme 2). Both protecting groups (N 6 -bis-BOC & di-O-isopropyl) of the phosphonate nucleoside were simultaneously removed using trimethylsilylbromide 15 to give nucleoside phosphonic acids 16. To synthesize the thioester-protected analogues, phosphonic acid nucleoside was reacted with thioester 16 17 in the presence of 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole (MSNT) 17 to provide the final t-bu-SATE prodrug 18 (Scheme 3).…”