Nucleotides. Part XLVI. The synthesis of phospholipid conjugates of antivirally active nucleosides by the improved phosphoramidite methodology

Abstract

AbstractThe application of the improved phosphoramidite strategy for the synthese of oligonucleotides using β‐eliminating protecting groups to phospholipid chemistry offers the possibility to synthesize phospholipid conjugates of AZT (6) and cordycepin. The synthesis of 3′‐azido‐3′‐deoxythymidine (6) was achieved by a new isolation procedure without chromatographic purification steps in an overall yield of 50%. Protected cordycepin ( = 3′‐de‐oxyadenosine) derivatives, the N6,2′‐bis[2‐(4‐nitrophenyl)ethoxycarbonyl]cordycepin (12) and the N6,5′‐bis[2‐(4‐nitrophenyl)ethoxycarbonyl]cordycepin (13) wre prepared by known methods and direct acylation of N6‐[2‐(4‐nitrophenyl)ethoxycarbonyl]cordycepin (9), respectively. These protected nucleosides and the 3′‐azido‐3′‐de‐oxythymidine (6) reacted with newly synthesized and properly characterized lipid‐phosphoramidites 21–25, catalyzed by 1H‐tetrazole, to the corresponding nucleoside‐phospholipid conjugates 26–38 in high yield. The deprotection was accomplished via β‐elimination with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) in aprotic solvents to give analytically pure nucleoside‐phospholipid diesters 39–51 as triethylammonium or sodium salts. The newly synthesized compounds were characterized by elemental analyses and UV and 1H‐NMR spectra.