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Nucleotides. Part XLVI . The synthesis of phospholipid conjugates of antivirally active nucleosides by the improved phosphoramidite methodology
Author(s) -
Sigmund Harald,
Pfleiderer Wolfgang
Publication year - 1996
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19960790210
Subject(s) - chemistry , phosphoramidite , nucleoside , acylation , phospholipid , cordycepin , yield (engineering) , organic chemistry , combinatorial chemistry , stereochemistry , oligonucleotide , catalysis , biochemistry , dna , materials science , membrane , metallurgy
The 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 N 6 ,2′‐bis[2‐(4‐nitrophenyl)ethoxycarbonyl]cordycepin ( 12 ) and the N 6 ,5′‐bis[2‐(4‐nitrophenyl)ethoxycarbonyl]cordycepin ( 13 ) wre prepared by known methods and direct acylation of N 6 ‐[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 1 H ‐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 1 H‐NMR spectra.