Use of the 2,4-dinitrobenzyl protecting group in the synthesis of phosphorodithioate analogues of oligodeoxyribonucleotides

✍ Scribed by Geoffrey M. Porritt; Colin B. Reese

• Book ID: 104222064
• Publisher: Elsevier Science
• Year: 1990
• Tongue: French
• Weight: 267 KB
• Volume: 31
• Category: Article
• ISSN: 0040-4039
• DOI: 10.1016/s0040-4039(00)88796-1

✦ Synopsis

Susnnary: The putative intermediate bis(l,2,4-triazolide) derivative (I) is used in the stepwise synthesis in solution of the phosphorodithioate analogue (l0) of thymiaylyl-(3'+5')-thymidylyl-(3'+5')-thymidine; the 2,4-dinitrobensyl (Dnb) group is used to protect phosphorodithioate internucleotide linkages. Due partly to the potential value of anti-sense oligonucleotides in anti-viral chemotherapyl, there has, in the past two years or so, been much interest2r3r4 in the synthesis of phosphorodithioate analogues of oligonucleotides. We very recently reported5 the conversion of 5'-O-(9-phenylxanthen-9-yl)thymidine 3'-phosphonodithioate (1) into the dinucleoside phosphonothioate derivative (2) and thence into the phosphorodithioate analogue (2) of thymidylyl-(3'+5')-thymidine. We now report the synthesis of the corresponding trinucleoside diphosphate analogue (lo), using a somewhat more efficient coupling procedure and the 2,4-dinitrobsnsyl (Dnb) group6 to protect the phosphorodithioate internucleotide linkages. PX PXO Ad (2) (2) PX -S-phenylxanthen-S-yl; Thy -tlqmin-l-y1 5'-O-(9-Phenylxanthen-9-yl)thymidine7 [(i), 1.5 arnol] was treated with a slight excess (1.8 mmol) of putative tris(l,2,4-triazolyl)phosphine5 [Scheme] in tetrahydrofuran solution at -35OC, and the assumed intermediate (I) was then allowed to react with 3'-oacetylthymidinee (2.1 xxsol). After 20 min, the reactants were allowed to warm up to room temperature and triethylamine (6.75 mnol) was added. Hydrogen sulphide was then bubbled into the resulting mixture. Following work-up and chromatography of the products, the fully-protected dinucleoside phosphonothioate (2). identical [6p(CDC13) 70.79, 72.161 to material prepared previously5 , was obtained in 60% overall yield based on (4). The latter