Attempts to suppress internucleotide cleavage during unblocking of oligonucleotide phosphotriester intermediates

✍ Scribed by Ryszard W. Adamiak; René Arentzen; Colin B. Reese

• Publisher: Elsevier Science
• Year: 1977
• Tongue: French
• Weight: 249 KB
• Volume: 18
• Category: Article
• ISSN: 0040-4039
• DOI: 10.1016/s0040-4039(01)93065-5

✦ Synopsis

Perhaps the most serious problem which we have encountered in the synthesis of oligonucleotides by the phosphotriester approach with phenyl and other aryl protecting groups'.

is the internucleotide cleavage which accompanies the removal of the latter protecting groups.

For example, in a recent study on the block synthesis of oligo-and poly-thymidylic acids in which phenyl protecting groups were used, we found2 that the extent of internucleotide cleavage was cu. 3% per phosphotriester function even under the most favourable conditions of alkaline hydrolysis. Thus loss of product during unblocking was considerable except for oligonucleotides of comparatively low molecular weight.

An obvious approach to the solution of this problem is to use an aryl protecting group derived from a phenol which is more acidic than phenol itself. However, it was clear from earlier studies3 that, if internucleotide cleavage was to be restricted to an acceptable amount, say, to cc. 0.5% per phosphotriester function, it would be necessary to use an aryl protecting group derived from a phenol with a pKa * 7.5.