EVALUATION OF 2'-HYDROXYL PROTECTION IN RNA-SYNTHESIS USING THE H-PHOSPHONATE APPROACH

A number of different protecting groups were compared with respect to their usefulness for protection of 2'-hydroxyl functions during synthe sis of oligoribonucleotides using the H-phosphonate approach. The comp arison was between the t-butyldimethylsilyl (t-BDMSi), the o-chloroben zoyl (o-ClBz), the tetrahydropyranyl (THP), the 1-(2-fluorophenyl)-4-m ethoxypiperidin-4-yl (Fpmp), the -(2-chloro-4-methylphenyl)-4-methoxyp iperidin-4-yl (Ctmp), and the 1-(2-chloroethoxy)ethyl (Cee) protecting groups. All these groups were tested in synthesis of dodecamers, (Up) (11)U and (Up)(11)A, using 5'-O-(4-monomethoxytrityl) or (4,4'-dimetho xytrityl) uridine H-phosphonate building blocks carrying the respectiv e 2'-protection. The performance of the t-BDMSi and o-CIBz derivatives were also compared in synthesis of (Up)(19)U. The most successful syn theses were clearly those where the t-butyldimethylsilyl group was use d. The o-chlorobenzoyl group also gave satisfactory results but seems somewhat limited with respect to synthesis of longer oligomers. The re sults with all tested acetal derivatives (Fpmp, Ctmp, Cee, THP) were m uch less successful due to some accompanying cleavage of internucleoti dic H-phosphonate functions during removal of 5'-O-protection (DMT).