Solid-phase synthesis of base-sensitive oligonucleotides

Oligonucleotides bearing N-acylated and O-alkylated nucleobases, biodegradable phosphate protections, cap-structures, internucleotidic H-phosphonates, methylphosphates, O-methylphosphorothioates and phosphotriesters are sensitive to nucleophiles, nucleopeptides are prone to beta-elimination and some of the dihydropyrimidines undergo retro condensation. None of them withstand the standard ammonolytic deprotection, but an alternative synthetic procedure should be adopted. In this review, orthogonal protecting group schemes and the N-unprotected methods for the solid-phase synthesis of these important oligonucleotides are presented.