Synthesis of Trinucleotide Building Blocks in Solution and on Solid Phase.

We have developed two methods, in solution and on solid phase, that give easy access to trinucleotide phosphoramidites capable of undergoing coupling reactions by the solid‐phase phosphoramidite approach. The solution protocol is characterized by application of 5′‐O‐dimethoxytrityl (DMT) and 3′‐O‐tert‐butyldimethylsilyl (TBDMS) as a pair of orthogonal protecting groups and 2‐cyanoethyl (CE) for protection of the phosphate. Starting with suitably functionalized monomers, synthesis proceeds in the 3′‐ to 5′‐direction, delivering the fully protected trinucleotide. The 3′‐O‐protecting group is cleaved followed by phosphitylation of the free 3′‐OH group. The solid‐phase protocol is based on standard phosphoramidite chemistry in conjunction with a dithiomethyl linkage connecting the 3′‐starting nucleoside to the polymer. The disulfide bridge can be cleaved under neutral conditions for release of the trinucleotide from the support preserving all other protecting groups. © 2018 by John Wiley & Sons, Inc.