Synthesis of novel exocyclic amino nucleosides by parallel solid-phase combinatorial strategy

Abstract A versatile parallel solid-phase combinatorial strategy was developed for the synthesis of large nucleoside libraries. Twelve libraries L1 - 12 of 1152 novel exocyclic triazinylamino nucleosides and one library L13 of 82 new substituted clitocine derivatives were synthesized in high quality as natural product mimic nucleosides on the semi-automated synthesizer. The polystyrene MMT-Cl resin was selected and utilized. The key intermediate resins 5 and 9 loaded with the corresponding scaffolds were prepared and validated with various amines before parallel synthesis. After a variety of amino building blocks were validated, 56 primary amines in 12 groups (building block set A) and 24 secondary amines in 3 groups (building block set B) were selected and utilized to combinatorialize the first and the second reactive sites on scaffold 5 for the synthesis of libraries L1 - 12 . Eighty-two amines (building block set C) were utilized for the synthesis of clitocine library L13 . Thirteen libraries of 1234 novel exocyclic amino nucleosides were all analyzed and characterized by high throughput LC-MS. 81.3–100% of the library members in 13 libraries show more than 60% purity, and 65.7–92.7% of the library members in these libraries show 80–100% purity. The strategy can be widely used for the synthesis of other diverse nucleoside libraries.