Diversity of Approaches to the Synthesis of Phosphoryl Guanidine Oligonucleotides

Abstract Phosphoryl guanidines represent a class of internucleotide phosphate modifications introduced at the oxidation step of automated solid-phase oligonucleotide synthesis. The procedures for obtaining these modifications are fully compatible with the standard reagent set and the protocols. Phosphoryl guanidine modifications enable not only altering the nature of the backbone but also introducing various substituents into the oligonucleotide structure. This study investigates the applicability of various alternative oxidation methods for the preparation of diverse representatives of phosphoryl guanidines bearing various substituents and explores the feasibility of implementing various synthetic schemes within these methods. In this work, the scope of the oxidative amination of phosphite triesters was expanded. Diverse representatives of the class were obtained both by introducing different guanidine residues and by using O-methyl isourea as a common precursor for the synthesis of various phosphoryl guanidines. The feasibility of using the oxidative amination of H-phosphonates via the Atherton–Todd reaction to obtain phosphoryl guanidine derivatives was demonstrated here. To obtain phosphoryl guanidine derivatives by oxidation of phosphite triesters with electron-deficient azides via the Staudinger reaction, new synthetic schemes for diaminocarbenium azides were implemented, enabling the preparation of asymmetric tetrasubstituted azides and unsubstituted guanyl azide. Using these azides, the corresponding phosphoryl guanidine derivatives were successfully obtained. The possibility of obtaining multiply modified oligonucleotides with various substituents on the guanidine group has been demonstrated. The proposed methods enabled a significant expansion of the structural diversity of phosphoryl guanidine oligonucleotide derivatives.