Development of novel methodologies for the synthesis of modified nucleobases and nucleosides

In order to prepare of new types of modified nucleobases, nucleosides and nucleotides, we develop novel original synthetic methodologies largely based on modern reactions catalyzed by transition metal complexes. Diverse types of cross-coupling reactions have been used for introduction of C-C bonds at positions 6, 2 or 8 in purines, at positions 6 or 7 of 7-deazapurines or at position 5 of pyrimidines. Synthesis of novel purines bearing functionalized C-substituents (aminoalkyl, hydroxyalkyl, carboxyalkyl, amino acid residue etc.) was also developed based on cross-coupling reactions of halopurines with functionalized organometallics. Regioselectivity of cross-coupling reactions is used for consecutive functionalizations of dihaloheterocycles. Aqueous-phase Suzuki or Sonogashira couplings were developed for direct modifications of unprotected nucleosides and nucleotides. Alkynyl-substituted nucleobases or nucleosides were used for transition-metal-catalyzed co-cyclotrimerizations to form aryl derivatives (collaboration with Prof. M. Kotora).

Alternative strategy for functionalization of heterocyclic nucleobases is based on diverse C-H activations. In the recent years, we have developed Pd-catalyzed direct C-H arylations of purines and purine nucleosides and applied it, in combination with cross-coupling reactions and aminations, in the synthesis of 2,6,8,9-tetrasubstituted purines and fused purine heterocycles. Also we have developed regioselective C-H arylations of uracils at position 5 or 6. Ir-catalyzed C-H borylation was used for functionalizations of 7-deazapurines. Several other types of C-H activations of nucleobases are currently under study.