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

Development of novel original methodologies for the synthesis of new types of modified nucleobases and nucleosides is one of our main interests.

Modified Purine Derivatives
We have focused on the synthesis of purine derivatives bearing carbon substituents (alkyl, alkenyl, alkynyl, aryl and hetaryl) in positions 2, 6 and/or 8. Such compounds are that are not easily accessible by conventional chemistry and they are of eminent interest due to their potential interactions with many enzymes, receptors and other cellular systems. Moreover, increased chemical and biological stability is expected in these compounds due to the hardly cleavable C-C bonds connecting the substituent with the purine moiety. Our methodologies heavily rely on transition metal catalyzed reactions rarely used in this field in the past.

Our major achievements in this field were the developments of Pd- or Fe-catalyzed cross-coupling reactions of halopurines with diverse types of organometallics. Efficient methods for introduction of all types of C-substituents (alkyl, alkenyl, alkynyl, aryl and hetaryl) to positions 2, 6 or 8 using different types of organometallics for each type of substituent. Regioselectiv cross-coupling reactions of 2,6- and 6,8-dihalopurines were used for selective introduction of two different substituents. Synthesis of novel purines bearing functionalized C-substituents (aminoalkyl, hydroxyalkyl, carboxyalkyl, amino acid residue etc.) is also based on cross-coupling reactions of halopurines with functionalized organometallics. In many cases, aqueous-phase cross-coupling reactions of unprotected nucleobases, nucleosides or nucleotides could be used for direct single-step modifications. Also alternative strategies based on direct C-H arylations and alkyne trimerizations have been developed.

C-Nucleosides
Novel C-nucleosides bearing diverse substituted aryl and hetaryl groups as surrogates of nucleobases are designed as tools for studying specificity and selectivity of DNA polymerases as well as potential candidates for extension of the genetic alphabet. Our novel modular methodology of their synthesis is based on preparation of halo-aryl-C-nucleoside intermediates that could be transformed to large series of derivatives by simple functional group transformations (cross-coupling reactions, nucleophilic substitutions).