Synthesis of Nucleobase-Functionalized Morpholino-Modified Nucleoside Monomers Through Palladium-Catalyzed Cross-Coupling Reactions

Morpholino-modified nucleoside analogues have widespread applications in developmental biology. To achieve nucleobase-functionalized forms of morpholino nucleosides, syntheses of 5-substituted cytidine, 8-substituted adenosine, and 8-substituted guanosine morpholino nucleoside monomers are described for the first time. The syntheses are based on the use of 5-iodocytidine, 8-bromoadenosine, and 8-bromoguanosine morpholino nucleosides as the key starting materials. These iodo or bromo derivatives have also been synthesized for the first time. Palladium-mediated cross-coupling reactions (Sonogashira, Suzuki, and Heck) were then employed with the halo derivatives to accomplish the substitutions. Different reaction conditions for C, A, and G were standardized to achieve the conversions. The strategy was devised in such a way that the useful N-trityl protecting groups remain at the end. The catalyst combinations used for Sonogashira, Suzuki, and Heck reactions were Pd(PPh3)2Cl2·CuI, Pd(dppf)Cl2·CH2Cl2, and Pd(OAc)2, respectively. Heck coupling between 5-iodocytidine monomer and methyl acrylate worked well, whereas with acrylonitrile the exocyclic amine of cytidine was found to form the aza-Michael adduct. In this context, treatment of iodocytidine with methyl acrylate under two different sets of conditions was found to produce either the Michael addition product or the Heck coupling product. Four of the functionalized morpholino monomers have been further confirmed by single-crystal X-ray structural analysis. All of these functionalized monomers were obtained in good to excellent overall yields.