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Synthesis of α-(R)-/γ-(S)-Dimethyl Substituted Peptide Nucleic Acid Submonomer Using Mitsunobu Reaction



One of the major challenges facing modern biochemical and biomedical technologies are
finding molecular tools for diagnosis and detection of genetic diseases. In this connection, several classes
of oligonucleotides have been developed that can recognize and bind to DNA and RNA with high
affinity and sequence selectivity and withstand enzymatic degradation by proteases and nucleases;
however, few can traverse the cell membrane on their own. One such promising class of nucleic acid
mimics developed in the last two decades which showed good results in vitro, are the peptide nucleic
acids (PNAs). New chiral α- and γ-peptide Nucleic Acid (PNA) submonomer with methyl substituents
in pseudopeptide backbone were synthesized via Mitsunobu reaction. The α-(R)-/γ-(S)-configuration of
the chiral centres will ensure the preorganization of the PNA oligomer into a right-handed helix. The
results obtained showed that Boc/Fmoc-submonomer compatible with Boc-protocol PNAs solid-phase
synthesis on an MBHA resin. We synthesized simple and efficient α-R-, γ-S-disubstituted PNA submonomer
based on L-Ala and D-Ala with the construction of the intermediate pseudopeptide moiety
by Mitsunobu reaction for subsequent use in the Boc-Protocol of solid phase PNA synthesis.
