| Peptide Nucleic Acid, or PNA, is a mimic of the natural nucleic acids with exceptional binding properties. As such, numerous applications in biochemistry, medicine, and biotechnology for PNA exist or have been proposed. However some of the limitations to the use of PNA include poor water solubility or low cellular uptake. The present work describes several methods for the preparation of modified nucleic acids, which could introduce a number of different functionalities that address these concerns, or open up the possibility for the preparation of PNA oligomers with interesting new properties.; First, within the realm of standard PNA synthesis, two important contributions have been made. A new, highly efficient method for the preparation of Ethyl N-(Boc-2-aminoethyl)glycinate and its hydrochloride salt has been described. The method is based on the reductive amination of ethyl glyoxylate hydrate, derived from diethyl tartrate, with mono-Boc-ethylenediamine.; Also, it has been demonstrated for the first time that PNA oligomer synthesis can proceed with cytosine monomers bearing no protecting group at the N4-position, although the purity of the crude product from a preliminary, unoptimized trial, was somewhat diminished versus a more conventional oligomer synthesis.; A new method of monitoring solid phase reactions using NMR was applied to the optimization of the Fukuyama-Mitsunobu amine synthesis, which is applicable in a proposed submonomer synthesis strategy for PNA oligomers. Each step of this synthesis was found to proceed much faster than had been reported, and an important deleterious side reaction was discovered. A single round of the submonomer synthesis was carried out, preparing a protected thymine monomer. However difficulties were encountered upon attempts to repeat the cycle (toward oligomers) and in the protection strategy for cytosine.; The concept of using uracil as a base which can be converted into N4-substituted cytosine in a post-oligomerization step which can happen concurrently with resin cleavage was developed.; Finally the palladium/copper catalyzed reaction of 5-iodopyrimidines in the context of PNA was developed. Conditions were determined to control whether simple Sonogashira cross-coupling, or a secondary annulation reaction occur, and either product can be obtained, depending upon experimental conditions. |
