Date of Award

Summer 8-20-2021

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor

Matthew Brichacek

Second Committee Member

Alice E Bruce

Third Committee Member

Mitchell R. Bruce

Additional Committee Members

William M Gramlich

Michael Kienzler

Abstract

Oligonucleotide based therapeutics have been pursued in the clinic for the treatment of many disease indications. However, unmodified oligonucleotides are polyanionic macromolecules with poor drug-like properties. Modifications of the phosphodiester backbone provide resistance to nucleases in vivo, making them more efficacious than unmodified nucleotides. However, these backbone modifications have added the structural complexity of a stereogenic phosphorus center. Stereochemically pure isomers exhibit differential efficiency dependent on its enantiopurity. The catalytic, stereocontrolled synthesis of a phosphorus-stereogenic center is challenging, and traditionally, depends on a resolution or use of stochiometric auxiliaries. Herein, asymmetric nucleophilic catalysis has been investigated to provide enantio-enriched phosphonates using phosphoramidite or H-phosphonate approaches. Both investigations utilized commercially available chiral catalysts with the enantioselectivity determined by HPLC on a chiral stationary phase. The requisite starting materials, phosphoramidite and H-phosphonates, have been prepared in racemic form with a variety of alcohol substituents. Chiral phosphonate products were synthesized in acceptable yield (33%-92%) and modest enantioselectivity (up to 62% ee) after identification of an appropriate chiral catalyst and optimization of the solvent, base, temperature, and stoichiometric additives. The potential applications of these approaches will be discussed in the context of catalysis and biotechnology. Following our interest in phosphorus nuclear magnetic resonance spectroscopy (31P NMR), quantitative analysis of phosphorus abundance in environmental samples was conducted. To prepare samples for NMR analysis pre- and post-treatment, extraction, dissolution, and pH adjustment were performed. Quantitatively accurate 31P NMR were acquired by optimizing delay time, proton decoupling parameters, and acquisition time.

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