Document Type
Honors Thesis
Major
Chemistry
Advisor(s)
Matthew Brichacek
Committee Members
William Gramlich, Margaret Killinger
Graduation Year
May, 2023
Publication Date
2025
Abstract
Antisense oligonucleotides (ASOs) are pharmacological tools that demonstrate selective inhibition of gene expression. These oligonucleotides are molecularly targeted agents capable of modifying specific biological pathways in order to stifle not just the symptoms of but also the propagation of disease. To be an effective drug, the ASO must have high bonding affinity for their RNA/DNA targets. However, the biological activity of the drug is dependent on the spatial arrangement of its atoms in three dimensions. Therefore, without proper adjustment to stereochemistry, unmodified oligonucleotides possess poor gene-silencing capabilities. To selectively tailor chiral drugs that optimize desired biological activity, new approaches were employed to synthesize enantiopure compounds. This study pursued the asymmetric synthesis of enantioselective chiral phosphonates with phosphodiester, phosphonamidite, and phosphonothioate backbones. To modify these molecules this project followed a two-step approach: 1) Asymmetric nucleophilic catalysts were synthesized and utilized to provide enantio-enriched products; 2) The enantioselective induction was determined by HPLC on a chiral stationary phase whilst structural analysis was performed by phosphorus NMR spectroscopy. In this study it was found that catalysts BTM, HBTM, PIP, 6-MeO-BTM, and 6-Nitro-BTM produced isopropyl (phenyl) phenyl-phosphinate in 40, 20, 10, 40, 0 % yields with 38, 36, 19, 38, and 0 % e.e. respectively. The piece of the oligonucleotide puzzle that this project addresses, provides for the scientific community, a synthetic model by which the enantiomeric yield of these phosphodiesters can be optimized. These implications aid in the process of providing effective pharmacological treatments of antisense technology.
Recommended Citation
Horvat, George, "Asymmetric Organocatalysts: Synthesis and Function in the Augmentation of Antisense Oligonucleotide Stereochemistry" (2025). Honors College. 974.
https://digitalcommons.library.umaine.edu/honors/974