Dissertation Defense: Eryn Nelson
Candidate: Eryn Nelson
Major: Chemistry
Advisor: Christian Wolf, Ph.D.
Title: Insights into the Racemization and Asymmetric Synthesis of Chiral Organofluorines and Advances in Chiroptical Sensing Methodology
The role of chirality within drug development underscores the importance of introducing novel asymmetric synthetic routes for complex, multifunctional compounds. This comes with many challenges often involving the need to control regioselectivity, diastereoselectivity, and enantioselectivity while maintaining high yields and broad functional group tolerance. While this is no trivial task, the development of high-throughput experimentation (HTE) allows many reactions to be carried out in parallel, thus streamlining asymmetric reaction development. However, the determination of absolute configuration and enantiopurity of chiral products often becomes a bottleneck in this process as traditional analytical tools such as chiral HPLC are serial techniques, allowing only one sample to be run at a time. Circular dichroism (CD) spectroscopy is amenable to HTE and overcomes those challenges by enabling rapid determination of enantiomeric excess (ee) and absolute configuration, in turn reducing waste production and increasing efficiency. This thesis presents novel strategies for both asymmetric reaction development and high-throughput analysis of a wide variety of chiral compounds to bridge the gap between stereoselective synthesis and subsequent analysis.
Chiroptical sensing of alcohols is often difficult due to their low nucleophilicity. An organocatalytic reaction using 4-dimethylaminopyridine (DMAP) was developed with an achiral isocyanate probe to carry out quantitative sensing of challenging aromatic and aliphatic alcohols and diols. The inexpensive probe also reacts quickly with amines and amino acids to induce strong UV and CD inductions above 300 nm. The applicability of this assay was demonstrated by accurate determination of absolute configuration, ee, and concentration of various samples containing phenylethylamine.
To expand the scope of CD sensing beyond traditionally privileged functional groups, an organometallic assay was developed leveraging η6-complex formation between chiral arenes and a Ru(II) piano stool complex. The “click-like” η6-formation occurs with arenes within minutes via irreversible acetonitrile displacement and enables sensing of a wide range of chiral analytes, including the first examples of CD sensing for aromatic tertiary amines, esters, and lactones. Additionally, this methodology was successfully applied in the chromatography-free analysis of an asymmetric epoxidation reaction.
The general impact of fluorinated chiral compounds in the life sciences has stimulated considerable interest in their synthesis and unique properties. The stereochemical integrity of organofluorines, however, is poorly understood and methods to understand their susceptibility to racemization would aid greatly in the development of dynamic kinetic resolution protocols and new asymmetric reactions. To this end, the enantioseparation and racemization of 2-aryl-2-fluoronitriles and 3-fluorooxindoles was carried out using chiral HPLC. The configurational stability of these compounds was evaluated under a variety of conditions to understand reaction kinetics and substitution effects.
Due to the significance of fluorinated pharmaceuticals, a three-component asymmetric carbofluorination of gem-difluoroalkenes was developed utilizing an inexpensive alkali metal fluoride as the nucleophilic fluoride source. The catalytic protocol developed overcomes challenges with competing β-fluoride elimination and stereocontrol. The reaction proceeds under mild and stoichiometric conditions to yield difunctionalized products with good yields and excellent enantioselectivities.