Master of Science
Michael A. Kerr
Donor acceptor cyclopropanes (DACs) are versatile organic building blocks used in the synthesis of many pharmaceutically relevant heterocycles. The combination of a high ring strain cyclopropane core and vicinal donor and acceptor substituents cause DACs to behave like 1,3-zwitterions. Recently, DACs have been activated by a hydrogen bond donor solvent in place of a Lewis acid catalyst, allowing the elimination of heavy metals commonly used in these transformations. Hexafluoroisopropanol (HFIP) as a hydrogen bond donor cosolvent was found to cause a downfield shift of the DACs electrophilic carbon in the 13C NMR spectrum. This indicates increased electrophilicity at this position (Structure A vs B). NMR spectroscopy titrations were used to study the host-guest interaction between DACs and HFIP. The data collected was compared to the effects of binding a Lewis acid catalyst such as scandium triflate (Sc(OTf)3). The HFIP conditions used previously by the Kerr group caused a further downfield shift than commonly used catalytic amounts of scandium triflate. To further expand the application of the HFIP method, the ring-opening addition reaction of DACs with thiol nucleophiles is reported here. Yields were comparable or slightly improved when compared to similar transformations that used a metal-based catalyst. Electron donating and withdrawing properties of the thiol reagents had very strong effects on the results, resulting in two sets of conditions for this methodology.
Summary for Lay Audience
New species of plants and fungi are constantly being discovered, while the number is debated some sources estimate that up to 6 million species of fungi could be present on Earth. Natural products, which are molecules isolated from various plants and fungi are also constantly being discovered. Many of these compounds have potentially useful biological properties for which further study is desired. Synthetic organic chemists are tasked with the challenge of recreating these natural products for further testing, as well as making similar products that could end up being useful things like drugs. Building these molecules can be a long process with many steps, and synthetic chemists rely on previously tested reactions they can use as steps toward their product. Method-oriented synthesis is the discovery of these reactions that can be used as steps. This contributes to the base knowledge of the scientific community. This thesis will discuss the development and results of a reaction along with analytical experiments to support the findings. The goal of this work was to eliminate the need for a metal catalyst in a field of chemistry that commonly relies on one to push the reaction forward. These catalysts are usually based around a metal that is toxic and expensive and therefore removing it is beneficial. Accompanying the results of this reaction are analytical studies that show how this new method can be more effective than the older metal catalyst methods.
Pamenter, Matthew H.J., "Hydrogen Bond Activation of Donor Acceptor Cyclopropanes" (2023). Electronic Thesis and Dissertation Repository. 9892.