Dissertations, Theses, and Capstone Projects

Date of Degree

9-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Ryan P. Murelli

Committee Members

Mark R. Biscoe

Wayne W. Harding

Subject Categories

Organic Chemistry

Keywords

Alpha-Hydroxytropolone, Oxidopyrylium Ylide, Troponoid Atropisomerism, Suzuki Cross-Coupling, Stereodivergent Stille Cross-Coupling Reaction, Highly Electron Poor Buchwald type Ligands

Abstract

Over the past years the Murelli lab has established research based on the synthesis and biological evaluations of alpha-hydroxytropolones (alpha-HTs). These seven-membered aromatic rings have three contiguous oxygen atoms that chelates to metals, thus, biologically having the ability to bind dinuclear metalloenzymes and promoting inhibition. Synthetic routes to alpha-HT’s are scarce and therefore has been the main driving force in developing efficient and general synthetic methods to obtain variations in alpha-HTs, enabling SAR studies. The Murelli lab have therefore developed an oxidopyrylium cycloaddition/ring-opening strategy that is able to generate polysubstituted alpha-HTs starting from kojic acid, a cheap and readily available reagent. Adding to this, the Murelli lab have developed a scalable and reproducible procedure that obtains oxidopyrylium ylide in high purity without the need for column chromatography. This has enabled the synthesis and biological evaluations of libraries of alpha-HTs for many human diseases including herpes simplex virus, hepatitis B virus and other human pathogens.

Atropisomerism is a form of chirality arising from conformational restriction of chiral axes and has an essential role in many compounds including, but not limited to, chiral ligands, and pharmaceutical drugs. Structural aspect of tropolones such as their large ring size, smaller bond angles, tropylium characteristics, potential ring-puckering, and configurational stability have enabled the synthesis of atropisomeric troponoid-benzenoid structures. Our ability to synthesize atropisomeric troponoid-benzenoid compounds, through cross-coupling reactions, paves the way for entry into a whole new ligand class and asymmetric catalysis in contrast to the abundant benzenoid based privileged ligands.

The Biscoe lab studies asymmetric C–C bond formation utilizing cross-coupling reactions such as Suzuki and Stille reactions. The Stille reaction is a chemical reaction that involves the use of organotin compounds with a variety of electrophiles. Stereospecific transfer of chirality using configurationally stable enantioenriched carbastannatranes, as the organotin coupling partner, has been realized with control over retention or inversion of stereochemistry. This is accomplished using palladium catalysis in combination with an electron deficient Buchwald type ligand and copper (I) salts.

Herein, we describe biological evaluations of synthetic alpha-HTs, identification of conditions for the atropselective cross-coupling of tropolones and benzenoid groups to generate axially chiral tropone-benzenoid biaryl systems. We also describe developments of cross-coupling methods that enables the stereospecific transfer of a stereogenic center utilizing the Stille reaction.

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