Cascade Reactions to Access Bioactive Scaffolds

Schlitzer, Steven

Cascade Reactions to Access Bioactive Scaffolds

dc.contributor.advisor	Sharma, Indrajeet
dc.contributor.author	Schlitzer, Steven
dc.contributor.committeeMember	Glatzhofer, Daniel
dc.contributor.committeeMember	Duerfeldt, Adam
dc.contributor.committeeMember	Richter-Addo, George
dc.contributor.committeeMember	Abraham, Eric
dc.date.accessioned	2020-07-29T15:18:49Z
dc.date.available	2020-07-29T15:18:49Z
dc.date.issued	2020-07-16
dc.date.manuscript	2020-07-16
dc.description.abstract	In the recent decade there has been a shift in drug development to favor planar, aromatic small molecules with easy synthetic access, despite centuries of research in bioactive natural products, which are often highly rigid, three-dimensional structures like spirocycles. These scaffolds remain underexplored in drug development efforts, predominantly due to the challenges associated with their synthesis, and lack of a general, convergent methodology. To address these challenges, we have designed an O–H Insertion/Conia-ene reaction cascade between homopropargylic alcohols and acceptor/acceptor diazo compounds, which uses dual Rh/Au+ catalytic system. This cascade occurs instantly at room temperature, and has been applied towards the synthesis of substituted tetrahydrofurans when linear diazo compounds are used. Thus far, the cascade accommodates a variety of substituted diazo compounds with carboxylic acids/alcohols to provide functionalized tetrahydrofurans, and g-butyrolactones, with a high degree of regio- and stereo-selectivity. Next, we were able to extend the utility of our O–H Insertion/Conia-ene reaction cascade towards the synthesis of spiroheterocycles by employing cyclic diazo substrates with propargylic alcohols. This convergent approach furnishes an array of spiroheterocycles by employing the same dual Rh/Au+ catalytic system in refluxing dichloromethane. This approach has proven general, and was used to synthesize a substrate scope of twenty-four substrates based on natural product scaffolds, including spirobarbituates, spiromeldrum’s acids, spirooxindoles, and the spirocyclic core of the pseurotin natural products. Lastly, we have extended our X–H Insertion/Conia-ene strategy towards uncommon nucleophiles, for the synthesis of sulfur- and all-carbon spirocycles. When propargylic thiols are employed as substrates with linear diazos, we have found that the S-H insertion reaction proceeds in high yield, and Conia-ene cyclization can be promoted when the reaction is conducted in a stepwise fashion. However, when the reaction is conducted in a single pot, we isolated a new, thiofuranofuran compound, which we expect forms via undesired 5-endo-dig cyclization of the propargylic thiol, followed by cyclopropanation and subsequent ring opening. Additionally, by changing our retrosynthetic approach to an intramolecular disconnection, we were able to synthesize an all-carbon spirocycle through a benzylic C-H Insertion/Conia-ene cascade, by using a catalytic mixture consisting of Rh2(HFB)4, ClAuPPh3, and CuOTf in refluxing dichloromethane. In an orthogonal research effort, we have also developed a metal-free cascade for the synthesis of aromatic heterocycles. This cascade uses precursors synthesized from readily accessible 2’-hydroxy/aminochalcones, and commences with a DBU-mediated intramolecular aldol condensation, which occurs within 90 minutes at room temperature, to generate a 1,3,5-triene. This triene is heated overnight (80 – 120 °C) to promote a 6p-electrocyclization, and oxidative aromatization to generate a new aromatic ring. This cascade has proven general, and has been applied towards the synthesis of benzo[c]coumarins, phenanthradinones, dibenzofurans, and carbazoles, up to a 1-gram scale. The cascade reactions developed throughout the course of this dissertation research provide new retrosynthetic strategies for the formation of natural product cores, which could be used to expand the chemical space in drug discovery.	en_US
dc.identifier.uri	https://hdl.handle.net/11244/325314
dc.subject	Organic Chemistry	en_US
dc.subject	Synthetic Chemistry	en_US
dc.subject	Diazo Chemistry	en_US
dc.subject	Cascade Chemistry	en_US
dc.subject	Organometallic Catalysis	en_US
dc.thesis.degree	Ph.D.	en_US
dc.title	Cascade Reactions to Access Bioactive Scaffolds	en_US
ou.group	College of Arts and Sciences::Department of Chemistry and Biochemistry	en_US