Date of Award

2020

Document Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry and Biochemistry

First Advisor

Brian W. Michel

Second Advisor

Sunil Kumar

Third Advisor

Michelle K. Knowles

Fourth Advisor

Andrei Kutateladze

Fifth Advisor

Deborah M. Ortega

Keywords

Alkyne, Annulation, Electronically biased, Polarized, Regioselective, Ynol ethers

Abstract

Transition metal-catalyzed alkyne annulations have developed into incredibly powerful synthetic tools over there the past quarter century. These reactions provide rapid access to important organic scaffolds such as indole, quinoline, isoquinoline, indene, and isocoumarin scaffolds. Transition metal mediated alkyne annulations have proven invaluable in synthetic fields, such as natural product total synthesis, by offering efficient pathways to otherwise synthetically difficult to access substrates.

Foundational works performed by chemist such as Larock, Ackermann, Satoh, and Miura have been established through relying upon the usage of symmetrical alkynes. When unsymmetrical alkynes are used in annulation processes mixtures of regioisomers are often isolated. While methodologies have been developed which regioselectively deliver annulation products, the regioselective nature of these reactions is often empirically determined and obtained with little synthetic design to impact the alkyne migratory insertion step of the catalytic cycle.

In recent years few examples of polarized, unsymmetrical alkynes have been sparingly used in transition metal alkyne annulations. Still, these limited examples provide the roadmap for how to regioselectively control alkyne annulations. Researchers have displayed that one class of polarized alkynes, ynol ethers, exhibit the ability to react regioselectively in transition metal-catalyzed migratory insertion processes. There has been little research focused on expanding this regioselective nature of ynol ethers into transition metal-catalyzed alkyne annulations. This dissertation provides the work we have accomplished in efforts to bridge this gap.

We have established the use of ynol ethers as compatible annulations partners in transition metal-catalyzed alkyne annulations. They have been utilized in the regioselective synthesis of diverse 4-oxy-substituted isoquinolinones. These substrates can be further functionalized into prolyl-4-hydroxylase domain inhibitor analogues. Ynol ethers were also employed to regioselectively facilitate the palladium catalyzed synthesis of complex indenol ethers. Through inhibiting the terminal step in this indene synthesis, -hydride elimination and intercepting the in-situ generated palladium intermediate, the isolation of an enantiomeric mixture of isomers was observed. To date we have partially optimized a regioselective, enantioselective, intermolecular Heck–Suzuki–Miyaura cascade reaction. Further investigation is necessary to fully understand regioselective transition metal-catalyzed ynol ether annulations, but the groundwork has been laid for this work to continue.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Provenance

Received from ProQuest

Rights holder

Brandon L. Coles-Taylor

File size

241 p.

File format

application/pdf

Language

en

Discipline

Chemistry, Organic chemistry

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