Date of Award

Fall 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Ellman, Jonathan

Abstract

Nitrogen heterocycles are present in almost two-thirds of U.S. FDA approved pharmaceuticals, garnering interest in the ability to rapidly access these structures displaying different functional groups. The first two chapters of this dissertation will discuss develop-ment of Cp*Rh(III)-catalyzed C–H activation to rapidly access two different classes of 5.6-fused nitrogen heterocycles. The third chapter describes the application of these heterocycles to the validation of a novel whole transcriptome RNA screen.Chapter 1 describes a three component reaction for the rapid assembly of pyra-zolopyrimidines from commercially available aminopyrazoles, aldehydes, and sulfoxo-nium ylides. The method was optimized for setup without the use of an inert atmosphere and to use a microwave reactor to allow for fast reaction times. A wide variety of functional groups were found to be compatible with the reaction conditions, including acidic and basic substituents. The first use of a formyl sulfoxonium ylide allowed to the preparation of products with a lower substitution pattern. Chapter 2 describes a method for coupling hydrazones derived from amino-pyrroles or azoles and aldehydes with alkynes to access pyrrolo- and azolopyridazines. This transformation represents a rare example of hydrazoyl C–H activation. The C–H activation also occurs without the use of a heteroatom directing group. A hydrazone with an alkyne moiety tethered to it was synthesized and subjected to the reaction conditions to access a tricyclic ring system, and studies were performed to further understanding of the reaction mechanism. Chapter 3 details a novel method developed by Professor Matt Simon’s lab (Yale Molecule Biology and Biophysics) for a single experiment screen to determine where a small molecule binds to the transcriptome. A collection of molecules based off of the drug risdiplam, which is known to bind RNA, were synthesized for validation of the method. Results from the screen of preliminary compounds are discussed.

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