Date of Award

Summer 2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Dockendorff, Chris

Second Advisor

Gardinier, James

Third Advisor

Reiter, Nicholas

Abstract

1. Dual amine/pi Lewis acid catalyst systems have been reported for intramolecular direct additions of aldehydes/ketones to unactivated alkynes and occasionally alkenes, but related intermolecular reactions are rare. We reasoned that bulky metal ligands and bulky amine catalysts could minimize catalyst poisoning and could facilitate certain examples of direct intermolecular additions of unactivated aldehydes/ketones to alkenes/alkynes. Density Functional Theory (DFT) ground state calculations on putative catalytic intermediates for alkyne versus organocatalyst complexation to the -acid, and also the key carbon-carbon bond formation were used to prioritize ligand/organocatalyst combinations. Our calculations suggested that PyBOX-Pt(II) catalysts for alkene/alkyne activation could be combined with certain organocatalysts for aldehyde activation. With such combinations, alkene/alkyne coordination to the -acid were calculated to be more exergonic than catalyst poisoning pathways. Consistent with the calculations, preformed enamines generated from the MacMillan imidazolidinone did not displace ethylene from a biscationic (t-Bu)PyBOX-Pt2+ complex. This novel catalytic system facilitated an intramolecular C-C bond formation with a formyl alkyne substrate, and modified conditions have recently extended this to an analogous intermolecular reaction. Investigations into alternative metal, ligand, organocatalyst, and substrate combinations are ongoing.2. The enzyme protein disulfide isomerase (PDI) is essential for the correct folding of proteins and the activation of certain cell surface receptors, and is a promising target for the treatment of cancer and thrombotic conditions. A previous high-throughput screen identified the commercial compound STK076545 as a promising PDI inhibitor. To confirm its activity and support further biological studies, a resynthesis was pursued of the reported -keto-amide with an N-alkylated pyridone at the -position. Numerous conventional approaches were complicated by undesired fragmentations or rearrangements. However, a successful 5-step synthetic route was achieved using an aldol reaction with an -pyridone allyl ester as a key step. An X-ray crystal structure of the final compound confirmed that the reported structure of STK076545 was achieved, however its lack of PDI activity and inconsistent spectral data suggest that the commercial structure was misassigned.

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