Thermolysis of Hypervalent Iodine Complexes: Synthesis of Fluorinated Radiotracers for Positron Emission Tomography and Synthesis of Quaternary α-Alkyl α-Aryl Amino Acids

Authors

Jayson J. Kempinger, University of Nebraska-LincolnFollow

First Advisor

Stephen G. DiMagno

Date of this Version

11-2016

Document Type

Article

Citation

Kempinger, J. J. "Thermolysis of Hypervalent Iodine Complexes: Synthesis of Fluorinated Radiotracers for Positron Emission Tomography and Synthesis of Quaternary α-Alkyl α-Aryl Amino Acids", Master’s Thesis, University of Nebraska, Lincoln, NE, 2016.

Comments

A THESIS Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Master of Science, Major: Chemistry, Under the Supervision of Professor Stephen G. DiMagno, Lincoln, Nebraska: November, 2016

Copyright 2016 Jayson J. Kempinger

Abstract

Hypervalent iodine complexes can be used to deliver a variety of functional groups to arenes. Delivery of fluorine‑18, in a manner compatible with positron emission tomography (PET), is especially attractive. Vizamyl^TM, an injectable solution of [¹⁸F]Flutemetamol, is currently used to diagnose and monitor the progression of Alzheimer’s Disease (AD), the most common form of dementia. AD affects 47.5 million people across the world as of 2015, and is projected to affect 1 in 85 people by 2050. An improved radiosynthesis of [¹⁸F]Flutemetamol via a diaryliodonium salt is described. The use of nonpolar solvents minimizes disproportionation and other side reactions, leading to higher fluorination yields. The use of an electron-withdrawing protecting group allows functionalization of the highly electron-rich aniline ring. Upon initial testing, thermolysis of this salt provides radiochemical yields (RCY) of more than twice that of the best previously reported syntheses. Another class of heterocycles, 2-aryl-5-fluorobenzimidazoles, was also investigated. A variety of these suspected anti-tumor, anti-microbial, and anti-inflammatory compounds were fluorinated for screening and additionally synthesized by thermolysis of diaryliodonium salts, suitable for radiosynthesis.

Hypervalent iodine complexes involving stabilized α‑nitroester enolates were developed and studied. Thermolysis of these diaryliodonium salts leads to selective formation of α‑alkyl α‑aryl α‑nitroesters, which can be reduced and hydrolyzed to form the analogous quaternary α‑alkyl α‑aryl amino acids. These unnatural quaternary amino acids have no enolizable proton, so racemization is not possible, and oxidation pathways that involve abstraction of the proton on the α‑carbon are also prevented. This convergent, rapid synthesis provides access to a variety of unnatural quaternary amino acids that can be used for screening and studying biological pathways. Synthesis of an enantiopure cyclophanyl-substituted diaryliodonium salt was investigated as a potential method for stereoselectively generating these compounds.

Adviser: Stephen G. DiMagno