Synthesis of bulky 1,4,7-triazacylcononanes, including asymmetric derivatives; Esterification by aryl-diselenide catalyzed redox condensation; 1-amino-3,4-difluorocyclopentane-1-carboxylic acids as PET imaging agents Pubblico

Abstract

Triazacyclononane and its N-substituted derivatives have been extensively applied as ligands in coordination chemistry and catalysis. While the coordination chemistry of tacn has reached a level of relative maturity, synthetic access to the tacn scaffold remains highly underdeveloped. To date, there are no examples of N-substituted tacn derivatives that contain a non-annulet stereocenter alpha to the annular N atoms, or unsymmetrically N-substituted derivatives where one or two R groups are tertiary. Reported herein is an efficient method for preparing the previously inaccessible derivatives of tacn described above, as well as improved routes to the industrially relevant compounds H3tacn and H4dtne.

The dehydrative condensation of alcohols and carboxylic acids to generate esters is classically performed in the presence of a Lewis or Brønsted acid, or by preactivation of the carboxylic acid to generate a powerful and highly acidic electrophile. An alternative approach to this transformation is reduction oxidation condensation (redox condensation), which involves the formal oxidative removal of “H2” and reductive removal of “O”, allowing for the coupling of carboxylic acids and alcohols under relatively milder conditions. Generally, esterification by redox condensation requires both a stoichiometric oxidant and reductant, rendering these protocols wasteful. In this work, a redox dehydration esterification of carboxylic acids and alcohols in the presence of a catalytic aryl diselenide oxidant with O2 as a terminal oxidant and triethylphosphite as the terminal reductant is described.

Reported herein is the cold synthesis, ¹⁸F radiosynthesis, and biological evaluation of the four stereoisomers of 1-amino-3,4-difluorocyclopentane-1-carboxylic acid (3,4-DFACPC), a series of non-natural amino acids for use in Positron Emission Tomography (PET). In vitro 9L, U87 ΔEGFR, and DU145 cancer cell line assays demonstrated that 3,4-DFACPCs are substrates primarily for system L transport, with some transport occurring via system ASC. In Fischer rats bearing 9L gliosarcoma tumors, [¹⁸F]3,4-DFACPCs showed high levels of uptake in tumors and good tumor to normal brain tissue ratios, suggesting that these compounds may be useful as PET radiotracers for imaging brain tumors. Additionally, biodistribution studies in healthy Fischer rats as well as uptake in DU145 cells collectively imply that [¹⁸F]3,4-DFACPCs may have promise for imaging prostate cancer.

Table of Contents

Chapter 1. Synthesis of Previously Inaccessible Derivatives of 1,4,7-Tri-R-1,4,7-Triazacyclononane,

Including Chiral Examples, and a Rapid Synthesis of the HCl Salts of H3tacn and H4dtne................1

1.1 Abstract ........................................................................................................................................2

1.2 Introduction .................................................................................................................................2

1.3 Results and Discussion .................................................................................................................5

1.4 Conclusions ................................................................................................................................23

1.5 Experimental Information and Characterization Data ...............................................................24

1.6 References ................................................................................................................................137

Chapter 2. Esterification by Redox Dehydration Using Diselenides as Catalytic Organooxidants..141

2.1 Abstract ....................................................................................................................................142

2.2 Introduction .............................................................................................................................143

2.3 Results and Discussion .............................................................................................................153

2.4 Conclusions ..............................................................................................................................160

2.5 Experimental Information and Characterization Data .............................................................161

2.6 References ................................................................................................................................198

Chapter 3. Synthesis and Biological Evaluation of the Stereoisomers of 1-Amino-3,4-

difluorocyclopentane-1-carboxylic acid (3,4-DFACPC) as PET Imaging Agents ...........................201

3.1 Abstract ...................................................................................................................................202

3.2 Introduction ............................................................................................................................202

3.3 Results and Discussion ............................................................................................................215

3.4 Conclusions .............................................................................................................................251

3.5 Experimental Information and Characterization Data ............................................................252

3.6 References ...............................................................................................................................339

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic Chemistry, Inorganic
Parola chiave	PET Imaging Coordination Chemistry Triazacyclononane Organic Synthesis Redox Dehydration
Committee Chair / Thesis Advisor	Lanny Liebeskind, Emory University
Committee Members	Frank McDonald, Emory University Nathan Jui, Emory University

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