Graduation Semester and Year
2023
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Chemistry
Department
Chemistry and Biochemistry
First Advisor
Carl J Lovely
Abstract
This thesis documents progress toward a total synthesis of the marine natural product palau'amine, a stereochemically dense hexacyclic pyrrole-imidazole alkaloid with pharmaceutically relevant anticancer, antifungal, and antibacterial activity. Also described herein are several miscellaneous synthesis projects and the application of computational NMR as an aid for solving structure elucidation problems. Chapter 1 is a continuation of our lab’s prior work utilizing vinylimidazoles in cycloaddition reactions to gain rapid access to scaffolds resembling dimeric pyrrole-imidazole alkaloids such as ageliferin or palau’amine. Mechanistic aspects of these cycloadditions for both inter- and intramolecular cases were probed via time-course NMR experiments and computational studies, which revealed solvent choice as being critical for reaction success and the occurrence of asynchronous transition states whose direction of asynchronicity varies according to the electron-withdrawing ability of the imidazole N-protecting group, respectively. Studies on reaction concentration also enabled the development of a simple and scalable room-temperature vinylimidazole Diels-Alder reaction. The second half of Chapter 1 explores transforming these Diels-Alder adducts into more advanced intermediates for use in the synthesis of pyrrole-imidazole alkaloids. Notably, a fluoride-induced intramolecular lactonization was developed which surprisingly retained the highly reactive enamine present in the initial Diels-Alder cycloadduct, allowing for functionalization at what later becomes the C17 position of palau’amine. Studies toward elaboration of this species are also presented. Chapter 2 covers two methodology studies, compounds from which were used by the Armstrong lab to assess the effectiveness of different chiral stationary phases for enantiomeric separations. The first of these methodology studies provides a route to access C2-functionalized imidazoles from aldehyde starting materials. The long term goal of this study is to eventually utilize this process with the more complex intermediates described in Chapter 1 to form one of the imidazole units present in palau’amine. The second methodology study surveys the compatibility of prearomatic oxazoles in ene reactions with various enophiles with modest yields being obtained for the majority of partners. The final chapter, Chapter 3, assesses the use of Boltzmann-weighted NMR chemical shift calculations for various structure elucidation challenges. The chapter opens with a discussion about practical aspects of performing these calculations, including the development of a user-friendly terminal-based program for facilitating all the necessary data and file manipulations. Next, we apply these calculations to the problem of determining the stereochemical outcome of spirocyclization reactions used in our palau’amine work, a problem not easily solvable by standard NMR techniques. We also study the effect of conformer ensemble quality by comparing the use of ensembles generated by different methods. From these studies, we see that this method performs well in distinguishing between spirocyclic diastereomers. Additionally, we apply this technique to a conformational analysis problem in collaboration with the Foss lab for their work on synthesizing bridged calix[4]arenes.
Keywords
Chemistry, Organic, Synthetic, Computational, Palau'amine, Pyrrole-imidazole, Alkaloids, Natural products, Marine natural products, Total synthesis, NMR, Computational NMR, Boltzmann-weighted chemical shift, Diels-Alder, Heterocyclic chemistry
Disciplines
Chemistry | Physical Sciences and Mathematics
License
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Fulton, Brandon, "Studies Toward a Total Synthesis of the Pyrrole-Imidazole Alkaloid Palau'amine and Computationally Assisted Stereochemical Elucidation" (2023). Chemistry & Biochemistry Dissertations. 277.
https://mavmatrix.uta.edu/chemistry_dissertations/277
Comments
Degree granted by The University of Texas at Arlington