Dissertation/Thesis Abstract

Synthesis and Study of Heteroatomic Spirocyclic Scaffolds
by Hilmey, David G., Ph.D., The Ohio State University, 2006, 351; 10835751
Abstract (Summary)

Work presented in this thesis will demonstrate the synthetic progress made toward, and study of, various natural and unnatural products that can be utilized in a supramolecular capacity through ionic or biomacromolecular coordination. We have developed trispirocyclic tetrahydrofuranyl systems anchored onto inositol scaffolds and covalently linked them to various systems. Drug conjugates with a tamoxifen unit spaced by an acetylene linker to the trispirotetrahydrofuranyl Li+ ionophores were made with potential to increase drug bioavailability. Also, long alkyl and acyl chains were synthetically linked to these ionophores and could be elaborated into lipid mimics. Finally, trispiro ethers were coupled to transition metal cationic binders containing bi- and terpyridine subunits resulting in heterocationic lithium and transition metal chelation in predictable and distinct regions of the same molecular structure.

The second area of spirocyclic research presented pertains to the synthesis and elaboration of 6-azaspiro[4.5]decane-1,7-dione into advanced intermediates of the natural products halichlorine and pinnaic acid. The spirocyclic core of these compounds imparts rigidity to their three-dimensional structures and thus provides for specific and potent supramolecular interactions in a biological setting. For example, these natural products demonstrate potential as anticancer agents through their inhibition of specific enzymes found in the inflammatory pathway. Utilization of a stereocontrolled, acid-promoted Beckmann rearrangement was key to the successful synthesis of 6-azaspiro[4.5]decane-1,7-dione. This ketone was then functionalized in a variety of ways including nucleophilic addition followed by reduction or acid induced rearrangement.

Finally, stereoisomeric groups of straight-chained spirocyclic substituted ligands were synthesized with consecutively installed tetrahydrofuranyl rings of varying chain length. With varying stereochemistry at each carbon atom of a carbon backbone, many isomers are possible. We have successfully completed the full set of bis- and tris-(THF) structures as well as a small sampling of twelve hexa-(THF) compounds, which provide an excellent cross section of all possible isomers. A number of these polyethers were then analyzed through X-ray crystallography and computational methods to reveal their relative stereochemistry as well as some very unique conformational arrangements. Through this study, we have demonstrated the interdependence of acyclic polyspiro-substituted stereochemistry on conformational adoption as well as deformation from expected gauche interactions.

Indexing (document details)
Advisor: Paquette, Leo
School: The Ohio State University
Department: Chemistry
School Location: United States -- Ohio
Source: DAI-B 79/09(E), Dissertation Abstracts International
Subjects: Chemistry
Keywords: Beckmann rearrangement, Ionophores, Pinacolic ring expansion, Pinnaic acid, Spirocycles, Supramolecular chemistry
Publication Number: 10835751
ISBN: 978-0-355-96732-6
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