Date on Master's Thesis/Doctoral Dissertation

5-2019

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Chemistry

Degree Program

Chemistry, PhD

Committee Chair

Luzzio. Frederick

Committee Member

Handa, Sachin

Committee Member

Grapperhaus, Craig

Committee Member

Schultz, David

Author's Keywords

thalidomide; teratogenesis; amino acids; protecting groups; DAST; Isoindolinones

Abstract

Thalidomide analogues were synthesized utilizing optimized click conditions from 3-azidoglutarimide and an array of arylacetylenes or N-ethynyl/N-propargyl phthalimide derivatives. The intermediate, 3-azidoglutarimde, was pivotal and yielded a new and scalable synthesis. The reaction conditions utilized a copper sulfate/sodium ascorbate system in aqueous tetrahydrofuran to propagate the dipolar cycloaddition reactions between the azidoglutarimide and the alkynyl coupling partners. The first explored substrates were substituted arylalkynes to optimize the click reaction. Arylalkynes selected were to exhibit similar electron deficient rings to mimic phthalimide. Along with the synthesis of click thalidomide analogues, click analogue of the antiangiogenic and more potent teratogenic thalidomide analogue EM-12 was prepared. The isoindolinone group can act interchangeably with the N-phthaloyl nitrogen protecting group in amino acids. Amino acid intermediates using the N-isoindolinone group are used to make natural and unnatural a-amino acid derivatives using a two-carbon synthon. Selective benzylic oxidation was performed with the N-isoindolinone group being converted to the N-phthaloyl group (65–98%), which could be conveniently removed with hydrazine. For preparation of N-isoindolinone protected amino acids, an array of side chains was installed on the isoindolinone-protected glycine equivalent. This was accomplished through selective deprotonation to demonstrate the utility of the N-protected isoindolinone synthon (51–93%). Selective oxidation is employed on the benzylicN-isoinodolinone with OxoneÒ/KBr and successfully converted the N-isoindolinone group to the N-phthaloyl group in simple substrates, but substrates bearing unsaturated or electron-rich side chains respond poorly to the oxidation. The alkoxylation of chiral N-phenethyl hydroxyisoindolinones were synthesized with diethylaminosulfur trifluoride and an array of primary and secondary alcohols. The mechanism by which synthesis alkoxyisoindolinones are synthesized is through generation of an N-acyliminium ion to allow alkoxylation. The alkoxylated product exhibits a diastereomeric ratio influenced by the chiral N-phenethyl with a favored diastereomer. The stereochemistry and mixture of diastereomers were observed through this reaction.

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