Degree Type

Dissertation

Date of Award

2014

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

George A. Kraus

Abstract

Natural products with their ever-growing potential applications in the drug discovery process have influenced many researchers to devise flexible and concise synthetic strategies towards these biologically active substances. As more complex and structurally unique natural products are isolated from plants or microorganisms, developing innovative synthetic tools become highly desirable to obtain them in sufficient quantities. Synthetic organic chemistry allows a thorough investigation of their biological properties and the endeavor enhances the dynamic evolution process of the field. With this in mind, we have developed new synthetic methodologies to synthesize meroterpenoid paracaseolide A and an important class of 3-methylcarbazole alkaloids. In addition, the same approach enabled a direct synthesis of fluorescent rosamine probes with practical applications.

The first chapter of the dissertation describes the total synthesis of potential anti-cancer agent (±)-paracaseolide A, which possesses a unique tetracyclic framework with concave and convex faces. The facile synthesis of the natural product was accomplished in 8 steps in 6.6% overall yield, utilizing multiple sulfoxide eliminations and a key tandem 1,4-conjugate addition/aldol reaction to introduce the necessary functional groups onto the tetracyclic bis-lactone scaffold. The synthetic strategy allows diverse analogue development through a common advanced intermediate.

The second chapter reveals a novel inverse electron-demand Diels-Alder (IEDDA) methodology to access biologically active and naturally-occurring 3-methylcarbazoles as well as synthetic derivatives using 3-chloroindoles and the 2-pyrone methyl coumalate. The transformation constitutes the first successful example of its kind; consequently extending the scope of indole dienophiles in the IEDDA reactions. The application of the single-pot Diels-Alder/decarboxylation/elimination domino sequence resulted in the metal-free generation of carbazole alkaloids with exclusive regioselectivity in up to 90% yield.

The last chapter focuses on the synthesis of rosamine probes to capitalize on a new strategy of an organolithium addition to a benzophenone imine-substituted xanthone. Subsequent acid-catalyzed deprotection and dehydration resulted in an efficient four-step synthesis from 3,6-dihydroxyxanthone. The condensed synthetic approach provides rapid access to desirable primary amine-functionalized multifunctional rosamine analogues in good yields for applications in live-cell imaging.

Copyright Owner

Tezcan Guney

Language

en

File Format

application/pdf

File Size

132 pages

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