Graduation Semester and Year

2011

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Carl Lovely

Abstract

An intramolecular Diels-Alder reaction of vinylimidazoles has been developed and applied towards the total synthesis of benzimidazole and tetrahydrobenzimidazole natural products, namely kealiiquinone and ageliferin. A common feature of many imidazole-containing natural products including those of interest in this dissertation is the presence of a 2-amino or 2-imidazolone substituent. A novel method for achieving C2 substitutions has been developed employing chloro-containing reagents. N-Chlorosuccinimide in conjunction with a base has been used to give 2-imidazolones directly from imidazolium salts. This method was then optimized through the use of sodium hypochlorite. This chemistry provides the desired 2-imidazolones in yields ranging from 46-88% in benzimidazole and 37-80% in simple imidazole systems. N-Chlorocarbamates have been used to give 2-iminoimidazoles in yields of 72-95% in benzimidazoles and 36-71% in simple imidazoles providing an intermediate that can be easily deprotected to unmask a 2-amino functionality. The major advantage of these procedures is the ease of functionalization without the need for strictly anhydrous conditions and the use of strong bases (i.e. BuLi and LDA). An approach to the total synthesis of kealiiquinone is described involving construction of a propynoate system containing a vinyl imidazole and an aryl substituted, which then participates in the intramolecular Diels-Alder chemistry. The resulting heterocycle was oxidized to give a benzimidazole intermediate, and utilizing the sodium hypochlorite oxidation protocol efficiently gave a 2-imidazolone intermediate in 74% from which the remaining quinone ring was constructed. Among the final transformations of this synthesis was a benzyl deprotection involving triflic acid which was effective at removing the benzyl group as well as an aryl methyl ether resulting in isolation of a phenol intermediate. Methylation protocols have been investigated; however, conditions for a chemoselective o-methylation have yet to be identified. The Diels-Alder chemistry of propynoates has been extended to access the core structure of ageliferin. Optimization was necessary at points leading up to and after the Diels-Alder reaction. The construction of a key ester intermediate was prepared from a propargyl alcohol directly using a cyano-mediated, tandem oxidation/substitution protocol greatly reducing the steps needed for the preparation of the propiolate derivative. Following the Diels-Alder reaction, the stereochemistry of ageliferin was set through a Pd(OAc)2 catalyzed hydrogenation of a double bond to give an all cis tetrahydrobenzimidazole intermediate. Methanolysis of a lactone functionality of this intermediate provided the desired trans relationship as a result of epimerization of the ring opened product, intersecting a previous route. Therefore, we have provided examples of benzimidazole and tetrahydrobenzimidazole alkaloids that can be accessed through an intramolecular Diels-Alder reaction of easily prepared propynoate systems. Continued studies are underway to achieve the final transformations of these target molecules, as well as utilizing intermediates of these syntheses to access related natural products, particularly in the case of ageliferin.

Disciplines

Chemistry | Physical Sciences and Mathematics

Comments

Degree granted by The University of Texas at Arlington

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