Synthetic methodologies toward the functionalization of benzhydrols and carbohydrates
Organoazides are highly versatile substrates that are often used as precursors to triazoles, amides, amines and imines. As dipolar functional groups, azides are routinely exploited in chemical biology as a means to append biomarkers onto macromolecules via cycloaddition reactions. Furthermore, the reduction of azides to amines serves as a convenient strategy for the installation of nitrogenous functional groups onto complex substrates. Herein, synthetic methodologies were developed for the direct azidation of benzhydryl alcohols and carbohydrates to afford diarylazidomethane analogues and glycosyl azides. In this work, reaction conditions were optimised to afford the targeted azide products in high yields. The use of non-explosive azidotrimethylsilane under Brønsted acid catalyzed conditions offers a safer alternative to existing methodologies with a simple experimental setup that does not require anhydrous conditions. Additionally, the reaction demonstrated excellent tolerance to a broad scope of unprotected functional groups including: amine, amide, aldehyde and alcohol. The successful application of these reaction conditions to benzyl- and acetyl-protected carbohydrates produced glycosyl azides in good yields. In addition, reaction conditions for the conversion of exo-glycals to tertiary glycosyl azides have been developed. The glycosylation reactions proceeded at room temperature with short reaction times and afforded the targeted products in high yields with virtually exclusive diastereoselectivity to the α-anomer in pyranose-based derivatives. Exo-glycals bearing alkyl, phenyl and alkynyl substituents were also well-tolerated. The scope of substrates was expanded to include mannoside, galactoside, arabinoside and riboside derivatives. As part of this study, the tertiary azides were shown to undergo inter- and intramolecular cycloaddition reactions with alkynes. Expanding our research program on exo-glycals led to the development of a metal-catalyzed direct coupling methodology between exo-glycals and aryl iodides in the presence of a catalytic amount of Pd(OAc)2. These cross-coupling reactions proceeded in high yields with exclusive selectivity to the Z-isomers. Moreover, the developed methodology demonstrated excellent functional group tolerance to electron-withdrawing groups including aldehydes, alcohols and carboxylic acids.
Networked Digital Library of Theses and Dissertations
University of Ontario Institute of Technology