Date of Completion

4-11-2019

Embargo Period

4-11-2019

Keywords

Carbohydrates, glycosides, antibiotics, synthesis, organic, catalysis

Major Advisor

Mark Peczuh

Associate Advisor

Nicholas Leadbeater

Associate Advisor

Dennis Wright

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The synthesis of glycosylated small molecule compound libraries remains a difficult challenge in the field of organic chemistry. Leading techniques are hindered by the requirement of optimization based on substrate, and the generation of non-classical glycoside products. The development of a platform which takes advanced glycoside intermediates and utilizes reactive handles on the aglycone for rapid diversification to final products has been completed in this research. Use of amino sugars, derived from known antibiotics, as the carbohydrate component of final compounds was intended to exploit known binding interactions with biomacromolecules. Final compounds indeed showed ability to inhibit bacterial protein synthesis in vitro and limit growth in culture, suggesting binding interactions were retained.

Development of new generations of therapeutics based on current classes of antibiotics remains a primary means of new drug discovery. The aminoglycoside family of antibiotics is no exception to this, as current members of this class show promise of improved pharmacological properties with diversification to their structures. Studies have been conducted but have not addressed novel alkylation patterns on the amino sugar component of these compounds. In this work we have shown the development of a synthetic methodology to access mono-, di-, and mixed- alkyl kanosamine sugars. Elaboration to glycosides and subsequent diversification efforts have led to the finding of novel bacterial protein synthesis inhibitors.

New catalytic methodologies can lead to powerful synthetic transformations which would be inaccessible or of great difficulty otherwise. In particular, asymmetric hydrogenation reactions, while simple in terms of chemical transformation, yield enantiomerically pure compounds which are of great importance to drug discovery efforts. In this work, the use of prochiral starting materials and an Iridium based catalytic system using bidentate chiral phosphine ligands has been shown to yield a wide range of 2-substituted 1,4-benzodioxanes with excellent enantioselectivities. Compound bearing this chemical motif are known to be privileged structures in medicinal chemistry and have great potential for further development to lead compounds.

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