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Date of Award

Spring 2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Supervisor

James McNulty

Language

English

Abstract

Tris(hydroxymethyl)aminomethane (THAM) was a readily-available and economical amino-triol that was viewed as having a large untapped potential as a starting material. The full chemoselective functionalization and differentiation of the amino group and the three primary alcohol residues present in THAM was extensively investigated. The development of this methodology allowed for the rapid assembly of a differentiated core that lead to existing and new potential drug scaffolds.

The discovery of a novel oxidative fragmentation and rearrangement process was made leading to the synthesis of differentiated oxazolidinone rings. This process allowed for the creation of novel chemical library situated around THAM-based oxazolidinones, as well as THAM-based 1,3-dioxanes.

THAM was also used as a starting material for sphingosine analogs, including sphingosine 1-phosphate (S1P) and anticancer S1K inhibitors. Selective functionalization of the amine and one alcohol within an oxazolidinone ring allowed access to a new family of Linezolid-type oxazolidinones as well. Additionally, various triazole-based compounds were prepared, which allowed access to a new family of potential antifungal agents based on the lead compound Fluconazole.

A total synthesis of the immunosuppressant molecule FTY720 was also reported, employing double Wittig-olefination protocol, from THAM. This synthesis avoided certain pitfalls that were present in previously documented literature methods. Along the pathway to FTY720, many intermediates and analogs were synthesized and tested for biological activity alongside the novel oxazolidinone compounds, resulting in interesting lead compounds for various biological applications. A UV-active FTY720 scaffold was also synthesized for potential future in vivo tracking of the immunosuppressant and its metabolites.

McMaster University Library

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