Abstract:
Three aspects of the protecting-group-free (PGF) synthesis of small molecules have been described in this thesis. In the first part, the PGF azasugar synthesis methodology was applied to 2-deoxy-D-glucose with the intention of selectively forming the six-membered azasugar 5-epi-fagomine. Surprisingly, four products were formed in the key I2-mediated carbamate annulation step, with a pyrrolidine being the major product after optimisation. This was formed in 15% yield. A mechanism that explains the formation of the four carbamates was proposed, which was supported by an investigation into related halocyclisation reactions.
The next part of this thesis describes the development of a new PGF methodology for the synthesis of conduramines, another class of biologically interesting molecules. Conduramines are amino polyhydroxy cyclohexenes and some conduramines have glycosidase inhibitory activity. These molecules are also useful precursors to a variety of biologically useful molecules including aminocyclitols and azasugars. The key steps in the PGF synthesis of conduramines are a Vasella-Barbier amination, a reaction that forms new C-C and C-N bonds concomitantly, and a ring closing metathesis in the presence of free hydroxyl and amine groups. To this end, a 4-deoxy 3-conduramine was prepared in just four steps and in 27% yield.
Finally, the preparation of an amine library and its biological testing for the identification of a new anti-tuberculosis drug is described. Two short syntheses were used to prepare alkenylamines and amines from the corresponding sugar, with various lipophilic groups attached to the amine. A 20-member amine library was prepared, and the compounds were tested for anti-mycobacterial activity in a mycobacterial growth inhibition assay. The most active compounds were subjected to further biological testing to determine their general cytotoxic properties. Two amines, arabinohexadecylamine and arabinohexadecylmethylamine, were identified as having the best potential for use as anti-tuberculosis drugs, and have been sent to Colorado State University for subsequent in vivo testing in a mouse model of tuberculosis.
