Physical organic studies of substituted norbornyl systems: aspects of mechanisms and chirality
- Authors: Singh, Alicia
- Date: 2017
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/50558 , vital:25999
- Description: Fenchone and camphor are essential natural products that are available optically pure and contribute to the chiral pool in asymmetric synthesis. Further, they are both derivatives of norbornane, a structure that undergoes a remarkable diversity of rearrangements in acidic conditions. This work explores two aspects of the camphor/fenchone derived systems. Firstly an attempt to clarify rearrangement mechanisms on a camphor system successfully via deuterium labelling and unsuccessfully via derivatization of fenchone (with rearrangement) to produce other 13C-labelled camphor substitutions, has resulted in confirmation of a theoretically proposed, highly concerted Wagner-Meerwein, 6,2 - hydride shift, Wagner-Meerwein rearrangement in competition with an associated 2,3-methide shift. Kinetics and activation parameters for many steps have been resolved in this rearrangement of the deuterium labelled camphor-derived tosylate system to two pairs of isotopomers. Further, the kinetics and formation of an unexpected pair of dimers encountered during the scheme for 13C labelling are investigated in detail. These dimers (forming during the initial stages of the synthetic scheme) are unusual in that they are not expected rotamers of each other, but diastereomers resulting from chirality of a sulfur atom in a sulfite moiety. A feasible mechanism of formation that matches the kinetics has been proposed in this unexpectedly complex system, and thermodynamic parameters have been determined. The second aspect of substituted norbornyl systems pertains to their chirality, and the influence of this chirality on reaction mixtures, with an aim to identify novel chiral micellar catalysts for use in heterogeneous reaction mixtures. Headway has been made towards the synthesis of the appropriate surfactants to be used in the construction of these micelles, but extensive molecular dynamics simulations have illustrated the feasibility of forming the stable chiral micelles in a dual-solvent system, and detail precisely the influence of chirality on surrounding media. These studies add important physical organic data as well as show the immense possibilities pertaining to substituted norbornane systems.
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Synthesis and bioassay of rationally designed DXR inhibitors as potential antimalarial lead compounds
- Authors: Nokalipa, Iviwe Cwaita
- Date: 2017
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/4888 , vital:20740
- Description: Globally, the eradication of malaria has been challenging due to the problem of resistance that past and currently available drugs exhibit. This is exacerbated by the inherent need for anti-malarial drugs to be affordable to the poverty-stricken majority that is primarily affected by this burden. This research has focused on the development of potential inhibitors of 1-deoxy-D- xylulose-5 phosphate reductoisomerase (DXR), an essential enzyme in the mevalonate- independent pathway for the biosynthesis of isoprenoids in Plasmodium falciparum. DXR mediates the isomerisation and reduction of 1-deoxy-D-xylulose-5-phosphate into 2-C- methyl-D-erithrytol 4-phosphate. This enzyme has been determined to be a target for the development of novel antimalarial agents and extensive molecular modelling has been undertaken to develop inhibitors that fit into the DXR active site. The in silico docking data have been used to inform the design and synthesis of various N-benzyl-substituted phosphoramidate ligands that were determined to have potential as novel substrate mimics of fosmidomycin, a known DXR inhibitor. Synthesis of the N-benzyl-substituted phosphoramidate ligands involved a nine-step sequence commencing from diethyl phosphoramidate. In all, some 40 compounds have been prepared, some of them new, and were fully characterized using NMR. Attention has also been given to the mass spectrometric fragmentation patterns exhibited by selected intermediates. Four of the final products were evaluated for in vitro antimalarial activity using a PLDH assay and exhibited IC50 values < 100 µM.
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