Studies towards the development of novel multidentate ligands
- Authors: Magqi, Nceba
- Date: 2007
- Subjects: Density functionals , Ligands , Ligands -- Design , Ligands -- Analysis , Camphor
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4358 , http://hdl.handle.net/10962/d1005023 , Density functionals , Ligands , Ligands -- Design , Ligands -- Analysis , Camphor
- Description: In this study, attention has been given to the design and synthesis of novel multidentate ligands for use in the construction of ruthenium-based metathesis catalysts, and their chelating potential has been explored by computer modelling at the Density Functional Theory (DFT) level. Both Kemp’s triacid (1,3,5-trimethyl-1,3,5-cyclohexanetricarboxylic acid) and D-(+)-camphor have been investigated as molecular scaffolds for the development of such ligands. However selective elaboration of the functional groups in Kemp’s triacid proved difficult to achieve, and the research has focused on the development of camphor derivatives. The synthesis of the camphor-based ligands has involved C-8 functionalisation and ring-opening of the bicyclic system to afford tridentate products. The formation of 9-iodocamphorquinone bis(ethylene ketal) together with the desired product, the 8-iodo isomer, has been confirmed by single crystal X-ray analysis of both compounds. Formation of the 9-iodo analogue has provided new insights into the intramolecular rearrangement of camphor skeleton, and the mechanistic implications have been assessed by coset analysis. Attempts to effect nucleophilic displacement of the 8-halogeno groups by nucleophilic donor moieties proved unexpectedly difficult and, coupled with the susceptibility of the carbonyl groups to nucleophilic attack, has led to the formation of novel tricyclic products, viz., 1,6-dimethyl-3-(2-pyridylamino)-4-oxatricyclo[4.3.0.0[superscript 3,7]]-2-nonanone and 6,7-dimethyl-3-(2-pyridylamino)-4-oxatricyclo -[4.3.0.0[superscript 3,7]]-2-nonanone. However the diphenylphosphine group was successfully introduced at C-8 and oxidative ring-opening of the camphor skeleton has afforded the tridentate ligands, 2-(diphenylphosphinoylmethyl)-1,2-dimethyl-1,3-cyclopentanedicarboxylic acid and 2-(diphenylphosphinoylmethyl)-1,3-bis(hydroxymethyl)1,2-dimethylcyclopentane. One- and two-dimensional NMR and, where appropriate, high-resolution MS methods have been used to characterise the products. Three [superscript 13]C NMR chemical shift prediction programmes, viz., ChemWindow and the MODGRAPH neural network and HOSE (Hierachially Ordered Spherical description of Environment), have been applied to representative compounds to assess their efficacy. While the predicted shifts correlated reasonably well with the experimental data, they proved to be insufficiently accurate to differentiate the isomeric systems examined.
- Full Text:
- Authors: Magqi, Nceba
- Date: 2007
- Subjects: Density functionals , Ligands , Ligands -- Design , Ligands -- Analysis , Camphor
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4358 , http://hdl.handle.net/10962/d1005023 , Density functionals , Ligands , Ligands -- Design , Ligands -- Analysis , Camphor
- Description: In this study, attention has been given to the design and synthesis of novel multidentate ligands for use in the construction of ruthenium-based metathesis catalysts, and their chelating potential has been explored by computer modelling at the Density Functional Theory (DFT) level. Both Kemp’s triacid (1,3,5-trimethyl-1,3,5-cyclohexanetricarboxylic acid) and D-(+)-camphor have been investigated as molecular scaffolds for the development of such ligands. However selective elaboration of the functional groups in Kemp’s triacid proved difficult to achieve, and the research has focused on the development of camphor derivatives. The synthesis of the camphor-based ligands has involved C-8 functionalisation and ring-opening of the bicyclic system to afford tridentate products. The formation of 9-iodocamphorquinone bis(ethylene ketal) together with the desired product, the 8-iodo isomer, has been confirmed by single crystal X-ray analysis of both compounds. Formation of the 9-iodo analogue has provided new insights into the intramolecular rearrangement of camphor skeleton, and the mechanistic implications have been assessed by coset analysis. Attempts to effect nucleophilic displacement of the 8-halogeno groups by nucleophilic donor moieties proved unexpectedly difficult and, coupled with the susceptibility of the carbonyl groups to nucleophilic attack, has led to the formation of novel tricyclic products, viz., 1,6-dimethyl-3-(2-pyridylamino)-4-oxatricyclo[4.3.0.0[superscript 3,7]]-2-nonanone and 6,7-dimethyl-3-(2-pyridylamino)-4-oxatricyclo -[4.3.0.0[superscript 3,7]]-2-nonanone. However the diphenylphosphine group was successfully introduced at C-8 and oxidative ring-opening of the camphor skeleton has afforded the tridentate ligands, 2-(diphenylphosphinoylmethyl)-1,2-dimethyl-1,3-cyclopentanedicarboxylic acid and 2-(diphenylphosphinoylmethyl)-1,3-bis(hydroxymethyl)1,2-dimethylcyclopentane. One- and two-dimensional NMR and, where appropriate, high-resolution MS methods have been used to characterise the products. Three [superscript 13]C NMR chemical shift prediction programmes, viz., ChemWindow and the MODGRAPH neural network and HOSE (Hierachially Ordered Spherical description of Environment), have been applied to representative compounds to assess their efficacy. While the predicted shifts correlated reasonably well with the experimental data, they proved to be insufficiently accurate to differentiate the isomeric systems examined.
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Synthesis of novel coumarin derivatives as potential inhibitors of HIV-1 protease
- Authors: Rose, Nathan Rolf
- Date: 2007 , 2013-07-01
- Subjects: Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4430 , http://hdl.handle.net/10962/d1007220 , Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Description: This research has focused on the development of novel coumann derivatives containing peptide-like side chains as potential HIV-1 protease inhibitors. The reaction of various salicylaldehyde derivatives with tert-butyl acrylate In the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO) has afforded a series of Baylis-Hillman adducts in moderate yield. Cyclisation of the adducts in the presence of HCI afforded the corresponding 3-(chloromethyl)coumarin derivatives, which have been reacted with various amine hydrochlorides in the presence of Proton Sponge® to afford a series of novel 3- (aminomethyl)coumarin derivatives, which were fully characterised by NMR and HRMS methods. Various approaches to the introduction of hydroxyl or amino groups at the C-4 position of coumarin and the 3-(chloromethyl)coumarin derivatives have been explored; these have included dihydroxylation of the coumarin double bond, and the synthesis of 4- benzylaminocoumarin derivatives as potential intermediates. The Vilsmeier-Haack and Mannich reactions have also been investigated as possible methods of introducing the desired peptide-like functionality. Computer modelling of selected structures has indicated that some of the novel 3- (aminomethyl)coumarin derivatives may exhibit activity as inhibitors of HIV-1 protease. The planned enzyme inhibition assays were unfortunately precluded by the aqueous insolubility of the selected compounds. Three ¹³C NMR chemical shift algorithms, viz., Modgraph Neural Network, Modgraph HOSE and Chern Window, have been applied to selected compounds prepared in this study. The Modgraph Neural Network algorithm was found, in all cases, to provide the most accurate correlations with the experimentally-determined chemical shifts. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Authors: Rose, Nathan Rolf
- Date: 2007 , 2013-07-01
- Subjects: Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4430 , http://hdl.handle.net/10962/d1007220 , Coumarins , Protease Inhibitors , Heterocyclic compounds -- Derivatives , HIV infections -- Treatment
- Description: This research has focused on the development of novel coumann derivatives containing peptide-like side chains as potential HIV-1 protease inhibitors. The reaction of various salicylaldehyde derivatives with tert-butyl acrylate In the presence of 1,4- diazabicyclo[2.2.2]octane (DABCO) has afforded a series of Baylis-Hillman adducts in moderate yield. Cyclisation of the adducts in the presence of HCI afforded the corresponding 3-(chloromethyl)coumarin derivatives, which have been reacted with various amine hydrochlorides in the presence of Proton Sponge® to afford a series of novel 3- (aminomethyl)coumarin derivatives, which were fully characterised by NMR and HRMS methods. Various approaches to the introduction of hydroxyl or amino groups at the C-4 position of coumarin and the 3-(chloromethyl)coumarin derivatives have been explored; these have included dihydroxylation of the coumarin double bond, and the synthesis of 4- benzylaminocoumarin derivatives as potential intermediates. The Vilsmeier-Haack and Mannich reactions have also been investigated as possible methods of introducing the desired peptide-like functionality. Computer modelling of selected structures has indicated that some of the novel 3- (aminomethyl)coumarin derivatives may exhibit activity as inhibitors of HIV-1 protease. The planned enzyme inhibition assays were unfortunately precluded by the aqueous insolubility of the selected compounds. Three ¹³C NMR chemical shift algorithms, viz., Modgraph Neural Network, Modgraph HOSE and Chern Window, have been applied to selected compounds prepared in this study. The Modgraph Neural Network algorithm was found, in all cases, to provide the most accurate correlations with the experimentally-determined chemical shifts. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
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