Synthesis of novel heterocyclic systems as potential inhibitors of HIV-1 enzymes
- Authors: Sekgota, Khethobole Cassius
- Date: 2020
- Subjects: Protease inhibitors , Heterocyclic compounds , HIV (Viruses) , Quinoline , Amides , Nuclear magnetic resonance , Antiretroviral agents , AIDS vaccines , Nitrobenzaldehyde , Propylphosphonic acid anhydride
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/146502 , vital:38531
- Description: This study has focussed on the application of Baylis-Hillman methodology in the development of efficient synthetic pathways to libraries of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones and indolizine-2-carboxamides and on an exploration of their medicinal potential. The approach to 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones involved a six-step pathway comprising: Baylis-Hillman reaction of 2-nitrobenzaldehyde derivatives and methyl acrylate to afford nitro-Baylis-Hillman adducts; thermal cyclisation of the adducts to give a range of 3-(acetoxymethyl)-2(1H)-quinolones in good to excellent yields; hydrolysis of the acetates; conversion of the resulting alcohols to the 3-chloromethyl analogues; amination; and, finally, acylation to afford the target amides. Variable temperature NMR methods were used to facilitate analysis of the ¹H and ¹³C NMR spectra which were complicated by internal rotation and cycloalkyl ring-flipping effects. On the other hand, the indolizine-2-carboxamides were obtained in several steps commencing with the Baylis-Hillman reaction of pyridine-2-carboxaldehyde and methyl acrylate. Thermal cyclisation of the Baylis-Hillman adduct afforded indolizine esters, hydrolysis of which gave the corresponding acids which served as precursors to the target indolizine-2-carboxamides. The final amidation step, however, proved to be particularly challenging. Various coupling strategies were explored to access indolizine-2-carboxamides. These included the use of 2,2,2-trifluoroethyl borate which showed limited promise, but propylphosphonic acid anhydride (T3P) proved to be the most effective coupling agent, permitting the formation of 24 novel indolizine-2-carboxamides from hydrazines, aliphatic amines and a range of heterocyclic amines. A high-field NMR-based kinetic study of the mechanism of the Baylis-Hillman reaction of pyridine-4-carboxaldehyde and methyl acrylate in the presence of 3-hydroxyquinuclidine in deuterated chloroform was initiated, reaction progress being followed by the automated collection of ¹H and DEPT 135 NMR spectra over ca. 24 hours using a high-field (600 MHz) NMR instrument. The results have provided critical new insights into the mechanism. NMR analysis has also been used to elucidate the multiplicity of signals associated with rotameric equilibria observed at ambient probe temperature. Variable temperature 1D- and 2D-NMR spectra were used to facilitate the unambiguous characterisation of the 2-quinolone benzamides and some of the indolizine-2-carboxamides. The 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones, together with selected precursors, and a number of the indolizine-2-carboxamides have been screened in vitro as potential HIV-1 enzyme inhibitors. A survey of the activity of the 2-quinolones against HIV-1 integrase, protease and reverse transcriptase revealed selective inhibition of HIV-1 integrase with the most active IN inhibitor, 3-[(cyclopentylamino)methyl-6-methoxy-2(1H)-quinolone 115e, producing residual enzyme activity of 40% at a concentration of 20 μM. Many of the 2-quinolones exhibited no significant cytotoxicity against HEK 293 cells at 20 μM concentrations. 3-[(N-Cyclohexylamino)methyl]-6-methoxy-2(1H)-quinolone 114e was the only compound to exhibit ant-plasmodial activity (55% pfLDH activity). The survey of indolizine-2-carboxamides also revealed encouraging inhibition against HIV-1 integrase. None of these compounds exhibited cytotoxicity at 20 μM against HEK 293 cells, while a number of them exhibited some activity against Plasmodium falciparum (3D7 strain) and Trypanosoma brucei. Selected indolizine-2-carboxamides exhibited significant anti-tubercular activity in the 7H9 CAS GLU Tx and 7H9 ADC GLU Tw media. In view of the inherent fluorescent character and biological potential of the synthesised indolizine-2-carboxamides, their photophysical properties were explored to establish their possible dual use as bio-imaging and therapeutic agents. The major absorption and corresponding emission bands, and the associated molar absorption coefficients (Ɛ) expressed in the form of log Ɛ were determined. Their high extinction coefficients, large Stokes shift and red-shifted emissions in the visible region indicate their potential for use as fluorophores.
- Full Text:
- Authors: Sekgota, Khethobole Cassius
- Date: 2020
- Subjects: Protease inhibitors , Heterocyclic compounds , HIV (Viruses) , Quinoline , Amides , Nuclear magnetic resonance , Antiretroviral agents , AIDS vaccines , Nitrobenzaldehyde , Propylphosphonic acid anhydride
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/146502 , vital:38531
- Description: This study has focussed on the application of Baylis-Hillman methodology in the development of efficient synthetic pathways to libraries of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones and indolizine-2-carboxamides and on an exploration of their medicinal potential. The approach to 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones involved a six-step pathway comprising: Baylis-Hillman reaction of 2-nitrobenzaldehyde derivatives and methyl acrylate to afford nitro-Baylis-Hillman adducts; thermal cyclisation of the adducts to give a range of 3-(acetoxymethyl)-2(1H)-quinolones in good to excellent yields; hydrolysis of the acetates; conversion of the resulting alcohols to the 3-chloromethyl analogues; amination; and, finally, acylation to afford the target amides. Variable temperature NMR methods were used to facilitate analysis of the ¹H and ¹³C NMR spectra which were complicated by internal rotation and cycloalkyl ring-flipping effects. On the other hand, the indolizine-2-carboxamides were obtained in several steps commencing with the Baylis-Hillman reaction of pyridine-2-carboxaldehyde and methyl acrylate. Thermal cyclisation of the Baylis-Hillman adduct afforded indolizine esters, hydrolysis of which gave the corresponding acids which served as precursors to the target indolizine-2-carboxamides. The final amidation step, however, proved to be particularly challenging. Various coupling strategies were explored to access indolizine-2-carboxamides. These included the use of 2,2,2-trifluoroethyl borate which showed limited promise, but propylphosphonic acid anhydride (T3P) proved to be the most effective coupling agent, permitting the formation of 24 novel indolizine-2-carboxamides from hydrazines, aliphatic amines and a range of heterocyclic amines. A high-field NMR-based kinetic study of the mechanism of the Baylis-Hillman reaction of pyridine-4-carboxaldehyde and methyl acrylate in the presence of 3-hydroxyquinuclidine in deuterated chloroform was initiated, reaction progress being followed by the automated collection of ¹H and DEPT 135 NMR spectra over ca. 24 hours using a high-field (600 MHz) NMR instrument. The results have provided critical new insights into the mechanism. NMR analysis has also been used to elucidate the multiplicity of signals associated with rotameric equilibria observed at ambient probe temperature. Variable temperature 1D- and 2D-NMR spectra were used to facilitate the unambiguous characterisation of the 2-quinolone benzamides and some of the indolizine-2-carboxamides. The 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones, together with selected precursors, and a number of the indolizine-2-carboxamides have been screened in vitro as potential HIV-1 enzyme inhibitors. A survey of the activity of the 2-quinolones against HIV-1 integrase, protease and reverse transcriptase revealed selective inhibition of HIV-1 integrase with the most active IN inhibitor, 3-[(cyclopentylamino)methyl-6-methoxy-2(1H)-quinolone 115e, producing residual enzyme activity of 40% at a concentration of 20 μM. Many of the 2-quinolones exhibited no significant cytotoxicity against HEK 293 cells at 20 μM concentrations. 3-[(N-Cyclohexylamino)methyl]-6-methoxy-2(1H)-quinolone 114e was the only compound to exhibit ant-plasmodial activity (55% pfLDH activity). The survey of indolizine-2-carboxamides also revealed encouraging inhibition against HIV-1 integrase. None of these compounds exhibited cytotoxicity at 20 μM against HEK 293 cells, while a number of them exhibited some activity against Plasmodium falciparum (3D7 strain) and Trypanosoma brucei. Selected indolizine-2-carboxamides exhibited significant anti-tubercular activity in the 7H9 CAS GLU Tx and 7H9 ADC GLU Tw media. In view of the inherent fluorescent character and biological potential of the synthesised indolizine-2-carboxamides, their photophysical properties were explored to establish their possible dual use as bio-imaging and therapeutic agents. The major absorption and corresponding emission bands, and the associated molar absorption coefficients (Ɛ) expressed in the form of log Ɛ were determined. Their high extinction coefficients, large Stokes shift and red-shifted emissions in the visible region indicate their potential for use as fluorophores.
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Application of computational methods in elucidating the isomerization step in the biosynthesis of coumarins
- Authors: Tshiwawa, Tendamudzimu
- Date: 2019
- Subjects: Coumarins , Isomerization , Biosynthesis , Organic compounds -- Synthesis , Cinnamic acid
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/67646 , vital:29124
- Description: The identity of the enzyme(s) responsible for the biosynthetic transformation of cinnamic acid derivatives to important, naturally occurring coumarins has yet to be established. This study constitutes a high-level theoretical analysis of the possibility that a recently reported molecular mechanism of the synthesis of coumarins from Baylis-Hillman adducts, may provide a viable model for three critical phases in the biosynthetic pathway Particular attention has been given to the first of these phases: i) E→Z isomerisation of the cinnamic acid precursor; ii) Cyclisation (lactonisation) to the hemi-acetal intermediate; and ii) Dehydration to afford the coumarin derivative. In order to accomplish this analysis, an enzyme capable, theoretically, of effecting this E→Z isomerisation required identification, and its potential involvement in the transformation mechanism explored. Combined Molecular Mechanics and high-level Quantum Mechanical/DFT calculations were used to access complementary models of appropriate complexes and relevant processes within the enzyme active sites of a range of eleven Chalcone Isomerase (CHI) enzyme candidates, the structures of which were downloaded from the Protein Data Bank. Detailed B3LYP/6-31+G(d,p) calculations have provided pictures of the relative populations of conformations within the ensemble of conformations available at normal temperatures. Conformations of several protonation states of cinnamic acid derivatives have been studied in this way, and the results obtained showed that coupled protonation and deprotonation of (E)-o-coumaric acid provides a viable approach to achieve the E→Z isomerization. In silico docking of the B3LYP/6-31+G(d,p) optimized (E)-o-coumaric acid derivatives in the active sites of each of the candidate CHI enzymes (CHI) revealed that (E)-o-coumaric acid fits well within the active sites of Medicago Sativa CHI crystallographic structures with 1FM8 showing best potential for not only accommodating (E)-o-coumaric acid , but also providing appropriate protein active site residues to effect the simultaneous protonation and deprotonation of the substrate , two residues being optimally placed to facilitate these critical processes. Further exploration of the chemical properties and qualities of selected CHI enzymes, undertaken using High Throughput Virtual Screening (HTVS), confirmed 1FM8 as a viable choice for further studies of the enzyme-catalysed E→Z isomerization of (E)-o-coumaric acid. A molecular dynamics study, performed to further evaluate the evolution of (E)-o-coumaric acid in the CHI active site over time, showed that the ligand in the 1FM8 active site is not only stable, but also that the desired protein-ligand interactions persist throughout the simulation period to facilitate the E→Z isomerization. An integrated molecular orbital and molecular mechanics (ONIOM) study of the 1FM8-(E)-o-coumaric acid complex, involving the direct protonation and deprotonation of the ligand by protein residues; has provided a plausible mechanism for the E → Z isomerization of (E)-o-coumaric acid within the 1FM8 active site; a transition state complex (with an activation energy of ca. 50 kCal.mol-1) has been located and its connection with both the (E)- and (Z)-o-coumaric acid isomer has been confirmed by Intrinsic Reaction Coordinate (IRC) calculations. More realistic models of the 1FM8-(E)-o-coumaric acid complex, with the inclusion of water solvent molecules, have been obtained at both the QM/MM and adaptive QM/MM levels which simulate the dynamic active site at the QM level. The results indicate that the simultaneous protonation and deprotonation of (E)-o-coumaric acid within the CHI enzyme is a water-mediated process – a conclusion consistent with similar reported processes. Visual inspection of the 1FM8-(Z)-o-coumaric acid complex reveals both the necessary orientation of the phenolic and carboxylic acid moieties of the (Z)-o-coumaric acid and the presence of appropriate, proximal active site residues with the potential to permit catalysis of the subsequent lactonisation and dehydration steps required to generate coumarin.
- Full Text:
- Authors: Tshiwawa, Tendamudzimu
- Date: 2019
- Subjects: Coumarins , Isomerization , Biosynthesis , Organic compounds -- Synthesis , Cinnamic acid
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/67646 , vital:29124
- Description: The identity of the enzyme(s) responsible for the biosynthetic transformation of cinnamic acid derivatives to important, naturally occurring coumarins has yet to be established. This study constitutes a high-level theoretical analysis of the possibility that a recently reported molecular mechanism of the synthesis of coumarins from Baylis-Hillman adducts, may provide a viable model for three critical phases in the biosynthetic pathway Particular attention has been given to the first of these phases: i) E→Z isomerisation of the cinnamic acid precursor; ii) Cyclisation (lactonisation) to the hemi-acetal intermediate; and ii) Dehydration to afford the coumarin derivative. In order to accomplish this analysis, an enzyme capable, theoretically, of effecting this E→Z isomerisation required identification, and its potential involvement in the transformation mechanism explored. Combined Molecular Mechanics and high-level Quantum Mechanical/DFT calculations were used to access complementary models of appropriate complexes and relevant processes within the enzyme active sites of a range of eleven Chalcone Isomerase (CHI) enzyme candidates, the structures of which were downloaded from the Protein Data Bank. Detailed B3LYP/6-31+G(d,p) calculations have provided pictures of the relative populations of conformations within the ensemble of conformations available at normal temperatures. Conformations of several protonation states of cinnamic acid derivatives have been studied in this way, and the results obtained showed that coupled protonation and deprotonation of (E)-o-coumaric acid provides a viable approach to achieve the E→Z isomerization. In silico docking of the B3LYP/6-31+G(d,p) optimized (E)-o-coumaric acid derivatives in the active sites of each of the candidate CHI enzymes (CHI) revealed that (E)-o-coumaric acid fits well within the active sites of Medicago Sativa CHI crystallographic structures with 1FM8 showing best potential for not only accommodating (E)-o-coumaric acid , but also providing appropriate protein active site residues to effect the simultaneous protonation and deprotonation of the substrate , two residues being optimally placed to facilitate these critical processes. Further exploration of the chemical properties and qualities of selected CHI enzymes, undertaken using High Throughput Virtual Screening (HTVS), confirmed 1FM8 as a viable choice for further studies of the enzyme-catalysed E→Z isomerization of (E)-o-coumaric acid. A molecular dynamics study, performed to further evaluate the evolution of (E)-o-coumaric acid in the CHI active site over time, showed that the ligand in the 1FM8 active site is not only stable, but also that the desired protein-ligand interactions persist throughout the simulation period to facilitate the E→Z isomerization. An integrated molecular orbital and molecular mechanics (ONIOM) study of the 1FM8-(E)-o-coumaric acid complex, involving the direct protonation and deprotonation of the ligand by protein residues; has provided a plausible mechanism for the E → Z isomerization of (E)-o-coumaric acid within the 1FM8 active site; a transition state complex (with an activation energy of ca. 50 kCal.mol-1) has been located and its connection with both the (E)- and (Z)-o-coumaric acid isomer has been confirmed by Intrinsic Reaction Coordinate (IRC) calculations. More realistic models of the 1FM8-(E)-o-coumaric acid complex, with the inclusion of water solvent molecules, have been obtained at both the QM/MM and adaptive QM/MM levels which simulate the dynamic active site at the QM level. The results indicate that the simultaneous protonation and deprotonation of (E)-o-coumaric acid within the CHI enzyme is a water-mediated process – a conclusion consistent with similar reported processes. Visual inspection of the 1FM8-(Z)-o-coumaric acid complex reveals both the necessary orientation of the phenolic and carboxylic acid moieties of the (Z)-o-coumaric acid and the presence of appropriate, proximal active site residues with the potential to permit catalysis of the subsequent lactonisation and dehydration steps required to generate coumarin.
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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.
- Full Text:
- 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 biological evaluation of novel thiazole-based compounds
- Authors: Olawode, Emmanual Oladayo
- Date: 2016
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/62955 , vital:28325
- Description: Thesis embargoed for one-year period. Expected date of release: April 2019
- Full Text:
- Authors: Olawode, Emmanual Oladayo
- Date: 2016
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/62955 , vital:28325
- Description: Thesis embargoed for one-year period. Expected date of release: April 2019
- Full Text:
Synthesis of chiral ketopinic acid-derived catalysts and their evaluation in asymmetric transformations
- Authors: Hassan, Yusuf
- Date: 2016
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/550 , vital:19969
- Description: Four new (+)-ketopinic acid-derived Mn(III) complexes, three of which possess pseudo C2- symmetry, were synthesised as chiral catalyst candidates. The ligands were prepared by refluxing (+)-ketopinic acid with ethane-1,2-diamine, the resolved (R,R)- and (S,S)-1,2-diaminocyclohexanes, and 1,2-diaminobenzene in chloroform. Treatment of the ligands with manganese(II) acetate tetrahydrate in refluxing ethanol afforded the respective complexes as brown amorphous powders. Characterisation of the ligands and the corresponding complexes was achieved using 1-D and 2-D NMR, IR spectroscopy, and elemental analysis. Various homogeneous asymmetric transformations, were investigated using these four complexes, viz., aldol, and Baylis-Hillman reactions, aza-Michael addition of piperidine to the Baylis-Hillman adducts, epoxidation, and ketone and imine reduction. Asymmetric aldol reactions of benzaldehyde with the aryl ketones, acetophenone, propiophenone, -tetralone, 4-nitroacetophenone, and 4-methoxyacetophenone, conducted in the presence of 10 mole % of the chiral catalysts, afforded enantioselectivities of up to 99% e.e. Asymmetric Baylis-Hillman reactions of methyl- and tert-butyl acrylates with pyridine-2- carbaldehyde, 6-methylpyridine-2-carbaldehyde, 5-chlorosalicylaldehyde, benzaldehyde, 4-chlorobenzaldehyde, and 2-nitrobenzaldehyde were conducted in the presence of catalyst 139 (10 mole %) to afford enantioselectivities of up to 44% e.e. Aza-Michael addition of piperidine to racemic Baylis- Hillman adducts in the presence of the catalyst 139 (10 mole %) was found to proceed with diastereoselectivities of up to 91% d.e. Asymmetric epoxidation of trans-methyl styrene, styrene, trans-stilbene, cis-stilbene, and indene, using a 5 mole % chiral catalyst loading and m-CPBA as the oxygen source, gave enantioselectivities of up to 32 % e.e. Asymmetric reductions of acetophenone, 3-chloropropiophenone, 4-hydroxyacetophenone, -tetralone, and 2-hydroxy-1-acetonapthone were investigated using NaBH4 as the reducing agent and a 10 mole % loading of the chiral catalysts. A stereoselectivity of 68% e.e. was obtained in the reduction of acetophenone, but attempts to reduce the selected imines to the corresponding chiral amines proved to be unsuccessful — even in the absence of the catalysts. It thus became apparent that the catalytic version of the reaction was not feasible.
- Full Text:
- Authors: Hassan, Yusuf
- Date: 2016
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/550 , vital:19969
- Description: Four new (+)-ketopinic acid-derived Mn(III) complexes, three of which possess pseudo C2- symmetry, were synthesised as chiral catalyst candidates. The ligands were prepared by refluxing (+)-ketopinic acid with ethane-1,2-diamine, the resolved (R,R)- and (S,S)-1,2-diaminocyclohexanes, and 1,2-diaminobenzene in chloroform. Treatment of the ligands with manganese(II) acetate tetrahydrate in refluxing ethanol afforded the respective complexes as brown amorphous powders. Characterisation of the ligands and the corresponding complexes was achieved using 1-D and 2-D NMR, IR spectroscopy, and elemental analysis. Various homogeneous asymmetric transformations, were investigated using these four complexes, viz., aldol, and Baylis-Hillman reactions, aza-Michael addition of piperidine to the Baylis-Hillman adducts, epoxidation, and ketone and imine reduction. Asymmetric aldol reactions of benzaldehyde with the aryl ketones, acetophenone, propiophenone, -tetralone, 4-nitroacetophenone, and 4-methoxyacetophenone, conducted in the presence of 10 mole % of the chiral catalysts, afforded enantioselectivities of up to 99% e.e. Asymmetric Baylis-Hillman reactions of methyl- and tert-butyl acrylates with pyridine-2- carbaldehyde, 6-methylpyridine-2-carbaldehyde, 5-chlorosalicylaldehyde, benzaldehyde, 4-chlorobenzaldehyde, and 2-nitrobenzaldehyde were conducted in the presence of catalyst 139 (10 mole %) to afford enantioselectivities of up to 44% e.e. Aza-Michael addition of piperidine to racemic Baylis- Hillman adducts in the presence of the catalyst 139 (10 mole %) was found to proceed with diastereoselectivities of up to 91% d.e. Asymmetric epoxidation of trans-methyl styrene, styrene, trans-stilbene, cis-stilbene, and indene, using a 5 mole % chiral catalyst loading and m-CPBA as the oxygen source, gave enantioselectivities of up to 32 % e.e. Asymmetric reductions of acetophenone, 3-chloropropiophenone, 4-hydroxyacetophenone, -tetralone, and 2-hydroxy-1-acetonapthone were investigated using NaBH4 as the reducing agent and a 10 mole % loading of the chiral catalysts. A stereoselectivity of 68% e.e. was obtained in the reduction of acetophenone, but attempts to reduce the selected imines to the corresponding chiral amines proved to be unsuccessful — even in the absence of the catalysts. It thus became apparent that the catalytic version of the reaction was not feasible.
- Full Text:
Novel applications of Morita-Baylis-Hillman methodology in organic synthesis
- Authors: Mciteka, Lulama Patrick
- Date: 2013 , 2013-04-22
- Subjects: Organic compounds -- Synthesis -- Research Asymmetric synthesis Asymmetry (Chemistry) Chemical reactions -- Research Camphor -- Research AZT (Drug) -- Research Chemical inhibitors -- Research Chemistry -- Methodology
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4439 , http://hdl.handle.net/10962/d1007598
- Description: The overall approach in the present investigation has been to explore applications of the Morita-Baylis-Hillman (MBH) reaction in asymmetric synthesis and in the continuation of systems with medicinal potential. To this end, a series of varied camphor-derived acrylate esters was prepared to serve as chiral substrates in asymmetric Morita-Baylis- Hillman reactions. Reduction of N-substituted camphor-10-sulfonamides afforded the 3- exo-hydroxy derivatives as the major products. Acylation of the corresponding sodium alkoxides gave the desired 3-exo-acrylate esters, isolation of which was complicated by concomitant formation of hydrochlorinated and diastereomeric competition products. Bulky camphorsulfonamides containing alkyl, dialkyl, aromatic and adamantyl groups were selected as N-substituents with the view of achieving stereoselective outcome in subsequent MBH reactions. The synthesis of novel camphor-derived Morita-Baylis-Hillman adducts using various pyridine-carboxaldehydes proceeded with exceptionally high yields with diastereoselectivities ranging from 7-33 % d.e. Both 1D and 2D NMR and HRMS techniques were employed to confirm the structures and an extensive study of the electropositive fragmentation patterns of a number of camphor-derived chiral acrylate esters was conducted. Attention has also been given to the application of MBH methodology in the construction of heterocyclic ‘cinnamate-like’ AZT conjugates which were designed to serve as dualaction HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. A number of pyridine carboxaldehyde-derived MBH adducts were synthesized using methyl, ethyl and t-butyl acrylates in the presence of 3-hydroxyquinuclidine (3-HQ) as catalyst. The yields for these reactions were excellent. The resulting MBH adducts were acetylated and subjected to aza-Michael addition using propargylamine. The resulting alkylamino compounds were then used in ‘Click reactions’ to form the targeted AZT-conjugates in moderate to excellent yield. In silico docking of computer modelled AZT-conjugates into the HIV-1 integrase and reverse transcriptase enzyme-active sites and potential hydrogen-bonding interaction with active-site amino acid residues were identified. The electrospray MS fragmentations of the AZT and the novel AZT-conjugates were also investigated and common fragmentation pathways were identified.
- Full Text:
- Authors: Mciteka, Lulama Patrick
- Date: 2013 , 2013-04-22
- Subjects: Organic compounds -- Synthesis -- Research Asymmetric synthesis Asymmetry (Chemistry) Chemical reactions -- Research Camphor -- Research AZT (Drug) -- Research Chemical inhibitors -- Research Chemistry -- Methodology
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4439 , http://hdl.handle.net/10962/d1007598
- Description: The overall approach in the present investigation has been to explore applications of the Morita-Baylis-Hillman (MBH) reaction in asymmetric synthesis and in the continuation of systems with medicinal potential. To this end, a series of varied camphor-derived acrylate esters was prepared to serve as chiral substrates in asymmetric Morita-Baylis- Hillman reactions. Reduction of N-substituted camphor-10-sulfonamides afforded the 3- exo-hydroxy derivatives as the major products. Acylation of the corresponding sodium alkoxides gave the desired 3-exo-acrylate esters, isolation of which was complicated by concomitant formation of hydrochlorinated and diastereomeric competition products. Bulky camphorsulfonamides containing alkyl, dialkyl, aromatic and adamantyl groups were selected as N-substituents with the view of achieving stereoselective outcome in subsequent MBH reactions. The synthesis of novel camphor-derived Morita-Baylis-Hillman adducts using various pyridine-carboxaldehydes proceeded with exceptionally high yields with diastereoselectivities ranging from 7-33 % d.e. Both 1D and 2D NMR and HRMS techniques were employed to confirm the structures and an extensive study of the electropositive fragmentation patterns of a number of camphor-derived chiral acrylate esters was conducted. Attention has also been given to the application of MBH methodology in the construction of heterocyclic ‘cinnamate-like’ AZT conjugates which were designed to serve as dualaction HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. A number of pyridine carboxaldehyde-derived MBH adducts were synthesized using methyl, ethyl and t-butyl acrylates in the presence of 3-hydroxyquinuclidine (3-HQ) as catalyst. The yields for these reactions were excellent. The resulting MBH adducts were acetylated and subjected to aza-Michael addition using propargylamine. The resulting alkylamino compounds were then used in ‘Click reactions’ to form the targeted AZT-conjugates in moderate to excellent yield. In silico docking of computer modelled AZT-conjugates into the HIV-1 integrase and reverse transcriptase enzyme-active sites and potential hydrogen-bonding interaction with active-site amino acid residues were identified. The electrospray MS fragmentations of the AZT and the novel AZT-conjugates were also investigated and common fragmentation pathways were identified.
- Full Text:
Bayliss-Hillman adducts as scaffolds for the construction of novel compounds with medicinal potential
- Authors: Idahosa, Kenudi Christiana
- Date: 2012
- Subjects: Antimalarials -- Research Malaria -- Chemotherapy -- Research AIDS (Disease) -- Treatment -- Research AIDS (Disease) -- Chemotherapy -- Research
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4410 , http://hdl.handle.net/10962/d1006763
- Description: This project has focused on exploring the application of Baylis-Hillman (BH) {a.k.a. Morita-Baylis-Hillman (MBH)} scaffolds in the construction of various compounds with medicinal potential. A series of 2-nitrobenzaldehydes has been treated under BH conditions, with two different activated alkenes, viz., (MVK) and methyl acrylate, using (DABCO) or (3-HQ) as catalyst. While most of the BH reactions were carried out at room temperature, some reactions were conducted using microwave irradiation. The resulting BH adducts have been subjected to dehydration, conjugate addition and allylic substitution to obtain appropriate intermediates, which have been used in turn, to synthesize possible lead compounds, viz., cinnamate esters as HIV-1 integrase inhibitors, 3-(aminomethyl)quinolines and quinolones as anti-malarials and cinnamate ester-AZT conjugates as dual-action HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. Conjugate addition reactions of methyl acrylate-derived BH β-hydroxy esters with the amines, piperidine, propargylamine and 2-amino-5-(diethylamino)pentane, has afforded a range of products as diastereomeric mixtures in moderate to excellent yields. Catalytic hydrogenation of the aminomethy β-hydroxy esters derivatives, using a palladium-oncarbon (Pd-C) catalyst, has afforded the corresponding, novel 3-aminomethyl-2- quinolone derivatives in moderate yields. Effective allylic substitution reactions of the MVK-derived BH β-hydroxy ketones (via a conjugate addition-elimination pathway) using in situ-generated HCl has afforded the corresponding α-chloromethyl derivatives, which have been reacted with various amines, including piperidine, piperazine, propargylamine and 2-amino-5-(diethylamino)pentane, to yield α-aminomethyl derivatives. Catalytic hydrogenation of selected α-aminomethyl derivatives, using a Pd-C catalyst, has afforded the corresponding, novel 3- (aminomethyl)-2-methylquinoline derivatives in low to moderate yields. A bioassay, conducted on a 6-hydroxy-2-methyl-3-[(piperidin-1-yl)methyl]quinoline isolated early in the study indicated anti-malarial activity and prompted further efforts in the synthesis of analogous compounds. Reaction of the methyl acrylate-derived BH adducts with POCl3 has provided access to α-(chloromethyl)cinnamate ester derivatives, which have been aminated to afford α- (aminomethyl)cinnamate ester derivatives as potential HIV-1 integrase inhibitors. The α- (propargylaminomethyl)cinnamates were used, in turn, as substrates for the “click chemistry” reaction with 3'-azido-3'-deoxythymidine (AZT– an azide and an established reverse transcriptase HIV-1 inhibitor) to afford cinnamate ester-AZT conjugates as potential dual-action HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. Computer modelling and docking studies of a cinnamate ester-AZT conjugate into the HIV-1 integrase and reverse transcriptase active-sites revealed potential hydrogen-bonding interactions with amino acid residues within the receptor cavities. The isolated products have been appropriately characterized using IR, 1- and 2-D NMR and HRMS techniques, while elucidation of the stereochemistry of the double bond in the BH-derived halomethyl derivatives has been assigned on the basis of NOE, computer modelling and X-ray crystallographic data.
- Full Text:
- Authors: Idahosa, Kenudi Christiana
- Date: 2012
- Subjects: Antimalarials -- Research Malaria -- Chemotherapy -- Research AIDS (Disease) -- Treatment -- Research AIDS (Disease) -- Chemotherapy -- Research
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4410 , http://hdl.handle.net/10962/d1006763
- Description: This project has focused on exploring the application of Baylis-Hillman (BH) {a.k.a. Morita-Baylis-Hillman (MBH)} scaffolds in the construction of various compounds with medicinal potential. A series of 2-nitrobenzaldehydes has been treated under BH conditions, with two different activated alkenes, viz., (MVK) and methyl acrylate, using (DABCO) or (3-HQ) as catalyst. While most of the BH reactions were carried out at room temperature, some reactions were conducted using microwave irradiation. The resulting BH adducts have been subjected to dehydration, conjugate addition and allylic substitution to obtain appropriate intermediates, which have been used in turn, to synthesize possible lead compounds, viz., cinnamate esters as HIV-1 integrase inhibitors, 3-(aminomethyl)quinolines and quinolones as anti-malarials and cinnamate ester-AZT conjugates as dual-action HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. Conjugate addition reactions of methyl acrylate-derived BH β-hydroxy esters with the amines, piperidine, propargylamine and 2-amino-5-(diethylamino)pentane, has afforded a range of products as diastereomeric mixtures in moderate to excellent yields. Catalytic hydrogenation of the aminomethy β-hydroxy esters derivatives, using a palladium-oncarbon (Pd-C) catalyst, has afforded the corresponding, novel 3-aminomethyl-2- quinolone derivatives in moderate yields. Effective allylic substitution reactions of the MVK-derived BH β-hydroxy ketones (via a conjugate addition-elimination pathway) using in situ-generated HCl has afforded the corresponding α-chloromethyl derivatives, which have been reacted with various amines, including piperidine, piperazine, propargylamine and 2-amino-5-(diethylamino)pentane, to yield α-aminomethyl derivatives. Catalytic hydrogenation of selected α-aminomethyl derivatives, using a Pd-C catalyst, has afforded the corresponding, novel 3- (aminomethyl)-2-methylquinoline derivatives in low to moderate yields. A bioassay, conducted on a 6-hydroxy-2-methyl-3-[(piperidin-1-yl)methyl]quinoline isolated early in the study indicated anti-malarial activity and prompted further efforts in the synthesis of analogous compounds. Reaction of the methyl acrylate-derived BH adducts with POCl3 has provided access to α-(chloromethyl)cinnamate ester derivatives, which have been aminated to afford α- (aminomethyl)cinnamate ester derivatives as potential HIV-1 integrase inhibitors. The α- (propargylaminomethyl)cinnamates were used, in turn, as substrates for the “click chemistry” reaction with 3'-azido-3'-deoxythymidine (AZT– an azide and an established reverse transcriptase HIV-1 inhibitor) to afford cinnamate ester-AZT conjugates as potential dual-action HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. Computer modelling and docking studies of a cinnamate ester-AZT conjugate into the HIV-1 integrase and reverse transcriptase active-sites revealed potential hydrogen-bonding interactions with amino acid residues within the receptor cavities. The isolated products have been appropriately characterized using IR, 1- and 2-D NMR and HRMS techniques, while elucidation of the stereochemistry of the double bond in the BH-derived halomethyl derivatives has been assigned on the basis of NOE, computer modelling and X-ray crystallographic data.
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Mechanistic studies of unusual Miruta-Baylis-Hillman reactions
- Authors: Nyoni, Dubekile
- Date: 2012
- Subjects: Chemical reactions Benzaldehyde Acrylonitrile Methyl acrylate Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4400 , http://hdl.handle.net/10962/d1006692
- Description: This study has focussed on the application of synthetic, kinetic and exploratory theoretical methods in elucidating the reaction mechanisms of four Morita-Baylis-Hillman (MBH) type reactions, viz, i) the reactions of the disulfide 2,2'-dithiodibenzaldehyde with various activated alkenes in the presence of DBU and Ph₃P, ii) the reactions of chromone-3-carbaldehydes with MVK, iii) the reactions of chromone-2-carbaldehydes with acrylonitrile and iv) with methyl acrylate. Attention has also been given to the origin of the observed regioselectivity in Michaelis-Arbuzov reactions of 3-(halomethyl)coumarins. Cleavage of the sulfur-sulfur bond of aryl and heteroaryl disulfides by the nitrogen nucleophile DBU has been demonstrated, and a dramatic increase in the rate of tandem MBH and disulfide cleavage reactions of 2,2'-dithiodibenzaldehyde with the activated alkenes, MVK, EVK, acrylonitrile, methyl acrylate and tert-butyl acrylate has been achieved through the use of the dual organo-catalyst system, DBU-Ph₃P – an improvement accompanied by an increase in the yields of the isolated products. Detailed NMR-based kinetic studies have been conducted on the DBU-catalysed reactions of 2,2'-dithiodibenzaldehyde with MVK and methyl acrylate, and a theoretical kinetic model has been developed and complementary computational studies using Gaussian 03, at the DFT-B3LYP/6-31G(d) level of theory have provided valuable insights into the mechanism of these complex transformations. Reactions of chromone-3-carbaldehydes with MVK to afford chromone dimers and tricyclic products have been repeated, and a novel, intermediate MBH adduct has been isolated. The mechanisms of the competing pathways have been elucidated by DFT calculations and the development of a detailed theoretical kinetic model has ensued. Unusual transformations in MBH-type reactions of chromone-2-carbaldehydes with acrylonitrile and methyl acrylate have been explored and the structures of the unexpected products have been established using 1- and 2-D NMR, HRMS and X-ray crystallographic techniques. Attention has also been given to the synthesis of 3-(halomethyl)coumarins via the MBH reaction, and their subsequent Michaelis-Arbuzov reactions with triethyl phosphite. An exploratory study of the kinetics of the phosphonation reaction has been undertaken and the regio-selectivity of nucleophilic attack at the 4- and 1'-positions in the 3-chloro- and 3-(iodomethyl)coumarins has been investigated by calculating Mulliken charges, LUMO surfaces and Fukui condensed local softness functions.
- Full Text:
- Authors: Nyoni, Dubekile
- Date: 2012
- Subjects: Chemical reactions Benzaldehyde Acrylonitrile Methyl acrylate Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4400 , http://hdl.handle.net/10962/d1006692
- Description: This study has focussed on the application of synthetic, kinetic and exploratory theoretical methods in elucidating the reaction mechanisms of four Morita-Baylis-Hillman (MBH) type reactions, viz, i) the reactions of the disulfide 2,2'-dithiodibenzaldehyde with various activated alkenes in the presence of DBU and Ph₃P, ii) the reactions of chromone-3-carbaldehydes with MVK, iii) the reactions of chromone-2-carbaldehydes with acrylonitrile and iv) with methyl acrylate. Attention has also been given to the origin of the observed regioselectivity in Michaelis-Arbuzov reactions of 3-(halomethyl)coumarins. Cleavage of the sulfur-sulfur bond of aryl and heteroaryl disulfides by the nitrogen nucleophile DBU has been demonstrated, and a dramatic increase in the rate of tandem MBH and disulfide cleavage reactions of 2,2'-dithiodibenzaldehyde with the activated alkenes, MVK, EVK, acrylonitrile, methyl acrylate and tert-butyl acrylate has been achieved through the use of the dual organo-catalyst system, DBU-Ph₃P – an improvement accompanied by an increase in the yields of the isolated products. Detailed NMR-based kinetic studies have been conducted on the DBU-catalysed reactions of 2,2'-dithiodibenzaldehyde with MVK and methyl acrylate, and a theoretical kinetic model has been developed and complementary computational studies using Gaussian 03, at the DFT-B3LYP/6-31G(d) level of theory have provided valuable insights into the mechanism of these complex transformations. Reactions of chromone-3-carbaldehydes with MVK to afford chromone dimers and tricyclic products have been repeated, and a novel, intermediate MBH adduct has been isolated. The mechanisms of the competing pathways have been elucidated by DFT calculations and the development of a detailed theoretical kinetic model has ensued. Unusual transformations in MBH-type reactions of chromone-2-carbaldehydes with acrylonitrile and methyl acrylate have been explored and the structures of the unexpected products have been established using 1- and 2-D NMR, HRMS and X-ray crystallographic techniques. Attention has also been given to the synthesis of 3-(halomethyl)coumarins via the MBH reaction, and their subsequent Michaelis-Arbuzov reactions with triethyl phosphite. An exploratory study of the kinetics of the phosphonation reaction has been undertaken and the regio-selectivity of nucleophilic attack at the 4- and 1'-positions in the 3-chloro- and 3-(iodomethyl)coumarins has been investigated by calculating Mulliken charges, LUMO surfaces and Fukui condensed local softness functions.
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Synthesis and evaluation of novel HIV-1 enzyme inhibitors
- Olomola, Temitope Oloruntoba
- Authors: Olomola, Temitope Oloruntoba
- Date: 2011
- Subjects: HIV infections -- Treatment HIV infections -- Chemotherapy HIV (Viruses) Enzyme inhibitors AZT (Drug) Reverse transcriptase Proteolytic enzymes Ligands Psoralens Resorcinol
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4369 , http://hdl.handle.net/10962/d1005034
- Description: This study has involved the design, synthesis and evaluation of novel HIV-1 enzyme inhibitors accessed by synthetic elaboration of Baylis-Hillman adducts. Several series of complex coumarin-AZT and cinnamate ester-AZT conjugates have been prepared, in high yields, by exploiting the click reaction between appropriate Baylis-Hillman derived precursors and azidothymidine (AZT), all of which have been fully characterised using spectroscopic techniques. These conjugates, designed as potential dual-action HIV-1 inhibitors, were tested against the appropriate HIV-1 enzymes, i.e. HIV-1 reverse transcriptase and protease or HIV-1 reverse transcriptase and integrase. A number of the ligands have exhibited % inhibition levels and IC50 values comparable to drugs in clinical use, permitting their identification as lead compounds for the development of novel dual-action inhibitors. In silico docking of selected ligands into the active sites of the respective enzymes has provided useful insight into binding conformations and potential hydrogen-bonding interactions with active-site amino acid residues. A series of furocoumarin carboxamide derivatives have been synthesised in four steps starting from resorcinol and these compounds have also been tested for HIV-1 integrase inhibition activity. The structures of unexpected products isolated from Aza-Baylis-Hillman reactions of N-tosylaldimines have been elucidated by spectroscopic analysis, and confirmed by single crystal X-ray analysis. A mechanism for what appears to be an unprecedented transformation has been proposed. Microwave-assisted SeO₂ oxidation of Baylis-Hillman-derived 3-methylcoumarins has provided convenient and efficient access to coumarin-3-carbaldehydes, and a pilot study has revealed the potential of these coumarin-3-carbaldehydes as scaffolds for the construction of tricyclic compounds. The HCl-catalysed reaction of tert-butyl acrylate derived Baylis-Hillman adducts has been shown to afford 3-(chloromethyl)coumarins and α-(chloromethyl)cinnamic acids, the Zstereochemistry of the latter being established by X-ray crystallography. ¹H NMR-based experimental kinetic and DFT-level theoretical studies have been undertaken to establish the reaction sequence and other mechanistic details. Base-catalysed cyclisation on the other hand, has been shown to afford 2H-chromene rather than coumarin derivatives.
- Full Text:
- Authors: Olomola, Temitope Oloruntoba
- Date: 2011
- Subjects: HIV infections -- Treatment HIV infections -- Chemotherapy HIV (Viruses) Enzyme inhibitors AZT (Drug) Reverse transcriptase Proteolytic enzymes Ligands Psoralens Resorcinol
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4369 , http://hdl.handle.net/10962/d1005034
- Description: This study has involved the design, synthesis and evaluation of novel HIV-1 enzyme inhibitors accessed by synthetic elaboration of Baylis-Hillman adducts. Several series of complex coumarin-AZT and cinnamate ester-AZT conjugates have been prepared, in high yields, by exploiting the click reaction between appropriate Baylis-Hillman derived precursors and azidothymidine (AZT), all of which have been fully characterised using spectroscopic techniques. These conjugates, designed as potential dual-action HIV-1 inhibitors, were tested against the appropriate HIV-1 enzymes, i.e. HIV-1 reverse transcriptase and protease or HIV-1 reverse transcriptase and integrase. A number of the ligands have exhibited % inhibition levels and IC50 values comparable to drugs in clinical use, permitting their identification as lead compounds for the development of novel dual-action inhibitors. In silico docking of selected ligands into the active sites of the respective enzymes has provided useful insight into binding conformations and potential hydrogen-bonding interactions with active-site amino acid residues. A series of furocoumarin carboxamide derivatives have been synthesised in four steps starting from resorcinol and these compounds have also been tested for HIV-1 integrase inhibition activity. The structures of unexpected products isolated from Aza-Baylis-Hillman reactions of N-tosylaldimines have been elucidated by spectroscopic analysis, and confirmed by single crystal X-ray analysis. A mechanism for what appears to be an unprecedented transformation has been proposed. Microwave-assisted SeO₂ oxidation of Baylis-Hillman-derived 3-methylcoumarins has provided convenient and efficient access to coumarin-3-carbaldehydes, and a pilot study has revealed the potential of these coumarin-3-carbaldehydes as scaffolds for the construction of tricyclic compounds. The HCl-catalysed reaction of tert-butyl acrylate derived Baylis-Hillman adducts has been shown to afford 3-(chloromethyl)coumarins and α-(chloromethyl)cinnamic acids, the Zstereochemistry of the latter being established by X-ray crystallography. ¹H NMR-based experimental kinetic and DFT-level theoretical studies have been undertaken to establish the reaction sequence and other mechanistic details. Base-catalysed cyclisation on the other hand, has been shown to afford 2H-chromene rather than coumarin derivatives.
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Synthesis of novel inhibitors of 1-Deoxy-D-xylulose-5-phosphate reductoisomerase as potential anti-malarial lead compounds
- Authors: Mutorwa, Marius Kudumo
- Date: 2011
- Subjects: Antimalarials -- Development Plasmodium falciparum Malaria -- Chemotherapy Drug development Lead compounds Phosphonates Phosphonic acids Ligands
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4372 , http://hdl.handle.net/10962/d1005037
- Description: This research has focused on the development of novel substrate mimics as potential DXR 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 (DOXP) into 2C-methyl-D-erithrytol 4-phosphate (MEP) and has been validated as an attractive target for the development of novel anti-malarial chemotherapeutic agents. Reaction of various amines with specially prepared 4-phosphonated crotonic acid in the presence of the peptide coupling reagent, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), has afforded a series of amido-phosphonate esters in moderate to good yields (48% - 73%) which, using a RuCl₃/CeCl₃/NaIO₄ catalyst system, have been dihydroxylated to furnish the dihydroxy-amido phosphonate ester pro-drugs; subsequent hydrolysis under microwave irradiation has afforded the corresponding phosphonic acids. A second series of potential inhibitors viz., 3-substituted aniline-derived phosphonate esters, their corresponding phosphonic acids and mono-sodium salts, have also been successfully synthesised. In these compounds, the essential functional groups are separated by one, two, three or four methylene groups, Deprotonation of the 3-substituted aniline substrates, followed by reaction with the appropriate ω-chloroalkanoyl chloride produced the ω-chloroamide intermediates, which were subjected to the Michaelis-Arbuzov reaction to afford the diethyl phosphonate esters in moderate to good yields (48% - 74%). Microwave-assisted TMSBrmediated cleavage of the phosphonate esters furnished the phosphonic acids, neutralisation of which afforded the mono-sodium salts. Furan-derived phosphate esters and phosphonic acids have been prepared as conformationally-restricted DOXP analogues. Functionalization at C-5 of the trityl-protected furan was achieved using the Vilsmeier-Haack formylation and Friedel-Crafts acylation reactions and, following de-tritylation, phosphorylation and oximation, using hydroxylamine hydrochloride, the novel oxime derivatives have been isolated as a third series of potential DXR inhibitors in very good yields (87% - 96%). Finally, in order to exploit an additional binding pocket in the PƒDXR active site, a series of N-benzylated phosphoramidic derivatives were obtained in seven steps from the starting material, diethyl phosphoramidate. The known inhibitors, fosmidomycin and its acetyl derivative FR900098, were also successfully synthesised as standards for STD-NMR binding and inhibition assays. In all, over 200 compounds (136 novel) have been prepared and appropriately characterised using 1-and 2-D NMR and IR spectroscopic analysis and, where necessary, HRMS or combustion analysis. Saturation Transfer Difference (STD) protein-NMR experiments, undertaken using selected compounds, have revealed binding of most of the ligands examined to EcDXR. Computersimulated docking studies have also been used to explore the preferred ligand-binding conformations and interactions between the ligands and essential DXR active-site residues, while DXR-enzyme inhibition assays of selected synthesised ligands have revealed certain patterns of inhibitory activity.
- Full Text:
- Authors: Mutorwa, Marius Kudumo
- Date: 2011
- Subjects: Antimalarials -- Development Plasmodium falciparum Malaria -- Chemotherapy Drug development Lead compounds Phosphonates Phosphonic acids Ligands
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4372 , http://hdl.handle.net/10962/d1005037
- Description: This research has focused on the development of novel substrate mimics as potential DXR 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 (DOXP) into 2C-methyl-D-erithrytol 4-phosphate (MEP) and has been validated as an attractive target for the development of novel anti-malarial chemotherapeutic agents. Reaction of various amines with specially prepared 4-phosphonated crotonic acid in the presence of the peptide coupling reagent, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), has afforded a series of amido-phosphonate esters in moderate to good yields (48% - 73%) which, using a RuCl₃/CeCl₃/NaIO₄ catalyst system, have been dihydroxylated to furnish the dihydroxy-amido phosphonate ester pro-drugs; subsequent hydrolysis under microwave irradiation has afforded the corresponding phosphonic acids. A second series of potential inhibitors viz., 3-substituted aniline-derived phosphonate esters, their corresponding phosphonic acids and mono-sodium salts, have also been successfully synthesised. In these compounds, the essential functional groups are separated by one, two, three or four methylene groups, Deprotonation of the 3-substituted aniline substrates, followed by reaction with the appropriate ω-chloroalkanoyl chloride produced the ω-chloroamide intermediates, which were subjected to the Michaelis-Arbuzov reaction to afford the diethyl phosphonate esters in moderate to good yields (48% - 74%). Microwave-assisted TMSBrmediated cleavage of the phosphonate esters furnished the phosphonic acids, neutralisation of which afforded the mono-sodium salts. Furan-derived phosphate esters and phosphonic acids have been prepared as conformationally-restricted DOXP analogues. Functionalization at C-5 of the trityl-protected furan was achieved using the Vilsmeier-Haack formylation and Friedel-Crafts acylation reactions and, following de-tritylation, phosphorylation and oximation, using hydroxylamine hydrochloride, the novel oxime derivatives have been isolated as a third series of potential DXR inhibitors in very good yields (87% - 96%). Finally, in order to exploit an additional binding pocket in the PƒDXR active site, a series of N-benzylated phosphoramidic derivatives were obtained in seven steps from the starting material, diethyl phosphoramidate. The known inhibitors, fosmidomycin and its acetyl derivative FR900098, were also successfully synthesised as standards for STD-NMR binding and inhibition assays. In all, over 200 compounds (136 novel) have been prepared and appropriately characterised using 1-and 2-D NMR and IR spectroscopic analysis and, where necessary, HRMS or combustion analysis. Saturation Transfer Difference (STD) protein-NMR experiments, undertaken using selected compounds, have revealed binding of most of the ligands examined to EcDXR. Computersimulated docking studies have also been used to explore the preferred ligand-binding conformations and interactions between the ligands and essential DXR active-site residues, while DXR-enzyme inhibition assays of selected synthesised ligands have revealed certain patterns of inhibitory activity.
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Application of Baylis-Hillman methodology in the construction of complex heterocyclic targets
- Ganto, Mlungiseleli MacDonald
- Authors: Ganto, Mlungiseleli MacDonald
- Date: 2009
- Subjects: Heterocyclic compounds -- Derivatives Heterocyclic chemistry
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4401 , http://hdl.handle.net/10962/d1006703
- Description: Baylis-Hillman reactions using various aromatic aldehydes, activated alkenes and catalysts have been used to: - access an extensive range of poly-heterocyclic products;explore chemoselectivity; and optimise reaction efficiency. Chromone-3-carbaldehydes and chromone-2-carbaldehydes, prepared via Vielsmeier-Haack and Kostanecki-Robinson methodology, respectively, have been used as Baylis-Hillman substrates with four different catalysts, viz., 1,4-diazabicyclo[2.2.2]octane (DABCO), 3-hydroxyquinuclidine (3-HQ), imidazole and N’,N’,N’,N’- tetramethylpropanediamine (TMPDA), and with methyl vinyl ketone (MVK), methyl acrylate, cyclic enones (2-cyclohexen-1-one, 2-cyclopenten-1-one and chromones) as activated alkenes. Reactions of the chromone- -carbaldehydes with MVK afforded dimeric Baylis-Hillman adducts when catalyzed by DABCO but when the same reactions were repeated using 3-HQ as catalyst, the dimeric products were accompanied by tricyclic Baylis-Hillman adducts. Use of excess MVK, however, led to mixtures of the normal Baylis-Hillman adducts and the tricyclic adducts – interestingly, with the apparent absence of the dimeric products. While reactions of chromone-3-carbaldehydes with methyl acrylate afforded the normal Baylis-Hillman adducts, the chromone-2- carbaldehydes produced, instead, rearrangement products, consistent with an earlier, single observation. Reactions of 2-nitrobenzaldehydes with cyclic enones using imidazole as catalyst afforded the normal Baylis-Hillman adducts, reductive cyclisation of the 2-cyclohexen-1- one and 2-cyclopenten-1-one adducts, using acetic acid and iron powder, afforded the corresponding quinoline erivatives. Treatment of cyclic enones with pyridine-2-carbaldehydes and quinoline-2-carbaldehydes using TMPDA as catalyst generally gave the expected Baylis-Hillman adducts. However, indolizine derivatives were isolated directly from Baylis-Hillman reactions involving pyridine-2-carbaldehydes and 2-cyclohexen-1-one. The remaining Baylis-Hillman adducts were cyclized to the corresponding indolizines by treatment with acetic anhydride both under reflux and under microwave-assisted conditions, the latter approach providing remarkably rapid and efficient access to the polycyclic products. Computer modelling studies have been conducted on selected polycyclic products at the Molecular Mechanics (MM), Quantum Mechanical (QM) and Density Functional (DFT) levels. The theoretical results have been used to calculate UV, IR and NMR absorption data, which have been compared, in turn, with the experimental spectroscopic data. Use has also been made of the estreNova NMR prediction programme and, generally, good agreement has been observed between the predicted and experimental spectroscopic data.
- Full Text:
- Authors: Ganto, Mlungiseleli MacDonald
- Date: 2009
- Subjects: Heterocyclic compounds -- Derivatives Heterocyclic chemistry
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4401 , http://hdl.handle.net/10962/d1006703
- Description: Baylis-Hillman reactions using various aromatic aldehydes, activated alkenes and catalysts have been used to: - access an extensive range of poly-heterocyclic products;explore chemoselectivity; and optimise reaction efficiency. Chromone-3-carbaldehydes and chromone-2-carbaldehydes, prepared via Vielsmeier-Haack and Kostanecki-Robinson methodology, respectively, have been used as Baylis-Hillman substrates with four different catalysts, viz., 1,4-diazabicyclo[2.2.2]octane (DABCO), 3-hydroxyquinuclidine (3-HQ), imidazole and N’,N’,N’,N’- tetramethylpropanediamine (TMPDA), and with methyl vinyl ketone (MVK), methyl acrylate, cyclic enones (2-cyclohexen-1-one, 2-cyclopenten-1-one and chromones) as activated alkenes. Reactions of the chromone- -carbaldehydes with MVK afforded dimeric Baylis-Hillman adducts when catalyzed by DABCO but when the same reactions were repeated using 3-HQ as catalyst, the dimeric products were accompanied by tricyclic Baylis-Hillman adducts. Use of excess MVK, however, led to mixtures of the normal Baylis-Hillman adducts and the tricyclic adducts – interestingly, with the apparent absence of the dimeric products. While reactions of chromone-3-carbaldehydes with methyl acrylate afforded the normal Baylis-Hillman adducts, the chromone-2- carbaldehydes produced, instead, rearrangement products, consistent with an earlier, single observation. Reactions of 2-nitrobenzaldehydes with cyclic enones using imidazole as catalyst afforded the normal Baylis-Hillman adducts, reductive cyclisation of the 2-cyclohexen-1- one and 2-cyclopenten-1-one adducts, using acetic acid and iron powder, afforded the corresponding quinoline erivatives. Treatment of cyclic enones with pyridine-2-carbaldehydes and quinoline-2-carbaldehydes using TMPDA as catalyst generally gave the expected Baylis-Hillman adducts. However, indolizine derivatives were isolated directly from Baylis-Hillman reactions involving pyridine-2-carbaldehydes and 2-cyclohexen-1-one. The remaining Baylis-Hillman adducts were cyclized to the corresponding indolizines by treatment with acetic anhydride both under reflux and under microwave-assisted conditions, the latter approach providing remarkably rapid and efficient access to the polycyclic products. Computer modelling studies have been conducted on selected polycyclic products at the Molecular Mechanics (MM), Quantum Mechanical (QM) and Density Functional (DFT) levels. The theoretical results have been used to calculate UV, IR and NMR absorption data, which have been compared, in turn, with the experimental spectroscopic data. Use has also been made of the estreNova NMR prediction programme and, generally, good agreement has been observed between the predicted and experimental spectroscopic data.
- Full Text:
ATP mimics as glutamine synthetase inhibitors : an exploratory synthetic study
- Authors: Salisu, Sheriff Tomilola
- Date: 2008
- Subjects: Glutamine synthetase Tuberculosis -- Treatment Tuberculosis -- Chemotherapy Adenosine triphosphate Adenosine triphosphate -- Synthesis Drug development
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4408 , http://hdl.handle.net/10962/d1006715
- Description: Using a mechanism-based approach to drug discovery, efforts have been directed towards developing novel ATP mimics that can act as GS inhibitors. The purine-based systems, adenosine, adenine and allopurinol, were identified as possible scaffolds for potential ATP mimics, while various meta-disubstituted benzenoid compounds, 3-aminobenzonitrile, 3-aminophenol, resorcinol, 3-aminobenzyl alcohol, 3-hydroxybenzoic acid and 3-aminobenzoic acid have been explored as adenine analogues. These compounds were treated with different alkylating and acylating agents. Allylation of all the substrates was achieved using allyl bromide and N-9 alkylation of protected allopurinol was effected using a number of specially prepared Baylis-Hillman adducts. Acylation of the benzenoid precursors with chloroacetyl chloride, acetoxyacetyl chloride, acryloyl chloride and specially prepared 2,3,4,5,6-pentaacetylgluconoyl chloride afforded the corresponding mono- and /or diacylated products in varying yields (4-96%). Elaboration of the alkylated and acylated products has involved the reaction of hydroxy systems with diethyl chloro phosphate and chloro derivatives with triethyl phosphite in Arbuzov-type reactions to afford phosphorylated products. In all cases, products were fully characterized using 1- and 2-D NMR analysis and, where appropriate, high-resolution mass spectrometry. The application of Modgraph and ChemWindow NMR prediction programmes has been explored and the resulting data have been compared with experimental chemical shift assignments to confirm chemical structures and, in some cases, to establish the position of allylation or acylation. Experimental assignments were found to be generally comparable with the Modgraph data, but not always with the ChemWindow values. The docking of selected products in the 'active-site' of GS and their structural homology with ATP, both in their free and bound conformations have been studied using the ACCELERYS Cerius² platform. All the selected ATP mimics exhibit some form of interaction with the 'active-site' residues, and a number of them appear to be promising GS ligands.
- Full Text:
- Authors: Salisu, Sheriff Tomilola
- Date: 2008
- Subjects: Glutamine synthetase Tuberculosis -- Treatment Tuberculosis -- Chemotherapy Adenosine triphosphate Adenosine triphosphate -- Synthesis Drug development
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4408 , http://hdl.handle.net/10962/d1006715
- Description: Using a mechanism-based approach to drug discovery, efforts have been directed towards developing novel ATP mimics that can act as GS inhibitors. The purine-based systems, adenosine, adenine and allopurinol, were identified as possible scaffolds for potential ATP mimics, while various meta-disubstituted benzenoid compounds, 3-aminobenzonitrile, 3-aminophenol, resorcinol, 3-aminobenzyl alcohol, 3-hydroxybenzoic acid and 3-aminobenzoic acid have been explored as adenine analogues. These compounds were treated with different alkylating and acylating agents. Allylation of all the substrates was achieved using allyl bromide and N-9 alkylation of protected allopurinol was effected using a number of specially prepared Baylis-Hillman adducts. Acylation of the benzenoid precursors with chloroacetyl chloride, acetoxyacetyl chloride, acryloyl chloride and specially prepared 2,3,4,5,6-pentaacetylgluconoyl chloride afforded the corresponding mono- and /or diacylated products in varying yields (4-96%). Elaboration of the alkylated and acylated products has involved the reaction of hydroxy systems with diethyl chloro phosphate and chloro derivatives with triethyl phosphite in Arbuzov-type reactions to afford phosphorylated products. In all cases, products were fully characterized using 1- and 2-D NMR analysis and, where appropriate, high-resolution mass spectrometry. The application of Modgraph and ChemWindow NMR prediction programmes has been explored and the resulting data have been compared with experimental chemical shift assignments to confirm chemical structures and, in some cases, to establish the position of allylation or acylation. Experimental assignments were found to be generally comparable with the Modgraph data, but not always with the ChemWindow values. The docking of selected products in the 'active-site' of GS and their structural homology with ATP, both in their free and bound conformations have been studied using the ACCELERYS Cerius² platform. All the selected ATP mimics exhibit some form of interaction with the 'active-site' residues, and a number of them appear to be promising GS ligands.
- Full Text:
Studies directed towards the synthesis of chromone carbaldehyde-derived HIV-1 protease inhibitors
- Authors: Molefe, Duduzile Mabel
- Date: 2008
- Subjects: Protease Inhibitors , HIV infections , HIV (Viruses) , AIDS (Disease) , Proteolytic enzymes , Heterocyclic compounds -- Derivatives , Chemical kinetics , Nuclear magnetic resonance spectroscopy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4526 , http://hdl.handle.net/10962/d1015542
- Description: A series of chromone-3-carbaldehydes have been prepared using Vilsmeier-Haack methodology while a corresponding series of chromone-2-carbaldeydes have been synthesized via the Kostanecki-Robinson reaction. Baylis-Hillman reactions have been conducted on both series of chromone carbaldehydes using three different catalysts, viz., 1,4-diazabicyclo(2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec- 7-ene (DBU) and 3-hydroxyquinuclidine (3HQ), and acrylonitrile, methyl acrylate and methyl vinyl ketone as the activated alkenes. These reactions have typically (but not always!) afforded both normal Baylis-Hillman and dimeric products. Attention has also been given to the use of 1-methyl-2-pyrrolidine (1-NMP), an ionic liquid, to replace normal organic solvents, and it has been found that, in the presence of DABCO, chromone-3-carbaldehydes afford the dimeric products alone. Reactions of chromone-3-carbaldehydes with methyl vinyl ketone have yielded unexpected, novel adducts, which appear to arise from preferential attack at C(2) in the chromone nucleus. Research on chromone-2-carbaldeydes under Baylis-Hillman conditions has also resulted in the formation of some interesting products instead of the expected Baylis-Hillman adducts. The Baylis-Hillman products have been explored as substrates for aza-Michael reactions using various amino derivatives including protected amino acids in the presence of the tetrabutylammonium bromide (TBAB) and the ionic liquid, 3-butyl-1- methylimidazoleboranetetrafluoride (BmimBF₄), as catalysts. The aza-Michael products have been targeted as truncated ritonavir analogues for investigation as potential HIV -1 protease inhibitors, and representative compounds have been subjected to enzyme inhibition assays to explore the extent and type of inhibition. Lineweaver-Burk and Dixon plots have indicated competitive inhibition in one case as well as non-competitive inhibition in another, and the inhibition constants (Ki) have been compared with that of the ritonavir. Computer modelling studies have also been conducted on selected chromonecontaining derivatives, using the ACCELRYS Cerius² platform. Interactive docking of the chromone-containing ligands into the HIV -1 protease receptor site, using the Ligandfit module, has indicated the importance of hydrogen-bonding interactions mediated by bridging water molecules situated in the receptor cavity. NMR spectroscopy has been used to elucidate complex and competing mechanistic pathways involved in the Baylis-Hillman reactions of selected 2-nitrobenzaldehydes with MVK in the presence of DABCO - reactions which afford the normal BaylisHillman product, the MVK dimer and syn- and anti-Baylis-Hillman type diadducts. The kinetic data confirm the concomitant operation of two pathways and reveal that, in the initial stage of the reaction, the product distribution is kinetically controlled, whereas in the latter stage, thermodynamic control results in the consumption of the normal Baylis-Hillman product and predominance of the anti-diadduct.
- Full Text:
- Authors: Molefe, Duduzile Mabel
- Date: 2008
- Subjects: Protease Inhibitors , HIV infections , HIV (Viruses) , AIDS (Disease) , Proteolytic enzymes , Heterocyclic compounds -- Derivatives , Chemical kinetics , Nuclear magnetic resonance spectroscopy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4526 , http://hdl.handle.net/10962/d1015542
- Description: A series of chromone-3-carbaldehydes have been prepared using Vilsmeier-Haack methodology while a corresponding series of chromone-2-carbaldeydes have been synthesized via the Kostanecki-Robinson reaction. Baylis-Hillman reactions have been conducted on both series of chromone carbaldehydes using three different catalysts, viz., 1,4-diazabicyclo(2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec- 7-ene (DBU) and 3-hydroxyquinuclidine (3HQ), and acrylonitrile, methyl acrylate and methyl vinyl ketone as the activated alkenes. These reactions have typically (but not always!) afforded both normal Baylis-Hillman and dimeric products. Attention has also been given to the use of 1-methyl-2-pyrrolidine (1-NMP), an ionic liquid, to replace normal organic solvents, and it has been found that, in the presence of DABCO, chromone-3-carbaldehydes afford the dimeric products alone. Reactions of chromone-3-carbaldehydes with methyl vinyl ketone have yielded unexpected, novel adducts, which appear to arise from preferential attack at C(2) in the chromone nucleus. Research on chromone-2-carbaldeydes under Baylis-Hillman conditions has also resulted in the formation of some interesting products instead of the expected Baylis-Hillman adducts. The Baylis-Hillman products have been explored as substrates for aza-Michael reactions using various amino derivatives including protected amino acids in the presence of the tetrabutylammonium bromide (TBAB) and the ionic liquid, 3-butyl-1- methylimidazoleboranetetrafluoride (BmimBF₄), as catalysts. The aza-Michael products have been targeted as truncated ritonavir analogues for investigation as potential HIV -1 protease inhibitors, and representative compounds have been subjected to enzyme inhibition assays to explore the extent and type of inhibition. Lineweaver-Burk and Dixon plots have indicated competitive inhibition in one case as well as non-competitive inhibition in another, and the inhibition constants (Ki) have been compared with that of the ritonavir. Computer modelling studies have also been conducted on selected chromonecontaining derivatives, using the ACCELRYS Cerius² platform. Interactive docking of the chromone-containing ligands into the HIV -1 protease receptor site, using the Ligandfit module, has indicated the importance of hydrogen-bonding interactions mediated by bridging water molecules situated in the receptor cavity. NMR spectroscopy has been used to elucidate complex and competing mechanistic pathways involved in the Baylis-Hillman reactions of selected 2-nitrobenzaldehydes with MVK in the presence of DABCO - reactions which afford the normal BaylisHillman product, the MVK dimer and syn- and anti-Baylis-Hillman type diadducts. The kinetic data confirm the concomitant operation of two pathways and reveal that, in the initial stage of the reaction, the product distribution is kinetically controlled, whereas in the latter stage, thermodynamic control results in the consumption of the normal Baylis-Hillman product and predominance of the anti-diadduct.
- Full Text:
Synthetic, spectrometric and computer modelling studies of novel ATP analogues
- Gxoyiya, Babalwa Siliziwe Blossom
- Authors: Gxoyiya, Babalwa Siliziwe Blossom
- Date: 2008
- Subjects: Spectrum analysis Tuberculosis -- Treatment Chemotherapy Adenosine triphosphate Adenosine triphosphate -- Synthesis Adenosine triphosphate -- Computer simulation Adenosine triphosphate -- Spectrometric imaging Glutamine synthetase Tuberculosis -- Chemotherapy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4386 , http://hdl.handle.net/10962/d1005051
- Description: This study has been concerned with the design and synthesis of A TP analogues with the potential to act as inhibitors of glutamine synthetase - a novel target for therapeutic intervention in the treatment of tuberculosis. Using a structural -analogy approach, various 3-indolylalkanoic acid, benzimidazole and pyrazolo[3,4-dJpyrimidine derivatives have been prepared and characterized. Alkylation of the heterocyclic bases using 4-(bromomethyl)-2,2-dimethyl-1 ,3-d ioxolane, 2-(bromomethoxy)ethyl acetate and 2-(chloroethoxy)ethanol in the presence of either NaH or BulOK afforded the corresponding N-alkylated derivatives of benzimidazole and 4-aminopyrazolo[3,4-dJpyrimidine (4-APP). Similar reactions with 3-indo lylalkanoic esters resulted in O-alkyl cleavage with the formation of new esters. Alkylation of benzimidazole with allyl bromide, 4-bromobutene and 2-methylbut-2-ene has also been shown to afford the corresponding l-alkenylbenzimidazoles in moderate to excellent yield (43-96%). Subsequent oxidation of these products using CTAP, gave the dihydroxy derivatives in poor to good yields (26-77%). Phosphorylation of various hydroxy derivatives of benzimidazole and 4-APP has been achieved using diethyl chlorophosphate to afford the corresponding monophosphate and 1,2-diphosphate esters. Glycosylation of each of the heterocyclic bases has been successfully achieved using 1,2,3,4,6-penta-O-acetyl-D-glucopyranose and SnCl4 in acetonitri le, while methanolysis of the resulting tetraacetates, using methanolic NaOMe, afforded the hydroxy derivatives in good yield (50-70%). Various 1- and 2-dimensional NMR spectroscopic methods (e.g., IH, 13C, lip, COSY, HSQC and HMBC) have been used to confirm the structures of the synthesized A IP analogues. The application of NMR prediction programmes has been explored, permitting assessment of their agreement with the experimental data and confirmation of assigned structures. High-resolution electron impact (EI) mass spectrometric data have been used to explore the mass fragmentation pathways exhibited by selected derivatives, and certain common fragmentations have been identified. Molecular modelling of selected products as potential glutamine synthetase ligands has been performed on the Accelrys Cerius2 platform, and interactive receptor-ligand docking studies have been conducted using the Ligand-Fit module. These studies have revealed possible hydrogen-boding interactions between the selected analogues and various amino acid residues in the glutamine synthetase active site.
- Full Text:
- Authors: Gxoyiya, Babalwa Siliziwe Blossom
- Date: 2008
- Subjects: Spectrum analysis Tuberculosis -- Treatment Chemotherapy Adenosine triphosphate Adenosine triphosphate -- Synthesis Adenosine triphosphate -- Computer simulation Adenosine triphosphate -- Spectrometric imaging Glutamine synthetase Tuberculosis -- Chemotherapy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4386 , http://hdl.handle.net/10962/d1005051
- Description: This study has been concerned with the design and synthesis of A TP analogues with the potential to act as inhibitors of glutamine synthetase - a novel target for therapeutic intervention in the treatment of tuberculosis. Using a structural -analogy approach, various 3-indolylalkanoic acid, benzimidazole and pyrazolo[3,4-dJpyrimidine derivatives have been prepared and characterized. Alkylation of the heterocyclic bases using 4-(bromomethyl)-2,2-dimethyl-1 ,3-d ioxolane, 2-(bromomethoxy)ethyl acetate and 2-(chloroethoxy)ethanol in the presence of either NaH or BulOK afforded the corresponding N-alkylated derivatives of benzimidazole and 4-aminopyrazolo[3,4-dJpyrimidine (4-APP). Similar reactions with 3-indo lylalkanoic esters resulted in O-alkyl cleavage with the formation of new esters. Alkylation of benzimidazole with allyl bromide, 4-bromobutene and 2-methylbut-2-ene has also been shown to afford the corresponding l-alkenylbenzimidazoles in moderate to excellent yield (43-96%). Subsequent oxidation of these products using CTAP, gave the dihydroxy derivatives in poor to good yields (26-77%). Phosphorylation of various hydroxy derivatives of benzimidazole and 4-APP has been achieved using diethyl chlorophosphate to afford the corresponding monophosphate and 1,2-diphosphate esters. Glycosylation of each of the heterocyclic bases has been successfully achieved using 1,2,3,4,6-penta-O-acetyl-D-glucopyranose and SnCl4 in acetonitri le, while methanolysis of the resulting tetraacetates, using methanolic NaOMe, afforded the hydroxy derivatives in good yield (50-70%). Various 1- and 2-dimensional NMR spectroscopic methods (e.g., IH, 13C, lip, COSY, HSQC and HMBC) have been used to confirm the structures of the synthesized A IP analogues. The application of NMR prediction programmes has been explored, permitting assessment of their agreement with the experimental data and confirmation of assigned structures. High-resolution electron impact (EI) mass spectrometric data have been used to explore the mass fragmentation pathways exhibited by selected derivatives, and certain common fragmentations have been identified. Molecular modelling of selected products as potential glutamine synthetase ligands has been performed on the Accelrys Cerius2 platform, and interactive receptor-ligand docking studies have been conducted using the Ligand-Fit module. These studies have revealed possible hydrogen-boding interactions between the selected analogues and various amino acid residues in the glutamine synthetase active site.
- Full Text:
Metathesis catalysts : an integrated computational, mechanistic and synthetic study
- Authors: Sabbagh, Ingrid Theresa
- Date: 2006
- Subjects: Metathesis (Chemistry) Catalysis Metal catalysts Chemical kinetics
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4397 , http://hdl.handle.net/10962/d1006208
- Description: An integrated approach to the design of potential rutheniun-based metathesis catalysts is described, in which closely defined synthetic forays provide the focus and rationale for detailed computational and mechanistic studies. The ground-state geometry of a 1st-generation Grubbs catalyst has been explored at the molecular mechanics, semi-empirical and DFT levels, and the resulting structures have been shown to compare favourably with literature data and with the structure of a known crystalline analogue. The DMol³ DFT code has also been shown to represent accurately both the geometry of the corresponding co-ordinatively unsaturated monophosphine derivative, and the ligand dissociation energy associated with its formation. A DFT free-energy profile of the degenerate metathesis of ethylene has been generated, using a truncated model of the 1st-generation Grubbs catalyst, permitting location, for the first time, of the three expected transition states and providing new information regarding the rate-determining step. DFT methods have been used to facilitate the design of a tridentate camphor-derived ligand for use in the construction of a novel Grubbs-type catalyst. The phosphine ligand dissociation energy of the putative catalyst and the ethylene metathesis energy profile of a truncated model have also been studies at the DFT level. The attempted synthesis of the proposed ligand proceeded via a novel 8-bromocamphoric anhydride intermediate and afforded several unexpected and novel products, including a cisfused γ-Iactone, and a bromo camphoric acid derivative. Single crystal X-ray analysis of the latter reveals a chiral, polymeric H-bonded packing arrangement, rendering it suitable for chiral inclusion studies. Computational methods, including the GAUSSIAN-based GIAO NMR prediction technique, were used to support the structural characterisation of the novel camphor derivatives. DFT-Ievel computational analysis of the C-8- and C-9 bromination of camphor has afforded theoretical insights which permit the reconciliation of two earlier empirical explanations regarding the regioselectivity of these transformations; moreover, the theoretical results suggest that a third, previously disregarded factor, plays a significant role. A coset analysis, in conjunction with DFT-Ievel energy profiling, has also been used to resolve conflicting opinions regarding the origin of the major byproduct. Computed electronic parameters (CEP's) have been calculated for the anionic ligands involved in a series of 2nd-generation Grubbs-Hoveyda-type catalysts, and used to explain some apparently anomalous trends in catalyst activity. A linear relationship between ligand CEP's and selected ¹H NMR chemical shifts has also been demonstrated and used to identify a transient ruthenium complex in solution. The ability of the malonate di-anion to bind to ruthenium in a bidentate manner has been explored and demonstrated, under suitable conditions. DFT methods have been used to design and assess the ruthenium-chelating potential of a novel tridentate malonate derivative. A synthetic pathway to this ligand has been designed and several novel heterocyclic intermediates have been isolated and characterised. An NMR-based kinetic study of the Grubbs-catalysed self-metathesis of l-octene has been completed, and the effects of temperature, concentration and solvent variations on the kinetic parameters have been studied. Application of the Guggenheim method and a simplified mechanistic model has permitted the accurate calculation of pseudorate constants for the initiation and, for the first time, the propagation phase of the reaction. Theoretical studies of this reaction at the DFT and molecular mechanics levels have been shown to support previous assumptions regarding the selectivity and temperature-dependence of metallacycle formation.
- Full Text:
- Authors: Sabbagh, Ingrid Theresa
- Date: 2006
- Subjects: Metathesis (Chemistry) Catalysis Metal catalysts Chemical kinetics
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4397 , http://hdl.handle.net/10962/d1006208
- Description: An integrated approach to the design of potential rutheniun-based metathesis catalysts is described, in which closely defined synthetic forays provide the focus and rationale for detailed computational and mechanistic studies. The ground-state geometry of a 1st-generation Grubbs catalyst has been explored at the molecular mechanics, semi-empirical and DFT levels, and the resulting structures have been shown to compare favourably with literature data and with the structure of a known crystalline analogue. The DMol³ DFT code has also been shown to represent accurately both the geometry of the corresponding co-ordinatively unsaturated monophosphine derivative, and the ligand dissociation energy associated with its formation. A DFT free-energy profile of the degenerate metathesis of ethylene has been generated, using a truncated model of the 1st-generation Grubbs catalyst, permitting location, for the first time, of the three expected transition states and providing new information regarding the rate-determining step. DFT methods have been used to facilitate the design of a tridentate camphor-derived ligand for use in the construction of a novel Grubbs-type catalyst. The phosphine ligand dissociation energy of the putative catalyst and the ethylene metathesis energy profile of a truncated model have also been studies at the DFT level. The attempted synthesis of the proposed ligand proceeded via a novel 8-bromocamphoric anhydride intermediate and afforded several unexpected and novel products, including a cisfused γ-Iactone, and a bromo camphoric acid derivative. Single crystal X-ray analysis of the latter reveals a chiral, polymeric H-bonded packing arrangement, rendering it suitable for chiral inclusion studies. Computational methods, including the GAUSSIAN-based GIAO NMR prediction technique, were used to support the structural characterisation of the novel camphor derivatives. DFT-Ievel computational analysis of the C-8- and C-9 bromination of camphor has afforded theoretical insights which permit the reconciliation of two earlier empirical explanations regarding the regioselectivity of these transformations; moreover, the theoretical results suggest that a third, previously disregarded factor, plays a significant role. A coset analysis, in conjunction with DFT-Ievel energy profiling, has also been used to resolve conflicting opinions regarding the origin of the major byproduct. Computed electronic parameters (CEP's) have been calculated for the anionic ligands involved in a series of 2nd-generation Grubbs-Hoveyda-type catalysts, and used to explain some apparently anomalous trends in catalyst activity. A linear relationship between ligand CEP's and selected ¹H NMR chemical shifts has also been demonstrated and used to identify a transient ruthenium complex in solution. The ability of the malonate di-anion to bind to ruthenium in a bidentate manner has been explored and demonstrated, under suitable conditions. DFT methods have been used to design and assess the ruthenium-chelating potential of a novel tridentate malonate derivative. A synthetic pathway to this ligand has been designed and several novel heterocyclic intermediates have been isolated and characterised. An NMR-based kinetic study of the Grubbs-catalysed self-metathesis of l-octene has been completed, and the effects of temperature, concentration and solvent variations on the kinetic parameters have been studied. Application of the Guggenheim method and a simplified mechanistic model has permitted the accurate calculation of pseudorate constants for the initiation and, for the first time, the propagation phase of the reaction. Theoretical studies of this reaction at the DFT and molecular mechanics levels have been shown to support previous assumptions regarding the selectivity and temperature-dependence of metallacycle formation.
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Applications of the Baylis-Hillman reaction in the synthesis of coumarin derivatives
- Authors: Musa, Musiliyu Ayodele
- Date: 2003
- Subjects: Coumarins Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4403 , http://hdl.handle.net/10962/d1006705
- Description: The reaction of specially prepared salicylaldehyde benzyl ethers with the activated alkenes, methyl acrylate or acrylonitrile, in the presence of the catalyst, DABCO, has afforded Baylis-Hillman products, which have been subjected to conjugate addition with either piperidine or benzylamine. Hydrogenolysis of these conjugate addition products in the presence of a palladium-on-carbon catalyst has been shown to afford the corresponding 3-substituted coumarins, while treatment of O-benzylated Baylis-Hillman adducts with HCl or HI afforded the corresponding 3-(halomethyl)coumarins directly, in up to 94%. The 3-(halomethyl)coumarins have also been obtained in excellent yields (up to 98%) and even more conveniently, by treating the unprotected Baylis-Hillman products with HCl in a mixture of AcOH and Ac₂O, obtained from tert-butyl acrylate and various salicylaldehydes. The generality of an established route to the synthesis of coumarins via an intramolecular Baylis-Hillman reaction, involving the use of salicylaldehyde acrylate esters in the presence of DABCO, has also been demonstrated. Reactions between the 3-(halomethyl)coumarins and various nitrogen and carbon nucleophiles have been shown to proceed with a high degree of regioselectivity at the exocyclic allylic centre to afford 3-substituted coumarin products. The electronimpact mass spectra of selected coumarin derivatives have been investigated using high-resolution and B/E linked scan data. Fragmentation pathways have been proposed and fragmentation modes associated with different coumarin-containing analogues have been compared. A series of coumarin-containing analogues of ritonavir (a clinically useful HIV-1 protease inhibitor) have been prepared and characterized. The synthetic approach has involved the coupling of coumarin derivatives with a hydroxyethylene dipeptide isostere to afford ritonavir analogues containing coumarin termini. An interactive docking procedure has been used to explore the docking of ritonavir and a coumarincontaining analogue into the enzyme active site.
- Full Text:
- Authors: Musa, Musiliyu Ayodele
- Date: 2003
- Subjects: Coumarins Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4403 , http://hdl.handle.net/10962/d1006705
- Description: The reaction of specially prepared salicylaldehyde benzyl ethers with the activated alkenes, methyl acrylate or acrylonitrile, in the presence of the catalyst, DABCO, has afforded Baylis-Hillman products, which have been subjected to conjugate addition with either piperidine or benzylamine. Hydrogenolysis of these conjugate addition products in the presence of a palladium-on-carbon catalyst has been shown to afford the corresponding 3-substituted coumarins, while treatment of O-benzylated Baylis-Hillman adducts with HCl or HI afforded the corresponding 3-(halomethyl)coumarins directly, in up to 94%. The 3-(halomethyl)coumarins have also been obtained in excellent yields (up to 98%) and even more conveniently, by treating the unprotected Baylis-Hillman products with HCl in a mixture of AcOH and Ac₂O, obtained from tert-butyl acrylate and various salicylaldehydes. The generality of an established route to the synthesis of coumarins via an intramolecular Baylis-Hillman reaction, involving the use of salicylaldehyde acrylate esters in the presence of DABCO, has also been demonstrated. Reactions between the 3-(halomethyl)coumarins and various nitrogen and carbon nucleophiles have been shown to proceed with a high degree of regioselectivity at the exocyclic allylic centre to afford 3-substituted coumarin products. The electronimpact mass spectra of selected coumarin derivatives have been investigated using high-resolution and B/E linked scan data. Fragmentation pathways have been proposed and fragmentation modes associated with different coumarin-containing analogues have been compared. A series of coumarin-containing analogues of ritonavir (a clinically useful HIV-1 protease inhibitor) have been prepared and characterized. The synthetic approach has involved the coupling of coumarin derivatives with a hydroxyethylene dipeptide isostere to afford ritonavir analogues containing coumarin termini. An interactive docking procedure has been used to explore the docking of ritonavir and a coumarincontaining analogue into the enzyme active site.
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Chemical studies of selected chromone derivatives
- Authors: Nchinda, Aloysius Tchangwe
- Date: 2002
- Subjects: Heterocyclic compounds
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4434 , http://hdl.handle.net/10962/d1007442
- Description: This investigation has been geared towards several aspects of chromone chemistry. Selected 2-(N,N-dimethylarnino)chromones have been synthesized via 2-hydroxyacetophenone boron difluoride complex intermediates, and potentiometric analysis of these compounds in ethanolwater has been used to determine the influence of substituents on their basicity. The pKa values have been found to lie within a narrow range (1.92 - 2.52), and the observed substituent effects have been rationalized with the aid of semi-empirical and ab initio molecular orbital calculations. An efficient route has been developed for the synthesis of the naturally-occurring chromone, "granulosin" [7,8-(methylenedioxy)-2-propylchromone], and several C-2 side chain analogues in good yields, by condensing 2'-hydroxy-3',4'-(methylenedioxy)acetophenone with a range of ethyl carboxylate esters. These compounds show significant cytotoxic activity against the brine shrimp, Artemia salina, and two of them, the 2-ethyl and 2-benzyl derivatives also show 100% activity as pesticides on Beet army worms (BAW). Another naturally-occurring chromone derivative, 5-hydroxy-2-isopropyl-7-methoxychromone, and four C-2 side chain analogues have been prepared in moderate yields. These compounds also show significant cytotoxic activity against the brine shrimp, Artemia salina, and it is apparent that the presence of the hydroxyl group at C-5 is critical for such activity. The electronimpact mass spectra of both series of chromone derivatives have been investigated, permitting the elucidation of characteristic fragmentation patterns. In work directed towards the synthesis of potential HIV -1 protease inhibitors, five novel chromone-containing analogues of the clinically useful drug, ritonavir, have been synthesized. The design strategy has involved the coupling of substituted chromone-2- carboxylic acids with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing chromone termini. An interactive docking procedure has been used to explore the docking of ritonavir and the novel chromone-containing analogues into ' the active site of the enzyme, and has indicated the capacity of the ritonavir analogues to form hydrogen-bonds with the HJV-l enzyme receptor. Various substituted cbromone-3-carbaldehydes, which have been synthesized from the corresponding o-hyclroxyacetophenones using Vilsmeier-Haack methodology, have been examined as substrates for Morita-Baylis-Hillman reactions, using 3-hyclroxyquinuclidine as the catalyst and arcylonitrile and methyl acrylate as the activated alkenes. Optimization of the reaction conditions has permitted efficient conversion of the cbromone-3-carbaldehydes to the Morita-Baylis-Hillman products and, in some cases, dimeric products, within 24 h. Heating of the Morita-Baylis-Hillman products, arising from reactions with methyl acrylate, at 80 ºC for 3 h in the presence of DABCO as catalyst, has been shown to effect transformation to the corresponding dimers in good yield.
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- Authors: Nchinda, Aloysius Tchangwe
- Date: 2002
- Subjects: Heterocyclic compounds
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4434 , http://hdl.handle.net/10962/d1007442
- Description: This investigation has been geared towards several aspects of chromone chemistry. Selected 2-(N,N-dimethylarnino)chromones have been synthesized via 2-hydroxyacetophenone boron difluoride complex intermediates, and potentiometric analysis of these compounds in ethanolwater has been used to determine the influence of substituents on their basicity. The pKa values have been found to lie within a narrow range (1.92 - 2.52), and the observed substituent effects have been rationalized with the aid of semi-empirical and ab initio molecular orbital calculations. An efficient route has been developed for the synthesis of the naturally-occurring chromone, "granulosin" [7,8-(methylenedioxy)-2-propylchromone], and several C-2 side chain analogues in good yields, by condensing 2'-hydroxy-3',4'-(methylenedioxy)acetophenone with a range of ethyl carboxylate esters. These compounds show significant cytotoxic activity against the brine shrimp, Artemia salina, and two of them, the 2-ethyl and 2-benzyl derivatives also show 100% activity as pesticides on Beet army worms (BAW). Another naturally-occurring chromone derivative, 5-hydroxy-2-isopropyl-7-methoxychromone, and four C-2 side chain analogues have been prepared in moderate yields. These compounds also show significant cytotoxic activity against the brine shrimp, Artemia salina, and it is apparent that the presence of the hydroxyl group at C-5 is critical for such activity. The electronimpact mass spectra of both series of chromone derivatives have been investigated, permitting the elucidation of characteristic fragmentation patterns. In work directed towards the synthesis of potential HIV -1 protease inhibitors, five novel chromone-containing analogues of the clinically useful drug, ritonavir, have been synthesized. The design strategy has involved the coupling of substituted chromone-2- carboxylic acids with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing chromone termini. An interactive docking procedure has been used to explore the docking of ritonavir and the novel chromone-containing analogues into ' the active site of the enzyme, and has indicated the capacity of the ritonavir analogues to form hydrogen-bonds with the HJV-l enzyme receptor. Various substituted cbromone-3-carbaldehydes, which have been synthesized from the corresponding o-hyclroxyacetophenones using Vilsmeier-Haack methodology, have been examined as substrates for Morita-Baylis-Hillman reactions, using 3-hyclroxyquinuclidine as the catalyst and arcylonitrile and methyl acrylate as the activated alkenes. Optimization of the reaction conditions has permitted efficient conversion of the cbromone-3-carbaldehydes to the Morita-Baylis-Hillman products and, in some cases, dimeric products, within 24 h. Heating of the Morita-Baylis-Hillman products, arising from reactions with methyl acrylate, at 80 ºC for 3 h in the presence of DABCO as catalyst, has been shown to effect transformation to the corresponding dimers in good yield.
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Applications of Baylis-Idllman methodology in the synthesis of chromene derivatives
- Authors: Nocanda, Xolani Wittleton
- Date: 2001
- Subjects: Heterocyclic chemistry , Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4556 , http://hdl.handle.net/10962/d1018257
- Description: The reaction of salicylaldehyde with various activated alkenes, viz., methyl vinyl ketone, ethyl vinyl ketone, phenyl vinyl sulfone, phenyl vinylsulfonate, acrolein and acrylonitrile, under Baylis-Hillman conditions, has been found to proceed with the chemoselective formation of chromene derivatives. The reaction conditions have been optimised and chromene derivatives have been obtained in isolated yields up to 87 %. The generality of the reaction, using 1,4-diazabicyclo[2.2.2]octane (DABCO), as the catalyst, and a heterogeneous (chloroform-water) solvent system, has been established using a range of salicylaldehyde derivatives,. including 2-hydroxynaphthaldehyde. The formation of chromene derivatives, under these conditions, has been assumed to proceed via an initial, Baylis-Hillman reaction, followed by cyclisation involving intramolecular conjugate addition, and subsequent dehydration. Evidence supporting this sequence has been obtained from the isolation ofBaylis-Hillman products from reactions involving the use of tertbutylclimethylsilyl-protected salicylaldehyde, 4-hydroxybenzaldehyde and tert-butyl acrylate as substrates. The potential of the ''Baylis-Hillman zwitterion" to participate as a donor species in Michael-type addition reactions has been explored and a series of climeric products has been isolated. The Baylis-Hillman methodology has also been successfully extended to the synthesis of sulfurcontaining heterocyclic systems, and a range of 3-substituted thiochromenes has been obtained in moderate yields, using 2,2'-dithiobenzaldehyde and various activated alkenes in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst. The electron-impact mass spectra of selected chromene and thiocbromene derivatives have been investigated permitting comparison of the fragmentation of the oxygen- and sulfur-containing analogues. In a study directed at the synthesis of potential HIV -1 protease inhibitors, chromene- and thiocbromene-containing analogues of the clinically useful drug, ritonavir, have been prepared. Thiochromene and chromene derivatives were converted to the corresponding 3 -carboxylic acids and coupled with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing cbromene and thiochromene termini in ca. 60% yield.
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- Authors: Nocanda, Xolani Wittleton
- Date: 2001
- Subjects: Heterocyclic chemistry , Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4556 , http://hdl.handle.net/10962/d1018257
- Description: The reaction of salicylaldehyde with various activated alkenes, viz., methyl vinyl ketone, ethyl vinyl ketone, phenyl vinyl sulfone, phenyl vinylsulfonate, acrolein and acrylonitrile, under Baylis-Hillman conditions, has been found to proceed with the chemoselective formation of chromene derivatives. The reaction conditions have been optimised and chromene derivatives have been obtained in isolated yields up to 87 %. The generality of the reaction, using 1,4-diazabicyclo[2.2.2]octane (DABCO), as the catalyst, and a heterogeneous (chloroform-water) solvent system, has been established using a range of salicylaldehyde derivatives,. including 2-hydroxynaphthaldehyde. The formation of chromene derivatives, under these conditions, has been assumed to proceed via an initial, Baylis-Hillman reaction, followed by cyclisation involving intramolecular conjugate addition, and subsequent dehydration. Evidence supporting this sequence has been obtained from the isolation ofBaylis-Hillman products from reactions involving the use of tertbutylclimethylsilyl-protected salicylaldehyde, 4-hydroxybenzaldehyde and tert-butyl acrylate as substrates. The potential of the ''Baylis-Hillman zwitterion" to participate as a donor species in Michael-type addition reactions has been explored and a series of climeric products has been isolated. The Baylis-Hillman methodology has also been successfully extended to the synthesis of sulfurcontaining heterocyclic systems, and a range of 3-substituted thiochromenes has been obtained in moderate yields, using 2,2'-dithiobenzaldehyde and various activated alkenes in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst. The electron-impact mass spectra of selected chromene and thiocbromene derivatives have been investigated permitting comparison of the fragmentation of the oxygen- and sulfur-containing analogues. In a study directed at the synthesis of potential HIV -1 protease inhibitors, chromene- and thiocbromene-containing analogues of the clinically useful drug, ritonavir, have been prepared. Thiochromene and chromene derivatives were converted to the corresponding 3 -carboxylic acids and coupled with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing cbromene and thiochromene termini in ca. 60% yield.
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Chemical studies of chromone derivatives
- Authors: Sabbagh, Liezel Veronica
- Date: 2001
- Subjects: Benzopyrans Heterocyclic compounds -- Derivatives Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4424 , http://hdl.handle.net/10962/d1006899
- Description:
This study has focussed on several aspects of chromone chemistry, viz., (i) the influence of remote substituents on the basicity of 2-(N,N-dimethylamino)chromones, (ii) MoritaBaylis-Hillman reactions of substituted chromone-3-carbaldehydes and (iii) an investigation into the application of chromone chemistry in the total synthesis of the marine natural product, Rietone A. Selected 2-(N,N-dimethylamino )chromones were prepared using two different methods; firstly, via cyclisation of salicylate-derived N,N-dimethyl-3;.(2-hydroxyphenyl)-3- oxopropanamide precursors and, secondly, via 2-hydroxyacetophenone boron difluoride complexes. ¹³C NMR analysis of the 6- and 7-methoxy-2-(N,N-dimethylamino)chromones confirmed that protonation occurs at the chromone carbonyl oxygen rather than the amino nitrogen - a conclusion supported by mol~cular orbital calculations. Potentiometric analysis of 2-(N,N-dimethylamino )chromones in ethanol-water afforded pKa (pK [subscript a]) values in the range 2.22 - 2.52. The observed trend has been rationalised in terms of substituent effects with the aid of molecular orbital calculations at the semi-empirical and ab initio levels, while hydrogen-bonding effects have been used to account for the apparently anomalous result obtained for the 6-nitro derivative. A series of seven substituted chromone-3-carbaldehydes, prepared by the application of Vilsmeier-Haack methodology to the corresponding 2-hydroxyacetophenones, have been examined as substrates for Morita-Baylis-Hillman reactions, using DABCO as the catalyst and three different activated alkenes, viz., methyl acrylate, methyl vinyl ketone and acrylonitrile. In all cases, with the exception of 6-nitrochromone-3-carbaldehyde, the reactions have been shown to afford the expected Morita-Baylis-Hillman products. Use of methyl acrylate and methyl vinyl ketone as the activated alkene has been observed to afford additional, unprecedented dimeric products, which have been unambiguously characterised using a combination of single crystal X-ray analysis and spectroscopic (high resolution MS and NMR) techniques. Different dimer-like adducts have been isolated from reactions in which acrylonitrile was used as the activated alkene, and the structures of these novel products have-been determined
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- Authors: Sabbagh, Liezel Veronica
- Date: 2001
- Subjects: Benzopyrans Heterocyclic compounds -- Derivatives Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4424 , http://hdl.handle.net/10962/d1006899
- Description:
This study has focussed on several aspects of chromone chemistry, viz., (i) the influence of remote substituents on the basicity of 2-(N,N-dimethylamino)chromones, (ii) MoritaBaylis-Hillman reactions of substituted chromone-3-carbaldehydes and (iii) an investigation into the application of chromone chemistry in the total synthesis of the marine natural product, Rietone A. Selected 2-(N,N-dimethylamino )chromones were prepared using two different methods; firstly, via cyclisation of salicylate-derived N,N-dimethyl-3;.(2-hydroxyphenyl)-3- oxopropanamide precursors and, secondly, via 2-hydroxyacetophenone boron difluoride complexes. ¹³C NMR analysis of the 6- and 7-methoxy-2-(N,N-dimethylamino)chromones confirmed that protonation occurs at the chromone carbonyl oxygen rather than the amino nitrogen - a conclusion supported by mol~cular orbital calculations. Potentiometric analysis of 2-(N,N-dimethylamino )chromones in ethanol-water afforded pKa (pK [subscript a]) values in the range 2.22 - 2.52. The observed trend has been rationalised in terms of substituent effects with the aid of molecular orbital calculations at the semi-empirical and ab initio levels, while hydrogen-bonding effects have been used to account for the apparently anomalous result obtained for the 6-nitro derivative. A series of seven substituted chromone-3-carbaldehydes, prepared by the application of Vilsmeier-Haack methodology to the corresponding 2-hydroxyacetophenones, have been examined as substrates for Morita-Baylis-Hillman reactions, using DABCO as the catalyst and three different activated alkenes, viz., methyl acrylate, methyl vinyl ketone and acrylonitrile. In all cases, with the exception of 6-nitrochromone-3-carbaldehyde, the reactions have been shown to afford the expected Morita-Baylis-Hillman products. Use of methyl acrylate and methyl vinyl ketone as the activated alkene has been observed to afford additional, unprecedented dimeric products, which have been unambiguously characterised using a combination of single crystal X-ray analysis and spectroscopic (high resolution MS and NMR) techniques. Different dimer-like adducts have been isolated from reactions in which acrylonitrile was used as the activated alkene, and the structures of these novel products have-been determined
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Design, synthesis and evaluation of silver-specific ligands
- Authors: Daubinet, André
- Date: 2001
- Subjects: Ligands Ligands -- Design Ligands -- Analysis Ligands -- Evaluation Silver -- Metallurgy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4308 , http://hdl.handle.net/10962/d1004966
- Description: Several series of ligands, designed to chelate silver(I) specifically in the presence of base metals, have been synthesised. The ligands include: - dithiodiamide compounds, prepared by the condensation of acetanilide derivatives with 1,2-dibromoethane; propanenitrile and propanoic ester derivatives prepared from pyridine-2-carbaldehyde via the Morita-Baylis-Hillman reaction; and novel malonamide ligands from the reaction of diethyl malonate with a range of primary amines. The malonamide derivatives were prepared under both conventional thermal and microwave-assisted conditions, the latter proving to be highly efficient. The ligands were all characterised using a combination of spectroscopic and, where appropriate, elemental analysis; in one case, the structural assignment was confirmed by single-crystal X-ray analysis. The fragmentation patterns in the electron-impact mass spectra of the malonamide derivatives have been explored using high-resolution and meta-stable peak scanning techniques. Complexes of the malonamide ligands with copper(II) and silver(I) have been synthesised, and examination of these complexes has revealed distinct differences in their co-ordination preferences towards silver(I) and copper(II). Tentative, computer-modelled structures for the complexes have been proposed using the available spectroscopic and elemental analysis data. Computer modelling, at the Molecular Mechanics level, has also been used to assess the capacity of the ligand systems to adopt conformations suitable for the chelation of tetrahedral silver(I). Solvent extraction studies have been undertaken using aqueous metal ion solutions and various organic solvents. The dithiodiamide derivatives typically presented solubility problems, but one of the ligands, N,N´-bis(3-chlorophenyl)-3,6-dithiaoctanediamide, exhibited significant but slow extraction of silver(I) into toluene. The malonamide derivatives, however, proved to be readily soluble in ethyl acetate and, in some cases, exhibited good to excellent selectivity for silver(I) in the presence of the base metals copper and lead. Atomic absorption analysis revealed rapid equilibration times (<15 min) and high extraction efficiencies over a wide pH range (2.78 - 9.0). Metal selectivity has been determined by ICP-MS analysis of the residual silver, copper and lead present in the aqueous phase after 15 min, and one of the ligands, N,N´-bis(2-benzylsulfanylethyl)malonamide, exhibits excellent (≥ 96 %) silver(I) specificity.
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- Authors: Daubinet, André
- Date: 2001
- Subjects: Ligands Ligands -- Design Ligands -- Analysis Ligands -- Evaluation Silver -- Metallurgy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4308 , http://hdl.handle.net/10962/d1004966
- Description: Several series of ligands, designed to chelate silver(I) specifically in the presence of base metals, have been synthesised. The ligands include: - dithiodiamide compounds, prepared by the condensation of acetanilide derivatives with 1,2-dibromoethane; propanenitrile and propanoic ester derivatives prepared from pyridine-2-carbaldehyde via the Morita-Baylis-Hillman reaction; and novel malonamide ligands from the reaction of diethyl malonate with a range of primary amines. The malonamide derivatives were prepared under both conventional thermal and microwave-assisted conditions, the latter proving to be highly efficient. The ligands were all characterised using a combination of spectroscopic and, where appropriate, elemental analysis; in one case, the structural assignment was confirmed by single-crystal X-ray analysis. The fragmentation patterns in the electron-impact mass spectra of the malonamide derivatives have been explored using high-resolution and meta-stable peak scanning techniques. Complexes of the malonamide ligands with copper(II) and silver(I) have been synthesised, and examination of these complexes has revealed distinct differences in their co-ordination preferences towards silver(I) and copper(II). Tentative, computer-modelled structures for the complexes have been proposed using the available spectroscopic and elemental analysis data. Computer modelling, at the Molecular Mechanics level, has also been used to assess the capacity of the ligand systems to adopt conformations suitable for the chelation of tetrahedral silver(I). Solvent extraction studies have been undertaken using aqueous metal ion solutions and various organic solvents. The dithiodiamide derivatives typically presented solubility problems, but one of the ligands, N,N´-bis(3-chlorophenyl)-3,6-dithiaoctanediamide, exhibited significant but slow extraction of silver(I) into toluene. The malonamide derivatives, however, proved to be readily soluble in ethyl acetate and, in some cases, exhibited good to excellent selectivity for silver(I) in the presence of the base metals copper and lead. Atomic absorption analysis revealed rapid equilibration times (<15 min) and high extraction efficiencies over a wide pH range (2.78 - 9.0). Metal selectivity has been determined by ICP-MS analysis of the residual silver, copper and lead present in the aqueous phase after 15 min, and one of the ligands, N,N´-bis(2-benzylsulfanylethyl)malonamide, exhibits excellent (≥ 96 %) silver(I) specificity.
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