A chemical investigation of Tulbaghia Violacea
- Authors: Burton, Stephanie Gail
- Date: 1990
- Subjects: Liliaceae , Plants -- Analysis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4528 , http://hdl.handle.net/10962/d1015725
- Description: Tulbaghia violacea, a member of the family Alliaceae is indigenous to the Eastern Cape and is widely used as a herbal remedy for various febrile and gastro-enteric ailments, particularly in young children. Adverse effects, and even fatalities, have been reported following treatment with the plant extract. The project has involved synthesis of model compounds, chromatographic analysis of flavonoid and other constituents of the plant, and examination of the volatile components. Some fifteen flavones were synthesised as chromatographic models and in the course of this work, the development of a new method for synthesis of carboxylic anhydrides was completed. Use of the flavone standards permitted identification of the flavonols kaempferol and quercetin in hydrolysed glycosidic plant extracts. In addition, several sugars were identified, viz., D-glucose, D-fructose, L-arabinose and D-galactose as free sugars, and D-glucose, D-galactose , 1-rhamnose, D- fucose, D-xylose, 1-arabinose and D-fructose as glycosidic sugars, by g.l.c. and g. c. - m. s. analysis of derivatives of isolated sugar mixtures. The presence in the plant extracts of steroidal saponins was also demonstrated. The sulphur compounds, 2,4,5,7-tetrathiaoctane-2,2-dioxide and 2,4,5,7-tetrathiaoctane were isolated from the plant and characterised spectroscopically. This result, together with analysis of volatiles from the plant, has led to a proposal concerning the nature and origin of sulphur compounds in Tulbaghia violacea, showing close correlation with the sulphur compounds in Allium species. Investigation of the biological activity of Tulbaghia violacea extracts showed bacteriostatic activity, particularly of extracts which had not been heated, and which had been prepared from mature plants. Treatment of isolated smooth muscle preparations with Tulbaghia violacea extracts indicated the presence of a β-adrenergic agonist having an inhibitory effect on normal muscle contraction. The results of the investigations indicate that while there may be some basis for use of the plant as an antibacterial, or to treat colic, the adverse effects, caused possibly by the sulphur compounds and/or steroidal saponins present, may override the beneficial effects.
- Full Text:
- Date Issued: 1990
- Authors: Burton, Stephanie Gail
- Date: 1990
- Subjects: Liliaceae , Plants -- Analysis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4528 , http://hdl.handle.net/10962/d1015725
- Description: Tulbaghia violacea, a member of the family Alliaceae is indigenous to the Eastern Cape and is widely used as a herbal remedy for various febrile and gastro-enteric ailments, particularly in young children. Adverse effects, and even fatalities, have been reported following treatment with the plant extract. The project has involved synthesis of model compounds, chromatographic analysis of flavonoid and other constituents of the plant, and examination of the volatile components. Some fifteen flavones were synthesised as chromatographic models and in the course of this work, the development of a new method for synthesis of carboxylic anhydrides was completed. Use of the flavone standards permitted identification of the flavonols kaempferol and quercetin in hydrolysed glycosidic plant extracts. In addition, several sugars were identified, viz., D-glucose, D-fructose, L-arabinose and D-galactose as free sugars, and D-glucose, D-galactose , 1-rhamnose, D- fucose, D-xylose, 1-arabinose and D-fructose as glycosidic sugars, by g.l.c. and g. c. - m. s. analysis of derivatives of isolated sugar mixtures. The presence in the plant extracts of steroidal saponins was also demonstrated. The sulphur compounds, 2,4,5,7-tetrathiaoctane-2,2-dioxide and 2,4,5,7-tetrathiaoctane were isolated from the plant and characterised spectroscopically. This result, together with analysis of volatiles from the plant, has led to a proposal concerning the nature and origin of sulphur compounds in Tulbaghia violacea, showing close correlation with the sulphur compounds in Allium species. Investigation of the biological activity of Tulbaghia violacea extracts showed bacteriostatic activity, particularly of extracts which had not been heated, and which had been prepared from mature plants. Treatment of isolated smooth muscle preparations with Tulbaghia violacea extracts indicated the presence of a β-adrenergic agonist having an inhibitory effect on normal muscle contraction. The results of the investigations indicate that while there may be some basis for use of the plant as an antibacterial, or to treat colic, the adverse effects, caused possibly by the sulphur compounds and/or steroidal saponins present, may override the beneficial effects.
- Full Text:
- Date Issued: 1990
A synthetic and spectrometric study of the initial phases in urea-formaldehyde resin formation
- Authors: Nocanda, Xolani Wittleton
- Date: 1998
- Subjects: Phenolic resins , Gums and resins, Synthetic
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4383 , http://hdl.handle.net/10962/d1005048 , Phenolic resins , Gums and resins, Synthetic
- Description: In a series ofpreIiminary studies of urea-formaldehyde reactions, the influence of the U:F molar ratio, the temperature and the catalyst were investigated. Subsequently, in a more rigorous evaluation of the influence of four variables on urea-formaldehyde resin formation, viz., U:F molar ratio, pH, temperature and reaction time, a set of twenty reactions were performed using a statistical approach. The results indicate that high resin viscosity is best achieved by using a high U:F molar ratio (1:2) and conducting the reaction at 90°C. Several basic components produced in urea-formaldehyde reactions have been synthesised, characterised by NMR spectroscopy, silylated using bis(trimethylsilyl)trifluoroacetamide and analysed by low resolution mass spectrometry. The use oftriazones as cross-linking agents has been investigated, and a series of 5-substituted triazones have been prepared and their mass fragmentation patterns explored using a combination of low and high resolution mass spectrometry. In order to facilitate interpretation of ¹³C NMR data obtained for U-F resins, internal rotation in various urea derivatives was investigated using variable temperature ¹H and ¹³C NMR spectroscopic study. Signal splittings observed below 247 K have been rationalised in terms of various rotameric structures.
- Full Text:
- Date Issued: 1998
- Authors: Nocanda, Xolani Wittleton
- Date: 1998
- Subjects: Phenolic resins , Gums and resins, Synthetic
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4383 , http://hdl.handle.net/10962/d1005048 , Phenolic resins , Gums and resins, Synthetic
- Description: In a series ofpreIiminary studies of urea-formaldehyde reactions, the influence of the U:F molar ratio, the temperature and the catalyst were investigated. Subsequently, in a more rigorous evaluation of the influence of four variables on urea-formaldehyde resin formation, viz., U:F molar ratio, pH, temperature and reaction time, a set of twenty reactions were performed using a statistical approach. The results indicate that high resin viscosity is best achieved by using a high U:F molar ratio (1:2) and conducting the reaction at 90°C. Several basic components produced in urea-formaldehyde reactions have been synthesised, characterised by NMR spectroscopy, silylated using bis(trimethylsilyl)trifluoroacetamide and analysed by low resolution mass spectrometry. The use oftriazones as cross-linking agents has been investigated, and a series of 5-substituted triazones have been prepared and their mass fragmentation patterns explored using a combination of low and high resolution mass spectrometry. In order to facilitate interpretation of ¹³C NMR data obtained for U-F resins, internal rotation in various urea derivatives was investigated using variable temperature ¹H and ¹³C NMR spectroscopic study. Signal splittings observed below 247 K have been rationalised in terms of various rotameric structures.
- Full Text:
- Date Issued: 1998
An investigation of reactions directed towards the synthesis of 2-methyl-2-(methylthio)propanal oxime
- Authors: Whittaker, Ruth Eleanor
- Date: 1995
- Subjects: Pesticides -- Synthesis , Insecticides , Aldicarb -- Synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4322 , http://hdl.handle.net/10962/d1004980 , Pesticides -- Synthesis , Insecticides , Aldicarb -- Synthesis
- Description: The processes leading to the formation of 2-methyl-2-(methylthio)propanal oxime, known industrially as aldicarb oxime, have been studied. The three stages of the synthesis, viz., chlorination, thiomethylation and oximation have been thoroughly investigated, with the aim of optimising the yield and purity of aldicarb oxime. Attention has been focused on the chlorination step, and the effects of altering various conditions have been determined; the reaction has been carried out in the absence and presence of heat, solvent and buffer, and the extent of chlorine addition has also been varied. These studies have led to some improvement in the yield for this step. Several simple and inexpensive methods for purifying contaminated batches of aldicarb oxime have also been examined. Possible aldicarb oxime contaminants, identified by GLC and GC-MS analysis, have been synthesised for use as chromatographic and spectroscopic standards, and confirmation of the presence of a number of these contaminants has been achieved. Aldehyde trimers have been found to be the primary contaminants present in aldicarb oxime and the thermal stability of these trimers, their corresponding monomers and aldicarb oxime itself has been studied using variable temperature ¹H NMR spectroscopy. Novel pyridine derivatives, with potential as aldicarb analogues, have been synthesised and characterised using spectroscopic methods.
- Full Text:
- Date Issued: 1995
- Authors: Whittaker, Ruth Eleanor
- Date: 1995
- Subjects: Pesticides -- Synthesis , Insecticides , Aldicarb -- Synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4322 , http://hdl.handle.net/10962/d1004980 , Pesticides -- Synthesis , Insecticides , Aldicarb -- Synthesis
- Description: The processes leading to the formation of 2-methyl-2-(methylthio)propanal oxime, known industrially as aldicarb oxime, have been studied. The three stages of the synthesis, viz., chlorination, thiomethylation and oximation have been thoroughly investigated, with the aim of optimising the yield and purity of aldicarb oxime. Attention has been focused on the chlorination step, and the effects of altering various conditions have been determined; the reaction has been carried out in the absence and presence of heat, solvent and buffer, and the extent of chlorine addition has also been varied. These studies have led to some improvement in the yield for this step. Several simple and inexpensive methods for purifying contaminated batches of aldicarb oxime have also been examined. Possible aldicarb oxime contaminants, identified by GLC and GC-MS analysis, have been synthesised for use as chromatographic and spectroscopic standards, and confirmation of the presence of a number of these contaminants has been achieved. Aldehyde trimers have been found to be the primary contaminants present in aldicarb oxime and the thermal stability of these trimers, their corresponding monomers and aldicarb oxime itself has been studied using variable temperature ¹H NMR spectroscopy. Novel pyridine derivatives, with potential as aldicarb analogues, have been synthesised and characterised using spectroscopic methods.
- Full Text:
- Date Issued: 1995
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:
- Date Issued: 2009
- 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:
- Date Issued: 2009
Application of Baylis-Hillman methodology in the synthesis of HIV-1 enzyme inhibitors
- Authors: Manyeruke, Meloddy Hlatini
- Date: 2015
- Subjects: HIV infections , Enzyme inhibitors , AZT (Drug) , Bioconjugates
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4540 , http://hdl.handle.net/10962/d1017920
- Description: The application of Baylis-Hillman methodology has afforded access to a range of β-hydroxypropionate ester-AZT conjugates as potential dual-action HIV-1 IN/RT inhibitors. Two families comprising a total of nine β-hydroxypropionate ester-AZT conjugates were synthesised. The first family was accessed using O-benzylated salicylaldehydes and methyl acrylate and the second from unprotected salicylaldehydes using tert-butyl acrylate as the activated alkene. Spectroscopic methods were employed to fully characterize the compounds. Propargylation of the respective Baylis-Hillman adducts was achieved via conjugate addition of propargylamine. The resulting products were then employed in Cu(I)-catalysed “click” reactions with azidothymidine (AZT) to yield the desired β-hydroxypropionate ester-AZT conjugates. Exploratory studies were also conducted to access 4-hydroxycoumarins from Baylis-Hillman derived adducts and to construct customized chiral Baylis-Hillman reaction sites. Many 4- hydroxycoumarins are known to exhibit a wide range of biological activities, and extending Baylis-Hillman methodology to access these systems is an important challenge. Two approaches were investigated. The first involved the formation of a 4-phthalimidocoumarin, aromatisation and hydrolysis of which was expected to lead to the 4-hydroxycoumarin target. The second, a variation of the first, involved the use of 4-(chrolomethyl)coumarin intermediates. Unfortunately, while various intermediates were prepared and characterised, neither approach led ultimately to the desired targets. N-substituted borneol-10-sulfonamides were constructed from camphor-10- sulfonyl chloride as chiral Baylis-Hillman reaction sites. In a preliminary study, however, none of the N-substituted borneol-10-sulfonamides exhibited Baylis-Hillman catalytic activity.
- Full Text:
- Date Issued: 2015
- Authors: Manyeruke, Meloddy Hlatini
- Date: 2015
- Subjects: HIV infections , Enzyme inhibitors , AZT (Drug) , Bioconjugates
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4540 , http://hdl.handle.net/10962/d1017920
- Description: The application of Baylis-Hillman methodology has afforded access to a range of β-hydroxypropionate ester-AZT conjugates as potential dual-action HIV-1 IN/RT inhibitors. Two families comprising a total of nine β-hydroxypropionate ester-AZT conjugates were synthesised. The first family was accessed using O-benzylated salicylaldehydes and methyl acrylate and the second from unprotected salicylaldehydes using tert-butyl acrylate as the activated alkene. Spectroscopic methods were employed to fully characterize the compounds. Propargylation of the respective Baylis-Hillman adducts was achieved via conjugate addition of propargylamine. The resulting products were then employed in Cu(I)-catalysed “click” reactions with azidothymidine (AZT) to yield the desired β-hydroxypropionate ester-AZT conjugates. Exploratory studies were also conducted to access 4-hydroxycoumarins from Baylis-Hillman derived adducts and to construct customized chiral Baylis-Hillman reaction sites. Many 4- hydroxycoumarins are known to exhibit a wide range of biological activities, and extending Baylis-Hillman methodology to access these systems is an important challenge. Two approaches were investigated. The first involved the formation of a 4-phthalimidocoumarin, aromatisation and hydrolysis of which was expected to lead to the 4-hydroxycoumarin target. The second, a variation of the first, involved the use of 4-(chrolomethyl)coumarin intermediates. Unfortunately, while various intermediates were prepared and characterised, neither approach led ultimately to the desired targets. N-substituted borneol-10-sulfonamides were constructed from camphor-10- sulfonyl chloride as chiral Baylis-Hillman reaction sites. In a preliminary study, however, none of the N-substituted borneol-10-sulfonamides exhibited Baylis-Hillman catalytic activity.
- Full Text:
- Date Issued: 2015
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:
- Date Issued: 2019
- 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:
- Date Issued: 2019
Application of the Baylis-Hillman methodology in the construction of novel heterocyclic derivatives
- Authors: Nyoni, Dubekile
- Date: 2008
- Subjects: Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4402 , http://hdl.handle.net/10962/d1006704
- Description: Baylis-Hillman reactions of 2,2’-dithiodibenzaldehyde with the acyclic alkenes, methyl vinyl ketone (MVK) and methyl acrylate have afforded the thiochromene derivatives in moderate yields, and this approach has been extended to the use of the cyclic alkenes, 2-cyclohexenone and 2-cyclopentenone to afford the tricyclic analogues. In all cases, reduction of the disulphide link and intramolecular cyclisation occurred in situ, and a preliminary kinetic study of this reaction using the acyclic substrates MVK and methyl acrylate was undertaken with the aim of elucidating the mechanism involved. The results obtained showed that the consumption of both 2,2’-dithiodibenzaldehyde and MVK and/or methyl acrylate followed 1st-order kinetics during the initial stages of the reaction, but then deviated from 1st-order linearity. The reaction with methyl acrylate was much slower than with MVK, and the kinetic data indicates the mechanism to be more complex than anticipated. Conjugate addition reactions of methyl acrylate-derived 2-nitrobenzaldehyde Baylis-Hillman adducts with the amines, piperidine and benzylamine, afforded a range of conjugate addition products as diastereomeric mixtures in excellent yield (80-100%). Catalytic hydrogenation of the conjugate addition products using a Pd-C catalyst in ethanol, has afforded the corresponding, novel 3-amino-2-quinolone derivatives in lower yield (22-37%).The application of [superscript 13]C NMR prediction programmes to selected compounds synthesized in this study has revealed reasonable correlations between the experimental and predicted values.
- Full Text:
- Date Issued: 2008
- Authors: Nyoni, Dubekile
- Date: 2008
- Subjects: Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4402 , http://hdl.handle.net/10962/d1006704
- Description: Baylis-Hillman reactions of 2,2’-dithiodibenzaldehyde with the acyclic alkenes, methyl vinyl ketone (MVK) and methyl acrylate have afforded the thiochromene derivatives in moderate yields, and this approach has been extended to the use of the cyclic alkenes, 2-cyclohexenone and 2-cyclopentenone to afford the tricyclic analogues. In all cases, reduction of the disulphide link and intramolecular cyclisation occurred in situ, and a preliminary kinetic study of this reaction using the acyclic substrates MVK and methyl acrylate was undertaken with the aim of elucidating the mechanism involved. The results obtained showed that the consumption of both 2,2’-dithiodibenzaldehyde and MVK and/or methyl acrylate followed 1st-order kinetics during the initial stages of the reaction, but then deviated from 1st-order linearity. The reaction with methyl acrylate was much slower than with MVK, and the kinetic data indicates the mechanism to be more complex than anticipated. Conjugate addition reactions of methyl acrylate-derived 2-nitrobenzaldehyde Baylis-Hillman adducts with the amines, piperidine and benzylamine, afforded a range of conjugate addition products as diastereomeric mixtures in excellent yield (80-100%). Catalytic hydrogenation of the conjugate addition products using a Pd-C catalyst in ethanol, has afforded the corresponding, novel 3-amino-2-quinolone derivatives in lower yield (22-37%).The application of [superscript 13]C NMR prediction programmes to selected compounds synthesized in this study has revealed reasonable correlations between the experimental and predicted values.
- Full Text:
- Date Issued: 2008
Application of the Baylis-Hillman reaction in the preparation of quinoline derivatives
- Authors: Pakade, Vusumzi Emmanuel
- Date: 2006 , 2013-06-11
- Subjects: Heterocyclic compounds -- Derivatives , Quinoline
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4442 , http://hdl.handle.net/10962/d1007669 , Heterocyclic compounds -- Derivatives , Quinoline
- Description: The reaction of various 2-nitrobenzaldehyde derivatives with methyl vinyl ketone (MVK) in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) has afforded the Baylis-Hillman adducts in moderate to good yield. Dissolution of the catalyst in the solvent before the addition of the aldehyde was observed to improve the yield. Reduction of the Baylis-Hillman adducts was effected by catalytic hydrogenation using a 10% palladium-on- carbon catalyst in ethanol to give quinoline and quinoline-N-oxide derivatives and, in some cases, acyclic reduction products. All products were characterised using NMR and, where appropriate, HRMS methods. Selected quinoline-N-oxides were successfully converted to their corresponding quinoline derivatives using phosphorus tribromide (PBr₃) and DMF as solvent. Conjugate addition of the benzylamine and piperidine nucleophiles to the Baylis-Hillman adducts was also investigated but proved problematic, with one of the substrates undergoing a retro-Baylis-Hillman reaction to afford the aldehyde in ca. 40% yield, but seemingly only traces of the required product. Perkin-type coupling of two 2-methylquinolines with benzaldehyde was successfully effected to afford the desired styrylquinoline derivatives confirming the potential of the Baylis-Hillman approach to the construction of the analogues of known HIV-1 integrase inhibitors. Three ¹³C NMR chemical shift prediction programmes, viz., Chem Window, neural network and HOSE (hierarchically ordered spherical description of environment) methods were applied to selected representative compounds prepared in the project. The results from the three programmes correlated reasonably well with the experimental carbon-13 chemical shift data for each of the selected compounds.
- Full Text:
- Date Issued: 2006
- Authors: Pakade, Vusumzi Emmanuel
- Date: 2006 , 2013-06-11
- Subjects: Heterocyclic compounds -- Derivatives , Quinoline
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4442 , http://hdl.handle.net/10962/d1007669 , Heterocyclic compounds -- Derivatives , Quinoline
- Description: The reaction of various 2-nitrobenzaldehyde derivatives with methyl vinyl ketone (MVK) in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) has afforded the Baylis-Hillman adducts in moderate to good yield. Dissolution of the catalyst in the solvent before the addition of the aldehyde was observed to improve the yield. Reduction of the Baylis-Hillman adducts was effected by catalytic hydrogenation using a 10% palladium-on- carbon catalyst in ethanol to give quinoline and quinoline-N-oxide derivatives and, in some cases, acyclic reduction products. All products were characterised using NMR and, where appropriate, HRMS methods. Selected quinoline-N-oxides were successfully converted to their corresponding quinoline derivatives using phosphorus tribromide (PBr₃) and DMF as solvent. Conjugate addition of the benzylamine and piperidine nucleophiles to the Baylis-Hillman adducts was also investigated but proved problematic, with one of the substrates undergoing a retro-Baylis-Hillman reaction to afford the aldehyde in ca. 40% yield, but seemingly only traces of the required product. Perkin-type coupling of two 2-methylquinolines with benzaldehyde was successfully effected to afford the desired styrylquinoline derivatives confirming the potential of the Baylis-Hillman approach to the construction of the analogues of known HIV-1 integrase inhibitors. Three ¹³C NMR chemical shift prediction programmes, viz., Chem Window, neural network and HOSE (hierarchically ordered spherical description of environment) methods were applied to selected representative compounds prepared in the project. The results from the three programmes correlated reasonably well with the experimental carbon-13 chemical shift data for each of the selected compounds.
- Full Text:
- Date Issued: 2006
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.
- Full Text:
- Date Issued: 2001
- 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.
- Full Text:
- Date Issued: 2001
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:
- Date Issued: 2003
- 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:
- Date Issued: 2003
Asymmetric induction in reactions of chiral carboxylic esters and silyl enol ethers
- Authors: Evans, Melanie Daryl
- Date: 1998
- Subjects: Ethers -- Synthesis Esters -- Synthesis Chirality Asymmetric synthesis Organic compounds -- Synthesis
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4409 , http://hdl.handle.net/10962/d1006762
- Description: Several camphor and pinane derivatives have been synthesised and evaluated for use as chiral auxiliaries in asymmetric synthesis. Various blocking groups have been attached to the camphor skeleton in attempts to improve stereofacial selectivity; these include α-methoxybenzyl and xylyl groups, and novel stereoisomeric ketal moieties derived from meso- and (R,R)-(-)-2,3-butanediol. Benzylation reactions carried out on the lithium enolates of ester derivatives of the camphor-derived chiral auxiliaries afforded α-benzylated products in 5-60% diastereomeric excess. Stereochemical aspects have been explored using high resolution NMR, X-ray crystallographic and computer modelling techniques, and hydrolysis of selected α-benzylated products has permitted the diasteroselective bias to be confirmed. Opposite configurations at the new stereogenic centre are clearly favoured by the xylyl and ketal blocking groups - an observation rationalised in terms of the presence or absence of chelating potential in the blocking group. Baylis-Hillman reactions carried out on a series of specially prepared camphor-derived acrylic esters containing the ketal blocking group exhibited both low diastereoselectivities (0-30% d.e.) and very long reaction times. Chiral silyl enol ethers, synthesised using both pinane and camphor derivatives as chiral auxiliaries, showed up to 20% diastereomeric excess in MCPBA oxidation, alkylation and Mukaiyama reactions. Attempts to bring the prochiral centre in the silyl enol ether substrates closer to the chiral auxiliary, and thus improve the stereofacial selectivity, proved unsuccessful. The silyl enol ether derivatives, however, display interesting fragmentation patterns in their electron impact mass spectra, which were investigated using a combination of high resolution MS, comparative low resolution MS and metastable peak analysis.
- Full Text:
- Date Issued: 1998
- Authors: Evans, Melanie Daryl
- Date: 1998
- Subjects: Ethers -- Synthesis Esters -- Synthesis Chirality Asymmetric synthesis Organic compounds -- Synthesis
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4409 , http://hdl.handle.net/10962/d1006762
- Description: Several camphor and pinane derivatives have been synthesised and evaluated for use as chiral auxiliaries in asymmetric synthesis. Various blocking groups have been attached to the camphor skeleton in attempts to improve stereofacial selectivity; these include α-methoxybenzyl and xylyl groups, and novel stereoisomeric ketal moieties derived from meso- and (R,R)-(-)-2,3-butanediol. Benzylation reactions carried out on the lithium enolates of ester derivatives of the camphor-derived chiral auxiliaries afforded α-benzylated products in 5-60% diastereomeric excess. Stereochemical aspects have been explored using high resolution NMR, X-ray crystallographic and computer modelling techniques, and hydrolysis of selected α-benzylated products has permitted the diasteroselective bias to be confirmed. Opposite configurations at the new stereogenic centre are clearly favoured by the xylyl and ketal blocking groups - an observation rationalised in terms of the presence or absence of chelating potential in the blocking group. Baylis-Hillman reactions carried out on a series of specially prepared camphor-derived acrylic esters containing the ketal blocking group exhibited both low diastereoselectivities (0-30% d.e.) and very long reaction times. Chiral silyl enol ethers, synthesised using both pinane and camphor derivatives as chiral auxiliaries, showed up to 20% diastereomeric excess in MCPBA oxidation, alkylation and Mukaiyama reactions. Attempts to bring the prochiral centre in the silyl enol ether substrates closer to the chiral auxiliary, and thus improve the stereofacial selectivity, proved unsuccessful. The silyl enol ether derivatives, however, display interesting fragmentation patterns in their electron impact mass spectra, which were investigated using a combination of high resolution MS, comparative low resolution MS and metastable peak analysis.
- Full Text:
- Date Issued: 1998
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:
- Date Issued: 2008
- 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:
- Date Issued: 2008
Baylis-Hillman derived benzopyrans and related systems : a synthetic and mechanistic study
- Authors: Robinson, Ross Stuart
- Date: 1998
- Subjects: Benzopyrans Coumarins Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4429 , http://hdl.handle.net/10962/d1007193
- Description: The Baylis-Hillman reaction between substituted salicylaldehydes and various acrylate species has been shown to afford complex reaction mixtures, careful chromatography of which has led to the isolation of an extensive range of novel compounds. One- and two-dimensional NMR spectroscopic, mass spectrometric and X-ray crystallographic analysis of these compounds have permitted identification of no less than eight general classes of chromene and coumarin derivatives. The formation of the various product types is attributed to cascades of successive reactions stemming, in each case, from a Baylis-Hillman product as the common intermediate. The mechanistic sequence involved in the formation of the various chromene and coumarin derivatives have been elucidated by examining isolated or specifically prepared compounds as putative reaction intermediates. Conjugate addition and acyl or allylic substitution by various nucleophiles appear to be common processes in the formation of the chromene and coumarin derivatives, and studies focussing on these processes have been undertaken. Reactions of Baylis-Hillman adducts have been carried out, using oxygen, sulfur and nitrogen nucleophiles, in order to explore stereoselectivity and regioselectivity trends. The results show that the reactions proceed with a very high degree of regioselectivity, affording conjugate addition rather than acyl substitution products. The diastereoselectivity observed for the addition products, however was typically low. A kinetic study to explore the regioselectivity of the reaction between various Baylis-Hillman derived halogeno esters and the nucleophile, methyl 3-oxobutanolate enloate, in two different base-solvent systems at high dilution was also undertaken. The reactions were monitored by ¹H NMR spectroscopy, and the results revealed that the reaction kinetics are more complex than originally anticipated. A mechanistic rationalisation is offered which is consistent with both the kinetic data and the observed regioselectivity trends.
- Full Text:
- Date Issued: 1998
- Authors: Robinson, Ross Stuart
- Date: 1998
- Subjects: Benzopyrans Coumarins Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4429 , http://hdl.handle.net/10962/d1007193
- Description: The Baylis-Hillman reaction between substituted salicylaldehydes and various acrylate species has been shown to afford complex reaction mixtures, careful chromatography of which has led to the isolation of an extensive range of novel compounds. One- and two-dimensional NMR spectroscopic, mass spectrometric and X-ray crystallographic analysis of these compounds have permitted identification of no less than eight general classes of chromene and coumarin derivatives. The formation of the various product types is attributed to cascades of successive reactions stemming, in each case, from a Baylis-Hillman product as the common intermediate. The mechanistic sequence involved in the formation of the various chromene and coumarin derivatives have been elucidated by examining isolated or specifically prepared compounds as putative reaction intermediates. Conjugate addition and acyl or allylic substitution by various nucleophiles appear to be common processes in the formation of the chromene and coumarin derivatives, and studies focussing on these processes have been undertaken. Reactions of Baylis-Hillman adducts have been carried out, using oxygen, sulfur and nitrogen nucleophiles, in order to explore stereoselectivity and regioselectivity trends. The results show that the reactions proceed with a very high degree of regioselectivity, affording conjugate addition rather than acyl substitution products. The diastereoselectivity observed for the addition products, however was typically low. A kinetic study to explore the regioselectivity of the reaction between various Baylis-Hillman derived halogeno esters and the nucleophile, methyl 3-oxobutanolate enloate, in two different base-solvent systems at high dilution was also undertaken. The reactions were monitored by ¹H NMR spectroscopy, and the results revealed that the reaction kinetics are more complex than originally anticipated. A mechanistic rationalisation is offered which is consistent with both the kinetic data and the observed regioselectivity trends.
- Full Text:
- Date Issued: 1998
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:
- Date Issued: 2012
- 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:
- Date Issued: 2012
Biocatalytic and biomimetic studies of polyphenol oxidase
- Authors: Burton, Stephanie Gail
- Date: 1994
- Subjects: Phenol oxidase Polyphenols Oxidases
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4028 , http://hdl.handle.net/10962/d1004088
- Description: Mushroom polyphenol oxidase (EC 1.14.18.1) was investigated to determine its potential for application as a biocatalyst in the synthesis of o-quinones, in organic medium. In order to determine the kinetic properties of the biocatalyst, a system was devised which comprised an immobilised polyphenol oxidase extract, functioning in chloroform. The system was hydrated by the addition of buffer. A simple method for the consistent measurement of reaction rates in this heterogenous system was designed and used to obtain detailed enzyme kinetic data relating to optimisation of reaction conditions and substrate specificity. The aqueous content of the system was optimised using p-cresol as a substrate. A crude, immobilised extract of Agaricus bisporus was used to hydroxylate and oxidise a range of selected p-substituted phenolic substrates, yielding, as the sale products, o-quinones. These products were efficiently reduced to catechols by extracting the reaction mixtures with aqueous ascorbic acid solution. The biocatalytic system was also successfully utilised to produce L-DOPA, the drug used to treat Parkinson's disease, from L-acetyl tyrosine ethyl ester (ATEE). Michaelis-Menten kinetics were used to obtain apparent Km and V values with respect to the selected phenolic substrates, and the kinetic parameters obtained were found to correlate well with the steric requirements of the substrates and with their hydrophobicity. In the course of the investigation, a novel ¹H NMR method was used to facilitate measurement of the UV molar absorption coefficients of the o-quinones in reaction mixtures, thus avoiding the necessity to isolate these unstable, water-sensitive products. The biocatalytic system was extended to a continuous process, in which the immobilised enzyme was shown to function successfully in the chloroform medium for several hours, with high conversion rates. Modifications, involving partial purification and the addition of a surfactant, were investigated to determine their effect on the kinetic parameters. The results obtained using partially purified enzyme indicated that the removal of extraneous protein and/or melanoid material lead to a reduced capacity for conversion of sterically demanding substrates. The addition of the anionic detergent, sodium dodecyl sulphate (SOS), enhanced the ability of the biocatalyst to bind and oxidise sterically demanding substrates. These effects are attributed to changes in the polar state of groups within the protein binding pocket, which result in altered flexibility and hydrophobicity. Computer modelling of several biomimetic dinuclear copper complexes also indicated the importance of flexibility for effective biocatalysis. Novel binuclear copper (II complexes, containing a flexible biphenyl spacer and imidazole or benzimidazole donors, were prepared and analysed using NMR, UV, AA and cyclic voltammetric techniques. The complexes were also shown, in a detailed kinetic study, to mimic the catecholase activity of polyphenol oxidase by oxidising 3,5-di-tertbutylcatechol, and to catalyse the coupling of the phenolic substrate 2,4-di-tert-butylphenol. However, the complexes were apparently too flexible to react with smaller substrates. These biomimetic complexes provided valuable insights into the nature of the dinuclear copper binding site.
- Full Text:
- Date Issued: 1994
- Authors: Burton, Stephanie Gail
- Date: 1994
- Subjects: Phenol oxidase Polyphenols Oxidases
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4028 , http://hdl.handle.net/10962/d1004088
- Description: Mushroom polyphenol oxidase (EC 1.14.18.1) was investigated to determine its potential for application as a biocatalyst in the synthesis of o-quinones, in organic medium. In order to determine the kinetic properties of the biocatalyst, a system was devised which comprised an immobilised polyphenol oxidase extract, functioning in chloroform. The system was hydrated by the addition of buffer. A simple method for the consistent measurement of reaction rates in this heterogenous system was designed and used to obtain detailed enzyme kinetic data relating to optimisation of reaction conditions and substrate specificity. The aqueous content of the system was optimised using p-cresol as a substrate. A crude, immobilised extract of Agaricus bisporus was used to hydroxylate and oxidise a range of selected p-substituted phenolic substrates, yielding, as the sale products, o-quinones. These products were efficiently reduced to catechols by extracting the reaction mixtures with aqueous ascorbic acid solution. The biocatalytic system was also successfully utilised to produce L-DOPA, the drug used to treat Parkinson's disease, from L-acetyl tyrosine ethyl ester (ATEE). Michaelis-Menten kinetics were used to obtain apparent Km and V values with respect to the selected phenolic substrates, and the kinetic parameters obtained were found to correlate well with the steric requirements of the substrates and with their hydrophobicity. In the course of the investigation, a novel ¹H NMR method was used to facilitate measurement of the UV molar absorption coefficients of the o-quinones in reaction mixtures, thus avoiding the necessity to isolate these unstable, water-sensitive products. The biocatalytic system was extended to a continuous process, in which the immobilised enzyme was shown to function successfully in the chloroform medium for several hours, with high conversion rates. Modifications, involving partial purification and the addition of a surfactant, were investigated to determine their effect on the kinetic parameters. The results obtained using partially purified enzyme indicated that the removal of extraneous protein and/or melanoid material lead to a reduced capacity for conversion of sterically demanding substrates. The addition of the anionic detergent, sodium dodecyl sulphate (SOS), enhanced the ability of the biocatalyst to bind and oxidise sterically demanding substrates. These effects are attributed to changes in the polar state of groups within the protein binding pocket, which result in altered flexibility and hydrophobicity. Computer modelling of several biomimetic dinuclear copper complexes also indicated the importance of flexibility for effective biocatalysis. Novel binuclear copper (II complexes, containing a flexible biphenyl spacer and imidazole or benzimidazole donors, were prepared and analysed using NMR, UV, AA and cyclic voltammetric techniques. The complexes were also shown, in a detailed kinetic study, to mimic the catecholase activity of polyphenol oxidase by oxidising 3,5-di-tertbutylcatechol, and to catalyse the coupling of the phenolic substrate 2,4-di-tert-butylphenol. However, the complexes were apparently too flexible to react with smaller substrates. These biomimetic complexes provided valuable insights into the nature of the dinuclear copper binding site.
- Full Text:
- Date Issued: 1994
Camphor-derived chiral auxiliaries in asymmetric synthesis
- Authors: Molema, Warner Evert
- Date: 1998
- Subjects: Asymmetric synthesis Chirality Camphor
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4417 , http://hdl.handle.net/10962/d1006848
- Description: The investigation has been focussed largely on the chemistry and stereo-directing potential of camphor-derived compounds. The major regioisomer produced on partial hydrolysis of N-benzylcamphorimide was identified, by one- and two-dimensional NMR and X-ray crystallography, as (+)-(1S,3R)-(N-enzylcarbamoyl)-2,3,3-trimethylcyclopentanecarboxylic acid, the methyl ester of which was shown to undergo an unexpected intramolecular rearrangement during LAH reduction to afford (1S,3R)-Nbenzyl-3-hydroxymethyl-2,2,3-trimethylcyclopentane carboxamide. Several tartrate- and camphor-derived diols have been investigated as chiral auxiliaries in various asymmetric reactions of corresponding acetals of α,β-unsaturated aldehydes. MCPBA epoxidation of the tartrate-derived acetals afforded epoxy acetals in 4-12% diastereomeric excess. The camphor-derived acetals were obtained solely as the exosubstituted diastereomers, the stereochemistry being confirmed by two-dimensional NMR spectroscopy and X-ray crystallography. Simmons-Smith cyclopropanation of these camphor-derived acetals afforded cyclopropyl products with diastereoselectivities of 4% d.e. for the bornane-2,10-diol acetal and 46->99% d.e. for the bomane-2,3-diol acetals. In order to increase diastereofacial selectivity, a camphor-derived diol having a bulky substituent at C-10 was prepared, viz., phenyl 2,3-dihydroxybomane-10sulfonate, and α,β-unsaturated acetals of this diol were shown to undergo Simmons-Smith cyclopropanation with complete topological control (>99% d.e.), the diastereoselectivities being conveniently determined by ¹H and ¹³C NMR spectroscopy. Computer modelling, with the software package HYPERCHEM®, was used to explore the stereochemical aspects of the Simmons-Smith cyclopropanation, and hydrolysis of one of the cyclopropyl acetals has permitted the diastereoselective bias to be confirmed. (+)-Pinane-2,3-diol was also investigated as a chiral auxiliary in the Simmons-Smith reactions of α,β-unsaturated aldehydes, and moderate diastereoselectivities (20-30% d.e.) were observed. In a series of exploratory studies, the Diels-Alder reaction of the 2,3-dihydroxybomane-10-sulfonate acetal of trans-cinnamaldehyde with cyclopentadiene afforded a single cycloadduct, while OSO₄ dihydroxylation, MCPBA oxidation and alkylation of chiral acetals produced from both bomane-2,3-diol and phenyl 2,3-dihydroxybomane-10-sulfonate were less selective.
- Full Text:
- Date Issued: 1998
- Authors: Molema, Warner Evert
- Date: 1998
- Subjects: Asymmetric synthesis Chirality Camphor
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4417 , http://hdl.handle.net/10962/d1006848
- Description: The investigation has been focussed largely on the chemistry and stereo-directing potential of camphor-derived compounds. The major regioisomer produced on partial hydrolysis of N-benzylcamphorimide was identified, by one- and two-dimensional NMR and X-ray crystallography, as (+)-(1S,3R)-(N-enzylcarbamoyl)-2,3,3-trimethylcyclopentanecarboxylic acid, the methyl ester of which was shown to undergo an unexpected intramolecular rearrangement during LAH reduction to afford (1S,3R)-Nbenzyl-3-hydroxymethyl-2,2,3-trimethylcyclopentane carboxamide. Several tartrate- and camphor-derived diols have been investigated as chiral auxiliaries in various asymmetric reactions of corresponding acetals of α,β-unsaturated aldehydes. MCPBA epoxidation of the tartrate-derived acetals afforded epoxy acetals in 4-12% diastereomeric excess. The camphor-derived acetals were obtained solely as the exosubstituted diastereomers, the stereochemistry being confirmed by two-dimensional NMR spectroscopy and X-ray crystallography. Simmons-Smith cyclopropanation of these camphor-derived acetals afforded cyclopropyl products with diastereoselectivities of 4% d.e. for the bornane-2,10-diol acetal and 46->99% d.e. for the bomane-2,3-diol acetals. In order to increase diastereofacial selectivity, a camphor-derived diol having a bulky substituent at C-10 was prepared, viz., phenyl 2,3-dihydroxybomane-10sulfonate, and α,β-unsaturated acetals of this diol were shown to undergo Simmons-Smith cyclopropanation with complete topological control (>99% d.e.), the diastereoselectivities being conveniently determined by ¹H and ¹³C NMR spectroscopy. Computer modelling, with the software package HYPERCHEM®, was used to explore the stereochemical aspects of the Simmons-Smith cyclopropanation, and hydrolysis of one of the cyclopropyl acetals has permitted the diastereoselective bias to be confirmed. (+)-Pinane-2,3-diol was also investigated as a chiral auxiliary in the Simmons-Smith reactions of α,β-unsaturated aldehydes, and moderate diastereoselectivities (20-30% d.e.) were observed. In a series of exploratory studies, the Diels-Alder reaction of the 2,3-dihydroxybomane-10-sulfonate acetal of trans-cinnamaldehyde with cyclopentadiene afforded a single cycloadduct, while OSO₄ dihydroxylation, MCPBA oxidation and alkylation of chiral acetals produced from both bomane-2,3-diol and phenyl 2,3-dihydroxybomane-10-sulfonate were less selective.
- Full Text:
- Date Issued: 1998
Chemical and spectroscopic studies of chromone derivatives
- Ramaite, Ipfani David Isaiah
- Authors: Ramaite, Ipfani David Isaiah
- Date: 1993 , 2012-11-16
- Subjects: Heterocyclic compounds -- Derivatives -- Research , Benzopyrans -- Research , Coumarins -- Research
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4422 , http://hdl.handle.net/10962/d1006888 , Heterocyclic compounds -- Derivatives -- Research , Benzopyrans -- Research , Coumarins -- Research
- Description: A number of biologically active chromones occur in plants (eg. Khellin) and research in this field has eventually led to the discovery of chromoglycic acid, which is widely used as a sodium salt in asthma therapy. Since biological activity may be related to acidity, a range of chromone-2-carboxylic acids have been prepared via Claisen acylation of substituted o- hydroxyacetophenones and their acid dissociation constants determined potentiometrically to explore substituent effects. From this study it has been found that introduction of certain groups does have a marked effect on acidity. A variety of acrylamide derivatives have been prepared via the dimethylamine-mediated ring opening of chromone-2-carboxamides which, in turn, were prepared from the chromone-2- carboxylic acids via the corresponding acid chlorides. Variable temperature NMR spectroscopy was employed to examine the effect of substituents on the rotational barriers and it has been found that for the acrylamides examined, ring substituents have little effect on the rotational barriers. A combination of low resolution, high resolution and meta-stable peak analysis has been used to study mass fragmentation patterns for a series of acrylamide derivatives. The proposed fragmentation pathways for selected peaks have been found to be common to all the spectra examined when differences in the atomic masses of substituents were taken into account.
- Full Text:
- Date Issued: 1993
- Authors: Ramaite, Ipfani David Isaiah
- Date: 1993 , 2012-11-16
- Subjects: Heterocyclic compounds -- Derivatives -- Research , Benzopyrans -- Research , Coumarins -- Research
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4422 , http://hdl.handle.net/10962/d1006888 , Heterocyclic compounds -- Derivatives -- Research , Benzopyrans -- Research , Coumarins -- Research
- Description: A number of biologically active chromones occur in plants (eg. Khellin) and research in this field has eventually led to the discovery of chromoglycic acid, which is widely used as a sodium salt in asthma therapy. Since biological activity may be related to acidity, a range of chromone-2-carboxylic acids have been prepared via Claisen acylation of substituted o- hydroxyacetophenones and their acid dissociation constants determined potentiometrically to explore substituent effects. From this study it has been found that introduction of certain groups does have a marked effect on acidity. A variety of acrylamide derivatives have been prepared via the dimethylamine-mediated ring opening of chromone-2-carboxamides which, in turn, were prepared from the chromone-2- carboxylic acids via the corresponding acid chlorides. Variable temperature NMR spectroscopy was employed to examine the effect of substituents on the rotational barriers and it has been found that for the acrylamides examined, ring substituents have little effect on the rotational barriers. A combination of low resolution, high resolution and meta-stable peak analysis has been used to study mass fragmentation patterns for a series of acrylamide derivatives. The proposed fragmentation pathways for selected peaks have been found to be common to all the spectra examined when differences in the atomic masses of substituents were taken into account.
- Full Text:
- Date Issued: 1993
Chemical studies of 1,5-benzodioxepanones
- Authors: Gelebe, Aifheli Carlson
- Date: 1991
- Subjects: Biochemistry , Pigments (Biology) , Benzopyrans
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4423 , http://hdl.handle.net/10962/d1006895 , Biochemistry , Pigments (Biology) , Benzopyrans
- Description: Chromone and flavanone derivatives were prepared by condensation of the corresponding 2-hydroxyacetophenones (with diethyl oxalate or the appropriate aromatic aldehyde respectively) and cyclisation of the condensation products. Saeyer-Villiger rearrangement of these flavanones, with MCPBA, resulted in expansion of the C-ring. Spectroscopic techniques have been used to establish the regioselectivity of the rearrangement and hence, the identity of the rearranged products as 1,5-benzodioxepan-4-ones. The 1,5-benzodioxepan-4-ones were subjected to detailed ¹H and ¹³C n.m.r. analysis and a combination of low and high resolution mass spectrometry has been used to study the mass fragmentation pathways of these ring-expanded products.
- Full Text:
- Date Issued: 1991
- Authors: Gelebe, Aifheli Carlson
- Date: 1991
- Subjects: Biochemistry , Pigments (Biology) , Benzopyrans
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4423 , http://hdl.handle.net/10962/d1006895 , Biochemistry , Pigments (Biology) , Benzopyrans
- Description: Chromone and flavanone derivatives were prepared by condensation of the corresponding 2-hydroxyacetophenones (with diethyl oxalate or the appropriate aromatic aldehyde respectively) and cyclisation of the condensation products. Saeyer-Villiger rearrangement of these flavanones, with MCPBA, resulted in expansion of the C-ring. Spectroscopic techniques have been used to establish the regioselectivity of the rearrangement and hence, the identity of the rearranged products as 1,5-benzodioxepan-4-ones. The 1,5-benzodioxepan-4-ones were subjected to detailed ¹H and ¹³C n.m.r. analysis and a combination of low and high resolution mass spectrometry has been used to study the mass fragmentation pathways of these ring-expanded products.
- Full Text:
- Date Issued: 1991
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
- Full Text:
- Date Issued: 2001
- 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
- Full Text:
- Date Issued: 2001
Chemical studies of necic acid analogues
- Guthrie-Strachan, Jeffry James
- Authors: Guthrie-Strachan, Jeffry James
- Date: 1997
- Subjects: Organic acids , Chemistry, Organic
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4425 , http://hdl.handle.net/10962/d1006909 , Organic acids , Chemistry, Organic
- Description: Various aldehydes have been reacted with methyl acrylate under Baylis-Hillman conditions, using DABCO as a catalyst, to afford a range of α-substituted acrylic esters containing an allylic hydroxy group. Selected Baylis-Hillman products have been brominated, hydrolysed and acetylated to afford substrates for the synthesis of necic acid analogues. The diastereo- and regioselectivity of nucleophilic attack, using sodium methylmercaptan, on the Baylis-Hillman products and selected brominated derivatives was investigated. The allylic hydroxy compounds favour conjugate addition with the generation of a new chiral centre, while the allylic bromo derivatives favour substitution (SN and SN') (S[subscript N] and S[subscript N]') with consequent loss of chirality. (E)-2-Isopropylcrotonic acid, a vital precursor in the synthesis of all stereoisomers of trachelanthic and viridifloric acid, was synthesised in an attempt to obtain the necic acid components required for total alkaloid synthesis of lycopsamine and its derivatives. This precursor and salicylic acid were then used to prepare esters of retronecine, a dihydroxy necine base obtained via extraction and consequent hydrolysis of retrorsine.
- Full Text:
- Date Issued: 1997
- Authors: Guthrie-Strachan, Jeffry James
- Date: 1997
- Subjects: Organic acids , Chemistry, Organic
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4425 , http://hdl.handle.net/10962/d1006909 , Organic acids , Chemistry, Organic
- Description: Various aldehydes have been reacted with methyl acrylate under Baylis-Hillman conditions, using DABCO as a catalyst, to afford a range of α-substituted acrylic esters containing an allylic hydroxy group. Selected Baylis-Hillman products have been brominated, hydrolysed and acetylated to afford substrates for the synthesis of necic acid analogues. The diastereo- and regioselectivity of nucleophilic attack, using sodium methylmercaptan, on the Baylis-Hillman products and selected brominated derivatives was investigated. The allylic hydroxy compounds favour conjugate addition with the generation of a new chiral centre, while the allylic bromo derivatives favour substitution (SN and SN') (S[subscript N] and S[subscript N]') with consequent loss of chirality. (E)-2-Isopropylcrotonic acid, a vital precursor in the synthesis of all stereoisomers of trachelanthic and viridifloric acid, was synthesised in an attempt to obtain the necic acid components required for total alkaloid synthesis of lycopsamine and its derivatives. This precursor and salicylic acid were then used to prepare esters of retronecine, a dihydroxy necine base obtained via extraction and consequent hydrolysis of retrorsine.
- Full Text:
- Date Issued: 1997