Synthesis and evaluation of novel HIV-1 enzyme inhibitors
- Olomola, Temitope Oloruntoba
- Authors: Olomola, Temitope Oloruntoba
- Date: 2011
- Subjects: HIV infections -- Treatment HIV infections -- Chemotherapy HIV (Viruses) Enzyme inhibitors AZT (Drug) Reverse transcriptase Proteolytic enzymes Ligands Psoralens Resorcinol
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4369 , http://hdl.handle.net/10962/d1005034
- Description: This study has involved the design, synthesis and evaluation of novel HIV-1 enzyme inhibitors accessed by synthetic elaboration of Baylis-Hillman adducts. Several series of complex coumarin-AZT and cinnamate ester-AZT conjugates have been prepared, in high yields, by exploiting the click reaction between appropriate Baylis-Hillman derived precursors and azidothymidine (AZT), all of which have been fully characterised using spectroscopic techniques. These conjugates, designed as potential dual-action HIV-1 inhibitors, were tested against the appropriate HIV-1 enzymes, i.e. HIV-1 reverse transcriptase and protease or HIV-1 reverse transcriptase and integrase. A number of the ligands have exhibited % inhibition levels and IC50 values comparable to drugs in clinical use, permitting their identification as lead compounds for the development of novel dual-action inhibitors. In silico docking of selected ligands into the active sites of the respective enzymes has provided useful insight into binding conformations and potential hydrogen-bonding interactions with active-site amino acid residues. A series of furocoumarin carboxamide derivatives have been synthesised in four steps starting from resorcinol and these compounds have also been tested for HIV-1 integrase inhibition activity. The structures of unexpected products isolated from Aza-Baylis-Hillman reactions of N-tosylaldimines have been elucidated by spectroscopic analysis, and confirmed by single crystal X-ray analysis. A mechanism for what appears to be an unprecedented transformation has been proposed. Microwave-assisted SeO₂ oxidation of Baylis-Hillman-derived 3-methylcoumarins has provided convenient and efficient access to coumarin-3-carbaldehydes, and a pilot study has revealed the potential of these coumarin-3-carbaldehydes as scaffolds for the construction of tricyclic compounds. The HCl-catalysed reaction of tert-butyl acrylate derived Baylis-Hillman adducts has been shown to afford 3-(chloromethyl)coumarins and α-(chloromethyl)cinnamic acids, the Zstereochemistry of the latter being established by X-ray crystallography. ¹H NMR-based experimental kinetic and DFT-level theoretical studies have been undertaken to establish the reaction sequence and other mechanistic details. Base-catalysed cyclisation on the other hand, has been shown to afford 2H-chromene rather than coumarin derivatives.
- Full Text:
- Date Issued: 2011
- Authors: Olomola, Temitope Oloruntoba
- Date: 2011
- Subjects: HIV infections -- Treatment HIV infections -- Chemotherapy HIV (Viruses) Enzyme inhibitors AZT (Drug) Reverse transcriptase Proteolytic enzymes Ligands Psoralens Resorcinol
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4369 , http://hdl.handle.net/10962/d1005034
- Description: This study has involved the design, synthesis and evaluation of novel HIV-1 enzyme inhibitors accessed by synthetic elaboration of Baylis-Hillman adducts. Several series of complex coumarin-AZT and cinnamate ester-AZT conjugates have been prepared, in high yields, by exploiting the click reaction between appropriate Baylis-Hillman derived precursors and azidothymidine (AZT), all of which have been fully characterised using spectroscopic techniques. These conjugates, designed as potential dual-action HIV-1 inhibitors, were tested against the appropriate HIV-1 enzymes, i.e. HIV-1 reverse transcriptase and protease or HIV-1 reverse transcriptase and integrase. A number of the ligands have exhibited % inhibition levels and IC50 values comparable to drugs in clinical use, permitting their identification as lead compounds for the development of novel dual-action inhibitors. In silico docking of selected ligands into the active sites of the respective enzymes has provided useful insight into binding conformations and potential hydrogen-bonding interactions with active-site amino acid residues. A series of furocoumarin carboxamide derivatives have been synthesised in four steps starting from resorcinol and these compounds have also been tested for HIV-1 integrase inhibition activity. The structures of unexpected products isolated from Aza-Baylis-Hillman reactions of N-tosylaldimines have been elucidated by spectroscopic analysis, and confirmed by single crystal X-ray analysis. A mechanism for what appears to be an unprecedented transformation has been proposed. Microwave-assisted SeO₂ oxidation of Baylis-Hillman-derived 3-methylcoumarins has provided convenient and efficient access to coumarin-3-carbaldehydes, and a pilot study has revealed the potential of these coumarin-3-carbaldehydes as scaffolds for the construction of tricyclic compounds. The HCl-catalysed reaction of tert-butyl acrylate derived Baylis-Hillman adducts has been shown to afford 3-(chloromethyl)coumarins and α-(chloromethyl)cinnamic acids, the Zstereochemistry of the latter being established by X-ray crystallography. ¹H NMR-based experimental kinetic and DFT-level theoretical studies have been undertaken to establish the reaction sequence and other mechanistic details. Base-catalysed cyclisation on the other hand, has been shown to afford 2H-chromene rather than coumarin derivatives.
- Full Text:
- Date Issued: 2011
Synthetic and physical organic studies of chromone derivatives
- Ramaite, Ipfani David Isaiah
- Authors: Ramaite, Ipfani David Isaiah
- Date: 1997
- Subjects: Benzopyrans Heterocyclic compounds -- Derivatives Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4380 , http://hdl.handle.net/10962/d1005045
- Description: A range of chromone-2-carboxylic acids has been prepared by condensing suitably substituted 2-hydroxyacetophenones with diethyl oxalate. pK₂ Studies of these acids revealed that 6- or 7-methoxy substituents decreased acidity while the 6-nitro group enhanced acidity; the strongest acid was the 3-chloro derivative, the increase in acidity being attributed to steric inhibition of acid-weakening delocalisation between the carboxyl group and the chromone system. Various chromone-2-carboxamides, derived from acid chloride precursors, were converted to polysubstituted acrylamides by nucleophilic ring-opening with selected amine nucleophiles. The main fragmentation patterns exhibited by these acrylamides were elucidated using a combination of low resolution, high resolution and meta-stable peak analysis, while the effect of substituents on the simultaneous internal rotation involving the carboxamide and enamine moieties were studied using dynamic NMR spectroscopy. Rotational barriers of ca. 67.1 kJmol ̄¹ and ca. 102 kJmol ̄¹ were found for the enamine and amide rotors, respectively. Several synthetic pathways were followed to prepare a series of 2-(N,N-dialkylamino)chromones which were subjected to detailed mass spectral analysis. In addition to substituent-specific fragmentations , the 2-aminochromones appear to fragment via 3 major pathways. The effect of substituents on the internal rotation of the amino moeity was investigated by variable temperature ¹H NMR spectroscopy and the resulting DNMR data was used to calculate the rotational barriers. Examination of the data reveals that the electron-releasing 6- and 7- substituents reduce the C-NMe₂ rotational barrier to ca. 43.5 kJmol ̄¹ , while the nitro analogue has the largest rotational barrier (ca. 46.1 kJmol ̄¹) because of the electron-withdrawing effect of this substituent.
- Full Text:
- Date Issued: 1997
- Authors: Ramaite, Ipfani David Isaiah
- Date: 1997
- Subjects: Benzopyrans Heterocyclic compounds -- Derivatives Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4380 , http://hdl.handle.net/10962/d1005045
- Description: A range of chromone-2-carboxylic acids has been prepared by condensing suitably substituted 2-hydroxyacetophenones with diethyl oxalate. pK₂ Studies of these acids revealed that 6- or 7-methoxy substituents decreased acidity while the 6-nitro group enhanced acidity; the strongest acid was the 3-chloro derivative, the increase in acidity being attributed to steric inhibition of acid-weakening delocalisation between the carboxyl group and the chromone system. Various chromone-2-carboxamides, derived from acid chloride precursors, were converted to polysubstituted acrylamides by nucleophilic ring-opening with selected amine nucleophiles. The main fragmentation patterns exhibited by these acrylamides were elucidated using a combination of low resolution, high resolution and meta-stable peak analysis, while the effect of substituents on the simultaneous internal rotation involving the carboxamide and enamine moieties were studied using dynamic NMR spectroscopy. Rotational barriers of ca. 67.1 kJmol ̄¹ and ca. 102 kJmol ̄¹ were found for the enamine and amide rotors, respectively. Several synthetic pathways were followed to prepare a series of 2-(N,N-dialkylamino)chromones which were subjected to detailed mass spectral analysis. In addition to substituent-specific fragmentations , the 2-aminochromones appear to fragment via 3 major pathways. The effect of substituents on the internal rotation of the amino moeity was investigated by variable temperature ¹H NMR spectroscopy and the resulting DNMR data was used to calculate the rotational barriers. Examination of the data reveals that the electron-releasing 6- and 7- substituents reduce the C-NMe₂ rotational barrier to ca. 43.5 kJmol ̄¹ , while the nitro analogue has the largest rotational barrier (ca. 46.1 kJmol ̄¹) because of the electron-withdrawing effect of this substituent.
- Full Text:
- Date Issued: 1997
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
Design, synthesis and evaluation of silver-specific ligands
- Authors: Daubinet, André
- Date: 2001
- Subjects: Ligands Ligands -- Design Ligands -- Analysis Ligands -- Evaluation Silver -- Metallurgy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4308 , http://hdl.handle.net/10962/d1004966
- Description: Several series of ligands, designed to chelate silver(I) specifically in the presence of base metals, have been synthesised. The ligands include: - dithiodiamide compounds, prepared by the condensation of acetanilide derivatives with 1,2-dibromoethane; propanenitrile and propanoic ester derivatives prepared from pyridine-2-carbaldehyde via the Morita-Baylis-Hillman reaction; and novel malonamide ligands from the reaction of diethyl malonate with a range of primary amines. The malonamide derivatives were prepared under both conventional thermal and microwave-assisted conditions, the latter proving to be highly efficient. The ligands were all characterised using a combination of spectroscopic and, where appropriate, elemental analysis; in one case, the structural assignment was confirmed by single-crystal X-ray analysis. The fragmentation patterns in the electron-impact mass spectra of the malonamide derivatives have been explored using high-resolution and meta-stable peak scanning techniques. Complexes of the malonamide ligands with copper(II) and silver(I) have been synthesised, and examination of these complexes has revealed distinct differences in their co-ordination preferences towards silver(I) and copper(II). Tentative, computer-modelled structures for the complexes have been proposed using the available spectroscopic and elemental analysis data. Computer modelling, at the Molecular Mechanics level, has also been used to assess the capacity of the ligand systems to adopt conformations suitable for the chelation of tetrahedral silver(I). Solvent extraction studies have been undertaken using aqueous metal ion solutions and various organic solvents. The dithiodiamide derivatives typically presented solubility problems, but one of the ligands, N,N´-bis(3-chlorophenyl)-3,6-dithiaoctanediamide, exhibited significant but slow extraction of silver(I) into toluene. The malonamide derivatives, however, proved to be readily soluble in ethyl acetate and, in some cases, exhibited good to excellent selectivity for silver(I) in the presence of the base metals copper and lead. Atomic absorption analysis revealed rapid equilibration times (<15 min) and high extraction efficiencies over a wide pH range (2.78 - 9.0). Metal selectivity has been determined by ICP-MS analysis of the residual silver, copper and lead present in the aqueous phase after 15 min, and one of the ligands, N,N´-bis(2-benzylsulfanylethyl)malonamide, exhibits excellent (≥ 96 %) silver(I) specificity.
- Full Text:
- Date Issued: 2001
- Authors: Daubinet, André
- Date: 2001
- Subjects: Ligands Ligands -- Design Ligands -- Analysis Ligands -- Evaluation Silver -- Metallurgy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4308 , http://hdl.handle.net/10962/d1004966
- Description: Several series of ligands, designed to chelate silver(I) specifically in the presence of base metals, have been synthesised. The ligands include: - dithiodiamide compounds, prepared by the condensation of acetanilide derivatives with 1,2-dibromoethane; propanenitrile and propanoic ester derivatives prepared from pyridine-2-carbaldehyde via the Morita-Baylis-Hillman reaction; and novel malonamide ligands from the reaction of diethyl malonate with a range of primary amines. The malonamide derivatives were prepared under both conventional thermal and microwave-assisted conditions, the latter proving to be highly efficient. The ligands were all characterised using a combination of spectroscopic and, where appropriate, elemental analysis; in one case, the structural assignment was confirmed by single-crystal X-ray analysis. The fragmentation patterns in the electron-impact mass spectra of the malonamide derivatives have been explored using high-resolution and meta-stable peak scanning techniques. Complexes of the malonamide ligands with copper(II) and silver(I) have been synthesised, and examination of these complexes has revealed distinct differences in their co-ordination preferences towards silver(I) and copper(II). Tentative, computer-modelled structures for the complexes have been proposed using the available spectroscopic and elemental analysis data. Computer modelling, at the Molecular Mechanics level, has also been used to assess the capacity of the ligand systems to adopt conformations suitable for the chelation of tetrahedral silver(I). Solvent extraction studies have been undertaken using aqueous metal ion solutions and various organic solvents. The dithiodiamide derivatives typically presented solubility problems, but one of the ligands, N,N´-bis(3-chlorophenyl)-3,6-dithiaoctanediamide, exhibited significant but slow extraction of silver(I) into toluene. The malonamide derivatives, however, proved to be readily soluble in ethyl acetate and, in some cases, exhibited good to excellent selectivity for silver(I) in the presence of the base metals copper and lead. Atomic absorption analysis revealed rapid equilibration times (<15 min) and high extraction efficiencies over a wide pH range (2.78 - 9.0). Metal selectivity has been determined by ICP-MS analysis of the residual silver, copper and lead present in the aqueous phase after 15 min, and one of the ligands, N,N´-bis(2-benzylsulfanylethyl)malonamide, exhibits excellent (≥ 96 %) silver(I) specificity.
- Full Text:
- Date Issued: 2001
Studies in asymmetric synthesis
- Authors: Learmonth, Robin Alec
- Date: 1991
- Subjects: Organic compounds -- Synthesis Stereochemistry Organosilicon compounds Chirality Chemical tests and reagents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4353 , http://hdl.handle.net/10962/d1005018
- Description: The concept of combining two well established areas of organic chemistry, viz., organosilicon chemistry and the use of chiral auxiliaries, into a viable, alternative method of asymmetric synthesis has only very recently begun to receive attention. At the outset of this investigation, no asymmetric reactions of silyl enol ethers, chiral by virtue of optically active substituents on the silicon, had been reported. A range of novel chiral silyl enol ethers have thus been prepared from a variety of ketones, including pinacolone, cyclohexanone, and α-tetralone, and employing menthol, borneol, and cholesterol as chiral auxiliaries. These preparations have been achieved via several distinct routes, including a novel convergent approach involving the isolation of either the chloro(menthyloxy)dimethylsilane or the (bornyloxy)chlorodimethylsilane. The MS and NMR spectra of these silyl enol ethers were examined in detail and, in the case of the crystalline cholesteryloxy silyl enol ether, the X-ray structure has been determined. The potential of chloroalkoxysilanes to act as general, chiral derivatizing agents has been established by the preparation of diastereomeric silyl acetal mixtures of racemic secondary alcohols (e.g. I-phenylethanol and 2-octanol). The experimental diastereomeric ratios, obtained by GLC and ¹H NMR spectroscopy, approached the expected value of unity, confirming the potential of the alkoxychlorosilanes as chiral probes. The chiral silyl enol ethers have been successfully oxidized to the corresponding α-siloxy ketones employing MCPBA, MMPP, and 2-(phenylsulphonyl)-3-phenyloxaziridine as oxidizing agents and the diastereomeric excesses obtained, which varied from 0 to 16%, indicated some potential for stereochemical control. Alkylation and hydroxyalkylation reactions of the silyl enol ethers have yielded the expected α-iert-butyl and β-hydroxy ketones in good to excellent material yields, with the enantiomeric excesses, as determined by chiral shift reagent studies, reaching 14%. To improve the stereo control in these reactions, attempts have been made to prepare chiral silyl enol ethers with auxiliaries possessing the potential for transition state complex co-ordination in the reactions under consideration. The preparation of such silyl enol ethers, incorporating the proline-derived auxiliaries, N-methyl-2-hydroxymethylpyrrolidine and 2-methoxymethylpyrrolidine met with only limited success. In an alternative approach, three derivatives of 2,3-dihydroxybornane have been prepared. However, two of these auxiliaries, viz., 3-exo-benzyloxy-2-exo-hydroxybornane and 3-exo-(1-methoxyethoxy)-2-exo-hydroxybornane failed to form silyl enol ethers, even under considerably more vigorous conditions than normally employed. The third derivative, 3,3-ethylenedioxy-2-hydroxybornane has been successfully utilized in the preparation of a pinacolone-derived chiral silyl enol ether. Hydroxyalkylation of this compound with benzaldehyde has yielded the β-hydroxyketone with significantly improved enantiomeric excess (26%) and a transition state complex has been proposed to rationalize this improvement.
- Full Text:
- Date Issued: 1991
- Authors: Learmonth, Robin Alec
- Date: 1991
- Subjects: Organic compounds -- Synthesis Stereochemistry Organosilicon compounds Chirality Chemical tests and reagents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4353 , http://hdl.handle.net/10962/d1005018
- Description: The concept of combining two well established areas of organic chemistry, viz., organosilicon chemistry and the use of chiral auxiliaries, into a viable, alternative method of asymmetric synthesis has only very recently begun to receive attention. At the outset of this investigation, no asymmetric reactions of silyl enol ethers, chiral by virtue of optically active substituents on the silicon, had been reported. A range of novel chiral silyl enol ethers have thus been prepared from a variety of ketones, including pinacolone, cyclohexanone, and α-tetralone, and employing menthol, borneol, and cholesterol as chiral auxiliaries. These preparations have been achieved via several distinct routes, including a novel convergent approach involving the isolation of either the chloro(menthyloxy)dimethylsilane or the (bornyloxy)chlorodimethylsilane. The MS and NMR spectra of these silyl enol ethers were examined in detail and, in the case of the crystalline cholesteryloxy silyl enol ether, the X-ray structure has been determined. The potential of chloroalkoxysilanes to act as general, chiral derivatizing agents has been established by the preparation of diastereomeric silyl acetal mixtures of racemic secondary alcohols (e.g. I-phenylethanol and 2-octanol). The experimental diastereomeric ratios, obtained by GLC and ¹H NMR spectroscopy, approached the expected value of unity, confirming the potential of the alkoxychlorosilanes as chiral probes. The chiral silyl enol ethers have been successfully oxidized to the corresponding α-siloxy ketones employing MCPBA, MMPP, and 2-(phenylsulphonyl)-3-phenyloxaziridine as oxidizing agents and the diastereomeric excesses obtained, which varied from 0 to 16%, indicated some potential for stereochemical control. Alkylation and hydroxyalkylation reactions of the silyl enol ethers have yielded the expected α-iert-butyl and β-hydroxy ketones in good to excellent material yields, with the enantiomeric excesses, as determined by chiral shift reagent studies, reaching 14%. To improve the stereo control in these reactions, attempts have been made to prepare chiral silyl enol ethers with auxiliaries possessing the potential for transition state complex co-ordination in the reactions under consideration. The preparation of such silyl enol ethers, incorporating the proline-derived auxiliaries, N-methyl-2-hydroxymethylpyrrolidine and 2-methoxymethylpyrrolidine met with only limited success. In an alternative approach, three derivatives of 2,3-dihydroxybornane have been prepared. However, two of these auxiliaries, viz., 3-exo-benzyloxy-2-exo-hydroxybornane and 3-exo-(1-methoxyethoxy)-2-exo-hydroxybornane failed to form silyl enol ethers, even under considerably more vigorous conditions than normally employed. The third derivative, 3,3-ethylenedioxy-2-hydroxybornane has been successfully utilized in the preparation of a pinacolone-derived chiral silyl enol ether. Hydroxyalkylation of this compound with benzaldehyde has yielded the β-hydroxyketone with significantly improved enantiomeric excess (26%) and a transition state complex has been proposed to rationalize this improvement.
- Full Text:
- Date Issued: 1991
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
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
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
Synthetic and spectroscopic studies of 1,4-benzodiazepine analogues
- Authors: Mphahlele, Malose Jack
- Date: 1994
- Subjects: Benzodiazepines Tranquilizing drugs
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4384 , http://hdl.handle.net/10962/d1005049
- Description: In this project, an extensive range of benzodiazepine analogues have been synthesised via Schmidt reaction of specially prepared flavanone, 4-quinolone and l-thioflavanone precursors; nitrogen insertion being effected by use of trimethylsilyl azide in trifluoroacetic acid. In some cases, several of the benzodiazepine analogues have also been prepared by alternative cyclisation routes. A detailed kinetic-mechanistic study of the Schmidt reaction of flavanones has been carried out using 'H NMR spectroscopy to explain the observed regiochemistry of nitrogen insertion. The reaction rates, for the formation of both amide and tetrazolo derivatives have been found to be influenced by the electronic effects of the A- and B-ring substituents. A series of benzodiazepine analogues have been shown to undergo regioselective A-ring chlorination with t-butylhypochlorite; the products being characterised by 'H NMR, IR and mass spectroscopy. The mass spectrometric fragmentation patterns of series of 2-aryl-4-quinolones, and 2-aryl-l ,4-benzodiazepinones and their tetrazolo[l ,5-dl analogues have been elucidated using a combination of low-resolution, high-resolution and metastable-peak analyses. The binding affinities of various benzodiazepine analogues for rat brain benzodiazepine receptors have been evaluated using a radioreceptor assay technique. Structure-activity relationships were investigated to establish the effects of various A-, B- and Coring substituents on binding affinity. The conformational preferences of selected systems have been studied using a combination of multi-pulse 'H NMR spectroscopy, X-ray crystallography and computer modelling techniques with a view to establishing the influence of conformation on binding affinity.
- Full Text:
- Date Issued: 1994
- Authors: Mphahlele, Malose Jack
- Date: 1994
- Subjects: Benzodiazepines Tranquilizing drugs
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4384 , http://hdl.handle.net/10962/d1005049
- Description: In this project, an extensive range of benzodiazepine analogues have been synthesised via Schmidt reaction of specially prepared flavanone, 4-quinolone and l-thioflavanone precursors; nitrogen insertion being effected by use of trimethylsilyl azide in trifluoroacetic acid. In some cases, several of the benzodiazepine analogues have also been prepared by alternative cyclisation routes. A detailed kinetic-mechanistic study of the Schmidt reaction of flavanones has been carried out using 'H NMR spectroscopy to explain the observed regiochemistry of nitrogen insertion. The reaction rates, for the formation of both amide and tetrazolo derivatives have been found to be influenced by the electronic effects of the A- and B-ring substituents. A series of benzodiazepine analogues have been shown to undergo regioselective A-ring chlorination with t-butylhypochlorite; the products being characterised by 'H NMR, IR and mass spectroscopy. The mass spectrometric fragmentation patterns of series of 2-aryl-4-quinolones, and 2-aryl-l ,4-benzodiazepinones and their tetrazolo[l ,5-dl analogues have been elucidated using a combination of low-resolution, high-resolution and metastable-peak analyses. The binding affinities of various benzodiazepine analogues for rat brain benzodiazepine receptors have been evaluated using a radioreceptor assay technique. Structure-activity relationships were investigated to establish the effects of various A-, B- and Coring substituents on binding affinity. The conformational preferences of selected systems have been studied using a combination of multi-pulse 'H NMR spectroscopy, X-ray crystallography and computer modelling techniques with a view to establishing the influence of conformation on binding affinity.
- Full Text:
- Date Issued: 1994
Chemical studies of selected chromone derivatives
- Authors: Nchinda, Aloysius Tchangwe
- Date: 2002
- Subjects: Heterocyclic compounds
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4434 , http://hdl.handle.net/10962/d1007442
- Description: This investigation has been geared towards several aspects of chromone chemistry. Selected 2-(N,N-dimethylarnino)chromones have been synthesized via 2-hydroxyacetophenone boron difluoride complex intermediates, and potentiometric analysis of these compounds in ethanolwater has been used to determine the influence of substituents on their basicity. The pKa values have been found to lie within a narrow range (1.92 - 2.52), and the observed substituent effects have been rationalized with the aid of semi-empirical and ab initio molecular orbital calculations. An efficient route has been developed for the synthesis of the naturally-occurring chromone, "granulosin" [7,8-(methylenedioxy)-2-propylchromone], and several C-2 side chain analogues in good yields, by condensing 2'-hydroxy-3',4'-(methylenedioxy)acetophenone with a range of ethyl carboxylate esters. These compounds show significant cytotoxic activity against the brine shrimp, Artemia salina, and two of them, the 2-ethyl and 2-benzyl derivatives also show 100% activity as pesticides on Beet army worms (BAW). Another naturally-occurring chromone derivative, 5-hydroxy-2-isopropyl-7-methoxychromone, and four C-2 side chain analogues have been prepared in moderate yields. These compounds also show significant cytotoxic activity against the brine shrimp, Artemia salina, and it is apparent that the presence of the hydroxyl group at C-5 is critical for such activity. The electronimpact mass spectra of both series of chromone derivatives have been investigated, permitting the elucidation of characteristic fragmentation patterns. In work directed towards the synthesis of potential HIV -1 protease inhibitors, five novel chromone-containing analogues of the clinically useful drug, ritonavir, have been synthesized. The design strategy has involved the coupling of substituted chromone-2- carboxylic acids with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing chromone termini. An interactive docking procedure has been used to explore the docking of ritonavir and the novel chromone-containing analogues into ' the active site of the enzyme, and has indicated the capacity of the ritonavir analogues to form hydrogen-bonds with the HJV-l enzyme receptor. Various substituted cbromone-3-carbaldehydes, which have been synthesized from the corresponding o-hyclroxyacetophenones using Vilsmeier-Haack methodology, have been examined as substrates for Morita-Baylis-Hillman reactions, using 3-hyclroxyquinuclidine as the catalyst and arcylonitrile and methyl acrylate as the activated alkenes. Optimization of the reaction conditions has permitted efficient conversion of the cbromone-3-carbaldehydes to the Morita-Baylis-Hillman products and, in some cases, dimeric products, within 24 h. Heating of the Morita-Baylis-Hillman products, arising from reactions with methyl acrylate, at 80 ºC for 3 h in the presence of DABCO as catalyst, has been shown to effect transformation to the corresponding dimers in good yield.
- Full Text:
- Date Issued: 2002
- Authors: Nchinda, Aloysius Tchangwe
- Date: 2002
- Subjects: Heterocyclic compounds
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4434 , http://hdl.handle.net/10962/d1007442
- Description: This investigation has been geared towards several aspects of chromone chemistry. Selected 2-(N,N-dimethylarnino)chromones have been synthesized via 2-hydroxyacetophenone boron difluoride complex intermediates, and potentiometric analysis of these compounds in ethanolwater has been used to determine the influence of substituents on their basicity. The pKa values have been found to lie within a narrow range (1.92 - 2.52), and the observed substituent effects have been rationalized with the aid of semi-empirical and ab initio molecular orbital calculations. An efficient route has been developed for the synthesis of the naturally-occurring chromone, "granulosin" [7,8-(methylenedioxy)-2-propylchromone], and several C-2 side chain analogues in good yields, by condensing 2'-hydroxy-3',4'-(methylenedioxy)acetophenone with a range of ethyl carboxylate esters. These compounds show significant cytotoxic activity against the brine shrimp, Artemia salina, and two of them, the 2-ethyl and 2-benzyl derivatives also show 100% activity as pesticides on Beet army worms (BAW). Another naturally-occurring chromone derivative, 5-hydroxy-2-isopropyl-7-methoxychromone, and four C-2 side chain analogues have been prepared in moderate yields. These compounds also show significant cytotoxic activity against the brine shrimp, Artemia salina, and it is apparent that the presence of the hydroxyl group at C-5 is critical for such activity. The electronimpact mass spectra of both series of chromone derivatives have been investigated, permitting the elucidation of characteristic fragmentation patterns. In work directed towards the synthesis of potential HIV -1 protease inhibitors, five novel chromone-containing analogues of the clinically useful drug, ritonavir, have been synthesized. The design strategy has involved the coupling of substituted chromone-2- carboxylic acids with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing chromone termini. An interactive docking procedure has been used to explore the docking of ritonavir and the novel chromone-containing analogues into ' the active site of the enzyme, and has indicated the capacity of the ritonavir analogues to form hydrogen-bonds with the HJV-l enzyme receptor. Various substituted cbromone-3-carbaldehydes, which have been synthesized from the corresponding o-hyclroxyacetophenones using Vilsmeier-Haack methodology, have been examined as substrates for Morita-Baylis-Hillman reactions, using 3-hyclroxyquinuclidine as the catalyst and arcylonitrile and methyl acrylate as the activated alkenes. Optimization of the reaction conditions has permitted efficient conversion of the cbromone-3-carbaldehydes to the Morita-Baylis-Hillman products and, in some cases, dimeric products, within 24 h. Heating of the Morita-Baylis-Hillman products, arising from reactions with methyl acrylate, at 80 ºC for 3 h in the presence of DABCO as catalyst, has been shown to effect transformation to the corresponding dimers in good yield.
- Full Text:
- Date Issued: 2002
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
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
Design, synthesis and evaluation of novel, metal complexing agents
- Authors: Hagemann, Justin Philip
- Date: 1997
- Subjects: Ligands Metal complexes
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4307 , http://hdl.handle.net/10962/d1004965
- Description: Various chelating ligands have been designed and synthesised; these include amino-amide ligands, tetraacetic acid systems and sulfur-containing amide ligands. Difficulties in the synthesis and purification of the amino-amide ligands were largely overcome, permitting the mono acylation of ethylenediamine and the synthesis of bis(2-aminoethyl)-2-benzylpropanediamide. Novel tetraacetic acid ligands, based on the propanediamide backbone and targeted as EDTA analogues, were obtained from their methyl and benzyl esters; but the instability of the tetraacids prevented their full characterisation. Bidentate, tridentate and tetradentate sulfur-containing monoamide ligands, based on the ortho-thio acetanilide moiety, were designed to specifically chelate platinum and palladium in the presence of base metals. In their synthesis, thiocyanation was used to introduce the orth-thio group on para-substituted anilines, and further functionalisation was achieved via appropriate protection of nucleophilic sulfur moieties. A range of tetradentate, sulfur-containing diamide ligands was also synthesised by reacting substituted 2-mercaptoacetanilides with 1,2- dibromoethane. Novel ligands were characterised by spectroscopic (¹H and ¹³C NMR; IR and M S) techniques and elemental (combustion and high resolution MS) analysis. Computer modelling and ¹H NMR chemical shift data have been used to explore the conformational preferences of the sulfur-containing acetanilide ligands. The macrocyclic ligands and systems with ortho-methylthio substituents appear to exhibit the greatest degree of coplanarity of the aromatic and amide functions. Solvent extraction studies revealed that the sulfur-containing amide ligands selectively extracted palladium(II) from platinum(II), copper(II}, nickel(II} and cobalt(II}. Even though the palladium(II} was extracted from an acidic medium, certain monoamide ligands were able to complex palladium(II) through their sulfur and deprotonated amide nitrogen donors, a trithia monoamide ligand being observed to displace all the chloride ligands on palladium to form a monomeric tetracoordinate complex. The diamide ligands, however, appeared to favour extraction of palladium(II) by coordination through their sulfur donors, forming 5-membered sulfur-sulfur chelates. In basic media (pH 8-9), selected sulfur-containing monoamide and diamide ligands have been shown to complex platinum(II) and palladium(II) through their sulfur and deprotonated amide nitrogen donors. At neutral pH, a dimercapto monoamide ligand has been shown to complex platinum from cisplatin with partial expulsion of the ammine ligands, while a macrocyclic trithia monoamide ligand has been observed to complex platinum from tetrachloroplatinate with concomitant deprotonation of the amide nitrogen. Where possible, the complexes were characterised by infrared and ¹H NMR spectroscopy and have also been studied using the computer modelling soft-ware programmes, Momec® and Hyperchem®.
- Full Text:
- Date Issued: 1997
- Authors: Hagemann, Justin Philip
- Date: 1997
- Subjects: Ligands Metal complexes
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4307 , http://hdl.handle.net/10962/d1004965
- Description: Various chelating ligands have been designed and synthesised; these include amino-amide ligands, tetraacetic acid systems and sulfur-containing amide ligands. Difficulties in the synthesis and purification of the amino-amide ligands were largely overcome, permitting the mono acylation of ethylenediamine and the synthesis of bis(2-aminoethyl)-2-benzylpropanediamide. Novel tetraacetic acid ligands, based on the propanediamide backbone and targeted as EDTA analogues, were obtained from their methyl and benzyl esters; but the instability of the tetraacids prevented their full characterisation. Bidentate, tridentate and tetradentate sulfur-containing monoamide ligands, based on the ortho-thio acetanilide moiety, were designed to specifically chelate platinum and palladium in the presence of base metals. In their synthesis, thiocyanation was used to introduce the orth-thio group on para-substituted anilines, and further functionalisation was achieved via appropriate protection of nucleophilic sulfur moieties. A range of tetradentate, sulfur-containing diamide ligands was also synthesised by reacting substituted 2-mercaptoacetanilides with 1,2- dibromoethane. Novel ligands were characterised by spectroscopic (¹H and ¹³C NMR; IR and M S) techniques and elemental (combustion and high resolution MS) analysis. Computer modelling and ¹H NMR chemical shift data have been used to explore the conformational preferences of the sulfur-containing acetanilide ligands. The macrocyclic ligands and systems with ortho-methylthio substituents appear to exhibit the greatest degree of coplanarity of the aromatic and amide functions. Solvent extraction studies revealed that the sulfur-containing amide ligands selectively extracted palladium(II) from platinum(II), copper(II}, nickel(II} and cobalt(II}. Even though the palladium(II} was extracted from an acidic medium, certain monoamide ligands were able to complex palladium(II) through their sulfur and deprotonated amide nitrogen donors, a trithia monoamide ligand being observed to displace all the chloride ligands on palladium to form a monomeric tetracoordinate complex. The diamide ligands, however, appeared to favour extraction of palladium(II) by coordination through their sulfur donors, forming 5-membered sulfur-sulfur chelates. In basic media (pH 8-9), selected sulfur-containing monoamide and diamide ligands have been shown to complex platinum(II) and palladium(II) through their sulfur and deprotonated amide nitrogen donors. At neutral pH, a dimercapto monoamide ligand has been shown to complex platinum from cisplatin with partial expulsion of the ammine ligands, while a macrocyclic trithia monoamide ligand has been observed to complex platinum from tetrachloroplatinate with concomitant deprotonation of the amide nitrogen. Where possible, the complexes were characterised by infrared and ¹H NMR spectroscopy and have also been studied using the computer modelling soft-ware programmes, Momec® and Hyperchem®.
- Full Text:
- Date Issued: 1997
Synthesis of chiral ketopinic acid-derived catalysts and their evaluation in asymmetric transformations
- Authors: Hassan, Yusuf
- Date: 2016
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/550 , vital:19969
- Description: Four new (+)-ketopinic acid-derived Mn(III) complexes, three of which possess pseudo C2- symmetry, were synthesised as chiral catalyst candidates. The ligands were prepared by refluxing (+)-ketopinic acid with ethane-1,2-diamine, the resolved (R,R)- and (S,S)-1,2-diaminocyclohexanes, and 1,2-diaminobenzene in chloroform. Treatment of the ligands with manganese(II) acetate tetrahydrate in refluxing ethanol afforded the respective complexes as brown amorphous powders. Characterisation of the ligands and the corresponding complexes was achieved using 1-D and 2-D NMR, IR spectroscopy, and elemental analysis. Various homogeneous asymmetric transformations, were investigated using these four complexes, viz., aldol, and Baylis-Hillman reactions, aza-Michael addition of piperidine to the Baylis-Hillman adducts, epoxidation, and ketone and imine reduction. Asymmetric aldol reactions of benzaldehyde with the aryl ketones, acetophenone, propiophenone, -tetralone, 4-nitroacetophenone, and 4-methoxyacetophenone, conducted in the presence of 10 mole % of the chiral catalysts, afforded enantioselectivities of up to 99% e.e. Asymmetric Baylis-Hillman reactions of methyl- and tert-butyl acrylates with pyridine-2- carbaldehyde, 6-methylpyridine-2-carbaldehyde, 5-chlorosalicylaldehyde, benzaldehyde, 4-chlorobenzaldehyde, and 2-nitrobenzaldehyde were conducted in the presence of catalyst 139 (10 mole %) to afford enantioselectivities of up to 44% e.e. Aza-Michael addition of piperidine to racemic Baylis- Hillman adducts in the presence of the catalyst 139 (10 mole %) was found to proceed with diastereoselectivities of up to 91% d.e. Asymmetric epoxidation of trans-methyl styrene, styrene, trans-stilbene, cis-stilbene, and indene, using a 5 mole % chiral catalyst loading and m-CPBA as the oxygen source, gave enantioselectivities of up to 32 % e.e. Asymmetric reductions of acetophenone, 3-chloropropiophenone, 4-hydroxyacetophenone, -tetralone, and 2-hydroxy-1-acetonapthone were investigated using NaBH4 as the reducing agent and a 10 mole % loading of the chiral catalysts. A stereoselectivity of 68% e.e. was obtained in the reduction of acetophenone, but attempts to reduce the selected imines to the corresponding chiral amines proved to be unsuccessful — even in the absence of the catalysts. It thus became apparent that the catalytic version of the reaction was not feasible.
- Full Text:
- Date Issued: 2016
- Authors: Hassan, Yusuf
- Date: 2016
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/550 , vital:19969
- Description: Four new (+)-ketopinic acid-derived Mn(III) complexes, three of which possess pseudo C2- symmetry, were synthesised as chiral catalyst candidates. The ligands were prepared by refluxing (+)-ketopinic acid with ethane-1,2-diamine, the resolved (R,R)- and (S,S)-1,2-diaminocyclohexanes, and 1,2-diaminobenzene in chloroform. Treatment of the ligands with manganese(II) acetate tetrahydrate in refluxing ethanol afforded the respective complexes as brown amorphous powders. Characterisation of the ligands and the corresponding complexes was achieved using 1-D and 2-D NMR, IR spectroscopy, and elemental analysis. Various homogeneous asymmetric transformations, were investigated using these four complexes, viz., aldol, and Baylis-Hillman reactions, aza-Michael addition of piperidine to the Baylis-Hillman adducts, epoxidation, and ketone and imine reduction. Asymmetric aldol reactions of benzaldehyde with the aryl ketones, acetophenone, propiophenone, -tetralone, 4-nitroacetophenone, and 4-methoxyacetophenone, conducted in the presence of 10 mole % of the chiral catalysts, afforded enantioselectivities of up to 99% e.e. Asymmetric Baylis-Hillman reactions of methyl- and tert-butyl acrylates with pyridine-2- carbaldehyde, 6-methylpyridine-2-carbaldehyde, 5-chlorosalicylaldehyde, benzaldehyde, 4-chlorobenzaldehyde, and 2-nitrobenzaldehyde were conducted in the presence of catalyst 139 (10 mole %) to afford enantioselectivities of up to 44% e.e. Aza-Michael addition of piperidine to racemic Baylis- Hillman adducts in the presence of the catalyst 139 (10 mole %) was found to proceed with diastereoselectivities of up to 91% d.e. Asymmetric epoxidation of trans-methyl styrene, styrene, trans-stilbene, cis-stilbene, and indene, using a 5 mole % chiral catalyst loading and m-CPBA as the oxygen source, gave enantioselectivities of up to 32 % e.e. Asymmetric reductions of acetophenone, 3-chloropropiophenone, 4-hydroxyacetophenone, -tetralone, and 2-hydroxy-1-acetonapthone were investigated using NaBH4 as the reducing agent and a 10 mole % loading of the chiral catalysts. A stereoselectivity of 68% e.e. was obtained in the reduction of acetophenone, but attempts to reduce the selected imines to the corresponding chiral amines proved to be unsuccessful — even in the absence of the catalysts. It thus became apparent that the catalytic version of the reaction was not feasible.
- Full Text:
- Date Issued: 2016
Synthetic and analytical studies of biomimetic metal complexes
- Authors: Wellington, Kevin Wayne
- Date: 2000
- Subjects: Biomimetics Metal complexes Metalloenzymes Metal ions Ligands
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4377 , http://hdl.handle.net/10962/d1005042
- Description: Several series of novel diamido, diamino and diimino ligands containing different spacers and heterocyclic donors have been synthesised. The spacers include the flexible biphenyl, the rigid 1,1 O-phenanthroline and various acyclic moieties, while the heterocyclic donors comprise pyridine, imidazole or benzimidazole groups. These ligands have been designed to complex copper and act as biomimetic models of the active site of the enzyme, tyrosinase, and their complexes with copper, cobalt, nickel and platinum have been analysed using microanalytical, IR, UV-Visible and cyclic voltammetric techniques. Attempted reduction of the biphenyl-based diimino ligands resulted in an unexpected intramolecular cyclisation affording azepine derivatives, the structures of which were elucidated with the aid of single crystal X-ray analysis of cobalt and nickel complexes. Computer modelling methods have been used to explore the conformational options of the copper complexes, and to assess the accessibility of the dinuclear copper site to substrate molecules. Computer modelling has also been used, in conjunction with the available analytical data, to visualise the possible structures of selected ligands and complexes. The copper complexes, although predominantly polymeric, were evaluated as biomimetic catalysts using 3,5-di-t-butylphenol and 3,5-di-t-butylcatechol as substrates. Some of the complexes clearly displayed biomimetic potential, exhibiting both phenolase and catecholase activity.
- Full Text:
- Date Issued: 2000
- Authors: Wellington, Kevin Wayne
- Date: 2000
- Subjects: Biomimetics Metal complexes Metalloenzymes Metal ions Ligands
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4377 , http://hdl.handle.net/10962/d1005042
- Description: Several series of novel diamido, diamino and diimino ligands containing different spacers and heterocyclic donors have been synthesised. The spacers include the flexible biphenyl, the rigid 1,1 O-phenanthroline and various acyclic moieties, while the heterocyclic donors comprise pyridine, imidazole or benzimidazole groups. These ligands have been designed to complex copper and act as biomimetic models of the active site of the enzyme, tyrosinase, and their complexes with copper, cobalt, nickel and platinum have been analysed using microanalytical, IR, UV-Visible and cyclic voltammetric techniques. Attempted reduction of the biphenyl-based diimino ligands resulted in an unexpected intramolecular cyclisation affording azepine derivatives, the structures of which were elucidated with the aid of single crystal X-ray analysis of cobalt and nickel complexes. Computer modelling methods have been used to explore the conformational options of the copper complexes, and to assess the accessibility of the dinuclear copper site to substrate molecules. Computer modelling has also been used, in conjunction with the available analytical data, to visualise the possible structures of selected ligands and complexes. The copper complexes, although predominantly polymeric, were evaluated as biomimetic catalysts using 3,5-di-t-butylphenol and 3,5-di-t-butylcatechol as substrates. Some of the complexes clearly displayed biomimetic potential, exhibiting both phenolase and catecholase activity.
- Full Text:
- Date Issued: 2000
The pyrrolizidine alkaloids of Senecio chrysocoma and Senecio paniculatus
- Authors: Logie, Catherine Gwynedd
- Date: 1996
- Subjects: Senecio -- Analysis Pyrrolizidines Botanical chemistry
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4339 , http://hdl.handle.net/10962/d1005000
- Description: In order to compare the pyrrolizidine alkaloid content of two closely related species, Senecio chrysocoma and S. paniculatus, nine populations of plants distributed between the two species, were examined. Three novel pyrrolizidine alkaloids, 7ß-angelyl-l-methylene-8∝-pyrrolizidine, 7ß-angelyl-l-methylene-8∝-pyrrolizidine and 7ß-angelyl-l-methyleneSO!-pyrrolizidine-4-oxide, as well as eight known pyrrolizidine alkaloids, 7-angelylhastanecine, 9-angelylhastanecine, 7-angelylplatynecine, 9-angelylplatynecine, 9-angelylplatynecine-4-oxide, sarracine, neosarracine and retrorsine, were isolated and identified by NMR and GC-MS techniques. Traces of five tiglyl isomers, 9-tiglylplatynecine, 9-tigl ylplatynecine-4-oxide, 7ß-tiglyl-l-methylene-8∝-pyrrolizidine, sarranicine and neosarranicine, were also isolated and tentatively identified; however, these compounds could have been artefacts of the extraction and analytical procedures. While both species of plant investigated, S. chrysocoma and S. paniculatus, were found to be morphologically different, their pyrrolizidine alkaloid content was, in fact, very similar. The presence of retrorsine in S. paniculatus plant extracts, but not in those from S. chrysocoma plants, was the only major chemical difference observed. It is perhaps significant that retrorsine was the only macrocyclic pyrrolizidine to be identified. A comprehensive, computerised database of physical data for pyrrolizidine alkaloids has been compiled, which has facilitated the identification of new pyrrolizidines and the examination of trends in proton and carbon-13 NMR data for pyrrolizidine alkaloids. A stereospecific synthesis of 7ß-angelyl-l-methylene-8∝-pyrrolizidine was undertaken toconfirm the absolute stereochemistry of the product isolated from S. chrysocoma and S. paniculatus. An inseparable 5:2 mixture of 7ß-angelyl-l-methylene-8∝-pyrrolizidine and 7ß-angelyl-l,2-didehydro-l-methyl-8∝-pyrrolizidine, together with a small amount of tiglyl isomer, was finally synthesised. The application of various chiral differentiating chromatographic and spectroscopic techniques confirmed that both the natural and synthetic products had the same stereochemistry, permitting the natural alkaloid to be identified as 7ß-angelyl-methylene-8∝-pyrrol izidine
- Full Text:
- Date Issued: 1996
- Authors: Logie, Catherine Gwynedd
- Date: 1996
- Subjects: Senecio -- Analysis Pyrrolizidines Botanical chemistry
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4339 , http://hdl.handle.net/10962/d1005000
- Description: In order to compare the pyrrolizidine alkaloid content of two closely related species, Senecio chrysocoma and S. paniculatus, nine populations of plants distributed between the two species, were examined. Three novel pyrrolizidine alkaloids, 7ß-angelyl-l-methylene-8∝-pyrrolizidine, 7ß-angelyl-l-methylene-8∝-pyrrolizidine and 7ß-angelyl-l-methyleneSO!-pyrrolizidine-4-oxide, as well as eight known pyrrolizidine alkaloids, 7-angelylhastanecine, 9-angelylhastanecine, 7-angelylplatynecine, 9-angelylplatynecine, 9-angelylplatynecine-4-oxide, sarracine, neosarracine and retrorsine, were isolated and identified by NMR and GC-MS techniques. Traces of five tiglyl isomers, 9-tiglylplatynecine, 9-tigl ylplatynecine-4-oxide, 7ß-tiglyl-l-methylene-8∝-pyrrolizidine, sarranicine and neosarranicine, were also isolated and tentatively identified; however, these compounds could have been artefacts of the extraction and analytical procedures. While both species of plant investigated, S. chrysocoma and S. paniculatus, were found to be morphologically different, their pyrrolizidine alkaloid content was, in fact, very similar. The presence of retrorsine in S. paniculatus plant extracts, but not in those from S. chrysocoma plants, was the only major chemical difference observed. It is perhaps significant that retrorsine was the only macrocyclic pyrrolizidine to be identified. A comprehensive, computerised database of physical data for pyrrolizidine alkaloids has been compiled, which has facilitated the identification of new pyrrolizidines and the examination of trends in proton and carbon-13 NMR data for pyrrolizidine alkaloids. A stereospecific synthesis of 7ß-angelyl-l-methylene-8∝-pyrrolizidine was undertaken toconfirm the absolute stereochemistry of the product isolated from S. chrysocoma and S. paniculatus. An inseparable 5:2 mixture of 7ß-angelyl-l-methylene-8∝-pyrrolizidine and 7ß-angelyl-l,2-didehydro-l-methyl-8∝-pyrrolizidine, together with a small amount of tiglyl isomer, was finally synthesised. The application of various chiral differentiating chromatographic and spectroscopic techniques confirmed that both the natural and synthetic products had the same stereochemistry, permitting the natural alkaloid to be identified as 7ß-angelyl-methylene-8∝-pyrrol izidine
- Full Text:
- Date Issued: 1996
Metathesis catalysts : an integrated computational, mechanistic and synthetic study
- Authors: Sabbagh, Ingrid Theresa
- Date: 2006
- Subjects: Metathesis (Chemistry) Catalysis Metal catalysts Chemical kinetics
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4397 , http://hdl.handle.net/10962/d1006208
- Description: An integrated approach to the design of potential rutheniun-based metathesis catalysts is described, in which closely defined synthetic forays provide the focus and rationale for detailed computational and mechanistic studies. The ground-state geometry of a 1st-generation Grubbs catalyst has been explored at the molecular mechanics, semi-empirical and DFT levels, and the resulting structures have been shown to compare favourably with literature data and with the structure of a known crystalline analogue. The DMol³ DFT code has also been shown to represent accurately both the geometry of the corresponding co-ordinatively unsaturated monophosphine derivative, and the ligand dissociation energy associated with its formation. A DFT free-energy profile of the degenerate metathesis of ethylene has been generated, using a truncated model of the 1st-generation Grubbs catalyst, permitting location, for the first time, of the three expected transition states and providing new information regarding the rate-determining step. DFT methods have been used to facilitate the design of a tridentate camphor-derived ligand for use in the construction of a novel Grubbs-type catalyst. The phosphine ligand dissociation energy of the putative catalyst and the ethylene metathesis energy profile of a truncated model have also been studies at the DFT level. The attempted synthesis of the proposed ligand proceeded via a novel 8-bromocamphoric anhydride intermediate and afforded several unexpected and novel products, including a cisfused γ-Iactone, and a bromo camphoric acid derivative. Single crystal X-ray analysis of the latter reveals a chiral, polymeric H-bonded packing arrangement, rendering it suitable for chiral inclusion studies. Computational methods, including the GAUSSIAN-based GIAO NMR prediction technique, were used to support the structural characterisation of the novel camphor derivatives. DFT-Ievel computational analysis of the C-8- and C-9 bromination of camphor has afforded theoretical insights which permit the reconciliation of two earlier empirical explanations regarding the regioselectivity of these transformations; moreover, the theoretical results suggest that a third, previously disregarded factor, plays a significant role. A coset analysis, in conjunction with DFT-Ievel energy profiling, has also been used to resolve conflicting opinions regarding the origin of the major byproduct. Computed electronic parameters (CEP's) have been calculated for the anionic ligands involved in a series of 2nd-generation Grubbs-Hoveyda-type catalysts, and used to explain some apparently anomalous trends in catalyst activity. A linear relationship between ligand CEP's and selected ¹H NMR chemical shifts has also been demonstrated and used to identify a transient ruthenium complex in solution. The ability of the malonate di-anion to bind to ruthenium in a bidentate manner has been explored and demonstrated, under suitable conditions. DFT methods have been used to design and assess the ruthenium-chelating potential of a novel tridentate malonate derivative. A synthetic pathway to this ligand has been designed and several novel heterocyclic intermediates have been isolated and characterised. An NMR-based kinetic study of the Grubbs-catalysed self-metathesis of l-octene has been completed, and the effects of temperature, concentration and solvent variations on the kinetic parameters have been studied. Application of the Guggenheim method and a simplified mechanistic model has permitted the accurate calculation of pseudorate constants for the initiation and, for the first time, the propagation phase of the reaction. Theoretical studies of this reaction at the DFT and molecular mechanics levels have been shown to support previous assumptions regarding the selectivity and temperature-dependence of metallacycle formation.
- Full Text:
- Date Issued: 2006
- Authors: Sabbagh, Ingrid Theresa
- Date: 2006
- Subjects: Metathesis (Chemistry) Catalysis Metal catalysts Chemical kinetics
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4397 , http://hdl.handle.net/10962/d1006208
- Description: An integrated approach to the design of potential rutheniun-based metathesis catalysts is described, in which closely defined synthetic forays provide the focus and rationale for detailed computational and mechanistic studies. The ground-state geometry of a 1st-generation Grubbs catalyst has been explored at the molecular mechanics, semi-empirical and DFT levels, and the resulting structures have been shown to compare favourably with literature data and with the structure of a known crystalline analogue. The DMol³ DFT code has also been shown to represent accurately both the geometry of the corresponding co-ordinatively unsaturated monophosphine derivative, and the ligand dissociation energy associated with its formation. A DFT free-energy profile of the degenerate metathesis of ethylene has been generated, using a truncated model of the 1st-generation Grubbs catalyst, permitting location, for the first time, of the three expected transition states and providing new information regarding the rate-determining step. DFT methods have been used to facilitate the design of a tridentate camphor-derived ligand for use in the construction of a novel Grubbs-type catalyst. The phosphine ligand dissociation energy of the putative catalyst and the ethylene metathesis energy profile of a truncated model have also been studies at the DFT level. The attempted synthesis of the proposed ligand proceeded via a novel 8-bromocamphoric anhydride intermediate and afforded several unexpected and novel products, including a cisfused γ-Iactone, and a bromo camphoric acid derivative. Single crystal X-ray analysis of the latter reveals a chiral, polymeric H-bonded packing arrangement, rendering it suitable for chiral inclusion studies. Computational methods, including the GAUSSIAN-based GIAO NMR prediction technique, were used to support the structural characterisation of the novel camphor derivatives. DFT-Ievel computational analysis of the C-8- and C-9 bromination of camphor has afforded theoretical insights which permit the reconciliation of two earlier empirical explanations regarding the regioselectivity of these transformations; moreover, the theoretical results suggest that a third, previously disregarded factor, plays a significant role. A coset analysis, in conjunction with DFT-Ievel energy profiling, has also been used to resolve conflicting opinions regarding the origin of the major byproduct. Computed electronic parameters (CEP's) have been calculated for the anionic ligands involved in a series of 2nd-generation Grubbs-Hoveyda-type catalysts, and used to explain some apparently anomalous trends in catalyst activity. A linear relationship between ligand CEP's and selected ¹H NMR chemical shifts has also been demonstrated and used to identify a transient ruthenium complex in solution. The ability of the malonate di-anion to bind to ruthenium in a bidentate manner has been explored and demonstrated, under suitable conditions. DFT methods have been used to design and assess the ruthenium-chelating potential of a novel tridentate malonate derivative. A synthetic pathway to this ligand has been designed and several novel heterocyclic intermediates have been isolated and characterised. An NMR-based kinetic study of the Grubbs-catalysed self-metathesis of l-octene has been completed, and the effects of temperature, concentration and solvent variations on the kinetic parameters have been studied. Application of the Guggenheim method and a simplified mechanistic model has permitted the accurate calculation of pseudorate constants for the initiation and, for the first time, the propagation phase of the reaction. Theoretical studies of this reaction at the DFT and molecular mechanics levels have been shown to support previous assumptions regarding the selectivity and temperature-dependence of metallacycle formation.
- Full Text:
- Date Issued: 2006
Synthesis of novel heterocyclic systems as potential inhibitors of HIV-1 enzymes
- Authors: Sekgota, Khethobole Cassius
- Date: 2020
- Subjects: Protease inhibitors , Heterocyclic compounds , HIV (Viruses) , Quinoline , Amides , Nuclear magnetic resonance , Antiretroviral agents , AIDS vaccines , Nitrobenzaldehyde , Propylphosphonic acid anhydride
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/146502 , vital:38531
- Description: This study has focussed on the application of Baylis-Hillman methodology in the development of efficient synthetic pathways to libraries of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones and indolizine-2-carboxamides and on an exploration of their medicinal potential. The approach to 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones involved a six-step pathway comprising: Baylis-Hillman reaction of 2-nitrobenzaldehyde derivatives and methyl acrylate to afford nitro-Baylis-Hillman adducts; thermal cyclisation of the adducts to give a range of 3-(acetoxymethyl)-2(1H)-quinolones in good to excellent yields; hydrolysis of the acetates; conversion of the resulting alcohols to the 3-chloromethyl analogues; amination; and, finally, acylation to afford the target amides. Variable temperature NMR methods were used to facilitate analysis of the ¹H and ¹³C NMR spectra which were complicated by internal rotation and cycloalkyl ring-flipping effects. On the other hand, the indolizine-2-carboxamides were obtained in several steps commencing with the Baylis-Hillman reaction of pyridine-2-carboxaldehyde and methyl acrylate. Thermal cyclisation of the Baylis-Hillman adduct afforded indolizine esters, hydrolysis of which gave the corresponding acids which served as precursors to the target indolizine-2-carboxamides. The final amidation step, however, proved to be particularly challenging. Various coupling strategies were explored to access indolizine-2-carboxamides. These included the use of 2,2,2-trifluoroethyl borate which showed limited promise, but propylphosphonic acid anhydride (T3P) proved to be the most effective coupling agent, permitting the formation of 24 novel indolizine-2-carboxamides from hydrazines, aliphatic amines and a range of heterocyclic amines. A high-field NMR-based kinetic study of the mechanism of the Baylis-Hillman reaction of pyridine-4-carboxaldehyde and methyl acrylate in the presence of 3-hydroxyquinuclidine in deuterated chloroform was initiated, reaction progress being followed by the automated collection of ¹H and DEPT 135 NMR spectra over ca. 24 hours using a high-field (600 MHz) NMR instrument. The results have provided critical new insights into the mechanism. NMR analysis has also been used to elucidate the multiplicity of signals associated with rotameric equilibria observed at ambient probe temperature. Variable temperature 1D- and 2D-NMR spectra were used to facilitate the unambiguous characterisation of the 2-quinolone benzamides and some of the indolizine-2-carboxamides. The 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones, together with selected precursors, and a number of the indolizine-2-carboxamides have been screened in vitro as potential HIV-1 enzyme inhibitors. A survey of the activity of the 2-quinolones against HIV-1 integrase, protease and reverse transcriptase revealed selective inhibition of HIV-1 integrase with the most active IN inhibitor, 3-[(cyclopentylamino)methyl-6-methoxy-2(1H)-quinolone 115e, producing residual enzyme activity of 40% at a concentration of 20 μM. Many of the 2-quinolones exhibited no significant cytotoxicity against HEK 293 cells at 20 μM concentrations. 3-[(N-Cyclohexylamino)methyl]-6-methoxy-2(1H)-quinolone 114e was the only compound to exhibit ant-plasmodial activity (55% pfLDH activity). The survey of indolizine-2-carboxamides also revealed encouraging inhibition against HIV-1 integrase. None of these compounds exhibited cytotoxicity at 20 μM against HEK 293 cells, while a number of them exhibited some activity against Plasmodium falciparum (3D7 strain) and Trypanosoma brucei. Selected indolizine-2-carboxamides exhibited significant anti-tubercular activity in the 7H9 CAS GLU Tx and 7H9 ADC GLU Tw media. In view of the inherent fluorescent character and biological potential of the synthesised indolizine-2-carboxamides, their photophysical properties were explored to establish their possible dual use as bio-imaging and therapeutic agents. The major absorption and corresponding emission bands, and the associated molar absorption coefficients (Ɛ) expressed in the form of log Ɛ were determined. Their high extinction coefficients, large Stokes shift and red-shifted emissions in the visible region indicate their potential for use as fluorophores.
- Full Text:
- Date Issued: 2020
- Authors: Sekgota, Khethobole Cassius
- Date: 2020
- Subjects: Protease inhibitors , Heterocyclic compounds , HIV (Viruses) , Quinoline , Amides , Nuclear magnetic resonance , Antiretroviral agents , AIDS vaccines , Nitrobenzaldehyde , Propylphosphonic acid anhydride
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/146502 , vital:38531
- Description: This study has focussed on the application of Baylis-Hillman methodology in the development of efficient synthetic pathways to libraries of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones and indolizine-2-carboxamides and on an exploration of their medicinal potential. The approach to 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones involved a six-step pathway comprising: Baylis-Hillman reaction of 2-nitrobenzaldehyde derivatives and methyl acrylate to afford nitro-Baylis-Hillman adducts; thermal cyclisation of the adducts to give a range of 3-(acetoxymethyl)-2(1H)-quinolones in good to excellent yields; hydrolysis of the acetates; conversion of the resulting alcohols to the 3-chloromethyl analogues; amination; and, finally, acylation to afford the target amides. Variable temperature NMR methods were used to facilitate analysis of the ¹H and ¹³C NMR spectra which were complicated by internal rotation and cycloalkyl ring-flipping effects. On the other hand, the indolizine-2-carboxamides were obtained in several steps commencing with the Baylis-Hillman reaction of pyridine-2-carboxaldehyde and methyl acrylate. Thermal cyclisation of the Baylis-Hillman adduct afforded indolizine esters, hydrolysis of which gave the corresponding acids which served as precursors to the target indolizine-2-carboxamides. The final amidation step, however, proved to be particularly challenging. Various coupling strategies were explored to access indolizine-2-carboxamides. These included the use of 2,2,2-trifluoroethyl borate which showed limited promise, but propylphosphonic acid anhydride (T3P) proved to be the most effective coupling agent, permitting the formation of 24 novel indolizine-2-carboxamides from hydrazines, aliphatic amines and a range of heterocyclic amines. A high-field NMR-based kinetic study of the mechanism of the Baylis-Hillman reaction of pyridine-4-carboxaldehyde and methyl acrylate in the presence of 3-hydroxyquinuclidine in deuterated chloroform was initiated, reaction progress being followed by the automated collection of ¹H and DEPT 135 NMR spectra over ca. 24 hours using a high-field (600 MHz) NMR instrument. The results have provided critical new insights into the mechanism. NMR analysis has also been used to elucidate the multiplicity of signals associated with rotameric equilibria observed at ambient probe temperature. Variable temperature 1D- and 2D-NMR spectra were used to facilitate the unambiguous characterisation of the 2-quinolone benzamides and some of the indolizine-2-carboxamides. The 3-[(N-cycloalkylbenzamido)methyl]-2(1H)-quinolones, together with selected precursors, and a number of the indolizine-2-carboxamides have been screened in vitro as potential HIV-1 enzyme inhibitors. A survey of the activity of the 2-quinolones against HIV-1 integrase, protease and reverse transcriptase revealed selective inhibition of HIV-1 integrase with the most active IN inhibitor, 3-[(cyclopentylamino)methyl-6-methoxy-2(1H)-quinolone 115e, producing residual enzyme activity of 40% at a concentration of 20 μM. Many of the 2-quinolones exhibited no significant cytotoxicity against HEK 293 cells at 20 μM concentrations. 3-[(N-Cyclohexylamino)methyl]-6-methoxy-2(1H)-quinolone 114e was the only compound to exhibit ant-plasmodial activity (55% pfLDH activity). The survey of indolizine-2-carboxamides also revealed encouraging inhibition against HIV-1 integrase. None of these compounds exhibited cytotoxicity at 20 μM against HEK 293 cells, while a number of them exhibited some activity against Plasmodium falciparum (3D7 strain) and Trypanosoma brucei. Selected indolizine-2-carboxamides exhibited significant anti-tubercular activity in the 7H9 CAS GLU Tx and 7H9 ADC GLU Tw media. In view of the inherent fluorescent character and biological potential of the synthesised indolizine-2-carboxamides, their photophysical properties were explored to establish their possible dual use as bio-imaging and therapeutic agents. The major absorption and corresponding emission bands, and the associated molar absorption coefficients (Ɛ) expressed in the form of log Ɛ were determined. Their high extinction coefficients, large Stokes shift and red-shifted emissions in the visible region indicate their potential for use as fluorophores.
- Full Text:
- Date Issued: 2020
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
Mechanistic studies of unusual Miruta-Baylis-Hillman reactions
- Authors: Nyoni, Dubekile
- Date: 2012
- Subjects: Chemical reactions Benzaldehyde Acrylonitrile Methyl acrylate Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4400 , http://hdl.handle.net/10962/d1006692
- Description: This study has focussed on the application of synthetic, kinetic and exploratory theoretical methods in elucidating the reaction mechanisms of four Morita-Baylis-Hillman (MBH) type reactions, viz, i) the reactions of the disulfide 2,2'-dithiodibenzaldehyde with various activated alkenes in the presence of DBU and Ph₃P, ii) the reactions of chromone-3-carbaldehydes with MVK, iii) the reactions of chromone-2-carbaldehydes with acrylonitrile and iv) with methyl acrylate. Attention has also been given to the origin of the observed regioselectivity in Michaelis-Arbuzov reactions of 3-(halomethyl)coumarins. Cleavage of the sulfur-sulfur bond of aryl and heteroaryl disulfides by the nitrogen nucleophile DBU has been demonstrated, and a dramatic increase in the rate of tandem MBH and disulfide cleavage reactions of 2,2'-dithiodibenzaldehyde with the activated alkenes, MVK, EVK, acrylonitrile, methyl acrylate and tert-butyl acrylate has been achieved through the use of the dual organo-catalyst system, DBU-Ph₃P – an improvement accompanied by an increase in the yields of the isolated products. Detailed NMR-based kinetic studies have been conducted on the DBU-catalysed reactions of 2,2'-dithiodibenzaldehyde with MVK and methyl acrylate, and a theoretical kinetic model has been developed and complementary computational studies using Gaussian 03, at the DFT-B3LYP/6-31G(d) level of theory have provided valuable insights into the mechanism of these complex transformations. Reactions of chromone-3-carbaldehydes with MVK to afford chromone dimers and tricyclic products have been repeated, and a novel, intermediate MBH adduct has been isolated. The mechanisms of the competing pathways have been elucidated by DFT calculations and the development of a detailed theoretical kinetic model has ensued. Unusual transformations in MBH-type reactions of chromone-2-carbaldehydes with acrylonitrile and methyl acrylate have been explored and the structures of the unexpected products have been established using 1- and 2-D NMR, HRMS and X-ray crystallographic techniques. Attention has also been given to the synthesis of 3-(halomethyl)coumarins via the MBH reaction, and their subsequent Michaelis-Arbuzov reactions with triethyl phosphite. An exploratory study of the kinetics of the phosphonation reaction has been undertaken and the regio-selectivity of nucleophilic attack at the 4- and 1'-positions in the 3-chloro- and 3-(iodomethyl)coumarins has been investigated by calculating Mulliken charges, LUMO surfaces and Fukui condensed local softness functions.
- Full Text:
- Date Issued: 2012
- Authors: Nyoni, Dubekile
- Date: 2012
- Subjects: Chemical reactions Benzaldehyde Acrylonitrile Methyl acrylate Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4400 , http://hdl.handle.net/10962/d1006692
- Description: This study has focussed on the application of synthetic, kinetic and exploratory theoretical methods in elucidating the reaction mechanisms of four Morita-Baylis-Hillman (MBH) type reactions, viz, i) the reactions of the disulfide 2,2'-dithiodibenzaldehyde with various activated alkenes in the presence of DBU and Ph₃P, ii) the reactions of chromone-3-carbaldehydes with MVK, iii) the reactions of chromone-2-carbaldehydes with acrylonitrile and iv) with methyl acrylate. Attention has also been given to the origin of the observed regioselectivity in Michaelis-Arbuzov reactions of 3-(halomethyl)coumarins. Cleavage of the sulfur-sulfur bond of aryl and heteroaryl disulfides by the nitrogen nucleophile DBU has been demonstrated, and a dramatic increase in the rate of tandem MBH and disulfide cleavage reactions of 2,2'-dithiodibenzaldehyde with the activated alkenes, MVK, EVK, acrylonitrile, methyl acrylate and tert-butyl acrylate has been achieved through the use of the dual organo-catalyst system, DBU-Ph₃P – an improvement accompanied by an increase in the yields of the isolated products. Detailed NMR-based kinetic studies have been conducted on the DBU-catalysed reactions of 2,2'-dithiodibenzaldehyde with MVK and methyl acrylate, and a theoretical kinetic model has been developed and complementary computational studies using Gaussian 03, at the DFT-B3LYP/6-31G(d) level of theory have provided valuable insights into the mechanism of these complex transformations. Reactions of chromone-3-carbaldehydes with MVK to afford chromone dimers and tricyclic products have been repeated, and a novel, intermediate MBH adduct has been isolated. The mechanisms of the competing pathways have been elucidated by DFT calculations and the development of a detailed theoretical kinetic model has ensued. Unusual transformations in MBH-type reactions of chromone-2-carbaldehydes with acrylonitrile and methyl acrylate have been explored and the structures of the unexpected products have been established using 1- and 2-D NMR, HRMS and X-ray crystallographic techniques. Attention has also been given to the synthesis of 3-(halomethyl)coumarins via the MBH reaction, and their subsequent Michaelis-Arbuzov reactions with triethyl phosphite. An exploratory study of the kinetics of the phosphonation reaction has been undertaken and the regio-selectivity of nucleophilic attack at the 4- and 1'-positions in the 3-chloro- and 3-(iodomethyl)coumarins has been investigated by calculating Mulliken charges, LUMO surfaces and Fukui condensed local softness functions.
- Full Text:
- Date Issued: 2012