Synthesis of triprenylated toluquinone and toluhydroquinone metabolites from a marine-derived Penicillium fungus
- Authors: Scheepers, Brent Ashley
- Date: 2007
- Subjects: Penicillium , Antineoplastic agents , Marine fungi , Quinone
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4373 , http://hdl.handle.net/10962/d1005038 , Penicillium , Antineoplastic agents , Marine fungi , Quinone
- Description: This project forms part of a collaborative effort between the marine natural products chemists at Rhodes University and the medical biochemists at the University of Cape Town’s School of Medicine. Our UCT collaborators tested the cytotoxicity of a group of toluhydroquinones and toluquinones (9-15) against the oesophageal cancer cell line WHCO1 and revealed that the triprenylated toluhydroquinone 11 and it’s oxidised analogue 12 were the most active. This thesis presents an investigation into the role of the polyprenyl side-chain in the cytotoxicity of compound 11 and it’s oxidised analogue 12 by synthesizing and testing the cytotoxicity of simplified analogues of this compound. The synthesis of the two ortho-prenylated toluhydroquinone analogues 5-methyl-2-[(2'E,6'E)-3',7' -dimethyl-2',6'-octadienyl]-1,4-benzenediol (19) and 5-methyl-2-[(2'E,6'E)-3',7',11'-trimethyl-2',6',10'-dodecatrienyl]-1,4-benzenediol (21) and their two ortho-prenylated toluquinone analogues, 5-methyl-2-[(2'E,6'E)-3',7'-dimethyl-2',6'-octadienyl]-2,5-cyclohexadiene-1,4-dione (20) and 5-methyl-2-[(2'E,6'E)-3',7',11'-trimethyl-2',6',10'-dodecatrienyl]-2,5-cyclohexadiene-1,4-dione (22) is described. Our initial attempts to couple geranyl bromide, farnesyl bromide and farnesal to the aromatic precursors m-cresol and 1,4-dimethoxy-2-methylbenzene using directed ortho-prenylation and phenoxide carbon-alkylation were unsuccessful. The four target analogues were eventually synthesized via the initial metal halogen exchange reaction between 1-bromo-2,5-dimethoxy-4-methylbenzene and geranyl bromide/farnesyl bromide using n-BuLi and TMEDA in ditheyl ether at 0 °C to yield 92 and 104 respectively in moderate yield. The demethylation of both compounds preceded smoothly using AgO giving the target analogues 20 and 22 in good yield (approx. 90 %). The reduction of quinones 20 and 22 with sodium dithionite gave 19 and 21 in quantitative yield. The synthesis reported here is the first regioselective synthesis of these compounds. The anti-oesophageal cancer activity of 19-22 and two commercially available non-prenylated analogues 17 and 18 were tested against WHCO1. The conclusion drawn from the anti-oesophageal cancer study was that the polyprenyl side-chain plays a negligable role in the cytotoxicity of compounds such as 11 and 9 against the oesophageal cancer cell line WHCO1.
- Full Text:
- Date Issued: 2007
- Authors: Scheepers, Brent Ashley
- Date: 2007
- Subjects: Penicillium , Antineoplastic agents , Marine fungi , Quinone
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4373 , http://hdl.handle.net/10962/d1005038 , Penicillium , Antineoplastic agents , Marine fungi , Quinone
- Description: This project forms part of a collaborative effort between the marine natural products chemists at Rhodes University and the medical biochemists at the University of Cape Town’s School of Medicine. Our UCT collaborators tested the cytotoxicity of a group of toluhydroquinones and toluquinones (9-15) against the oesophageal cancer cell line WHCO1 and revealed that the triprenylated toluhydroquinone 11 and it’s oxidised analogue 12 were the most active. This thesis presents an investigation into the role of the polyprenyl side-chain in the cytotoxicity of compound 11 and it’s oxidised analogue 12 by synthesizing and testing the cytotoxicity of simplified analogues of this compound. The synthesis of the two ortho-prenylated toluhydroquinone analogues 5-methyl-2-[(2'E,6'E)-3',7' -dimethyl-2',6'-octadienyl]-1,4-benzenediol (19) and 5-methyl-2-[(2'E,6'E)-3',7',11'-trimethyl-2',6',10'-dodecatrienyl]-1,4-benzenediol (21) and their two ortho-prenylated toluquinone analogues, 5-methyl-2-[(2'E,6'E)-3',7'-dimethyl-2',6'-octadienyl]-2,5-cyclohexadiene-1,4-dione (20) and 5-methyl-2-[(2'E,6'E)-3',7',11'-trimethyl-2',6',10'-dodecatrienyl]-2,5-cyclohexadiene-1,4-dione (22) is described. Our initial attempts to couple geranyl bromide, farnesyl bromide and farnesal to the aromatic precursors m-cresol and 1,4-dimethoxy-2-methylbenzene using directed ortho-prenylation and phenoxide carbon-alkylation were unsuccessful. The four target analogues were eventually synthesized via the initial metal halogen exchange reaction between 1-bromo-2,5-dimethoxy-4-methylbenzene and geranyl bromide/farnesyl bromide using n-BuLi and TMEDA in ditheyl ether at 0 °C to yield 92 and 104 respectively in moderate yield. The demethylation of both compounds preceded smoothly using AgO giving the target analogues 20 and 22 in good yield (approx. 90 %). The reduction of quinones 20 and 22 with sodium dithionite gave 19 and 21 in quantitative yield. The synthesis reported here is the first regioselective synthesis of these compounds. The anti-oesophageal cancer activity of 19-22 and two commercially available non-prenylated analogues 17 and 18 were tested against WHCO1. The conclusion drawn from the anti-oesophageal cancer study was that the polyprenyl side-chain plays a negligable role in the cytotoxicity of compounds such as 11 and 9 against the oesophageal cancer cell line WHCO1.
- Full Text:
- Date Issued: 2007
Structural and stereochemical investigations of terrestrial and marine pyrone metabolites
- Authors: Collett, Lynne Alison
- Date: 1997
- Subjects: Metabolites , Stereochemistry , Siphonaria
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4348 , http://hdl.handle.net/10962/d1005013 , Metabolites , Stereochemistry , Siphonaria
- Description: This thesis presents an investigation into the chemistry of 6 substituted 5, 6-dihydro-a-pyrone compounds. A comprehensive review of these compounds was published in 1989 and the subsequent literature is covered in an updated review presented below. Eight 6-substituted 5,6-dihydro-a-pyrone metabolites from three different South African plant species Cryptocarya latijolia, Syncolostemon densiflorus, and Syncolostemon argenteus have been the subject of structural and stereochemical investigations. The absolute stereochemistry of the known compound "triacetate" from C. latijolia has been established as 6R-[2R,4S,6S-(triacetyloxy)heptylJ-5,6-dihydro-2H-pyran-2-one (74) using CD and acetonide formation with subsequent application of the modified Moshers method. The absolute stereochemistry of the related metabolite "diacetate", also from C. latijolia, has been assigned as 6R-[2S,4S-diacetyloxypentylJ-5,6-dihydro-2H-pyran-2-one (76). In addition, the outstanding stereochemistry at C-5' in syndenolide, from S. densiflorus, followed from conversion to its diacetonide and subsequent NMR analysis. Syndenolide is therefore 6R-[5S-(acetoxy)-IR,2R,3S-(trihydroxy)-heptylJ-5,6- dihydro-2H -pyran-2-one. The genus Syncolostemon has proved to be a rich source of a-pyrone compounds and the chemistry of S. argenteus, not investigated previously, was examined as part of an ongoing search for new 5,6-dihydro-a-pyrones. The study yielded five new a-pyrone natural products, synargentolide A-E. The structure of synargentolide A (82) has been assigned as 6R[4R,5R,6S-triacetyloxy-lE-heptenylJ-5,6-dihydro-2H-pyran-2-one using CD and NMR techniques. The structures of synargentolide B (87), C (92) and E (94) also followed from a detailed NMR analysis and the stereochemistry tentatively assigned based on CD and NMR data. Synargentolide D (93) was thermally unstable, and a paucity of material prevented stereochemical investigations, however the structure was determined from initial NMR analysis. The marine molluscs of the genus Siphonaria have only become the subject of chemical studies in the last fifteen years. These molluscs characteristically produce polypropionate type natural products. A review of Siphonarian polypropionate metabolites containing a pyrone functionality is presented. Examination of an endemic South African species Siphonaria serrata yielded one novel polypropionate metabolite containing a ),-pyrone functionality, siserrone A (131). The structure of this compound was unambiguously established using standard NMR experiments. The relative stereochemisty of the hemi-ketal moiety was assigned from a careful analysis of the ROESY NMR spectrum and the stereochemisty of the acyclic portion determined from a comparison of the 13C and 'H NMR data of a degradation product with the corresponding data of a synthetic compound. It was also established that the modified Moshers method could not be used to determine the absolute stereochemistry of the secondary hydroxy I substituent at C-11. The absolute stereochemistry of 131 was thus assigned in accordance with the proven stereochemistry of Siphonarian metabolites.
- Full Text:
- Date Issued: 1997
- Authors: Collett, Lynne Alison
- Date: 1997
- Subjects: Metabolites , Stereochemistry , Siphonaria
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4348 , http://hdl.handle.net/10962/d1005013 , Metabolites , Stereochemistry , Siphonaria
- Description: This thesis presents an investigation into the chemistry of 6 substituted 5, 6-dihydro-a-pyrone compounds. A comprehensive review of these compounds was published in 1989 and the subsequent literature is covered in an updated review presented below. Eight 6-substituted 5,6-dihydro-a-pyrone metabolites from three different South African plant species Cryptocarya latijolia, Syncolostemon densiflorus, and Syncolostemon argenteus have been the subject of structural and stereochemical investigations. The absolute stereochemistry of the known compound "triacetate" from C. latijolia has been established as 6R-[2R,4S,6S-(triacetyloxy)heptylJ-5,6-dihydro-2H-pyran-2-one (74) using CD and acetonide formation with subsequent application of the modified Moshers method. The absolute stereochemistry of the related metabolite "diacetate", also from C. latijolia, has been assigned as 6R-[2S,4S-diacetyloxypentylJ-5,6-dihydro-2H-pyran-2-one (76). In addition, the outstanding stereochemistry at C-5' in syndenolide, from S. densiflorus, followed from conversion to its diacetonide and subsequent NMR analysis. Syndenolide is therefore 6R-[5S-(acetoxy)-IR,2R,3S-(trihydroxy)-heptylJ-5,6- dihydro-2H -pyran-2-one. The genus Syncolostemon has proved to be a rich source of a-pyrone compounds and the chemistry of S. argenteus, not investigated previously, was examined as part of an ongoing search for new 5,6-dihydro-a-pyrones. The study yielded five new a-pyrone natural products, synargentolide A-E. The structure of synargentolide A (82) has been assigned as 6R[4R,5R,6S-triacetyloxy-lE-heptenylJ-5,6-dihydro-2H-pyran-2-one using CD and NMR techniques. The structures of synargentolide B (87), C (92) and E (94) also followed from a detailed NMR analysis and the stereochemistry tentatively assigned based on CD and NMR data. Synargentolide D (93) was thermally unstable, and a paucity of material prevented stereochemical investigations, however the structure was determined from initial NMR analysis. The marine molluscs of the genus Siphonaria have only become the subject of chemical studies in the last fifteen years. These molluscs characteristically produce polypropionate type natural products. A review of Siphonarian polypropionate metabolites containing a pyrone functionality is presented. Examination of an endemic South African species Siphonaria serrata yielded one novel polypropionate metabolite containing a ),-pyrone functionality, siserrone A (131). The structure of this compound was unambiguously established using standard NMR experiments. The relative stereochemisty of the hemi-ketal moiety was assigned from a careful analysis of the ROESY NMR spectrum and the stereochemisty of the acyclic portion determined from a comparison of the 13C and 'H NMR data of a degradation product with the corresponding data of a synthetic compound. It was also established that the modified Moshers method could not be used to determine the absolute stereochemistry of the secondary hydroxy I substituent at C-11. The absolute stereochemistry of 131 was thus assigned in accordance with the proven stereochemistry of Siphonarian metabolites.
- Full Text:
- Date Issued: 1997
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