Synthesis of the talaromycins A, B, C and E and synthetic studies towards ephedradine C
Synthesis of the talaromycins A, B, C and E and synthetic studies towards ephedradine C
Studies towards the synthesis of talaromycins A, B, C, and E are described. Novel syntheses of the alkynes cis and trans 5-(ethynyl)-2-(1-methyl)ethyl-1,3-dioxane (140a,b) and 2,2-diethyl-5-ethynyl-1,3-dioxane (159) were developed. The key olefinic spiroketals (3S', 6R', 9R')-9-ethyl-3-hydoxymethyl-1,7-dioxaspiro[5.5]undec-4-ene (125) and (3R')-9-ethyl-3-hydroxymethyl-1,7-dioxaspiro[5.5]undec-4-ene (174) were prepared as a 1:2 mixture in four steps from alkyne (159) and 5-ethyl[2H]pyran-2-one (128). The t-BDMS and benzyl derivatives of spiroketals (125) and (174) were prepared giving (3S', 6R', 9R')-3-[t-butyldimethyl)siloxy]methyl-9-ethyl-1,7-dioxaspiro[5.5]undec-4-ene (175) and (3S', 6R', 9R')-3-benzyloxymethyl-9-ethyl-1,7-dioxaspiro[5.5]undec-4-ene (57), and (3R', 6R', 9R,)-3-[(t-butyldimethyl)siloxylmethyl-9-ethyl-1,7-dioxaspiro[5.5]undec-4-ene (176) and (3R', 6R', 9R')-3-benzyloxymethyl-9-ethyl-1,7-dioxaspiro[5.5]undec-4-ene (205) from (125) and (174) respectively. The hydration of spiroketals (175), (176), (57) and (205) was studied. Talaromycin A and C were prepared from (174) and talaromycin B and E prepared from (125) via a regioselective chlorohydration, reductive de-chlorination and de-protection sequence. Studies towards the total synthesis of ephedradines A-D are described with particular reference to ephedradine C. The tri-protected spermine equivalent N-(tert-butoxylcarbonyl)-11-cyano-4-(p-toluenesulphonyl) diazaundecy-1-amine (286) was prepared. The trans-dihydrobenzo[b]furan (2R', 3R',)-2-(3,4-dimethoxyphenyl)-5-formyl-3-(methoxycarbonyl)-2,3-dihydrobenzo[b]furan (282) was prepared from methyl 2-[2-benzyloxy-5-(dimethoxymethyl)phenyl]-3-(3,4-dimethoxyphenyl)-3-hydroxypropionate (299) via a cationic cyclisation procedure. `Imine-aldol' conditions involving α -unsubstituted enolate equivalents were studied in connection with the construction of the β-aminoamide substructure in the ephedradines. The spermine unit (286) and dihydrobenzo[b]furan moiety (282) were coupled to give N-(tert-butoxycarbonyl)-11-cyano-9- [(2R, 3R)-2-(dimethoxyphenyl)-5-formyl-2,3-dihydrobenzo[b]furan-3-ylcarbonyl]-4-p-toluenesulphonyl-4,9-diazaundecyl-1-amine (311) and construction of the ephedradine skeleton, via an `imine-macrocyclisation' and `imine-aldol' protocol, was investigated. (DX77372)
University of Southampton
1988
Boyes, Alastair Leslie
(1988)
Synthesis of the talaromycins A, B, C and E and synthetic studies towards ephedradine C.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Studies towards the synthesis of talaromycins A, B, C, and E are described. Novel syntheses of the alkynes cis and trans 5-(ethynyl)-2-(1-methyl)ethyl-1,3-dioxane (140a,b) and 2,2-diethyl-5-ethynyl-1,3-dioxane (159) were developed. The key olefinic spiroketals (3S', 6R', 9R')-9-ethyl-3-hydoxymethyl-1,7-dioxaspiro[5.5]undec-4-ene (125) and (3R')-9-ethyl-3-hydroxymethyl-1,7-dioxaspiro[5.5]undec-4-ene (174) were prepared as a 1:2 mixture in four steps from alkyne (159) and 5-ethyl[2H]pyran-2-one (128). The t-BDMS and benzyl derivatives of spiroketals (125) and (174) were prepared giving (3S', 6R', 9R')-3-[t-butyldimethyl)siloxy]methyl-9-ethyl-1,7-dioxaspiro[5.5]undec-4-ene (175) and (3S', 6R', 9R')-3-benzyloxymethyl-9-ethyl-1,7-dioxaspiro[5.5]undec-4-ene (57), and (3R', 6R', 9R,)-3-[(t-butyldimethyl)siloxylmethyl-9-ethyl-1,7-dioxaspiro[5.5]undec-4-ene (176) and (3R', 6R', 9R')-3-benzyloxymethyl-9-ethyl-1,7-dioxaspiro[5.5]undec-4-ene (205) from (125) and (174) respectively. The hydration of spiroketals (175), (176), (57) and (205) was studied. Talaromycin A and C were prepared from (174) and talaromycin B and E prepared from (125) via a regioselective chlorohydration, reductive de-chlorination and de-protection sequence. Studies towards the total synthesis of ephedradines A-D are described with particular reference to ephedradine C. The tri-protected spermine equivalent N-(tert-butoxylcarbonyl)-11-cyano-4-(p-toluenesulphonyl) diazaundecy-1-amine (286) was prepared. The trans-dihydrobenzo[b]furan (2R', 3R',)-2-(3,4-dimethoxyphenyl)-5-formyl-3-(methoxycarbonyl)-2,3-dihydrobenzo[b]furan (282) was prepared from methyl 2-[2-benzyloxy-5-(dimethoxymethyl)phenyl]-3-(3,4-dimethoxyphenyl)-3-hydroxypropionate (299) via a cationic cyclisation procedure. `Imine-aldol' conditions involving α -unsubstituted enolate equivalents were studied in connection with the construction of the β-aminoamide substructure in the ephedradines. The spermine unit (286) and dihydrobenzo[b]furan moiety (282) were coupled to give N-(tert-butoxycarbonyl)-11-cyano-9- [(2R, 3R)-2-(dimethoxyphenyl)-5-formyl-2,3-dihydrobenzo[b]furan-3-ylcarbonyl]-4-p-toluenesulphonyl-4,9-diazaundecyl-1-amine (311) and construction of the ephedradine skeleton, via an `imine-macrocyclisation' and `imine-aldol' protocol, was investigated. (DX77372)
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Published date: 1988
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Local EPrints ID: 460975
URI: http://eprints.soton.ac.uk/id/eprint/460975
PURE UUID: e399804e-c46a-41fb-9743-bd35a4a574ec
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Date deposited: 04 Jul 2022 18:33
Last modified: 04 Jul 2022 18:33
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Author:
Alastair Leslie Boyes
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