The bisspiroketal moiety of epi-17-Deoxy-(0-8)-salinomycin : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University
| dc.contributor.author | Williams, Geoffrey Martyn | |
| dc.date.accessioned | 2013-03-21T03:23:19Z | |
| dc.date.available | 2013-03-21T03:23:19Z | |
| dc.date.issued | 1991 | |
| dc.description.abstract | The synthesis of 2-(3,4-epoxy-3-methylbutan-1-yl)-1 ,7 -dioxaspiro[S.S]undec-4-ene 188 is described, the key step in it's formation being an addition of the lithium acetylide derivative of S-tert-butyldiphenylsilyloxy-2-methyl-2-trimethylsilyloxy-7 -octyn-1-ptoluenesulphonate 182 to o-valerolactone. The epoxide 188 was then converted to the hydroxy spiroketal 4-(1,7-dioxaspiro[S.S]undec-4-en-2-yl)-2-methyl-2-butanol 149 which underwent a Barton-type oxidative cyclisation to afford both the cis- and trans-2,2-dimethyl- 1,6,8-trioxadispiro[ 4.1.S.3]pentadec-13-enes 192 and 152. The ring system of this latter compound is analogous to the unsaturated bisspiroketal present in the polyether antibiotic epi-17-deoxy-(0-8)-salinomycin 8. Subsequently the route was modified to afford the trans- and cis-(2-methyl-1,6,8- trioxadispiro[4.1.S.3]pentadec-13-en-2-yl)methanols 211-214, since it was expected this terminal hydroxyl group would provide a 'handle' by which these molecules could be further elaborated. This required conversion of the epoxide 1 8 8 t o 4-(1,7- dioxaspiro[S.S]undec-4-en-2-yl)-1-iodo-2-methyl-2-butanol 200, which was followed by a Barton-type oxidative cyclisation, to give the cis- and trans-2-iodomethyl-2-methyl-1,6,8- trioxadispiro[4.1.S.3]pentadec-13-enes 201-204, which were then converted to the alcohols 211-214. The techniques used to construct these relatively simple bisspiroketal analogues were then applied to an enantioselective synthesis of the bisspiroketal portion of epi-17 -deoxy-(0- 8)-salinomycin. The two key intermediates required for this were (l'S, 3R, SS, 6S)-(+)-6- [1'-(tert-butyldiphenylsilyloxymethyl)propyl]-3,S-dimethyl-tetrahydropyran-2-one 84 and (SR, 2S)- and (SS, 2S)-2-methyl-2,S-bis(trimethylsilyloxy)-7-octyn-1-p-toluenesulphonate 231. The lactone 84 was prepared, using Evans' directed aldol methodology, from (4R, SS)-(+ )-4-methyl-3-(1'-oxobutyl)-S-phenyloxazolidin-2-one 219 and (S)-( + )-2,4-dimethyl- 4-pentenal 218. The acetylene 231 was prepared from levulinic acid 174, and the procedure incorporated a resolution step which enabled the 2S configuration of 231 to be introduced. The lactone 84 and the the lithium acetylide derivative of acetylene 231 were combined and subsequently converted to the (1"S, 2S, 2'S, 6'R, 8'S, 9'S, ll'R)-(-)- and (l"S, 2S, 2'R, 6'R, 8'S, 9'S, ll'R)-(+)-4-{8-[1-(tert-butyldiphenylsilyloxymethyl)propyl] -9,11-dimethyl-1,7 -dioxaspiro[S.S]undec-4-en-2-yl}-1-iodo-2-methyl-2-butanols 245 and 246. These hydroxy spiroketals were transformed, again using the Barton-type oxidative cyclisation methodology, to the cis-(l'S, 2S, SR, 7S, 9S, lOS, 12R)-(-)- and the trans( l'S, 2S, SS, 7S, 9S, lOS, 12R)-(-)-9-[l-(tert-butyldiphenylsilyloxymethyl)propyl]-2- iodomethyl-2,10,12-trimethyl-1 ,6,8-trioxadispiro[ 4.1.S.3]pentadec-13-ene 248 and 247, the latter of which resembles precisely the corresponding portion of epi-17-deoxy-(0-8)salinomycin. In addition, the termini of the bisspiroketal 247 are selectively functionalised, which will allow further elaboration to the entire natural product 8. The synthesis of the cis- and trans- 2, 2 - dimethyl-1S-hydroxy-1, 6, 8 - trioxadispiro[4.1.S.3]pentadec-13-enes 156 and 159, and of cis-2,2-dimethyl-13-hydroxy- 1,6,8-trioxadispiro[4.1.S.3]pentadec-14-ene 268 is described. These were formed firstly by allylic bromination of the cis- and trans-2,2-dimethyl-1,6,8-trioxadispiro[4.1.S.3]pentadec- 13-enes 192 and 152 to give the cis- and trans-1S-bromo - 2 , 2- dimethyl - 1 , 6 , 8- trioxadispiro[ 4.1.S. 3 ]pentadec-13-enes 262 and 265, and cis-13-bromo-2,2-dimeth y l- 1,6,8-trioxadispiro[4.1.S.3]pentadec-14-ene 261. These bromides were then displaced by an oxygen nucleophile to afford the alcohols 268, 156, 159, a procedure which involved both SN2 and anti-SN2' processes. | en |
| dc.identifier.uri | http://hdl.handle.net/10179/4231 | |
| dc.language.iso | en | en |
| dc.publisher | Massey University | en_US |
| dc.rights | The Author | en_US |
| dc.subject | Antibiotics | en |
| dc.subject | Carboxylic acids | en |
| dc.subject | Ethers | en |
| dc.subject | Ionophores | en |
| dc.title | The bisspiroketal moiety of epi-17-Deoxy-(0-8)-salinomycin : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University | en |
| dc.type | Thesis | en |
| massey.contributor.author | Williams, Geoffrey Martyn | en |
| thesis.degree.grantor | Massey University | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) | en |
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