Synthesis of a regioisomer of the 3C-protease inhibitor (-)-thysanone

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dc.contributor.advisor Woodgate, P. D. en
dc.contributor.advisor Brimble, M. en Houghton, Scott Ian en 2020-06-02T04:39:35Z en 2020-06-02T04:39:35Z en 2005 en
dc.identifier.uri en
dc.description Full text is available to authenticated members of The University of Auckland only. en
dc.description.abstract The first two sections of this thesis describe two approaches to the synthesis of (-)-thysanone 1 (Diagram 1), the first via a Diels-Alder cycloaddition strategy, the second via using a Hauser annulation strategy. The third section reports the synthesis of the 6,8-dimethoxy regioisomer 303 of (-)-thysanone 1 using a Hauser annulation strategy. The Diels-Alder approach (Scheme 2) to (-)-thysanone 1 started with oxidation of nitrophenol 147 to 2,6-dibromobenzoquinone 146 and subsequent reduction and selective methylation at 04 to give 3,5-dibromo-4-methoxyphenol 156. Allylation gave 3,5-dibromo-4-methoxyphenyl allyl ether 153, which after laisen rearrangement gave 2-allyl-3,5-dibromo-4-methoxyphenol 159. Oxidation of methoxyphenol 159 to give quinone 138 and Diels-Alder cycloaddition with 1,3-bis(trimethylsiloxy)-l-methoxybuta-1,3-diene 137 gave 2-allyl-3-bromo-5,7-dihydroxy-1,4-naphthoquinone 174. 1,3-Bis(trimethylsiloxy)-1 -methoxybuta-1,3-diene 137 was synthesised from methyl acetoacetate 145 in two steps. Difficulties encountered in the synthesis of 2-allyl-3-bromo-5,7-dihydroxy-l,4-naphthoquinone 174 and subsequent protection of the free hydroxy groups in naphthoquinone 174 caused the abandonment of this strategy in favour of a phthalide annulation strategy. The second approach to (-)-thysanone 1 using a Hauser annulation strategy (Scheme 3) started from 2,4-dihydroxybenzoic acid 232, which was methylated to give 2,4-dimethoxybenzoic acid 231. Benzoic acid 231 was converted to A A-diethyl 2.4- dimethoxybenzamide 230 and formylated to give A,A-diethyl 2,4-dimethoxy-6-formylbenzamide 229. Hydrolysis led to the formation of 3-hydroxy-5,7-dimethoxy-(3A)-isobenzofuran-l-one 228 which was converted to 3-cyano-5,7-dimethoxy-(37/)-isobenzofuran-l-one 226. Hauser annulation with acrylonitrile 227 gave 2-cyano-l,4-dihydroxy-6,8-dimethoxynaphthalene 253 in very poor yield. Annulation with ethyl acrylate 185 gave ethyl l,4-dihydroxy-6,8-dimethoxynaphthalene-2-carboxylate 255 in an acceptable yield. Naphthalene 255 was oxidised to give ethyl 6,8-dimethoxy-1.4- naphthoquinone-2-carboxylate 274, which was acetonylated to give ethyl 3-acetonyl-6,8-dimethoxy-1,4-naphthoquinone-2-carboxylate 282. Difficulties experienced in the synthesis, particularly the Hauser annulation led to the failure of this approach. An alternative route via addition of A,A-diethyl 2,4-dimethoxy-6-methylbenzamide 292 to a pyranone (Scheme 4) was also investigated with no success. The third chapter makes use of a Hauser annulation strategy to prepare the 6,8-dimethoxy regioisomer 303 of (-)-thysanone 1 (Scheme 5). In an analogous manner to the preceding chapter, 3,5-dimethoxy benzoic acid 315 was converted to 3-cyano-4,6-dimethoxy(37Z)-isobenzofuran-l-one 311. Annulation with ethyl acrylate 185 led to the formation of ethyl l,4-dihydroxy-5,7-dimethoxynaphthalenalene-2-carboxylate 310. Oxidation gave ethyl 5,7-dimethoxy-l,4-naphthoquinone-2-carboxylate 309 which was allylated to give ethyl 3-allyl-5,7-dimethoxy-l,4-naphthoquinone-2-carboxylate 308. Reductive methylation gave ethyl 3-allyl-l,4,5,7-tetra methoxynaphthalene-2-carboxylate 307, which was converted to ethyl 3-acetonyll, 4,5,7-tetramethoxy-l,4-naphthalene-2-carboxylate 306. Chiral reduction gave (2 \S')-ethyl 3 -(2'-hydroxypropyl)-1,4,5,7-tetramethoxynaphthalene-2-carboxylate 305 in 65 % e.e., which was cyclised to give (3S)-3-methyl-5,6,8,10-tetramethoxynaphtho-[2,3-c]-pyran-l-one 333. The lactone was reduced to (1 S,3S)-1 -hydroxy-3 -methyl-5, 6,8,10-tetramethoxynaphtho-[2,3-c]-pyran 304 and oxidised to give (15,35)-6,8-dimethoxy-1 -hydroxy-3 -methylpyrano [2,3 -c] -1,4-naphthoquinone 303. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA99161557714002091 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. en
dc.rights Restricted Item. Full text is available to authenticated members of The University of Auckland only. en
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dc.title Synthesis of a regioisomer of the 3C-protease inhibitor (-)-thysanone en
dc.type Thesis en Chemistry en The University of Auckland en Doctoral en PhD en
dc.rights.holder Copyright: The author en

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