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

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.