Concise formal total synthesis of hybocarpone and related naturally occurring naphthazarins.
A concise formal total synthesis of the cytotoxic bisnaphthazarin derivative hybocarpone has been completed through the development of routes to the synthetic precursor, 3-ethyl-2-hydroxy-5,7,8-trimethoxy-6-methyl-1,4-naphthoquinone. The oxidation of 3-ethyl-1,2,4,5,7,8-hexamethoxy-6-methylnaphthalene under Rapoport conditions gave 3-ethyl-2-hydroxy-5,7,8-trimethoxy-6-methyl-1,4-naphthoquinone in modest yields after basic hydrolysis. In addition, treatment of 3-ethyl-1,2,4,5,7,8-hexamethoxy-6-methylnaphthalene with boron tribromide provided access to the naturally occurring naphthazarin, boryquinone. The analogous oxidative demethylation of 3,6-dimethyl-1,2,4,5,7,8-hexamethoxynaphthalene and 3-ethyl-1,2,4,5,7,8-hexamethoxynaphthalene resulted in the synthesis of 2,5,7,8-tetrahydroxy-3,6-dimethyl-1,4-naphthoquinone (aureoquinone) and 3-ethyl-2,5,7,8-tetrahydroxy-1,4-naphthoquinone, respectively. An alternative selective synthetic route to 3-ethyl-2-hydroxy-5,7,8-trimethoxy-6-methyl-1,4-naphthoquinone was also developed utilizing an intramolecular Claisen condensation of methyl 2-butyryl-3,5,6-trimethoxy-4-methylphenylacetate with concomitant in situ aerial oxidation.
Chai
Christina L L
CL
Department of Chemistry, Australian National University, Canberra ACT 0200, Australia. christina_chai@ices.a-star.edu.sg
Elix
John A
JA
Moore
Felicity K E
FK
D000478:Alkylation; D008011:Lichens / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry*; D010648:Phenylacetates / Q000737:chemistry
D009281:Naphthalenes; D009285:Naphthoquinones; D010648:Phenylacetates; C512017:hybocarpone; C031721:naphthalene; C005503:naphthazarin; C025136:phenylacetic acid