The synthesis of 9-O-Methylpaepalantine and Dehydroxanthomegnin: Related Isocoumarin-Containing Natural Products

The first synthesis of two related isocoumarin-containing natural products, 9-O-methylpaepalantine and dehydroxanthomegnin is described. Commencing with 2,4-dimethoxybenzaldehyde and utilizing the Stobbe reaction as a key step resulted in the formation of the required naphthalene containing compound, ethyl 4-acetoxy-3-allyl-6,8-dimethoxynaphthalene-2-carboxylate. O-Allylation of 4-hydroxy-6,8-dimethoxynaphthalene-2-carboxylate followed by a Claisen rearrangement afforded the naphthol, ethyl 3-allyl-4-hydroxy-6,8-dimethoxynaphthalene-2-carboxylate. Introduction of a methoxy substituent onto the 1-position of the naphthalene nucleus utilizing a PIFA-mediated method afforded, after O-methylation, ethyl 3-allyl-1,4,6,8-tetramethoxynaphthalene-2-carboxylate. Reduction of the ester was followed by oxidation to the aromatic acid, utilizing firstly a PCC oxidation and then a Pinnick oxidation to afford 3-allyl-1,4,6,8-tetramethoxynaphthalene-2-carboxylic acid. Wacker oxidation of the aromatic acid resulted in the formation of 5,7,9,10-tetramethoxy-3-methyl-1H-benzo[g]isochromen-1-one, which was then converted into 9-O-methylpaepalantine by treatment with boron trichloride. Utilizing similar synthetic methodology dehydroxanthomegnin was synthesized in thirteen steps commencing from 2,4,5-trimethoxybenzaldehyde in an overall yield of 1.3 %.