Efficient Synthesis of Furochromone and Furocoumarin Natural Products (Khellin, Pimpinellin, Isophellopterin) by Thermal Rearrangement of 4-Furyl-4-hydroxycyclobutenones

Article abstract of DOI:10.1021/jo00253a002

Diethyl squarate was converted in three steps to a highly functionalized benzofuran 6b, which served as an intermediate in a high yield synthesis of khellinone (9), a versatile precursor to a variety of linear furochromones, including the natural product khellin.The use of dimethyl squarate gave a similar benzofuran intermediate 6a, which was used in the first total syntheses of the furocoumarins pimpinellin (14) and isophellopterin (15).The key benzofuran intermediates were prepared by thermal rearrangement of (trimethylsilyl)ethynyl-substituted 4-furanyl-4-hydroxycyclobutenones 2a,b.The alkynyl moiety of 6b was readily converted to the acetyl group of khellinone by mercury-catalyzed hydrolysis.Alternatively, the TMS protecting group in 6a was removed, and the lithium acetylide was treated with methyl chloroformate.The resulting trimethoxybenzofuran was treated with CAN to generate the quinone.Catalytic hydrogenation gave reduction of the quinone to the hydroquinone and alkyne to the cis-alkene.Simultaneous lactonization gave the desired coumarin 13.Methylation of this at the phenolic site gave pimpinellin (14).The same phenol was prenylated to give isophellopterin (15).Finally, oxidation of the phenol with CAN gave a previously unknown orthoquinone, (16), and angular isomer of psoralenquinone.