Synthetic Studies on Furan-fused Polycyclic Natural Products and Its Derivatives

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Halenaquinol and sodium salt of its sulfate were isolated from the Okinawan sponge Xestospongia sapra by Kitagawa and co-workers in 1985. These interesting marine natural products possess the significant biological activities such as cytotoxic, antibiotic protein tyrosine kinase inhibitory activities, especially, the sodium salt of sulfate showed unique anti-virus activity. We designed the furan-fused polycyclic compound based on the structure of sodium salt of sulfate as a new type of anti-virus agent, and applied the o-quinozimethane chemistry as the key step for the construction of the above polycyclic ring system. The thermal reaction of the benzocyclobutenes, precursors of oquinozimethane, proceeded nicely to give the intramolecular [4+2] cycloaddition products as a single isomers. The stereochemistry at the newly formed quartanary benzylic and dihydrofuran position was determined to be cis form by an X-ray analysis. This stereoselectivity could be rationalized in term of secondary orbital effect between the electron deficient o-quinozimethane ring and electron rich furan ring in the retro-electron-demanded Diels-Alder reaction. Consequently, the reaction proceeded via the endo transition state to afford the cis products. Among the compound synthesized above, the TIPS derivative showed significant activity against Sendai virus, and inhibited the growth of the virus at the concentration more than 1.25μg/mL.