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

Halenaquinol及其硫酸盐是由Kitagawa等人于1985年从冲绳海绵Xestospongia Sapra中分离得到的。这些有趣的海洋天然产物具有显著的生物活性，如细胞毒性、抗生素蛋白酪氨酸激酶抑制活性，特别是硫酸钠具有独特的抗病毒活性。我们设计了一种基于硫酸钠结构的呋喃稠合多环化合物作为一种新型的抗病毒剂，并应用邻喹喹基甲烷化学作为构建上述多环环体系的关键步骤。苯并环丁烯是奥喹唑烷的前体，它们的热反应进行得很好，得到了分子内[4+2]环加成产物作为单一异构体。通过X-射线分析，确定了新形成的四氢呋喃、苄基和二氢呋喃位置的立体化学为顺式。这种立体选择性可以通过逆电子要求的Diels-Alder反应中的缺电子邻喹氨基甲烷环和富电子呋喃环之间的二次轨道效应来解释。因此，反应通过endo过渡态进行，得到顺式产物。在所合成的化合物中，TIPS衍生物对仙台病毒具有显著的抗病毒活性，当浓度大于1.25μg/mL时，对病毒的生长有抑制作用。

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.