Synthesis of ent-Nanolobatolide

摘要

Neurodegeneration is a physiological phenomenon characterized by the progressive loss either of neurons or their function. The prevalence of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, has placed an ever-increasing burden on the healthcare system as a result of the debilitating social and economical impact of these diseases. Indeed, the search for effective therapeutic intervention for these detrimental diseases continues to be of high priority on the global health agenda, and the identification of novel chemical entities that possess neuroprotective properties has an undisputed role in this context. In 2009, Sheu and co-workers reported the isolation and structural elucidation of nanolobatolide, a novel C18 terpenoid obtained from the extracts of Formosan soft coral Sinularia nanolobata. Besides its structural intricacy, the biological effects of nanolobatolide on the neurological system were particularly fascinating. At a concentration of 10 μm, nanolobatolide not only displayed a cytotoxic effect against microglial cells, but was also found to exhibit anti-neuro-inflammatory activity with a 45.5 reduction in the INF-γ stimulated expression of proinflammatory protein iNOS relative to the control cells, which were treated only with INF-γ. Furthermore, nanolobatolide showed a neuroprotective effect in the 6-OHDA (6-hydroxydopamine) induced neurotoxicity of neuroblastoma SH-SY5Y, with neuroprotective activities ranging between 41.4 and 83.3 across the 0.01-10 um concentration range. The novel molecular architecture of nanolobatolide, coupled with its impressive biological properties, prompted us to undertake its synthesis. Herein we report the total synthesis of entnanolobatolide ((—)-1; Scheme 1), through a strategy that also provided evidence in support of its biogenetic origin.