A Unified Approach for the Stereoselective Total Synthesis of Pyridone Alkafoids and Their Neuritogenic Activity

摘要

The enhancement of cognitive function, memory, and learning in healthy human subjects by application of chemical compounds is becoming more prevalent in our knowledge-focused society. The use of such compounds also constitutes a promising approach to address the deleterious effects of neurodegenerative diseases.In the search for novel lead structures traditional medicine is an important resource. For instance in China, entomopathogenic fungi such as Cordyceps and their extracts have been used for centuries to strengthen the immune system and improve cognitive function. Many of these fungi contain pyridone alkaloids, for example, pretenellin B (1), tenellin (2), and bassianin (4). A few years ago Hamburger and co-workers disclosed the structures of additional representatives isolated from the entomopathogenic fungi Paecilomyces farinosus and Paecilomyces militaris: the farinosones A (5) and B (6) as well as militarinone D (9). Farinosone A (5) induces and enhances neurite outgrowth in the PC-12 cell line, which would be in line with the postulated positive effects on learning and cognition. However, it remains unclear, whether pyridone alkaloids—in particular (pre)-tenellin B, (pre)-bassianin, and militarinone D—generally display neuritogenic activity. To address this question, a unified synthetic approach towards the total synthesis of this family of natural products would be desirable and would also provide access to putative natural products such as pyridones 3, 7, and 8.