Studies On Total Synthesis Of Chaetoglobins A And B,Two Representative Dimeric Azaphilonoids

Azaphilonoids are a unique family of natural polyketides generated by terrestrial or marine fungi.Nearly 400 azaphilonoids have been isolated and characterized in the literatures.Many of these compounds have been reported to exihibit a wide spectrum of important physiological activities,while,very limited advances have been achieved in medicinal research and organic synthesis.Chaetoglobins A and B were isolated from the endophytic Chaetomium globosum by the Tan Renxiang's research group of Nanjing University in 2008.Both of them were found to present biological activities and novel structural characteristics.Among them,the dimeric alkaloid chaetoglobin A significantly inhibits cell proliferation of breast cancer cells MCF-7 and intestinal cancer cells SW1116.chaetoglobins A and B are characterized with the dimeric azaphilone core structure and linked linked by an sp2C-sp2 C bond.The C2-symmetrical structures contain four stereogenic carbo-center and one axial chirality.In recent years,our research group has successfully achieved the total synthesis of chaetoglobin A via a dehydrative oxidative coupling reaction of phenolic precursors,and unambiguously assigned the absolute stereochemistry of the two natural products by aid of X-ray crystallographical analysis.However,poor stereochemical controls in the key reactions still remains as a problem in the total synthesis yet.In this work,we continued to study a new efficient total synthesis of chaetoglobins A,using the intramolecular asymmetric aryl-aryl oxidation coupling and futher bi-directional modification of the side chains of dimeric precursor.The expected optically pure diphenolic precursor was successfully achieved.Futher formylation on the aromatic ring and oxidative dearomatization successfully afforded the azaphilone core.The late-stage synthesis toward an asymmetric synthesis is still in progress.