Total syntheses of ?-lactone containing natural products: I. total synthesis of belactosin C II. synthetic studies toward spongiolactone

摘要

The recently isolated bacterial metabolites, belactosins A-C from a fermentationbroth of Streptomyces sp. UCK14, uniquely contain a ?-lactone dipeptide motif andexhibit anticancer activities. The enantioselective synthesis of (-)-belactosin C andderivatives was accomplished in a concise manner employing the tandem, Mukaiyamaaldol-lactonizaton (TMAL) process and test their bioactivities. . One approach involveda distal double diastereoselective TMAL reaction with a dipeptide glyoxamide, whereasa second approach involved amide coupling of a dipeptide with a ?-lactone carboxylicacid, obtained via the TMAL process employing a chiral silyl ketene acetal. Enzymaticassays showed that the belactosins act as the dual inhibitors of the proteasome and thethioesterase domain of fatty acid synthase.Spongiolactone which uniquely contains a cyclopentyl-fused ?-lactone wasisolated in 1986 from Spongi-onellagracilis No biological activity have been reportedfor this compound; however, the acylating potential of the resident ?-lactone warrantsscreening for potential activity. After many setbacks in the synthesis of spongiolactone,significant progress has been made. Importantly, NCAL process also enabled a concise construction of [3.2.0]-bicyclo ?-lactone, which is the key structure in thespongiolactone synthesis and only a few steps remained to complete the synthesis.