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



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The recently isolated bacterial metabolites, belactosins A-C from a fermentation broth of Streptomyces sp. UCK14, uniquely contain a ?-lactone dipeptide motif and exhibit anticancer activities. The enantioselective synthesis of (-)-belactosin C and derivatives was accomplished in a concise manner employing the tandem, Mukaiyama aldol-lactonizaton (TMAL) process and test their bioactivities. . One approach involved a distal double diastereoselective TMAL reaction with a dipeptide glyoxamide, whereas a second approach involved amide coupling of a dipeptide with a ?-lactone carboxylic acid, obtained via the TMAL process employing a chiral silyl ketene acetal. Enzymatic assays showed that the belactosins act as the dual inhibitors of the proteasome and the thioesterase domain of fatty acid synthase. Spongiolactone which uniquely contains a cyclopentyl-fused ?-lactone was isolated in 1986 from Spongi-onellagracilis No biological activity have been reported for this compound; however, the acylating potential of the resident ?-lactone warrants screening 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 the spongiolactone synthesis and only a few steps remained to complete the synthesis.