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

Abstract

The recently isolated bacterial metabolites, belactosins A-C from a fermentation broth of Streptomyces sp. UCK14, uniquely contain a β-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 β-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 β-lactone was isolated in 1986 from Spongi-onellagracilis No biological activity have been reported for this compound; however, the acylating potential of the resident β-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 β-lactone, which is the key structure in the spongiolactone synthesis and only a few steps remained to complete the synthesis.