Total syntheses of (+)- and (–)- tetrapetalones A and C.


The total syntheses of polyketide natural products (–)-/(+)-tetrapetalone A and (–)-/(+)-tetrapetalone C are described. In 2003, during their pursuit for novel lipoxygenase inhibitors, Hirota and coworkers reported the isolation and characterization of tetrapetalone A from Streptomyces sp. USF-4727 found growing in a soil sample in Yada, Shizouka City, Japan. Subsequent studies in 2004 led to the discovery of three new members of the tetrapetalone family that are each thought to be biosynthetically derived from tetrapetalone A. Common to this family of polyketide natural products, is a unique architecture containing a tetracyclic aglycone that possesses a tetramic acid, an azepine ring fused to a p-quinol, and 5-membered ring linked to a ß-rhodinose moiety. Synthetically, our approach toward the tetrapetalones involves early preparation of a masked tetramic acid unit that is elaborated by way of a Lewis acid promoted conjugate addition. Further oxidation and a Friedel-Crafts acylation reaction lead to an azepine containing intermediate. A variety of strategies were explored to elaborate this versatile compound, with ultimate success hinging upon a key C-H activation that produces a substrate suitable for advancement to the tetracyclic aglycone by way of a classical Heck cyclization reaction. A chiral resolution utilizing an enantiopure glycosyl donor permits not only ß-selective installation of the rhodinose moiety, but also sets the stage for access to enantiopure natural products. The synthesis concludes with an aryl oxidation reaction followed by unveiling the tetramic acid to deliver tetrapetalone A. Further oxidation gives access to tetrapetalone C.