A synthetic approach to 3-acyltetramic acid and application to the total synthesis of Epicoccamide D

Naturally accoutring 3-acyltetramic acids1,2 (3-acylpyrrolodin-2,4diones, 1) are core structural skeletons that have been found in various biological active products, such as magnesidin A(antibiotic activity)3a, tenuazonic acid (antiviral and antitumor activity)3b, Sch 213766 (anti-HIV activity)3C, the melophlins (antitumor activity)3d, and the macrocidins ( herbicidal activity). 3f Three new tetramic acid derivatives, epicoccamides B-D, have recently been isolated from an Epicoccum sp. associated with the tree fungus Pholiota squarrosa. The derivative with the longest chain, epicoccamide D, induces morphogenesis and pigment formation in surface cultures of fungus Phoma destructive at concentration of 1.7nM. Despite the great significance of 3-acyltetramic acids, the development of a comprehensive and general protocol for the synthesis of this type of compounds has substantially not been achieved.4-10 We have developed an efficient synthetic sequence for the construction of N-methyl- 3-acylteramic acids. The strategy was applied to the synthesis of the natural compound Epicoccamide