Structural Revision, Stereochemical Assignment and Total Synthesis of Gephyronic Acid

STRUCTURAL REVISION, STEREOCHEMICAL ASSIGNMENT AND TOTAL SYNTHESIS OF GEPHYRONIC ACIDAbstractbyLionel NicolasGephyronic acid is natural product exhibiting potent anti-cancer and antibiotic activities. This linear polyketide was isolated in 1995 by Sasse, HÌÄå¦fle and Reichenbach from the myxobacteria Archangium gephyra found in a soil sample collected on the island of Mallorca. Gephyronic acid exists as separable mixture of open keto-alcohol and closed hemiketal, but only its gross structure was reported. Gephyronic acid inhibits growth of yeast and molds (MIC 1Ì¢‰âÂ'25 Ìâåµg/ml) and has a cytostatic effect on several mammalian cell cultures (IC50 10Ì¢‰âÂ'60 ng/mL). In vitro translation assay on rabbit reticulocytes and wheat germ extracts demonstrates that it specifically inhibits eukaryotic protein synthesis; IC50 values of 66Ì¢‰âÂ'80 ng/mL respectively.The lack of knowledge on the absolute stereochemistry severely limits an understanding of its conformational properties, the synthetic preparation of bulk quantities for detailed biological analysis, and the design of analogues for SAR studies. Spectroscopic analysis, confirmed by fragment synthesis, showed that the original structure of gephyronic acid was misassigned. Indeed, the diol moiety present at position C12-C13 is a trisubstituted epoxide. The newly proposed structure of gephyronic acid provides further insights on the structural relation between these related inhibitors of eukaryotic protein synthesis. Structural similarities were found between the C8-C17 region of tedanolide, the C5-C15 region of myriaporone 3/4, and the C13-C23 region of gephyronic acid. Additionally, the closed form of gephyronic acid shows similarities with the pyran region of the pederin class of polyketides. Thus, gephyronic acid represents a potential pharmacophoric link between structurally distinct classes of biological active polyketides with related modes of action.A synthetic effort has also been designed to prepare gephyronic acid. Two equally complex fragments corresponding to the C1-C8 and C9-C17 regions were synthesized. An unprecedented anti-Mukaiyama aldol reaction coupled the two synthetic fragments and deoxygenation provided us with the synthetic product. Matching spectroscopic data with the natural product show that we successfully establish the first total synthesis of gephyronic acid.