Synthesis and Biological Evaluation of Gephyronic Acid Derivatives: Initial Steps towards the Identification of the Biological Target of Polyketide Inhibitors of Eukaryotic Protein Synthesis

Coupled to the development of a total synthesis of gephyronic acid, a series of diastereomeric analogues and their precursors have been prepared by employing complementary aldol strategies for the key coupling step of fragments 4 and 5 . A biological evaluation revealed the importance of the epoxide for the cytotoxicity against L‐929 (mouse fibroblast) and KB‐3‐1 (HeLa clone, human cervix carcinoma derived) cell lines. Moreover, variation of the configuration of the C3–C5 stereotriad and the C1 carboxylic acid were found to be important features. Improved activities compared with the natural product were observed when the carboxy terminus at C1 was replaced by a methyl ester or PMB‐protected alcohol. Surprisingly, the derivatives (8 R )‐ 17d and (8 S )‐ 16a showed antibacterial activity against Pseudomonas aeruginosa .