Total Synthesis and Immunosuppressive Activity of (−)-Pateamine A and Related Compounds:  Implementation of a β-Lactam-Based Macrocyclization

The asymmetric synthesis of the potent immunosuppressive agent (−)-pateamine A isolated from the marine sponge Mycale sp. is described. A key strategy employed in the synthesis was a β-lactam-based macrocyclization to form the 19-membered dilactone macrolide. The synthesis confirms the relative and absolute stereochemistry as 3R,5S,10S,24S and sets the stage for studies into the mechanism of action of pateamine A. Other studies and findings made in the course of the synthesis and described herein include the following: (1) a Stille coupling can be competitive with π-allyl formation, (2) SmI2 effects a mild N−O cleavage of N-benzyloxy-β-lactams, (3) the synthesis of a pateamine A-dexamethasone hybrid molecule for use in a yeast three-hybrid assay was accomplished, and (4) IC50 values were determined for synthetic and natural pateamine A and related compounds in the interleukin 2 reporter gene assay.