Enantioselective total synthesis of (+)-ieodomycin A, (+)-ieodomycin B, and their three stereoisomers.

We describe a divergent and enantioselective total synthesis of (+)-ieodomycin A and (+)-ieodomycin B with three stereoisomers. The main advantage of the present synthesis is the late-stage elaboration of the side chain, which would afford a wide range of structurally diverse analogs with interesting bioactivities.

Total Synthesis and Bioactivity Profile of (+)-Ieodomycins A and B and their Stereoisomers.

Herein, we report the first- and second-generation syntheses of (+)-ieodomycins A and B and their stereoisomers via the late-stage elaboration of their conjugated E-diene side chains. Key steps for successful synthesis included Keck asymmetric allylation to introduce a hydroxyl group at the C5 position, consecutive Wipf's carboalumination modification, iodination, Sharpless asymmetric dihydroxylation, one-carbon homologation via cyanation, Mukaiyama lactonization, and Stille cross-coupling to form the conjugated E-diene moiety. Further, the preliminary in vitro bioactivity profile against various disease-related molecular targets and cell lines was investigated. Results indicated that compounds 30b and 30c, diastereoisomers of (+)-ieodomycin B (2), serve as α-glucosidase inhibitors, while compounds 30b and 30d inhibit the angiotensin-converting enzyme.