Total Synthesis of Complex & Unstable Nine-membered Enediynes

The kedarcidin and C1027 chromophores are formidable targets for total synthesis. Herein, we describe viable routes to these highly unstable natural products. Over the 20 or so years of studying these nine-membered enediyne chromophores, several new methods may now be highlighted from our efforts: stereoselective epoxyalkyne formation, atropselective Pd/Cu-Sonogashira coupling, 2-deoxy-α-glycosylation, CeX3-mediated enediyne cyclisation, and SmI2-based reductive olefination. Further application of these methods to the biomimetic study of the putative enediyne-precursors of the cyanosporasides, sporolides, and fijiolides are also summarized. In particular, I will present biomimetic evidence of a p-benzyne diradical species reacting in either a radical mode (hydrogen abstraction) or ionic mode (chloride attack) at the same sterically exposed site, leading to either monochlorinated cyanosporaside A or cyanosporaside B, respectively. The ionic monochlorination of the cycloaromatized p-benzyne of the C1027 enediyne core to generate the fijiolide aglycon framework will also be presented