Homo-Clavulyne: Evaluation of a One-Atom Ring Expansion Strategy to Stabilize the Nine-Membered Ring Enediyne Biosynthetic Precursor

Abstract Streptomyces clavuligerus biosynthesizes a nine-membered ring enediyne that spontaneously cycloaromatizes to a 1,4-benzenoid diradical enroute to the clavulynes. Since nature also produces several isolable and exceedingly cytotoxic metabolites featuring 10-membered ring enediynes, we reasoned that a ring-expanded “homo-clavulyne” enediyne might be accessible by the concepts and methods of organic synthesis, isolable, and useful as a new molecular warhead with therapeutic applications. The design of a 10-membered ring homo-clavulyne enediyne and our circumstantial evidence for its existence are described herein.