Biomimetic Total Synthesis of Cyanosporaside Aglycons from a Single Enediyne Precursor through Site-Selective p-Benzyne Hydrochlorination

The cyanosporasides A–F are a collection of monochlorinated benzenoid derivatives isolated from the marine actinomycetes Salinispora and Streptomyces sp. All derivatives feature one of two types of cyanocyclopenta[a]indene frameworks, which are regioisomeric in the position of a single chlorine atom. It is proposed that these chloro‐substituted benzenoids are formed biosynthetically through the cycloaromatization of a bicyclic nine‐membered enediyne precursor. Herein, we report the synthesis of such a bicyclic precursor, its spontaneous transannulation into a p‐benzyne, and its differential 1,4 hydrochlorination reactivity under either organochlorine or chloride‐salt conditions. Our bioinspired approach culminated in the first regiodivergent total synthesis of the aglycons A/F and B/C, as well as cyanosporasides D and E. In addition, empirical insights into the site selectivity of a natural‐like p‐benzyne, calculated to be a ground‐state triplet diradical, to hydrogen, chlorine, and chloride sources are revealed. (Di)radical behavior: A close synthetic mimic of an elusive bicyclic nine‐membered enediyne is shown to spontaneously rearrange into a transient p‐benzyne diradical. This diradical reacts both radically (by H ion) and ionically (by Cl addition) at the same sterically exposed C6 site, thus revealing its central role in the biosynthesis of all monochlorinated cyanosporasides A to F.