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

Angewandte Chemie International Edition
2014.0

Abstract

<jats:title>Abstract</jats:title><jats:p>The cyanosporasides A–F are a collection of monochlorinated benzenoid derivatives isolated from the marine actinomycetes <jats:italic>Salinispora</jats:italic> and <jats:italic>Streptomyces</jats:italic> sp. All derivatives feature one of two types of cyanocyclopenta[<jats:italic>a</jats:italic>]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 <jats:italic>p</jats:italic>‐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 <jats:italic>p</jats:italic>‐benzyne, calculated to be a ground‐state triplet diradical, to hydrogen, chlorine, and chloride sources are revealed.

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