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Biomimetic Total Synthesis of Cyanosporaside Aglycons from a Single Enediyne Precursor through Site‐Selective p ‐Benzyne Hydrochlorination
Author(s) -
Yamada Kei,
Lear Martin J.,
Yamaguchi Takaya,
Yamashita Shuji,
Gridnev Ilya D.,
Hayashi Yujiro,
Hirama Masahiro
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201408416
Subject(s) - chemistry , enediyne , aryne , bicyclic molecule , total synthesis , reactivity (psychology) , dehydrohalogenation , stereochemistry , chlorine , chloride , combinatorial chemistry , medicinal chemistry , organic chemistry , catalysis , pathology , medicine , alternative medicine
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.