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Asymmetric Total Synthesis of Heronamides A–C: Stereochemical Confirmation and Impact of Long‐Range Stereochemical Communication on the Biological Activity
Author(s) -
Kanoh Naoki,
Itoh Shunya,
Fujita Kohei,
Sakanishi Kohei,
Sugiyama Ryosuke,
Terajima Yuta,
Iwabuchi Yoshiharu,
Nishimura Shinichi,
Kakeya Hideaki
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201600569
Subject(s) - stereochemistry , total synthesis , antifungal , biological activity , chemistry , biosynthesis , structure–activity relationship , chemical synthesis , biochemistry , biology , in vitro , enzyme , microbiology and biotechnology
Heronamides are biosynthetically related metabolites isolated from marine‐derived actinomycetes. Heronamide C shows potent antifungal activity by targeting membrane phospholipids possessing saturated hydrocarbon chains with as‐yet‐unrevealed modes of action. In spite of their curious hypothesized biosynthesis and fascinating biological activities, there have been conflicts in regard to the reported stereochemistries of heronamides. Here, we describe the asymmetric total synthesis of the originally proposed and revised structures of heronamide C, which unambiguously confirmed the chemical structure of this molecule. We also demonstrated nonenzymatic synthesis of heronamides A and B from heronamide C, which not only proved the postulated biosynthesis, but also confirmed the correct structures of heronamides A and B. Investigation of the structure–activity relationship of synthetic and natural heronamides revealed the importance of both long‐range stereochemical communication and the 20‐membered macrolactam ring for the biological activity of these compounds.