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Total Synthesis and Biological Evaluation of Rakicidin A and Discovery of a Simplified Bioactive Analogue
Author(s) -
Tsakos Michail,
Clement Lise L.,
Schaffert Eva S.,
Olsen Frank N.,
Rupiani Sebastiano,
Djurhuus Rasmus,
Yu Wanwan,
Jacobsen Kristian M.,
Villadsen Nikolaj L.,
Poulsen Thomas B.
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201509926
Subject(s) - chemistry , depsipeptide , aldol reaction , polyketide , total synthesis , combinatorial chemistry , stereochemistry , enantioselective synthesis , coupling reaction , biological activity , organic chemistry , biochemistry , biosynthesis , in vitro , catalysis , enzyme
We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem‐like leukemia cells. Key transformations include a diastereoselective organocatalytic cross‐aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist‐type Horner—Wadsworth—Emmons (HWE) macrocyclization, and a new DSC‐mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia‐selective activity.