Angewandte Chemie - International Edition p. 1030 - 1035 (2016)
Update date:2022-08-05
Topics:
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.
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. Take my breath away: Rakicidin A, a depsipeptide natural product with hypoxia-selective antitumour activity, is comprised of a ring system containing sensitive and congested functionalities. A modular asymmetric synthesis and initial biological evaluation of the natural product, and the discovery of a simplified analogue displaying strongly enhanced hypoxia selectivity is reported.
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