Stereospecific Synthesis of 23-Hydroxyundecylprodiginines and Analogues and Conversion to Antimalarial Premarineosins via a Rieske Oxygenase Catalyzed Bicyclization

Facile and highly efficient synthetic routes for the synthesis of (<i>S</i>)- and (<i>R</i>)-23-hydroxyundecylprodiginines ((23<i>S</i>)-<b>2</b>, and (23<i>R</i>)-<b>2</b>), 23-ketoundecylprodiginine (<b>3</b>), and deuterium-labeled 23-hydroxyundecylprodiginine ([23-<i>d</i>]-<b>2</b>) have been developed. We demonstrated a novel Rieske oxygenase MarG catalyzed stereoselective bicyclization of (23<i>S</i>)-<b>2</b> to premarineosin A (<b>4</b>), a key step in the tailoring process of the biosynthesis of marineosins, using a <i>marG</i> heterologous expression system. The synthesis of various A–C-ring functionalized prodiginines <b>32</b>–<b>41</b> was achieved to investigate the substrate promiscuity of MarG. The two analogues <b>32</b> and <b>33</b> exhibit antimalarial and cytotoxic activities stronger than those of the marineosin intermediate <b>2</b>, against Plasmodium falciparum strains (CQ^S-D6, CQ^R-Dd2, and 7G8) and hepatocellular HepG2 cancer cell line, respectively. Feeding of <b>34</b>–<b>36</b> to Streptomyces venezuelae expressing <i>marG</i> led to production of novel premarineosins, paving a way for the production of marineosin analogues via a combinatorial synthetic/biosynthetic approach. This study presents the first example of oxidative bicyclization mediated by a Rieske oxygenase