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

[Image: see text] Facile and highly efficient synthetic routes for the synthesis of (S)- and (R)-23-hydroxyundecylprodiginines ((23S)-2, and (23R)-2), 23-ketoundecylprodiginine (3), and deuterium-labeled 23-hydroxyundecylprodiginine ([23-d]-2) have been developed. We demonstrated a novel Rieske oxygenase MarG catalyzed stereoselective bicyclization of (23S)-2 to premarineosin A (4), a key step in the tailoring process of the biosynthesis of marineosins, using a marG heterologous expression system. The synthesis of various A–C-ring functionalized prodiginines 32–41 was achieved to investigate the substrate promiscuity of MarG. The two analogues 32 and 33 exhibit antimalarial and cytotoxic activities stronger than those of the marineosin intermediate 2, against Plasmodium falciparum strains (CQ(S)-D6, CQ(R)-Dd2, and 7G8) and hepatocellular HepG2 cancer cell line, respectively. Feeding of 34–36 to Streptomyces venezuelae expressing marG 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.