Stereospecific Synthesis of23-Hydroxyundecylprodigininesand Analogues and Conversion to Antimalarial Premarineosins via aRieske Oxygenase Catalyzed Bicyclization

摘要

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.