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

Abstract

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 (CQS-D6, CQR-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.

Structure, Chemical Synthesis, and Biosynthesis of Prodiginine Natural Products

“…Although the marineosins are structurally distinct from other prodiginines, they appear to derive from undecylprodigiosin via a series of redox transformations, including one that is similar to the oxidative carbocyclization reactions involved in streptorubin B and metacycloprodigiosin biosynthesis (see section 4.7). A total synthesis of the two compounds remains elusive, but recent studies by Reynolds and co-workers 92 have established the absolute stereochemistry to be as shown in Figure 25.…”

Prodigiosin Inhibits Proliferation, Migration, and Invasion of Nasopharyngeal Cancer Cells

“…Different substitutions of PG C-6 methoxy could also affect potency. Molecular modification based on these results led to the development of new PG derivatives with higher activity indices than that of parent molecule [18].…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…149) for synthesis of Hagens gland lactones [493]; (8) 1-octene with an amino acid derived acrylate ester [494], and with a homoallylic alcohol derivative [495]; (9) 1-decene with a vinyl-γ-lactone derivative for preparation of disparlures [496]; (10) 1-tridecene with a homoallylic alcohol derivative for preparation of a nonadecylphenol natural product [497], and with an allyl ether connected to a bis(carbohydrate) system (also employs 1-pentadecene or an allylglycerol derivative) [498]; (11) A c c e p t e d M a n u s c r i p t 28 antimalarial premarineosins [508]; (20) benzyl 13-tetradecenoate (158) and an alkene protected polyol derivative (e.g. 157) for total synthesis of penarolide sulfate A2 [509]; (21) a 1,5-diene ester derivative and an allylic alcohol derivative [510]; (22) styrene derivatives with a vinyltetrahydropyran for preparation of rhoiptelol B [511], with allylic diol for preparation of ginger diols [512], and with an alkene-phosphine oxide (e.g.…”