Richard Dehn

Molecular Basis of Elansolid Biosynthesis: Evidence for an Unprecedented Quinone Methide Initiated Intramolecular Diels–Alder Cycloaddition/Macrolactonization

Elansolids A1/A2 (1) and B1–B3 (2–4) and the structurally unusual and highly reactive elansolid A3 (5) are new metabolites from the gliding bacterium Chitinophaga sancti (formerly Flexibacter spec. ; Scheme 1). While elansolid A2 (1*) shows antibiotic activity against Gram-positive bacteria in the range of 0.2 to 64 mgmL 1 and cytotoxicity against L929 mouse fibroblast cells with an IC50 value of 12 mgmL , the atropisomer elansolid A1 (1) is significantly less active. 3] The elansolids feature a bicyclo[4.3.0]nonane core which in the case of elansolids A1/A2 is part of a 19-membered macrolactone. Elansolid B1 is the corresponding seco acid of elansolids A1/A2, while the elansolids B2 and B3 are workup artifacts that result from nucleophilic addition of methanol and NH3, respectively, to

Elansolid A, a Unique Macrolide Antibiotic from Chitinophaga sancti Isolated as Two Stable Atropisomers†

Bacterial species of the genera Flexibacter and Chitinophaga are known to produce biologically active peptides of relevance to anti-infective research because of their interesting mechanisms of action. For instance, the formadicins, monocyclic b-lactam antibiotics from Flexibacter alginoliquefaciens, act selectively against pseudomonads and have proven to be hydrolysis-resistant against various types of b-lactamases. The anti-MRSA dipeptides TAN-1057A–D isolated from Flexibacter sp. were shown to inhibit peptide elongation during the bacterial translation. Early work on Flexibacter strains by Steinmetz, Gerth, and H fle resulted in the isolation of a group of novel metabolites named elansolids. The planar structure of the major component was elucidated by spectroscopic methods, degradation by cross-methathesis with ethylene, and biosynthetic reasoning as elansolid A1 (1). Later, in the course of our biological screening of extracts from non-myxobacterial gliding bacteria we re-investigated in depth the family of elansolids produced by Flexibacter sancti, a species recently reclassified as Chitinophaga sancti (comb. nov.). The elansolids are the first polyketide-derived macrolides from the genus Chitinophaga.

Precursor-Directed Syntheses and Biological Evaluation of New Elansolid Derivatives

The antibiotic elansolid C1 (8) was isolated from Chitinophaga sancti strain FxGBF13 after fermentation in the presence of anthranilic acid. Remarkably, 8 was also obtained by addition of anthranilic acid to a crude fermentation extract containing the macrolide elansolid A2 (1*). This Michael‐type conjugate addition allowed us to generate 21 new derivatives of elansolid C1 (9–29) by using various nucleophiles. Biological activities of all derivatives were evaluated against Staphylococcus aureus, Micrococcus luteus, and the mouse cell line L929.

Total Synthesis of the Antibiotic Elansolid B1

The antibiotic elansolid B1 was prepared by a convergent strategy that relied on a highly diastereoselective, biomimetic intramolecular Diels-Alder cycloaddition (IMDA) that furnished the tetrahydroindane unit. Other key features are a double Sonogashira cross-coupling and a substrate-controlled Yamamoto aldol reaction.

Total and Semi-Syntheses of Antimicrobial Thuggacin Derivatives

The total and semi-synthesis of 13 new macrolactones derived from thuggacin, which is a secondary metabolite from the myxobacterium Sorangium cellulosum, are reported. The thuggacins have attracted much attention due to their strong antibacterial activity, particularly towards Mycobacterium tuberculosis. This study focuses on 1) thuggacin derivatives that cannot equilibrate by transacylation between the three natural thuggacins A-C, 2) the roles of the thiazole ring, and 3) the hexyl side chain at C2. Semi-synthetic O-methylation at C17 suppressed the transacylations without a substantial loss of antibacterial activity. Exchanging the C17-C25 side chain for simplified hydrophobic chains led to complete loss of antibacterial activity. Exchange of the thiazole by an oxazole ring or removal of the hexyl side chain at C2 had no substantial effect on the biological properties.