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

Abstract

Elansolids A1/A2 (1) [1] and B1-B3 (2-4) and the structurally unusual and highly reactive elansolid A3 (5) [2] 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 mg mL À1 and cytotoxicity against L929 mouse fibroblast cells with an IC 50 value of 12 mg mL À1 , the atropisomer elansolid A1 (1) is significantly less active. [2,3] 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 NH 3 , respectively, to

Precursor‐Directed Syntheses and Biological Evaluation of New Elansolid Derivatives

“…In our previous report, we showed that 1 and 1* differ in their biological activity 1. Both showed the lowest MIC against M. luteus (MIC 0.3 μg mL −1 for 1* , 1 was less active); against methicillin‐resistant S. aureus MRS3, 1* had a MIC of 4.2 μg mL −1 while 1 showed no growth inhibition up to 33 μg mL −1 .…”

“…Both showed the lowest MIC against M. luteus (MIC 0.3 μg mL −1 for 1* , 1 was less active); against methicillin‐resistant S. aureus MRS3, 1* had a MIC of 4.2 μg mL −1 while 1 showed no growth inhibition up to 33 μg mL −1 . Noteworthy, elansolid A2 ( 1* ) and the quinone methide A3 ( 7 ) had identical MICs, but differed in their cytotoxicity:2 against the mouse fibroblast cell line L929, 1* showed cytotoxicity at 12 μg mL −1 , 7 was less toxic (33 μg mL −1 ), and 1 was nontoxic up to 40 μg mL −1 1. 2…”

“…Recently, the first polyketide antibiotic from the gliding bacterium Chitinophaga sancti (formerly Flexibacter sancti ) was reported as elansolid A ( 1 ). Remarkably, elansolid A ( 1 ) occurs as two distinct atropisomers, A1 and A2 ( 1 and 1* ), with a differently folded macrolide ring 1. During isolation of 1 / 1* from the fermentation extracts, three ring‐opened analogues, elansolids B1 to B3 ( 2 – 4 ), were isolated.…”

Discoipyrroles A–D: Isolation, Structure Determination, and Synthesis of Potent Migration Inhibitors from Bacillus hunanensis

“…Other examples of de novo non-enzymatic natural products synthesis include jadomycin (DNA alkylator) 20 , elansolid (antibiotic) 21 and the ammosamides (quinone reductase 2 inhibitors, myosin modifiers). 22 In these examples, the non-enzymatic reaction pathway has been exploited to generate analogs with enhanced biological activity.…”

Lessons and revelations from biomimetic syntheses

“…In situ cycloisomerization of 70 and simultaneous dehydration and dearomatization of a synthon corresponding to 71 would produce exocyclic enol ether (74) and o-quinone methide (75), respectively. These would be primed for intermolecular hetero-Diels-Alder cycloaddition to assemble the berkelic acid skeleton 102 . Indeed, these transformations worked under Ag(I) catalysis in one pot, and, after deprotection, berkelic acid was obtained in good yield (Fig.…”