Total Synthesis of Aetokthonotoxin, the Cyanobacterial Neurotoxin Causing Vacuolar Myelinopathy

Abstract

Aetokthonotoxin has recently been identified as the cyanobacterial neurotoxin causing Vacuolar Myelinopathy, a fatal neurologic disease, spreading through a trophic cascade and affecting birds of prey such as the bald eagle in the USA. Here, we describe the total synthesis of this specialized metabolite. The complex, highly brominated 1,2’‐biindole could be synthesized via a Somei‐type Michael reaction as key step. The optimised sequence yielded the natural product in five steps with an overall yield of 29 %.

Synthesis of Aza‐Heterocyclic Compounds with N‐Tosylhydrazones: Formation of Bi‐Indoles via Reductive Molybdenum Catalysis

“…synthesized 1,2‐biindole via a Somei‐type Michael reaction (Scheme 2d), [13] which requires the presence of a Michael acceptor on the indole, thereby limiting the scope of this reaction. Moreover, the reaction with disubstitued indoles does not proceed due to steric or stereoelctronic effects [10b] . Importantly, it should be emphasized that all of the aforementioned strategies necessitated the use of harsh reaction conditions to achieve the formation of bi‐indole derivatives, with yields typically ranging from 15 to 60%.…”

Exploration of cyanobacteria as bioremediation candidates to reduce phosphorus contamination

“…High phosphorus in water bodies can also induce cyanobacterial blooms. Some cyanobacteria produce cyanotoxins and water contaminated with cyanotoxins is a threat to public health due to these toxins targeting tissues and organs in mammals such as the nervous system, skin, gastrointestinal tract, respiratory system [2], and white matter in the brain and spinal cord [3].…”

From Tryptophan to Toxin: Nature’s Convergent Biosynthetic Strategy to Aetokthonotoxin

“…LC-MS analysis of the reaction mixture revealed the formation of a new pentabrominated product only in the full reaction but absent in all negative controls. The identity of the enzymatic product was confirmed as AETX ( 1 ) based on coelution with a chemically synthesized standard (Figure ). In our hands, 2 and 3 were the only two monomers coupled by AetB when given a mixture of other indole monomers (e.g., 5-bromoindole ( 7 ), 5,7-dibromoindole ( S2 )), thus corroborating our proposal that indole functionalization takes place prior to the coupling step (Figure S9).…”

“…Cytochrome P450 enzymes are known to catalyze biaryl coupling reactions, and we anticipated that AetB might fulfill such a role in catalyzing the final reaction sequence in AETX ( 1 ) biosynthesis. To test this hypothesis, we chemically synthesized the two brominated indole building blocks 5,7-dibromo-indole-3-carbonitrile ( 2 ) and 2,3,5-tribromoindole ( 3 ) following established literature procedures . AetB was then incubated with substrates 2 and 3 along with spinach ferredoxin (Fdx) and spinach ferredoxin reductase (FdR) and NADPH to complement electron transfer.…”

“…To test this hypothesis, we chemically synthesized the two brominated indole building blocks 5,7dibromo-indole-3-carbonitrile (2) and 2,3,5-tribromoindole (3) following established literature procedures. 16 AetB was then incubated with substrates 2 and 3 along with spinach ferredoxin (Fdx) and spinach ferredoxin reductase (FdR) and NADPH to complement electron transfer. LC-MS analysis of the reaction mixture revealed the formation of a new pentabrominated product only in the full reaction but absent in all negative controls.…”