Synthesis of Saxitoxin Biosynthetic Intermediates: Reveal the Mechanism for Formation of its Tricyclic Skeleton in Biosynthesis

The synthesis and biosynthesis of the complex saxitoxin (STX) structure have garnered significant interest. Previously, we hypothesized that the tricyclic skeleton of STX originates from the monocyclic precursor 11‐hydroxy‐IntC’2 during biosynthesis, although direct evidence has been lacking. In thi...

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Published in:Chemistry, an Asian journal an Asian journal, 2024-10, Vol.19 (24), p.e202400834-n/a
Main Authors: Hirozumi, Ryosuke, Hakamada, Mayu, Minowa, Takashi, Cho, Yuko, Kudo, Yuta, Konoki, Keiichi, Oshima, Yasukatsu, Nagasawa, Kazuo, Yotsu‐Yamashita, Mari
Format: Article
Language:English
Subjects:
Aza-Michael addition
Biosynthesis
Cyanobacteria
Cyanobacteria - chemistry
Cyanobacteria - metabolism
Cyanobacterium
Molecular Structure
Reaction mechanisms
Saxitoxin
Saxitoxin - biosynthesis
Saxitoxin - chemical synthesis
Saxitoxin - chemistry
Saxitoxin - metabolism
Stereoisomerism
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Summary:The synthesis and biosynthesis of the complex saxitoxin (STX) structure have garnered significant interest. Previously, we hypothesized that the tricyclic skeleton of STX originates from the monocyclic precursor 11‐hydroxy‐IntC’2 during biosynthesis, although direct evidence has been lacking. In this study, we identified conditions to synthesize a proposed tricyclic biosynthetic intermediate, 12,12‐dideoxy‐decarbamoyloxySTX (dd‐doSTX), along with its 6‐epimer (6‐epi‐dd‐doSTX) and a bicyclic compound, in a single step from di‐Boc protected 11‐hydroxy‐IntC’2. The reaction mechanism involves successive aza‐Michael addition of a guanidino amine to the conjugated olefin. Notably, both dd‐doSTX and 6‐epi‐dd‐doSTX were detected in a toxin‐producing cyanobacterium, suggesting that the biosynthetic enzymes may generate these compounds via similar mechanisms. Saxitoxin biosynthetic intermediate 7 and its 6‐epimer (10) along with 14 were synthesized from 13 in a single step, probably via aza‐Michael addition reaction. Compounds 7 and 10 were identified in the toxin‐producing cyanobacterium Dolichospernum circinale (TA04). These results suggest that saxitoxin tricyclic skeleton would be biosynthetically constructed via similar mechanism to this chemical reaction.
ISSN:1861-4728
1861-471X
1861-471X
DOI:10.1002/asia.202400834