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

Ryosuke Hirozumi; Mayu Hakamada; Takashi Minowa; Yuko Cho; Yuta Kudo; Keiichi Konoki; Yasukatsu Oshima; Kazuo Nagasawa; Mari Yotsu-Yamashita

doi:10.1002/asia.202400834

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

Chem Asian J. 2024 Sep 20:e202400834. doi: 10.1002/asia.202400834. Online ahead of print.

Authors

Ryosuke Hirozumi¹, Mayu Hakamada¹, Takashi Minowa¹, Yuko Cho¹, Yuta Kudo², Keiichi Konoki¹, Yasukatsu Oshima³, Kazuo Nagasawa⁴, Mari Yotsu-Yamashita⁵

Affiliations

¹ Tohoku University, Graduate School of Agricultural Science, JAPAN.
² Tohoku University, The Frontier reserach Institute for Interdisciplinary Sciences, JAPAN.
³ Tohoku University, Graduate School of Life Sciences, JAPAN.
⁴ Tokyo University of Agriculture and Technology, Department of Biotechnology and Life Science, JAPAN.
⁵ Tohoku University, Graduate School of Agricultural Science, 468-1 Aramaki-Aza-Aoba. Aoba-ku, 980-0845, Sendai, JAPAN.

PMID: 39305001
DOI: 10.1002/asia.202400834

Abstract

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.

Keywords: saxitoxin, biosynthesis, aza-Michael addition, cyanobacterium.