An Improved Synthesis of (−)-5,11-Dideoxytetrodotoxin

Abstract

We describe an improved synthesis of (-)-5,11-dideoxytetrodotoxin from an enone, which was used for synthesis of tetrodotoxin and its analogues in this laboratory. One of the major modifications was to establish a two-step guanidinylation of trichloroacetamide of a highly functionalized intermediate, which allowed us to prepare (15)N(2)-labeled 5,11-dideoxytetrodotoxin for biosynthetic investigations.

First Identification of 5,11-Dideoxytetrodotoxin in Marine Animals, and Characterization of Major Fragment Ions of Tetrodotoxin and Its Analogs by High Resolution ESI-MS/MS

“…The authentic (−)-5,11-dideoxyTTX (2.0 ng) (synthesized) [49] and 6,11-dideoxyTTX (3.7 ng) (purified from pufferfish [31]) were independently applied to high resolution ESI-LC-MS (Q-TOF MS) in AutoMS/MS mode. AutoMS/MS function automatically collects fragment spectra across each LC/MS peak.…”

“…The toxicity of synthesized (−)-5,11-dideoxyTTX [49] to mice (ddY, male) was examined by intraperitoneal injection. The mice (body weight 18 g) injected with (−)-5,11-dideoxyTTX (10 µg) did not show any symptoms, suggesting that the toxicity of this compound is more than 550 µg/kg.…”

“…Nishikawa and Isobe et al , reported stereocontrolled synthesis of (−)-5,11-dideoxyTTX as an unnatural analog of TTX in 1999 [45,46,47], and Isobe et al developed an analytical method for TTXs using LC-quadrupole-time of flight (Q-TOF) MS [48]. Furthermore, Adachi and Nishikawa et al recently reported an improved synthesis of this compound [49]. Although Kotaki and Shimizu [38] isolated 1- N -hydroxy-5,11-dideoxyTTX from the newt, Taricha granulosa , 5,11-dideoxyTTX has not been previously found in either marine or terrestrial animals.…”

Syntheses of cyclic guanidine-containing natural products

“…42,266-292 They first accomplished the synthesis of 5,11-dideoxytetrodotoxin in 1999. 275,277,286 They then achieved the syntheses of 8,11-dideoxytetrodotoxin 279,282 and 11-deoxytetrodotoxin ( 3a ), 278 in 2002. Following these successes, they completed the synthesis of tetrodotoxin ( 3 ) in 2003, 281 reported an improved route in 2004, 283,284 and finished the synthesis of chiriquitoxin ( 194 ) in 2014.…”

Puffer fish and its consumption: To eat or not to eat?

“…Several groups have synthesized TTX ( Figure 2) using glucose as a precursor molecule (50,51) .The key intermediate compound for the synthesis of TTX can be obtained from either quinone (50) or carbohydrate (49) . Ohyabu et al (52) achieved the asymmetric synthesis of tetrodotoxin from 2-acetoxy-tri-O-acetyl-D-glucal.…”