Novel and Stereocontrolled Synthesis of (±)-Tetrodotoxin frommyo-Inositol

Abstract

[reactions: see text] The novel and stereocontrolled synthesis of (+/-)-tetrodotoxin from myo-inositol is described. The key steps involve the stepwise oxidation of hydroxyl groups to the carbonyl function, followed by the addition of specific nucleophiles, including the successive spiro alpha-chloroepoxide formation and its ring-opening with the azide anion, to give the desired branched chain structures (5-->6, 17-->18-->19-->20 and 23-->24-->25) with the desired regio- and stereoselectivities in high yields. The stepwise conversion of the alpha-azido aldehyde 25 to the delta-lactone 29, followed by reduction of the azide, introduction of a guanidine moiety, aldehyde formation, and deprotection, produced the (+/-)-tetrodotoxin.

Syntheses of cyclic guanidine-containing natural products

“…309-313 They used myo -inositol as the carbon source of the central cyclohexane ring to achieve the racemic synthesis in 2005, 310 and D-glucose as the chiral building block to accomplish the asymmetric synthesis of 3 in 2008. 311 …”

The Chemical Synthesis of Tetrodoxin: An Ongoing Quest

“…Their first major success was the synthesis of racemic TTX from (achiral) myo -inositol [47]. Drawing upon their own work in the carbohydrate field, they considered that a key step toward lactone 121 , an analog of the Isobe intermediate 113 , could be the nucleophilic opening of chloroepoxide 123 with azide ion (Scheme 20).…”

An Efficient Total Synthesis of Optically Active Tetrodotoxin from Levoglucosenone

“…In 2003, we reported the first asymmetric total synthesis of tetrodotoxin,9 and shortly thereafter, Hinman and Du Bois reported another asymmetric total synthesis based on a different strategy 10. Thus, tetrodotoxin is still one of the most attractive and challenging natural products in total synthesis 11. 12 On the other hand, since chemical modification of naturally occurring tetrodotoxin has been extremely limited because of its structural complexity as well as its unique chemical properties, the preparation of tetrodotoxin‐related compounds such as labeled tetrodotoxin by total synthesis has been highly desired for biochemical experiments.…”