A stereoselective and efficient total synthesis of optically active tetrodotoxin (TTX) is described. A polyfunctionalized key cyclitol compound containing branched-chains for the synthesis of TTX was prepared from D-glucose employing the Henry reaction (Nitro aldol reaction) as the key transformation. Stereoselective construction of the alpha-azido-aldehyde branched-chain was achieved via the key spiro alpha-chloroepoxide intermediate.

[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.