Natural product synthesis Tetrodotoxin

Nishikawa, T, Urabe, D., and Isobe, M. (2004) Natural product synthesis An efficient total synthesis of optically active tetrodotoxin. Angew. Chem. Int. Ed., 43, 4782—4785. 

Tetrodotoxin, a complex natural product containing several six-membered rings joined together, is a poison isolated from the ovaries and liver of the puffer fish, so named because the fish inflates itself into a ball when alarmed. Eating fish tainted with trace amounts of this potent toxin results in weakness, paralysis, and eventually death. One step in the synthesis of tetrodotoxin involves forming a six-membered ring by a Diels-Alder reaction. 

Arguably the most complex natural product in which carbenoid C-H insertion has recently been applied as a key step is (-)-tetrodotoxin, 196, synthesized by Du Bois and coworkers in 2003 (Scheme 48) [139], In this example of carbenoid insertion a to the oxygen atom of 194, Rh2(HNOCCPh3)4 (25c) was found to be the best catalyst for this diastereospecific transformation. Notably, this total synthesis also employs a rhodium-mediated nitrene insertion at a later point in the route. 

Although originally named after the tetraodontidae fish, it is now very apparent that the occurrence of tetrodotoxin is not restricted to this family. In fact it is not even the unique preserve of one phylum, as it has been identified in a series of taxonomically unrelated animals representing at least five different phyla, as noted above. The toxin has no obvious similarity to any known animal or plant natural product, so its synthesis does not merely result from the simple modification of a related (non-toxic) precursor. Whilst it was thought that tetrodotoxin only occurred in fish and newts, it was just possible that the toxin had been "invented" twice... 

Some interesting examples of levoglucosenone s application in the synthesis of natural products and rare carbohydrates have been reported (58-81). Indeed, levoglucosenone has been used in the synthesis of (+)-multistriatin (58,72-73), Prelog-Djerassi lactonic acid (58,59) md (-)-a//o-yohimbane (61) The synthesis of indole alkaloid reserpine (61), and serricomin (58), as well as tetrodotoxin (53,62) were also reported from levoglucosenone or its functionalized derivatives and was reviewed earlier by us (1). 

The Ferrier carbocyclization reaction of an enol-acetate substrate gives an a,p-dihydroxy-cyclohexanol derivative (see Schemes 12.7 and 12.81. This transformation would be effective for the chiral synthesis of inositol derivatives. A retrosynthetic plan for the marine natural product tetrodotoxin 88 based on the enol-acetate version of Ferrier carbocyclization is shown in Scheme 12.22. Tetrodotoxin 88 was planned to be synthesized from lactone 89, the precursor of which would be highly functionalized cyclohexane 90. Cyclohexane 90 was envisioned to arise from cyclohexanone 91. For the preparation of 91, Ferrier carbocyclization of enol acetate 92 would be a suitable transformation. d-Glucose derivative 93 possessing an exo-methylene at C-3 would serve as a promising precursor of 92. 

A review has appeared on the use of l,2 5,6-di-<9-isopropylidene-a-D-rj o-hexos-3-ulose as a chiral template for synthesis and the potential of cyclitols in the synthesis of a range of natural products has been summarized. "Novel reactions of carbohydrates discovaed en route to natural products" is the intriguing title of a paper describing approaches to tetrodotoxin from 1,6-anhydro-D-mannose.3... 

Other important example of the Claisen rearrangement reaction is the synthesis of a functionalized template during a long asymmetric synthetic route to natural product, tetrodotoxin, accomplished by Isobe [18]. The rearrangement reaction is the... 

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