Analogue anatoxin

One of the most popular methods for creating the anatoxin-a skeleton is by transannular cyclization of a suitably substituted cyclooctene. This approach was used in the first synthesis of racemic anatoxin-a (Campbell et al. 1979). They carried out two different methodologies in order to reach the 9-azabicyclo[4.2.1]nonane structure (Scheme 7.3). The 1,5-cyclooctadiene (10) starting compound was transformed into the methyl amine 11 which was treated with hypobromous acid to produce the desired bicycle 12 as a mixture of diastereoisomers in 29% overall yield, with some amount of the azabicyclo[3.2.1] analogue (Bastable etal. 1972). 

The desired bicycle 58 was obtained but oddly the enantiopuiity of the previous intermediate was lost, and the bicycle was a completely racemic mixture. It was an unexpected result in view of the previous work by Somfai describing the same reaction leading to enantiopure product from the Af-tosyl analogue (with a methoxy instead ethoxy group in the a-position) (Skrinjar et al. 1992 Somfai and Ahman 1992). Although there was no logical explanation for these discrepancies, they proposed that the racemization could go via hydride abstraction by the iminium ion. As a result, a different ( )-anatoxin-a synthesis was completed by deprotection (TMSI) (Manfre et al. 1992) in 65% yield (9% overall for nine steps). 

Anatoxin-a is a useful core structure for nicotinic drug design. For this reason, synthetic approaches to anatoxin-a are still active research areas, open to new proposals, and the search for new analogues that would act like drugs in the treatment of brain disease is still an important task in medicinal chemistry (Breiiung 2004). 

Brough, RA., Gallagher, T., Thomas, P., Wonnacott, S., Baker, R., Abdul Malik, K.M., and Hursthouse, M.B. 1992. Synthesis and X-Ray crystal structure of 2-acetyl-9-azabicyclo[4.2.1]nonan-3-one. A conformationally locked s-cis analogue of anatoxin-a. J Chem Soc Chem Commun 1087-1089. 

Hardegger, E., and Ott, H. 1955. Konfiguration des cocains und derivate der ecgoninsaure. Helv ChimActa 38, 312-320. Hernandez, A., and Rapoport, H. 1994. Conformationally constrained analogues of anatoxin, chirospecific synthesis of s-trans carbonyl ring-fused analogues. J Org Chem 59, 1058-1066. 

Sardina, F.I, Howard, M.H., Koskinen, A.M.P., and Rapoport, H. 1989. Chirospecific synthesis of nitrogen and side chain modified analogues of (+)-anatoxin. J Org Chem 54, 4654-4660. 

Swanson, K.L., Aronstam, R.S., Wotmacott, S., Rapoport, H., and Albuquerque, E.X. 1991. Nicotinic pharmacology of anatoxin analogues. 1. side-chain structure-activity-relationships at peripheral agonist and noncompetitive antagonist sites. 

The synthetic aspects of anatoxin-a (AN) and analogues are discussed in a separate chapter of this text, and the analytical methods for anatoxins are the subject of a separate review to be published elsewhere. A number of reviews have demonstrated the importance of understanding toxic cyanobacteria as potential environmental and health hazards as well as a resource of bioactive molecules (Harada 1999 Skulberg 2000 Briand et al. 2003). AN was one of the first cyanobacterial toxins to be chemically and functionally characterized and its high neurotoxicity has attracted extensive research activity. 

Table 8.1. Distribution of anatoxin-a and analogues and toxic incidents...

Neuiotoxins produced by cyanobacteria (blue-green algae), such as saxitoxin and analogues, and anatoxin a [96],... 

Cyanobacterial Neurotoxins, Anatoxin-A and Analogues Detection and Analysis... 

In 1992, a methylene analogue of AN, homoanatoxin-a (HMAN) (Figure 38.1 R=C2H5), was isolated from Planktothrix (Oscillatoria) formosa in Norway (Skulberg et al., 1992). AN and HMAN act by enhancing the release of acetylcholine (ACh) from peripheral cholinergic nerves (Lilleheil et al, 1997). HMAN is much less common than AN but has been found in Ireland and Japan (Furey et al., 2003a), (Namikoshi et al., 2003). Anatoxin-a(s) is structurally umelated to AN but was also... 

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